F R O M T H E E X P E R T S I N E N D O C R I N O L O G Y

2 0 2 5 E N D O C R I N E C A S E M A N A G E M E N T:
MEET THE PROFESSOR
FROM THE EXPERTS IN ENDOCRINOLOGY

ENDO 2025
MEET THE PROFESSOR

ENDOCRINE
CASE MANAGEMENT
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The Endocrine Society is the world’s largest, oldest, and most active organization working to advance the clinical
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endocrinology.

Clinical Practice Chair, ENDO 2025

Barbara Gisella Carranza Leon, MD

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ISBN: 978-1-936704-51-4
eISBN: 978-1-936704-52-1
 ENDO 2025
CONTENTS

ADIPOSE TISSUE, APPETITE, OBESITY, AND LIPIDS

Weight-Loss Pharmacotherapy in the Spectrum of Obesity Care. . . . . . . . . . . . . . . . . . . . . . . .2
José O. Alemán, MD, PhD

Metabolic Dysfunction-Associated Steatotic Liver Disease: Tips for Endocrinologists. . . . .11

Eveline Bruinstroop, MD, PhD, and A. G. (Onno) Holleboom, MD, PhD

Atypical and Secondary Etiologies of Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17

Andrew T. Kraftson, MD

Treatment of Obesity in Patients With Complex Comorbidities.. . . . . . . . . . . . . . . . . . . . . . . .25

Tirissa J. Reid, MD, DABOM

ADRENAL
How to Manage Bilateral Adrenal Masses.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .32
Jérôme Bertherat, MD, PhD

Management of Metastatic Pheochromocytomas and Paragangliomas. . . . . . . . . . . . . . . . .40

Camilo Jimenez, MD

Evaluation and Management of Postmenopausal Androgen Excess . . . . . . . . . . . . . . . . . . . .45

Michael W. O’Reilly, MD, PhD, and Wiebke Arlt, MD, DSc

BONE AND MINERAL METABOLISM

Managing Calcium Disorders in Pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .56
Natasha M. Appelman-Dijkstra, MD, PhD

Long-Term Complications of Mild Asymptomatic Primary Hyperparathyroidism:

To Treat or Not to Treat?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63
Ghada El-Hajj Fuleihan, MD, MPH

Addressing Bone Health in Underweight Individuals Across the Lifespan . . . . . . . . . . . . . . .73

Pouneh K. Fazeli, MD, MPH, and Selma Feldman Witchel, MD

Complex Cases in Hypophosphatemia: Navigating Diagnostic and

Treatment Challenges of Low Phosphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .81
Eva S. Liu, MD

ENDO 2025 • Contents iii

CARDIOVASCULAR ENDOCRINOLOGY
Management of Patients With Elevated Lipoprotein(a). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .90
David Saxon, MD, MSc

Interpreting Adrenal Vein Sampling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .97

Michael Stowasser, MBBS, PhD

Managing Severe Hypertriglyceridemia: Best Practices and New Approaches . . . . . . . . . 104

Lisa R. Tannock, MD

DIABETES AND VASCULAR DISEASE

Monitoring Diabetes Control Using Hemoglobin A1c and Continuous
Glucose Monitoring: Advantages and Pitfalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Shichun Bao, MD, PhD

SGLT-2 Inhibitor Therapy in Type 2 Diabetes: Advantages and Pitfalls. . . . . . . . . . . . . . . . 122

Aidar R. Gosmanov, MD, DMSc

Optimal Use of Diabetes Technology in the Clinical Management of Diabetes. . . . . . . . . . 131

Rayhan Lal, MD

Addressing Racial Health and Health Care Inequities in Diabetes. . . . . . . . . . . . . . . . . . . . 135

Alyson K. Myers, MD

Management of Cystic Fibrosis–Related Diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

Melissa Putman, MD

Optimizing Health After Gestational Diabetes: What’s Next?. . . . . . . . . . . . . . . . . . . . . . . . 150

Ellen W. Seely, MD

Integrating Quality Improvement into Inpatient Diabetes Care.. . . . . . . . . . . . . . . . . . . . . . 157

Sonali Thosani, MD

GENERAL ENDOCRINOLOGY
Complications of Novel Nonimmunotherapy Cancer Treatments . . . . . . . . . . . . . . . . . . . . . 166
Afreen Shariff, MD, and Randol Kennedy, MD

NEUROENDOCRINOLOGY AND PITUITARY

Challenging Cases of Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
Mirjam Christ-Crain, MD

Stalk Lesions of the Pituitary Gland. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

Dana Erickson, MD

iv ENDO 2025 • Endocrine Case Management

 Management of Pituitary Tumors During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
Andrea Glezer, MD, PhD

Craniopharyngiomas in Adults: Modern Management and Changes in the Paradigm. . . 203

Emmanuel Jouanneau, MD, PhD, and Gerald Raverot, MD, PhD

Therapeutic Use Exemption in Elite Sport: The Endocrinologist as the

Expert for Hormonal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Alan D. Rogol, MD, PhD

Perioperative Management of Pituitary Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

Whitney W. Woodmansee, MD, MA

PEDIATRIC AND ADOLESCENT ENDOCRINOLOGY

Management of Patients With Congenital Adrenal Hyperplasia During Transition Care. 228
Tânia Bachega, MD, PhD

How to Approach Children With Short Stature Not Responding to

Growth Hormone Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
Stefano Cianfarani, MD

State-of-the-Art Management of Turner Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

Claus H. Gravholt, MD, PhD

Pediatric Obesity: Challenges and Solutions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

Ashley Shoemaker, MD, MSCI

REPRODUCTIVE ENDOCRINOLOGY
Hormone Management in Aging Transgender Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Danit Ariel, MD, MS, and Micol S. Rothman, MD

Amenorrhea Management in Overweight and Underweight Women.. . . . . . . . . . . . . . . . . 264

Daniel A. Dumesic, MD

THYROID BIOLOGY AND CANCER

Management of Hyperthyroidism-Related Complications. . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Grigoris Effraimidis, MD, PhD

Update on the Management of Nonhereditary Medullary Thyroid Carcinoma. . . . . . . . . . 284

Rossella Elisei, MD

Oncocytic Thyroid Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292

Ian Ganly, MD, MS, PhD

ENDO 2025 • Contents v

 Special Diets for Thyroid Health: Fact or Fiction? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
Angela M. Leung, MD, MSc

The Unhappy Patient With Hypothyroidism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

Marco Medici, MD, PhD, MSc, and Maria Papaleontiou, MD

Navigating Thyroid Eye Disease: From Diagnosis to Management. . . . . . . . . . . . . . . . . . . . 316

Marius N. Stan, MD

TUMOR BIOLOGY
Landscape of Genetic Alterations in Well-Differentiated Thyroid Cancer
in Pediatric Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
Andrew J. Bauer, MD

APPENDIX
Color Gallery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CG1

vi ENDO 2025 • Endocrine Case Management

ENDO 2025
FACULTY

2025 Endocrine Case Management: Meet the Professor Faculty

José O. Alemán, MD, PhD Grigoris Effraimidis, MD, PhD Andrew T. Kraftson, MD
New York University Langone Health University of Thessaly and University University of Michigan
General Hospital of Larissa
Natasha M. Appelman- Rayhan Lal, MD
Dijkstra, MD, PhD Ghada El-Hajj Fuleihan, MD, MPH Stanford University
Leiden University Medical Center American University of Beirut
Angela M. Leung, MD, MSc
Danit Ariel, MD, MS Rossella Elisei, MD University of California Los Angeles
Stanford University University Hospital of Pisa David Geffen School of Medicine
School of Medicine and University of Pisa and Veterans Affairs Greater Los
Angeles Healthcare System
Wiebke Arlt, MD, DSc Dana Erickson, MD
Medical Research Council Mayo College of Medicine Eva S. Liu, MD
Laboratory of Medical Sciences Brigham and Women’s Hospital
Pouneh K. Fazeli, MD, MPH and Harvard Medical School
Tânia Bachega, MD, PhD University of Pittsburgh Medical
São Paulo University Center Presbyterian Hospital Marco Medici, MD, PhD, MSc
School of Medicine Erasmus Medical Center
Ian Ganly, MD, MS, PhD
Shichun Bao, MD, PhD Memorial Sloan Kettering Alyson K. Myers, MD
Vanderbilt University Medical Center Cancer Center Montefiore Einstein

Andrew J. Bauer, MD Andrea Glezer, MD, PhD Michael W. O’Reilly, MD, PhD
Children’s Hospital of Philadelphia University of São Paulo Royal College of Surgeons in Ireland
and University of Pennsylvania Medical School Hospital
Perelman School of Medicine Maria Papaleontiou, MD
Aidar R. Gosmanov, MD, DMSc University of Michigan
Jérôme Bertherat, MD, PhD Albany Medical College and Stratton
Paris Cité University and Veterans Affairs Medical Center Melissa Putman, MD
Cochin Hospital Harvard Medical School and
Claus H. Gravholt, MD, PhD Massachusetts General Hospital
Eveline Bruinstroop, MD, PhD Aarhus University Hospital
Amsterdam UMC Gerald Raverot, MD, PhD
A. G. (Onno) Holleboom, MD, PhD Claude Bernard University,
Mirjam Christ-Crain, MD, PhD Amsterdam UMC Cancer Research Center of Lyon,
University Hospital Basel, and Hospices Civils de Lyon
University of Basel Camilo Jimenez, MD
University of Texas MD Tirissa J. Reid, MD, DABOM
Stefano Cianfarani, MD Anderson Cancer Center Columbia University Vagelos College
University of Rome, ‘Bambino of Physicians and Surgeons
Gesù’ Children’s Hospital, Emmanuel Jouanneau, MD, PhD
and Karolinska Institute Hospices Civils de Lyon, Claude Alan D. Rogol, MD, PhD
Bernard University, and Cancer University of Virginia
Daniel A. Dumesic, MD Research Center of Lyon
University of California Los Angeles Micol S. Rothman, MD
David Geffen School of Medicine Randol Kennedy, MD University of Colorado
Duke University School of Medicine School of Medicine

ENDO 2025 • Faculty vii

 David Saxon, MD, MSc Ashley Shoemaker, MD, MSCI Sonali Thosani, MD
University of Colorado School Vanderbilt University Medical Center MD Anderson Cancer Center
of Medicine and Rocky
Mountain Regional Veterans Marius N. Stan, MD Selma Feldman Witchel, MD
Affairs Medical Center Mayo Clinic-Rochester University of Pittsburgh
Medical Center Children’s
Ellen W. Seely, MD Michael Stowasser, MBBS, PhD Hospital of Pittsburgh
Brigham and Women’s Hospital University of Queensland
and Mass General Brigham Frazer Institute and Princess Whitney W. Woodmansee, MD, MA
Alexandra Hospital University of Florida
Afreen Shariff, MD
Duke University School of Medicine Lisa R. Tannock, MD
and Duke Cancer Institute Queen’s University

Annual Meeting Steering Committee (AMSC)

Niki Karavitaki, MSc, Robin Peeters, MD, PhD – Monica Laronda, PhD –
PhD – AMSC Chair Clinical Science Chair Basic Science Chair
University of Birmingham Erasmus Universiteit Ann & Robert H. Lurie Children’s
Hospital of Chicago
Barbara Gisella Carranza Leon,
MD – Clinical Practice Chair
Vanderbilt University Medical Center

Annual Meeting Steering Committee Clinical Peer Reviewers

Ana Paula Abreu Metzger, MD, PhD Ole-Petter Hamnvik, MBBCh Elizabeth N. Pearce, MD, MSc
Olga Astapova, MD, PhD BAO, MMSc, MRCPI Luca Persani, MD, PhD
Irina Bancos, MD Edward Chiaming Hsiao, MD, PhD Julie Refardt, MD, PhD
Laura Boucai, MD Hebatullah M. Ismail, MD Yumie Rhee, MD, PhD
Davide Calebiro, MD Suzanne Jan De Beur, MD Laura Torchen, MD
Diane Donegan, MBBCh BAO, MRCPI Srividya Kidambi, MD Elena Tsourdi, MD
David A. Ehrmann, MD Katja Kiseljak-Vassiliades, DO W. Edward Visser, MD, PhD
Christa E. Flueck, MD Raghavendra Mirmira, PhD, MD Jun Yang, MBBS, PhD
Oksana Hamidi, DO Connie Baum Newman, MD Elaine Wei-Yin Yu, MD
Gabrielle Page-Wilson, MD

viii ENDO 2025 • Endocrine Case Management

ENDO 2025
OVERVIEW

OVERVIEW LEARNING OBJECTIVES

Endocrine Case Management: Meet the Professor is designed Endocrine Case Management: Meet the Professor will allow
to provide physicians with a concise and high-quality learners to assess their knowledge of all aspects of
review of more than 40 common and rare endocrine endocrinology, diabetes, and metabolism.
disorders to help you keep your practice current. It
consists of case-based clinical vignettes and rationales Upon completion of this educational activity, learners
written by experts in all areas of endocrinology, will be able to:
diabetes, and metabolism.
• Recognize clinical manifestations of endocrine and
metabolic disorders and select among current
ACCREDITATION STATEMENT options for diagnosis, management, and therapy.
The Endocrine Society is accredited by
the Accreditation Council for • Identify risk factors for endocrine and metabolic
Continuing Medical Education to disorders and develop strategies for prevention.
provide continuing medical education
• Evaluate endocrine and metabolic manifestations of
(CME) for physicians. The Endocrine Society has
systemic disorders.
received Accreditation with Commendation.
• Use existing resources pertaining to clinical
The Endocrine Society designates this enduring material guidelines and treatment recommendations for
for a maximum of 30 AMA PRA Category 1 Credits™. endocrine and related metabolic disorders to guide
Physicians should claim only the credit commensurate diagnosis and treatment.
with the extent of their participation in the activity.
TARGET AUDIENCE
MAINTENANCE OF CERTIFICATION Endocrine Case Management: Meet the Professor provides
Successful completion of this case-based education to clinicians interested in
CME activity, which includes improving patient care.  
participation in the
evaluation component,
STATEMENT OF INDEPENDENCE
enables the participant to earn up to 30 MOC points in
As a provider of CME accredited by the Accreditation
the American Board of Internal Medicine’s (ABIM)
Council for Continuing Medical Education, the
Maintenance of Certification (MOC) program. It is the
Endocrine Society has a policy of ensuring high-quality
CME activity provider’s responsibility to submit
content in this educational activity that is balanced,
participant completion information to the Accreditation
independent, objective, and scientifically rigorous. The
Council for Continuing Medical Education for the
scientific content of this activity was developed under
purpose of granting ABIM MOC credit.
the supervision of the Endocrine Society’s Annual
CME credits and/or MOC points for the activities Meeting Steering Committee.
related to this material must be claimed by June 30,
2027. For questions about content or obtaining CME DISCLOSURE POLICY
credit or MOC points, please contact the Endocrine The faculty, committee members, and staff who are in
Society at [email protected]. position to control the content of this activity are
required to disclose to the Endocrine Society and to
learners any relevant financial relationship(s) of the
individual or spouse/partner that have occurred within
the last 12 months with any commercial interest(s)

ENDO 2025 • Overview ix

 whose products or services are related to the content. A. G. (Onno) Holleboom, MD, PhD Merck, Novo
Financial relationships are defined by remuneration in Nordisk, Boehringer Ingelheim, Inventiva, Echosens
any amount from the commercial interest(s) in the form Camilo Jimenez, MD Merck, Exelixis, Inc (research
of grants; research support; consulting fees; salary; support)
ownership interest (e.g., stocks, stock options, or
ownership interest excluding diversified mutual funds); Randol Kennedy, MD Abbott Diabetes Care, Adaptyx
honoraria or other payments for participation in Biosciences, Biolinq, Capillary Biomedical, Deep Valley
speakers’ bureaus, advisory boards, or boards of Labs, Gluroo, Portal Diabetes, Tidepool, ProventionBio,
directors; or other financial benefits. The intent of this Lilly, Sanofi
disclosure is not to prevent planners with relevant Eva S. Liu, MD Inozyme
financial relationships from planning or delivery of
Marco Medici, MD, PhD, MSc ACE Pharmaceuticals
content, but rather to provide learners with information
that allows them to make their own judgments of Alyson K. Myers, MD Eli Lilly & Company, Travel
whether these financial relationships may have Support for the ExCEL program
influenced the educational activity with regard to Melissa Putman, MD Anagram Therapeutics, Vertex
exposition or conclusion. The Endocrine Society has Pharmaceuticals
reviewed all disclosures and resolved or managed all
identified conflicts of interest, as applicable. Tirissa J. Reid, MD, DABOM UpToDate
Alan D. Rogol, MD, PhD Ascendis Pharma, Tolmar,
The Endocrine Society has reviewed these relationships Lumos Pharma, ALK Pharma, Comprehensive Drug
to determine which are relevant to the content of this Testing, United States Anti-Doping Agency, World
activity and resolved any identified conflicts of interest Anti-Doping Agency
for these individuals.
Afreen Shariff, MD Merck, Novartis Pharmaceuticals,
Citrus Oncology, UpToDate
The following faculty reported relevant financial relationship(s)
during the content development process for this activity: Ashley Shoemaker, MD, MSCI Soleno Therapeutics,
Rhythm Pharmaceuticals
José O. Alemán, MD, PhD Novo Nordisk (consultant)
Marius N. Stan, MD Argenx, Genentech Inc, Ethyreal
Wiebke Arlt, MD, DSc Diurnal; Roche Diagnostics,
Bio, Lessen Inc, Merida, MingHui, Avilar, Viridian
Bayer Inc, Organon Laboratories, Crinetics, Spruce
(consultant)
Bioscience, European Society of Endocrinology
Selma Feldman Witchel, MD Neurocrine
Andrew J. Bauer, MD IBSA Pharm, Egetis Pharm
Biosciences Inc
(consultant)
Jérôme Bertherat, MD, PhD HRA Pharma, Recordati The following faculty reported no relevant financial relationships:
RD, Novo Nordisk Natasha M. Appelman-Dijkstra, MD, PhD; Danit
Eveline Bruinstroop, MD, PhD Aligos, Madrigal Ariel, MD, MS; Tânia Bachega, MD, PhD; Shichun
Bao, MD, PhD; Mirjam Christ-Crain, MD, PhD;
Stefano Cianfarani, MD Novo Nordisk, Sandoz
Grigoris Effraimidis, MD, PhD; Ghada El-Hajj
Daniel A. Dumesic, MD Ferring Pharmaceuticals, Fuleihan, MD, MPH; Rossella Elisei, MD; Ian Ganly,
Organon Laboratories, Spruce Biosciences Inc, Precede MD, MS, PhD; Andrea Glezer, MD, PhD; Claus H.
Biosciences Inc, Ferring Research Institute Gravholt, MD, PhD; Emmanuel Jouanneau, MD,
Dana Erickson, MD Camurus, Crinetics (advisory PhD; Andrew T. Kraftson, MD; Rayhan Lal, MD;
board) Angela M. Leung, MD, MSc; Michael W. O’Reilly,
MD, PhD; Maria Papaleontiou, MD; Gerald
Pouneh K. Fazeli, MD, MPH Regeneron
Raverot, MD, PhD; Micol S. Rothman, MD; David
Pharmaceuticals, Crinetics (research support and
Saxon, MD, MSc; Ellen W. Seely, MD; Michael
consultant); Quest Diagnostics, Corcept, Chiesi
Stowasser, MBBS, PhD; Lisa R. Tannock, MD;
(consultant)
Sonali Thosani, MD; and Whitney W.
Aidar R. Gosmanov, MD, DMSc Eli Lilly & Company Woodmansee, MD, MA
(research support paid to institution), BMJ Open Diabetes
Research & Care (associate editor)

x ENDO 2025 • Endocrine Case Management

The following AMSC peer reviewers reported relevant Katja Kiseljak-Vassiliades, DO HRA Pharma
financial relationships: (advisory board)
Irina Bancos, MD Adrenas, HRA Pharma, Corcept, Raghavendra Mirmira, PhD, MD Journal of Clinical
Recordati (advisory board); HRA Pharma, Corcept, Endocrinology and Metabolism (editor); Veralox
Sparrow Pharmaceutics, Recordati (consultant); Elsevier Therapeutics (advisory board); Veralox Therapeutics,
(writer); Recordati, NIH (funding for investigator-initiated HiberCell, Inc (investigator-initiated award)
award); DynaMed (reviewer) Connie Baum Newman, MD Food and Drug
Barbara Gisella Carranza Leon, MD Novartis, IONIS Association (FDA) for Endocrinologic and Metabolic
Pharmaceutical Inc, NIH, FH Foundation, Regenxbio, Inc Diseases (advisory committee and consultant); Federation
(coinvestigator); Maintenance of Certification Committee: of Medical Women of Canada (honorarium)
American Board of Obesity Medicine (member) Gabrielle Page-Wilson, MD Strongbridge Biopharma,
Diane Donegan, MB BCh BAO, MRCPI Corcept, Recordati Rare Diseases, Inc, Xeris BioPharma (advisory
Recordati (investigator); Camarus (advisory board) board); Xeris BioPharma (consultant)
David A. Ehrmann, MD UpToDate (editor); NIH Elizabeth N. Pearce, MD, MSc Iodine Global Network
(grant recipient) (management council); Journal of Clinical Endocrinology
Christa E. Flueck, MD European Society Paediatric and Metabolism, DynaMed-thyroid (editor); National
Endocrinology (advisory board); Novo Nordisk, Merck, Dairy Council, Merck China Symposium (speaker);
Pfizer, Sandoz, Swiss National Science Foundation, American Thyroid Association (Guidelines Task Force);
European Society Paediatric Endocrinology (grant World Health Organization (advisory panel)
recipient); Novo Nordisk, Pfizer, EffRx (consultant); Luca Persani, MD, PhD Merck, Egetis, Sandoz
Sandoz (speaker); Hormone Research Paediatrics (editor) (advisory board); Merck (speaker); Journal of Clinical
Oksana Hamidi, DO Corcept Therapeutics, Crinetics Endocrinology and Metabolism, European Thyroid
Pharmaceuticals, Neurocrine Biosciences, Recordati Association, European Thyroid Journal, Pituitary
Rare Diseases, Camurus (advisory board); Xeris Pharma Society, Pituitary (editor)
(speaker) Yumie Rhee, MD, PhD American Society of Bone and
Ole-Petter Hamnvik, MB BCh BAO, MMSc, MRCPI Mineral Research (ambassador); Korean Endocrine
New England Journal of Medicine (education editor) Society, Korean Society of Bone and Mineral Research
(committee); JCEM Case Reports (editor)
Edward Chiaming Hsiao, MD, PhD International
FOP Association, FD/MAS Alliance, International Laura Torchen, MD Levo therapeutics, IBSA Pharma
Clinical Council on FOP (advisory board); Endocrine (investigator)
Journal, Journal of Bone and Mineral Research (editor); Elena Tsourdi, MD Amgen, Kyowa Kirin, UCB,
Clementia Pharmaceuticals/Ipsen Pharmaceuticals, Alexion, Ascendis (clinical studies); Amgen, UCB,
Ultragenyx (research investigator) Ascendis (advisory boards and lectures); UCB, Takeda,
Suzanne Jan De Beur, MD American Society of Bone Ascendis (educational grants)
and Mineral Research (past president); XLH Network, W. Edward Visser, MD, PhD Egetis Therapeutics
Current Osteoporosis Reports, Ultragenyx, Kyowa Kirin, (royalties [institution])
Ascendis (advisory board); Bone Reports (editorial board); Elaine Wei-Yin Yu, MD Amgen (grant recipient)
Mereo, Kyowa Kirin, Calcilytics (researcher); NIH, FDA
(grant reviewer); PCORI (investigator) The following AMSC members reported no relevant financial
relationships:
Niki Karavitaki, MSc, PhD European
Neuroendocrine Association (advisory board); HRA Ana Paula Abreu Metzger, MD, PhD; Olga
Pharma (editor); Recordati Rare Diseases, HRA Pharma, Astapova, MD, PhD; Laura Boucai, MD; Davide
Pfizer, Ipsen, Conselient Health (speaker) Calebiro, MD; Hebatullah M. Ismail, MD; Julie
Refardt, MD, PhD; and Jun Yang, MBBS, PhD
Srividya Kidambi, MD TOPS Inc (medical editor and
director)

ENDO 2025 • Overview xi

 DISCLAIMERS ACKNOWLEDGMENT OF
The information presented in this activity represents COMMERCIAL SUPPORT
the opinion of the faculty and is not necessarily the The activity is not supported by educational grant(s) or
official position of the Endocrine Society. other funds from any commercial supporters.

USE OF PROFESSIONAL JUDGMENT:

The educational content in this activity relates to basic AMA PRA CATEGORY 1 CREDIT™
principles of diagnosis and therapy and does not (CME) INFORMATION
substitute for individual patient assessment based on the To receive a maximum of 30 AMA PRA Category 1
health care provider’s examination of the patient and Credits™, participants must complete the online
consideration of laboratory data and other factors interactive module and activity evaluation located at
unique to the patient. Standards in medicine change as the Endocrine Society’s Center for Learning:
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xii ENDO 2025 • Endocrine Case Management

 COMMON ABBREVIATIONS IN MEET THE PROFESSOR

ACTH = corticotropin GH = growth hormone NPH insulin = neutral protamine

ACE inhibitor = angiotensin-converting GHRH = growth hormone–releasing Hagedorn insulin
enzyme inhibitor hormone PCSK9 inhibitor = proprotein
ALT = alanine aminotransferase GLP-1 receptor agonist = glucagonlike convertase subtilisin/kexin 9 inhibitor
AST = aspartate aminotransferase peptide 1 receptor agonist PET = positron emission tomography

BMI = body mass index GnRH = gonadotropin-releasing PSA = prostate-specific antigen

hormone PTH = parathyroid hormone
CNS = central nervous system
hCG = human chorionic gonadotropin PTHrP = parathyroid hormone–related
CT = computed tomography
HDL = high-density lipoprotein protein
DHEA = dehydroepiandrosterone
HIV = human immunodeficiency virus SGLT-2 inhibitor = sodium-glucose
DHEA-S = dehydroepiandrosterone
HMG-CoA reductase inhibitor = cotransporter 2 inhibitor
sulfate
3-hydroxy-3-methylglutaryl coenzyme A SHBG = sex hormone–binding globulin
DNA = deoxyribonucleic acid
reductase inhibitor T3 = triiodothyronine
DPP-4 inhibitor = dipeptidyl-peptidase
IGF-1 = insulinlike growth factor 1 T4 = thyroxine
4 inhibitor
LDL = low-density lipoprotein TPO antibodies = thyroperoxidase
DXA = dual-energy x-ray
absorptiometry LH = luteinizing hormone antibodies
FDA = Food and Drug Administration MCV = mean corpuscular volume TRH = thyrotropin-releasing hormone

FGF-23 = fibroblast growth factor 23 MIBG = meta-iodobenzylguanidine TRAb = TSH-receptor antibodies

FNA = fine-needle aspiration MRI = magnetic resonance imaging TSH = thyrotropin

FSH = follicle-stimulating hormone VLDL = very low-density lipoprotein

ENDO 2025 • Overview xiii

ADIPOSE TISSUE,
APPETITE, OBESITY,
AND LIPIDS
Weight-Loss Pharmacotherapy
in the Spectrum of Obesity Care
José O. Alemán, MD, PhD. Laboratory of Translational Obesity Research, NYU Langone
Health, New York, NY; Department of Medicine, Margaret Corbin Campus of the VA New York
Harbor Health Care System, New York, NY; Holman Division of Endocrinology, Diabetes and
Metabolism, New York University Langone Health, New York, NY; Email: [email protected]

Educational Objectives 10% total body weight loss (TBWL).5 However,

newer second-generation drugs, such as the GLP-1
After reviewing this chapter, learners should be
agonist semaglutide, induce up to 17.4% weight
able to:
loss from baseline in individuals without diabetes.
• Recognize obesity as a chronic disease with Similar to lifestyle interventions, of those
relevant comorbidities. who achieve at least 10% TBWL, many struggle
to maintain this weight loss achieved with
• Describe FDA-approved and in-development
antiobesity medications.6 Bariatric surgery induces
obesity pharmacotherapy as an adjunct to
more durable weight loss than pharmacotherapy
lifestyle intervention for weight loss.
or lifestyle interventions alone. More recently,
• Discuss the spectrum of obesity care, including endoscopic bariatric surgery, such as intragastric
dietary, pharmacologic, and surgical therapies. balloons and endoscopic sleeve gastroplasty, has
offered a less-invasive option for weight loss.7
Similar to other interventions for weight loss,
there remains a common issue of weight regain or
Significance of the weight-loss plateau after surgical interventions.
Clinical Problem Studies have examined the benefit of combination
therapy with antiobesity pharmacotherapy and
The prevalence of obesity in adults in the United
endoscopic interventions, which results in more
States increased to more than 40% in recent years.1
effective weight loss.6 There are currently 6 FDA-
Obesity contributes to metabolic complications,
approved medications for the long-term treatment
such as type 2 diabetes, dyslipidemia, hypertension;
of obesity, including orlistat, phentermine/
increased risk of mechanical complications, such
topiramate, naltrexone/bupropion, liraglutide,
as osteoarthritis and obstructive sleep apnea;
semaglutide, and tirzepatide. Their effectiveness
and comorbid diseases, including several major
in treating postbariatric weight regain remains an
cancers.2 Weight loss of 5% to 10% reduces
active area of investigation. Herein, we present
obesity-related complications and improves
the pivotal trial evidence for each approved
quality of life.3 Lifestyle interventions are currently
obesity pharmacotherapy agent, as well as the
the first-line therapy for weight loss; however,
emerging data of its combination with available
weight loss is difficult to maintain with lifestyle
bariatric procedures.
intervention alone.4 The emergence of various
pharmacotherapies for weight loss has significantly
changed the landscape of obesity management
over the past decade. Most approved first-
generation antiobesity medications result in 5% to

2 ENDO 2025 • Endocrine Case Management

Practice Gaps banding, with a mean weight loss of 9 ± 3 kg in
study participants compared with 3 ± 2 kg in the
• Six medications are FDA-approved for the placebo group after 8 months of treatment with
long-term treatment of obesity, including orlistat, 120 mg 3 times daily.9 It was thought
orlistat, phentermine/topiramate, naltrexone/ that perhaps orlistat was effective particularly
bupropion, liraglutide, semaglutide, and for the high-calorie liquid diet required after
tirzepatide, yet their effectiveness in bariatric procedures, which is often high in fat.
combination or sequence is not established. Due to orlistat’s mechanism, it also interferes
with the absorption, and therefore effectiveness,
• New drugs, such as retatrutide and
of drugs, such as warfarin, amiodarone,
orforglipron, are currently being evaluated
cyclosporine, levothyroxine, and fat-soluble
for their efficacy in weight-loss management
vitamins, which modifies their effectiveness.
causing weight loss of similar magnitude to
The only contraindications include pregnancy,
that of procedures.
breastfeeding, and cholestasis. However, despite
• Surgical options, such as bariatric surgery, these adverse effects, drug interactions, and some
induce more durable weight loss than contraindications, orlistat remains a widely used,
pharmacotherapy or lifestyle interventions easily accessible therapy for weight loss.
alone. Recently, endoscopic bariatric surgery
has offered a less-invasive option for weight
loss. These procedures remain underused Phentermine and
despite known longer-term effectiveness in Phentermine/Topiramate
weight loss and maintenance. Phentermine and phentermine/topiramate are
• The addition of pharmacotherapy has been currently approved for weight-loss management
shown to be a promising tool to address the in the United States and came to the market as
common issue of weight regain or weight-loss combination therapy in 2012.10 Phentermine
plateau after surgical bariatric interventions. and phentermine/topiramate have been studied
The choice of optimal pharmacotherapy to as adjunct therapy for weight loss for bariatric
support weight-loss procedures remains surgery and have been shown to be viable
unknown. options for weight loss in patients with weight
regain or weight-loss plateau after bariatric
• The optimal timing of obesity
surgery. In a retrospective study of patients who
pharmacotherapy with surgical and endoscopic
had undergone Roux-en-Y gastric bypass or
interventions requires further investigation.
laparoscopic adjustable gastric banding, patients
on phentermine lost 6.45 kg (12.8% excess weight
Discussion loss), and those on phentermine/topiramate lost
3.81 kg (12.9% excess weight loss) at 90 days post
Orlistat
surgery, but this study was limited by a short-term
Orlistat was FDA-approved for the treatment of follow-up period.11 An open-label trial of patients
obesity in 1999.8 It is widely available, both as an with a BMI of 50 kg/m2 or higher who planned
over-the-counter medication at a dosage of up to to undergo laparoscopic sleeve gastrectomy were
60 mg 3 times daily and at prescription dosages prescribed phentermine/topiramate 7.5/46-
up to 120 mg 3 times daily. Orlistat can address 15/92 mg or no therapy for at least 3 months
weight-loss plateaus after weight-loss surgeries, preoperatively and 2 years postoperatively.
such as adjustable gastric banding. The drug was Investigators found that the combination therapy
associated with weight loss in a nonrandomized group (phentermine/topiramate + laparoscopic
intervention study of 38 patients experiencing sleeve gastrectomy) lost more than twice as
a weight-loss plateau after adjustable gastric

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 3

much weight compared with control participants bariatric procedures. The first placebo-controlled
in the preoperative period (28.1 kg vs 12.3 kg) trial of adjunctive GLP-1 agonist therapy in
and lost 11.2% more initial weight than control patients with diabetes after bariatric surgery found
participants 2 years after surgery.12 Also, after a significant mean weight change from baseline to
2 years of treatment, a higher proportion of week 26 for patients receiving liraglutide, 1.8 mg
patients in the phentermine/topiramate plus daily, compared with placebo.15 There was also a
laparoscopic sleeve gastrectomy group achieved a significant reduction in hemoglobin A1c between
BMI of less than 40 kg/m2 than participants who the groups, favoring liraglutide. A retrospective
had laparoscopic sleeve gastrectomy alone, thus study of patients with previous bariatric surgery
favoring adjunct therapy for longer-term weight who experienced weight recidivism (>10%
loss after laparoscopic sleeve gastrectomy. weight regain from lowest postsurgical weight),
inadequate weight loss (<20% weight loss from
initial assessment or presurgical weight), and
Naltrexone/Bupropion
weight-loss plateau (patient desired further weight
Naltrexone and bupropion are both FDA approved loss) found that those who had been on high-
as monotherapies for indications other than dosage liraglutide had median weight loss of 7.1%
weight loss but were approved by the US FDA in at 16 weeks and 9.7% at 28 weeks of therapy.16
2014 as combination therapy for long-term weight GLP-1 receptor agonists have variably been
management in patients with obesity.13 While the shown to be effective adjunctive therapy for
efficacy of combination therapy has been studied as weight loss among patients who have undergone
pharmacotherapy, to date, there are no studies of endoscopic bariatric interventions. Endoscopic
the individual efficacies of naltrexone, bupropion, bariatric procedures, such as endoscopic sleeve
or combination therapy in the postbariatric gastroplasty and intragastric balloons, face the
surgery population. Randomized controlled trials same challenges of weight regain and inadequate
of obesity pharmacotherapy often exclude patients weight loss as surgical bariatric procedures. A
with a history of bariatric surgery as a control. retrospective study of 26 matched patients who
Given the proposed mechanism of naltrexone/ underwent endoscopic sleeve gastroplasty were
bupropion for weight loss as a mediator of appetite offered liraglutide 5 months after endoscopic
in the hypothalamus, perhaps it would be useful sleeve gastroplasty and found a significant total
adjunct therapy for patients experiencing weight body weight loss after 7 months of treatment
regain, inadequate weight loss, or weight-loss (1 year after endoscopic sleeve gastroplasty)
plateau due to dietary indiscretion after bariatric compared with weight loss in patients who
or endoscopic bariatric surgery. declined treatment (24.72% vs 20.51%, P <
.001).17 While liraglutide plus endoscopic sleeve
Liraglutide gastroplasty showed promising results, a study
of liraglutide after intragastric balloon found
The development of GLP-1 receptor agonists
that combination therapy did not decrease the
dramatically changed the landscape of weight loss
risk of weight regain 6 months after balloon
pharmacotherapy. Liraglutide, a GLP-1 receptor
removal.14 This study of 108 patients who received
agonist with 97% homology for human GLP-1,
intragastric balloons alone vs intragastric balloons
given as a once-daily subcutaneous injection, was
plus liraglutide 1 month after intragastric balloons
approved by the US FDA for the treatment of
insertion found higher mean weight loss after
type 2 diabetes in 2013 and for weight loss at a
combination therapy. However, after adjusting
higher dosage in 2014.14 While liraglutide alone
for covariates, the intragastric balloon alone
has shown efficacy for weight loss, it has also
group had higher mean body weight loss at time
been demonstrated as a useful adjunct to bariatric
of intragastric balloon removal and higher odds
surgeries and more recently for endoscopic

4 ENDO 2025 • Endocrine Case Management

of treatment success 6 months after intragastric months with no difference between Roux-en-Y
balloon removal. Of note, significantly more gastric bypass or sleeve gastrectomy. The timing
patients in the intragastric balloon alone group of the initiation of adjunct pharmacotherapy is an
tolerated the therapy for 6 months (54 vs 46%; P important factor in determining how to optimize
= .038), but there were otherwise no significant the use of obesity drugs, such as semaglutide, for
differences between the groups regarding weight-loss recidivism after bariatric surgery.
gastrointestinal symptoms, pain, early intragastric Of note, the patients in those studies received
balloon removal or migration, or small-bowel a maximum dosage of semaglutide, 1.0 mg
obstruction. Liraglutide was discontinued 1 month subcutaneously weekly, as it had not yet been
after intragastric balloon removal. Although this approved for obesity at that time. Perhaps
study did not find decreased weight regain with the higher dosage of semaglutide that is now
combination therapy, perhaps the timing of the approved for weight loss (2.4 mg weekly) would
initiation and termination of liraglutide could have yield even greater weight-loss results in this
yielded different results. patient population.

Semaglutide Tirzepatide
Semaglutide, a newer GLP-1 receptor agonist Tirzepatide is the first dual gastric inhibitory
classified as second generation due to increased peptide (GIP) and GLP-1 co-agonist approved
magnitude of weight loss, is given as a weekly in the United States for the treatment of type 2
subcutaneous injection for both diabetes and diabetes and obesity in the absence of diabetes.19
weight management. It was FDA approved for GIP is also an incretin hormone that, like GLP-
type 2 diabetes in 2017 and for chronic weight 1, provides glucose-dependent insulin secretion
management in adults with obesity or overweight from pancreatic β cells. Both GIP and GLP-1 are
with at least 1 weight-related condition in June thought to play a role in appetite and satiety. The
2021. Semaglutide has been extensively studied safety profile is comparable to that of other GLP-1
as an adjunct therapy for patients who have receptor agonists, with the most common adverse
undergone bariatric surgery and have weight effects being a dose-dependent increase in mild
regain or weight-loss plateau after surgery. A to moderate and transient gastrointestinal events,
Swiss study reviewed patients who experienced such as nausea, diarrhea, and vomiting and rare
weight regain after surgery who received 6 fatal adverse effects, severe hypoglycemia, acute
months of GLP-1 receptor agonist therapy with pancreatitis, and cholelithiasis or cholecystitis.20
either semaglutide or liraglutide. Of patients who The SURMOUNT-1 trial of tirzepatide among
had a mean weight regain of 15.1% and received patients with obesity who did not have diabetes
semaglutide (1.0 mg subcutaneously weekly or demonstrated an average weight loss of 15%,
14 mg orally daily) for at least 6 months, nearly 19.5%, and 20.9% over 72 weeks of treatment with
one-quarter had total body weight loss of 15% or tirzepatide, 5 mg, 10 mg, and 15 mg, respectively
more. Combined with results from a liraglutide (vs 3.1% in the placebo group). In this trial, more
group, the authors concluded that two-thirds than 35% of participants in the highest-dosage
of weight regain after bariatric surgery can be tirzepatide group had more than 25% weight
safely lost with GLP-1 receptor agonist therapy.18 reduction.21 For comparison, bariatric surgery
Another study of patients with weight regain or has been shown to result in estimated weight
insufficient weight loss found significant weight reduction up to 30% at 1 year after surgery. The
loss during semaglutide treatment with a mean integration of lifestyle, GLP-1 receptor agonists
of –10.3 kg at 6 months.18 The mean time from (liraglutide, semaglutide, tirzepatide), and
surgery to initiation of semaglutide was 64.7 endoscopic interventions and surgery after 12

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 5

months will be a key point of clinical comparison. weight loss than each modality alone, and that it
Tirzepatide was approved for weight loss in 2022 address the chronic nature of obesity and weight
as a new class of antiobesity medications, and management requiring multimodal therapies.
it is a valuable addition to available weight-loss Optimal timing for pharmacotherapy initiation
pharmacotherapies and may be an effective adjunct with bariatric intervention (both surgical and
therapy for surgical and endoscopic weight-loss endoscopic) remains unclear. In a prospective
interventions. study of 1000 consecutive patients undergoing
endoscopic sleeve gastroplasty, the greatest rate of
weight loss was observed within the first 6 months
Summary following the procedure. Average percentage
Our multidisciplinary group at the Margaret TBWL at 1-, 3-, 6-, 9-, 12-, and 18-month
Corbin (Manhattan) Campus of the VA New follow-up was 8.9% ± 2.9%, 10.5% ± 4.5%, 13.7% ±
York Harbor Healthcare System initiated care 6.8%, 15.2% ± 8.3%, 15.0% ± 7.7%, 14.8% ± 8.5%,
for veterans with obesity and excess weight respectively, with a plateau in weight loss observed
complications in 2017, and since this time at 9 months after the procedure.22 Obesity
has integrated obesity pharmacotherapy with medications could be considered during this
endoscopic bariatric therapies into combined deceleration in weight loss following endoscopic
therapy. In our initial 1-year follow-up cohort sleeve gastroplasty before any weight regain. This
study, we observed that weight-loss outcomes finding is corroborated by a study by Badurdeen
were significantly greater in the combined et al, in which patients who had undergone
cohort compared with outcomes in the bariatric endoscopic sleeve gastroplasty and opted to
endoscopy-only cohort. In comparison, all weight- take liraglutide 5 months after the procedure
loss parameters were significantly greater in the had superior weight loss compared with those
combined therapy cohort at 12 months compared who underwent endoscopic sleeve gastroplasty
with parameters in the obesity pharmacotherapy alone.17 GLP-1 receptor agonist initiation at
cohort. This difference, specifically percentage the onset of endoscopic bariatric intervention
change in BMI and percentage excess weight loss, may increase adverse effects, such as nausea and
was sustained at 24 months. In a cohort of 58 abdominal pain. However, in a recent study of 58
patients who underwent outpatient intragastric patients randomly assigned to either semaglutide
balloons or endoscopic sleeve gastroplasty or placebo just 1 month after endoscopic sleeve
and had at least 12 months of follow-up data, gastroplasty, those in the semaglutide cohort had
43% of patients were also trialed on obesity approximately 7% higher TBWL compared with
pharmacotherapy with phentermine/topiramate, TBWL in the placebo group, and there were no
bupropion/naltrexone, liraglutide, or semaglutide. serious adverse effects.17
At 1-year follow-up after endoscopic bariatric A qualitative study of 16 patients examining
therapies, there was no difference in TBWL, weight-loss patterns after gastric bypass described
change in BMI, or excess weight loss between patterns that may help inform the optimal timing
intragastric balloons and endoscopic sleeve of pharmacotherapy. In the “honeymoon” period
gastroplasty cohorts. By year 3, excess weight immediately after surgery and continuing for 6 to
loss was significantly greater in patients who had 12 months, weight loss was significant and rapid.
undergone endoscopic sleeve gastroplasty (40.4% ± This was followed by a weight “stabilization”
31.6%) compared with patients who had received period, followed by a “work begins” period
intragastric balloons (17.4% ± 19.8%) (P = .025). when patients needed to implement cognitive
These promising longitudinal results suggest and behavioral effort to maintain weight loss.
combination of obesity pharmacotherapy and Participants who regained weight reported a
bariatric endoscopy results in greater sustained return to previous dietary habits, including lack

6 ENDO 2025 • Endocrine Case Management

of portion control, snacking, and emotional Results of dexamethasone-suppression testing are
eating.23 Pharmacotherapies that specifically negative for hypercortisolism.
decrease appetite, such as GLP-1 receptor agonists,
phentermine/topiramate, and naltrexone/ On the basis of published randomized
bupropion, may play a role in ameliorating these controlled trials, which of the following
habits to prevent weight regain in the months FDA-approved medications for type
to years following bariatric surgery. Further 2 diabetes would provide the greatest
studies are needed to determine the optimal improvement from baseline in glycemic
timing of combining pharmacotherapy with control (by hemoglobin A1c) and adjunct
bariatric interventions to maximize weight loss weight loss after 1 year of treatment?
and tolerability. A. Metformin, 1 g twice daily
B. Tirzepatide, 15 mg weekly
Clinical Case Vignettes C. Semaglutide, 1 mg weekly
D. Liraglutide, 1.8 mg daily
Case 1
A 61-year-old man with class 3 obesity (BMI Answer: B) Tirzepatide, 15 mg weekly
= 42 kg/m2) complicated by type 2 diabetes,
Several FDA-approved medications for type
hypertension, hyperlipidemia, and severe
2 diabetes provide weight-loss benefit, as
osteoarthritis presents for an initial weight
demonstrated by their pivotal diabetes trials, and
management evaluation. His medical history is
have a separate indication approval for patients
relevant for laparoscopic sleeve gastrectomy 6
with obesity but no diabetes. Of the medications
years before his initial visit, causing weight loss
listed, tirzepatide (Answer B) is associated with the
from a peak weight of 392 lb (177.8 kg) to a nadir
greatest glycemic improvement and weight loss. In
weight of 224 lb (101.6 kg). Over the ensuing 6
the 1995 SURPASS-4 trial comparing once-weekly
years, he slowly regained weight to his current
subcutaneous tirzepatide with daily subcutaneous
320 lb (145.2 kg). Social history is relevant for
insulin glargine, people with type 2 diabetes
master’s degree education and no toxic habits.
(mean hemoglobin A1c, 8.52%), BMI ≥25 kg/m2,
His father has obesity and type 2 diabetes. His
and high cardiovascular risk, the mean reduction
current medications include insulin glargine,
in hemoglobin A1c with tirzepatide, 10 and 15
40 units daily; insulin lispro, 18 units before each
mg, over 25 weeks was greater than with insulin
meal; metformin, 1000 mg orally twice daily;
glargine (–2.43 and –2.58 percentage points,
atorvastatin; tamsulosin; omeprazole; lisinopril;
respectively, vs –1.44 percentage points with
amlodipine; atenolol; hydrochlorothiazide; aspirin;
insulin glargine). Subsequently, in the SURPASS-2
and naproxen as needed.
study comparing tirzepatide with semaglutide
On physical examination, his pulse rate is
weekly in 1878 patients with type 2 diabetes who
76 beats/min and blood pressure is 140/83 mm Hg.
were not reaching glycemic goals with metformin
His height is 68 in (172.7 cm), and weight is 318 lb
monotherapy, the reduction in hemoglobin
(144.2 kg) (BMI = 41.6 kg/m2). Waist circumference
A1c was superior with tirzepatide (–2 to –2.3
is 51 in (129.5 cm). He has android fat distribution
percentage points vs –1.86 percentage points
without acanthosis or dark striae.
with semaglutide). Overall, small differences
Laboratory test results: in glycemic efficacy favor tirzepatide over
subcutaneous semaglutide (1 mg) or liraglutide.
Hemoglobin A1c = 7.1% (54 mmol/mol)
TSH = 3.07 mIU/L
Weight-loss outcomes in the pivotal diabetes trials
LDL cholesterol = 61 mg/dL (SI: 1.58 mmol/L) showed tirzepatide resulted in greater weight
Triglycerides = 73 mg/dL (SI: 0.82 mmol/L) loss than subcutaneous semaglutide (1 mg). In
Creatinine = 0.6 mg/dL (SI: 53.0 µmol/L)

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 7

turn, weight loss was generally greater with daily, as well as resistance exercise to build muscle
subcutaneous semaglutide (–6 kg) than 1.8 mg mass. He returns now, after 1 year of combined
liraglutide (–3.5 kg). therapy, with concerns of increased appetite and
Interestingly, the use of liraglutide for weight regain.
postbariatric weight regain has been studied
rigorously in patients following Roux-en-Y gastric Which of the following treatment options
bypass. Lofton et al conducted a 56-week, double- is most likely to result in weight-loss
blind, placebo-controlled study in 132 participants maintenance over the next 6 months?
who achieved 25% TBWL status post Roux-en-Y A. Orlistat, 120 mg 3 times daily
gastric bypass and regained 10% TBWL after B. Endoscopic sleeve gastroplasty
reaching nadir weight. Eighteen to 120 months
C. Semaglutide, 1 mg weekly
after Roux-en-Y gastric bypass, participants were
randomized assigned to receive liraglutide, 3.0 mg D. Naltrexone/bupropion, 32/360 mg daily
daily, or placebo with lifestyle counseling regularly Answer: B) Endoscopic sleeve gastroplasty
for 56 weeks. Trial recruitment was limited; 53.4%
of the placebo group and 65% of the liraglutide Bariatric endoscopy is emerging as an alternative
group completed the trial due to the COVID-19 reversible procedure simulating bariatric surgery
pandemic. The percentage change in TBWL from that overlaps in efficacy with second-generation
baseline to 56 weeks was 28.8% (8.5, 229.2 to 9.7) antiobesity medications, such semaglutide and
and 1.1% (3.5, 27.9 to 5.99) in the liraglutide and tirzepatide. Since 2015, several endoscopic
placebo groups, respectively. In the liraglutide bariatric and metabolic therapies have been
and placebo groups, 76% and 17% of participants approved by the US FDA for use in patients
achieved 5% TBWL at 56 weeks, while 51% and with BMI greater than 30 kg/m2, which could
26.0% of the liraglutide group achieved 10% and potentially address the treatment gap for patients
15% TBWL, respectively. None of the placebo with lower weights. These therapies fall into
group lost 10% TBWL. Twenty-one percent 2 categories: space-occupying devices (gastric
of participants receiving liraglutide surpassed balloons and transpyloric shuttle) and gastric
postoperative nadir weight. No participants on remodeling (endoscopic gastroplasty [US FDA
placebo met this goal. Studies for semaglutide and approved for tissue apposition]), used for
tirzepatide as treatment for postbariatric weight remodeling of the stomach anatomy to achieve
regain are ongoing. weight loss. The reported weight loss with the
available endoscopic bariatric and metabolic
therapies ranges from about 10% (gastric
Case 1, Continued
balloons)7 to 16% (endoscopic gastroplasty)24 with
This patient was treated with weight-centric a low rate of serious adverse events.
management of type 2 diabetes at a time when Peak reported weight loss for endoscopic
liraglutide, 1.8 mg weekly, was the most effective bariatric and metabolic therapies occurs after 6
medication providing weight and glycemic months of device placement or tissue apposition.
benefit in type 2 diabetes. Implementation of A detailed meta-analysis of endoscopic sleeve
strict caloric restriction to 1500 calories daily, a gastroplasty collated available primary evidence
low-carbohydrate diet, and liraglutide, 1.8 mg in assessing effectiveness of endoscopic sleeve
daily, resulted in clinically significant weight loss gastroplasty of 16% weight loss from baseline
of 20% from baseline weight to a recent nadir at 6 months.24 In contrast, peak weight loss
weight of 255 lb (115.7 kg) and freedom from for antiobesity medications occurs at 52 weeks
insulin. Weight-loss maintenance required the or later, as reported in the STEP trials of
addition of phentermine-topiramate, 7.5/46 mg semaglutide.25 In this study, weight loss with

8 ENDO 2025 • Endocrine Case Management

semaglutide at 28 weeks approximated 12% from towards higher adiposity with complications
baseline, and weight loss of 14.9% was reported (Figure).
from baseline at the formal 68-week study end • Understanding the individual mechanisms,
point. The effectiveness of other antiobesity tolerability, and efficacy of each of these
medications is commonly reported 1 year after weight-loss drugs is essential to inform
intervention, with orlistat inducing 2.9% to 3.4% how they may best be used not only as
weight loss and naltrexone/bupropion inducing monotherapy, but also how they may be
4.8% weight loss below those of endoscopic sleeve powerful adjuncts to endoscopic and surgical
gastroplasty. A final consideration with endoscopic bariatric procedures.
bariatric and metabolic therapies, such as sleeve
gastroplasty, is the possibility of weight regain, • Some studies have already demonstrated the
which often requires antiobesity medication utility of the combination of bariatric surgery
support beyond 6 months after the procedure. and pharmacotherapy for optimizing weight
loss. With the increased use of less-invasive
bariatric procedures, such as endoscopic
Key Learning Points surgeries, more studies are needed to evaluate
the role of weight-loss drugs as adjunct
• The number of safe and effective options for therapy with such procedures.
the pharmacotherapy treatment of obesity is
• The optimal timing of adjunct obesity
increasing rapidly. New and improved weight
pharmacotherapy also requires further
loss drugs continue to emerge, and several new
investigation to help provide patients with
multiagonist and multihormonal therapies
the most effective, tolerable, and long-lasting
will hopefully be approved for obesity in the
weight loss achievable.
near future and push the treatment envelope

Figure. Spectrum of Care for Obesity According to BMI

Future AOMs
BMI 25 30 35 40 >40
(kg/m2)
Lifestyle AOMs Bariatric Bariatric
Treatment -1st Gen: Endoscopy Surgery
Options >27 with orlistat,
comorbidities phentermine/ 2nd Gen AOMs
-AOMs topiramate,
bupropion/ >35 with
naltrexone, comorbidities:
liraglutide Bariatric
Surgery
-2nd Gen:
semaglutide,
tirzepatide
The spectrum of care for obesity by BMI reflects increasing overlap between AOMs and procedures, including bariatric endoscopy and bariatric surgery.
[Color—Print (Color Gallery page CG3) or web & ePub editions]

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 9

References
1. Centers of Disease Control and Prevention. Adult Obesity Prevalence Maps. US 14. Mosli MM, Elyas M. Does combining liraglutide with intragastric balloon
Department of Health and Human Services; 2023. insertion improve sustained weight reduction? Saudi J Gastroenterol.
2. Aleman JO, Eusebi LH, Ricciardiello L, Patidar K, Sanyal AJ, Holt PR. 2017;23(2):117-122. PMID: 28361843
Mechanisms of obesity-induced gastrointestinal neoplasia. Gastroenterology. 15. Miras AD, Perez-Pevida B, Aldhwayan M, et al. Adjunctive liraglutide
2014;146(2):357-373. PMID: 24315827 treatment in patients with persistent or recurrent type 2 diabetes after
3. Mertens IL, Van Gaal LF. Overweight, obesity, and blood pressure: the effects metabolic surgery (GRAVITAS): a randomised, double-blind, placebo-
of modest weight reduction. Obes Res. 2000;8(3):270-278. PMID: 10832771 controlled trial. Lancet Diabetes Endocrinol. 2019;7(7):549-559. PMID:
4. Dombrowski SU, Knittle K, Avenell A, Araujo-Soares V, Sniehotta FF. Long 31174993
term maintenance of weight loss with non-surgical interventions in obese 16. Rye P, Modi R, Cawsey S, Sharma AM. Efficacy of high-dose liraglutide as
adults: systematic review and meta-analyses of randomised controlled trials. an adjunct for weight loss in patients with prior bariatric surgery. Obes Surg.
BMJ. 2014;348:g2646. PMID: 25134100 2018;28(11):3553-3558. PMID: 30022424
5. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management 17. Badurdeen D, Hoff AC, Hedjoudje A, et al. Endoscopic sleeve gastroplasty
of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol plus liraglutide versus endoscopic sleeve gastroplasty alone for weight loss.
Metab. 2015;100(2):342-362. PMID: 25590212 Gastrointest Endosc. 2021;93(6):1316-1324.e1. PMID: 33075366
6. Dave N, Dawod E, Simmons OL. Endobariatrics: a still underutilized 18. Lautenbach A, Wernecke M, Huber TB, et al. The potential of semaglutide
weight loss tool. Curr Treat Options Gastroenterol. 2023;21(2):172-184. PMID: once-weekly in patients without type 2 diabetes with weight regain or
37284352 insufficient weight loss after bariatric surgery-a retrospective analysis. Obes
7. Popov VB, Ou A, Schulman AR, Thompson CC. The impact of intragastric Surg. 2022;32(10):3280-3288. PMID: 35879524
balloons on obesity-related co-morbidities: a systematic review and meta- 19. Nauck MA, D’Alessio DA. Tirzepatide, a dual GIP/GLP-1 receptor co-
analysis. Am J Gastroenterol. 2017;112(3):429-439. PMID: 28117361 agonist for the treatment of type 2 diabetes with unmatched effectiveness
8. Lucas E, Simmons O, Tchang B, Aronne L. Pharmacologic management regrading glycaemic control and body weight reduction. Cardiovasc Diabetol.
of weight regain following bariatric surgery. Front Endocrinol (Lausanne). 2022;21(1):169. PMID: 36050763
2022;13:1043595. PMID: 36699042 20. Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones:
9. Zoss I, Piec G, Horber FF. Impact of orlistat therapy on weight reduction in Similarities and differences. J Diabetes Investig. 2010;1(1-2):8-23. PMID:
morbidly obese patients after implantation of the Swedish adjustable gastric 24843404
band. Obes Surg. 2002;12(1):113-117. PMID: 11868286 21. Jastreboff AM, Aronne LJ, Ahmad NN, et al; SURMOUNT-1 Investigators.
10. Bray GA, Fruhbeck G, Ryan DH, Wilding JP. Management of obesity. Lancet. Tirzepatide once weekly for the treatment of obesity. N Engl J Med.
2016;387(10031):1947-1956. PMID: 26868660 2022;387(3):205-216. PMID: 35658024
11. Schwartz J, Chaudhry UI, Suzo A, et al. Pharmacotherapy in conjunction 22. Alqahtani A, Al-Darwish A, Mahmoud AE, Alqahtani YA, Elahmedi M.
with a diet and exercise program for the treatment of weight recidivism or Short-term outcomes of endoscopic sleeve gastroplasty in 1000 consecutive
weight loss plateau post-bariatric surgery: a retrospective review. Obes Surg. patients. Gastrointest Endosc. 2019;89(6):1132-1138. PMID: 30578757
2016;26(2):452-458. PMID: 26615406 23. Lynch A. “When the honeymoon is over, the real work begins:” Gastric
12. Ard JD, Beavers DP, Hale E, Miller G, McNatt S, Fernandez A. Use of bypass patients’ weight loss trajectories and dietary change experiences. Soc Sci
phentermine-topiramate extended release in combination with sleeve Med. 2016;151:241-249. PMID: 26820572
gastrectomy in patients with BMI 50 kg/m(2) or more. Surg Obes Relat Dis. 24. Hedjoudje A, Abu Dayyeh BK, Cheskin LJ, et al. Efficacy and safety of
2019;15(7):1039-1043. PMID: 31147285 endoscopic sleeve gastroplasty: a systematic review and meta-analysis. Clin
13. Yanovski SZ, Yanovski JA. Naltrexone extended-release plus bupropion Gastroenterol Hepatol. 2020;18(5):1043-1053. e4. PMID: 31442601
extended-release for treatment of obesity. JAMA. 2015;313(12):1213-1214. 25. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in
PMID: 25803343 adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002.
PMID: 33567185

10 ENDO 2025 • Endocrine Case Management

Metabolic Dysfunction-
Associated Steatotic
Liver Disease: Tips for
Endocrinologists
Eveline Bruinstroop, MD, PhD. Department of Endocrinology and Metabolism, Amsterdam
Gastroenterology Endocrinology and Metabolism Institute, Amsterdam UMC, Amsterdam,
The Netherlands; Email: [email protected]

A. G. (Onno) Holleboom, MD, PhD. Department of Vascular Medicine, Amsterdam

Gastroenterology Endocrinology and Metabolism Institute, Amsterdam UMC, Amsterdam,
The Netherlands; Email: [email protected]

Educational Objectives hepatocytes and activation of nonparenchymal cells,

a condition known as MASH. In patients with type
After reviewing this chapter, learners should be
2 diabetes, the prevalence of MASLD worldwide is
able to:
65%. A greater proportion (15%) of patients with
• Describe the importance and methods of diabetes progress from MASH to the advanced
screening for metabolic dysfunction-associated fibrotic stages of the disease compared with patients
steatotic liver disease (MASLD) in patients who do not have diabetes, and this can ultimately
with diabetes and obesity. culminate in liver-related complications. Half of
patients with advanced fibrosis eventually develop
• Take MASLD into account while managing
cirrhosis.1,2 Complications include decompensated
diabetes.
cirrhosis and hepatocellular carcinoma, both of
• Identify the horizon for medical treatment which are rising in prevalence. Currently, MASH
of fibrotic metabolic dysfunction-associated is the reason for liver transplantation in 27% of
steatohepatitis (MASH). the patients without hepatocellular carcinoma. In
patients with hepatocellular carcinoma, however,
MASH is the most common indication for liver
transplantation.3
Significance of the Most patients with diabetes and obesity never
Clinical Problem progress to end-stage liver disease. Yet, it has
been shown that managing MASLD is important,
MASLD has become the most common liver
even in patients with milder and less progressive
disease, driven by the worsening epidemic of
forms of MASLD. Indeed, each incremental step
obesity and diabetes. The overall global prevalence
along MASLD progression is associated with a
of MASLD is 30% in the general population, with
concomitant increase in the risk of atherosclerotic
3% of all children affected.1 MASLD starts with
cardiovascular events and mortality, independent
the increased accumulation of fat within the liver
of common drivers of MASLD and atherosclerotic
(steatosis), which can lead to necroinflammation of

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 11

cardiovascular disease.3,4 In addition, MASLD stratified for MASLD with clinically significant
and type 2 diabetes have a reciprocal relationship fibrosis using a calculated fibrosis-4 index even if
in that type 2 diabetes and hyperinsulinemia they have normal liver enzymes.”7
drive lipid accumulation and lipogenesis in the
liver, while hepatic insulin resistance driven by
lipotoxicity can in turn trigger gluconeogenesis
Practice Gaps
and thus hyperglycemia, giving rise to or
• Uncertainty about which screening tests
compounding type 2 diabetes.5,6
should be used for MASLD.
Therefore, in addition to screening for
dyslipidemia, oculopathy, nephropathy, and • Difficulty discerning which diabetes
neuropathy, MASLD should be screened for treatments may also have benefit for MASLD.
and treated as appropriate in patients with type • Lack of familiarity with the 3 pillars of
2 diabetes and obesity. This is also highlighted treatment for MASLD.
in the recommendations for screening in the
American Diabetes Association 2023 guideline
(Chapter 4: Comprehensive Medical Evaluation
Discussion
and Assessment of Comorbidities: Standards of Which Screening Tests Should I Use?
Care in Diabetes): “Adults with type 2 diabetes It is important to estimate organ damage due to
or prediabetes, particularly those with obesity MASLD (ie, the presence of significant fibrosis).
or cardiometabolic risk factors/established Therefore, tests have been developed aimed at
cardiovascular disease, should be screened/risk ruling out advanced liver fibrosis corresponding to

Figure. Screening Strategy for MASLD

Screening strategy for MASLD, formerly known as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The strategy is based
on a 2-tier testing approach starting with FIB-4 and, when necessary, vibration-controlled transient elastography (VCTE). Patients with high suspicion of
advanced fibrosis should be referred to a specialized liver clinic for further evaluation.10
Reprinted with permission from Vieira Barbosa J &, Lai M. Hepatol Commun, 2020; 5(2): 158-167. © The Authors. Published by Wiley Periodicals LLC on
behalf of American Association for the Study of Liver Diseases.
[Color—Print (Color Gallery page CG3) or web & ePub editions]

12 ENDO 2025 • Endocrine Case Management

a histological stage of severe liver fibrosis (ie, F3 Table. Clinical Trials Investigating Efficacy
of Antidiabetes Drugs on MASLD
stage and higher). F3 stage designates the presence
of bridging fibrosis between portal tracts. Medication Effects on MASLD
Several noninvasive approaches have been
Pioglitazone, 30 mg Reduction in steatosis and
developed for ruling out advanced MASLD inflammation, no improvement
fibrosis, without the need for liver biopsy. The fibrosis stage11

most commonly used is the Fibrosis-4 score (FIB- GLP-1 receptor agonist Reduction in steatosis,
4), where broadly available parameters, including (semaglutide, 2.4 mg) MASH, and fibrosis (interim
analyses)12,13
age, AST and ALT levels, and platelet count, are
GLP-1 receptor agonist Reduction in steatosis, MASH14
used to calculate a score (age * AST / [0.001 * (liraglutide, 1.8 mg)
platelets * sqr(ALT]).8,9 Several calculators are
GLP-1/GIP (tirzepatide) Reduction in steatosis, MASH15
available online and some laboratories and medical
centers directly report this score to enhance ease of SGLT-2 inhibitors No histopathological
studies, possible reduction in
use. Dependent on the FIB-4 score (lower cutoff = steatosis16-18
1.3), additional screening may be required (Figure,
preceding page).
efinopegdutide. Also promising are the FGF-
21 analogues efruxifermin and pegozafermin
Which Diabetes Treatments
(which, among many other effects, deflect ingested
May Benefit Patients With carbohydrates away from liver), the fatty acid
Different Stages of MASLD? synthase inhibitor denifanstat, and the pan-
Several clinical trials have investigated the efficacy peroxisome proliferator–activated receptor agonist
of known antidiabetes drugs on MASLD (Table). lanifibranor.22
In addition, the BRAVES trial found
significant histological reductions in fibrotic
What Are the 3 Pillars of MASLD at bariatric surgery, including both Roux-
MASLD Treatment? en-Y gastric bypass and sleeve gastrectomy.21 This
The cornerstone of MASLD treatment remains prospective evidence is supported by a large meta-
lifestyle intervention with the aim of an 8% to analysis of bariatric procedures for clinical obesity
10% weight reduction. There is some histological and MASLD.23
evidence that combined lifestyle intervention
(hypocaloric diet and aerobic exercise) inducing
weight loss can improve MASLD, including
Clinical Case Vignettes
steatohepatitis and fibrosis,19,20 but most of the Case 1
evidence for these interventions is based on A 67-year-old woman with type 2 diabetes and
liver imaging (ultrasonography or MRI) gauging obesity (BMI = 33 kg/m2) is referred after not
steatosis only. achieving glycemic goals (hemoglobin A1c = 9%
The thyroid hormone receptor β-agonist [75 mmol/mol]) with a combination of metformin
resmetirom was the first drug to receive FDA and sulfonylureas. Laboratory assessment showed
approval in 2024 for the treatment of MASLD no signs of chronic kidney disease, and there are
with advanced fibrosis in the United States. no clinical signs of retinopathy or polyneuropathy.
Several additional pharmaceutical agents that Following the American Diabetes Association
are in late-stage development for fibrotic guidelines, the patient is also screened for MASLD.
MASLD and cirrhotic MASH include the GLP-1
receptor agonist semaglutide and dual hormone
agonists, such as tirzepatide, survodutide, and

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 13

By using the FIB-4 score based on age, AST, Based on the patient’s FIB-4 score, which
ALT, and blood platelet counts, the aim of the following is the best next step?
is to rule out which of the following? A. There is a low risk of advanced liver fibrosis
A. Significant steatosis (>5% intrahepatic fat with currently no need for further investigation;
content) reassess FIB-4 score in 2 to 3 years
B. Liver fibrosis of any stage (F1-F4) B. There is an indeterminate risk of advanced
C. Advanced liver fibrosis (stage F3 and higher) liver fibrosis; recommend performing a liver
D. Decompensated liver cirrhosis stiffness measurement by vibration-controlled
transient elastography
Answer: C) Advanced liver fibrosis C. There is a high risk of advanced liver fibrosis;
(stage F3 and higher) recommend liver biopsy
A FIB-4 score less than 1.3 has a high negative Answer: A) There is a low risk of advanced
predictive value for advanced fibrosis (≥F3), liver fibrosis with currently no need for further
whereas a positive result should prompt investigation; reassess FIB-4 score in 2 to 3 years
further investigation. Although FIB-4 may be
inferior to other serum-based fibrosis markers The FIB-4 score is 1.05, which represents a low
(ELF, FIBROSpect II) and imaging-based risk of advanced liver fibrosis (<1.3).7,8 No further
elastography methods, it is recommended as a action is currently needed, and the FIB-4 score
first-line assessment for general practitioners can be reassessed in 2 to 3 years. A FIB-4 score
and endocrinologists based on its simplicity and of 2.67 or higher is considered to indicate a high
minimal cost. Disadvantages of the FIB-4 score risk of advanced liver fibrosis. Scores between 1.3
include low accuracy in patients 35 years or younger and 2.67 signal indeterminate risk. The American
and the possible requirement of different cutoffs Diabetes Association guideline recommends
for subgroups of patients with various conditions, patients with either an indeterminate risk or high
including diabetes.8,9 FIB-4 is not a test to identify risk score receive a liver stiffness measurement
steatosis, which can be measured qualitatively by vibration-controlled transient elastography,
with ultrasonography and quantified by controlled which is a well-validated ultrasound-based test for
attenuation parameter or magnetic resonance fibrosis. A liver stiffness measurement less than
spectroscopy. The test is validated specifically for 8.0 kPa excludes advanced fibrosis with a good
advanced fibrosis and does not rule out earlier negative predictive value.7
signs of fibrosis (F1 and F2), which can be present
on liver histology. Also, it does not rule out the Case 2
presence of decompensated liver cirrhosis, which
A 67-year-old woman with type 2 diabetes and
depends mainly on clinical factors, such as ascites.
obesity (BMI = 33 kg/m2) is referred after not
achieving glycemic goals (hemoglobin A1c = 9%
Case 1, Continued [75 mmol/mol]) with a combination of metformin
The patient has the following laboratory results and sulfonylureas. Screening for MASLD showed
documented: an indeterminate FIB-4 score.
AST = 25 U/L (SI: 0.42 µkat/L) Laboratory test results:
ALT = 32 U/L (SI: 0.53 µkat/L)
Platelet count = 170 × 103/µL (SI: 170 × 109/L) AST = 40 U/L (SI: 0.67 µkat/L)
ALT = 32 U/L (SI: 0.53 µkat/L)
With these values combined with age, the FIB-4 Platelet count = 170 × 103/µL (SI: 170 × 109/L)
score can be calculated.
Liver stiffness is determined to be 7.0 kPa with a
controlled attenuation parameter of 310 dB/min.

14 ENDO 2025 • Endocrine Case Management

The measurements from this test improvements in histological activity and fibrosis
indicate which of the following? markers after 72 weeks of treatment.13 Significant
A. No signs of MASLD histological reductions of fibrotic MASLD after
B. Presence of steatosis bariatric surgery have also been shown.19
C. Presence of steatosis and fibrosis
Case 3
Answer: B) Presence of steatosis
A 67-year-old woman with type 2 diabetes and
A liver stiffness value less than 8.0 kPa indicates no obesity (BMI = 33 kg/m2) is referred after not
presence of advanced fibrosis. Controlled attenuation achieving glycemic goals (hemoglobin A1c = 9%
parameter is a feature that is implemented in the [75 mmol/mol]) with a combination of metformin
FibroScan device, which can also quantify liver and a sulfonylurea. Laboratory assessment shows
steatosis by attenuation of the ultrasound beam as no signs of chronic kidney disease, and she has no
it passes through the liver. Different cut offs have clinical signs of retinopathy or polyneuropathy.
been applied with values of 288 dB/min or higher Screening for MASLD shows a high FIB-4 score.
generally considered indicative of steatosis.8 Overall,
Laboratory test results:
the results are consistent with the presence of
MASLD with steatosis but lack of fibrosis. AST = 50 U/L (SI: 0.84 µkat/L)
ALT = 44 U/L (SI: 0.73 µkat/L)
Platelet count = 100 × 103/µL (SI: 100 × 109/L)
Case 2, Continued
Liver stiffness measurement is 18.0 kPa, which
Which of the following is the best next
step to improve this patient’s glycemic indicates advanced fibrosis.
control, obesity, and MASLD?
Should the patient be referred to a hepatologist?
A. Combined pharmacological treatments
A. Yes
targeting not only glycemic control but also
obesity, MASLD, and cardiovascular risk B. No
B. Lifestyle interventions aimed at 8% to 10% Answer: A) Yes
weight loss
C. Bariatric surgery Patients with advanced liver fibrosis should be
referred to an hepatologist to (1) exclude other
D. All of the above causes of fibrosis; (2) consider performing liver
Answer: D) All of the above biopsy; (3) perform follow-up for potential
progression to (decompensated) cirrhosis and
To improve glycemic control, obesity, and MASLD consider hepatocellular carcinoma screening; and
progression, lifestyle measures, pharmacological (4) consider treatment of liver fibrosis.
interventions, and surgical options should be
explored (Answer D). The cornerstone of MASLD
treatment remains lifestyle intervention with the aim
Case 3, Continued
of 8% to 10% weight reduction. Several trials have Which of the following registered
been performed investigating the effects of known treatments for advanced liver
diabetes medications on MASLD (Table), including fibrosis is currently available?
pioglitazone, GLP-1 receptor agonists, GLP-1/GIP A. Semaglutide
dual agonists, and SGLT-2 inhibitors. The interim B. Tirzepatide
analyses from the phase 3 ESSENCE trial with 2.4- C. Resmetirom
mg semaglutide once weekly showed significant
D. Lanifibranor

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 15

Answer: C) Resmetirom • When choosing pharmacological treatment(s)
for diabetes, the presence of MASLD and
The thyroid hormone receptor β-agonist resmetirom obesity should be taken into account.
(Answer C) is currently the only conditionally
FDA-registered treatment for MASLD. However, • Patients with advanced liver fibrosis should be
other drugs are currently in development in clinical referred to a hepatologist for further diagnosis,
trials, including semaglutide (Answer A), tirzepatide follow-up, and treatment.
(Answer B), and lanifibranor (Answer D). • Optimal diabetes management remains
important in patients with MASLD and should
focus on lifestyle, pharmacological treatment,
Key Learning Points and possible surgical treatment.
• Patients with diabetes should be screened for
MASLD with the FIB-4 score based on age,
AST, ALT, and platelet count.

References
1. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry Linda. 12. Sanyal AJ, Chalasani N, Kowdley KV, et al; NASH CRN. Pioglitazone,
The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med.
nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2010;362(18):1675-1685. PMID: 20427778
2023;77(4):1335-1347. PMID: 36626630 13. Newsome PN, Buchholtz K, Cusi K, et al; NN9931-4296 Investigators.
2. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic
Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis steatohepatitis. N Engl J Med. 2021;384(12):1113-1124. PMID: 33185364
using paired biopsies: implications for prognosis and clinical management. J 14. Newsome PN, Sanyal A, Kliers I, et al. Phase 3 ESSENCE trial: semaglutide in
Hepatol. 2015;62(5):1148-1155. PMID: 25477264 metabolic dysfunction-associated steatohepatitis (MASH) [AASLD abstract
3. Younossi ZM, Stepanova M, Al Shabeeb R, et al. The changing epidemiology of 5018]. Presented at: The Liver Meeting; November 15-19, 2024; San Diego,
adult liver transplantation in the United States in 2013-2022: The dominance of CA.
metabolic dysfunction-associated steatotic liver disease and alcohol-associated 15. Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy
liver disease. Hepatol Commun. 2023;8(1):e0352. PMID: 38126928 in patients with non-alcoholic steatohepatitis (LEAN): a multicentre,
4. Younossi ZM, Golabi P, Price JK, et al. The global epidemiology of double-blind, randomised, placebo-controlled phase 2 study. Lancet.
nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among 2016;387(10019):679-690. PMID: 26608256
patients with type 2 diabetes. Clin Gastroenterol Hepatol. 2024;22(10):1999- 16. Loomba R, Hartman ML, Lawitz EJ, et al; SYNERGY-NASH Investigators.
2010.e8. PMID: 38521116 Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver
5. Simon TG, Roelstraete B, Hagström H, Sundström J, Ludvigsson JF. Non- fibrosis. N Engl J Med. 2024;391(4):299-310. PMID: 38856224
alcoholic fatty liver disease and incident major adverse cardiovascular events: 17. Kuchay MS, Krishan S, Mishra SK, et al. Effect of empagliflozin on liver
results from a nationwide histology cohort. Gut. 2022;71(9):1867-1875. fat in patients with type 2 diabetes and nonalcoholic fatty liver disease: a
PMID: 34489307 randomized controlled trial (E-LIFT Trial). Diabetes Care. 2018;41(8):1801-
6. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. 1808. PMID: 29895557
Sources of fatty acids stored in liver and secreted via lipoproteins in patients 18. Harrison SA, Manghi FP, Smith WB, et al. Licogliflozin for nonalcoholic
with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343-1351. steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a
PMID: 15864352 study. Nat Med. 2022;28(7):1432-1438. PMID:
7. Ter Horst KW, Gilijamse PW, Versteeg RI, et al. Hepatic diacylglycerol- 19. Ong Lopez AMC, Pajimna JAT. Efficacy of sodium glucose cotransporter 2
associated protein kinase Cε translocation links hepatic steatosis to hepatic inhibitors on hepatic fibrosis and steatosis in non-alcoholic fatty liver disease:
insulin resistance in humans. Cell Rep. 2017;19(10):1997-2004. PMID: an updated systematic review and meta-analysis. Sci Rep. 2024;14(1):2122.
28591572 PMID: 38267513
8. ElSayed NA, Aleppo G, Aroda VR, et al; on behalf of the American 20. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss
Diabetes Association. 4. Comprehensive medical evaluation and assessment through lifestyle modification significantly reduces features of nonalcoholic
of comorbidities: standards of care in diabetes-2023. Diabetes Care. steatohepatitis. Gastroenterology. 2015;149(2):367-378.e5. PMID: 25865049
2023;46(Suppl 1):S49-S67. PMID: 36507651 21. Verrastro O, Panunzi S, Castagneto-Gissey L, et al. Bariatric-metabolic
9. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD practice surgery versus lifestyle intervention plus best medical care in non-alcoholic
guidance on the clinical assessment and management of nonalcoholic fatty steatohepatitis (BRAVES): a multicentre, open-label, randomised trial. Lancet.
liver disease. Hepatology. 2023;77(5):1797-1835. PMID: 36727674 2023;401(10390):1786-1797. PMID: 25865049
10. Vali Y, van Dijk AM, Lee J, et al; LITMUS investigators. Precision in liver 22. Ratziu V, Francque S, Sanyal A. Breakthroughs in therapies for NASH and
diagnosis: varied accuracy across subgroups and the need for variable thresholds remaining challenges. J Hepatol. 2022;76(6):1263-1278. PMID: 35589249
in diagnosis of MASLD. Liver Int. 2025;45(2):e16240. PMID: 39865358 23. Lee Y, Doumouras AG, Yu J, et al. Complete resolution of nonalcoholic fatty
11. Vieira Barbosa J, Lai M. Nonalcoholic fatty liver disease screening in type liver disease after bariatric surgery: a systematic review and meta-analysis.
2 diabetes mellitus patients in the primary care setting. Hepatol Commun. Clin Gastroenterol Hepatol. 2019;17(6):1040-1060.e11. PMID: 30326299
2020;5(2):158-167.

16 ENDO 2025 • Endocrine Case Management

Atypical and Secondary
Etiologies of Obesity
Andrew T. Kraftson, MD. Department of Internal Medicine, University of Michigan,
Ann Arbor, MI; Email: [email protected]

Educational Objectives best way to define obesity and how to apply this
definition to clinical care.2 As obesity is the most
After reviewing this chapter, learners should be
common chronic condition in adults, classification
able to:
and treatment guidelines have a large magnitude
• Identify the patient population that should be of impact on many stakeholders in myriad clinical,
screened for atypical or secondary etiologies of psychosocial, and economic ways. Scientific and
obesity. technological advancements have paved the way
for expanding obesity treatment options; however,
• Describe the differential diagnosis for atypical
these treatments come with their own health risks
and secondary etiologies of obesity.
and economic costs. Consequently, it has become
• Identify and incorporate appropriate screening increasingly important to have effective obesity
and confirmatory testing for atypical etiologies screening and classification tools to guide public
of obesity in clinical practice. health policies and individualized care.
Within this context, we risk homogenizing
obesity and missing atypical and/or secondary
causes of the condition when weight and BMI
Significance of the are exclusively used to define and classify obesity.
Clinical Problem Unlike the most prevalent, multifactorial form
of obesity, excess weight can result from various
Obesity is a common condition that can present in
hormonal, metabolic, psychological, iatrogenic,
myriad ways. There are often some fundamental
and/or genetic etiologies. Identifying these
commonalities that characterize conventional
exceptional cases is clinically important because
obesity, but occasionally there are cases that
the effects on medical management can be
provoke the question, “Could there be an atypical
significant. However, widespread biochemical,
cause of the weight issue?” To understand when
dynamic, genetic, or radiographic screening for
atypical causes should be considered, it is helpful to
these uncommon causes would be economically
provide some background.
wasteful, be of low clinical yield, and could have
Obesity is characterized by excess adipose
detrimental consequences. As such, there is a
tissue caused by various genetic, epigenetic,
pressing need to increase clinical awareness,
biologic, psychosocial, environmental, and
improve history/physical examination skills, and
behavioral factors.1 It is a complex, systemic,
develop practical guidelines to facilitate focused,
chronic illness marked by a fluctuating, remitting,
appropriate, and accurate screening for atypical
and reactivating course. Additionally, obesity poses
and/or secondary etiologies of obesity.
a higher risk of developing other medical issues
that are referred to as obesity-related diseases.
While our scientific understanding of obesity
has advanced, many questions remain about the

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 17

Practice Gaps Discussion
Rather than the broad, multifactorial way that
• Most health care providers have limited conventional forms of obesity develop, atypical
training in obesity medicine. forms of obesity are distinguished by their discrete
• It is essential for clinicians to consider atypical pathophysiologic disruptions in the weight
and secondary forms of obesity based on regulatory system. This chapter’s discussion
clinical history and physical examination focuses on clearly identifiable atypical and
findings. secondary forms as summarized in Figure 1.
• There is a need to conduct testing/screening In clinical practice, most patients are coping
for atypical and secondary forms of obesity with the common form of multifactorial, polygenic
in a focused, clinically appropriate, and obesity. However, clinicians are confronted by
economically sensitive manner. consultations that can lead to either over testing
or undertesting for atypical/secondary causes of
• It is important to understand how testing
obesity, such as concerns for hormonal causes of
results will influence further evaluation of
obesity, discrepancies between caloric intake and
obesity and management decisions.
weight, insurance requirements for medication,

Figure 1. Atypical and Secondary Etiologies of Obesity

[Color—Print (Color Gallery page CG4) or web & ePub editions]

18 ENDO 2025 • Endocrine Case Management

or pressure from medical personnel or patients to Medical History
initiate obesity treatments.
In addition to the standard elements of a
While many are familiar with common,
comprehensive obesity-related history,
established obesity clinical practice guidelines,3,4
questioning can be refined to improve
there may be some practical elements of history
identification of possible atypical cases of obesity.
taking that need to be bolstered.
Signs, Symptoms, and Physical
Weight History Examination Findings
As illustrated Figure 2, the weight history can Sudden weight changes can be indicative of
illuminate various trends that could increase atypical causes of obesity. Questions should be
or decrease pretest probability of atypical or asked to identify signs/symptoms of hormonal
secondary forms of obesity. dysfunction, change in mental status, and/or
initiation of weight-positive medications.
Similarly, patients should receive a physical
Genetics examination to screen for atypical obesity causes,
The weight history can be the early clue of possible taking care to distinguish between physical
genetic forms of atypical obesity.5 Conventional findings that are specific vs nonspecific.
forms of obesity are polygenic in nature. However, In the absence of compelling history or
atypical forms of obesity can be the result of physical findings, secondary hormonal dysfunction
monogenic defects. Regardless of any other becomes much less likely, which makes most
factors, childhood onset of severe obesity (ie, BMI hormonal screening (beyond thyroid testing) low
≥97th percentile) should prompt consideration of yield and not cost-effective.
monogenic forms of obesity.

Figure 2. Various Weight Trends

[Color—Print (Color Gallery page CG4) or web & ePub editions]

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 19

Mental Health 18 years, she weighed 140 lb (63.5 kg) (BMI =
The connection between obesity and mental 24.8 kg/m2). In her 20s, weight was stable in the
health is complex and incompletely understood.6 range of 140 to 150 lb (63.5-68.0 kg). Pregnancy-
However, it is critical to assess mental health related weight gain was easily lost. However,
status and pharmacotherapy. Testing for she had gradual weight gain since age 40 years
hypercortisolism should be avoided in the absence and current weight is 197 lb (89.4 kg) (BMI =
of other compelling indications.7 34.9 kg/m2). After 12 weeks in the program,
her weight is 166 lb (75.3 kg). She feels good
Medications and is ready to transition to the partial meal
Although iatrogenesis is well-understood to replacement plan (3 meal replacement products +
contribute to excess weight, the important (but 1 conventional meal). At the 18-week dietitian-
time-consuming) step of medication review should only appointment, her weight is 163 lb (73.9 kg).
not be forgotten (Figure 1).8 but the patient notes some fatigue and hair loss. At
the 24-week physician visit, her weight is 176 lb
Eating Patterns, Hunger, and Cravings (79.8 kg), despite reported adherence to the partial
Learning about eating patterns and individual meal replacement diet.
experiences with hunger and cravings can have
diagnostic and therapeutic value.9,10 Monogenic Without any other information provided,
forms of obesity are more likely to cause which of these statements is most likely true?
hyperphagia, which is defined as pathological, A. Total meal replacement therapy is not a good
insatiable hunger,11 whereas binge-eating fit for her given inadequate weight loss at
disorder is marked by pronounced eating, even 3 months
in the absence of hunger, and is associated with a
B. Partial meal replacement therapy is not a
diminished sense of control over eating.12
good fit for her given weight regain seen at
6 months
Response to Obesity-Modifying Treatments
It is useful to compare the patient’s clinical C. Symptoms are likely consequences of rapid
outcomes with expected treatment response.13–16 weight loss, including muscle weakness
If responses are markedly discrepant from from sarcopenia and hair loss from telogen
projections, this may prompt screening for effluvium
atypical and secondary forms of obesity. However, D. Clinical picture is concerning for an atypical
discrepancies between reported caloric intake and cause of weight gain
weight trajectory do not automatically necessitate E. Clinical picture is consistent with a common
a workup for atypical obesity.17 response to the transition from total meal
replacement to partial meal replacement
Clinical Case Vignettes Now, for more information:
Case 1 At the 24-week physician visit, the patient
mentions that fatigue and hair loss have worsened.
A 59-year-old woman with a history for obesity,
The hair loss includes the scalp but also arms,
gastroesophageal reflux disease, and dyslipidemia
legs, and axillae. She notes whole-body swelling,
presents to the weight management program for
facial puffiness, and ruddy complexion. She finds it
consideration of total meal replacement for 12
difficult to rise from sitting or to climb stairs. On
weeks, partial meal replacement for another 4
examination, her blood pressure is 186/92 mm Hg
to 12 weeks, and then individualized dietary and
(compared with 121/58 mm Hg at the visit 12
behavioral recommendations thereafter. Weight
weeks ago). She has facial plethora and round
history reveals normal childhood weight. At age

20 ENDO 2025 • Endocrine Case Management

facies, hair thinning/loss, and notable proximal for treatment of obesity complicated by
muscle weakness of her upper legs. multiple conditions, including type 2 diabetes.
Presurgical weight was 366 lb (166.0 kg) (height
With this additional information, = 69 in [175.3 cm]; BMI = 54 kg/m2). Based on a
now which of the previous answer prediction model, expected 12-month nadir weight
options is most likely true? was projected to be 273 lb (123.8 kg). Postsurgical
Answer: D) Clinical picture is concerning weights were as follows:
for an atypical cause of weight gain
6 months: 292 lb (132.4 kg)
This patient had a good response to treatment 12 months: 294 lb (133.4 kg)
with meal replacement therapy. While some 24 months: 324 lb (147.0 kg)
degree of weight regain is expected during On self-assessment, she considers dietary
the dietary transition process, the rapidity and adherence to be high and estimates that she
magnitude of weight gain despite reported dietary consumes 1200 to 1500 calories per day. She
adherence is concerning (Answer D). However, describes issues with both satiation and satiety
the signs, symptoms, and physical exam findings despite surgery. However, she feels uncomfortable
are the keys to the case. Given the clinical picture, if she eats more than 1.5 cups at a sitting. No
screening for hypercortisolism was conducted, evidence of an eating disorder was found on
and the patient was found to have a pituitary screening. Clinically, she feels fine, and her mental
macroadenoma. Surgical pathology results were health is stable aside from frustration about her
consistent with an ACTH-producing tumor. weight. Physical examination findings are notable
With or without the supplemental for generalized obesity and negative for features of
information, Answer A would be incorrect since hypercortisolism or unusual fat distribution. She is
15% weight loss represents a good response to tearful when discussing weight struggles.
meal replacement therapy. Answer B would also
be incorrect since some degree of weight regain Which of the following is
commonly occurs in the transition from total most likely to be true?
to partial meal replacement. Therefore, without A. Imaging should be ordered to evaluate stomach
the supplemental history, Answer E could have size given her high degree of hunger
been correct. While mild muscle weakness and
B. Hypothyroidism is the most likely reason that
hair loss can occur with meal replacement–
the nadir weight projection was not achieved
associated weight loss, it would not fit with the
and that weight regain occurred
clinical picture presented with the supplemental
information. Of note, this particular patient C. Obtaining a complete weight history could
had DXA at baseline and at 12 weeks (as part of help guide next steps in evaluation and
research), and only a modest loss of lean body management
mass was seen (from 36,300 g down to 35,400 g). D. Screening for hypercortisolism should be
Telogen effluvium is common with rapid weight conducted next
loss but would not be associated with loss of arm, E. No additional evaluation is needed, and caloric
leg, or axillary hair. intake should be reduced to 800 to 1000
calories per day
Case 2 Answer: C) Obtaining a complete weight history could
A 27-year-old woman presents to the postbariatric help guide next steps in evaluation and management
endocrinology clinic for a second opinion and
transfer of care due to weight regain. Two years Taking a complete weight history (Answer C)
ago, the patient underwent sleeve gastrectomy can provide valuable information. In this case, the

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 21

patient revealed that weight issues started before He is now wondering whether methimazole
age 5 years. Additionally, she had an extensive can be stopped. His current regimen is 10 mg daily,
family history of obesity. She was referred for and he has missed a few doses in the past month.
genetic testing and found to have an MC4R His current TSH concentration is 0.22 mIU/L
pathogenic variant and was able to participate in a (reference range, 0.3-5.5 mIU/L). He is encouraged
clinical trial of setmelanotide. to continue methimazole at the dosage of 10 mg
Gastric enlargement is not a common cause daily (and to take it more consistently), and his
of increased hunger after bariatric surgery (thus, TSH concentration is 2.2 mIU/L 8 weeks later.
Answer A is incorrect). Additionally, she describes His weight has been fluctuating between 260 and
good portion control consistent with expectations 265 lb (117.9-120.2 kg).
after sleeve gastrectomy.
Hypothyroidism (Answer B) is not a common Which of the following is true?
cause of primary nonresponse to bariatric surgery, A. Methimazole is the iatrogenic cause of his
nor is it a common cause of weight regain. weight issue and the dosage should be lowered
Furthermore, hypothyroidism would not explain to see if weight control can be improved
her lifelong weight issues. B. His weight gain is likely multifactorial in
There are no signs/symptoms of nature and is less likely to be due to an atypical
hypercortisolism, and screening for this condition form of obesity
(Answer D) would be of low yield and obtaining a
C. Methimazole should be discontinued, and
weight history should be done before testing.
definitive thyroid treatment should be pursued
Further restricting calories (Answer E) despite
since either radioactive iodine ablation or
likely high hunger levels would be both ineffective
thyroidectomy would have superior weight
and punitive.
outcomes
D. Testing for a monogenic form of obesity
Case 3 would be the best next step in evaluation
A 53-year-old man is followed up in postbariatric E. Testing for hypercortisolism is contraindicated
endocrinology clinic. Twelve months after in this situation
surgery, he exceeded projections by 10 lb (4.5 kg)
when he reached a nadir weight of 206 lb (93.4 kg) Answer: B) His weight gain is likely
(down from 285 lb [129.3 kg]). By 36 months multifactorial in nature and is less likely to
after surgery, his weight was 228 lb (103.4 kg). be due to an atypical form of obesity
Despite the gain, he felt satisfied with his weight
Before the onset of Graves disease, the patient
and the “easy” routine and declined the offer of
was experiencing weight regain in the setting of
obesity-modifying medication. Thyroid function
some laxity in his dietary routine and a trajectory
was checked and was normal. Forty-eight months
that is commonly seen 3 years after surgery.
after surgery, he was surprised to learn that his
He had significant weight loss associated with
weight was 192 lb (87.1 kg) despite no obvious
hyperthyroidism that was subsequently addressed.
dietary changes. On extensive questioning,
With resolution of hyperthyroidism, it is expected
his only pertinent symptom was fatigue and
that weight can be modestly higher than the
examination findings were unremarkable.
pre-Graves baseline.18 Afterwards, gaining
Workup was initiated for unintentional causes
13% weight beyond the pre-Graves baseline
of weight loss, and he was found to have Graves
in a period of 2 years would not necessarily be
disease. Methimazole was started, and he became
considered pathological.
euthyroid. Over the next 2 years, he had gradual
Given the clinical picture and laboratory test
weight gain to 260 lb (117.9 kg).
results, it is unlikely that either thyroid disease

22 ENDO 2025 • Endocrine Case Management

or methimazole (Answers A and C) is a major unlikely that he has a monogenic form of obesity
determinant of the patient’s weight. Additionally, (Answer D).
neither radioactive iodine ablation nor While it is unlikely that he has
thyroidectomy is weight-negative when compared hypercortisolism (Answer E) in the absence
with methimazole. of suggestive signs/symptoms, there are no
Considering the patient’s history of normal contraindications for screening, and it would be
weight in childhood and early adulthood, it is reasonable to consider.

Figure 3. Screening for Atypical and Secondary Forms of Obesity.5,7,12,18-24

[Color—Print (Color Gallery page CG5) or web & ePub editions]

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 23

Key Learning Points • Because atypical and secondary forms of
obesity are both important and uncommon,
• Obesity is the most common chronic illness there is a risk of over screening and
in adults and is caused by multifactorial, underscreening.
polygenic factors in most cases. • A comprehensive medical and weight history
• Atypical and secondary forms of obesity can result in screening that is both medically
are clinically important and are managed appropriate and cost-effective.
differently than conventional forms of obesity. • A summary of the approach to atypical and
secondary obesity screening is shown in
Figure 3, preceding page .

References
1. Apovian CM. Obesity: definition, comorbidities, causes, and burden. Am J 13. Rothberg AE, McEwen LN, Kraftson AT, Fowler CE, Herman WH. Very-
Manag Care. 2016;22(Suppl 7):s176s-185. PMID: 27356115 low-energy diet for type 2 diabetes: an underutilized therapy? J Diabetes
2. Rubino F, Cummings DE, Eckel RH, et al. Definition and diagnostic criteria Complications. 2014;28(4):506-510. PMID: 24849710
of clinical obesity. Lancet Diabetes Endocrinol. 2025;13(3):221-262. PMID: 14. Lean ME, Leslie WS, Barnes AC, et al. 5-year follow-up of the randomised
39824205 Diabetes Remission Clinical Trial (DiRECT) of continued support for weight
3. Elmaleh-Sachs A, Schwartz JL, Bramante CT, Nicklas JM, Gudzune KA, Jay loss maintenance in the UK: an extension study. Lancet Diabetes Endocrinol.
M. Obesity management in adults: a review. JAMA. 2023;330(20):2000-2015. 2024;12(4):233-246. PMID: 38423026
PMID: 38015216 15. Salminen P, Grönroos S, Helmiö M, et al. Effect of laparoscopic sleeve
4. Garvey WT, Mechanick JI, Brett EM, et al; Reviewers of the AACE/ACE gastrectomy vs Roux-en-Y gastric bypass on weight loss, comorbidities,
Obesity Clinical Practice Guidelines. American Association of Clinical and reflux at 10 years in adult patients with obesity: the SLEEVEPASS
Endocrinologists and American College of Endocrinology comprehensive randomized clinical trial. JAMA Surg. 2022;157(8):656-666. PMID: 35731535
clinical practice guidelines for medical care of patients with obesity. Endocr 16. Kraftson A, Cain-Nielsen AH, Lockwood A, et al. Predicting early weight loss
Pract. 2016;22(Suppl 3):1-203. PMID: 27219496 failure using a bariatric surgery outcomes calculator and weight loss curves.
5. Mahmoud R, Kimonis V, Butler MG. Genetics of obesity in humans: a Obes Surg. 2022;32(12):3932-3941. PMID: 36253661
clinical review. Int J Mol Sci. 2022;23(19):11005. PMID: 36232301 17. Lichtman SW, Pisarska K, Berman ER, et al. Discrepancy between self-
6. Taylor VH, McIntyre RS, Remington G, Levitan RD, Stonehocker B, Sharma reported and actual caloric intake and exercise in obese subjects. N Engl J Med.
AM. Beyond pharmacotherapy: understanding the links between obesity and 1992;327(27):1893-1898. PMID: 1454084
chronic mental illness. Can J Psychiatry. 2012;57(1):5-12. PMID: 22296962 18. Kyriacou A, Kyriacou A, Makris KC, Syed AA, Perros P. Weight gain
7. Baid SK, Rubino D, Sinaii N, Ramsey S, Frank A, Nieman LK. Specificity following treatment of hyperthyroidism-a forgotten tale. Clin Obes.
of screening tests for Cushing’s syndrome in an overweight and obese 2019;9(5):e12328. PMID: 31267667
population. J Clin Endocrinol Metab. 2009;94(10):3857-3864. PMID: 19602562 19. Luppino FS, de Wit LM, Bouvy PF, et al. Overweight, obesity, and
8. Kumar RB, Aronne LJ. Iatrogenic obesity. Endocrinol Metab Clin North Am. depression: a systematic review and meta-analysis of longitudinal studies.
2020;49(2):265-273. PMID: 32418589 Arch Gen Psychiatry. 2010;67(3):220-229. PMID: 20194822
9. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. 20. Clutter WE. Screening for Cushing’s syndrome in an era of epidemic obesity.
Central nervous system control of food intake and body weight. Nature. Mo Med. 2011;108(2):104-106. PMID: 21568231
2006;443(7109):289-295. PMID: 16988703 21. Laurberg P, Knudsen N, Andersen S, Carlé A, Pedersen IB, Karmisholt J.
10. Berridge KC, Robinson TE. Liking, wanting, and the incentive-sensitization Thyroid function and obesity. Eur Thyroid J. 2012;1(3):159-167. PMID:
theory of addiction. Am Psychol. 2016;71(8):670-679. PMID: 27977239 24783015
11. Heymsfield SB, Avena NM, Baier L, et al. Hyperphagia: current concepts 22. Thomas V, Rallapalli S, Kapoor N, Kalra S. Weight gain and thyroid in
and future directions proceedings of the 2nd International Conference on women: the coexisting confounders. J Pak Med Assoc. 2022;72(9):1871-1873.
Hyperphagia. Obesity (Silver Spring). 2014;22(0 1):S1-S17. PMID: 24574081 PMID: 36280997
12. Herman BK, Deal LS, DiBenedetti DB, Nelson L, Fehnel SE, Brown TM. 23. Kelly DM, Jones TH. Testosterone and obesity. Obes Rev. 2015;16(7):581-606.
Development of the 7-Item Binge-Eating Disorder Screener (BEDS-7). Prim PMID: 25982085
Care Companion CNS Disord. 2016;18(2):10.4088/PCC. PMID: 27486542 24. Feltner C, Peat C, Reddy S, et al. Screening for eating disorders in adolescents
and adults: evidence report and systematic review for the US Preventive
Services Task Force. JAMA. 2022;327(11):1068-1082. PMID: 35289875

24 ENDO 2025 • Endocrine Case Management

Treatment of Obesity in Patients
With Complex Comorbidities
Tirissa J. Reid, MD, DABOM. Department of Medicine, Division of Endocrinology, Diabetes,
and Metabolism, Columbia University Vagelos College of Physicians & Surgeons, New York,
NY; Email: [email protected]

Educational Objectives clinical trials evaluating the efficacy of AOMs in

any of these populations, clinicians lack informed
After reviewing this chapter, learners should be
guidance regarding the management of obesity in
able to:
these settings.
• Explain how complex medical conditions can
exacerbate weight gain and make weight loss Practice Gaps
more difficult.
• Identify which antiobesity medications • The efficacy of AOMs in patients pre– and
(AOMs) may be contraindicated in patients post–organ transplantation is unknown. Given
with specific psychiatric diagnoses and their tenuous clinical status, these patients
symptoms. have not been included in trials for AOMs, and
• Recognize that in patients with eating clinical guidelines do not provide guidance for
disorders and obesity, the therapeutic goals clinical management of this population.
must be modified to primarily focus on • There are no studies guiding the use of AOMs
achieving remission of the eating disorder and in patients with significant psychopathology,
minimizing the focus on weight loss. as they are typically excluded from these
medication trials. In addition, guidance for
the clinical management of this population is
lacking in clinical guidelines.
Significance of the • Patients with eating disorders and obesity are
Clinical Problem excluded from AOM clinical trials, so efficacy
Patients with complex medical histories, complex and guidance regarding their use is lacking.
medication regimens, and clinically tenuous
status are often excluded from clinical trials for Discussion
AOMs, which limits knowledge regarding the
Patients with complex medical histories, eating
appropriateness and efficacy of AOMs in these
disorders, or severe psychopathology are often
populations. Patients who are pre– or post–organ
excluded from clinical trials for AOMs. At the
transplant and those with severe psychopathology
same time, we know that many patients in these
are included in this group. In these patients,
groups are at greater risk for obesity, whether
weight management often takes a back seat to
due to their underlying disorders or medication
treating more acute symptoms. Additionally,
adverse effects.
patients with a history of an eating disorder are
typically excluded from clinical trials for AOMs.
Given that there are currently no large-scale

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 25

Patients Requiring Organ in these patients, even though they may be at
Transplantation increased risk for weight gain.
Patients with anxiety or depression may avoid
Patients requiring organ transplantation have outdoor activities, which then limits physical
an increased risk for obesity due to a variety of activity. Increased weight may also result from
factors. Before transplantation, patients may increased stress, anxiety affecting sleep, or, in
often experience fatigue and debility to some cases of depression, psychomotor slowing leading
degree, which significantly limits physical activity to dramatically reduced physical activity.2 Many
and may lead to weight gain. Patients with common psychiatric medications have weight
severe pulmonary disease often require frequent gain as an adverse effect. Even newer generations
treatment with high-dose steroids, which are of antidepressants have clinically significant
known promote weight gain by increasing appetite weight gain as an adverse effect (in up to 40% of
and worsening insulin resistance. patients).3 One small study of 244 patients with
In patients who have already received an organ obesity and mental health diagnoses were treated
transplant, there are factors that increase the risk with AOMs for 52 weeks.4 While the results
for obesity. These factors include long-term use of showed these medications were effective, resulting
steroids or other immunosuppressive medications in a 12% mean total body weight loss, there was
that may have weight gain as an adverse effect, as also some worsening psychopathology noted with
well as significant continued physical limitations. certain medications (depression increased for
In addition, we know that elevated BMI is a some on topiramate). Further studies are needed
relative contraindication to transplantation for to expound upon the risk/benefits of antiobesity
a variety of organs, as there is some evidence of pharmacotherapy in these patients, particularly
increased rates of graft dysfunction and mortality given that this study concluded in 2018, before the
in these patients. While there are data regarding FDA approval of weekly incretin agonists for the
the efficacy of metabolic and bariatric surgery in treatment of obesity.
some transplant recipients, there remain patients
who are too clinically frail to withstand additional
surgery or who are unwilling to undergo bariatric Patients With Eating Disorders
surgery. Data regarding appropriate and effective Studies have found 40% to 50% of patients with
AOM options in this group of patients are lacking.1 eating disorders also have obesity depending on
the patient population examined.5 Some patients
Patients With Psychiatric Conditions with eating disorders present seeking weight
management. There are some data on the efficacy
While patients with psychiatric conditions, such of lifestyle interventions6 and bariatric surgery in
as anxiety or depression, are not automatically patients with treated eating disorders.7 In patients
excluded from clinical trials for AOMs, those with untreated eating disorders, interventions
with symptoms that are not fully controlled targeting weight loss, such as lifestyle intervention
or those who are on multiple medications are or AOMs, are not recommended as first-line
not included. This makes sense in that it allows therapies. Providers should be familiar with the
for precise determination of new symptoms recommended treatment paradigm to apply when
related to the medication being tested. Complex treating patients with an eating disorder, such as
medication regimens also increase the possibility bulimia nervosa, and obesity.8 While weight loss
of interactions with medications being tested is not recommended as the primary therapeutic
in clinical trials. While these reasons are objective in patients with untreated eating
understandable, it leaves a paucity of data disorders, there are situations where a patient may
regarding how to most effectively treat obesity need to lose weight to improve a weight-related

26 ENDO 2025 • Endocrine Case Management

comorbidity or qualify for a necessary surgery, try another incretin agonist because of the severe
such as orthopedic operation. In these cases, little adverse effects she experienced with liraglutide.
is known regarding the appropriate choice of
AOM, as these patients are typically excluded from Of the following medications approved by
clinical trials of AOMs.9 the US FDA to treat diabetes, which would be
Further research is needed to assess the safety the best addition to her medication regimen
and efficacy of AOMs in patients with obesity and to help the patient reach her weight-loss goal?
complex medical conditions to help guide clinician A. Pioglitazone
management. B. Glyburide
C. Sitagliptin
Clinical Case Vignettes D. Acarbose
Case 1 E. Dapagliflozin
A 50-year-old woman with Hermansky-Pudlak Answer: E) Dapagliflozin
syndrome, interstitial lung disease, type 2 diabetes,
and class 2 obesity (status post sleeve gastrectomy Common chronic medications used to treat
3 years ago) presents for assistance with weight diabetes have distinct effects on weight.10 In
loss to qualify for lung transplantation. Before her addition to understanding their potential to
first pregnancy at age 20 years, her weight was improve glycemic control, providers should
115 lb (52.2 kg) and height was 61 in (154.9 cm), become familiar with their effects on weight. In
(BMI = 21.7 kg/m2). Over 30 years, her weight patients with obesity, providers should aim to
increased to 275 lb (124.7 kg) (BMI = 52.0 = minimize the use of medications that promote
kg/m2) and was accelerated during 2 pregnancies weight gain and preferentially use medications that
(60 lb [27.2 kg] and 30 lb [13.6 kg]) and steroid are weight neutral or promote weight loss.11
tapers for pulmonary disease. Dapagliflozin (Answer E) and other SGLT-2
From a peak weight of 275 lb (124.7 kg), she inhibitors have been shown to cause weight loss.12
lost 45 lb (20.4 kg) with lifestyle changes and Pioglitazone (Answer A) has the potential to
23 lb (10.4 kg) with metformin and liraglutide. increase weight, given its adverse effect of edema.
However, she discontinued both medications due Glyburide and all sulfonylureas cause weight gain
to adverse effects of diarrhea and vomiting. She by increasing insulin secretion.
lost 33 lb (15.0 kg) with sleeve gastrectomy, but Sitagliptin (Answer C) and other DPP-4
regained weight after surgery to 188 lb (85.3 kg) inhibitors are weight-neutral and are not the best
(BMI = 35.5 kg/m2). Intensified lifestyle changes options for this patient who is hoping to lose weight.
have not resulted in weight loss. A goal weight Acarbose (Answer D) has been shown to be
of 160 lb (72.6 kg) is necessary to meet criteria weight-neutral or cause only mild weight loss.
for lung transplantation listing. Her current
medications are levofloxacin and a multivitamin. Case 2
On physical examination, she has albinism and
A 26-year-old woman with class 3 obesity and
central obesity.
weight-related comorbidities of obstructive sleep
Laboratory test results: apnea and prediabetes presents for assistance
with weight loss. Medical history also includes
Hemoglobin A1c = 6.8% (51 mmol/mol)
TSH, normal
depression, severe anxiety, attention deficit–
Creatinine, normal hyperactivity disorder, and Tourette syndrome.
She has been overweight since age 15 years
Her insurer does not cover AOMs, and she reports when she started aripiprazole, followed by rapid
limited disposable income. She is not willing to

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 27

weight gain for 1 year and gradual weight gain anxiety.13 They also increase the risk of serotonin
thereafter. Previous weight-loss attempts include syndrome when used together with a selective
in-person intensive lifestyle interventions, visits serotonin reuptake inhibitor.
with a dietitian, and lifestyle intervention via Liraglutide (Answer B) and tirzepatide
phone app, which is ongoing. Total weight loss (Answer D) may be used concomitantly with
has not exceeded 5% with any intervention. selective serotonin reuptake inhibitors or
Her psychiatrist has adjusted her medications to serotonin norepinephrine reuptake inhibitors
prevent further weight gain, and aripiprazole was without increasing the risk for serotonin
recently discontinued. Current medications are syndrome, and they are not associated with
atomoxetine (selective norepinephrine reuptake anxiety as an adverse effect. Given its greater mean
inhibitor for attention deficit–hyperactivity weight loss and less frequent dosing, tirzepatide
disorder), escitalopram, buspirone, clonazepam, is preferred over liraglutide,14 and tirzepatide is
clonidine, and ethinyl estradiol/norgestimate. also FDA-approved to treat moderate-to-severe
Family history includes obesity in several first- obstructive sleep apnea in patients with obesity.
degree relatives. Review of systems is notable for
loud snoring, heat intolerance, and excess facial Case 3
hair. Menses are regular.
On physical examination, her height is 62 in A 38-year-old woman with a history of bulimia
(157.5 cm) and weight is 282 is lb (127.9 kg) (BMI (in partial remission), depression, anxiety, class
= 51.6 kg/m2). She does not appear acromegalic 3 obesity, and weight-related comorbidities
or cushingoid. Her Ferriman-Gallwey score is 8. (polycystic ovary syndrome, hypertension,
She has no acne or reddish-purplish striae. She gastroesophageal reflux disease, and osteoarthritis)
has acanthosis nigricans in the axillae and multiple presents for assistance with weight loss to improve
skin tags. Her mood and affect are normal. her knee pain and eliminate antihypertensive
medication. She recalls being overweight since age
Laboratory test results: 10 years, with further weight gain exacerbated by
Hemoglobin A1c = 6.1% (43 mmol/mol) depression and antidepressant medications.
TSH, normal Previous weight-loss attempts have included
Liver enzymes, normal multiple structured commercial lifestyle
Creatinine, normal interventions, increased physical activity, and
IGF-1 normal visits with a dietitian. Current medications
are hydrochlorothiazide, clonazepam,
Which of the following AOMs would be lamotrigine, vortioxetine (selective serotonin
most appropriate to start in this patient? reuptake inhibitor), and venlafaxine (selective
A. Phentermine norepinephrine reuptake inhibitor—tapering off).
On physical examination, her height is 69 in
B. Liraglutide (175.3 cm) and weight is 280 lb (127.0 kg) (BMI =
C. Naltrexone/bupropion 41.3 kg/m2). Acanthosis nigricans is present in the
D. Tirzepatide axillae and on the neck. She has central obesity.
E. Phentermine/topiramate
Laboratory test results:
Answer: D) Tirzepatide Hemoglobin A1c = 5.9% (41 mmol/mol)
Fasting insulin = 34 µIU/mL (SI: 236.1 pmol/L)
Phentermine (Answer A), phentermine/topiramate
(Answer E), and naltrexone/bupropion (Answer She would like to initiate medication therapy but is
C) all have the possible adverse effect of anxiety not amenable to using an injection.
and should not be used in a patient with severe

28 ENDO 2025 • Endocrine Case Management

In addition to a referral to a behavioral with modest weight loss in patients who have an
therapist well-versed in treating elevated BMI and prediabetes.15 Another study
patients with eating disorders, which found that metformin was able to effect a 6.4%
of the following medications is most placebo-subtracted weight loss in comparison with
appropriate for this patient to assist placebo in patients with obesity, with greater weight
her in reaching her health goals? loss in patients who had severe insulin resistance,
A. Phentermine making this a good option for this patient.16
B. Phentermine/topiramate
C. Off-label metformin Key Learning Points
D. Naltrexone/bupropion
• Medication-induced weight gain is
E. Tirzepatide
common in pre– and post–organ transplant
Answer: C) Off-label metformin recipients. Other mechanisms of weight gain
in these patients include deconditioning
In patients with eating disorders, the main goal pretransplantation, as their clinical status
of therapy is to achieve complete remission deteriorates prior to transplant.
of the eating disorder; weight loss is not the
primary goal. There are instances where weight • Common long-term medications used to treat
loss may also be important, such as reducing comorbid disorders can be used to assist with
pain due osteoarthritis. Cognitive behavioral weight loss.
therapy has been shown to be the most effective • Patients with severe psychiatric comorbidities
treatment for bulimia. There is insufficient and obesity often have contraindications to
evidence to determine which AOMs are best in multiple AOMs due to medication interactions
patients with eating disorders, as this patient or possible AOM adverse effects, such as
population is typically excluded from clinical anxiety. Incretin therapies are often used in
trials. If weight loss is desired, it is important these patients without exacerbating psychiatric
to focus any therapies, including medications, conditions and without increasing the risk for
on the goal of improving health. In this patient serotonin syndrome in patients on selective
with bulimia in partial remission, phentermine serotonin reuptake inhibitors.
(Answer A), phentermine/topiramate (Answer • Goals of therapy in patients with current,
B), and naltrexone/bupropion (Answer D) are all or history of, eating disorders and obesity
contraindicated, due to the potential to heighten should not focus on weight loss, but instead
the already elevated seizure risk with bulimia. on improvements in health and other
These same medications also have the risk of comorbidities, using proven interventions.
worsening anxiety. This patient has stated that Interdisciplinary care is key. Several AOMs
she will not use an injection, so incretin agonists, are contraindicated in patients with bulimia
such as tirzepatide (Answer E), are not an option. nervosa, including phentermine and
While metformin is not FDA-approved to treat naltrexone/bupropion (due to the bupropion
polycystic ovary syndrome, prediabetes, or weight component).
loss, it is sometimes used off-label (Answer C)
for each of these conditions. This patient has
a known history of polycystic ovary syndrome
and prediabetes and physical examination signs
and laboratory evidence consistent with insulin
resistance. The Diabetes Prevention Program
trial demonstrated that metformin is able to assist

ENDO 2025 • Adipose Tissue, Appetite, Obesity, and Lipids 29

References
1. Ghanem OM, Pita A, Nazzal M, et al; SAGES & ASTS. Obesity, organ failure, 8. Ralph AF, Brennan L, Byrne S, et al. Management of eating disorders
and transplantation: a review of the role of metabolic and bariatric surgery for people with higher weight: clinical practice guideline. J Eat Disord.
in transplant candidates and recipients. Surg Endosc. 2024;38(8):4138-4151. 2022;10(1):121. PMID: 35978344
PMID: 38951240 9. Camacho-Barcia L, Giel KE, Jiménez-Murcia S, et al. Eating disorders and
2. Christensen SM, Varney C, Gupta V, Wenz L, Bays HE. Stress, psychiatric obesity: bridging clinical, neurobiological, and therapeutic perspectives.
disease, and obesity: an Obesity Medicine Association (OMA) clinical practice Trends Mol Med. 2024;30(4):361-379. PMID: 38485648
statement (CPS) 2022. Obes Pillars. 2022;4:100041. PMID: 37990662 10. Domecq JP, Prutsky G, Leppin A, et al. Clinical review: drugs commonly
3. Uguz F, Sahingoz M, Gungor B, Aksoy F, Askin R. Weight gain and associated with weight change: a systematic review and meta-analysis. J Clin
associated factors in patients using newer antidepressant drugs. Gen Hosp Endocrinol Metab. 2015;100(2):363-370. PMID: 25590213
Psychiatry. 2015;37(1):46-48. PMID: 25467076 11. Barenbaum SR, Kumar RB, Aronne LJ. Management of medication-induced
4. Tham M, Chong TWH, Jenkins ZM, Castle DJ. The use of anti-obesity weight gain. Gastroenterol Clin North Am. 2023;52(4):751-760. PMID:
medications in people with mental illness as an adjunct to lifestyle 37919025
interventions - Effectiveness, tolerability and impact on eating behaviours: 12. Akhanli P, Hepşen S, Arslan İE, et al. Impact of 24-week dapagliflozin
a 52-week observational study. Obes Res Clin Pract. 2021;15(1):49-57. PMID: treatment on body weight, body composition, and cardiac risk indicators of
33257207 patients with type-2 diabetes mellitus. Turk J Med Sci. 2023;53(5):1178-1184.
5. da Luz FQ, Hay P, Touyz S, Sainsbury A. Obesity with comorbid eating PMID: 38813008
disorders: associated health risks and treatment approaches nutrients. 13. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a
2018;10(7):829. PMID: 29954056 systematic and clinical review. JAMA. 2014;311(1):74-86. PMID: 24231879
6. McDonald JB, Rancourt D. Treating bulimia nervosa and achieving medically 14. Henderson K, Lewis, Sloan CE, Bessesen DH, Arterburn D. Effectiveness and
required weight loss: a case study. Cognitive Behavioral Pract. 2023;30(1):146- safety of drugs for obesity. BMJ. 2024;384:e072686. PMID: 38527759
159. 15. Knowler WC, Barrett-Connor E, Fowler SE, et al; Diabetes Prevention
7. Hilbert A, Staerk C, Strömer A, et al. Nonnormative eating behaviors Program Research Group. Reduction in the incidence of type 2 diabetes
and eating disorders and their associations with weight loss and quality with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403.
of life during 6 years following obesity surgery. JAMA Netw Open. PMID: 11832527
2022;5(8):e2226244. PMID: 35951326 16. Seifarth C, Schehler B, Schneider HJ. Effectiveness of metformin on weight
loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes.
2013;121(1):27-31. PMID: 23147210

30 ENDO 2025 • Endocrine Case Management

ADRENAL
How to Manage Bilateral
Adrenal Masses
Jérôme Bertherat, MD, PhD. Genomics and Signaling of Endocrine Tumors Team, INSERM
U1016, CNRS UMR8104, Cochin Institute, Paris Cité University, Paris, France; Department
of Endocrinology, Reference Center for Rare Adrenal Diseases, Cochin Hospital, Paris,
France; Email: [email protected]

Educational Objectives investigations are designed to assess the possibility

of hypersecretion, primarily of cortisol, or
After reviewing this chapter, learners should be
more rarely of aldosterone or catecholamines.2
able to:
Hormonal testing also helps identify adrenal
• Describe the various causes of bilateral adrenal insufficiency, especially when the adrenal
masses. glands are the site of metastases or infectious or
inflammatory infiltration.
• Perform the diagnostic workup of bilateral
adrenal masses.
• Guide the management of bilateral adrenal Practice Gaps
masses.
• Adrenal incidentalomas are bilateral in 10% to
15% of cases. However, the bilateral nature in
asymmetric forms can be underdiagnosed, and
systematic analysis of the contralateral adrenal
Significance of the
gland is important for adrenal incidentaloma
Clinical Problem management.
Bilateral adrenal masses are most often discovered • Multidisciplinary expertise is important for
incidentally, during evaluation of adrenal proper diagnosis and management of bilateral
incidentalomas. Adrenal incidentalomas are adrenal masses.
common in the general population (1% to 5%,
or even higher in individuals approaching age • Although it is important to not miss
70 years), and 10% to 15% of incidentalomas are malignancy (especially metastasis) in patients
bilateral.1 More rarely, these bilateral masses are with bilateral adrenal incidentalomas, they are
revealed by symptoms of steroid or catecholamine most frequently benign adrenocortical lesions.
hypersecretion. Occasionally, bilateral lesions are • Distinguishing mild forms of bilateral
discovered during the investigation of adrenal macronodular adrenal hyperplasia (PBMAH)
insufficiency. The diagnostic approach seeks from bilateral adrenocortical adenomas on
to establish the nature of the adrenal lesions, imaging is often difficult; however, clinical
primarily on the basis of imaging characteristics. management based on assessment of cortisol
Most often, the lesions are of the same type autonomous secretion and comorbidities is
on both sides, but sometimes there may be a similar.
lesion of a different type on each side. Rigorous • The management of patients with mild
imaging analysis is therefore essential for initial autonomous cortisol secretion and benign
characterization. At the same time, hormonal

32 ENDO 2025 • Endocrine Case Management

 bilateral adrenocortical lesions on the basis The diagnostic approach to bilateral adrenal
of comorbidities should be discussed on incidentalomas is similar to that of unilateral
an individual basis and cannot yet be fully incidentalomas. CT is the most commonly
supported by evidence-based medicine.3 used initial imaging to characterize the lesions.
• There is lack of awareness that bilateral Benign adrenal cortical lesions most often have
pheochromocytomas occur most often in a spontaneous density of less than 10 Hounsfield
patients with genetic etiologies and require a units on CT. However, a higher spontaneous
systematic genetic consultation.4 In PBMAH, a density does not rule out a benign lesion. In this
genetic cause (most often an ARMC5 variant) is context, MRI can provide additional information.
identified in about 20% of affected patients.5,6 If a malignant lesion is suspected, 18FDG PET may
be useful, and in the case of bilateral metastases,
the primary tumor may also be visualized.
Discussion Endocrine investigations begin with a
The various etiologies of bilateral adrenal masses search for clinical evidence of hypercortisolism,
are listed in Table 1. The most frequent lesions hyperaldosteronism, or pheochromocytoma.
are benign bilateral adrenocortical lesions. The search for signs of adrenal insufficiency,
These may be bilateral adenomas or PBMAH. particularly if imaging or clinical findings
Bilateral pheochromocytoma is very often suggest metastatic malignancy (solid tumor or
genetic in origin. PBMAH is genetic in 20% to hemopathy), is important because it can represent
25% of cases. In a syndromic setting, bilateral a therapeutic emergency.
lesions may also be observed, for example, in Biological investigations include an electrolyte
persons with multiple endocrine neoplasia type panel and blood glucose measurement to check for
1 (adrenocortical tumors), von Hippel–Lindau hypokalemia and diabetes. Autonomous cortisol
syndrome, or multiple endocrine neoplasia type 2 secretion is evaluated with a 1-mg dexamethasone-
(pheochromocytomas). suppression test, with a normal serum cortisol
cutoff value of 1.8 µg/dL or less (≤50 nmol/L).

Table 1. Etiology of Bilateral Adrenal Masses

Similar lesions on both sides Different or similar lesions on both sides

Bilateral adrenocortical adenoma • Adrenocortical adenoma
• Nonfunctioning • Myelolipoma
• Mild autonomous cortisol secretion • Cyst
• Overt Cushing syndrome • Hemorrhage
• Primary aldosteronism • Ganglioneuroma
• Adrenal sex steroid excess (extremely rare) • Schwannoma
Macronodular bilateral adrenal hyperplasia • Pheochromocytoma
• Mild autonomous cortisol secretion • Adrenocortical carcinoma
• Overt Cushing syndrome • Adrenal metastases
• Primary aldosteronism • Adrenal lymphoma
• Nonfunctioning • Adrenal sarcoma
• Adrenal sex steroid excess (extremely rare) • Adrenal neuroblastoma
Micronodular bilateral adrenal hyperplasia and primary • Hemangioma
pigmented nodular adrenocortical disease
• Infiltrative infectious disease (tuberculosis, histoplasmosis,
Cushing disease cryptococcosis)
Ectopic ACTH syndrome • Infiltrative inflammatory disease (sarcoidosis, amyloidosis,
Congenital adrenal hyperplasia Erdheim-Chester disease, etc)

ENDO 2025 • Adrenal 33

In patients with incidentalomas and no specific secretion (low ACTH). In the case of mild or overt
signs of Cushing syndrome, a serum cortisol value Cushing syndrome, the differential diagnosis
greater than 1.8 µg/dL (>50 nmol/L), usually between an ACTH-independent cause and an
repeated after few months to reduce false-positive ACTH-dependent cause is important because
results, is classified as mild autonomous cortisol management differs (Table 2).
secretion (MACS). This warrants screening
for comorbidities (diabetes, hypertension,
osteoporosis, obesity, etc). If the adrenal masses
Clinical Case Vignettes
are not typical of bilateral benign adrenocortical
lesions, evaluation for pheochromocytoma Case 1
should be done by measuring plasma or urinary
Bilateral adrenal masses are found on CT (Figure
metanephrines. If arterial hypertension or
1, following page) performed for lumbar pain in a
hypokalemia is present, aldosterone and renin
73-year-old man. On the right adrenal gland, a
should be measured. In the absence of autonomous
16-mm nodule is identified with an unenhanced
cortisol secretion, adrenal insufficiency should
density of 12 Hounsfield units. On the left
be ruled out with a cosyntropin-stimulation test.
adrenal gland, a 25-mm nodule is identified with
If adrenal insufficiency or autonomous cortisol
an unenhanced density of 24 Hounsfield units.
secretion is detected, ACTH measurement is useful
His medical history is relevant for hypertension
to confirm the adrenal primary nature of adrenal
treated for 5 years, type 2 diabetes, sleep apnea,
insufficiency (high ACTH) or cortisol autonomous
and transient stroke. Current medications

Table 2. Differential Diagnosis of Bilateral Benign Similar Adrenocortical Masses

Bilateral macronodular Bilateral adrenal ACTH-dependent nodular Partial glucocorticoid

Characteristics adrenal hyperplasia adenomas hyperplasia resistance syndrome

Clinical • Mild or overt clinical signs • Bilateral Overt clinical symptoms and • Possible arterial
presentation or comorbidities of Cushing incidentalomas comorbidities of Cushing hypertension
syndrome syndrome are typical in chronic
• Mild or overt • Possible hirsutism
Cushing disease or ectopic
• Bilateral incidentalomas clinical signs or
ACTH syndrome leading to • Possible fatigue
comorbidities of
nodular adrenal hyperplasia
Cushing syndrome • No signs of overt
Cushing syndrome

Imaging Bilateral enlargement Bilateral nodules Bilateral enlargement of both • Bilateral nodular
of both adrenal glands without internodular adrenal glands hyperplastic adrenals
and macronodules with hyperplasia
• Rarely very large
internodular hyperplasia

Hormonal • Normal or high urinary free • Normal or high • High urinary free cortisol • High urinary free
characteristics cortisol urinary free cortisol cortisol
• Normal/high ACTH
• Low/suppressed ACTH • Low/suppressed • Normal/high ACTH
• Higher DHEA-S
ACTH
• Normal or elevated • Possible elevated
• Partial suppression after
17-hydroxyprogesterone • Normal 17-hydroxy- adrenal androgens
dexamethasone-suppression
progesterone
• Normal or low DHEA-S test • Possible altered
• Partial or lack aldosterone-to-renin
• Partial or lack of • Response to desmopressin/
of cortisol ratio
cortisol suppression CRH in Cushing’s disease,
suppression after
after dexamethasone- less frequent in benign • Reduced cortisol
dexamethasone-
suppression test neuroendocrine tumors with suppression after
suppression test
ectopic ACTH dexamethasone-
• Possible elevated
suppression test
aldosterone-to-renin ratio

Adapted from Bertherat J et al. Endocrine Review, 2023; 44(4): 567–628. © The Authors. Published by Oxford University Press on behalf of the
Endocrine Society.

34 ENDO 2025 • Endocrine Case Management

include metformin, insulin, amlodipine, Figure 1.
hydrochlorothiazide, valsartan, bisoprolol, and
acetylsalicylate.
On physical examination, his weight is 187.4 lb
(85 kg) (BMI = 29 kg/m2). His blood pressure is
124/75 mm Hg.
Laboratory test results:
Sodium = 139 mEq/L (SI: 139 mmol/L)
Potassium = 4.6 mEq/L (SI: 4.6 mmol/L)
Creatinine = 1.10 mg/dL (SI: 97 µmol/L)
Hemoglobin A1c = 6.4% (46 mmol/mol)
Serum cortisol after 1 mg dexamethasone = 1.3 µg/dL
(SI: 35 nmol/L)
Aldosterone = 8.3 ng/dL (8.3-23.6 ng/dL)
(SI: 229 pmol/L [33-655 pmol/L])
Renin = 11 µIU/mL (3-40 µIU/mL)
Urinary metanephrine = 770 µg/24 h (49-217 µg/24 h)
(SI: 3851 nmol/d [250-1100 nmol/d])
Urinary normetanephrine = 842 µg/24 h
(92-440 µg/24 h) (SI: 4595 nmol/d
[500-2400 nmol/d])

Which of the following is the

best recommendation?
A. 18FDG PET
B. 18F FDOPA PET
C. Replacing hydrochlorothiazide with
spironolactone
D. Biopsy
E. Simple follow-up with a CT in 6 months
[Color—Print (Color Gallery page CG6) or web & ePub editions]
Answer: B) F FDOPA PET
18

The imaging findings and the urinary Which of the following is the
metanephrine and normetanephrine most likely diagnosis?
measurements, which show a moderate but A. Left pheochromocytoma
likely significant increase, are suggestive of B. Right adrenal cancer
pheochromocytoma. In this patient with an C. Primary bilateral macronodular adrenal
apparently sporadic presentation, performing 18F hyperplasia
FDOPA PET (Answer B) would be the best next
step to evaluate for pheochromocytoma. D. Bilateral adrenal adenomas
E. Bilateral myelolipoma
Case 1, Continued Answer: A) Left pheochromocytoma
An 18F FDOPA PET is performed (Figure 2, The 18F FDOPA PET shows unilateral uptake
following page). in the left adrenal gland (SUV 3.6) and no

ENDO 2025 • Adrenal 35

Figure 2.

[Color—Print (Color Gallery page CG6) or web & ePub editions]

Figure 3.

[Color—Print (Color Gallery page CG6) or web & ePub editions]

contralateral or extra-adrenal tracer uptake. This The 2 main nodules in the right adrenal gland
is highly suggestive of a pheochromocytoma have unenhanced density less than 10 Hounsfield
(Answer A). After left laparoscopic adrenalectomy, units, while the additional smaller nodules have
pathologic examination confirmed a a density between 10 and 15 Hounsfield units.
pheochromocytoma and chromogranin A The nodules in the left adrenal gland have an
immunostaining was positive (preoperative unenhanced density less than 10 Hounsfield units.
chromogranin A circulating level was 2 times Medical history is relevant for hypertension
normal). Based on CT imaging characteristics and treated for 15 years and cardiac arrythmia.
results of the dexamethasone-suppression test, the Current medications are amlodipine, perindopril,
right adrenal nodule was classified as a benign, indapamide, atenolol, fluindione, and potassium
nonsecreting adenoma. supplementation.
On physical examination, his weight is 240 lb
(109 kg) (BMI = 32 kg/m2). Blood pressure is
Case 2
157/92 mm Hg. There is truncal obesity and facial
Bilateral multiple adrenal nodules are found on erythrosis. There are no catabolic signs.
CT performed for abdominal pain in a 68-year-old
man (Figure 3). Laboratory test results:

36 ENDO 2025 • Endocrine Case Management

 Sodium = 144 mEq/L (SI: 144 mmol/L) Which of the following is the best advice?
Potassium = 3.5 mEq/L (SI: 3.5 mmol/L)
Creatinine = 1.2 mg/dL (SI: 107 µmol/L)
A. Bilateral adrenalectomy
Glucose = 106.3 mg/dL (SI: 5.9 mmol/L) B. Pasireotide
Hemoglobin A1c = 6% (42 mmol/mol) C. Brain MRI
Cortisol after 1 mg dexamethasone = 3.8 µg/dL
(>1.8 µg/dL) (SI: 106 nmol/L [>50 nmol/L]) D. Adrenal imaging in all first-degree relatives
Urinary free cortisol = 34.8 µg/24 h (54.4 µg/24 h) E. 1-mg dexamethasone-suppression test in all
(SI: 96 nmol/d [<142 nmol/d])
first-degree relatives
Morning cortisol = 17.9 µg/dL (4.5-24.0 µg/dL)
(SI: 495 nmol/L [124-662 nmol/L]) Answer: C) Brain MRI
ACTH = 9.1 pg/mL (<59.1 pg/mL) (SI: <2 pmol/L
[<13 pmol/L]) An ARMC5 pathogenic variant is found in about
Late-night salivary cortisol = 0.40 µg/dL
(<0.14 µg/dL) (SI: 11.0 nmol/L [<3.9 nmol/L]) 20% of index patients with primary bilateral
Aldosterone = 14.2 ng/dL (1.2-23.6 ng/dL) macronodular adrenal hyperplasia. About half
(SI: 393 pmol/L [33-655 pmol/L]) of ARMC5 index patients diagnosed today have
Renin = 46 µIU/mL (3-40 µIU/mL) been initially evaluated for bilateral adrenal
incidentalomas. An ARMC5 pathogenic variant
Which of the following is the can be associated with meningioma, thus justifying
most likely diagnosis? brain imaging (Answer C). The finding of an
ARMC5 pathogenic variant in an index patient
A. Adrenal bilateral metastasis of a lung cancer
offers the possibility of genetic familial screening.
B. Nonclassic congenital adrenal hyperplasia Adrenal evaluation (imaging and hormonal assays)
C. Bilateral adrenal cancer would only be recommended in relatives carrying
D. Primary bilateral macronodular adrenal the ARMC5 pathogenic variant. Treatment of
hyperplasia mild autonomous cortisol secretion in primary
E. Carney complex bilateral macronodular adrenal hyperplasia is
based on the evaluation of comorbidities (diabetes,
Answer: D) Primary bilateral hypertension, obesity, osteoporosis). Among the
macronodular adrenal hyperplasia therapies that can be discussed on an individual
basis are unilateral adrenalectomy (but not
The nodules are benign adrenocortical lesions, not bilateral adrenalectomy, at least not as first-line
cancer. Hormonal investigations demonstrate mild treatment) or steroidogenesis inhibitors.
autonomous cortisol secretion, which is present
in most cases of incidentally discovered primary
bilateral macronodular adrenal hyperplasia Case 3
(Answer D). Nonclassic congenital adrenal A 69-year-old man presents with moderate weight
hyperplasia would not be associated with low loss (11.0 lb [5 kg]) in a 4-month period and
ACTH and mild autonomous cortisol secretion. unusual asthenia with dizziness. He has a 12-year
Carney complex can cause overt Cushing history of hypertension treated with amlodipine
syndrome due to bilateral micronodular adrenal and enalapril/hydrochlorothiazide and a 4-year
hyperplasia in children and young adults. history of type 2 diabetes treated with metformin.
On physical examination, his temperature is
Case 2, Continued 97.9°F (36.6°C), pulse rate is 88 beats/min, and
blood pressure is 107/66 mm Hg. His weight is
Genetic analysis reveals an ARMC5 pathogenic 165.3 lb (75 kg) (BMI = 22.7 kg/m2).
variant.

ENDO 2025 • Adrenal 37

Laboratory test results: Leukocyte count = 5600/µL (SI: 5.6 × 109/L)
C-reactive protein = 11 mg/L (SI: 104.8 nmol/L)
Sodium = 131 mEq/L (SI: 131 mmol/L) Hemoglobin A1c = 6.5% (48 mmol/mol)
Potassium = 4.7 mEq/L (SI: 4.7 mmol/L) Liver enzymes, normal
Creatinine = 0.75 mg/dL (SI: 66 µmol/L) TSH = 2.4 mIU/L
Hemoglobin = 12.9 g/dL (SI: 129 g/L)
Whole-body CT reveals bilateral adrenal masses
(right, 56 × 43 mm; left, 128 × 85 mm) (Figure 4A).
Figure 4. An 18FDG PET shows high uptake (SUV = 11-18)
in both adrenal masses and no other abnormal
lesions (Figure 4B).

Which of the following should

be recommended now?
A. Morning circulating ACTH and serum cortisol
measurement
B. Chromogranin A measurement
C. Corticotropin-releasing hormone test
D. Immediate adrenal biopsy
E. Adrenal vein sampling
Answer: A) Morning circulating ACTH
and serum cortisol measurement
This patient has signs suggestive of adrenal
insufficiency, and basal ACTH and cortisol
measurements (Answer A) are important to
confirm this diagnosis. If the results demonstrate
elevated ACTH and low cortisol, this would be
enough evidence to start rapidly substitutive
therapy with hydrocortisone. If this is not the case,
cosyntropin-stimulation testing would be advised.
Chromogranin A (Answer B) is a
marker of neuroendocrine tumor including
pheochromocytoma, but its specificity and sensitivity
precludes its use as a first-line investigation.
Corticotropin-releasing hormone testing
(Answer C) would only be indicated in the setting
of ACTH-dependent Cushing syndrome.
Adrenal vein sampling (Answer E) would only
be relevant if unilateral adrenalectomy for steroid
excess (mostly primary aldosteronism) were
being discussed.
Adrenal biopsy (Answer D) cannot be
performed before the results of metanephrine/
normetanephrine assays to rule out
pheochromocytoma.
[Color—Print (Color Gallery page CG7) or web & ePub editions]

38 ENDO 2025 • Endocrine Case Management

Case 3, Continued should be stopped, and the indication for the
antihypertensive drug should be reevaluated.
The following laboratory test results are
Diuretics are not recommended for patients with
documented:
primary adrenal insufficiency. Adrenal biopsy
ACTH = 59.1 pg/mL (<2.9 pg/mL) (SI: 42 pmol/L (Answer D) is indicated since pheochromocytoma
[<13.0 pmol/L]) has been excluded and this patient is likely to have
Cortisol = 8.8 µg/dL (SI: 243 nmol)
adrenal destruction by an infiltrative malignant
Cortisol post cosyntropin-stimulation test =
10.3 µg/dL (>18.5 µg/dL) (SI: 283 nmol/L tumor. The biopsy confirmed the diagnosis of
[>510 nmol/L]) high-grade B-cell lymphoma, and the patient was
Renin = 179 µIU/mL (2.8-39.9 µIU/mL) immediately started on cytotoxic chemotherapy.
Aldosterone = 1.2 ng/dL (1.2-2.4 ng/dL)
(SI: 32 pmol/L [32.5-65.5 pmol/L])
Urinary normetanephrine = 460.4 µg/24 h Key Learning Points
(125.4-483.9 µg/24 h) (SI: 2514 nmol/d
[677-2642 nmol/d]) • Bilateral adrenal masses are most frequently
Urinary metanephrine = 70.0 µg/24 h
(43.0-260.0 µg/24 h) (SI: 355 nmol/d found incidentally.
[218-1318 nmol/d]) • Rigorous imaging analysis is the initial key
step to ascertain the nature of the masses and
Which of the following should should determine whether the nature of the
be recommended? lesion is similar on both sides.
A. Adrenalectomy • The most frequent cause is benign bilateral
adrenocortical lesions (adenomas or primary
B. Replace amlodipine with spironolactone
bilateral macronodular adrenal hyperplasia)
C. Plan an outpatient consultation in 1 week to causing mild autonomous cortisol secretion.
prescribe glucocorticoid substitutive therapy
• Management of benign bilateral adrenocortical
D. Adrenal biopsy
lesions causing mild autonomous cortisol
E. 1-mg dexamethasone-suppression test secretion is based on comorbidities, which
Answer: D) Adrenal biopsy are common and sometimes uncontrolled in
these patients.
This patient has a clinically significant primary • Patients with bilateral infiltrative lesions
adrenal insufficiency, and glucocorticoid and (infectious, inflammatory, or malignant)
mineralocorticoid therapy should be started should be screened for adrenal insufficiency.
immediately. The diuretic (hydrochlorothiazide)

References
1. Fassnacht M, Tsagarakis S, Terzolo M, et al. European Society of international expert Consensus statement. Nat Rev Endocrinol. 2024;20(3):168-
Endocrinology clinical practice guidelines on the management of adrenal 184. PMID: 38097671
incidentalomas, in collaboration with the European Network for the Study of 5. Bertherat J, Bourdeau I, Bouys L, Chasseloup F, Kamenický P, Lacroix A.
Adrenal Tumors. Eur J Endocrinol. 2023;189(1):G1-G42. PMID: 37318239 Clinical, pathophysiologic, genetic, and therapeutic progress in primary
2. Sweeney AT, Hamidi O, Dogra P, et al. Clinical review: the approach to bilateral macronodular adrenal hyperplasia. Endocr Rev. 2023;44(4):567-628.
the evaluation and management of bilateral adrenal masses. Endocr Pract. PMID: 36548967
2024;30(10):987-1002. PMID: 39103149 6. Bouys L, Vaczlavik A, Cavalcante IP, et al; COMETE and ENSAT Networks.
3. Pelsma ICM, Fassnacht M, Tsagarakis S, et al. Comorbidities in mild The mutational landscape of ARMC5 in primary bilateral macronodular
autonomous cortisol secretion and the effect of treatment: systematic review adrenal hyperplasia: an update. Orphanet J Rare Dis. 2025;20(1):51. PMID:
and meta-analysis. Eur J Endocrinol. 2023;189(4):S88-S101. PMID: 37801655. 39910635
4. Taïeb D, Nölting S, Perrier ND, et al. Management of phaeochromocytoma
and paraganglioma in patients with germline SDHB pathogenic variants: an

ENDO 2025 • Adrenal 39

Management of Metastatic
Pheochromocytomas
and Paragangliomas
Camilo Jimenez, MD. Department of Endocrine Neoplasia and Hormonal
Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas; Email:
[email protected]

Educational Objectives pathogenic variants in the gene encoding succinate

dehydrogenase subunit B (SDHB).1,2 Metastases
After reviewing this chapter, learners should be
most frequently happen in regional and distant
able to:
lymph nodes (80%), the skeleton (72%), and the
• Identify clinical predictors of metastases. liver and lungs (50%). Patients with MPPGLs are
at risk of complications due to their frequently
• Describe the current evidence-based
large tumor burden, tumor location, speed of
pharmacotherapeutic agents used to
progression of the disease, and excessive secretion
treat individuals living with metastatic
of catecholamines–mainly norepinephrine.
pheochromocytomas and paragangliomas
MPPGLs are an orphan disease. The diagnosis of
(MPPGLs).
MPPGLs is frequently delayed, therapeutic options
• Identify emerging therapies for patients with are limited, and for most part systemic therapies
MPPGLs. are not curative. In addition, medications are very
expensive and are often not covered by private or
public insurance plans, as most of them are not
approved by regulatory agencies. High-specific-
Significance of the activity iodine-131 (131I) MIBG (HSA 131I-MIBG)
Clinical Problem is to date the first and only FDA-approved
medication to treat MPPGLs.3 Unfortunately, HSA
Pheochromocytomas and paragangliomas (PPGLs) 131
I-MIBG was discontinued in clinical practice
are rare neuroendocrine tumors. Approximately
due to its high manufacturing cost, sophisticated
1000 new cases of PPGLs are diagnosed annually
administration, lack of familiarity of most
in the United States. Of these, 25% are metastatic.
providers with its prescription, and a substantial
The World Health Organization acknowledges
amount of misleading information published in
that all PPGLs have the potential to metastasize
scientific literature.4,5
and recommends that these tumors be classified
as nonmetastatic or metastatic, rather than
using the traditional classifications of benign or Practice Gaps
malignant. The risk of metastases is increased
in patients with sympathetic extraadrenal • There is a lack of awareness among many
tumors, pheochromocytomas larger than health care providers regarding the diagnosis
5 cm, pheochromocytomas with periadrenal fat and treatment of MPPGLs.
infiltration, and PPGLs associated with germline

40 ENDO 2025 • Endocrine Case Management

• It is crucial for clinicians to tailor treatments and have shown that patients with apparently
for patients with MPPGLs in an individualized sporadic MPPGLs frequently exhibit a worse
manner. prognosis when compared with prognosis of SDHB
• There is a lack of awareness of the complexity carriers.11-13 Currently, the speed of progression,
of the treatment of MPPGLs. the severity of symptoms, the presence of
comorbidities, and the patient’s performance status
determine how and when to treat MPPGLs.14
Discussion Systemic therapies for patients with
MPPGLs have a very heterogeneous nature, and progressive MPPGLs include chemotherapy,
their clinical behavior is difficult to predict. The tyrosine kinase inhibitors, radiopharmaceuticals,
results of different populational studies indicate and hypoxia-inducible factor 2α inhibitors.
that the overall survival rates of patients with Medications are classified as effective, active, and
MPPGLs vary from 30% to 60% at 5 years after emerging therapies depending on the evidence
initial diagnosis.6,7 Progression-free survivorship derived from prospective studies dedicated
rate at 1 year is 50%.8 Although most MPPGLs to patients with MPPGLs. Medications that
progress over time, some exhibit very fast are considered effective are those that have
progression leading to elevated mortality rates prospectively demonstrated improved clinical
in a matter of a few weeks or months after outcomes when compared with either placebo
their initial discovery. Other MPPGLs exhibit or standard of care (randomized prospective
slow progression over time. These tumors will clinical trials) and have demonstrated acceptable
require intervention or systemic therapy at some toxicity. Medications that are considered active
point during their course. Conversely, there are those that have demonstrated improved
are some MPPGLs that will exhibit minimal clinical outcomes with acceptable toxicity.
or no progression over time; these patients are Treatment outcomes have not been compared
frequently asymptomatic. If symptomatic, their with either placebo or standard of care (single-arm
symptoms are usually mild and easy to control prospective clinical trials). Emerging therapies are
with supportive measures, such as the use of currently being evaluated in prospective clinical
α- and β-adrenergic blockers. Furthermore, trials from which the final results have not been
these patients may achieve a normal lifespan published yet. These medications have not yet
and subsequently they may not need systemic been demonstrated to be active and/or safe.
therapies, as currently the available treatments Systemic therapies include chemotherapy
are not curative and are frequently associated (cyclophosphamide, vincristine, and dacarbazine
with adverse events that may alter the individual’s or temozolomide), tyrosine kinase inhibitors
quality of life.7,8 Together the last 2 groups of (cabozantinib, sunitinib), radiopharmaceuticals
patients contribute to the higher progression-free (HSA 131I-MIBG, low-specific-activity (LSA)
survival rates that are seen, in general, in patients 131
I-MIBG, 177Lu-DOTATATE), and hypoxia-
with MPPGLs when compared with progression- inducible factor 2α inhibitors (belzutifan).
free survival rates associated with other cancers. Cyclophosphamide, vincristine, and
Symptom severity, the presence of complications dacarbazine chemotherapy has been demonstrated
such as skeletal-related events (eg, pathologic to be active against MPPGLs. It works fast and
fractures), and close follow-up help to determine is associated with tumor size reduction, disease
the aggressiveness of the disease.9,10 Although stabilization, improvement of symptoms of
some retrospective studies have suggested that catecholamine excess, and perhaps improvement
the presence of germline pathogenic variants in of survivorship.15,16 Toxicity is substantial and
the SDHB gene predict a very aggressive outcome, includes bone marrow suppression, neuropathy,
other studies have failed to demonstrate this and gastrointestinal disease.16,17 Temozolomide is
an emerging therapy evaluated in a clinical trial.

ENDO 2025 • Adrenal 41

 Tyrosine kinase inhibitors have been variant in the SDHB gene. One year after surgery,
demonstrated to be effective (sunitinib) or he is found to have multiple abdominal nodules,
active (cabozantinib) against MPPGLs.18,19 These the largest of which measures 3 cm. He has mild
medications also work fast and are associated abdominal discomfort. Plasma normetanephrines
with tumor size reduction, disease stabilization, are normal. DOTATATE PET reveals multiple
and improvement of symptoms of catecholamine peritoneal and retroperitoneal implants. The
excess. Toxicity includes hypertension, patient is treated with 177Lu-DOTATATE. Three
catecholamine crisis, and fatigue.18-20 months after finishing this therapy, the largest
Radiopharmaceuticals works slowly. They nodule has decreased 10% in size when compared
are mainly associated with disease stabilization with baseline imaging studies. The other nodules
and improvement of symptoms of catecholamine are stable, and there are no new lesions. The
excess and slow improvement of biomarkers.3,21 patient is asymptomatic. Seven months after
Tumor size reduction has been described with finishing treatment with 177Lu-DOTATATE,
MIBG.3,22 Adverse effects include bone marrow he reports abdominal distention and pain and
suppression and catecholamine crisis.22 HSA difficulty breathing while on his back. CT reveals
131
I-MIBG is an exception, as it does not cause diffuse tumor enlargement, new peritoneal
hypertension or catecholamine crisis.3 HSA nodules, ascites, pronounced collateral circulation,
131
I-MIBG is an active medication against and a 7-cm mass that encases the iliac vessels.
MPPGLs. LSA 131I-MIBG and 177Lu-DOTATATE
are emerging therapies. Which of the following is the best
Belzutifan is a small molecule that potently therapeutic approach for this patient?
inhibits hypoxia-inducible factor 2α.23 Thanks A. Cyclophosphamide, vincristine, and
to the actions of belzutifan, pathways involved dacarbazine chemotherapy
in tumor angiogenesis, inflammation, cell B. Cabozantinib
proliferation, and tumor spread might be mitigated.
C. Sunitinib
Most patients experience anemia due to inhibition
of the synthesis of erythropoietin in the kidneys; in D. Repeat therapy with 177Lu-DOTATATE
many patients, the anemia is asymptomatic and does E. Observation
not require intervention.24 Occasionally, patients
Answer: A) Cyclophosphamide, vincristine,
require supportive treatment with red blood cell
and dacarbazine chemotherapy
transfusion or recombinant erythropoietin. A
few patients experience transient and frequently The patient has disease that has progressed rapidly
asymptomatic hypoxia, which is usually corrected over a short period. The disease exploded shortly
with exercise. Belzutifan is currently being after finishing therapy with 177Lu-DOTATATE.
evaluated in a phase 2 clinical trial. A lot of The patient has a large tumor burden, and his
excitement exists regarding belzutifan, as it targets symptoms are overwhelming. The best approach
the “heart” of most MPPGLs. is to treat the patient with cyclophosphamide,
vincristine, and dacarbazine chemotherapy
Clinical Case Vignettes (Answer A). Chemotherapy works rapidly, and
tumor responses can be impressive. Although
Case 1 cabozantinib and sunitinib work fast as well,
A 43-year-old man has abdominal pain, and the vascular encasement and the collateral
abdominal CT reveals a 12-cm paraganglioma. His circulation represent a relative contraindication
blood pressure is normal. He has no symptoms to antiangiogenic medications. Cabozantinib and
of catecholamine excess. He undergoes surgical sunitinib might predispose to fistula formation
resection. Genetic testing reveals a pathogenic and bleeding.

42 ENDO 2025 • Endocrine Case Management

Case 2 such as MIBG (Answer D). MIBG works slowly
but progressively over time, and responses can
A 48-year-old man presented with palpitations,
be durable. The patient was treated with HSA
panic attacks, and hypertension 10 years ago. 131
I-MIBG. The symptoms of catecholamine excess
Plasma normetanephrines were elevated.
disappeared. He discontinued antihypertensive
Abdominal CT revealed a 7-cm right
medications. The tumors decreased in size by 35%
pheochromocytoma. The patient underwent
when compared with baseline. The patient has been
surgical resection. His symptoms subsided and
asymptomatic and with stable disease for 5 years.
blood pressure normalized. No additional follow-
up was provided. The patient presented 6 months
ago with lower back pain. Blood pressure was Case 3
150/100 mm Hg. MRI demonstrated 3 osteolytic A 36-year-old man presents with a 3-cm right
lesions in the lumbar spine with no evidence of neck paraganglioma. The patient is asymptomatic.
cord compression. CT identified 5 metastatic Genetic testing reveals a pathogenic variant in
lesions to the liver. The largest lesion measured the SDHD gene. DOTATATE PET reveals 6
2.5 cm. Plasma normetanephrines were elevated. small skeletal lesions. Plasma normetanephrines
FDG-PET confirmed the findings observed on are normal. Bone biopsy confirms a metastatic
CT and MRI. MIBG scan demonstrated MIBG paraganglioma. DOTATATE PET 3 months later
uptake in all lesions. The bone lesions were treated shows stable disease. DOTATATE PET 12 months
with stereotactic beam radiation therapy. He later shows no tumor changes. The patient is
started α-adrenergic blockade, and blood pressure asymptomatic.
normalized. Imaging studies obtained 3 months
after radiation therapy revealed stable disease. Which of the following is the best
Six months later, some of the liver lesions had therapeutic approach for this patient?
increased in size. The largest lesion measured 3 cm. A. Cyclophosphamide, vincristine, and
The patient has noticed occasional dacarbazine chemotherapy
palpitations. He has excellent performance status.
B. Cabozantinib
FDG-PET shows decreased glucose uptake in
the bone lesions but no new lesions. Plasma C. Sunitinib
normetanephrines are increased when compared D. MIBG
with baseline studies 6 months ago. E. Observation

Which of the following is the best Answer: E) Observation

therapeutic approach for this patient?
This patient would benefit from observation
A. Cyclophosphamide, vincristine, and (Answer E). Although he has a metastatic
dacarbazine chemotherapy paraganglioma, the disease is asymptomatic and
B. Cabozantinib is not progressive. Some patients with MPPGLs
C. Sunitinib exhibit indolent outcomes. These patients may
D. MIBG never exhibit disease progression. For patients
with stable disease, it is better to just watch
E. Observation
and wait, as current systemic therapies are not
Answer: D) MIBG curative and are associated with adverse effects. It
is not clear why in some patients with MPPGLs
This patient has disease that has progressed slowly the disease stops growing; these are fortunate
over a period of 6 months. He does not have a large individuals. Nevertheless, long-term follow-up is
tumor burden. The best approach is to treat this recommended in these situations.
patient with a radiopharmaceutical medication,

ENDO 2025 • Adrenal 43

Key Learning Points • Patients with MPPGLs that secrete
adrenaline and/or noradrenaline must have
• The indication for systemic therapy is a normal blood pressure in preparation for
determined by the speed of disease progression treatment with chemotherapy, tyrosine
and the severity of the clinical symptoms. kinase and selective RET inhibitors, and
radiopharmaceuticals (eg, LSA 131I-MIBG and
• In most patients, it is not possible to predict a 177
Lu-DOTATATE).
response to therapy based on tumor genotype.

References
1. Ayala-Ramirez M, Feng L, Johnson MM, et al. Clinical risk factors for 13. Hescot S, Curras-Freixes M, Deutschbein T, et al. Prognosis of malignant
malignancy and overall survival in patients with pheochromocytomas and pheochromocytoma and paraganglioma (MAPP-Prono Study): a European
sympathetic paragangliomas: primary tumor size and primary tumor location Network for the Study of Adrenal Tumors retrospective study. J Clin
as prognostic indicators. J Clin Endocrinol Metab. 2011;96(3):717-725. PMID: Endocrinol Metab. 2019;104(6):2367-2374. PMID: 30715419
21190975 14. Fischer A, Del Rivero J, Wang K, Nolting S, Jimenez C. Systemic therapy for
2. Jimenez C, Ma J, Roman Gonzalez A, et al. TNM staging and overall survival patients with metastatic pheochromocytoma and paraganglioma. Best Pract
in patients with pheochromocytoma and sympathetic paraganglioma. J Clin Res Clin Endocrinol Metab. 2025;39(1):101977. PMID: 39880697
Endocrinol Metab. 2023;108(5):1132-1142. PMID: 36433823 15. Averbuch SD, Steakley CS, Young RC, et al. Malignant pheochromocytoma:
3. Pryma DA, Chin BB, Noto RB, et al. Efficacy and safety of high-specific- effective treatment with a combination of cyclophosphamide, vincristine, and
activity 131I-MIBG therapy in patients with advanced pheochromocytoma or dacarbazine. Ann Intern Med. 1988;109(4):267-273. PMID: 3395037
paraganglioma. J Nucl Med. 2019;60(5):623-630. PMID: 30291194 16. Ayala-Ramirez M, Feng L, Habra MA, et al. Clinical benefits of systemic
4. Jha A, Taieb D, Carrasquillo JA, et al. High-specific-activity-131I-MIBG chemotherapy for patients with metastatic pheochromocytomas or
versus 177Lu-DOTATATE targeted radionuclide therapy for metastatic sympathetic extra-adrenal paragangliomas: insights from the largest single-
pheochromocytoma and paraganglioma. Clin Cancer Res. 2021;27(11):2989- institutional experience. Cancer. 2012;118(11):2804-2812. PMID: 22006217
2995. PMID: 33685867 17. Niemeijer ND, Alblas G, van Hulsteijn LT, Dekkers OM, Corssmit EP.
5. Nastos K, Cheung VTF, Toumpanakis C, et al. Peptide receptor radionuclide Chemotherapy with cyclophosphamide, vincristine and dacarbazine for
treatment and (131)I-MIBG in the management of patients with metastatic/ malignant paraganglioma and pheochromocytoma: systematic review and
progressive phaeochromocytomas and paragangliomas. J Surg Oncol. meta-analysis. Clin Endocrinol (Oxf). 2014;81(5):642-651. PMID: 25041164
2017;115(4):425-434. PMID: 28166370 18. Baudin E, Goichot B, Berruti A, et al. Sunitinib for metastatic progressive
6. Hamidi O, Young WF Jr, Iniguez-Ariza NM, et al. Malignant phaeochromocytomas and paragangliomas: results from FIRSTMAPPP,
pheochromocytoma and paraganglioma: 272 patients over 55 years. J Clin an academic, multicentre, international, randomised, placebo-controlled,
Endocrinol Metab. 2017;102(9):3296-3205. PMID: 28605453 double-blind, phase 2 trial. Lancet. 2024;403(10431):1061-1070. PMID:
7. Jimenez C, Rohren E, Habra MA, et al. Current and future treatments for 38402886
malignant pheochromocytoma and sympathetic paraganglioma. Curr Oncol 19. Jimenez C, Habra MA, Campbell MT, et al. Cabozantinib in patients
Rep. 2013;15(4):356-371. PMID: 23674235 with unresectable and progressive metastatic phaeochromocytoma or
8. Hescot S, Leboulleux S, Amar L, V et al. One-year progression-free paraganglioma (the Natalie Trial): a single-arm, phase 2 trial. Lancet Oncol.
survival of therapy-naive patients with malignant pheochromocytoma and 2024;25(5):658-667. PMID: 38608693
paraganglioma. J Clin Endocrinol Metab. 2013;98(10):4006-4012. PMID: 20. Jimenez C, Fazeli S, Roman-Gonzalez A. Antiangiogenic therapies
23884775 for pheochromocytoma and paraganglioma. Endocr Relat Cancer.
9. Jimenez C, Baudrand R, Uslar T, Bulzico D. Perspective review: lessons 2020;27(7):R239-R254. PMID: 32369773
from successful clinical trials and real-world studies of systemic therapy for 21. Jimenez C, Chin BB, Noto RB, et al. Biomarker response to high-
metastatic pheochromocytomas and paragangliomas. Ther Adv Med Oncol. specific-activity I-131 meta-iodobenzylguanidine in pheochromocytoma/
2024;16:17588359241301359. PMID: 39574494 paraganglioma. Endocr Relat Cancer. 2023;30(2):e220236. PMID: 36472300
10. Sukrithan V, Perez K, Pandit-Taskar N, Jimenez C. Management of 22. Gonias S, Goldsby R, Matthay KK, et al. Phase II study of high-dose
metastatic pheochromocytomas and paragangliomas: when and what. Curr [131I]metaiodobenzylguanidine therapy for patients with metastatic
Probl Cancer. 2024;51:101116. PMID: 39024846 pheochromocytoma and paraganglioma. J Clin Oncol. 2009;27(25):4162-4168.
11. Amar L, Baudin E, Burnichon N, et al. Succinate dehydrogenase B gene PMID: 19636009
mutations predict survival in patients with malignant pheochromocytomas 23. Toledo RA, Jimenez C, Armaiz-Pena G, Arenillas C, Capdevila J, Dahia PLM.
or paragangliomas. J Clin Endocrinol Metab. 2007;92(10):3822-3828. PMID: Hypoxia-inducible factor 2 alpha (HIF2alpha) inhibitors: targeting genetically
17652212 driven tumor hypoxia. Endocr Rev. 2023;44(2):312-322. PMID: 36301191
12. Roman-Gonzalez A, Zhou S, Ayala-Ramirez M, Shen C, Waguespack SG, 24. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma
Habra MA, et al. Impact of surgical resection of the primary tumor on overall in von Hippel-Lindau disease. N Engl J Med. 2021;385(22):2036-2046. PMID:
survival in patients with metastatic pheochromocytoma or sympathetic 34818478
paraganglioma. Ann Surg. 2018;268(1):172-178. PMID: 28257320

44 ENDO 2025 • Endocrine Case Management

Evaluation and Management
of Postmenopausal
Androgen Excess
Michael W. O’Reilly, MD, PhD. Androgens in Health and Disease Research Group,
Academic Division of Endocrinology, Department of Medicine, Royal College of Surgeons in
Ireland (RCSI), Dublin, Ireland; Email: [email protected]

Wiebke Arlt, MD, DSc. Medical Research Council Laboratory of Medical Sciences, London,
United Kingdom; Email: [email protected]

Educational Objectives loss, or polycythemia. Most adolescents and

women of reproductive age who present with
After reviewing this chapter, learners should be
androgen excess have underlying polycystic ovary
able to:
syndrome (PCOS).2 However, other primary
• Describe the presentation pattern, clinical underlying pathologies must be excluded in a
signs, and symptoms of androgen excess in subset of patients harboring red-flag clinical
postmenopausal women, including red-flag features, such as severe androgen excess, rapidly
symptoms for underlying neoplastic disease. progressive symptoms or signs, or presentation
in the postmenopausal phase of life. In particular,
• Identify biochemical signatures that assist
postmenopausal patients have a significantly
clinicians in distinguishing adrenal vs ovarian
increased likelihood of underlying neoplastic
pathology in women with androgen excess.
ovarian, adrenal, or pituitary disease compared
• Guide the biochemical workup and imaging with the likelihood in women of reproductive age,
approach in patients presenting with regardless of the severity of androgen excess.3
postmenopausal androgen excess, including A detailed clinical history, targeted physical
dynamic testing. examination, and evaluation of the pattern and
severity of biochemical disturbances are critical to
rationalize the requirement and strategy for further
biochemical, radiological, and, where appropriate,
Significance of the genetic investigations. Although androgen excess
Clinical Problem in women with PCOS is closely correlated with
adverse metabolic health outcomes throughout
Androgen excess is defined as clinical or
their lifetime, severe biochemical disturbances or
biochemical evidence of increased production of
overt virilization are rarely observed in PCOS.
androgenic steroids in women. It is observed in
This chapter will review the presentation,
up to 10% of women of reproductive age and less
evaluation, and management of androgen excess
commonly in postmenopausal women.1 Androgen
in postmenopausal women. We will examine
excess typically manifests clinically as hirsutism or
biochemical signals that signpost towards ovarian,
acne, but more severe and prolonged exposure can
adrenal, or potentially neoplastic or malignant
lead to overt virilization, including clitoromegaly,
disease, as well as nuances to distinguish adrenal
deepening of the voice, female-pattern hair

ENDO 2025 • Adrenal 45

from ovarian pathology and lateralization of imaging can generally proceed to surgical
unilateral tumors. intervention without delay, particularly in the case
of suspected adrenocortical carcinoma. However,
incidental adnexal masses occur frequently in
Practice Gaps postmenopausal women, with a prevalence
of 3.3% to 18.0% in asymptomatic women.
• There is limited awareness among clinicians
Similarly, adrenal incidentalomas are detected
regarding careful biochemical phenotyping
in at least 5% of the general population, most of
in postmenopausal patients presenting with
which are benign and nonfunctioning. While
androgen excess.
androgen-producing adrenal tumors are typically
• Clinicians may be uncomfortable with apparent on imaging, ovarian tumors may remain
biochemical thresholds for increased radiologically occult because of their small size.6
testosterone or other androgen levels above Therefore, an incidental adrenal adenoma may not
which adrenal, ovarian, or other imaging be the source of androgen excess.
should be triggered. As LH is the central regulator of ovarian
• Dynamic investigations such as GnRH androgen synthesis, a GnRH-suppression test
analogue/GnRH antagonist testing or can be used to confirm an ovarian source of
dexamethasone-suppression testing are androgen production in cases where this is
underused in clinical practice, as clinicians may clinically or biochemically suspected (eg, isolated
be uncomfortable interpreting their findings. or predominant increase in serum testosterone).
There is also underuse of diagnostic tests such GnRH analogues induce a prolonged stimulation
as ovarian and adrenal vein sampling, which of GnRH receptors in pituitary gonadotroph
can be highly valuable in selected cases. cells, leading to desensitization and subsequent
downregulation of these receptors. The net
effect is to suppress gonadotropins, with
Discussion subsequent suppression of testosterone in cases
A detailed list of the causes of androgen excess of gonadotropin-dependent ovarian testosterone
in both premenopausal and postmenopausal secretion. This response is typically observed
women are listed in the Table, following page. in ovarian hyperthecosis, but it is also common
Clinical features of androgen excess in women in virilizing ovarian tumors.7 This test is not of
include hirsutism, acne, and alopecia. A focused diagnostic utility if gonadotropin suppression is
history should include assessment of the severity already evident at baseline, as this finding confirms
and duration of symptoms, as well as rapidity gonadotropin-independent androgen excess, as
of onset.4 Clinical examination should assess for observed in poorly controlled congenital adrenal
acanthosis nigricans and skin tags, which are hyperplasia, adrenocortical carcinoma, and a
clinical features of severe insulin resistance, as well proportion of patients with virilizing ovarian
as cushingoid features such as violaceous striae, tumors. GnRH analogue or antagonists can also be
bruising, and proximal muscle weakness. Adipose used as long-term therapy in patients with ovarian
tissue distribution should be examined to look for androgen excess who are not candidates for
signs of lipodystrophy. Examination of external surgery or would like to avoid this intervention.
genitalia may not be indicated unless the patient In exceptional cases, when uncertainty
reports specific clinical signs such as clitoromegaly persists after dynamic testing and cross-sectional
or other features of overt virilization. imaging, simultaneous ovarian and adrenal vein
Patients with clinical and biochemical features sampling may aid in localizing the source of
of severe androgen excess and with a detected androgen excess. In this interventional radiology
adrenal or ovarian tumor on cross-sectional procedure, the adrenal and ovarian veins are

46 ENDO 2025 • Endocrine Case Management

Table. Causes of Androgen Excess in Women

Prevalence or Rapidity
Condition incidence Virilization of onset Supportive biochemical features Other features

Polycystic ovary 8%-13% of Not Insidious, Mild-to-moderate elevations of Oligomenorrhea/

syndrome premenopausal observed often since serum T, typically <145 ng/dL amenorrhea
women puberty (SI: <5 nmol/L)
Increased AMH
Elevated A4 and DHEA-S observed
Increased metabolic risk
in the mild-to-moderate range
with variable degrees of
depending on assay
insulin resistance clinically
depending on BMI

Ovarian 9.3% of Often Insidious Increased serum T ranging from mild Bilateral enlarged ovaries/
hyperthecosis postmenopausal present to severe elevations (sometimes increased ovarian volume
women with >290 ng/dL (SI: >10 nmol/L) on ultrasonography
androgen excess
Adrenal androgens usually normal Histology shows ovarian
stromal hyperplasia with
>50% suppression of serum T on
cellular luteinization
GnRH analogue test
May be observed in
patients with insulin
resistance and T2D

Virilizing 2.7% of Present in Variable Increased serum T usually Difficult to visualize on

ovarian tumor postmenopausal 50% >145 ng/dL (SI: >5 nmol/L) imaging; asymmetry may
women with be suggestive.
T >290 ng/dL (SI: >10 nmol/L) more
androgen excess
likely VOT than OHT MRI has higher PPV
(78%) and NPV (100%)
A4 and/or E2 may also be increased
than ultrasonography for
Adrenal androgens (eg, DHEA-S) detecting VOTs
usually normal
MRI has 83% sensitivity
Inhibin B and AMH may be increased and 80% specificity for
distinguishing VOT from
Variable suppression with GnRH
OHT
analogue test with significant
overlap with OHT; no suppression Role for FDG-PET in
if fully autonomous or suppressed selected cases if other
gonadotropins imaging equivocal or
negative

Nonclassic 1%-10% in Virilization Insidious, Increased 17-OHP as diagnostic Basal morning follicular
congenital women with at birth often since hallmark; typically >290 ng/dL phase 17-OHP >145 ng/dL
adrenal androgen excess in classic puberty (SI: >10 nmol/L) at baseline (SI: >5 nmol/L) progress to
hyperplasia depending on cases cosyntropin-stimulation
Variable elevation of serum A4 and T
population only; overt test
studied virilization DHEA-S is usually low in treated
Stimulated 17-OHP
unusual in patients
on cosyntropin-
nonclassic
stimulation test
>990 ng/dL (SI: >30 nmol/L)
is diagnostic

Adrenocortical 1 to 2 cases Often Usually Severe elevation in serum T Unilateral adrenal mass
carcinoma per million present rapid (3-6 (>145 ng/dL [SI: >5 nmol/L] may should be visible on cross-
population per months) be observed; T rarely elevated in sectional imaging
year isolation
Severe but variable elevations in
DHEA-S and/or A4
Clinical and biochemical cortisol
excess (ACTH-independent) with
failed overnight dexamethasone-
suppression test may be observed
Increased adrenal steroid precursors
on steroid metabolome analysis

ENDO 2025 • Adrenal 47

 Prevalence or Rapidity
Condition incidence Virilization of onset Supportive biochemical features Other features

Cushing disease 1.8- to .2 cases Seldom Variable Highly variable; serum T/DHEA-S/A4 Discriminant features:
per million present may be normal or elevated violaceous abdominal
population per striae, proximal muscle
Failed overnight dexamethasone-
year weakness, osteoporosis
suppression test with detectable or
1% of elevated ACTH levels at baseline Nonspecific features:
premenopausal abdominal obesity,
May coexist with gonadotropin
women with interscapular fat pad,
deficiency
androgen excess, bruising, hypertension
and 4% of
postmenopausal
women with
androgen excess

Severe insulin Not clearly May be Most Serum T ranges from normal to Ovulatory dysfunction,
resistance5 defined; may be present commonly extremely elevated (>576 ng/dL
polycystic ovarian
congenital or in severe insidious [SI: >20 nmol/L)
morphology
acquired cases from
Severely increased plasma insulin
puberty; Acanthosis nigricans
Most common in and HOMA-IR and suppressed
exacerbated
severe obesity plasma adiponectin Often family history of T2D
by weight
but also seen
gain Usually high triglycerides, low HDL Lipodystrophy or
in lean people
cholesterol, evidence of fatty liver (if centripetal obesity
or those with Rarely
not, then consider INSR pathogenic
mild obesity and can be Wide range of syndromic
variant or anti-INSR antibodies)
lipodystrophy or acute and features
insulin-signaling fulminant
defects in acquired
autoimmune
insulin
resistance
(type B IR)

Acromegaly Prevalence: 2.8- Seldom Insidious Elevated IGF-1; failure to suppress Coarsening of facial
13.7 cases per present onset growth hormone below 0.4 ng/mL on features; enlarged hands;
100,000 oral glucose tolerance testing interdental separation;
thyroid goiter; evidence
Incidence: 0.2- Often biochemical evidence of
of cardiomyopathy in
1.1 cases per androgen excess in women
advanced cases
100,000 per year

Abbreviations: A4, androstenedione; AMH, antimullerian hormone; E2, estradiol; INSR, insulin receptor; NPV, negative predictive value; OHT, ovarian
hyperthecosis; PCOS, polycystic ovary syndrome; PPV, positive predictive value; T, testosterone; T2D, type 2 diabetes; VOT, virilizing ovarian tumor.
Reprinted from Elhassan YS et al. Clinical Endocrinology, 2025, 1-27. https://doi.org/10.1111/cen.15265 © The Authors. Clinical Endocrinology is published by
John Wiley & Sons Ltd.

cannulated simultaneously; peripheral, adrenal and When ovarian disease is suspected, pelvic MRI
ovarian venous effluent sampling is undertaken and transvaginal ultrasonography should be
to demonstrate differential gradients in androgen performed. FDG-PET can be considered if these
levels.8 However, in postmenopausal women in are negative. Cross-sectional adrenal imaging
whom fertility preservation is not a consideration, should be performed in those with biochemical
it is not essential to lateralize the source of ovarian evidence of adrenal androgen excess (increased
androgen excess, and bilateral oophorectomy can androstenedione or DHEA-S) or in those with
be considered. evidence of ACTH-dependent Cushing syndrome.
The primary objective of imaging in the A targeted history and exam are required to
workup of patients with severe androgen identify those patients who harbor non-PCOS
excess is to identify structural culprit adrenal pathology, particularly among those presenting
or ovarian pathology and also to distinguish with atypical or red-flag features such as rapid
between incidental and clinically relevant lesions. symptoms onset or overt virilization. Systematic

48 ENDO 2025 • Endocrine Case Management

Figure. Clinical Algorithm for Evaluation and Management of Androgen Excess

Reprinted from Elhassan YS et al. Clinical Endocrinology, 2025, 1-27. https://doi.org/10.1111/cen.15265 © The Authors. Clinical Endocrinology is published by
John Wiley & Sons Ltd.
[Color—Print (Color Gallery page CG7) or web & ePub editions]

interrogation of circulating serum testosterone excess should be investigated promptly due to

and adrenal androgen precursors, in tandem with the age-related decline in androgens in normal
other markers, such as 17-hydroxyprogesterone physiological circumstances.
and gonadotropins, can identify signature patterns
suspicious for underlying adrenal, pituitary, and
ovarian disease and guide imaging strategies
Clinical Case Vignettes
accordingly. Serum testosterone concentrations Case 1
below 145 ng/dL (<5 nmol/L) measured using A 59-year-old woman presents with a 6-month
liquid chromatography–tandem mass spectrometry history of hirsutism, weight gain, and abdominal
in premenopausal women typically do not warrant striae. She has developed hypertension, and her
further evaluation in women with clinical features hemoglobin A1c is elevated at 6.5% (47 mmol/mol).
otherwise consistent with PCOS. However, in She reports increasing breathlessness and
postmenopausal women, any degree of androgen ankle edema.

ENDO 2025 • Adrenal 49

 On physical examination, she has violaceous or ketoconazole are effective in this setting.
striae, bruising, and facial plethora. Her blood Definitive treatment may consist of adrenalectomy
pressure is 158/97 mm Hg. or cytotoxic chemotherapy or a combination
of both, depending on the extent of the
Laboratory test results: primary disease.
Serum testosterone = 118.1 ng/dL (SI: 4.1 nmol/L)
DHEA-S = >1000 µg/dL (SI: >27.1 µmol/L)
Androstenedione = 1613 ng/dL (SI: 56.3 nmol/L) Case 2
17-Hydroxyprogesterone = 406.9 ng/dL A 68-year-old woman presents with a 3- to 4-year
(SI: 12.3 nmol/L) history of facial hirsutism, requiring frequent
FSH = <1.0 mIU/mL (SI: <1.0 IU/L)
LH = <1.0 mIU/mL (SI: <1.0 IU/L) topical cosmetic interventions. Symptoms include
Estradiol = <25.1 pg/dL (SI: <92.1 pmol/L) frontotemporal alopecia, altered body odor,
ACTH = <5 pg/mL (SI: <1.1 pmol/L) deepening of the voice, and changes in the size and
Cortisol = 56.7 µg/dL (SI: 1565 nmol/L) appearance of external genitalia. Medical history
includes hypertension, chronic kidney disease, and
Which of the following is this osteoporosis. She had no fertility concerns during her
patient’s most likely diagnosis? reproductive years, with 5 uneventful pregnancies.
A. PCOS She underwent vaginal hysterectomy for uterine
B. Adrenocortical carcinoma prolapse 9 years ago (with ovarian preservation).
C. Virilizing ovarian tumor Initial laboratory test results:
D. Congenital adrenal hyperplasia
Serum testosterone = 1190 ng/dL (SI: 41.3 nmol/L)
Answer: B) Adrenocortical carcinoma Androstenedione = 264.7 ng/dL (SI: 9.24 nmol/L)
DHEA-S = 107.4 µg/dL (SI: 2.9 µmol/L)
This patient has preferential elevation of adrenal Gonadotropins, values in the postmenopausal range
Hematocrit = 50.4% (SI: 0.504)
androgens. The increase in serum testosterone in
Hemoglobin = 16.4 g/dL (SI: 164 g/L)
this context is likely due to peripheral conversion
of androstenedione and other precursors. She An overnight dexamethasone-suppression test is
has clinical features of Cushing syndrome. Her performed to exclude glucocorticoid excess, which
biochemistry confirms adrenal androgen excess reveals appropriate suppression of serum cortisol
along with evidence of ACTH-independent to less than 1.8 µg/dL (SI: <50 nmol/L).
hypercortisolism. The best next step in her
evaluation is adrenal imaging, as well as CT of the Which of the following is this
chest/thorax/abdomen. An adrenal mass in the patient’s most likely diagnosis?
presence of adrenal androgen excess is diagnostic A. PCOS
of adrenocortical carcinoma (Answer B) until B. Adrenocortical carcinoma
proven otherwise.9
C. Virilizing ovarian tumor
Elevation of 17-hydroxyprogesterone may also
be observed in the setting of malignant adrenal D. Severe insulin resistance
neoplasms. This presentation is not consistent Answer: C) Virilizing ovarian tumor
with late-onset congenital adrenal hyperplasia,
either in terms of the rapidity of clinical onset This patient’s most likely diagnosis is a virilizing
or the clinical and biochemical evidence of ovarian tumor (Answer C). The pattern of
adrenal hypercortisolism. Pharmacotherapy androgen elevation is consistent with an
to control cortisol excess, hyperandrogenism, ovarian source, with predominant elevation
and hypertension are required urgently. Agents of testosterone and normal adrenal androgens.
such as mitotane, spironolactone, metyrapone, The severity of the testosterone elevation (up to

50 ENDO 2025 • Endocrine Case Management

40-fold higher than expected postmenopausal virilizing ovarian tumors. In malignant lesions,
levels) would be extremely unusual in the setting testosterone secretion is less likely to remain under
of ovarian hyperthecosis. In premenopausal gonadotropin regulation, so, in theory, failure
women, serum testosterone levels with severe to suppress testosterone after GnRH raises the
insulin resistance syndromes may be significantly clinical suspicion of a malignancy.
elevated (sometimes >570 ng/dL [>20 nmol/L]). As this patient was postmenopausal and had an
However, onset in the postmenopausal phase incidental ovarian finding, bilateral oophorectomy
of life would be considered very unusual. was performed. Subsequent histology identified a
Intriguingly, despite the severity of the 2-cm lipid-rich tumor with a low mitotic count,
testosterone elevation, gonadotropins are not consistent with a benign ovarian steroid cell
suppressed, a finding not unusual even in virilizing tumor. Her symptoms fully resolved after surgery.
ovarian tumors, although they tend to be lower In women of reproductive age, selective ovarian
than levels observed with ovarian hyperthecosis. vein sampling could be considered in the context
Baseline suppression of gonadotropins is of fertility preservation to lateralize the source of
predictive of malignant potential with virilizing neoplastic testosterone secretion. Testosterone
ovarian tumors in a number of case series.10 levels normalized within 4 weeks of bilateral
This patient’s serum testosterone suppressed oophorectomy.
fully 28 days after GnRH analogue injection,
consistent with a gonadotropin-dependent ovarian Case 3
source. Typical GnRH preparations include
triptorelin, 3 mg administered via intramuscular A 67-year-old multiparous woman is referred with
injection, with measurement of gonadotropins a 15-year history of hirsutism. Symptom onset was
and serum testosterone at baseline and again after during the sixth decade of life. She was previously
28 days. Alternative options include using GnRH evaluated at another institution, without definitive
antagonists such as cetrorelix at a dose of 3 mg via pathology identified. The patient removes hair on
subcutaneous injection, although some of these a daily basis. Additional symptoms of androgen
preparations may not be available or approved for excess include frontal hair thinning. There are
use in all centers or countries. GnRH antagonists no symptoms concerning for overt virilization
have the added advantage of avoiding the early or glucocorticoid excess. Her medical history
surge in gonadotropins and testosterone in the first is notable for primary hypothyroidism and
7 days after administration that can be seen with hypertension. She has 4 biological children.
GnRH analogues. Importantly, these prolonged On physical examination, her BMI is
tests are not likely to be appropriate for patients in 48.2 kg/m2. There are no overt features of insulin
whom malignancy is highly suspected and prompt resistance or Cushing syndrome. Initial testing
treatment is required. Examples include patients confirms biochemical androgen excess.
with large adrenal or adnexal masses or with Laboratory test results:
suppression of gonadotropins at baseline.
Imaging in this case revealed a right-sided, Serum testosterone = 216 ng/dL (SI: 7.5 nmol/L)
3-cm ovarian mass. Theoretically, GnRH Serum androstenedione = 501.4 ng/dL
(SI: 17.5 nmol/L)
testing should distinguish between ovarian DHEA-S = 107.4 µg/dL (SI: 2.9 µmol/L)
hyperthecosis and virilizing ovarian tumors
due to autonomous androgen secretion in the
context of virilizing ovarian tumors. However,
real-world data highlight significant overlap in
serum testosterone response to GnRH analogues
in patients with ovarian hyperthecosis and

ENDO 2025 • Adrenal 51

Which of the following is this Key Learning Points
patient’s most likely diagnosis?
Clinical Evaluation
A. PCOS
B. Adrenocortical carcinoma • Postmenopausal women who present with
C. Virilizing ovarian tumor clinical features or suspicion of androgen
D. Ovarian hyperthecosis excess should be assessed for hirsutism, acne,
female-pattern hair loss, and virilization.
Answer: D) Ovarian hyperthecosis
• Older patient age and rapid onset and
Ovarian hyperthecosis (Answer D) results progression of symptoms should be considered
from hyperplasia of androgen-secreting theca predictive factors for underlying non-PCOS
cells in the ovary. It is thought that some of pathology.
the steroidogenically inactive ovarian stromal • Assessment for syndrome-specific clinical
cells differentiate into theca-like cells capable features should be undertaken (eg, Cushing
of producing androgens. Thus, they are spread syndrome, severe insulin resistance).
through the ovarian stroma and are not purely
• Women with a suspicion for neoplastic
associated with the ovarian follicles. These theca
androgen excess should be urgently referred to
cells produce androgens under the influence of LH.
a center with relevant expertise.
This condition usually occurs after menopause,
when LH concentrations are high and the ovaries
have few, if any, remaining follicles able to Biochemical Evaluation
aromatize androgens to estrogen. The cause of
ovarian hyperthecosis is unknown, but genetic • Testosterone, SHBG, androstenedione,
factors may be implicated. High insulin levels DHEA-S, 17-hydroxyprogesterone, estradiol,
are also associated with this condition. Although LH, FSH, and free testosterone should be
androgens can increase insulin concentrations, measured in all women presenting clinical
hyperinsulinemia is likely to be the primary driver features or suspicion of androgen excess.
of hyperthecosis, albeit potentiated by positive • Samples for the investigation of androgen
feedback from increased androgens. excess should be collected in the morning
Ovarian hyperthecosis is often associated with following an overnight fast.
significant elevations of serum testosterone, with
• In postmenopausal women, any biochemical
relative preservation of adrenal androgens such
evidence of androgen excess should trigger
as DHEA-S. Androstenedione may be elevated,
urgent ovarian and/or adrenal imaging.
as it can also arise from ovarian theca cells. It is
commonly associated with insulin resistance, • Caution must be used in applying absolute
obesity, and metabolic disorders. Imaging, such cutoffs for serum androgens above which
as MRI, can be helpful to distinguish ovarian investigations such as adrenal and pelvic
hyperthecosis from virilizing ovarian tumors. imaging should be triggered. This is due to the
Testosterone levels suppress in response to GnRH wide variability in assay methods in clinical
analogues. Definitive treatment in postmenopausal laboratories across centers and countries.
women involves bilateral oophorectomy, although • Androgen measurement with liquid
GnRH analogue therapy could be considered in chromatography–tandem mass spectrometry
patients who prefer not to undergo surgery or are should be undertaken when possible because
not good surgical candidates. of the limitations with immunoassays,
including cross-reactivity at low circulating
androgen concentrations. In centers where

52 ENDO 2025 • Endocrine Case Management

 immunoassays are used, a second sample excess, although it is not necessary in patients
should be run by liquid chromatography– with a suspicious adrenal mass who are likely
tandem mass spectrometry if the to have ACTH-independent (and therefore
immunoassay-based androgen measurement likely malignant) adrenal androgen generation.
does not align with the clinical picture.
• Dynamic testing (eg, GnRH analogue test or Imaging
96-hour dexamethasone-suppression test)
should be considered in selected patients to • If clinical indications suggest non-PCOS
aid in localizing the source of androgen excess. pathology, cross-sectional imaging of the
Triptorelin should be administered at a dose ovaries and/or adrenal glands should be
of 3 mg via intramuscular injection, with performed as appropriate.
measurement of gonadotropins and serum • Pelvic MRI should be performed if an ovarian
androgens at baseline and after 28 days. A tumor is strongly suspected.
prolonged dexamethasone-suppression test
(0.5 mg QDS for 96 hours, due to the long • Urgent cross-sectional imaging (CT or MRI)
half-life of DHEA-S) is recommended in the should be performed if adrenal pathology is
investigation of suspected adrenal androgen suspected.

References
1. Elhassan YS, Idkowiak J, Smith K, et al. Causes, patterns, and severity of 6. Hirschberg AL. Approach to investigation of hyperandrogenism in a
androgen excess in 1205 consecutively recruited women. J Clin Endocrinol postmenopausal woman. J Clin Endocrinol Metab. 2023;108(5):1243-1253.
Metab. 2018;103(3):1214-1223. PMID: 29342266 PMID: 36409990
2. Escobar-Morreale HF, Carmina E, Dewailly D, et al. Epidemiology, diagnosis 7. Doyle LM, Cussen L, McDonnell T, O’Reilly MW. Clinical utility of GnRH
and management of hirsutism: a consensus statement by the Androgen Excess analogues in female androgen excess: highlighting diagnostic and therapeutic
and Polycystic Ovary Syndrome Society. Hum Reprod Update. 2012;18(2):146- applications. JCEM Case Rep. 2023;1(5):luad108. PMID: 37908205
170. PMID: 22064667 8. Tng E-L, Tan JM-M. Dexamethasone suppression test versus selective
3. Cussen L, McDonnell T, Bennett G, Thompson CJ, Sherlock M, O’Reilly ovarian and adrenal vein catheterization in identifying virilizing tumors in
MW. Approach to androgen excess in women: clinical and biochemical postmenopausal hyperandrogenism-a systematic review and meta-analysis.
insights. Clin Endocrinol (Oxf). 2022;97(2):174-186. PMID: 35349173 Gynecol Endocrinol. 2021;37(7):600-608. PMID: 33660585
4. Dennedy MC, Smith D, O’Shea D, McKenna TJ. Investigation of patients 9. Bancos I, Taylor AE, Chortis V, et al; ENSAT EURINE-ACT Investigators.
with atypical or severe hyperandrogenaemia including androgen-secreting Urine steroid metabolomics for the differential diagnosis of adrenal
ovarian teratoma. Eur J Endocrinol. 2010;162(2):213-220. PMID: 19906851 incidentalomas in the EURINE-ACT study: a prospective test validation
5. Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LC. The insulin-related study. Lancet Diabetes Endocrinol. 2020;8(9):773-781. PMID: 32711725
ovarian regulatory system in health and disease. Endocr Rev. 1999;20(4):535- 10. Yance VRV, Marcondes JAM, Rocha MP, et al. Discriminating between
582. PMID: 10453357 virilizing ovary tumors and ovary hyperthecosis in postmenopausal
women: clinical data, hormonal profiles and image studies. Eur J Endocrinol.
2017;177(1):93.102. PMID: 28432270

ENDO 2025 • Adrenal 53

BONE AND MINERAL
METABOLISM
Managing Calcium
Disorders in Pregnancy
Natasha M. Appelman-Dijkstra, MD, PhD. Internal Medicine, Division of
Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Email:
[email protected]

Educational Objectives after birth. Severe maternal hypocalcemia may

impair the transfer of calcium across the placenta,
After reviewing this chapter, learners should be
causing hypocalcemia in the fetus.
able to:
Pregnancy induces physiological changes,
• Develop management plans tailored to the including increased intestinal calcium absorption
type of calcium disorder and gestational stage. driven by elevated 1,25-dihydroxyvitamin D
levels and altered PTHrP dynamics, which can
• Recognize and mitigate potential maternal and
obscure the presentation of calcium disorders.
fetal complications of calcium disorders.
Mismanagement of these conditions can
• Identify and diagnose calcium disorders lead to adverse outcomes, including preterm
in pregnant patients based on clinical and delivery, fetal growth restriction, and long-
laboratory findings. term health effects for the neonate. Given these
risks, proper identification and management of
calcium disorders are important to minimize
complications. This highlights the need for
Significance of the improved awareness, tailored diagnostic
Clinical Problem approaches, and management strategies to address
these potentially life-threatening conditions
Calcium disorders during pregnancy, including
effectively. Citations 1 through 5 provide
hypocalcemia and hypercalcemia, present unique
additional background information and are used as
challenges due to their profound implications
references throughout the whole chapter.
for both maternal and fetal health. Maternal
hypocalcemia can result in neuromuscular
irritability, tetany, seizures, and cardiac Practice Gaps
arrhythmias, posing significant risks to the
mother’s well-being. In contrast, maternal • Limited awareness of physiological changes in
hypercalcemia is associated with complications, calcium metabolism during pregnancy among
such as nephrolithiasis, pancreatitis, and acute clinicians.
kidney injury, which can exacerbate pregnancy- • Variability in the diagnostic thresholds and
related physiological stress. For the fetus, management strategies for calcium disorders
disruptions in maternal calcium homeostasis during pregnancy.
can affect the placenta, causing calcifications and
subsequent negative consequences. In addition, • Lack of consensus on the safety and timing
maternal hypercalcemia can suppress fetal of interventions, including the use of calcium
PTH secretion, potentially leading to neonatal supplements, vitamin D analogues, and other
hypocalcemia, tetany, and even seizures shortly calcium-modifying information.

56 ENDO 2025 • Endocrine Case Management

• Underrecognition of the risks and Hypocalcemia in Pregnancy
management of fetal and neonatal
Hypocalcemia in pregnancy is mainly caused by
complications associated with maternal
hypoparathyroidism. The clinical presentation of
calcium imbalances.
hypocalcemia in pregnancy often includes muscle
spasms and cramps or tetany. In more severe cases,
Discussion patients may experience seizures due to increased
Pregnancy induces changes in calcium homeostasis neuronal excitability or arrhythmias resulting
to accommodate the growing fetal demand for from altered cardiac conduction.
calcium, particularly during the third trimester. Management of hypocalcemia in pregnancy
These changes involve complex physiological depends on its severity and underlying cause. Mild
adaptations that ensure adequate calcium availability cases can often be addressed with oral calcium
while protecting maternal calcium stores. and vitamin D supplementation, while severe
One of the primary changes is an increase cases necessitate intravenous calcium replacement
in intestinal calcium absorption, driven by a rise to rapidly restore serum calcium levels. Close
in circulating levels of 1,25-dihydroxyvitamin D monitoring of maternal calcium levels and fetal
(calcitriol), which may be 2 to 3 times higher than health is essential, as untreated hypocalcemia
nonpregnant levels. This increase in calcitriol may lead to complications such as preterm labor,
is facilitated by placental production of vitamin intrauterine growth restriction, or impaired
D-binding protein and enhanced renal conversion neonatal skeletal development. Collaboration
of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin between endocrinologists, obstetricians, and
D, mediated by increased activity of the other health care providers is crucial to optimize
1α-hydroxylase enzyme. The upregulation of outcomes for both the mother and fetus.
calcitriol enhances calcium absorption in the
maternal gastrointestinal tract, allowing the mother Hypercalcemia in Pregnancy
to meet the substantial calcium demands of the fetus Hypercalcemia during pregnancy is a rare but
without excessive reliance on bone resorption. clinically significant condition that can arise from
In addition to enhanced absorption, maternal various etiologies, each with distinct implications for
skeletal calcium mobilization provides a secondary maternal and fetal health. The most common cause
mechanism to supply calcium to the fetus. This is is primary hyperparathyroidism (PHPT), which
particularly evident in the later stages of pregnancy is typically due to a parathyroid adenoma or, less
when fetal bone mineralization rates increase. The commonly, parathyroid hyperplasia. Other potential
placental production of PTHrP plays a key role in causes of hypercalcemia include malignancy, such
this process, promoting bone resorption to release as metastases to bone or paraneoplastic syndromes
calcium into the maternal circulation. Unlike PTH, associated with ectopic PTHrP production.
PTHrP can achieve this effect without significantly Although rare in pregnancy, these malignancy-
altering maternal serum calcium or phosphate levels, associated cases require prompt recognition and
reflecting the finely tuned balance of maternal and intervention. Additionally, excessive calcium or
fetal calcium needs. Although total serum calcium vitamin D supplementation can also result in
levels decrease during pregnancy, this is largely due hypercalcemia. This underscores the importance
to hemodilution caused by the 30% to 50% increase of cautious dosing and close monitoring of
in maternal plasma volume. However, ionized supplementation in pregnant patients.
calcium—the biologically active form of calcium— Hypercalcemia can have serious maternal
remains stable and should be measured to assess the complications, such as nephrolithiasis, pancreatitis,
calcium levels throughout pregnancy. peptic ulcer disease, hypertension, and fatigue,
which can complicate pregnancy management. For

ENDO 2025 • Bone and Mineral Metabolism 57

the fetus, hypercalcemia poses significant risks, Imaging Studies
including fetal growth restriction, because altered Imaging may be necessary to evaluate
calcium dynamics can impair normal placental potential causes of calcium imbalances, such as
function and nutrient delivery. Furthermore, identifying parathyroid adenomas in primary
maternal hypercalcemia suppresses fetal hyperparathyroidism or assessing skeletal
parathyroid gland function, potentially leading to pathology. When imaging is required, special
neonatal hypocalcemia after delivery. Neonatal precautions should be taken to minimize fetal
hypocalcemia can manifest as seizures, tetany, or radiation exposure:
other neuromuscular symptoms that may require
urgent intervention. • Ultrasonography is the first-line imaging
Management of hypercalcemia during modality for evaluating parathyroid glands
pregnancy depends on the underlying cause and or kidneys given its demonstrated safety in
the severity of the condition. Mild hypercalcemia pregnancy.
can often be managed conservatively with • MRI can be considered for more detailed
adequate hydration and dietary adjustments, while anatomical assessments when necessary, as it
severe cases or those due to PHPT may necessitate does not use ionizing radiation.
more aggressive interventions. Parathyroidectomy • CT or nuclear imaging should generally be
in the second trimester is considered safe and avoided during pregnancy unless absolutely
effective for treating PHPT in selected cases. critical, and radiation exposure should be
Cinacalcet might be useful as well, but the minimized with appropriate shielding and
safety of the drug during pregnancy is still to be dosing adjustments.
debated. A multidisciplinary approach involving
endocrinologists, obstetricians, and neonatologists Additional Considerations
is crucial in providing comprehensive care. Diagnostic approaches must also include a
thorough review of the patient’s medical history,
including prior diagnoses of calcium disorders,
Diagnosis medication use (eg, calcium or vitamin D
Accurate diagnosis of calcium disorders in supplementation), and any symptoms suggestive
pregnancy requires careful consideration of of systemic conditions, such as malignancy
physiological changes and a strategic approach or granulomatous disease. Family history of
to minimize risks to both mother and fetus. disorders, such as multiple endocrine neoplasia
Pregnancy induces alterations in calcium syndromes or other genetic conditions affecting
metabolism, which must be accounted for when calcium metabolism, should also be explored.
evaluating laboratory and clinical findings. By using a careful and comprehensive
Due to the hemodilution and hypoalbuminemia diagnostic strategy, clinicians can accurately
commonly seen in pregnancy, total serum calcium identify the etiology of calcium imbalances
levels may appear lower than normal even in the in pregnancy while ensuring maternal and
absence of a true calcium imbalance. However, fetal safety.
ionized calcium levels are unaffected by changes in
albumin and provide a more accurate assessment
of calcium status in pregnant patients. If ionized
Management Principles for
calcium measurement is not available, corrected Calcium Disorders in Pregnancy
calcium can be calculated using the serum albumin Effective management of calcium disorders
level, although this is less precise. during pregnancy requires a balance between
maternal safety and fetal well-being. Management
strategies should be tailored based on the severity

58 ENDO 2025 • Endocrine Case Management

of symptoms, underlying etiology, and gestational ԗ Initial rate: 200-300 mL/h until
age. The following section discusses the key rehydration is achieved; adjust to maintain
principles for addressing hypocalcemia and adequate urine output.
hypercalcemia in pregnant patients.
• Pharmacological intervention:
Management of Hypocalcemia
Acute Symptomatic Hypocalcemia ԗ Bisphosphonates: these agents are
Acute hypocalcemia presenting with tetany, generally avoided in pregnancy due to
seizures, or cardiac arrhythmias necessitates urgent potential fetal skeletal effects.
correction using intravenous calcium gluconate. ԗ Cinacalcet: although not approved for the
Typical dosing is 1 to 2 g of calcium gluconate use during pregnancy, there have been
administered slowly over 10 to 20 minutes. reports of cinacalcet use during pregnancy,
Continuous cardiac monitoring is recommended but the benefits should be considered on an
to prevent arrhythmias during administration. individual basis.
The patient’s regimen is transitioned to oral
therapy once the acute episode is resolved. Surgical Management
Oral calcium supplementation is used as
• If hypercalcemia is caused by a parathyroid
maintenance therapy. The mainstay of treatment
adenoma, parathyroidectomy is typically
is calcium carbonate (1-2 g elemental calcium
deferred until the second trimester to
daily) taken with food to enhance absorption.
minimize risks to the fetus. Second-trimester
Active vitamin D analogues, such as calcitriol
surgery has been shown to have lower rates of
(0.25-1.0 mcg daily), are used to enhance intestinal
miscarriage and preterm labor.
calcium absorption and address deficiencies in
1,25-dihydroxyvitamin D production, especially • Maternal calcium levels should be optimized to
in cases of hypoparathyroidism or kidney ensure stable hydration status preoperatively.
dysfunction. Regular assessment of serum calcium,
phosphorus, and 24-hour urinary calcium levels General Management Considerations
is essential to balance effective treatment while • Serial measurements of ionized calcium, serum
avoiding complications, such as hypercalciuria or calcium, and relevant biomarkers are crucial
nephrocalcinosis. during treatment.
Management of Hypercalcemia • Fetal monitoring may be required in cases of
severe maternal calcium imbalance, as both
Mild Hypercalcemia
hypocalcemia and hypercalcemia can affect
Mild hypercalcemia (serum calcium <12 mg/dL
fetal bone mineralization and parathyroid
[<3.0 mmol/L]) without significant symptoms
function.
can often be managed with hydration and dietary
calcium restriction. Adequate hydration helps Fetal and Neonatal Considerations
prevent nephrolithiasis and maintains renal Managing maternal calcium disorders during
calcium clearance. pregnancy requires careful attention to fetal
and neonatal health, as disruptions in maternal
Severe or Symptomatic Hypercalcemia calcium homeostasis can have profound effects
on the developing fetus and newborn. Routine
• Intravenous hydration: severe hypercalcemia
fetal ultrasonography is critical for assessing fetal
(serum calcium >14 mg/dL [>3.5 mmol/L])
growth and development, as maternal calcium
or symptomatic cases require aggressive
imbalances—particularly hypercalcemia—are
hydration with normal saline to enhance renal
associated with intrauterine growth restriction.
calcium excretion.

ENDO 2025 • Bone and Mineral Metabolism 59

Close monitoring of fetal skeletal formation is and the neonatal period. Coordination among
necessary, as both hypocalcemia and hypercalcemia obstetricians, endocrinologists, and neonatologists
can influence bone mineralization. Severe is essential for comprehensive care.
maternal hypercalcemia may lead to abnormal
ossification or delayed bone growth.
Maternal calcium disorders can affect placental
Clinical Case Vignettes
health, and close surveillance is warranted to Case 1
ensure appropriate nutrient and calcium transfer A 35-year-old woman (G3, P1) at 20 weeks’
to the fetus. gestation is referred for asymptomatic
• Neonatal calcium levels hypercalcemia detected on routine prenatal
laboratory testing. She has no history of kidney
ԗ Newborns of mothers with hypercalcemia stones, fractures, or gastrointestinal symptoms.
are at risk for neonatal hypocalcemia, a She does not take calcium or vitamin D
rebound effect caused by the suppression supplements. Her first pregnancy was uneventful.
of fetal PTH production in utero.
Laboratory test results:
ԗ Early and frequent monitoring of serum
calcium levels in the first 48 to 72 hours Total calcium = 11.2 mg/dL (8.5-10.5 mg/dL)
post delivery is recommended to detect (SI: 2.8 mmol/L [2.1-2.6 mmol/L])
Ionized calcium = 5.9 mg/dL (4.5-5.3 mg/dL)
and address hypocalcemia promptly. (SI: 1.48 mmol/L [1.12-1.32 mmol/L])
PTH = 8 pg/mL (15-65 pg/mL) (SI: 0.85 pmol/L
• Symptoms of neonatal hypocalcemia [1.59-6.90 pmol/L])
25-Hydroxyvitamin D = 42 ng/mL (20-50 ng/mL)
ԗ Symptoms may include jitteriness, (SI: 104.8 nmol/L [49.9-124.8 nmol/L])
1,25-Dihydroxyvitamin D = 80 pg/mL (30-
irritability, poor feeding, lethargy, and
80 pg/mL) (SI: 208 pmol/L [78-208 pmol/L])
seizures. Creatinine = 0.7 mg/dL (SI: 61.9 µmol/L)
ԗ Prompt recognition and treatment are Phosphorus = 2.6 mg/dL (2.5-4.5 mg/dL)
(SI: 0.84 mmol/L [0.81-1.45 mmol/L])
critical to prevent complications, such
as cardiac arrhythmias or long-term Neck ultrasonography shows no parathyroid
developmental delays. adenoma. A family history of hypercalcemia is
noted, although no family member has had surgery
Preventive Strategies to address it.
ԗ Optimizing maternal calcium and vitamin
D status during pregnancy through Which of the following is this
adequate supplementation and careful patient’s most likely diagnosis?
monitoring can reduce the risk of neonatal A. Primary hyperparathyroidism
complications. B. Familial hypocalciuric hypercalcemia
ԗ Avoiding excessive maternal calcium C. Hypercalcemia of malignancy
or vitamin D supplementation during D. Vitamin D intoxication
pregnancy is equally important to
prevent fetal parathyroid suppression and Answer: B) Familial hypocalciuric hypercalcemia
subsequent neonatal hypocalcemia. Hypercalcemia in pregnancy has a broad
differential diagnosis, but misdiagnosis can
By addressing both maternal and fetal needs, lead to inappropriate management, such as
clinicians can reduce the potential adverse unnecessary surgery. The key pitfall is assuming all
outcomes of calcium disorders during pregnancy hypercalcemia in pregnancy is due to PHPT, while

60 ENDO 2025 • Endocrine Case Management

familial hypocalciuric hypercalcemia (FHH) is an Which of the following is the
important alternative diagnosis. This pregnant most appropriate next step in
patient has a low PTH concentration (not this patient’s management?
suppressed but inappropriately normal), a family A. Encourage hydration and monitor calcium
history of hypercalcemia, and mild hypercalcemia levels, deferring surgery until after delivery
with no classic PHPT symptoms. Pregnancy can B. Proceed with parathyroidectomy in the second
unmask FHH due to increased calcium absorption. trimester
FHH is caused by pathogenic variants in the
C. Start cinacalcet to control hypercalcemia
gene encoding the calcium-sensing receptor
(CASR), leading to a higher set point for calcium D. Initiate bisphosphonate therapy to lower
homeostasis. The key test to distinguish FHH calcium
from PHPT is measuring calcium in a 24-hour Answer: B) Proceed with parathyroidectomy
urine collection. FHH shows low urinary calcium in the second trimester
excretion (calcium-to-creatinine clearance ratio
<0.01), whereas PHPT has normal or high urinary PHPT is the most common cause of hypercalcemia
calcium excretion. However, these results can be in pregnancy. Untreated maternal hypercalcemia
blunted in pregnancy and in such cases genetic increases the risk of complications, including
testing often holds the key to diagnosis. nephrolithiasis, pancreatitis, hypertension, and
preeclampsia, as well as neonatal hypocalcemia
and tetany due to fetal suppression of parathyroid
Case 2
function. Parathyroidectomy (Answer B) is
A 32-year-old woman (G2, P1) at 18 weeks’ the only curative treatment for PHPT, and it
gestation is referred for evaluation of eliminates the risks associated with prolonged
hypercalcemia. She reports fatigue, mild nausea, maternal hypercalcemia. The second trimester
and intermittent constipation but has no polyuria is the safest period for surgery, minimizing risks
or nephrolithiasis. There is no family history of of both fetal loss (higher in the first trimester)
endocrine disorders. and preterm labor (higher in the third trimester).
Laboratory test results: Studies show improved pregnancy outcomes with
parathyroidectomy compared with outcomes
Calcium = 11.5 mg/dL (8.5-10.5 mg/dL) associated with conservative management.
(SI: 2.9 mmol/L [2.1-2.6 mmol/L]) Conservative management is considered if
Ionized calcium = 6.0 mg/dL (4.5-5.3 mg/dL)
(SI: 1.5 mmol/L [1.12-1.32 mmol/L]) hypercalcemia is mild and asymptomatic, but
PTH = 95 pg/mL (15-65 pg/mL) (SI: 10.1 pmol/L given this patient’s persistent hypercalcemia
[1.6-6.9 pmol/L]) and symptoms, deferring surgery would
25-Hydroxyvitamin D = 30 ng/mL (20-50 ng/mL) increase maternal and fetal risks. Calcimimetics
(SI: 74.9 nmol/L [49.9-124.8 nmol/L]) are not recommended in pregnancy due to
Creatinine = 0.7 mg/dL (SI: 61.9 µmol/L)
insufficient safety data, and bisphosphonates
Neck ultrasonography identifies a 1.8-cm are contraindicated in pregnancy because they
hypoechoic lesion posterior to the right thyroid cross the placenta and can impair fetal bone
lobe. A review of previous records shows development. Thus, parathyroidectomy in the
persistent hypercalcemia for at least 2 years, second trimester is the preferred treatment to
although she was asymptomatic before pregnancy. optimize maternal and fetal outcomes.
The patient is concerned about maternal and
fetal risks.

ENDO 2025 • Bone and Mineral Metabolism 61

Case 3 Hypoparathyroidism during pregnancy requires
careful calcium and vitamin D management to
A 29-year-old woman (G1, P0) at 14 weeks’
avoid maternal and fetal complications. Pregnancy
gestation presents for evaluation of muscle cramps,
increases intestinal calcium absorption due to
perioral tingling, and fatigue. She underwent total
placental production of 1,25-dihydroxyvitamin D,
thyroidectomy for papillary thyroid carcinoma 2
but PTH is still essential for calcium homeostasis.
years ago but was lost to follow-up. She is taking
The goal is to maintain calcium in the low-normal
levothyroxine but no other medications.
range (8.0-8.5 mg/dL [2.0-2.1 mmol/L]) to avoid
Laboratory test results: both maternal symptoms and fetal hypercalcemia,
which can suppress neonatal parathyroid function.
Calcium = 7.1 mg/dL (8.5-10.5 mg/dL)
(SI: 1.8 mmol/L [2.1-2.6 mmol/L])
Drugs that can be initiated are active vitamin
Ionized calcium = 3.6 mg/dL (4.5-5.3 mg/dL) D metabolites and oral calcium supplements.
(SI: 0.9 mmol/L [1.12-1.32 mmol/L]) Intravenous calcium and high-dosage vitamin D are
Phosphorus = 5.5 mg/dL (2.5-4.5 mg/dL) used for severe or symptomatic hypocalcemia, but
(SI: 1.78 mmol/L [0.81-1.45 mmol/L]) they are not needed for long-term management.
PTH = <5 pg/mL (15-65 pg/mL) (SI: <0.5 pmol/L
[1.6-6.9 pmol/L])
PTH analogues are not approved for use in
25-Hydroxyvitamin D = 32 ng/mL (20-50 ng/mL) pregnancy due to unknown fetal effects. Thus, oral
(SI: 79.9 nmol/L [49.9-124.8 nmol/L]) calcium and calcitriol are the standard treatment for
Creatinine = 0.6 mg/dL (SI: 53.0 µmol/L) hypoparathyroidism during pregnancy, ensuring
both maternal and fetal safety.
The patient is diagnosed with postsurgical
hypoparathyroidism with symptomatic hypocalcemia.
Key Learning Points
Which of the following is the most
appropriate treatment approach for • Pregnancy induces physiological adaptations
this patient during pregnancy? in calcium metabolism that can mask or
A. Intravenous calcium gluconate and high- exacerbate underlying disorders.
dosage vitamin D analogues • Maternal calcium disorders require a
B. Calcium supplementation with calcitriol to multidisciplinary approach, involving
maintain calcium in the lower normal range obstetrics, endocrinology, and neonatology.
C. Teriparatide (PTH analogue) for long-term • Tailored management based on gestational
management age and severity of the disorder is critical for
D. No treatment is necessary, as pregnancy optimizing outcomes.
increases calcium absorption naturally • Close monitoring of fetal growth and neonatal
Answer: B) Calcium supplementation with calcitriol calcium levels is essential to prevent long-term
to maintain calcium in the lower normal range complications.

References
1. Kovacs CS. Maternal mineral and bone metabolism during pregnancy, lactation, 4. Appelman-Dijkstra NM, Pilz S. Approach to the patient: management
and post-weaning recovery. Physiol Rev. 2016;96(2):449-547. PMID: 29053801 of parathyroid diseases across pregnancy. J Clin Endocrinol Metab.
2. Kovacs CS, Ralston SH. Physiology and pathophysiology of bone turnover 2023;108(6):1505-1513. PMID: 36546344
during pregnancy, lactation, and post-weaning recovery. Endocr Rev. 5. Bollerslev J, Rejnmark L, Zahn A, et al; 2021 PARAT Working Group.
2023;44(1):1-34. PMID: 36546344 European expert consensus on practical management of specific aspects
3. Eastell R, et al. Management of endocrine disease: bone and mineral of parathyroid disorders in adults and in pregnancy: recommendations of
metabolism in pregnancy and lactation. Eur J Endocrinol. 2022;186(1):R1-R13. the ESE Educational Program of Parathyroid Disorders. Eur J Endocrinol.
PMID: 34863037 2022;186(2):R33-R63. PMID: 34863037

62 ENDO 2025 • Endocrine Case Management

Long-Term Complications of
Mild Asymptomatic Primary
Hyperparathyroidism:
To Treat or Not to Treat?
Ghada El-Hajj Fuleihan, MD, MPH. Calcium Metabolism and Osteoporosis Program,
American University of Beirut, Beirut, Lebanon; Email: [email protected]

Educational Objectives meta-analyses that constitute the basis for

the guidelines.3-9
After reviewing this chapter, learners should be
PHPT is a common disease of mineral
able to:
metabolism, only second in frequency to
• Define primary hyperparathyroidism (PHPT) osteoporosis. It is most commonly a disease of
and distinguish its phenotypes: symptomatic, postmenopausal women. Its prevalence and
asymptomatic (with end-organ damage), and incidence vary widely globally.5 In North America
normocalcemic. and Western Europe, PHPT mostly presents as an
asymptomatic disease due to the wide availability
• Describe the long-term complications of
of serum calcium measurement on automated
asymptomatic PHPT.
chemistry analyzers. However, even asymptomatic
• Articulate a management plan for PHPT can incur end-organ damage, manifesting
asymptomatic PHPT. as a decrease in bone density or quality, fractures,
kidney stones, or nephrocalcinosis, in 20% to
50% of affected individuals.6 In many countries
of the developing world, PHPT is still mostly a
Significance of the symptomatic (>80%) and severe disease (“bones,
Clinical Problem stones and moans”) due to a lack of routine serum
biochemical screening.
This Meet the Professor session capitalizes on
work and proceedings from the Fifth International
Workshop on PHPT. The work was led by 4 task Practice Gaps
forces comprising 50 international experts and was The shift in the presentation of PHPT from
published in a dedicated supplement in the Journal a predominantly symptomatic condition to
of Bone and Mineral Research in the November 2022 an asymptomatic and mild disease in western
issue. The supplement provides a comprehensive populations has presented several challenges.
update and clinical recommendations on the Subclinical nephrolithiasis and vertebral
evaluation and management of this disease, fractures are common in patients with mild
based on GRADE methodology.1,2 It consists of and asymptomatic disease, but they can be
7 manuscripts, including a summary statement, missed unless searched for. Normocalcemic
a manuscript describing methodology, several PHPT (NPHPT) is often diagnosed without
narrative reviews, systematic reviews, and

ENDO 2025 • Bone and Mineral Metabolism 63

the fulfillment of rigorous criteria. While affect calcium absorption, medications (denosumab,
observational and cross-sectional studies bisphosphonates, anticonvulsants, lithium,
continue to show associations between PHPT phosphorus).5,6
and cardiovascular and neuropsychological
abnormalities, their causal relationship is Clinical Phenotypes of PHPT
uncertain. Limited new data are available on the
natural history of skeletal, renal, cardiovascular, Symptomatic PHPT: associated with marked
neuropsychological, neuromuscular hypercalcemia (moderate or severe) or overt
manifestations, and quality of life. Randomized (clinically detected) skeletal and kidney
controlled clinical trials have not demonstrated a complications that may include osteitis fibrosa
consistent long-term benefit of parathyroidectomy cystica and/or fractures, chronic kidney disease,
vs observation on nonclassic manifestations. nephrolithiasis, and/or nephrocalcinosis.
Knowledge and management gaps arise because Asymptomatic PHPT: no overt symptoms or
of the heterogeneity of participants with PHPT signs on presentation; typically discovered
reported in western cohort studies and in by biochemical screening. Two forms of
randomized clinical trials and the lack of clear asymptomatic PHPT are defined after evaluation
phenotype identification in published series. of the skeleton and kidneys:
• The natural history of the various phenotypes • With target-organ involvement discovered
of asymptomatic PHPT is unclear. upon performing the recommended
• The beneficial effects of interventions in the radiologic procedures (eg, x-ray of the
various subgroups of PHPT remain unclear. thoracolumbar spine [detecting asymptomatic
fractures] or ultrasonography of the kidneys
[detecting asymptomatic nephrolithiasis or
Discussion
nephrocalcinosis])
Definition of PHPT • Without target-organ involvement
Hypercalcemic PHPT: an elevated serum calcium
level adjusted for albumin in the presence of an NPHPT: may be symptomatic or asymptomatic,
elevated or inappropriately normal intact PTH with/without target organ involvement.
level (using either a second- or third-generation
assay) on 2 occasions at least 2 weeks apart. Classic and Nonclassic
Familial hypercalcemic hypocalciuria is the most
Target Organs in PHPT and
common condition in the differential diagnosis of
hypercalcemic PHPT. Disease Complications
Symptomatology may be related to disease chronicity
NPHPT: normal adjusted total calcium and normal and development of end-organ damage, severity of
ionized calcium levels along with elevated intact the serum calcium elevation, or the rapidity with
PTH level (using either a second- or third- which it is increased. Mild hypercalcemia usually
generation assay) on at least 2 occasions over 3 to implies an albumin-adjusted serum calcium value
6 months after all alternative causes for secondary less than 1 mg/dL (<0.25 mmol/L) above upper
hyperparathyroidism have been ruled out. Secondary normal limit (ie, <11.4 mg/dL [<2.85 mmol/L]) for
causes include a serum 25-hydroxyvitamin D value most laboratories. Moderate hypercalcemia indicates
less than 30 ng/mL (<75 nmol/L), chronic kidney an albumin-adjusted serum calcium value of 11.4
disease (eGFR <60 mL/min/1.73 m2), renal calcium to 14.0 mg/dL (2.85-3.50 mmol/L), and severe
loss (idiopathic hypercalciuria, and loop diuretics), hypercalcemia indicates an albumin-adjusted serum
and diseases of the gastrointestinal tract known to calcium value greater than 14 mg/dL (>3.5 mmol/L).

64 ENDO 2025 • Endocrine Case Management

Disease causality has been clearly established only clinical phenotype of asymptomatic patients
for biochemical abnormalities and for skeletal and with evidence of target-organ involvement. This
kidney manifestations, namely manifestations that is based on evidence of reversal of biochemical
are reversible with parathyroidectomy (Figure).6 abnormalities, kidney, and bone complications
The Table (following page) details PTH effects on cell (improvement in bone mineral density) after
targets, resulting pathophysiological changes, and parathyroidectomy in both conditions.4 The data
clinical implications. become scarcer in asymptomatic patients with
mild PHPT who have no evidence of target-organ
involvement.
Management Plan for Asymptomatic
A thorough clinical evaluation of patients with
PHPT, Including Surgical Indications confirmed PHPT is instrumental in guiding disease
Unless surgery is contraindicated, management. Evaluation includes a detailed
parathyroidectomy is the recommended family history of hypercalcemia, a careful clinical
management for symptomatic patients, who by history to assess symptoms, review of laboratory
definition (for the most part) have end-organ findings (including multiple serum calcium levels
involvement. The same approach applies to the over years before presentation and of intake of

Figure. Symptoms and Organ Involvement in Patients With PHPT

Symptoms and complications depend on disease severity. Causality is implied from evidence by reversal with surgery or from mechanistic studies. Causal in
is red, and association in green.
*Moderate to severe hypercalcemia may cause changes in mental status or cognitive function that are often reversible with correction of the serum calcium.
Reprinted from El-Hajj Fuleihan G et al. J Bone Miner Res, 2022; 37(11): 2330-2350. © The Authors. Published by Wiley Periodicals LLC on behalf of
American Society for Bone and Mineral Research
[Color—Print (Color Gallery page CG8) or web & ePub editions]

ENDO 2025 • Bone and Mineral Metabolism 65

medications that may affect PTH dynamics), life, and/or cardiovascular indices because
thorough screening for target-organ involvement, the evidence is inconclusive.”4 Because of
and the request of additional laboratory studies limited data in NPHPT, the panel of experts
(Box, following page).4 could not recommend surgery.4-6 In practice,
In patients with asymptomatic PHPT, the parathyroidectomy is, however, performed in
panel recommends surgery to cure the disease patients with NPHPT if evidence of end-organ
(strong recommendation/high-quality evidence, damage is present. Preoperative localization is
GRADE 1A). The panel states: “Although less successful in normocalcemic disease than in
parathyroidectomy is an option for all patients, hypercalcemic disease due to hyperplasia. Surgery
with concurrence of the patient and the physician should always be performed by an experienced
and if there are no contraindications, the panel parathyroid surgeon.
recommends surgery in all those in whom one or Preoperative localization is not recommended
more of the following is present (including those for diagnostic purposes, but it is recommended for
who are asymptomatic, 4).” The conditions are those who are going to have parathyroid surgery.
listed in the right column of the Box (following Available modalities include ultrasonography,
page). Surgery cannot be recommended to sestamibi scintigraphy, including SPECT-CT,
improve neurocognitive function, quality of parathyroid 4-dimensional CT, and MRI. PET-CT

Table. Effects of PTH on Classic and Nonclassic Target Organs and Ultimate Effects on Clinical Manifestations

Target organ PTH cell target PTH-regulated function Pathophysiologic changes Clinical implications

Kidney Distal tubule Calcium reabsorption Hypercalcemia (with Hypercalcemic syndrome

contributions from gut and of increased mortality
Proximal and distal Phosphate reabsorption
bone)
tubules Fatigue/muscle weakness
Bicarbonate reabsorption
Hypophosphatemia
Distal tubule Nephrocalcinosis
Proximal tubule 1α-Hydroxylase Hyperchloremic acidosis
Kidney stones
Hypercalciuria (indirectly)

Gut Proximal and distal Indirect through Hypercalciuria Kidney stones

intestine 1,25-dihydroxyvitamin
D-dependent increased calcium
intestinal absorption

Bone Osteoblast Bone turnover High bone turnover Fracture

Bone loss

Cardiovascular Cardiomyocyte Hypercalcemia-dependent Arrythmias Possible increase in

system mortality
Cardiac valves Interaction with RAAS Left ventricular hypertrophy
Heart failure
Smooth muscle cells Hypercalcemia-dependent Heart failure
vasodilatation Decreased blood pressure
Soft-tissue calcification
Interaction with RAAS Hypertension
Decreased blood pressure
Hypertension*

Central nervous Axons Hypercalcemia Apoptosis*

system
Cross-reactivity with PTH2R Stress response, anxiety*

Skeletal/muscle Myotube Muscle weakness

Dermis Fibroblasts/hair Possible role in hair growth/ None known in nongenetic No known
follicles differentiation forms of PHPT

* Possible PTH effect.

Reprinted from Minisola S et al. J Bone Miner Res, 2022; 37(11): 2315-29. © The Authors. Published by Wiley Periodicals LLC on behalf of American Society
for Bone and Mineral Research.

66 ENDO 2025 • Endocrine Case Management

Box. Evaluation of Patients With PHPT and Indications for Parathyroidectomy

How should patients with PHPT be evaluated? For which patients is parathyroidectomy an option?

1. Biochemical: Measure adjusted total serum calcium (ionized if 1. Serum calcium >1 mg/dL (>0.25 mmol/L) above the upper
NPHPT is a consideration), phosphorus, intact PTH, 25-hydroxyvitamin normal limit or
D, creatinine; bone turnover may be added
2. Skeletal involvement: fracture by vertebral fracture
2. Skeletal: Three-site DXA (lumbar spine, hip, distal one-third radius); assessment or vertebral x-ray or bone mineral density by
imaging for vertebral fractures (vertebral fracture assessment or T-score ≤ –2.5 at any site or
vertebral x-rays); trabecular bone score if available
3. Kidney involvement: estimated glomerular filtration rate
3. Kidneys: Estimated glomerular filtration rate or preferably, creatinine or creatinine clearance <60 mL/min; nephrocalcinosis or
clearance, 24-hour urinary calcium and for biochemical risk factors for nephrolithiasis by x-ray, ultrasonography, or other imaging
stones; imaging for nephrolithiasis/nephrocalcinosis modality; hypercalciuria (eg, >250 mg/24 h in women; >300
mg/24 h in men) or
4. Nonclassic manifestations (neurocognitive, quality of life,
cardiovascular): there are no data to support routine evaluation for 4. Age <50 years (no other indications are necessary; age
these putative manifestations <50 years is a sufficient indication)
5. Genetic: genetic evaluation should be considered for patients
younger than 30 years, those with multigland disease by history or
imaging, and/or those with a family history of hypercalcemia and/or a
syndromic disease

Reprinted from Bilezikian JP et al. J Bone Miner Res, 2022; 37(11): 2293-314. © The Authors. Published by Wiley Periodicals LLC on behalf of American
Society for Bone and Mineral Research.

with choline and methionine is used in Europe, There was a very minimal increase in serum calcium
but it is considered research methodology in the over time, and PTH levels and urinary calcium
United States. There is no consensus on the best levels remained stable, as did 25-hydroxyvitamin
imaging protocol. It depends on institutional D and 1,25-dihydroxyvitamin D2 levels. Bone
availability, radiologist expertise, the preference density decreased in some patients after 10 years,
of the surgeon, and cost. The positive predictive especially at cortical sites. Thirty-seven percent
values, on average, are lowest for ultrasonography of the cohort developed 1 or more indications for
(76%). Positive predictive values for sestamibi surgery during the 15 years of follow-up, including
SPECT and 4-dimensional CT are 80% and 90%, hypercalcemia, hypercalciuria, or reduced bone
respectively. For all modalities, localization is mineral density.10 Despite the scare evidence at the
less accurate for multiglandular disease than time, parathyroidectomy was a valid consideration
for solitary adenomas: “The most important in view of the long-term complications of mild
pre-op localization challenge in primary asymptomatic PHPT.11
hyperparathyroidism is to localize the parathyroid In those who are not going to have
surgeon,” stated the late Dr. John Dopman, an parathyroid surgery, pharmacologic options can
interventional radiologist at the National Institutes be considered to reduce serum calcium or to
of Health in 1975. increase bone density (as a surrogate for fracture
risk reduction in general). US FDA indications
for a calcimimetic agent, such as cinacalcet, for
Medical Management and Monitoring
PHPT include control of advanced disease, namely
There may be instances where parathyroid a serum calcium concentration greater than
surgery is not necessarily an option, such as when 1 mg/dL (>0.25 mmol/L) above the upper normal
guidelines are not met, patients opt for nonsurgical limit, in case parathyroidectomy is not indicated or
management, there is a history of previous neck the patient declines surgery.
surgery (or surgeries), thus rendering surgery The expert panel developed recommendations
problematic, or there are coexisting medical issues. from systematic and narrative reviews regarding
The natural history of mild hyperparathyroidism nutritional and pharmacologic interventions.4
over 15 years has been assessed in a cohort study.10

ENDO 2025 • Bone and Mineral Metabolism 67

• Calcium intake/supplementation: as per no dry mouth, and no cognitive dysfunction.
Institute of Medicine guidelines 1000 to 1200 She has had no loss of height and no fractures
mg of calcium daily or kidney stones. She has never been on lithium
• Vitamin D supplementation: aim for a serum or thiazides. There is no known family history
25-hydroxyvitamin D concentration ≥30 ng/ of hypercalcemia. Dietary calcium intake is
mL (≥75 nmol/L) approximately 500 mg elemental calcium daily. She
exercises by walking twice weekly and swimming
• Cinacalcet is useful to reduce the serum twice weekly. Her medical history is positive for
calcium level essential hyperlipidemia that worsened slightly
• Effective options to increase bone density are after menopause. She takes no medications except
alendronate or denosumab for calcium, 500 mg daily, and vitamin D, 800 IU
• A combination of cinacalcet with a daily (20 mcg daily).
bisphosphonate or denosumab,4 to reduce Physical examination findings are normal, and
serum calcium and increase bone density there is no kyphosis.

Monitoring for patients who do not undergo Laboratory test results:

parathyroidectomy should include serum calcium Serum calcium = 10.8 mg/dL (8.5-10.2 mg/dL)
and 25-hydroxyvitamin vitamin D measurement (SI: 2.7 mmol/L [2.15-2.55 mmol/L])
annually, skeletal visualization with 3-site DXA Phosphate = 3.8 mg/dL (SI: 1.2 mmol/L)
every 1 to 2 years, vertebral x-ray, vertebral Creatinine = 0.9 mg/dL (SI: 79.6 µmol/L)
Albumin = 4.2 mg/dL (SI: 42 g/L)
fracture assessment or trabecular bone score if
clinically indicated, creatinine clearance annually,
Which of the following
abdominal imaging if clinically indicated, and
assessments are needed now?
24-hour urinary calcium excretion if clinically
indicated. In normocalcemic or hypercalcemic A. Serum PTHrP and calcitriol measurement
patients with PHPT monitored medically, B. Genetic testing for familial hypocalciuric
parathyroid surgery should be recommended if the hypercalcemia
serum calcium concentration is consistently 1 mg/ C. Calcium/creatinine clearance ratio and PTH
dL (>0.25 mmol/L) above the upper normal limit measurement
or if the patient develops a low-trauma fracture, D. Review of documented calcium levels over the
a kidney stone, a significant reduction in bone last few years
mineral density exceeding the least significant
change at any site, or a significant reduction in Answer: C) Calcium/creatinine clearance
creatinine clearance (averaging more than 3 mL ratio and PTH measurement and D) Review of
per minute over 1 to 2 years, if associated with documented calcium levels over the last few years
other changes that indicate deterioration).
This patient is unlikely to have a malignancy
in view of her lack of symptoms and mild
Clinical Case Vignettes hypercalcemia. Vitamin D intoxication from
active forms or from tumors secreting calcitriol
Case 1
(benign or malignant) are less likely. There is no
A 52-year-old woman presents for evaluation of suspicion for familial hypocalciuric hypercalcemia,
a high serum calcium concentration picked up as affected patients are usually younger. Genetic
on routine laboratory testing by her primary care tests are expensive and are not warranted for
physician. She is asymptomatic except for mild this patient yet. The next step is confirmation of
fatigue. She underwent menopause 2 years ago elevated serum calcium along with a concomitant
and has tolerable hot flashes. She has no polyuria, measurement of PTH and 24-hour urinary calcium

68 ENDO 2025 • Endocrine Case Management

and creatinine excretion to calculate the calcium/ in individuals with PHPT, while it is less than
creatinine clearance ratio. It is always helpful to 0.01 in individuals with familial hypocalciuric
review old laboratory values to assess the onset and hypercalcemia. However, values between 0.01 and
duration of hypercalcemia. Calcium is expected to 0.02 can be found in 30% to 40% of individuals
be slightly lower, on average, before menopause with either condition.
than after menopause, due to estrogen’s masking of This patient’s calcium/creatinine clearance
the bone resorptive effect of PTH. ratio is 0.027, and her family members (parents,
4 siblings, and 2 children) all have calcium
concentrations below 10 mg/dL (<2.5 mmol/L).
Case 1, Continued
DXA shows osteopenia, spine T-score of –2.0, hip
Laboratory test results: T-score of –1.2, and forearm T-score of –1.2. Her
FRAX is below the country-specific threshold,
Repeated calcium =10.9 mg/dL (SI: 2.8 mmol/L) and the trabecular bone score is 1.30. Vertebral
PTH = 76 pg/mL (15-76 pg/mL) (SI: 8.1 pmol/L fracture assessment is negative for compression
[1.6-8.1 pmol/L])
Creatinine = 0.9 mg/dL (SI: 79.6 µmol/L) fractures, and kidney ultrasonography is negative
Urinary calcium = 300 mg/24 h (SI: 7.5 mmol/d) for nephrocalcinosis and kidney stones.
Urinary creatinine = 900 mg/24 h In summary, this patient has had elevated
calcium on 2 occasions, inappropriately normal PTH
What are the indicated tests at this point? (upper normal limit), high 24-hour urinary calcium
A. Obtain labs on the patient's parents, siblings, excretion and calcium/creatinine clearance ratio,
and children negative family history, and normal serum calcium
B. Determine bone mineral density of the spine, levels in first-degree relatives. The patient has
hip, and forearm and trabecular bone score PHPT. The diagnosis can be further confirmed with
and obtain vertebral fracture assessment or genetic testing, but this is not needed at this point.
lateral spine films
C. Perform kidney ultrasonography Case 1, Continued
D. Order genetic testing for familial hypocalciuric After an informed discussion on benefits and risks
hypercalcemia of surgery and a discussion of alternative treatment
E. A, B, and C options, the patient is referred for surgery.

Answer: E) A, B, and C Which criterion does the patient fulfill for

consideration of surgical intervention?
PHPT is more common than familial hypocalciuric
hypercalcemia, although the prevalence of the A. Osteopenia
latter has been shown to be higher than expected B. Elevated 24-hour urinary calcium excretion
as evidenced by examination of large repositories.5 C. Low trabecular bone score
While PHPT can incur end-organ damage to D. None of the above
the skeleton and kidney, familial hypocalciuric
hypercalcemia is a benign condition, with no Answer: B) Elevated 24-hour urinary calcium excretion
deleterious effects on these organ systems. It is
The indications for parathyroidectomy are listed in
inherited in an autosomal dominant pattern,
the right column of the Box. The one that applies
and review of laboratory values of first-degree
to the patient is high urinary calcium excretion
relatives is important. The calcium/creatinine
(Answer B). Biological age matters more than
clearance ratio may be useful to distinguish PHPT
chronological age, so the age cutoff is not absolute.
from familial hypocalciuric hypercalcemia. A
ratio greater than 0.02 is more likely to be present

ENDO 2025 • Bone and Mineral Metabolism 69

Case 2 autonomy was clinically detectable through her
biochemical abnormalities.
A 30-year-old woman with bipolar disorder is self-
referred for evaluation of hypercalcemia. She feels
well and has no concerns or physical ailments. She Case 2, Continued
has no gastrointestinal symptoms and no history At this point, what is the best
of fractures or kidney stones. Review of systems is advice for this patient?
otherwise negative. Her family history is negative A. Discontinue lithium now
for hypercalcemia or endocrine disorders. She has
taken lithium, 300 mg twice daily, for 10 years. B. Immediately consult a surgeon for
parathyroidectomy
Laboratory test results: C. Consult her psychiatrist for tapering of lithium
Serum calcium = 11 mg/dL (8.5-10.2 mg/dL) and switching to alternative therapy
(SI: 2.75 mmol/L [2.15-2.55 mmol/L]) (review D. Do nothing and monitor calcium and PTH
of her yearly labs reveals her serum calcium has every year
been slowly rising over the last 10 years)
Creatinine, normal Answer: C) Consult her psychiatrist for tapering
Albumin, normal
of lithium and switching to alternative therapy
PTH = 120 pg/mL (15-76 pg/mL) (SI: 12.7 pmol/L
[1.6-8.1 pmol/L]) Lithium increases serum total and ionized
Serum calcium = 10.9 mg/dL (SI: 2.7 mmol/L)
Albumin, normal calcium and intact PTH levels within weeks,
but these remain within the normal range in
Review of laboratory studies of her family most individuals.12 In a study of lithium-treated
members reveals no hypercalcemia. women (mean age, 40 years) followed up for
5 years, the mean baseline ionized calcium was
Which of the following is the most lower and intact PTH levels were higher in the
likely etiology of her hypercalcemia? lithium-treated group than in the control group,
A. Familial hyperparathyroidism although they were still within the normal range.13
B. Secondary hyperparathyroidism Lithium seems to affect the signal transduction
pathway for calcium sensing by interfering with
C. Lithium-induced hypercalcemia and PHPT
the calcium-sensing receptor at the level of
D. Lithium-induced hypercalcemia independent parathyroid and kidney. Parathyroid autonomy,
of PTH with both adenomas and 4-gland hyperplasia, has
Answer: C) Lithium-induced hypercalcemia and PHPT been described in this condition. It is therefore
possible that lithium unmasks adenomas in
This patient may have sporadic or familial PHPT, patients with preexisting parathyroid lesions
although these scenarios are less likely in view within a few years of starting therapy or induces
of her young age (unlikely to be sporadic) and parathyroid hyperplasia with more long-term
the negative family history PHPT (unlikely to be therapy. If lithium therapy is short term and can
familial), and laboratory studies of family members be tapered and stopped without exacerbating the
did not detect hypercalcemia. Her rise in calcium psychiatric condition, hypercalcemia may resolve.
is gradual and coincides with the start of lithium Long-term lithium therapy may have other
therapy. The patient may have thus developed de adverse consequences, such as hypothyroidism,
novo PHPT from long-term lithium intake, which nephrogenic diabetes insipidus, and kidney
decreased the sensitivity of the calcium-sensing failure. The effect on the skeleton is unclear. This
receptor to calcium and gradually shifted the PTH- patient was asked to see her psychiatrist to try to
calcium set point to the right until parathyroid find an alternative treatment to lithium monitor

70 ENDO 2025 • Endocrine Case Management

calcium and PTH levels. In such a scenario, The patient has started alendronate, 70 mg once
if normalization does not occur within a few weekly, and vitamin D, 10,000 units once weekly.
months, consideration of parathyroidectomy The patient's laboratory data are shown in the Table.
with a neck exploration approach is reasonable On sestamibi scan, subtraction images show
considering the patient’s age. abnormal focal uptake in the left neck projecting
over the left lower thyroid pole, which is
suspicious for an active left inferior parathyroid
Case 3
adenoma.
A 60-year-old woman with dyslipidemia,
hypertension, and osteoporosis is referred after Which of the following is the
her primary care physician felt a nodule in her most likely diagnosis?
thyroid gland. Neck ultrasonography performed A. PHPT
at an outside hospital shows a 7 × 9 × 8-mm
B. Secondary hyperparathyroidism
posteroinferior left thyroid lobe nodule, consistent
with parathyroid adenoma. Menopause was at C. NPHPT
age 56 years, and she has never had a fracture. She D. B and C
has had no kidney stones. Her family history is
Answer: D) B and C
negative for hypercalcemia.
Medications are candesartan, nebivolol, PHPT is a condition characterized by an
pravastatin, and magnesium. elevated albumin-adjusted serum calcium level
On physical examination, her height is 65.0 in with an elevated PTH level (using second- or
(165 cm) and weight is 143.3 lb (65 kg) (BMI = third-generation assays), documented on 2
23.8 kg/m2). Blood pressure is 120/80 mm Hg. occasions at least 2 weeks apart.2 Secondary
Bone mineral density assessed (at an outside hyperparathyroidism is a condition characterized
facility) September 2024 is as follows: by an appropriate physiologic response of elevated
Spine T-score = –2.0 PTH level to an initial hypocalcemic stimulus, such
Hip T-score = –1.0 as what occurs in the setup of a malabsorptive
Forearm T-score = –0.8 syndrome, hypercalciuria, or kidney failure, in an

Sept 2024 Sept 2024 Jan 2025 Feb 2025

Analyte Outside lab Your lab Outside lab Your lab

Calcium (lab reference 9.7 mg/dL 9.5 mg/dL 9.8 mg/dL

range: 8.5-10.5 mg/dL)

Phosphate 3.8 mg/dL 3.2 mg/dL

PTH 73 pg/mL 40 pg/mL (second- 80 pg/mL 40.7 pg/mL (second-

generation) generation)

(lab reference range: (lab reference range: (lab reference range: 9-47 (lab reference range:
15-65 pg/mL) 15-76 pg/mL) pg/mL) 15-76 pg/mL)

25-Hydroxyvitamin D 35 ng/mL 42 ng/mL

Creatinine 0.7 mg/dL

Other labs TSH = 1.9 mIU/L 24 hour Ionized calcium =

Albumin, normal 1.4 mmol/L
Calcium = 408 mg
Creatinine = 1.3 g (lab reference range:
Volume = 4.2 L 1.15-1.4 mmol/L)
Albumin, normal

ENDO 2025 • Bone and Mineral Metabolism 71

attempt to normalize serum calcium level. NPHPT preoperative localizing studies, which complicates
is characterized by persistently normal albumin- their surgical management.14 This is a challenging,
adjusted total and ionized serum calcium levels on yet common, scenario that various experts may
at least 2 consecutive measurements at least a week approach differently.
apart over a 3- to 6-month period, confirmed by
elevated PTH levels. Other diseases and drugs
that cause high PTH levels should be excluded.5
Key Learning Points
Positive radiologic tests are not diagnostic of
• A definite diagnosis of PHPT should be
PHPT. False-positive sestamibi scans have been
established using the accepted revised definitions.
noted in patients with underlying thyroid disease
at a rate reaching 15% to 20%. • Patients with PHPT should be systematically
Based the data in the vignette, this patient assessed for silent end-organ involvement.
may have hypercalciuria with secondary • If NPHPT is suspected, secondary causes
hyperparathyroidism or NPHPT. Patients with of normal calcium and high PTH should be
NPHPT do not usually have elevated urinary ruled out.
calcium levels. They may have evidence of • Radiologic procedures are indicated to guide
skeletal or kidney involvement (eg, osteoporosis, parathyroidectomy and not to diagnose PHPT.
nephrolithiasis). The natural history of NPHPT
is unclear in part because studies have not always • Parathyroidectomy is the only curative
used consistent terminology and the heterogenous intervention for PHPT, but it is not
nature of cohorts. In the latest guidelines, surgical recommended for individuals with NPHPT.
intervention was not recommended for patients • Cinacalcet lowers serum calcium and PTH,
with NPHPT because of lack of evidence of any but it does not improve bone mineral density
benefit on end-organs after parathyroidectomy. or hypercalciuria. Bisphosphonates and
Furthermore, patients with NPHPT are more denosumab maintain or modestly increase
likely to have multiglandular disease and negative bone mineral density.

References
1. Civitelli R, Rosen C. Parathyroid disorders special sections. J Bone Miner Res. review and meta-analysis of randomized controlled trials. Bone Miner Res.
2022;37(11):2288-2289. PMID: 36223904 2022;37(11):2351-2372. PMID: 36054175
2. Bilezikian JP, Khan AA, Clarke BL, Mannstadt M, Potts JT, Brandi ML. The 9. Bilezikian JP, Silverberg SJ, Bandeira F, et al. Management of primary
fifth international workshop on the evaluation and management of primary hyperparathyroidism. J Bone Miner Res. 2022;37(11):2391-2403. PMID: 36054638
hyperparathyroidism. J Bone Miner Res. 2022;37(11):2290-2292. PMID: 36245277 10. Rubin M, Bilezikian JP, McMahon DJ, et al. The natural history of primary
3. Yao L, Guyatt G, Ye Z, et al. Methodology for the guidelines on evaluation hyperparathyroidism with or without parathyroid surgery after 15 years. J
and management of hypoparathyroidism and primary hyperparathyroidism. J Clin Endocrinol Metab. 2008;93(9):3462-3470. PMID: 18544625
Bone Miner Res. 2022;37(11):2404-2410. PMID: 36053800 11. El-Hajj Fuleihan G. Hyperparathyroidism: time to reconsider current clinical
4. Bilezikian JP, Khan AA, Silverberg SJ, et al; International Workshop on decision paradigms? J Clin Endocrinol Metab. 2008;93(9):3302-3304. PMID:
Primary Hyperparathyroidism. Evaluation and management of primary 18772461
hyperparathyroidism: summary statement and guidelines from the fifth 12. El-Hajj Fuleihan G, Silverberg S. Pathogenesis and etiology of primary
international workshop. J Bone Miner Res. 2022;37(11):2293-2314. PMID: hyperparathyroidism. UpToDate. Wolters Kluwer.
36245251 13. Haden ST, Stoll AL, McCormick S, Scott J, El-Hajj Fuleihan G. Alterations
5. Minisola S, Arnold A, Belaya Z, et al. Epidemiology, pathophysiology, and in parathyroid dynamics in lithium-treated subjects. J Clin Endocrinol Metab.
genetics of primary hyperparathyroidism. J Bone Miner Res. 2022;37(11):2315- 1997;82(9):2844-2848. PMID: 9284708
2329. PMID: 36245271 14. Liu Y, Gregory NS, Andreopoulou P, Kashyap S, Cusano N. Approach to the
6. El-Hajj Fuleihan G, Chakhtoura M, Cipriani C, et al. Classical and patient: normocalcemic primary hyperparathyroidism. J Clin Endocrinol Metab.
nonclassical manifestations of primary hyperparathyroidism. J Bone Miner Res. 2025;110(3):e868-e877. PMID: 39319404
2022;37(11):2330-2350. PMID: 36245249
*References 1 through 9 are part of the publications from the 5th International
7. Perrier N, Lang BH, Farias LCB, et al. Surgical aspects of primary
Workshop on Primary Hyperparathyroidism published in the Journal of Bone and
hyperparathyroidism. J Bone Miner Res. 2022;37(11):2373-2390. PMID: 36054175
Mineral Research in the 2022 Fall issue.
8. Ye Z, Silverberg SJ, Sreekanta A, et al. The efficacy and safety of medical and
surgical therapy in patients with primary hyperparathyroidism: a systematic

72 ENDO 2025 • Endocrine Case Management

Addressing Bone Health in
Underweight Individuals
Across the Lifespan
Pouneh K. Fazeli, MD, MPH. Division of Endocrinology, Department of Medicine, UPMC
Presbyterian Hospital, University of Pittsburgh, Pittsburgh, PA; Email: [email protected]

Selma Feldman Witchel, MD. Division of Pediatric Endocrinology, Department of

Pediatrics, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA;
Email: [email protected]

Educational Objectives to prolonged caloric deprivation have long-term

health consequences, including loss of bone mass
After reviewing this chapter, learners should be
and increased fracture risk.2 Chronic conditions
able to:
associated with undernutrition that affect bone
• Explain the relationship between bone health health are listed in the Box. Herein, 3 situations
and nutrition. representing different age groups are presented.
• Describe the hormonal basis of low bone
Box. Chronic Medical Conditions Associated
mineral density (BMD) in anorexia nervosa. With Increased Risk of Low BMD
• Distinguish idiopathic hypogonadotropic
Malabsorption/decreased caloric intake
hypogonadism from avoidant restrictive food
• Crohn disease
disorder (ARFID) and anorexia nervosa.
• Ulcerative colitis
• Cystic fibrosis
• Systematic lupus erythematosus

Significance of the • Ankylosing spondylitis

• Celiac disease
Clinical Problem • Cancer and cancer treatments
States of negative energy balance result in • Solid organ transplant
hormonal adaptations that help maintain a state • Anorexia nervosa
of euglycemia and shunt energy expenditure • Avoidant restrictive food disorder
away from processes that are unnecessary for • Chronic kidney disease
survival. These adaptations lead to upregulation • Extreme prematurity and low birth weight
of counterregulatory hormones, including GH Endocrine dysfunction
and cortisol, and redirect energy away from • Hyperthyroidism
reproduction and IGF-1 dependent processes, • Type 1 diabetes
neither of which is critical for survival.1 Regardless • Adrenal insufficiency
of the cause of the state of negative energy balance,
these adaptations are important for survival
during periods of undernutrition.1 Adaptations

ENDO 2025 • Bone and Mineral Metabolism 73

Practice Gaps Calcitriol concentrations are also lower in the fetus
than in the mother. Intact FGF-23 concentrations
• There is a lack of awareness of the role of tend to be normal or slightly low.3 The placenta
hypophosphatemia in metabolic bone disease and possibly the parathyroid glands produce
of prematurity. PTHrP. Chronic placental insufficiency may be
associated with intrauterine growth restriction
• It is important for clinicians to understand
and impaired phosphate transfer. Fetal skeletal
potential causes of bone loss in states of
mineralization is largely independent of maternal
undernutrition, as bone loss is rarely due to
vitamin D status.3
nutrient deficiency.
Throughout pregnancy, the placenta is the
• Although hypoestrogenemia due to major source of calcium. The cutting of the
hypogonadotropic hypogonadism is a common placenta is the switch that transforms regulation
finding in anorexia nervosa, combined oral of mineral homeostasis in the newborn. Loss of
contraceptives (COCs) are not effective in placental calcium transport accompanied by the
increasing BMD in this population. onset of breathing, respectively, decreases calcium
transport and increases blood pH. This postnatal
Discussion decline in serum calcium stimulates increased PTH
secretion. Calcitriol concentrations also increase.
Fetal Skeletal Health The intestines then become the major calcium
Skeletal health begins in utero. At approximately source. The kidneys start to reabsorb minerals and
8 to 12 weeks’ gestation, the primary ossification bone turnover contributes additional minerals
centers appear in the vertebrae and long bones. to the circulation. FGF-23 becomes more active
Fetal bone mineral accretion is highly dependent in the regulation of serum phosphorus, renal
on the active transport of calcium from the phosphorus excretion, and calcitriol synthesis
maternal to fetal circulation. The placenta also and catabolism. Initially, intestinal calcium
actively transports phosphorus and magnesium absorption is passive. The high lactose content of
from the maternal circulation. Fetal intestinal breast milk initially facilitates passive intestinal
mineral absorption is limited to the minerals calcium absorption as the calcitriol-dependent
excreted by the fetal kidney into amniotic fluid and active intestinal absorption pathways mature and
swallowed by the fetus. become functional.3
Typically, 30 g of calcium and 20 g of
phosphate are deposited in the full-term fetal Bone Health and Undernutrition
skeleton by term; most of this mineral accretion
occurs during the third trimester. For the average
Among Adolescents and Adults
fetus, calcium accretion increases from 60 mg Among adolescents and adults, the major causes of
per day at 24 weeks’ gestation to 300 to 350 mg undernutrition can be classified into 2 etiologies:
of calcium per day between 35 and 40 weeks’ chronic medical conditions and psychiatric
gestation. Phosphate accretion also increases from etiologies. Chronic medical conditions are often
40 mg per day at week 24 to 200 mg per day in the associated with malabsorption, undernutrition,
last 5 weeks of gestation.3 or excessive energy demands. With appropriate
Total and ionized calcium concentrations, diagnosis and ongoing treatment, weight generally
phosphorus, and magnesium concentrations are improves. Psychiatric etiologies include anorexia
usually greater in the fetus than in the mother.3 nervosa and ARFID.
The higher fetal calcium concentrations suppress The psychiatric causes of undernutrition
PTH secretion, resulting in lower fetal PTH are more challenging to treat, with anorexia
concentrations compared with the mother’s. nervosa having a long-term remission rate of
approximately 60% 2 decades after diagnosis.4

74 ENDO 2025 • Endocrine Case Management

Anorexia nervosa is a chronic psychiatric disorder Which of the following is the most likely
most commonly starting during adolescence.5 etiology of this infant’s fractures?
The lifetime prevalence of anorexia nervosa A. Prematurity
is estimated to be 1.4% in women and 0.2% in B. Osteogenesis imperfecta
men.6 The Diagnostic and Statistical Manual of
C. Metabolic bone disease of prematurity
Mental Disorders, 5th Edition, criteria for anorexia
nervosa include a low body weight in the setting D. X-linked hypophosphatemic rickets due to
of fear of weight gain. This results in self-induced PHEX pathogenic variant
inappropriate caloric intake. ARFID is a more E. Vitamin D–dependent rickets due to CYP27B1
recently described psychiatric condition in which pathogenic variant
there is food avoidance and a low-weight state,
but not due to fear of gaining weight or due to Answer: C) Metabolic bone disease of prematurity
a medical condition. Individuals with ARFID Although this baby is preterm, prematurity alone
may avoid eating because of a fear of choking, (Answer A) cannot explain his bone disease.
for example, or may simply not eat due to lack of Compared with term babies, preterm babies
interest in food. lack sufficient calcium and phosphorus storage
because they are deprived of third-trimester
Clinical Case Vignettes calcium and phosphorus transport across the
placenta. Extremely preterm and low–birth weight
Case 1 babies can develop metabolic bone disease of
A newborn boy is the 625 g product of a 26-week prematurity (MBDP) (Answer C), as is the case in
gestation (weight percentile, 3.4). He required this vignette. MBDP is characterized by decreased
mechanical ventilation for 7 days and now has mineralization of the preterm infant skeleton due
chronic lung disease treated with furosemide and to insufficient calcium and phosphorus accretion.
caffeine. He had 1 episode of medical necrotizing Peak MBDP occurrence is typically between 4 and
enterocolitis necessitating interruptions of enteral 8 weeks of postnatal age.7 Approximately 20% of
feeds. At 59 days of age, routine chest radiography very low–birth weight infants with gestational age
identified rib fractures at various stages of healing. younger than 32 weeks develop MBDP.8 Rachitic
There is no family history of bone diseases changes and fractures may or may not be observed.
or rickets. MBDP sometimes goes undetected until marked
demineralization is present with loss of 20% to
Laboratory test results while on total parenteral 40% of bone mineral content.
nutrition: The differential diagnosis of fractures in
Serum calcium = 9.9 mg/dL (9.0-11.0 mg/dL) neonates include osteogenesis imperfecta,
(SI: 2.5 mmol/L [2.3-2.8 mmol/L]) hypophosphatasia, X-linked hypophosphatemic
Serum phosphorus = 3.5 mg/dL (4.0-8.0 mg/dL) rickets, and zinc deficiency. This baby’s physical
(SI: 1.1 mmol/L [1.3-2.6 mmol/L]) exam and x-ray findings are inconsistent with the
Alkaline phosphatase = 1035 U/L (150-420 U/L)
(SI: 17.3 µkat/L [2.51-7.01 µkat/L]) features of osteogenesis imperfecta (Answer B).
25-Hydroxyvitamin D = 38 ng/mL (20-80 ng/mL) Vitamin D–dependent rickets due to CYP27B1
(SI: 94.8 nmol/L [49.9-199.7 nmol/L]) variants (Answer E) is unlikely because the infant
Intact PTH = 63 pg/mL (15-65 pg/mL) has normal calcium and PTH values.
(SI: 6.7 mmol/L [1.6-6.9 mmol/L]) Although some biochemical findings are similar
Tubular reabsorption of phosphate = 95% (78%-91%)
for MBDP and X-linked hypophosphatemic rickets
(Answer D), the lack of a family history and this
patient’s clinical course suggest that MBDP is
the most likely diagnosis. In addition, X-linked

ENDO 2025 • Bone and Mineral Metabolism 75

hypophosphatemic rickets, due to PHEX variants, mineral balance to enable extra-uterine maturation
is associated with low tubular reabsorption of while minimizing long-term sequelae. In summary,
phosphate, whereas MBDP is characterized by normal numerous nutritional and biomechanical factors
to elevated tubular reabsorption of phosphate. contribute to MBDP in low–birth weight and
The loss of the third trimester mineral bolus is extremely low–birth weight preterm babies.
exacerbated postnatally by impaired calcium and Currently, the optimal approach is prevention.
phosphorus supplementation/absorption, resulting Prevention involves diets containing appropriate
in a suboptimally mineralized new and remodeled calcium, phosphate, and vitamin D concentrations;
skeletal system. Human milk typically has a screening; and fracture prevention. Formulas
vitamin D concentration of 25 to 50 IU/L, which is specially designed for preterm infants or human
insufficient to maintain serum 25-hydroxyvitamin milk supplemented with fortifiers should be used
D levels greater than 20 ng/mL (>50 nmol/L) for enteral feeds. While no optimal calcium to
in premature infants. In addition to insufficient phosphorus ratio for intake has been validated, a
vitamin D concentration, preterm human 1.5 to 1.7:1 calcium to phosphorus ratio appears to
milk lacks sufficient calcium and phosphorous. be reasonable.11
Formulas designated for term infants, soy formulas, Screening for MBDP should begin at 4 to 6
and lactose-free formulas should be avoided weeks of age for infants with risk factors (Table,
because their inadequate mineral and vitamin D following page). Monitoring should be repeated
concentrations may contribute to MBDP. every 1 to 2 weeks.12 Major risk factors include
Vitamin D deficiency leads to hypocalcemia, birth weight less than 1500 g, gestational age
secondary hyperparathyroidism, and phosphaturia. younger than 28 weeks, parenteral nutrition for
Appropriate supplementation is essential. The longer than 4 weeks with insufficient enteral
recommended vitamin D dosage is 400 IU daily feeds, and use of medications with negative
(10 mcg daily) in healthy term and preterm effects on bone. Screening should include serum
infants.9 For very low–birth weight infants, 200 calcium, phosphorus, and alkaline phosphatase.
IU daily (5 mcg daily) can be used and increased Low serum phosphorus values (<4 mg/dL
to 400 IU (10 mcg) when the infant weighs more [<1.3 mmol/L] for more than 1 to 2 weeks) and/or
than 1500 g and is tolerating enteral nutrition. alkaline phosphatase values greater than 600 U/L
Nevertheless, MBDP is generally not responsive to (>193.8 µkat/L) warrant additional investigation
vitamin D or calcitriol treatment.10 for MBDP. Caveats regarding serum alkaline
The primary factor contributing to MBDP phosphatase include that it can be elevated in liver
is phosphorus deficiency. Additional factors disease or decreased by zinc deficiency and use
contributing to MBDP include chronic placental of glucocorticoids. Another potentially helpful
insufficiency, inadequate postnatal intestinal screening test for MBDP is a tubular reabsorption
calcium and phosphorus absorption, parenteral of phosphate value greater than 95% accompanied
nutrition, necrotizing enterocolitis, chronic by hypophosphatemia, which reflects complete
lung disease, fluid restriction, and reduced renal phosphate reabsorption in an effort to
physical activity. In necrotizing enterocolitis compensate for inadequate phosphate intake.12
with bowel resection or other postsurgical However, samples for tubular reabsorption of
short-gut complications, calcium absorption phosphate calculations are best obtained in the
can be compromised, resulting in hypocalcemia. fasting state, which might be difficult to collect
Medications, such as glucocorticoids, loop diuretics, from preterm infants who feed frequently
methylxanthines, anticoagulants, and CYP450 3A4 or require continuous parenteral nutrition.
inducers, may also contribute to the development PTH concentrations greater than 100 pg/mL
of MBDP. Care of very low–birth weight babies (>10.6 pmol/L) suggest MBDP. With additional
involves titrating caloric intake, fluid balance, and validation, low FGF-23 concentrations might prove

76 ENDO 2025 • Endocrine Case Management

to be another marker for MBDP.13 To prevent long-term outcomes for infants with MBDP and
fractures, bedside signage indicating the need for adult osteopenia/osteoporosis.
safe handling of high-risk infants can be displayed.
Physical therapy can be used and taught to parents. Case 2
Table. Risk Factors Associated With A 30-year-old woman who has been running since
Development of MBDP high school, and currently runs 42 miles per week,
experienced a tibial stress fracture. Her primary care
Risk Factor Mechanism
physician performed DXA, which showed a T-score
Prematurity (<28 weeks’ Deprivation of third trimester of –2.9 (Z-score, –2.9) at the L1-L4 spine. The left
gestation) in utero transfer of calcium
and phosphate femoral neck T-score was –2.5 (Z-score, –2.5) and
left total hip T- and Z-scores were both –2.3. She
Low birth weight Impaired placental mineral
transfer in utero was referred to endocrinology for further evaluation.
Parenteral nutrition for >4 Limited calcium and
She reports no relevant medical or surgical history,
weeks’ duration phosphate supplementation and medications include a calcium citrate plus
Necrotizing enterocolitis Disrupted enteral feeds, vitamin D supplement twice daily and a combined
poor gut function, decreased oral contraceptive pill. She underwent menarche at
calcium and phosphate
absorption age 15.5 years and was started on a COC at the age
of 17 years old for “irregular menses.” Review of
Failure to tolerate formulas or Decreased calcium and
human milk fortifiers with high phosphate absorption systems are negative for gastrointestinal symptoms;
mineral content she has no abdominal pain or constipation. She
Chronic lung disease Fluid restriction, need for loop follows a gluten-free and dairy-free diet and uses an
diuretics and glucocorticoids, app on her phone to count her caloric intake.
high energy needs
On physical examination, her blood pressure
Decreased physical activity Increased bone resorption,
reduced bone formation
is 90/60 mm Hg and pulse rate is 45 beats/min.
Her height is 65 in (165.1 cm), and weight is 100 lb
Glucocorticoid treatment Increased bone resorption,
reduced bone formation
(45.4 kg) (BMI = 16.6 kg/m2). She has lanugo hair
on her arms.
Loop diuretics (eg, furosemide) Hypercalciuria

CYP450 3A4 inducers (eg, Induce vitamin D metabolism Laboratory test results:
phenobarbital)
Calcium = 9.8 mg/dL (SI: 2.5 mmol/L)
Methylxanthines (eg, caffeine Increased bone resorption Albumin, normal
and theophylline)
25-Hydroxyvitamin D = 35 ng/mL (SI: 87.4 nmol/L)
Anticoagulants Reduced bone formation

Aluminum in parenteral Reduced bone formation Which of the following is the most
nutrition and other parental likely cause of this patient’s low BMD?
supplements
A. Vitamin D deficiency
Data regarding long-term outcome are B. Primary hyperparathyroidism
heterogeneous. Most reports indicate that preterm C. Low body weight resulting in low
children remain shorter than term peers and have IGF-1, hypercortisolemia, and functional
decreased areal BMD.14 Among young adults born hypothalamic amenorrhea
preterm, even after accounting for height and D. All of the above
weight, areal BMD at the femoral neck is significantly
decreased, suggesting a role for additional influences, Answer: C) Low body weight resulting
such as physical activity.15 Currently adequate in low IGF-1, hypercortisolemia, and
evidence-based data are unavailable regarding functional hypothalamic amenorrhea

ENDO 2025 • Bone and Mineral Metabolism 77

In low-weight eating disorders, low BMD is vitamin D deficiency (Answer A) should be
very common, particularly in women with screened for and treated in patients who have
anorexia nervosa. Greater than 85% of women low BMD, vitamin D deficiency is an unlikely
with anorexia nervosa have a BMD greater cause of low BMD in someone on a twice daily
than one standard deviation below the mean of supplement. In a patient who is on vitamin D
women at their peak BMD.16 Although BMD is supplementation with a normal calcium level,
lower in both adolescents and adult women with primary hyperparathyroidism (Answer B) is also
anorexia nervosa compared with similarly aged unlikely to be the explanation for low BMD.
normal-weight individuals, this low BMD is Multiple hormonal adaptations that occur in
not associated with fracture history, despite the states of undernutrition with resultant low body
fact that girls and women with anorexia nervosa weight likely contribute to low BMD. Functional
have a high prevalence of fractures. Therefore, hypothalamic amenorrhea shunts energy away
although BMD should be followed to evaluate the from the hypothalamic-pituitary-ovarian axis.
trajectory of BMD loss, it may not be a predictor Functional hypothalamic amenorrhea results in a
of fracture in this population. Importantly, low low-estrogen state that is associated with increased
BMI, regardless of the cause (anorexia nervosa or bone resorption. Longer duration of amenorrhea
ARFID), is associated with low BMD.17 Although is associated with lower BMD in anorexia nervosa.
data on ARFID-associated low BMD are limited, Long-term consequences may develop when the
it is possible that the same factors that affect eating disorder begins before attainment of peak
BMD in anorexia nervosa may also result in low bone mass.20 However, importantly, estradiol-
BMD in ARFID. Among the potential causes for containing COCs do not increase BMD relative to
low BMD, vitamin D deficiency can be excluded placebo in the setting of anorexia nervosa.21 Lower,
because she has a normal vitamin D concentration. more physiologic doses of estradiol, predominantly
Hyperparathyroidism is unlikely since her serum in transdermal form, are beneficial for low BMD
calcium concentration is normal. Thus, her low in adolescents.22 Transdermal estradiol is also
BMD is most likely attributed to anorexia nervosa currently being studied in a randomized controlled
accompanied by low IGF-1, hypercortisolemia, and study in adults after pilot data suggested benefit.
functional hypothalamic amenorrhea (Answer C). The lack of efficacy of COCs in improving BMD
Although the patient does not present with is due to suppression of hepatic IGF-1 secretion by
a diagnosis of anorexia nervosa, the clinician oral estrogen. Transdermal estradiol may improve
should be highly suspicious of this diagnosis BMD because the transdermal route has minimal
based on her BMI of less than 18.5 kg/m2 and her effects on IGF-1 concentrations.23,24 In addition, GH
restrictive dietary history, including counting her resistance leads to decreased IGF-1 concentrations in
daily caloric intake. This patient has osteoporosis underweight states.25 In anorexia nervosa, low IGF-1
based on both the International Society for concentrations are associated with low BMD and,
Clinical Densitometry definition, which defines therefore, may be a cause of low BMD in low-weight
premenopausal low BMD as a Z-score of –2 or states.26 Recombinant human (rh) IGF-1 has been
less coupled with a secondary cause of low BMD studied as a treatment for low BMD in anorexia
(the patient is low weight and likely has anorexia nervosa. Nine months of rhIGF-1 combined with
nervosa), or the International Osteoporosis oral estrogen increases BMD in adults.27 In contrast,
Foundation definition, which is based on a T-score in adolescents, 12 months of the combination
of less than –2.5, in addition to a secondary cause of transdermal estradiol and rhIGF-1 does not
of osteoporosis.18,19 Many patients with anorexia increase BMD when compared with the effects of
nervosa present without a known diagnosis of transdermal estradiol alone.28
anorexia nervosa and, therefore, it is important Cortisol levels are increased in the setting
to remain vigilant about the possibility. Although of physiologic stress, such as the chronic

78 ENDO 2025 • Endocrine Case Management

undernutrition characteristic of anorexia C. Stop COCs and reassess after 3 months
nervosa.29 High cortisol levels have been D. Encourage weight gain
associated with low BMD in anorexia nervosa
and therefore may also contribute to low BMD Answer: C) Stop COCs and reassess after 3 months
in this setting.30 Importantly, because cortisol
This patient was diagnosed with idiopathic
is a counterregulatory hormone and is critical
hypogonadotropic hypogonadism in the setting
for maintaining euglycemia during states of
of significant weight loss and low body weight
starvation, we would not consider treating
due to ARFID. Although it is possible that she
hypercortisolemia in anorexia nervosa.
has idiopathic hypogonadotropic hypogonadism,
it is also possible that the low gonadotropins
Case 3 and low estradiol levels typical of idiopathic
A 26-year-old woman presents to an adult hypogonadotropic hypogonadism were due to
endocrine clinic with a history of idiopathic hypogonadotropic hypogonadism in the setting
hypogonadotropic hypogonadism. She reports of low body weight. Now that the patient has a
being diagnosed with primary amenorrhea at age 16 normal body weight, the COCs can be discontinued
years at which time ARFID was also diagnosed. Her to see if she is able to cycle without exogenous
medical records from that time document a normal hormones and clarify the diagnosis (Answer C).
sense of smell and a reported weight loss of 60 lb If menstrual cycles do not resume in the absence
(27.2 kg). Her lowest weight was noted to be 105 lb of exogenous hormones, we would perform an
(47.6 kg), with a height of 67 in (170.2 cm) (BMI amenorrhea evaluation that would include assessing
= 16.4 kg/m2). The patient reported not eating at thyroid function and measuring FSH, LH, estradiol,
that time due to lack of hunger or interest in food. prolactin, and hCG. It is important to counsel the
She had a full endocrine evaluation for primary patient that she could become pregnant once she
amenorrhea, which included karyotype analysis stops COCs. Additional weight gain does not need
(46,XX) and pelvic ultrasonography. Findings on to be encouraged because she now has a normal
pelvic ultrasonography were normal apart from BMI and her weight has been stable.
a small uterus. There was no family history of Individuals with ARFID are often significantly
infertility or anosmia. She was started on low-dose underweight. Substantial nutritional deficiencies
oral estradiol followed by cyclic progesterone. At may exist. Although ARFID was considered an
age 19 years, her regimen was transitioned to a eating disorder affecting primarily infants and
COC pill. Her lack of interest in eating diminished children, individuals across the age spectrum
and she gained enough weight to achieve a normal can be affected. Some individuals are dependent
BMI. She recently saw an adult endocrinologist who on oral supplements or tube feeding. Psychiatric
told her that she has idiopathic hypogonadotropic comorbidities, such as anxiety, obsessive-
hypogonadism, would need to remain on COCs compulsive, and trauma-related disorders, are
until menopause, and would likely need medical common among individuals with ARFID.
assistance to achieve pregnancy. She presents for
a second opinion regarding this diagnosis. Her Key Learning Points
current BMI is 21 kg/m2, and she reports stable
weight for the last 5 years. • Underweight states, regardless of the etiology,
are a common cause of low BMD throughout
Which of the following is the best next step? the lifespan.
A. Continue COCs • Treating providers must be aware of the
B. Transition to a hormone replacement therapy multiple effects of undernutrition on bone
dose of transdermal estradiol + progesterone metabolism.

ENDO 2025 • Bone and Mineral Metabolism 79

• In adolescents and adults, psychiatric causes of • Although hypoestrogenemia is a cause of low
low body weight are a common cause of low BMD in anorexia nervosa, combined COCs
BMD, but they are often underdiagnosed. are not effective in increasing BMD in this
population.

References
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2. Fazeli PK, Klibanski A. Effects of anorexia nervosa on bone metabolism. Disorder. Bone. 2020;134:115307. PMID: 32142910
Endocr Rev. 2018;39(6):895-910. PMID: 30165608 18. Shuhart CR, Yeap SS, Anderson PA, Jankowski LG, Lewiecki EM, Morse
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PMID: 31786156 DXA cross-calibration and least significant change, spinal cord injury, peri-
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PMID: 28002660 19. Ferrari S, Bianchi ML, Eisman JA, et al; IOF Committee of Scientific Advisors
5. Bulik CM, Reba L, Siega-Riz AM, Reichborn-Kjennerud T. Anorexia Working Group on Osteoporosis Pathophysiology. Osteoporosis in young
nervosa: definition, epidemiology, and cycle of risk. Int J Eat Disord. adults: pathophysiology, diagnosis, and management. Osteoporos Int.
2005;37(Suppl S2-S9). PMID: 15852310 2012;23(12):2735-2748. PMID: 22684497
6. Galmiche M, Déchelotte P, Lambert G, Tavolacci MP. Prevalence of eating 20. Biller BM, Saxe V, Herzog DB, Rosenthal DI, Holzman S, Klibanski A.
disorders over the 2000-2018 period: a systematic literature review. Am J Clin Mechanisms of osteoporosis in adult and adolescent women with anorexia
Nutr. 2019;109(5):1402-1413. PMID: 31051507 nervosa. J Clin Endocrinol Metab. 1989;68(3):548-54. PMID: 2493036
7. Faienza MF, D’Amato E, Natale MP, et al. Metabolic bone disease of 21. Thavaraputta S, Fazeli PK. Estrogen for the treatment of low bone mineral
prematurity: diagnosis and management. Front Pediatr. 2019;7:143. PMID: density in anorexia nervosa. J Psychiatr Brain Sci. 2022;7(3):e220004. PMID:
31032241 35874115
8. Perrone M, Casirati A, Stagi S, et al. Don’t forget the bones: incidence and 22. Misra M, Katzman D, Miller KK, et al. Physiologic estrogen replacement
risk factors of metabolic bone disease in a cohort of preterm infants. Int J Mol increases bone density in adolescent girls with anorexia nervosa. J Bone Miner
Sci. 2022;23(18):10666. PMID: 36142579 Res. 2011;26(10):2430-2438. PMID: 21698665
9. Abrams SA; Committee on Nutrition. Calcium and vitamin d requirements 23. Weissberger AJ, Ho KK, Lazarus L. Contrasting effects of oral and
of enterally fed preterm infants. Pediatrics. 2013;131(5):e1676-e1683. PMID: transdermal routes of estrogen replacement therapy on 24-hour growth
23629620. hormone (GH) secretion, insulin-like growth factor I, and GH-binding
10. Venkataraman PS, Tsang RC, Steichen JJ, Grey I, Neylan M, Fleischman AR. protein in postmenopausal women. J Clin Endocrinol Metab. 1991;72(2):374-
Early neonatal hypocalcemia in extremely preterm infants. High incidence, 381. PMID: 1991807
early onset, and refractoriness to supraphysiologic doses of calcitriol. Am J Dis 24. Kam GY, Leung KC, Baxter RC, Ho KK. Estrogens exert route- and dose-
Child. 1986;140(10):1004-1008. PMID: 3755862 dependent effects on insulin-like growth factor (IGF)-binding protein-3 and
11. Rowe JC, Goetz CA, Carey DE, Horak E. Achievement of in utero retention the acid-labile subunit of the IGF ternary complex. J Clin Endocrinol Metab.
of calcium and phosphorus accompanied by high calcium excretion in very 2000;85(5):1918-22. PMID: 10843175
low birth weight infants fed a fortified formula. J Pediatr. 1987;110(4):581- 25. Fazeli PK, Klibanski A. Determinants of GH resistance in malnutrition. J
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12. Grover M, Ashraf AP, Bowden SA, et al. Invited mini review metabolic bone 26. Grinspoon S, Miller K, Coyle C, et al. Severity of osteopenia in estrogen-
disease of prematurity: overview and practice recommendations. Horm Res deficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin
Paediatr. 2025;98(1):40-50. PMID: 38211570 Endocrinol Metab. 1999;84(6):2049-2055. PMID: 10372709
13. Llorente-Pelayo S, Docio P, Arriola S, et al. Role of fibroblast growth 27. Grinspoon S, Thomas L, Miller K, Herzog D, Klibanski A. Effects of
factor-23 as an early marker of metabolic bone disease of prematurity. BMC recombinant human IGF-I and oral contraceptive administration on bone
Pediatr. 2024;24(1):418. PMID: 38951759 density in anorexia nervosa. J Clin Endocrinol Metab. 2002;87(6):2883-2891.
14. Xie LF, Alos N, Cloutier A, Béland C, Dubois J, Nuyt AM, Luu TM. The PMID: 12050268
long-term impact of very preterm birth on adult bone mineral density. Bone 28. Singhal V, Bose A, Slattery M, et al. Effect of transdermal estradiol and
Rep. 2018;10:100189. PMID: 30627597 insulin-like growth factor-1 on bone endpoints of young women with
15. Balasuriya CND, Evensen KAI, Mosti MP, et al. Peak bone mass and bone anorexia nervosa. J Clin Endocrinol Metab. 2021;106(7):2021-2035. PMID:
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28453635 adrenal hormones: a systematic review and meta-analysis. Eur J Endocrinol.
16. Miller KK, Grinspoon SK, Ciampa J, Hier J, Herzog D, Klibanski A. Medical 2023;189(3):S64-S73. PMID: 37669399
findings in outpatients with anorexia nervosa. Arch Intern Med. 2005;165(5):561- 30. Lawson EA, Donoho D, Miller KK, et al. Hypercortisolemia is associated
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19837921

80 ENDO 2025 • Endocrine Case Management

Complex Cases in
Hypophosphatemia: Navigating
Diagnostic and Treatment
Challenges of Low Phosphate
Eva S. Liu, MD. Division of Endocrinology, Diabetes, and Hypertension, Brigham and
Women’s Hospital/Harvard Medical School, Boston, MA; Email: [email protected]

Educational Objectives of phosphate homeostasis may result. Causes of

hypophosphatemia include inherited and acquired
After reviewing this chapter, learners should be
disorders and disorders of altered phosphate load
able to:
and absorption. Symptoms of hypophosphatemia
• Illustrate the endocrine regulation of can be nonspecific, including myalgias, joint
phosphate homeostasis. pain, and fatigue. Moreover, treatments of
hypophosphatemia often lead to significant
• Identify and diagnose causes of
adverse effects, such as gastrointestinal distress
hypophosphatemia in the clinic.
or secondary/tertiary hyperparathyroidism.
• Manage disorders of hypophosphatemia. Therefore, it is important for health care providers
to consider hypophosphatemic disorders in their
patient workup and to be aware of the potential
effects of medications used to treat these disorders.
Significance of the
Clinical Problem Practice Gaps
Extracellular phosphate is a critical regulator
of skeletal homeostasis, with 85% of phosphate • There is a lack of awareness among health
localized to the skeleton/teeth and 15% in the care providers of the different causes of
soft tissue and extracellular fluid.1 Phosphate hypophosphatemia.
plays an essential role in regulating growth plate • There is a lack of awareness among health care
maturation, with low serum phosphate leading to providers regarding the treatment options and
rickets in children.2 Phosphate is also important potential effects of medications used to treat
for skeletal mineralization and structure, where disorders of hypophosphatemia.
in combination with calcium it forms the
hydroxyapatite necessary for mineralization
of skeletal tissues. Insufficient phosphate
Discussion
therefore results in osteomalacia. Dietary
intake and hormones, including PTH, FGF- Diet, Intestine, and Kidney
23, and 1,25-dihydroxyvitamin D3, all regulate Sixty to sixty-five percent of dietary phosphate
phosphate homeostasis. When one or multiple is absorbed in the small intestine.3 Circulating
regulators of phosphate is abnormal, disorders phosphate is filtered through the kidney, with 70%

ENDO 2025 • Bone and Mineral Metabolism 81

of the filtered load being reabsorbed in the renal promoting the expression of NPT2b and enhances
proximal tubules.4 Sodium phosphate transporter phosphate reabsorption in the proximal renal
2b (NPT2b) is expressed in the intestine, while tubules. Dietary phosphate is also an important
NPT2a/NPT2c are expressed in the proximal renal regulator of 1,25-dihydroxyvitamin D3, with
tubules to enable phosphate uptake in the intestine rodent and human studies demonstrating
and kidney, respectively.5,6 Renal reabsorption of that phosphate deprivation leads to increased
phosphate increases until reaching a threshold production of 1,25-dihydroxyvitamin D3.
termed the maximum tubular reabsorption rate FGF-23 is predominantly synthesized by
for phosphate (TmP), which is normalized to osteocytes and acts to decrease serum phosphate
glomerular filtration rate (GFR). TmP/GFR is a levels by (1) decreasing NPT2a/NPT2c expression
measure of renal tubular reabsorption. in the kidney, leading to increased renal phosphate
wasting and (2) inhibiting the expression of
renal 1α-hydroxylase (CYP27B1) and increasing
PTH, 1,25-Dihydroxyvitamin D3,
CYP24a1 expression, which together decreases
and FGF-23 1,25-dihydroxyvitamin D3 levels. DMP1, PHEX,
PTH promotes renal phosphate excretion ENPP1, and FAM20C all regulate FGF-23 levels.
by decreasing protein expression of sodium Inactivating pathogenic variants in these genes
phosphate transporters NPT2a/c in the proximal result in enhanced serum FGF-23 levels and thus
renal tubules. In contrast, the active form of hypophosphatemia (Figure).7
vitamin D, 1,25-dihydroxyvitamin D3, enhances
phosphate resorption in the small intestine by

Figure. Regulation of Phosphate Homeostasis

Dietary phosphate is absorbed in the gut by sodium phosphate transporter (NPT) 2b (NPT2b) and filtered by the kidneys. In the small intestine, phosphate
transport is predominantly regulated by NPT2b. 1,25-dihydroxyvitamin D (1,25[OH]2D) increases Pit-2 expression in the small intestine, which also leads
to phosphate absorption. PTH binds to the PTHR1 to reduce NPT2a and NPT2c protein levels, resulting increased renal loss of phosphate. FGF-23 is
predominantly expressed in bone and binds to the FGFR with α-Klotho (KL) as coreceptor in the kidneys. Urinary phosphate excretion increases with
decreased renal proximal tubule expression of NPT2a and NPT2c. FGF-23 also stimulates 24-hydroxlase expression, and it reduces 1α-hydroxylase. The
combined net effects of the actions of FGF-23 in the proximal renal tubules are decreased serum levels of phosphate and 1,25-(OH)2D. FGF-23 expression
is reduced by PHEX, DMP1, ENPP1, and FAM20C. Consequently, lack of these negative regulators leads to increased secretion of biologically active FGF-23,
resulting in hypophosphatemia. GALNT3 glycosylates and thus stabilizes FGF-23; lack of this enzyme enhances FGF-23 degradation, thereby reducing
urinary phosphate excretion.
Reprinted from Liu ES and Juppner H “Chapter 20: Disorders of Phosphate Homeostasis” in Radovich S and Misra M, Eds. Pediatric Endocrinology, 4th
Edition: Springer 2024; 499-526.
[Color—Print (Color Gallery page CG9) or web & ePub editions]

82 ENDO 2025 • Endocrine Case Management

Disorders of Hypophosphatemia rickets. Adults with XLH have osteomalacia
and develop osteoarthritis and enthesopathy.
Many disorders of phosphate homeostasis lead to
All patients with XLH have impaired skeletal
hypophosphatemia; the most common FGF-23–
mineralization and are thus at risk for
mediated and non–FGF-23–mediated disorders
pseudofractures/fractures and dental caries/
encountered in the clinic are discussed herein.
abscesses. Conventional treatment includes
FGF-23–Mediated Disorders phosphate supplementation with calcitriol
(Table). Due to the risk of secondary/tertiary
X-Linked Hypophosphatemia hyperparathyroidism and nephrocalcinosis with
X-linked hypophosphatemia (XLH) is phosphate supplements, the goal of conventional
characterized by X-linked dominant pathogenic therapy is not to normalize serum phosphate
variants in the PHEX gene, and it is the most levels.8 Burosumab (Table), the humanized anti-
common form of inheritable rickets. PHEX FGF23 antibody, is FDA approved for treatment
pathogenic variants lead to high circulating of children and adults with XLH. Burosumab
levels of FGF-23, which in turn result in maintains serum phosphate levels in the low-
hypophosphatemia and impaired production of normal range without increasing urinary calcium
1,25-dihydroxyvitamin D3. Affected individuals and also improves quality of life, healing of
present in childhood with impaired growth and pseudofractures, and bone mineralization.9,10

Table. Therapies for Disorders of Hypophosphatemia

Therapy Administration Effects

Burosumab Children Decrease in vitamin D levels

X-linked hypophosphatemia: 6 months-18 years old
Rash
<10 kg: 1 mg/kg every 2 weeks
≥10 kg: 0.8 mg/kg every 2 weeks Local site reaction
Tumor-induced osteomalacia: 2-18 years old Restless leg syndrome (in adults)
0.4 mg/kg every 2 weeks, up to 180 mg/dose
Headache, cough, fever (in children)
Adults
X-linked hypophosphatemia: 1 mg/kg subcutaneously, up to
90 mg every 4 weeks
Tumor-induced osteomalacia: 0.5 mg/kg subcutaneously every
4 weeks, up to 2 mg/kg subcutaneously every 2 weeks (not to
exceed 180 mg)

Oral phosphate Infants Gastrointestinal symptoms (diarrhea,

(sodium phosphate or Starting 40 mg elemental phosphorus/kg per day in divided nausea, stomach pain)
potassium phosphate) doses
Muscle cramps/pain
Children
Hypocalcemia
>4 years old, adults: starting 250 mg daily (up to 250-500 mg 4
times daily) Secondary hyperparathyroidism

Active vitamin D Calcitriol Symptoms due to hypercalcemia (thirst,

nausea, bone pain) or hyperphosphatemia
Children
(muscle cramps, joint pain)
Starting 10-20 ng/kg per dose
Adults
Starting 0.25 mcg per dose
Alfacalcidol (not available in United States)
Starting 0.25 mcg per dose

Vitamin D Vitamin D3 (cholecalciferol): 400 IU, up to 50,000 IU per dose Can cause hypercalcemia at high dosages
Vitamin D (ergocalciferol): 400 IU, up to 50,000 IU per dose

ENDO 2025 • Bone and Mineral Metabolism 83

Tumor-Induced Osteomalacia Dietary Phosphate Deficiency
Tumors can produce FGF-23, leading to tumor- Hypophosphatemia due to very low dietary intake
induced osteomalacia (TIO). Such tumors are is rare, but it has been seen in children with
predominantly mesenchymal in origin and are kwashiorkor. Chronic ingestion of phosphate
often slow growing and located in obscure areas, binders, including calcium acetate or sevelamer,
making them difficult to localize on imaging. or aluminum- or magnesium-containing antacids
Imaging with 68Ga-DOTATATE PET/CT has the can present with low serum phosphate levels.
highest sensitivity/specificity for localizing these Disorders that compromise the ability of the
tumors.11 Surgical resection is curative, but if the gastrointestinal tract to absorb phosphate, such as
tumor cannot be found or completely resected, bariatric surgery, celiac disease, severe diarrhea,
therapy with calcitriol/phosphate supplementation and small-bowel resection, also may lead to
or burosumab is initiated to improve mineral hypophosphatemia. In these disorders, vitamin D
ion and hormone levels, prevent skeletal deficiency and/or malabsorption of calcium leads
complications, and improve quality of life.12 to increased PTH levels, which in turn increases
urinary phosphate wasting.7 Treatment includes
Fibrous Dysplasia replacement of calcium and phosphate by diet
In fibrous dysplasia (FD), normal bone is replaced or supplement.
by fibrous bone, leading to skeletal deformity,
pain, and fracture. FD can manifest on its own
or as part of McCune-Albright syndrome,
Clinical Case Vignettes
characterized by postzygotic pathogenic Case 1
variants in GNAS.13 Patients with FD can have A 50-year-old man has a history of XLH
high serum FGF-23 levels, with the degree of complicated by enthesopathy and osteoarthritis. For
resultant hypophosphatemia correlating with the past 10 years, he has been taking oral phosphate
disease severity. Low phosphate is treated with supplements up to a dosage of 750 mg 4 times daily
phosphate/calcitriol, or potentially burosumab. and calcitriol up to 0.5 mcg twice daily, leading to
Treatments that can be considered include the development of tertiary hyperparathyroidism
bisphosphonates (may improve bone pain) and for which he underwent parathyroidectomy. After
denosumab (decrease activity of bone lesions). surgery, he was treated with lower dosages of
oral phosphate and optimized dosages of calcitriol
Non–FGF-23–Mediated Disorders
to maintain normocalcemia and normal serum
PTH levels. Due to the significant and worsening
Fanconi Syndrome
knee pain, he consulted with an orthopedist and
Impaired proximal renal tubule function leads
has decided to purse bilateral osteotomies and
to proximal renal tubular acidosis and renal
knee replacements. He subsequently stopped
wasting of amino acids, bicarbonate, potassium,
conventional therapy and started burosumab and
glucose, and phosphate. Since the urinary
continues on cholecalciferol, 2000 international
phosphate loss can result in rickets/osteomalacia,
units daily (50 mcg daily). He has undergone 1
phosphate supplementation with calcitriol
osteotomy and the contralateral osteotomy is
supplementation is used to treat the complications
scheduled in a few months.
of hypophosphatemia. Fanconi syndrome can
result from acquired secondary conditions, such Follow-up laboratory test results:
as multiple myeloma or amyloidosis, or exposure
Serum phosphate = 2.5 mg/dL (2.4-4.3 mg/dL)
to toxic metals or medications, such as tenofovir
(SI: 0.8 mmol/L [0.8- 1.4 mmol/L])
or cisplatin.7 Serum calcium = 10.3 mg/dL (8.8-10.7 mg/dL)
(SI: 2.6 mmol/L [2.2-2.7 mmol/L])

84 ENDO 2025 • Endocrine Case Management

 PTH = 71 pg/mL (SI: 7.53 pmol/L) that acts as an allosteric activator of the calcium-
25-Hydroxyvitamin D = 39 ng/dL (97.3 nmol/L) sensing receptor, when administered with
burosumab has been reported to help suppress
Which of the following is the serum PTH levels and decrease serum calcium
most appropriate next step in levels in patients with XLH who have tertiary
this patient’s management? hyperparathyroidism.16
A. Stop burosumab and restart oral phosphate His PTH and calcium levels are mildly
supplements elevated; therefore, a repeat parathyroidectomy
B. Refer for repeat parathyroidectomy (Answer B) is not yet indicated.
C. Continue burosumab and start cinacalcet
D. Change cholecalciferol to ergocalciferol, Case 2
50,000 international units weekly (1250 mcg A 60-year-old woman has a history of osteopenia
weekly) and T-cell large granular lymphocytic leukemia.
E. Increase the dosage of burosumab Her clinical course has been complicated by
development of stage 3 kidney insufficiency and
Answer: C) Continue burosumab and start cinacalcet
Fanconi syndrome, thought to be secondary
Burosumab is the humanized FGF-23–blocking to interstitial infiltration of the renal proximal
antibody that is FDA approved for the treatment tubules by lymphoid. She was treated with oral
of children and adults with XLH. Unlike cyclophosphamide, but this did not improve her
conventional therapy, burosumab is able to urinary wasting of potassium, glucose, phosphate,
sustain serum phosphate levels in the low-normal and bicarbonate. For the hypophosphatemia, she
range without altering serum or urinary calcium is started on potassium phosphate, 250 mg tablets
levels. Burosumab therapy improves skeletal (3 tablets in the morning, 2 tablets at lunch, and 3
mineralization, fracture healing, and ambulatory tablets at dinner).
function in treated patients with XLH.9,14
Subsequent laboratory test results:
Therefore, since this patient is going for additional
orthopedic procedures, burosumab should Serum phosphate, normal
not be stopped. Also, he has remnant tertiary Serum PTH = 62 pg/mL (15-65 pg/mL)
(SI: 6.6 pmol/L [1.6-6.9 pmol/L])
hyperparathyroidism, so restarting oral phosphate
supplements (Answer A), which can worsen Her serum PTH concentration increases to
hyperparathyroidism, would not be appropriate. 110 pg/mL (11.7 pmol/L) over the next year.
His 25-hydroxyvitamin D level is normal;
therefore, changing cholecalciferol to Which of the following would be most
ergocalciferol (Answer D) is not indicated. appropriate next step in managing
The goal of burosumab is to maintain this patient’s hypophosphatemia?
phosphate in the low-normal range, in part to A. Stop her phosphate supplements
prevent nephrocalcinosis. Burosumab is associated
B. Decrease phosphate supplements and add
with increased PTH levels in treated patients with
calcitriol
XLH with higher phosphate levels on prolonged
therapy.15 Therefore, increasing the burosumab C. Refer for parathyroidectomy
dosage (Answer E) is not necessary. D. Stop her phosphate supplements and start
This patient has remnant tertiary burosumab
hyperparathyroidism. Discontinuing calcitriol E. No change in treatment, recommend yearly
and starting burosumab increased his serum PTH kidney ultrasonography
levels. Cinacalcet (Answer C), a calcimimetic

ENDO 2025 • Bone and Mineral Metabolism 85

Answer: B) Decrease phosphate (1.1 mmol/L) (reference range, 2.4-4.3 mg/dL
supplements and add calcitriol [0.8-1.4 mmol/L]) over a few years. She does not
consume dairy in her diet or take calcium/vitamin
Fanconi syndrome is a defect in the proximal renal D supplements. On further workup, her kidney
tubules, leading to urinary wasting electrolytes, function is normal.
bicarbonate, glucose and phosphate. Treatment
for this resultant hypophosphatemia includes Laboratory test results:
a combination of oral phosphate supplements
Serum calcium = 8.7 mg/dL (8.8-10.7 mg/dL)
and calcitriol, with the goal of serum phosphate (SI: 2.2 mmol/L [SI: 2.2-2.7 mmol/L])
being in the low-normal range. It is not Serum PTH = 73 pg/mL (15-65 pg/mL)
recommended that phosphate supplements (SI: 7.7 pmol/L [1.6-6.9 pmol/L])
be used increase serum phosphate levels to 25-Hydroxyvitamin D = 20 ng/dL (SI: 50 nmol/L)
FGF-23 = 23 pg/mL (SI: >59 pg/mL)
normal levels due to the risk of development
Serum phosphate = 3.1 mg/dL (2.4-4.3 mg/dL)
of secondary hyperparathyroidism, which can (SI: 1.0 mmol/L [0.8-1.4 mmol/L])
eventually lead to tertiary hyperparathyroidism Calcium-to-creatinine ratio = 0.004
and nephrocalcinosis. In circulation, the TmP/GFR = 2.8 mg/dL (2.6-3.8 mg/dL)
reabsorbed phosphate binds to calcium, leading (SI: 0.9 mmol/L [0.8-1.2 mmol/L])
to a decrease in serum calcium and subsequent
secondary hyperparathyroidism.17 Therefore, it is Which of the following is the most likely
recommended that daily phosphate supplements etiology of this patient’s hypophosphatemia?
be administered along with calcitriol (Answer B), A. Inadequate calcium and phosphate intake
which can increase renal and intestinal absorption B. XLH
of phosphate and also suppress serum PTH levels. C. Primary hyperparathyroidism
Stopping the phosphate supplements
D. Vitamin D deficiency
(Answer A) would cause the patient to have
persistent hypophosphatemia and is therefore not E. Fanconi syndrome
recommended. Answer: A) Inadequate calcium and phosphate intake
She has secondary hyperparathyroidism from
taking phosphate supplements alone; therefore, Patients with XLH (Answer B) can have
parathyroidectomy (Answer C) is not indicated. inappropriately normal serum FGF-23 levels in
Burosumab therapy (Answer D) is indicated the setting of hypophosphatemia. However, at
for FGF-23–mediated hypophosphatemia, the time of laboratory blood draw, this patient
such as XLH and TIO, and therefore it is not had normal serum FGF-23 and phosphate levels,
recommended as treatment for this patient. making XLH an unlikely diagnosis.
Since the serum PTH levels have begun to This patient’s laboratory workup shows a
rise, it would not be advised to leave her on the low-normal serum calcium level accompanied by a
high dosages of oral phosphate supplement alone low renal calcium-to-creatinine ratio. In primary
(Answer E). While she is on oral phosphate and hyperparathyroidism, elevated PTH levels are
calcitriol, she should have intermittent kidney accompanied by normal or elevated serum calcium
ultrasonography to monitor for nephrocalcinosis. levels and normal or increased urine calcium-to-
creatinine ratio, thus ruling out the diagnosis of
primary hyperparathyroidism (Answer C).
Case 3
Impaired vitamin D action can lead to
A 47-year-old woman with osteopenia and decreased renal resorption and intestinal
history of vitamin D deficiency presents with reabsorption of calcium and phosphate, resulting
intermittent low serum phosphate levels that in low serum calcium and phosphate levels and
range from 1.6 mg/dL (0.5 mmol/L) to 3.4 mg/dL secondary hyperparathyroidism. However, this

86 ENDO 2025 • Endocrine Case Management

patient’s serum vitamin D levels are normal per PTH and calcium levels. It is often used as adjuvant
the Institute of Medicine guidelines. Therefore, therapy for patients with hypercalcemia mediated
she currently does not meet the criterion for by high serum PTH levels. Since this patient has
vitamin D deficiency (Answer D). low serum calcium levels, cinacalcet would not be
Fanconi syndrome (Answer E) is characterized the appropriate therapy.
by renal phosphate wasting. This patient has a The 2024 Endocrine Society guidelines
normal TmP/GFR, making Fanconi syndrome an recommend that a generally heathy adult should
unlikely diagnosis. adhere to the recommended daily allowance of
This patient has a history of vitamin D vitamin D established by the Institute of Medicine.
deficiency, low-normal serum calcium, and a low According to these guidelines, the recommended
renal calcium-to-creatinine ratio, supporting daily allowance of vitamin D3 is 600 international
a history of low dietary intake of calcium and units (15 mcg) for adults 70 years and younger and
phosphate. The serum PTH levels are likely 800 international units (20 mcg) for adults older
elevated secondary to the decrease in serum than 71 years.18 Therefore, this patient should be
calcium, where this elevation in PTH results in encouraged to initiate vitamin D supplements to
increased loss of urinary phosphate, which in meet the daily intake recommendation (Answer
combination with inadequate dietary dairy intake E), but since she is not vitamin D deficient (per
leads to low serum phosphate. The intermittent serum 25-hydroxyvitamin D levels), she does not
nature of the hypophosphatemia may be due need to be treated for vitamin D deficiency with
to inconsistent dietary intake of calcium- and ergocalciferol (Answer C).
phosphate-rich foods (Answer A). The intermittent low serum phosphate
levels may be secondary to low dairy intake
and mild hyperparathyroidism in the setting
Case 3, Continued
of low calcium intake. Therefore, while oral
Which of the following initial treatments phosphate supplements (Answer D) would
for hypophosphatemia would be improve serum phosphate levels, they would not
appropriate to offer this patient? address the primary issue of low dietary intake
A. Start burosumab of calcium and phosphate. Also, oral phosphate
B. Start cinacalet supplements result in comorbidities, including
C. Start ergocalciferol, 50,000 international units worsening secondary hyperparathyroidism and
weekly (1250 mcg weekly) nephrocalcinosis.
It is likely that this patient has inadequate
D. Start oral phosphate supplements
dietary intake of calcium and phosphate. Since
E. Encourage dairy intake and start calcium and the Institute of Medicine recommends a daily
cholecalciferol supplements dietary intake of 1000 mg calcium from diet or
Answer: E) Encourage dairy intake and start supplements for women younger than 50 years,
calcium and cholecalciferol supplements this patient should be encouraged to take a balance
of dairy and calcium supplements to meet the daily
Burosumab (Answer A) is a humanized FGF- recommended calcium intake (Answer E).
23–blocking antibody that is FDA approved for
the treatment of XLH and TIO. Since it unlikely
that this patient has either diagnosis, there is no
indication to start this therapy.
Cinacalcet (Answer B) is a calcimimetic that
acts as an allosteric activator of the calcium-
sensing receptor, leading to a decrease in serum

ENDO 2025 • Bone and Mineral Metabolism 87

Key Learning Points • Oral phosphate supplements should be
accompanied by calcitriol to prevent secondary
• PTH, FGF-23, and 1,25-dihydroxyvitamin hyperparathyroidism.
D3 are key hormones that regulate phosphate • In patients with continued high PTH levels,
homeostasis. burosumab may need to be accompanied
• Multiple causes for hypophosphatemia exist, by additional agents, such as cinacalcet, to
which can be divided into FGF-23 and non– decrease serum PTH and/or calcium levels.
FGF-23–mediated disorders.

References
1. Imel EA, Econs MJ. Approach to the hypophosphatemic patient. J Clin 11. El-Maouche D, Sadowski SM, Papadakis GZ, et al. 68Ga-DOTATATE for
Endocrinol Metab. 2012;97(3):696-706. PMID: 22392950 tumor localization in tumor-induced osteomalacia. J Clin Endocrinol Metab.
2. Sabbagh Y, Carpenter TO, Demay MB. Hypophosphatemia leads to rickets by 2016;101(10):3575-3581. PMID: 27533306
impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc Natl 12. Jan de Beur SM, Miller PD, Weber TJ, et al. Burosumab for the treatment of
Acad Sci. 2005;102(27):9637-9642. PMID: 15976027 tumor-induced osteomalacia. J Bone Miner Res. 2021;36(4):627-635. PMID:
3. Nordin BEC, ed. Calcium, Phosphate, and Magnesium Metabolism: Clinical 33338281
Physiology and Diagnostic Procedures. Longman; 1976. 13. Collins MT, Singer FR, Eugster E. McCune-Albright syndrome and
4. Tenenhouse HS. Cellular and molecular mechanisms of renal phosphate the extraskeletal manifestations of fibrous dysplasia. Orphanet J Rare Dis.
transport. J Bone Miner Res. 1997;12(2):159-164. PMID: 9041046 2012;7(Suppl 1):S4. PMID: 22640971
5. Sabbagh Y, Giral H, Caldas Y, Levi M, Schiavi SC. Intestinal phosphate 14. Briot K, Portale AA, Brandi ML, et al. Burosumab treatment in adults
transport. Adv Chronic Kidney Dis. 2011;18(2):85-90. PMID: 21406292 with X-linked hypophosphataemia: 96-week patient-reported outcomes
6. Murer H, Hernando N, Forster I, Biber J. Proximal tubular phosphate and ambulatory function from a randomised phase 3 trial and open-label
reabsorption: molecular mechanisms. Physiol Rev. 2000;80(4):1373-1409. extension. RMD Open. 2021;7(3):e001714. PMID: 34548383
PMID: 11015617 15. Zhukouskaya VEA, Berkenou J, Audrain C, Bardet C, Chaussain C,
7. Hewison M, Bouillon R, Giovannucci E, Goltzman D, Meyer M, Welsh J. Rothenbuhler A, Linglart A. Hyperparathyroidism after 3 years of
Feldman and Pike’s Vitamin D: Volume 2: Disease and Therapeutics. Elsevier; burosumab in children affected with X-linked hypophosphatemia. Annales
2024. d’Endocrinologie. 2023;84(5):544.
8. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician’s 16. Takashi, Y. et al. Combined treatment by burosumab and a calcimimetic can
guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26(7):1381- ameliorate hypophosphatemia due to excessive actions of FGF23 and PTH in
1388. PMID: 21538511 adult XLH with tertiary hyperparathyroidism: a case report. Front Endocrinol
9. Insogna KL, Rauch F, Kamenicky P, et al. Burosumab improved (Lausanne). 2022;13:1004624. PMID: 36531500
histomorphometric measures of osteomalacia in adults with X-linked 17. Alon US, Levy-Olomucki R, Moore WV, Stubbs J, Liu S, Quarles D.
hypophosphatemia: a phase 3, single-arm, international trial. J Bone Miner Calcimimetics as an adjuvant treatment for familial hypophosphatemic
Res. 2019;34(12):2183-2191. PMID: 31369697 rickets. Clin J Am Soc Nephrol. 2008;3(3):658-664. PMID: 18256372
10. Insogna KL, Briot K, Imel EA, et al; AXLES 1 Investigators. A 18. Demay MB, Pittas AG, Bikle DD, et al. Vitamin D for the prevention of
randomized, double-blind, placebo-controlled, phase 3 trial evaluating disease: an Endocrine Society clinical practice guideline. J Clin Endocrinol.
the efficacy of burosumab, an anti-FGF23 antibody, in adults with 2014;109(8):1907-1947. PMID: 38828931
X-linked hypophosphatemia: week 24 primary analysis. J Bone Miner Res.
2018;33(8):1383-1393. PMID: 29947093

88 ENDO 2025 • Endocrine Case Management

CARDIOVASCULAR
ENDOCRINOLOGY
Management of Patients
With Elevated Lipoprotein(a)
David Saxon, MD, MSc. Division of Endocrinology, Metabolism, and Diabetes, University
of Colorado School of Medicine, Rocky Mountain Regional VAMC, Aurora, CO; Email:
[email protected]

Educational Objectives highly variable in size (300-800 kDa) due to more

than 40 isoforms and 10 apo(a) subtypes, and
After reviewing this chapter, learners should be
it possesses proatherogenic, proinflammatory,
able to:
and prothrombotic properties, the latter
• Identify the role of lipoprotein(a) (Lp[a]) as characteristic owing to apo(a) being homologous
an independent cardiovascular risk factor and to plasminogen.2
describe its pathophysiologic mechanisms. Lp(a) levels above 30 mg/dL (>75 nmol/L)
are associated with increased ASCVD risk and are
• Explain current guideline recommendations
thought to be elevated in more than 1.4 billion
for Lp(a) screening and identify practice gaps
people worldwide.3 Lp(a) levels of 50 mg/dL or
that contribute to its underuse in clinical
higher (≥125 nmol/L) or higher are associated
practice.
with very high risk of ASCVD and can increase
• Evaluate available and emerging strategies the calculated 10-year ASCVD risk. Elevated levels
for managing patients with elevated Lp(a), are also a risk factor for stroke and calcific aortic
including risk factor modification, lipid stenosis. In a global population with established
apheresis, and investigational therapies in CVD, elevated Lp(a) levels were observed in the
clinical trials. following proportions: 27.9% had levels greater
than 50 mg/dL (>125 nmol/L), 20.7% had levels
greater than 70 mg/dL (>175 nmol/L), 12.9%
had levels greater than 90 mg/dL (>225 nmol/L),
Significance of the and 26.0% had levels greater than 150 mg/dL
Clinical Problem (>375 nmol/L).4
Lp(a) was first identified in 1963 by Kare
Cardiovascular disease (CVD) remains a leading
Berg, and subsequent decades of research have
cause of death worldwide.1 Advancements
provided a comprehensive understanding of
in pharmacologic therapy and public health
its epidemiology, genetics, physiology, and
interventions have substantially reduced
pathophysiology. Its levels are largely genetically
morbidity and mortality; however, even among
determined, driven by the codominant expression
aggressively treated patients in the setting of
of 2 LPA alleles. However, nongenetic factors such
secondary prevention, residual risk persists for
as pregnancy, menopause, hypothyroidism, and
atherosclerotic cardiovascular disease (ASCVD).
kidney insufficiency or failure may increase Lp(a).
A unique target for addressing residual risk
Accurate measurement of Lp(a) is challenging
is Lp(a), a lipoprotein structurally similar to
due to the variable size of apo(a), and results can
LDL but distinguished by the presence of
be confusing because 2 different measurement
apolipoprotein (a) (apo a), which is covalently
approaches are used—either mg/dL or nmol/L.
bound to apolipoprotein B100 (apo B). Lp(a) is

90 ENDO 2025 • Endocrine Case Management

Clinicians may encounter both forms of Clinical Guideline Recommendations
measurement in practice, but the recommended Regarding Lp(a) Testing
gold standard ELISA method is calibrated
in nmol/L, thus reflecting the number of Evolving societal guideline recommendations
Lp(a) particles.2 and statements highlight the growing role of
Lp(a) measurement in CVD risk stratification and
reinforce the need for broader clinical awareness
Practice Gaps of this condition. In the 2018 Multisociety
Cholesterol Guidelines, Lp(a) was considered a
• Screening for Lp(a) remains underused, risk enhancer, and testing was suggested in those
reflecting a lack of awareness about current with a family history of premature ASCVD or
guidelines and the importance of identifying unexplained ASCVD who did not have major
this condition. risk factors. However, universal Lp(a) screening
• There is a lack of clinical consensus on how to was not recommended.6 Subsequently, between
care for patients with elevated Lp(a), leaving 2019 and 2022, several guidelines and statements
many clinicians unsure about the optimal from Canada and Europe identified Lp(a) as a
approach. cardiovascular risk enhancer and went further by
recommending testing at least once in all adults.7-9
• While no medications specifically targeting
The 2020 Endocrine Society Clinical Practice
elevated Lp(a) are FDA-approved,
Guideline on Lipid Management in Patients
endocrinologists should be aware of several
with Endocrine Disorders recommended Lp(a)
ongoing phase 3 clinical trials of such
measurement in adults with a family history
therapies.
of premature ASCVD or a personal history of
ASCVD, or a family history of high Lp(a).10 In
Discussion 2024, the National Lipid Association published
As previously mentioned, elevated Lp(a) levels an Lp(a) Scientific Statement that advised
are an independent risk factor for CVD, stroke, testing all adults at least once for Lp(a) and
and calcific aortic stenosis. However, despite recommended selective screening in high-risk
widespread acceptance of the health risks posed youth (<18 years old) with suspected or confirmed
by elevated Lp(a), rates of Lp(a) screening are familial hypercholesterolemia, ischemic stroke
very low, perhaps because no proven targeted of unknown cause, a first-degree relative with
therapies to lower Lp(a) thus far exist. In one premature ASCVD, or a first-degree relative with
analysis of Lp(a) testing in individuals with various elevated Lp(a).11
CVD conditions and individuals undergoing
cardiac testing across 6 academic medical centers Current Approach to Care of
associated with the University of California from Patients With High Lp(a)
2012 to 2021, only 0.3% of more than 5.5 million
people had undergone Lp(a) testing.5 In patients without a history of ASCVD who have
Now is a pivotal time for endocrinologists to high Lp(a), cardiovascular risk factors should be
deepen their understanding of Lp(a), as recent evaluated, including LDL cholesterol (LDL-C),
clinical guideline recommendations are shaping blood pressure, cigarette smoking history, and
Lp(a) testing practices, strategies have emerged to venous thrombosis, and management of these risk
guide the management of patients with elevated factors should be intensified. Imaging of coronary
Lp(a), and promising therapies are advancing artery calcium (CAC) should be considered
through clinical trials with the potential to because CAC scores of 100 or greater in patients
transform care. with the highest Lp(a) levels (upper quintile) are
associated with increased ASCVD risk.12 Since

ENDO 2025 • Cardiovascular Endocrinology 91

no targeted pharmacologic therapy indicated for Therapies Under Investigation
Lp(a) lowering currently exists, current CVD for Lp(a) Lowering
risk reduction in the face of elevated Lp(a) should
focus on aggressive management of modifiable Now is an exciting time for targeted Lp(a)
traditional risk factors. Recently, reviews by therapies, with at least 5 drugs currently in
Reyes-Soffer et al and Ellberg and Bhatia outlined development that work through various
strategies that can be used to manage patients mechanisms (Table 2). Among these, 3 therapies—
with elevated Lp(a) based on current available pelacarsen, olpasiran, and lepodisiran—are either
evidence.13,14 Table 1 summarizes interventions for fully enrolled or actively enrolling in phase 3
reducing LDL-C and Lp(a). cardiovascular outcome trials.15-17 Approval of
these medications will require evidence that they
reduce Lp(a) and provide cardiovascular benefit.

Table 1. Approach to Treatment of Elevated Lp(a)

Treatment modality Mechanism and rationale Considerations

Statin therapy Reduces overall CVD risk but does not Essential for overall risk reduction, but does not
lower—and may slightly increase—Lp(a) address Lp(a)-specific risk
levels; residual risk can be mitigated by
aggressive LDL-C or apo B lowering

PCSK9 inhibitors (evolocumab, Lowers LDL-C and reduces Lp(a) levels by Not FDA-approved for Lp(a) lowering; potential
alirocumab) ~23%-27% role in residual risk management

Lipid apheresis The only FDA-approved treatment for Reserved for patients at highest risk with Lp(a)
high Lp(a); removes apo B–containing >60 mg/dL (>150 nmol/L) and LDL-C >100 mg/dL
lipoproteins, including Lp(a) (>2.59 mmol/L) with CVD

Aspirin in primary prevention Potentially beneficial in patients at high Not broadly recommended for primary prevention
risk with elevated Lp(a) but may have selective benefit

Prolonged DAPT in secondary Extended DAPT (>1 year) may reduce May benefit select secondary prevention patients
prevention CVD risk in patients with high Lp(a) with high Lp(a); further validation needed

Cascade screening of family Identifies individuals at risk through Recommended by guidelines for family screening,
members familial testing particularly in familial hypercholesterolemia
programs

Enrollment in clinical trials Emerging Lp(a)-targeted therapies under Future Lp(a)-lowering therapies may transform
investigation treatment strategies

Abbreviations: CVD, cardiovascular disease; DAPT, dual antiplatelet therapy; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a).

Table 2. Targeted Lp(a) Therapies in Development

Lp(a) lowering and administration

Drug Name Mechanism frequency Trial name and stage

Pelacarsen Antisense oligonucleotide ~80%; once monthly injection Phase 3: HORIZON (fully enrolled)

Olpasiran Small interfering RNA 90%+; every 6 months injection Phase 3: OCEAN(a) (fully enrolled)

Lepodisiran Small interfering RNA 90%+; every 6 months injection Phase 3: ACCLAIM-Lp(a) (enrolling)

Zerlasiran Small interfering RNA 80%+; every 4- or 6-months injection in Phase 2: completed
phase 2 trial

Muvalaplin Oral small molecule inhibitor 47.6%-85.8% reductions in phase 2 Phase 2: completed
study using various daily oral doses

92 ENDO 2025 • Endocrine Case Management

These investigational treatments use different The 2024 National Lipid Association Scientific
approaches, including antisense oligonucleotides, Statement recommends that all adults have Lp(a)
small interfering RNA molecules, and an oral measured at least once (Answer B), as Lp(a) is
small molecule inhibitor, some of which have largely genetically determined and remains stable
demonstrated the ability to reduce Lp(a) levels over a lifetime. Testing can help identify individuals
between 80% and 99%. Additionally, these at increased risk for ASCVD, particularly those who
medications vary in their dosing schedules, with may not have other traditional risk factors.
some administered as infrequently as every Lp(a) screening is recommended regardless of
6 months. The HORIZON trial, evaluating whether a person has already developed clinical
pelacarsen, is the furthest along, with an expected ASCVD (thus, Answer A is incorrect). Waiting
completion date in early 2026. until ASCVD manifests may delay appropriate risk
assessment and preventive strategies.
Lp(a) testing is not limited to individuals
Clinical Case Vignettes with an LDL-C value greater than
Case 1 190 mg/dL (>4.92 mmol/L), although it is
A 45-year-old man with hypertension and a family particularly relevant in this population (thus,
history of premature coronary artery disease Answer C is incorrect).
(father had a myocardial infarction at age 50 years) While individuals with familial
presents for a routine CVD risk assessment. hypercholesterolemia should be screened for
Lp(a), testing is recommended for all adults, not
Lipid panel: just those with familial hypercholesterolemia
LDL-C =110 mg/dL (SI: 2.85 mmol/L)
(thus, Answer D is incorrect).
HDL-C = 48 mg/dL (SI: 1.24 mmol/L) A first-degree relative with elevated Lp(a) is an
Triglycerides = 120 mg/dL (SI: 1.36 mmol/L) indication for selective screening in youth, but this
criterion does not apply to general adult screening,
He has never been tested for Lp(a). which is advised for everyone at least once in their
lifetime (thus, Answer E is incorrect).
According to the 2024 National Lipid
Association Scientific Statement, which
of the following is the most appropriate Case 2
approach to Lp(a) testing in this patient? A 58-year-old woman with a history of myocardial
A. No testing is needed unless he develops clinical infarction at age 52 years, hypertension, and type 2
ASCVD diabetes presents for CVD risk assessment. She is
B. Lp(a) testing is reasonable as part of routine asymptomatic but is concerned about her long-
adult screening term heart health. Her current medications include
C. Lp(a) testing is only recommended in patients atorvastatin, 40 mg daily; ezetimibe, 10 mg daily;
with LDL-C >190 mg/dL (>4.92 mmol/L) metformin, 1000 mg twice daily; and lisinopril,
10 mg daily.
D. Lp(a) testing should only be performed in the
presence of familial hypercholesterolemia Laboratory test results:
E. Lp(a) testing is only indicated if the patient has Total cholesterol = 180 mg/dL (SI: 4.65 mmol/L)
a first-degree relative with Lp(a) >40 mg/dL LDL-C = 78 mg/dL (SI: 2.02 mmol/L)
(>100 nmol/L) High-density lipoprotein cholesterol (HDL-C) =
42 mg/dL (SI: 1.09 mmol/L)
Answer: B) Lp(a) testing is reasonable Triglycerides = 120 mg/dL (SI: 1.36 mmol/L)
as part of routine adult screening Apo B = 85 mg/dL (0.85 g/L)
Lp(a) = 52 mg/dL (SI: 130 nmol/L)

ENDO 2025 • Cardiovascular Endocrinology 93

Her blood pressure is well controlled at levels and may even cause a slight increase. Also,
118/72 mm Hg. She does not smoke cigarettes. simvastatin has less LDL-C–lowering potential
She exercises regularly and has a healthy diet. than high-dosage atorvastatin. The 80 mg dosage
Her father had a myocardial infarction at age 50, of atorvastatin is the highest available. Increasing
and her younger brother, age 55 years, recently the statin dosage would reduce LDL-C and
underwent coronary artery bypass grafting. ASCVD risk, but it would not directly address the
She expresses concern about her elevated Lp(a) patient’s Lp(a)-mediated risk.
and asks about treatment options. You change the Lipid apheresis (Answer C) is typically
dosage of atorvastatin to 80 mg daily to further reserved for patients at very high risk of
lower LDL-C. ASCVD who have both severely elevated
Lp(a) and uncontrolled LDL-C (>100 mg/dL
Which of the following is the [>2.59 mmol/L]) despite maximal lipid-lowering
most appropriate next step in therapy. This patient’s LDL-C concentration
her lipid management? was 78 mg/dL (2.02 mmol/L) on atorvastatin,
A. Switch atorvastatin to simvastatin to lower 40 mg daily. Given the potential for additional
Lp(a) medication adjustments to further lower LDL-C,
B. Initiate a PCSK9 inhibitor to lower both lipid apheresis is not currently necessary.
LDL-C and Lp(a) Discontinuing statin therapy (Answer D) is
incorrect because statins remain a cornerstone of
C. Recommend lipid apheresis
CVD prevention and significantly reduce ASCVD
D. Discontinue statin therapy, as it may increase risk. While statins do not lower Lp(a), stopping
Lp(a) levels this therapy would remove a critical intervention
Answer: B) Initiate a PCSK9 inhibitor for LDL-C reduction and overall CVD risk
to lower both LDL-C and Lp(a) management.

PCSK9 inhibitors (evolocumab, alirocumab) lower

Case 3
LDL-C and have been shown in clinical trials
to reduce Lp(a) levels by approximately 23% to A 56-year-old man with a history of premature
27%. This makes them an appropriate next step coronary artery disease, hypertension, and
in patients at high risk who have elevated Lp(a) hyperlipidemia presents for lipid management. He
and residual ASCVD risk despite treatment with a underwent percutaneous coronary intervention
high-intensity statin plus ezetimibe. This patient at age 50 years and has since been on maximally
would benefit from the addition of a medication tolerated statin therapy plus ezetimibe. His
that targets PCSK9 (monoclonal antibodies to LDL-C remains well-controlled at 58 mg/dL
PCSK9 or a small interfering RNA) (Answer (1.50 mmol/L), but his Lp(a) level is markedly
B). The PCSK9 inhibitor would reduce LDL-C elevated at 85 mg/dL (210 nmol/L). He has
further and may also reduce Lp(a) by 23% to 27% a strong family history of early myocardial
to mitigate some of the Lp(a)-associated risk. infarction, with his father experiencing a
Another option for lowering LDL-C would be to myocardial infarction at age 48 years. The patient
switch atorvastatin to rosuvastatin, 20 or 40 mg is concerned about his residual CVD risk and asks
daily. An LDL-C concentration of 78 mg/dL about emerging treatments for Lp(a) lowering.
(2.02 mmol/L) is too high for a patient with a
history of myocardial infarction.
Switching atorvastatin to simvastatin to lower
Lp(a) (Answer A) is incorrect because while statins
lower LDL-C effectively, they do not reduce Lp(a)

94 ENDO 2025 • Endocrine Case Management

Which of the following investigational relevant. Anacetrapib is a CETP inhibitor that
therapies could the patient be informed was shown to modestly lower Lp(a), but it is not
about that are in phase 3 trials for Lp(a) available for clinical use. Lomitapide is used for
lowering and reduction of CVD risk? homozygous familial hypercholesterolemia, and it
A. Inclisiran, evinacumab, and bempedoic acid does not significantly affect Lp(a). Mipomersen, an
B. Niacin, colesevelam, and icosapent ethyl antisense oligonucleotide targeting apo B100, was
withdrawn from the market due to safety concerns
C. Anacetrapib, lomitapide, and mipomersen
and is not an Lp(a)-lowering therapy.
D. Pelacarsen, olpasiran, and lepodisiran
Answer: D) Pelacarsen, olpasiran, and lepodisiran Key Learning Points
Pelacarsen, olpasiran, and lepodisiran (Answer D)
• Lp(a) is an independent risk factor for
are investigational therapies currently in phase 3
ASCVD, stroke, and calcific aortic stenosis.
clinical outcome trials specifically targeting Lp(a)
Genetics determines Lp(a) levels in 90% of
lowering and reduction in CVD risk. These agents
people with high Lp(a). Its proatherogenic,
are antisense oligonucleotides (pelacarsen) or
proinflammatory, and prothrombotic
small interfering RNAs (olpasiran and lepodisiran)
properties contribute to residual CVD risk,
designed to reduce hepatic LPA gene expression,
even in patients with well-controlled LDL-C.
thereby lowering Lp(a) levels, which have been
implicated in residual CVD risk. • Despite its recognized role in cardiovascular
While inclisiran, evinacumab, and bempedoic risk stratification, Lp(a) screening remains
acid (Answer A) are used in lipid management, infrequent in clinical practice. The 2024
they do not primarily target Lp(a). Inclisiran is National Lipid Association Scientific
a small interfering RNA that reduces PCSK9 Statement advises that all adults should have
levels, leading to LDL-C lowering, but it has Lp(a) measured at least once in their lifetime.
minimal impact on Lp(a). Evinacumab is an • While no FDA-approved pharmacologic
ANGPTL3 inhibitor approved for LDL-C therapy exists for Lp(a) lowering, current
lowering in individuals with homozygous familial management focuses on aggressive LDL-C
hypercholesterolemia, and it does not substantially and overall CVD risk reduction. Strategies
affect Lp(a). Bempedoic acid inhibits ATP citrate include statins (despite their neutral or slight
lyase to reduce LDL-C, but it has no significant Lp[a]-raising effect), PCSK9 inhibitors (which
role in Lp(a) reduction. modestly lower Lp[a] by ~25%), lipid apheresis
Niacin, colesevelam, and icosapent ethyl for patients at high risk, and extended
(Answer B) are not in phase 3 trials for Lp(a) antiplatelet therapy in select patients.
lowering. While niacin can modestly reduce Lp(a), • A new generation of targeted Lp(a)-lowering
it is no longer recommended for this purpose therapies, including pelacarsen, olpasiran, and
due to a lack of cardiovascular outcome benefit lepodisiran, have shown promising reductions
and poor tolerability. Colesevelam is a bile acid in Lp(a) levels of greater than 80%. These
sequestrant that primarily lowers LDL-C and has investigational drugs are in phase 3 clinical
no meaningful effect on Lp(a). Icosapent ethyl, an trials with CVD end points.
omega-3 fatty acid derivative, has demonstrated
cardiovascular benefits in patients with moderate
hypertriglyceridemia, but it does not lower Lp(a).
Anacetrapib, lomitapide, and mipomersen
(Answer C) are lipid-altering drugs that are either
not in phase 3 trials or are no longer clinically

ENDO 2025 • Cardiovascular Endocrinology 95

References
1. GBD 2017 Causes of Death Collaborators. Global, regional, and national age- prevention of cardiovascular disease in adults. Can J Cardiol. 2021;37(8):1129-
sex-specific mortality for 282 causes of death in 195 countries and territories, 1150. PMID: 33781847
1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. 9. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic
Lancet. 2018;392(10159):1736-1788. PMID: 30496103 cardiovascular disease and aortic stenosis: a European Atherosclerosis Society
2. Reyes-Soffer G, Ginsberg HN, Berglund L, et al. Lipoprotein(a): a consensus statement. Eur Heart J. 2022;43(39):3925-3946. PMID: 36036785
genetically determined, causal, and prevalent risk factor for atherosclerotic 10. Newman CB, Blaha MJ, Boord JB, et al. Lipid management in patients with
cardiovascular disease: a scientific statement from the American Heart endocrine disorders: an Endocrine Society clinical practice guideline. J Clin
Association. Arterioscler Thromb Vasc Biol. 2022;42(1):e48-e60. PMID: Endocrinol Metab. 2020;105(12):dgaa674. PMID: 32951056
34647487 11. Koschinsky ML, Bajaj A, Boffa MB, et al. A focused update to the 2019 NLA
3. Tsimikas S, Fazio S, Ferdinand KC, et al. NHLBI Working Group scientific statement on use of lipoprotein(a) in clinical practice. J Clin Lipidol.
recommendations to reduce risk of cardiovascular disease and aortic stenosis. 2024;18(3):e308-e319. PMID: 38565461
J Am Coll Cardiol. 2018;71(2):177-192. PMID: 29325642 12. Mehta A, Vasquez N, Ayers CR, et al. Independent association of
4. 4. Nissen SE, Wolski K, Cho L, et al. Lipoprotein(a) levels in a global lipoprotein(a) and coronary artery calcification with atherosclerotic
population with established atherosclerotic cardiovascular disease. Open Heart. cardiovascular risk. J Am Coll Cardiol. 2022;79(8):757-768. PMID: 35210030
2022;9(2):e002060. PMID: 36252994 13. Reyes-Soffer G, Yeang C, Michos ED, Boatwright W, Ballantyne CM. High
5. Bhatia HS, Hurst S, Desai P, Zhu W, Yeang C. Lipoprotein(a) testing trends lipoprotein(a): Actionable strategies for risk assessment and mitigation. Am J
in a large academic health system in the United States. J Am Heart Assoc. Prev Cardiol. 2024;18:100651. PMID: 38646021
2023;12(18):e031255. PMID: 37702041 14. Ellberg CC, Bhatia HS. Strategies for management of patients with elevated
6. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ lipoprotein(a). Curr Opin Lipidol. 2024;35(5):234-240. PMID: 39145610
ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the 15. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al; AKCEA-
Management of Blood Cholesterol: A Report of the American College of APO(a)-LRx Study Investigators. Lipoprotein(a) reduction in persons with
Cardiology/American Heart Association Task Force on Clinical Practice cardiovascular disease. N Engl J Med. 2020;382(3):244-255. PMID: 31893580
Guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350. PMID: 30586774 16. O’Donoghue ML, Rosenson RS, Gencer B, et al. Small interfering
7. Authors/Task Force Members, ESC Committee for Practice Guidelines RNA to reduce lipoprotein(a) in cardiovascular disease. N Engl J Med.
(CPG), ESC National Cardiac Societies. 2019 ESC/EAS guidelines for the 2022;387(20):1855-1864. PMID: 36342163
management of dyslipidaemias: lipid modification to reduce cardiovascular 17. Nissen SE, Linnebjerg H, Shen X, et al. Lepodisiran, an extended-duration
risk. Atherosclerosis. 2019;290:140-205. PMID: 31591002 short interfering RNA targeting lipoprotein(a): a randomized dose-ascending
8. 8. Pearson GJ, Thanassoulis G, Anderson TJ, et al. 2021 Canadian clinical trial. JAMA. 2023;330(21):2075-2083. PMID: 37952254
Cardiovascular Society guidelines for the management of dyslipidemia for the

96 ENDO 2025 • Endocrine Case Management

Interpreting Adrenal
Vein Sampling
Michael Stowasser, MBBS, PhD. Endocrine Hypertension Research Centre, University
of Queensland Frazer Institute, Princess Alexandra Hospital, Brisbane, Australia; Email:
[email protected]

Educational Objectives addressing aldosterone excess.3 Approximately

25% of patients with PA have unilateral forms
After reviewing this chapter, learners should be
(most commonly aldosterone-producing adenoma
able to:
[APA]), for which ADX has the potential to cure
• Describe implementation strategies that, or markedly improve control of hypertension
when applied before and during adrenal vein and biochemical PA. In contrast, ADX is rarely
sampling (AVS), can enhance procedure undertaken in patients with bilateral PA (who
success and interpretability of results. make up most of the remainder of cases), as it
is much less likely to provide such clinical and
• Determine, based on AVS results, whether
biochemical benefits. Instead, patients with
successful adrenal vein cannulation has
bilateral PA are usually treated with MRAs. As
been achieved and whether the patient has
a group, surgically treated patients demonstrate
a bilateral or unilateral variety of primary
superior outcomes in terms of hypertension
aldosteronism (PA).
control, incidence of cardiovascular and kidney
• Identify factors that can lead to inconclusive morbidities, and improved quality of life compared
AVS results and steps that can be undertaken with patients with PA who are treated with
to overcome them. MRAs.4 Distinguishing unilateral from bilateral
PA is therefore a critical step in the selection of
optimal treatment options.
Because adrenal imaging by CT or MRI lacks
Significance of the reliability, and newer scintigraphic approaches,
Clinical Problem while promising, are still in development, AVS
remains the favored approach for distinguishing
Accounting for at least 5% to 13% of patients with
unilateral from bilateral forms of PA. Guidelines
hypertension, PA is now recognized to be the most
suggest that AVS be performed in almost all
prevalent and specifically treatable (potentially
patients diagnosed with PA who desire and are
curable) secondary endocrine form.1,2 Detection is
otherwise suitable candidates for ADX should they
paramount, as these patients are at considerably
be found to have unilateral disease.2 However, AVS
higher risk of cardiovascular and kidney morbidity
is not widely available and requires considerable
compared with blood pressure–matched patients
expertise to ensure acceptable rates of cannulation
with essential hypertension, and yet this increased
success, generation of reliable data, and correct
morbidity is ameliorated and quality of life is
result interpretation. In the wake of new clinical
improved by surgical intervention (unilateral
guidelines that currently recommend screening
adrenalectomy [ADX]) or medical treatment
for PA among all patients with hypertension,5 the
(most commonly mineralocorticoid receptor
demand for AVS is likely to increase markedly
antagonist [MRA]) specifically directed toward

ENDO 2025 • Cardiovascular Endocrinology 97

in coming years, making it timely and of vital suppressed, and, when feasible, medications that
importance to upscale availability of this important stimulate renin should be withdrawn before AVS
procedure and ensure it is performed correctly and (≥4 weeks for MRAs and diuretics; ≥2 weeks for
results are interpreted accurately. ACE inhibitors, angiotensin II receptor blockers,
and dihydropyridine calcium channel blockers).6
Contrast‐enhanced CT should be performed to
Practice Gaps localize the adrenal veins and thereby increase the
chance of successful cannulation.8
• There is an urgent need to expand AVS services
Concomitant autonomous cortisol secretion,
to meet the demand among a rapidly growing
which may occur in as many as 5% to 18% of
number of patients being diagnosed with PA.
patients with PA,9,10 can confound the interpretation
• There is a lack of awareness of optimal of AVS results.11,12 Cortisol production from an
approaches to prepare patients for AVS, adrenal adenoma may be sufficient to cause ACTH
skillfully perform the procedure, and suppression and contralateral suppression of
accurately interpret results. cortisol secretion. As a result, cannulation may be
• Disparity exists among institutions regarding incorrectly deemed unsuccessful on the contralateral
how AVS is performed and how results are side. In addition, increased cortisol production on
interpreted. the side of the adenoma may lower the aldosterone-
to-cortisol ratio on that side and thereby mask
lateralization. Because of these issues, some
Discussion groups recommend performing a 1-mg overnight
AVS involves cannulation of both adrenal veins and dexamethasone-suppression test before AVS.6
measuring aldosterone and cortisol levels in adrenal While mild autonomous cortisol excess is unlikely
vein (AV) and peripheral vein (PV) samples. There to significantly alter cannulation or lateralization
are numerous variations in AVS protocols related to outcomes during AVS, in individuals with a cortisol
patient preparation, performance of the procedure, value greater than 5 µg/dL (>137 nmol/L) after
and interpretation of results. Guidelines attempting a 1-mg dexamethasone-suppression test, lower
to harmonize AVS approaches have thus recently selectivity index values have been reported.13
been developed.6,7 In such patients, it can be useful to measure an
additional marker, such as plasma metanephrine,
Patient Preparation to assess for selectivity and lateralization of
aldosterone production.
Before performing AVS, potentially confounding
factors should be controlled when possible.
Lateralization on AVS depends on the gland Performing AVS
contralateral to the source of aldosterone In Brisbane hypertension units, AVS is performed
excess being suppressed in terms of aldosterone in the morning (when endogenous ACTH levels
production. This, in turn, depends on the renin- are highest, ensuring maximal ACTH-induced
angiotensin II system (RAS) also being suppressed. stimulation of aldosterone and cortisol production)
Certain factors (eg, medications) that stimulate and following overnight recumbency (thereby
the RAS may lead to inadequate suppression of avoiding confounding effects of postural changes on
the contralateral adrenal and loss of lateralization. aldosterone levels).14 Administration of sedatives,
In addition to measuring plasma potassium and anesthetic agents, and narcotics are avoided for at
plasma renin, an inventory of medications should least 24 hours before AVS because of their potential
be assessed 4 to 6 weeks before AVS. Hypokalemia to suppress steroid production. A radiologist highly
(which can decrease adrenal aldosterone skilled in AVS collects samples from each of the
production) should be corrected, renin should be

98 ENDO 2025 • Endocrine Case Management

adrenal veins and, simultaneously with each AV (we prefer 3) for nonstimulated AVS and at least
sample, from a PV (antecubital fossa vein, inferior 5 for ACTH-stimulated AVS indicating adequate
vena cava well below the adrenal veins, or iliac sampling.6,19-21 In highly experienced units, success
vein). At least 2 samples are collected from each side rates can reach 90% or higher.8,18 Aids to successful
to maximize the chances of successful sampling and cannulation include using CT to localize the
as a safeguard should sample handling issues occur. adrenal veins before AVS,8 restricting the number
A learning curve has been well described in of AVS proceduralists at each center, and using
AVS.15,16 Success rates by a single operator improved point-of-care plasma cortisol measurement to
from 50% to 60% to 80% to 95% after 30 to 50 permit semiquantitative comparison of AV and PV
procedures were performed, with more than 15 to 25 cortisol levels within minutes of collection.22
procedures needed per year to maintain a success rate AV samples can differ considerably in the
of approximately 95% over 8 years.16 If fewer than degree to which they are “diluted” with non-
20 procedures at a site are performed annually, these AV blood. Because of this, direct comparison
should be performed by a single operator.16 of aldosterone concentrations in these samples
Several groups use exogenous ACTH frequently gives misleading results. Calculating
(cosyntropin) stimulation during AVS to the aldosterone-to-cortisol ratio for each AV and
(1) maximize AV/PV cortisol gradients, (2) PV sample corrects for differences in dilution. In
reduce fluctuations in steroid secretion during unstimulated AVS, if the average AV aldosterone-
nonsimultaneous AVS, and (3) stimulate aldosterone to-cortisol ratio on 1 side is at least 2 times
production by APAs and thus avoid sampling higher than the simultaneous PV ratio, with a
during a period of secretion “quiescence.”2,17,18 ratio no higher than peripheral on the other side
ACTH stimulation may, however, lead to loss of (contralateral suppression), lateralization has
lateralization by stimulating the contralateral gland been demonstrated, indicating that unilateral
in patients with unilateral PA. ACTH stimulation ADX should cure or improve the patient’s
can assist subtype differentiation in patients whose hypertension.3,23 Criteria for lateralization vary
basal AVS results were inconclusive because widely from one institution to another.6,7,21 Many
of apparent quiescence in terms of aldosterone centers rely only on the comparison of aldosterone-
production (ie, AV aldosterone/cortisol levels lower to-cortisol ratios on 1 side vs the other (the
than peripheral) on both sides at the time of AVS.19,20 lateralization index), with lateralization defined as
Administration of cosyntropin as an intravenous the ratio on the higher side being at least 4 times
infusion (50 mcg/h) ensures adequate and stable greater than that on the lower side. It is possible
concentrations at the time of sampling. that the presence of contralateral suppression is of
Should the 2 adrenal veins be cannulated particular importance for predicting hypertension
sequentially or simultaneously? Simultaneous cure or improvement in the subgroup whose
sampling avoids biological variations in steroid lateralization indices fall between 2.0 and 4.0, and
production over time, but it is more difficult less so for those with indices greater than 4.0.
to achieve. If sequential sampling is used, the As stated above, in patients who demonstrate
right (which is harder to cannulate) should be cortisol values greater than 5 µg/dL (>137 nmol/L)
cannulated first to minimize the time between after a 1-mg dexamethasone suppression, it can
sampling the 2 sides.6,19-21 be useful to measure an additional marker, such as
plasma metanephrine, to assess for selectivity and
lateralization of aldosterone production. Suggested
Result Interpretation
thresholds using metadrenaline in place of cortisol
Adequacy of AVS is assessed by examining the include a selectivity index greater than 12 and a
gradient between AV and PV cortisol levels (the lateralization index greater than 4.24
selectivity index), with gradients of at least 2 to 3

ENDO 2025 • Cardiovascular Endocrinology 99

Clinical Case Vignettes Answer: B) Left unilateral adrenal
aldosterone production
Case 1
A 56-year-old woman with hypertension, In this AVS, successful cannulation of both adrenal
unprovoked hypokalemia, a markedly elevated plasma veins is confirmed by the demonstration of AV-
aldosterone-to-renin ratio, a positive seated saline- to-PV cortisol ratios (selectivity indices) of 5.0
suppression test (confirming PA), and an 8-mm or greater (in this case, 28 to 55) for all samples
nodule in the left adrenal gland on CT scanning collected. The left AV aldosterone-to-cortisol
undergoes AVS with cosyntropin stimulation several ratios are more than twice PV values, and those on
weeks after correction of hypokalemia and while the right side are lower than the PV (contralateral
receiving verapamil, hydralazine, and prazosin. suppression), consistent with left unilateral
aldosterone production. Furthermore, the left AV
AVS results are shown in the Table. aldosterone-to-cortisol ratios are more than 30
times those on the right, which well exceeds the
Which of the following is the most accurate cutoff lateralization index for unilateral PA of 4.0 or
interpretation of the AVS results? higher. Although the cortisol-corrected aldosterone
A. Bilateral adrenal aldosterone production levels on the right side are much lower than the PV
B. Left unilateral adrenal aldosterone production values, the absolute aldosterone levels are higher
than the PV values (which is often the case, even in
C. Right unilateral adrenal aldosterone production
unstimulated AVS), emphasizing the importance
D. Neither adrenal producing significant amounts of comparing aldosterone-to-cortisol ratios rather
of aldosterone than uncorrected aldosterone levels for the purpose
E. Inconclusive; 1 or both adrenal veins not of lateralization. As is usually the case, cortisol levels
successfully cannulated are higher on the right than on the left, probably
because the left AV receives inflow from the
phrenic vein, which dilutes steroid levels.

Table. Case 1

Cortisol AV-to-PV Aldosterone-to-

Time of collection Site of collection Aldosterone Cortisol ratio cortisol ratio

08:30 Right AV 1 306.2 ng/dL 1324.8 µg/dL 49 0.2

(SI: 8493 pmol/L) (SI: 36,548 nmol/L)

08:30 PV 58.4 ng/dL 27.3 µg/dL 2.1

(SI: 1621 pmol/L) (SI: 754 nmol/L)

08:36 Right AV 2 282.0 ng/dL 1489.9 µg/dL 55 0.2

(SI: 7823 pmol/L) (SI: 41,103 nmol/L)

08:36 PV 59.6 ng/dL 27.2 µg/dL 2.2

(SI: 1652 pmol/L) (SI: 751 nmol/L)

08:42 Left AV 1 5407.4 ng/dL 741.2 µg/dL 28 7.3

(SI: 150,000 pmol/L) (SI: 20,447 nmol/L)

08:42 PV 62.4 ng/dL 26.5 µg/dL 2.4

(SI: 1732 pmol/L) (SI: 731 nmol/L)

08:45 Left AV 2 576.7 ng/dL 881.0 µg/dL 33 6.2

(SI: 15,999 pmol/L) (SI: 24,305 nmol/L)

08:45 PV 62.2 ng/dL 27.1 µg/dL 2.4

(SI: 1726 pmol/L) (SI: 747 nmol/L)

Abbreviations: AV, adrenal vein; PV, peripheral vein.

100 ENDO 2025 • Endocrine Case Management

Case 2 gradient of only 1.0, adequate AV samples were
obtained on the second attempt (gradient 37)
A 64-year-old hypertensive, normokalemic man
and with both attempts when cannulating the
has elevated aldosterone-to-renin ratios while off
left AV. If the unsuccessful sample is ignored, the
interfering medications. He has a positive result on a
demonstration of aldosterone-to-cortisol ratios
seated saline-suppression test, and a 12-mm nodule
being higher than peripheral on both sides, the
in the right adrenal gland is identified on CT. He
lack of contralateral suppression (defined as a
undergoes AVS during cosyntropin infusion while
contralateral suppression index of <1.0) on the
receiving verapamil, prazosin, and moxonidine.
lower (left) side, and right/left aldosterone-to-
AVS results are shown in the Table. cortisol ratios (lateralization indices) less than 2 to 4
all support bilateral adrenal aldosterone production.
Which of the following is the most accurate In this case, reliance on CT alone would to have led
interpretation of the AVS results? to an incorrect diagnosis of right unilateral PA and
A. Bilateral adrenal aldosterone production potentially inappropriate surgery.
B. Left unilateral adrenal aldosterone production
C. Right unilateral adrenal aldosterone production Case 3
D. Neither adrenal producing significant amounts A 48-year-old man with hypertension,
of aldosterone unprovoked hypokalemia, elevated plasma
E. Inconclusive; 1 or both adrenal veins not aldosterone-to-renin ratios, a positive result on a
successfully cannulated seated saline-suppression test, and a 6-mm nodule
in the left adrenal gland on CT undergoes AVS
Answer: A) Bilateral adrenal aldosterone production without cosyntropin stimulation in the morning
after overnight recumbency several weeks after
While the first sampling attempt of the right AV
correction of hypokalemia and while receiving
was unsuccessful based on the AV-to-PV cortisol
verapamil SR and hydralazine.

Table. Case 2

Cortisol AV-to-PV Aldosterone-to-

Time of collection Site of collection Aldosterone Cortisol ratio cortisol ratio

09:23 Right AV 1 23.4 ng/dL 34.1 µg/dL 1.0 0.7

(SI: 650 pmol/L) (SI: 940 nmol/L)

09:23 PV 22.5 ng/dL 34.1 µg/dL 0.7

(SI: 623 pmol/L) (SI: 942 nmol/L)

09:26 Right AV 2 3721.5 ng/dL 1343.8 µg/dL 37 2.8

(SI: 103,235 pmol/L) (SI: 37,074 nmol/L)

09:26 PV 21.1 ng/dL 36.6 µg/dL 0.6

(SI: 586 pmol/L) (SI: 1009 nmol/L)

09:28 Left AV 1 1692.5 ng/dL 904.9 µg/dL 25 1.0

(SI: 46,949 pmol/L) (SI: 24,965 nmol/L)

09:28 PV 23.2 ng/dL 36.8 µg/dL 0.6

(SI: 643 pmol/L) (SI: 1014 nmol/L)

09:29 Left AV 2 1967.6 ng/dL 1026.4 µg/dL 29 1.9

(SI: 54,581 pmol/L) (SI: 28,317 nmol/L)

09:29 PV 22.0 ng/dL 35.1 µg/dL 0.6

(SI: 609 pmol/L) (SI: 967 nmol/L)

Abbreviations: AV, adrenal vein; PV, peripheral vein.

ENDO 2025 • Cardiovascular Endocrinology 101

AVS results are shown in the Table. before AVS and in very stressed patients in whom
early stimulation of aldosterone by ACTH may
Which of the following is the most accurate have been followed by suppression. Much less
interpretation of the AVS results? likely explanations include an ectopic (extra-
A. Bilateral adrenal aldosterone production adrenal) source of aldosterone excess, aberrant
B. Left unilateral adrenal aldosterone production venous draining of an APA, or placement of the
catheter into a branch vein that is distal to, and not
C. Right unilateral adrenal aldosterone
receiving blood from, the tumor. It is probable,
production
however, that neither adrenal gland was producing
D. Neither adrenal producing significant amounts much aldosterone at the time of sampling.
of aldosterone In our experience, whereas unilateral disease
E. Inconclusive; 1 one or both adrenal veins not comprises only 25% to 30% of patients with PA,
successfully cannulated approximately 50% of patients who demonstrate
this pattern have lateralization on repeat AVS.25
Answer: D) Neither adrenal producing
As a result, we routinely offer these patients repeat
significant amounts of aldosterone
AVS, preferably with cosyntropin stimulation,
In this unstimulated AVS, although both AVs have which seems to lessen the chance of a similar
been successfully cannulated based on the AV-to- pattern occurring.
PV cortisol gradients of 3.0 or higher, both left
and right AV aldosterone-to-cortisol gradients Key Learning Points
are no higher than peripheral. This is usually
because sampling has been undertaken during a • AVS is the most reliable method of
quiescent phase of aldosterone production. We distinguishing unilateral (surgically
have observed this to occur after patients have correctable) from bilateral (usually treated
received a sedating agent or narcotic in the hours medically) forms of PA.

Table. Case 3

Cortisol AV-to-PV Aldosterone-to-cortisol

Time of collection Site of collection Aldosterone Cortisol ratio ratio

09:10 Right AV 1 97.3 ng/dL 244.7 µg/dL 21 0.4

(SI: 2700 pmol/L) (SI: 6750 nmol/L)

09:10 PV 7.0 ng/dL 11.7 µg/dL 0.4

(SI: 194 pmol/L) (SI: 324 nmol/L)

09:13 Right AV 2 126.5 ng/dL 254.5 µg/dL 20 0.5

(SI: 3510 pmol/L) (SI: 7020 nmol/L)

09:13 PV 8.0 ng/dL 12.7 µg/dL 0.6

(SI: 222 pmol/L) (SI: 351 nmol/L)

09:18 Left AV 1 116.8 ng/dL 195.7 µg/dL 17 0.7

(SI: 3240 pmol/L) (SI: 5400 nmol/L)

09:18 PV 9.0 ng/dL 11.7 µg/dL 0.8

(SI: 250 pmol/L) (SI: 324 nmol/L)

09:20 Left AV 2 122.6 ng/dL 205.5 µg/dL 16 0.6

(SI: 3402 pmol/L) (SI: 5670 nmol/L)

09:20 PV 9.0 ng/dL 12.7 µg/dL 0.7

(SI: 250 pmol/L) (SI: 351 nmol/L)

Abbreviations: AV, adrenal vein; PV, peripheral vein.

102 ENDO 2025 • Endocrine Case Management

• Established criteria exist for assessing whether • Correct result interpretation is dependent
AVs have been successful cannulated and for on awareness of the importance of optimal
distinguishing unilateral from bilateral forms patient preparation (including withdrawal of
of PA. medications that affect renin and aldosterone
• Success rates for AV cannulation can be levels); criteria for cannulation success and
enhanced with experienced operators, lateralization for both ACTH-stimulated and
maintaining a high throughput, performing nonstimulated procedures; and the effects
contrast CT of the adrenal glands before AVS, of time of day, postural changes, stress, and
use of ACTH stimulation, and point-of-care administration of sedating or narcotic agents
cortisol measurement during the procedure. leading up to the procedure.

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1. Reincke M, Bancos I, Mulatero P, Scholl UI, Stowasser M, Williams TA. a retrospective cohort study. Eur J Endocrinol. 2022;187(5):637-650. PMID:
Diagnosis and treatment of primary aldosteronism. Lancet Diabetes Endocrinol. 36070424
2021;9(12):876-892. PMID: 34798068 14. Stowasser M, Gordon RD. Primary aldosteronism. Best Pract Res Clin
2. Funder JW, Carey RM, Mantero F, et al. The management of primary Endocrinol Metab. 2003;17(4):591-605. PMID: 14687591
aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society 15. Vonend O, Ockenfels N, Gao X, et al. Adrenal venous sampling: evaluation
clinical practice guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916. of the German Conn’s registry. Hypertension. 2011;57(5):990-995. PMID:
PMID: 26934393 21383311
3. Stowasser M, Gordon RD. Primary aldosteronism: changing definitions and 16. Jakobsson H, Farmaki K, Sakinis A, Ehn O, Johannsson G, Ragnarsson O.
new concepts of physiology and pathophysiology both inside and outside the Adrenal venous sampling: the learning curve of a single interventionalist with
kidney. Physiol Rev. 2016;96(4):1327-1384. PMID: 27535640 282 consecutive procedures. Diagn Interv Radiol. 2018;24(2):89-93. PMID:
4. Samnani S, Cenzer I, Kline GA, et al. Time to benefit of surgery vs targeted 29467114
medical therapy for patients with primary aldosteronism: a meta-analysis. J 17. Monticone S, Satoh F, Giacchetti G, et al. Effect of adrenocorticotropic
Clin Endocrinol Metab. 2024;109(3):e1280-e1289. PMID: 37946600 hormone stimulation during adrenal vein sampling in primary aldosteronism.
5. McEvoy JW, McCarthy CP, Bruno RM, et al. 2024 ESC guidelines for Hypertension. 2012;59(4):840-846. PMID: 22331382
the management of elevated blood pressure and hypertension. Eur Heart J. 18. Young WF, Stanson AW. What are the keys to successful adrenal venous
2024;45(38):3912-4018. sampling (AVS) in patients with primary aldosteronism? Clin Endocrinol (Oxf).
6. Yang J, Bell DA, Carroll R, et al. Adrenal vein sampling for primary 2009;70(1):14-17. PMID: 19128364
aldosteronism: recommendations from the Australian and New Zealand 19. Wolley M, Thuzar M, Stowasser M. Controversies and advances in adrenal
Working Group. Clin Endocrinol (Oxf). 2025;102(1):31-43. PMID: 39360599 venous sampling in the diagnostic workup of primary aldosteronism. Best
7. Monticone S, Viola A, Rossato D, et al. Adrenal vein sampling in primary Pract Res Clin Endocrinol Metab. 2020;34(3):101400. PMID: 32115358
aldosteronism: towards a standardised protocol. Lancet Diabetes Endocrinol. 20. Wolley MJ, Ahmed AH, Gordon RD, Stowasser M. Does ACTH improve
2015;3(4):296-303. PMID: 24831990 the diagnostic performance of adrenal vein sampling for subtyping primary
8. Daunt N. Adrenal vein sampling: how to make it quick, easy, and successful. aldosteronism? Clin Endocrinol (Oxf). 2016;85(5):703-709. PMID: 27213822
Radiographics. 2005;25(Suppl 1):S143-S158. PMID: 16227488 21. Rossi GP, Barisa M, Allolio B, et al. The Adrenal Vein Sampling International
9. Buffolo F, Pieroni J, Ponzetto F, et al. Prevalence of cortisol cosecretion in Study (AVIS) for identifying the major subtypes of primary aldosteronism. J
patients with primary aldosteronism: role of metanephrine in adrenal vein Clin Endocrinol Metab. 2012;97(5):1606-1614. PMID: 22399502
sampling. J Clin Endocrinol Metab. 2023;108(9):e720-e725. PMID: 36974473 22. Yoneda T, Karashima S, Kometani M, et al. Impact of new quick gold
10. Fallo F, Bertello C, Tizzani D, et al. Concurrent primary aldosteronism nanoparticle-based cortisol assay during adrenal vein sampling for primary
and subclinical cortisol hypersecretion: a prospective study. J Hypertens. aldosteronism. J Clin Endocrinol Metab. 2016;101(6):2554-2561. PMID:
2011;29(9):1773-1777. PMID: 21720261 27011114
11. Goupil R, Wolley M, Ahmed AH, Gordon RD, Stowasser M. Does 23. Stowasser M, Gordon RD, Rutherford JC, Nikwan NZ, Daunt N, Slater GJ.
concomitant autonomous adrenal cortisol overproduction have the potential Diagnosis and management of primary aldosteronism. J Renin Angiotensin
to confound the interpretation of adrenal venous sampling in primary Aldosterone Syst. 2001;2(3):156-169. PMID: 33234000
aldosteronism? Clin Endocrinol (Oxf). 2015;83(4):456-461. PMID: 25683582 24. Carroll RW, Corley B, Feltham J, et al. The value of plasma metanephrine
12. Kline GA, So B, Campbell DJT, et al. Apparent failed and discordant adrenal measurements during adrenal vein sampling. Endocr Connect.
vein sampling: a potential confounding role of cortisol cosecretion? Clin 2024;13(2):e230300. PMID: 38055778
Endocrinol (Oxf). 2022;96(2):123-131. PMID: 34160833 25. Wolley M, Gordon RD, Pimenta E, et al. Repeating adrenal vein sampling
13. Heinrich DA, Quinkler M, Adolf C, et al. Influence of cortisol cosecretion on when neither aldosterone/cortisol ratio exceeds peripheral yields a high
non-ACTH-stimulated adrenal venous sampling in primary aldosteronism: incidence of aldosterone-producing adenoma. J Hypertens. 2013;31(10):2005-
2009. PMID: 24107732

ENDO 2025 • Cardiovascular Endocrinology 103

Managing Severe
Hypertriglyceridemia: Best
Practices and New Approaches
Lisa R. Tannock, MD. Dean, Faculty of Health Sciences, Queen’s University, Kingston,
Ontario, Canada; Email: [email protected]

Educational Objectives providers are unsure what to do about elevated

triglycerides.
After reviewing this chapter, learners should be
Triglycerides have wide variability both
able to:
within individuals and across populations. While
• Identify the patient population that should there is not a standardized definition of “severe
be treated. hypertriglyceridemia,” in general it is stated to
be triglyceride levels at which the risk of acute
• Describe the current evidence-based guidelines
pancreatitis is high—often considered to be
for treatment of hypertriglyceridemia.
above 800 to 1000 mg/dL (9.04-11.30 mmol/L).
• Discuss the risks and benefits of lipid-lowering However, triglycerides are a particularly labile
therapy, including combination therapy. lipid and can vary within an individual over
• Discuss the use of lipid-lowering medications time and be influenced by food intake, exercise,
in pregnancy. alcohol consumption, and medication use, among
other factors. Thus, providers and patients may
not necessarily recognize when the triglyceride
levels become “severe,” and this can cause missed
Significance of the opportunities to treat and prevent an episode of
acute pancreatitis.
Clinical Problem
Further compounding the situation is a
Elevated triglyceride levels are a common common misperception that combination lipid-
occurrence in the setting of comorbidities, such as lowering therapy with agents targeting LDL
obesity, diabetes, metabolic syndrome, and chronic cholesterol (eg, statins) and agents targeting
inflammatory diseases. While it has long been triglycerides (eg, fibrates) can be dangerous.
known that severe hypertriglyceridemia can cause This can lead to provider hesitancy to provide
acute pancreatitis, the role of elevated triglycerides prescription therapy for patients with or at risk of
in atherosclerotic cardiovascular disease (ASCVD) severe hypertriglyceridemia. Another challenge
has remained controversial. However, current is that hesitancy around combination therapy
guidelines do indicate that elevated triglycerides can lead to missed opportunities to provide
are a contributing risk factor and should be ASCVD-reducing LDL cholesterol–targeted
addressed.1 Given that most health care providers therapies in patients with a history of triglyceride-
are focused on ASCVD risk reduction, the induced pancreatitis.
primary focus of lipid management has been on
LDL-lowering therapies, and many health care

104 ENDO 2025 • Endocrine Case Management

Practice Gaps Classification of
Hypertriglyceridemia
• Lack of awareness of how to identify patients
Various guidelines and committees have slightly
at risk of severe hypertriglyceridemia.
different classification of triglyceride levels. Table 1
• Hesitancy to prescribe combination lipid- reflects the Endocrine Society classification.3
lowering therapy for patients with or at
risk of severe hypertriglyceridemia and/ Table 1. Classification of Triglyceride Levels
or for patients with a history of severe
hypertriglyceridemia and acute pancreatitis Classification Triglyceride concentration

who also have increased ASCVD risk. Normal <150 mg/dL

(SI: <1.70 mmol/L)
• Lack of comfort in treating pregnant women
Mild hypertriglyceridemia 150-199 mg/dL
with hypertriglyceridemia. (SI: 1.70-2.25 mmol/L)

Moderate hypertriglyceridemia 200-999 mg/dL

Discussion (SI: 2.26-11.29 mmol/L)

Severe hypertriglyceridemia 1000-1999 mg/dL

Triglyceride Metabolism (SI: 11.30-22.59 mmol/L)

Triglycerides are a lipid molecule found on Very severe >2000 mg/dL

chylomicrons (produced by the gut) and VLDL hypertriglyceridemia (SI: >22.60 mmol/L)

particles (produced by the liver) and their Reprinted from Berglund L et al. J Clin Endocrinol Metab, 2012; 97(9):
respective remnant particles. Collectively, these 2969-2989. © by The Endocrine Society.

particles are termed triglyceride-rich lipoproteins The plasma composition of lipid particles varies
(TRL). Dietary triglycerides consumed in a among individuals, but when fasting triglycerides
fatty meal are hydrolyzed in the intestine to free are greater than 1000 mg/dL (>11.30 mmol/L),
fatty acids and monoglycerides; these are then chylomicrons are present in addition to VLDL.
absorbed by enterocytes and resynthesized to form Individuals with triglyceride levels greater than
triglycerides. The intestinal enterocytes reassemble 1000 mg/dL (>11.30 mmol/L), and especially
triglycerides into chylomicrons containing greater than 2000 mg/dL (>22.60 mmol/L), are
apolipoprotein (apo) B48. The chylomicrons considered to be at high risk for acute pancreatitis.
are released from the cells into the lymphatic
system, move into the thoracic duct, and then
enter plasma. Chylomicrons are metabolized by Genetic Causes of High Triglycerides
lipoprotein lipase (LPL) to yield smaller particles There are a number of genetic causes of
termed chylomicron remnants. Chylomicrons and hypertriglyceridemia (Table 2, following page).
chylomicron remnants are taken up by the liver. Patients with severe hypertriglyceridemia often
Both lipids derived from chylomicron remnants have genetic causes or predispositions to high
and those synthesized de novo are reassembled triglycerides, although environmental factors also
in the liver as VLDL particles containing apo B100 have a role. For a review, see the article by Dron
and are secreted into the plasma. VLDL particles and Hegele.4
are also metabolized by LPL, which generates Individuals with monogenic
atherogenic remnant particles. Free fatty acids hypertriglyceridemia often have elevated
liberated by the action of LPL on TRLs can be triglycerides throughout the lifespan and
directed to adipose tissue for storage or used by may present in infancy. Polygenic causes
other tissues (eg, skeletal muscle, heart) as energy of hypertriglyceridemia have variable ages
substrates. For more details, see the chapter by of presentation.
Boren and Taskinen.2

ENDO 2025 • Cardiovascular Endocrinology 105

Table 2. Genetic Causes of Hypertriglyceridemia

Syndrome Genetic cause Typical triglyceride levels

Monogenic familial chylomicronemia LPL deficiency >1000 mg/dL

(SI: >11.30 mmol/L)
Apolipoprotein C-II deficiency
Apolipoprotein A-V pathogenic variants
LMF1 pathogenic variants
GPIHP1 deficiency

Polygenic chylomicronemia Unknown >1000 mg/dL

(SI: >11.30 mmol/L)

Familial hypertriglyceridemia Unknown, likely polygenic 200-1000 mg/dL

(SI: 2.26-11.30 mmol/L)

Dysbetalipoproteinemia or type 3 Apolipoprotein E2/E2 and other polygenic 200-1000 mg/dL

hyperlipoproteinemia susceptibility (SI: 2.26-11.30 mmol/L)

Familial combined hyperlipidemia Polygenic 200-1000 mg/dL

(SI: 2.26-11.30 mmol/L)

Causes of Acute Elevations Many medications can also trigger elevations

in Triglycerides in triglycerides:
Environmental factors can affect triglyceride • Antipsychotic medications (clozapine,
metabolism, particularly but not exclusively in olanzapine)
patients with underlying genetic predisposition • β-Adrenergic blockers
to hypertriglyceridemia (also termed the “second
hit”). Factors can affect triglyceride production • Bile acid–binding agents (due to the risk
and/or triglyceride metabolism. Common acquired of increasing triglycerides, these agents are
and environmental factors include: generally contraindicated in patients with
triglycerides >400 mg/dL [>4.52 mmol/L])
• Alcohol • Estrogens (especially oral estrogens) and
• High-calorie diet (fat, glucose, and fructose) the selective estrogen receptor modulators
• Hypothyroidism tamoxifen, raloxifene, clomiphene
• Insulin resistance (associated with obesity, • Glucocorticoids
metabolic syndrome, type 2 diabetes, • HIV antiretroviral medications
pregnancy, chronic kidney failure, chronic • Immunosuppressants (cyclosporine,
inflammatory conditions, etc) everolimus, sirolimus)
• Multiple myeloma • Retinoic acids
• Pregnancy • Thiazide diuretics
• Kidney diseases (nephrotic syndrome,
glomerulonephritis) Lability of Triglycerides
In addition, although less common than the Humans spend a significant amount of time
factors listed above, additional endocrine disorders in a postprandial state, and some individuals
associated with elevated triglycerides are type 1 have dramatic postprandial elevations of TRLs.
diabetes, Cushing syndrome, acromegaly, polycystic These patients tend to have saturation of the
ovarian syndrome, and male hypogonadism.5 LPL removal system and can experience a rapid

106 ENDO 2025 • Endocrine Case Management

increase of triglyceride levels after consumption Triglyceride Lowering and
of high-fat meals; this can be exacerbated by Combination Therapy
consumption of simple sugars, fructose, and
alcohol in susceptible individuals. However, most Due to the significant impact of diet on
guidelines are based on measurements of fasting triglycerides, a low-fat/low-sugar diet and
triglycerides, which can lead to providers missing weight loss, especially when combined with
patients at risk of severe hypertriglyceridemia and increased physical activity, can induce triglyceride
associated complications. reductions of 10% to 70%. In patients with severe
hypertriglyceridemia, intermittent fasting or
consumption of a diet with total fat less than 15%
High Triglycerides and of daily calories can reduce triglycerides. The
Risk of Pancreatitis Endocrine Society’s Lipid Management in Patients
Hypertriglyceridemia-induced pancreatitis is a with Endocrine Disorders Clinical Practice
common cause of acute pancreatitis (gallstone- Guideline recommends the use of pharmacologic
induced and alcohol-induced pancreatitis are treatment as adjunct to diet and exercise to prevent
the leading causes). The incidence of acute pancreatitis in adults with fasting triglyceride
pancreatitis is estimated to be up to 5% in levels above 500 mg/dL (>5.65 mmol/L).5 Table
patients with triglyceride concentrations greater 3 indicates the expected triglyceride lowering of
than 1000 mg/dL (>11.30 mmol/L) and up to common lipid-lowering agents.
20% in patients with triglycerides greater than
2000 mg/dL (>22.60 mmol/L).6 While the Table 3. Expected Triglyceride Lowering
With Common Lipid-Lowering Agents
mechanism(s) underlying hypertriglyceridemia-
induced acute pancreatitis are not fully Agent Expected triglyceride reduction
understood, theories include toxicity induced by Statins 10%-30%
triglyceride lipolysis and high levels of free fatty
Ezetimibe Up to 10%
acids, as well as hyperviscosity leading to decreased
microcirculation and pancreatic ischemia.7 Niacin 35%-50%

PCSK9 inhibitors Up to 25%

Triglycerides in ASCVD Bile acid binders No change or increase

In addition to being a risk factor for acute Bempedoic acid No change

pancreatitis, guidelines consider chronic Icosapent ethyl 20%-45%

hypertriglyceridemia to be a risk-enhancing factor Fibrates 35%-50%
for ASCVD, related to the atherogenic potential
of TRLs, particularly remnant particles. The Although there have been warnings of increased
American College of Cardiology recommends risks of adverse effects with statin and fibrate
lifestyle interventions (low-fat/calorie diet combinations, randomized controlled trials
and avoidance of alcohol) and consideration of and meta-analyses have demonstrated the
addition of triglyceride-reducing medications safety and efficacy of using these drugs in
(icosapent ethyl or fibrates) to maximally tolerated combination, particularly when fenofibrate is
statin therapy in patients with triglyceride the triglyceride-reducing agent used.8,9 However,
concentrations greater than 500 mg/dL due to longstanding concerns about increased
(>5.65 mmol/L).1 toxicity, many providers are reluctant to use these
medications in combination, thus potentially
depriving patients of benefit.

ENDO 2025 • Cardiovascular Endocrinology 107

New and Potential Therapies fibrates in the second trimester.11 Pancreatitis
in pregnancy confers a high risk for fetal loss,
Since patients with familial chylomicronemia
particularly in the first trimester.
syndrome are often minimally responsive or
nonresponsive to currently available triglyceride-
lowering agents due to a lack of LPL activity, new Clinical Case Vignettes
therapies are urgently needed. Approaches to
Case 1
antagonize apo CIII are the most promising. Apo
CIII increases triglyceride levels via inhibiting A 48-year-old woman with a history of
LPL and decreasing hepatic clearance of TRLs. hypertriglyceridemia-induced pancreatitis
Thus, targeting apo CIII has emerged as a presents for routine follow-up. She reports that
therapeutic approach. In Europe, volanesorsen, she has followed management advice and is now
an unconjugated antisense oligonucleotide against consuming a very low-fat diet. She continues to
APOC3 mRNA, has been shown to reduce take icosapent ethyl, 2 g twice daily; fenofibrate,
triglyceride levels and reduce the risk of acute 137 mg daily; and atorvastatin, 20 mg daily. The
pancreatitis. However, volanesorsen has not table shows her current and previous (6 months
been approved in the United States. Olezarsen ago) lipid panels, on the same lipid-lowering
is a conjugated antisense oligonucleotide against medications. She has ongoing fatigue, some
APOC3 mRNA that was recently approved in puffiness in her hands and feet, and hot flashes,
the United States based on its ability to decrease for which she recently started estrogen and
triglyceride levels by approximately 50% with no progesterone therapy.
major adverse effects.10 Parameter Current 6 months ago

Total cholesterol 238 mg/dL 160 mg/dL

Triglycerides in Pregnancy (SI: 6.16 mmol/L) (SI: 4.14 mmol/L)

Estrogens increase triglyceride levels by Triglycerides 1548 mg/dL 660 mg/dL

(SI: 17.49 mmol/L) (SI: 7.46 mmol/L)
stimulating hepatic triglyceride production.
In women with a genetic predisposition to HDL cholesterol 24 mg/dL 32 mg/dL
(SI: 0.62 mmol/L) (SI: 0.83 mmol/L)
hypertriglyceridemia, pregnancy can impose
significant increased risk for the development of
severe hypertriglyceridemia and acute pancreatitis. Which of the following is the first
In pregnant patients at high risk, omega-3 priority in this patient’s management?
fatty acids and fibrates have been used with A. Advise a lower-carbohydrate diet
no apparent adverse outcomes. Fibrates were B. Assess alcohol intake
considered category C in pregnancy until 2015 C. Discontinue estrogen and progesterone
when these categories were eliminated by the therapy
US FDA. The 2018 FDA label for the fenofibrate
D. Measure kidney function
Tricor states that data in pregnant women are
insufficient to determine the risk of major birth E. Measure TSH
defects, miscarriage, or adverse maternal or fetal Answer: C) Discontinue estrogen therapy
outcomes and that this drug should be used during
pregnancy only if the potential benefit justifies the The patient in this vignette has known
potential risk to the fetus. For patients at high risk hypertriglyceridemia and a history of acute
of triglyceride-induced complications (triglyceride pancreatitis. However, on her current
>500 mg/dL [>5.65 mmol/L]) during pregnancy, medications, her triglyceride levels have been
the National Lipid Association recommends use relatively well controlled. She now presents
of dietary interventions, omega-3 fatty acids, or with a significant increase in triglycerides,

108 ENDO 2025 • Endocrine Case Management

but fortunately she has no symptoms of acute Fasting lipid panel:
pancreatitis. Numerous environmental and
Total cholesterol = 238 mg/dL (<200 mg/dL
dietary factors affect triglyceride metabolism, [optimal]) (SI: 6.16 mmol/L [<5.18 mmol/L])
including hypothyroidism, high-carbohydrate Triglycerides = >1400 mg/dL (<150 mg/dL
diet, kidney dysfunction (in particular, nephrotic [optimal]) (SI: >15.82 mmol/L [<1.70 mmol/L])
syndrome), medications (eg, estrogen), alcohol HDL cholesterol = 22 mg/dL (>60 mg/dL [optimal])
(SI: 0.57 mmol/L [>1.55 mmol/L])
intake, and others. However, in patients with
Fasting glucose = 136 mg/dL (70-99 mg/dL)
genetic hypertriglyceridemia, such as the patient (SI: 7.5 mmol/L [3.9-5.5 mmol/L])
in this vignette, estrogen therapy is a relative
contraindication and is the most likely contributor Which of the following is the best next step?
to the dramatic increase in her triglyceride levels. A. Admit to the hospital and initiate intravenous
Discontinuing estrogen (Answer C) is the best insulin therapy
next step.
While hypothyroidism can lead to slower lipid B. Admit to the hospital and initiate
metabolism, the relative change in triglyceride plasmapheresis
levels tends to be minimal,12 and measuring TSH C. Initiate a very low-fat diet
(Answer E) is not the highest priority. D. Initiate statin therapy
When patients consume a low-fat diet, the E. Initiate omega-3 fatty acids and fenofibrate
relative consumption of carbohydrates increases,
and these carbohydrates can lead to increased fatty Answer: E) Initiate omega-3 fatty acids and fenofibrate
acid synthesis and increased triglyceride levels.13,14
This asymptomatic pregnant patient
However, this would be unlikely to cause such a
has incidentally discovered severe
degree of triglyceride elevation, and advising a
hypertriglyceridemia. While her triglycerides
lower-carbohydrate diet (Answer B) is not the best
are significantly elevated, she has no symptoms
next step.
suggesting acute pancreatitis. Thus, while
Kidney dysfunction and nephrotic syndrome
treatment should be initiated, it is not an
can cause significant changes in lipid metabolism;
emergency, and she does not require hospital
however, there are no indications in the vignette
admission (Answers A and B). If she had
that this patient has nephrotic syndrome. While
symptoms suggestive of pancreatitis, then
measuring kidney function (Answer D) would be
plasmapheresis could be considered; however,
prudent, it is not the most important next step.
plasmapheresis should not be initiated unless
Finally, while alcohol consumption can raise
a trial of medical management has failed. Her
triglycerides, especially in the postprandial stage,15
fasting glucose is elevated, indicating she likely
and assessing alcohol consumption (Answer B)
has diabetes, which is another risk factor possibly
is prudent, there is no information suggesting an
contributing to her hypertriglyceridemia. Unless
increase in alcohol consumption.
her glucose level was much higher and she had
acute pancreatitis, there is no indication for
Case 2 intravenous insulin therapy now.
A 27-year-old woman is referred by her While omega-3 fatty acids and fibrates
obstetrician who noticed that her blood looked (Answer E) are considered pregnancy category
like a strawberry milkshake after a blood draw for C (risk in pregnancy cannot be ruled out), she is
recent labs. She is 14 weeks pregnant, takes no at high risk for pancreatitis due to her elevated
medications other than a prenatal multivitamin, triglycerides, which confers both fetal and
and has no concerns on review of systems. maternal risks. Thus, initiation of triglyceride-
lowering therapy is the best next step.16,17

ENDO 2025 • Cardiovascular Endocrinology 109

 Although statin therapy (Answer D) Which of the following changes to his lipid-
could be considered in pregnancy for severe lowering therapy should be recommended?
hypercholesterolemia, statins have weak triglyceride- A. Add ezetimibe
lowering effects and are not the best next step. B. Add fenofibrate
Providing dietary advice for a low-fat
C. Add niacin
diet (Answer C) is appropriate for both her
lipid disorder and presumptive diabetes, D. Change atorvastatin to rosuvastatin, 40 mg
but it is insufficient to address her risk and daily
pharmacotherapy should be initiated. E. Recommend no changes
Answer: B) Add fenofibrate
Case 3
The patient in this vignette was sent for
A 52-year-old man is referred for assessment
consultation for cardiovascular risk but is actually
of cardiovascular risk reduction. He has never
at high risk of severe hypertriglyceridemia. He is
had an atherosclerotic cardiac event and has
on appropriate statin therapy for cardiovascular
no cardiac symptoms. However, 5 years ago
risk. Three months ago, his fasting triglyceride
he had acute pancreatitis thought to be due to
concentration was elevated, but his direct LDL-
hypertriglyceridemia. He has a history of type 2
cholesterol concentration was almost at goal
diabetes diagnosed 5 years ago, which is currently
(his LDL-cholesterol goal would be <70 mg/dL
treated with metformin and glargine insulin once
[<1.81 mmol/L] given his diabetes). However, a
daily. He is a former cigarette smoker but quit
nonfasting lipid panel today demonstrates very
5 years ago at the time of diabetes diagnosis. He
high triglyceride levels, conferring increased risk
tries to eat a healthy diet but struggles, and he
for acute pancreatitis. His glycemic control has
acknowledges that he consumes alcohol most days
worsened, likely contributing to the triglyceride
of the week. He takes atorvastatin, 40 mg daily,
elevation. Given his previous episode of acute
and has been hesitant to increase the dosage. He
pancreatitis and his elevated triglycerides, the
also takes metoprolol, gabapentin, and sertraline.
acute risk of pancreatitis is the top priority, and a
The consultation information includes a
triglyceride-lowering drug (fenofibrate [Answer
fasting lipid panel from 3 months ago:
B]) should be added to his regimen.
Total cholesterol = 183 mg/dL (<200 mg/dL Changing atorvastatin to rosuvastatin (Answer
[optimal]) (SI: 4.74 mmol/L [<5.18 mmol/L]) D) or adding ezetimibe (Answer A) would help
Triglycerides = 602 mg/dL (<150 mg/dL [optimal])
reduce his cardiovascular risk but would not lower
(SI: 6.80 mmol/L [<1.70 mmol/L])
HDL cholesterol = 31 mg/dL (>60 mg/dL [optimal]) his triglycerides very much.
(SI: 0.80 mmol/L [>1.55 mmol/L]) Adding niacin (Answer C) could lower
Direct LDL cholesterol = 72 mg/dL (<100 mg/dL triglycerides, but niacin is poorly tolerated and could
[optimal]) (SI: 1.86 mmol/L [<2.59 mmol/L]) lead to further deterioration in glycemic control.
Hemoglobin A1c = 7.8% (4.0%-5.6%) (62 mmol/mol
Doing nothing (Answer E) is not appropriate
[20-38 mmol/mol])
given his acute pancreatitis risk and cardiovascular
You decide to repeat the lipid panel even though risk. Using combination statin plus fibrate therapy
he ate breakfast 2 hours ago (he reports stopping is indicated to address both his cardiovascular and
at a fast-food restaurant on his way to clinic). hypertriglyceridemia risk.
Total cholesterol = 262 mg/dL (SI: 6.79 mmol/L)
Triglycerides = 1368 mg/dL (SI: 15.46 mmol/L)
HDL cholesterol = 22 mg/dL (SI: 0.57 mmol/L)
LDL cholesterol, cannot be calculated
Hemoglobin A1c = 8.2% (66 mmol/mol)

110 ENDO 2025 • Endocrine Case Management

Key Learning Points • Severe hypertriglyceridemia in pregnancy
confers high risk for fetal loss due to
• Severe hypertriglyceridemia conveys risk for pancreatitis. Neither fibrates nor statins are
acute pancreatitis; providers should consider contraindicated in pregnancy. Fenofibrate may
both cardiovascular risk reduction and be used cautiously in women at high risk who
prevention of acute pancreatitis in patients have severe hypertriglyceridemia. The use of
with high triglycerides. statins in pregnancy is discouraged except in
women with familial hypercholesterolemia,
• Environmental, medical, and lifestyle
other severe LDL increases, or ASCVD when
factors can significantly raise triglycerides
the benefits outweigh the risks.
in susceptible individuals; providers should
screen and remove or treat contributing • Nonfasting triglyceride levels may be a better
factors. indicator of risk than fasting triglyceride levels.

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5. Newman CB, Blaha MJ, Boord JB, et al. Lipid management in patients with 14. Schwarz, J. M., P. Linfoot, D. Dare, and K. Aghajanian. 2003. Hepatic de novo
endocrine disorders: an Endocrine Society clinical practice guideline. J Clin lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming
Endocrinol Metab. 2020;105(12):dgaa674. PMID: 32951056 high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets.
6. Rawla PT, Sunkara KC, Thandra KC, Gaduputi V. Hypertriglyceridemia- Am J Clin Nutr 77: 43-50.
induced pancreatitis: updated review of current treatment and preventive 15. Van de Wiel, A. 2012. The effect of alcohol on postprandial and fasting
strategies. Clin J Gastroenterol. 2018;11(6):441-448. PMID: 29923163 triglycerides. Int J Vasc Med 2012: 862504.
7. Meng Y, Han P, Ma X, He Y, Chen H, Ren H. Research progress on 16. Gupta, M., B. Liti, C. Barrett, P. D. Thompson, and A. B. Fernandez. 2022.
the mechanism of acute hypertriglyceridemic pancreatitis. Pancreas. Prevention and Management of Hypertriglyceridemia-Induced Acute
2024;53(8):e700-e709. PMID: 38696438 Pancreatitis During Pregnancy: A Systematic Review. Am J Med 135: 709-714.
8. Keech A, Simes RJ, Barter P, et al; FIELD Study Investigators. Effects of long- 17. Schatoff, D., I. Y. Jung, and I. J. Goldberg. 2024. Lipid Disorders and
term fenofibrate therapy on cardiovascular events in 9795 people with type Pregnancy. Endocrinol Metab Clin North Am 53: 483-495.
2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet.
2005;366(9500):1849-1861. PMID: 16310551

ENDO 2025 • Cardiovascular Endocrinology 111

DIABETES AND
VASCULAR DISEASE
Monitoring Diabetes Control
Using Hemoglobin A1c and
Continuous Glucose Monitoring:
Advantages and Pitfalls
Shichun Bao, MD, PhD. Division of Diabetes, Endocrinology, and Metabolism, Department of
Medicine, Vanderbilt University Medical Center, Nashville, TN; Email: [email protected]

Educational Objectives stress, or medications affect their glucose levels

and how to prevent hypoglycemia3; however,
After reviewing this chapter, learners should be
many factors can affect the accuracy of CGM.4
able to:
Cost and accessibility, sensor calibration, skin
• Explain the advantages and pitfalls of sensitivity, and user overload can be problems.
hemoglobin A1c (HbA1c) and continuous Health care providers must be able to identify
glucose monitoring (CGM). problems with glucose monitoring, investigate
potential causes, provide better education,
• Identify potential causes of glucose monitoring
and deliver high-quality care to patients using
discrepancies.
personalized approaches.
• Manage CGM therapy using a personalized
approach.
Practice Gaps
• Lack of awareness of the conditions that can
affect HbA1c and CGM accuracy.
Significance of the
Clinical Problem • Insufficient knowledge about different features
of various CGMs and skills related to CGM
Monitoring glycemic control using HbA1c and problem-solving.
CGM each has advantages and pitfalls. HbA1c is
a useful tool for the diagnosis and management • Lack of extensive training on CGM ordering
of diabetes and is generally an excellent marker for different patient populations, data analysis,
of overall glycemic control for the preceding 8 and management.
to 12 weeks.1 However, HbA1c does not capture
short-term glucose fluctuations or hypoglycemic Discussion
episodes. It may not reflect recent improvements
Monitoring glycemic control using HbA1c and
or deteriorations in glycemic control. HbA1c
CGM has advantages and pitfalls. HbA1c is formed
accuracy can be affected by many conditions.2
by the concentration-dependent nonenzymatic
CGM provides real-time glucose readings,
linkage of glucose to the N-terminal valine of the
allowing users to see immediate changes in glucose
hemoglobin β chain.5 It is an excellent marker of
levels all the time and track glucose trends, which
overall glycemic control during the time frame
can help them understand how food, exercise,

114 ENDO 2025 • Endocrine Case Management

of the 120-day lifespan of a normal erythrocyte chronic blood loss, can cause falsely lowered
and is routinely used for both management and HbA1c results. Patients with end-stage kidney
diagnosis of diabetes.2 Four basic methodologies disease generally have falsely low HbA1c values,
are used for HbA1c measurement, as standardized primarily due to the associated chronic anemia
by the National Glycohemoglobin Standardization with increased erythrocyte turnover.
Program (NGSP): immunoassay, ion-exchange
high-performance liquid chromatography (HPLC), CGM is widely used, especially in the last few
boronate affinity HPLC, and enzymatic assays.6 years, as part of diabetes management, and
Point-of-care (POC) HbA1c measurements are should be recommended to every person with
generally immunoassay-based. POC HbA1c is diabetes who is on insulin treatment.8 CGM
commonly used in the provider’s office to obtain provides real-time glucose readings, allowing
immediate results and provide feedback for timely users to see immediate changes in glucose levels
adjustment in the treatment regimen. POC values all the time and track glucose trends, which helps
can have small variations from values obtained users understand how food, exercise, stress, and
in the central laboratory, and this is attributed to medications affect their glucose levels and how to
different methodologies.7 prevent hypoglycemia.3 Over-the-counter CGM
The main pitfalls of HbA1c: has been increasingly used by people without
diabetes who are seeking personalized insight into
1. HbA1c does not capture short-term glucose metabolic health, behavioral motivation, enhanced
fluctuations and hypoglycemic episodes. athletic performance, and early detection of
It may not reflect recent improvements or glucose dysregulation.9
deteriorations in glycemic control. The main pitfalls of CGM:
2. Multiple conditions can interfere with HbA1c 1. Many factors affect the accuracy of CGM
results in 2 basic ways: direct interference with systems
the assay’s ability to accurately detect glycated ԗ Physiological factors: lag time (typically 5- to
hemoglobin molecules, and physiologic 15-minute delay in blood glucose changes
factors that alter the concentration of HbA1c and CGM readings), hydration levels, body
in the patient’s blood in such a way that it no temperature, and sweat can affect CGM
longer accurately reflects glycemic control. readings.
Hemoglobin variants can directly interfere
with some assays’ detection of glycated ԗ Device-related factors: sensor placement,
hemoglobin. The degree of interference sensor calibration, sensor age, and
depends on the assay used, leading to insertion site issues can affect CGM
artificially increased or decreased results.6 readings.
Conversely, any condition that prolongs ԗ Environmental factors: compression artifacts,
erythrocyte survival, such as asplenia, or that altitude, and electromagnetic interference
decreases erythrocyte turnover, such as iron can affect CGM performance.
deficiency anemia, B12 deficiency, or folate ԗ Medication and substance interference:
deficiency anemia, can cause falsely elevated acetaminophen, hydroxyurea, vitamin C,
HbA1c. Uremia and chronic ingestion of salicylic acid, tetracycline, mannitol, etc,
alcohol, salicylates, opioids, or lead poisoning can affect certain CGM readings.
have also been associated with falsely elevated
ԗ Calibration time errors: calibration should
HbA1c.2 Similarly, any condition that shortens
be done during stable glucose periods,
the life of erythrocytes or is associated with
not during times of rapid blood glucose
increased erythrocyte turnover, such as
changes.
splenomegaly, hemolytic anemia, or acute or

ENDO 2025 • Diabetes and Vascular Disease 115

 ԗ Sensor adhesion and movement: Loose or meter data shows that she is checking fingerstick
poor adhesion, movement, or improper blood glucose on average 0.5 times a day, usually
attachment can affect the sensor’s ability to fasting in the morning or before dinner, with
provide accurate readings. a 3-month average glucose concentration of
ԗ Individual variability: skin composition 138 mg/dL (7.7 mmol/L) (range, 110-164 mg/dL
(differences in skin thickness, body fat [6.1-9.1 mmol/L]), A repeat HbA1c measurement
distribution and immune response (in by a central laboratory is 9.2% (77 mmol/mol).
some cases, the body may mount an Her fructosamine concentration is 340 µmol/L
immune response against the sensor, (reference range, 170-285 µmol/L).
causing inflammation or irritation of
surrounding skin) can cause inaccurate Which of the following is the best
next step given this patient’s goal?
CGM readings.
A. Add glimepiride
2. Cost and accessibility: CGM can be expensive B. Add long-acting insulin
and may not be accessible for everyone due C. Add short-acting insulin
to insurance coverage or out-of-pocket costs. D. Instruct her to measure fingerstick blood
Coverage and the ordering process vary for glucose 3 to 4 times a day, before meals
different patient populations (via formulary and at bedtime, and return in 3 months to
prescription plan vs Duel Medical Equipment measure HbA1c
coverage). E. Instruct her to measure fingerstick blood
3. User overload: The constant flow of data glucose 3 to 4 times a day, before meals and at
and glucose alerts can be overwhelming for bedtime, initiate a blinded professional CGM,
some individuals. Insufficient training on and reassess in 2 weeks
how to properly use CGM can cause data
misinterpretation, anxiety, and frustration for Answer: E) Instruct her to measure fingerstick
both patients and providers. blood glucose 3 to 4 times a day, before meals
and at bedtime, initiate a blinded professional
CGM, and reassess in 2 weeks
Clinical Case Vignettes HbA1c has been routinely used for management
Case 1 and diagnosis of diabetes. HbA1c is generally an
excellent marker of overall glycemic control for
A 54-year-old African American woman with the preceding 8 to 12 weeks; however, it does
type 2 diabetes is treated with dapagliflozin, not capture short-term glucose fluctuations or
10 mg daily; metformin, 1000 mg twice daily; hypoglycemic episodes. It may also not reflect
and liraglutide subcutaneous injection, 1.8 mg recent improvements or deteriorations in glycemic
daily. The only other medication she takes is control. POC HbA1c values can have small
irbesartan/hydrochlorothiazide, 300/25 mg daily, variations from central laboratory measurements
for hypertension, and she takes no supplements. of HbA1c, which is attributed to the different
She needs a knee replacement for severe arthritis methodologies. HbA1c accuracy can be affected
and was told she could not have surgery until her by many conditions; therefore, the result should
HbA1c is below 8.0% (<64 mmol/mol). Her recent be interpreted with caution. This patient’s HbA1c
HbA1c measurement was 9.5% (80 mmol/mol), did not correlate with her fingerstick blood
and she needs help to decrease this value. Her glucose values, with much lower-than-expected
POC HbA1c value in the clinic today is 10.8% fingerstick blood glucose readings based on
(95 mmol/mol). Review of her home glucose her high HbA1c measurement, which could be

116 ENDO 2025 • Endocrine Case Management

due to her infrequent fingerstick blood glucose (Answer E), should be considered to investigate
sampling and missed high readings. While more the big discrepancy between this patient’s HbA1c
frequent measurement of blood glucose should and fingerstick blood glucose values. In this case,
be recommended, inaccurate HbA1c should also a blinded CGM trial would be a good option, so
be suspected. the patient would not see her CGM readings and
Fructosamine can be used as an alternative subsequently change her lifestyle, which could
analyte to monitor glycemic control in patients affect readings during the CGM trial period.
with known or suspected inaccurate HbA1c. This patient was placed on a 14-day blinded
Fructosamine refers to the product formed by professional CGM and was told to come back
nonenzymatic reaction of glucose and albumin and in 2 weeks for reevaluation. Simply measuring
reflects a much shorter period of glycemic control fingerstick blood glucose more frequently and
than HbA1c (about 20 days vs 120 days), due to coming back in 3 months to measure HbA1c
the shorter half-life of albumin.5 Unfortunately, (Answer D) would delay her surgery unnecessarily.
conditions such as nephrotic syndrome and Medications that could cause hypoglycemia
cirrhosis can interfere with fructosamine (Answers A, B, and C) should not be added before
measurement,10 and these values must be confirming the accuracy of her high HbA1c.
interpreted with the clinical context in mind.
This patient’s fructosamine concentration was Case 1, Continued
slightly elevated at 340 µmol/L (reference range,
170-285 µmol/L), which should correlate to an Her CGM and glucose meter data are
estimated HbA1c value of 8.0% (64 mmol/mol) and downloaded at her 2-week follow-up visit. Her
an average glucose concentration of 180 mg/dL CGM ambulatory glucose profile shows an
(9.9 mmol/L),5 suggesting her HbA1c could be average glucose concentration of 165 mg/dL
falsely elevated. (9.1 mmol/L), 73% of readings in the target range
In the meantime, an alternative method of of 70 to 180 mg/dL (3.9-10.0 mmol/L), and an
glucose monitoring, such as a professional CGM estimated HbA1c of 7.4% (57 mmol/mol) (Figure),10

Figure.

LibreView daily patterns report shows ambulatory glucose profile with average sensor glucose of 165 mg/dL (9.2 mmol/L), 73% readings within the target
range of 70 to 180 mg/dL (3.9-10.0 mmol/L), and an estimated HbA1c of 7.4% (57 mmol/mol). Dark and light shading shows 25th-75th and 10th-90th
percentiles, respectively.
[Color—Print (Color Gallery page CG9) or web & ePub editions]

ENDO 2025 • Diabetes and Vascular Disease 117

correlating reasonably well with her fingerstick variant analysis revealed an HbC percentage of
blood glucose data (average 3.4 readings 31%, consistent with HbC trait. HbC trait has been
per day, mean glucose concentration of reported to be a cause of inappropriately elevated
142 mg/dL (7.9 mmol/L) (range 108-181 mg/dL HbA1c.12Hemolytic anemia and acute or chronic
[6.0-10.0 mmol/L]). You tell her that her HbA1c blood loss can cause falsely low, not high, HbA1c
was falsely higher and that you will explain this results. Therefore, studies to evaluate hemolytic
to her surgeon, so her surgery does not need to anemia and its causes (Answers A and B) are not
be delayed. She asks why her HbA1c is falsely high indicated. This patient did not have a history
and wonders what additional tests could be done of chronic alcohol ingestion or lead poisoning
to evaluate the possible cause. She does not use (Answers D and E).
alcohol, salicylate, vitamin C, or opioids and has In conclusion, CGM is a valuable tool to assess
no history of asplenia. discordance between HbA1c and fingerstick blood
glucose values and to guide subsequent diabetes
Which of the following management. HbA1c values are useful in most
should be ordered next? cases, but they can also be subject to elevations
A. Hematocrit and lactate dehydrogenase or depressions that are not indicative of the
measurement patient’s clinical picture and must be interpreted
B. Bone marrow biopsy with the clinical context in mind. An alternative
assay or analyte can also be used to investigate
C. Hematocrit, iron, folic acid, and vitamin B12
the discrepancy. With the availability of relatively
measurement and hemoglobin electrophoresis
easier-to-use, lower-cost, and longer-duration
D. Blood alcohol measurement CGM, clinicians should consider using CGM to
E. Blood lead measurement investigate the accuracy of HbA1c and the reliability
of fingerstick blood glucose and to explore the
Answer: C) Hematocrit, iron, folic acid, and vitamin
causality of discrepancy with HbA1c.
B12 measurement and hemoglobin electrophoresis
Conditions that prolong erythrocyte survival, Case 2
such as asplenia, or that decreases erythrocyte
turnover, such as iron deficiency anemia, vitamin A 72-year-old woman with type 1 diabetes uses
B12 deficiency, or folate deficiency anemia can a Medtronic insulin pump. She has a history
cause falsely elevated HbA1c. Uremia and chronic of mini stroke with some weakness in her left
ingestion of alcohol, salicylates, opioids, or hand. She also has thrombocythemia treated
lead poisoning have also been associated with with hydroxyurea and clopidogrel. She does not
falsely elevated HbA1c.2 The patient’s hematocrit, take high-dosage vitamin C. Her POC HbA1c in
creatinine, iron, folic acid, and vitamin B12 levels the clinic office is 8.1% (65 mmol/mol). She has
were all within reference range. been using a glucose meter to monitor her blood
Hemoglobin (Hb) variants, including HbS, glucose 3 to 4 times per day. Her meter download
HbC, or HbF, are found in approximately 7% of reveals frequent hyperglycemia but also frequent
the world’s population and in about 10% of the hypoglycemia with glucose readings in the range
African American population,10 and they can of 50 to 60 mg/dL (2.8-3.3 mmol/L). CGM is
directly interfere with some assays’ detection of recommended.
glycated hemoglobin. The degree of interference
depends on the assay used.2 The best next step
in this patient’s care is to measure hematocrit,
iron, folic acid, and vitamin B12 and perform
hemoglobin electrophoresis (Answer C). Her Hb

118 ENDO 2025 • Endocrine Case Management

Which CGM should be considered as readings or sensor failures. Clopidogrel reduces
the first choice for this patient? platelet function, which may increase the risk
A. Disposable CGM not interfered by platelet of bruising or minor bleeding when inserting a
count CGM sensor, but platelet count (Answer A) and
B. Disposable CGM not interfered by clopidogrel (Answer C) generally do not directly
hydroxyurea interfere with CGM accuracy. A disposable CGM
not interfered by hydroxyurea (Answer B), such
C. Disposable CGM not interfered by clopidogrel
as Abbott’s CGM, is easy to use and could be
D. Implantable CGM not interfered by considered as the first choice for this patient.
hydroxyurea Abbott’s CGM can be affected by high levels of
E. Blinded professional CGM vitamin C.15 Taking more than 500 mg of vitamin
C a day may lead to falsely higher sensor glucose
Answer: B) Disposable CGM not readings. This patient is not on high-dosage
interfered by hydroxyurea vitamin C. An implantable CGM not interfered
Managing type 1 diabetes in elderly patients by hydroxyurea (Answer D) such as Eversense
presents unique challenges. Age-related factors, CGM, could also be an option. It is not interfered
such as cognitive decline, physical limitations, by hydroxyurea, although could be affected
and coexisting medical conditions, can complicate by tetracycline and mannitol, causing falsely
glycemic control and increase risks of both lower and higher sensor readings, respectively.16
hyperglycemia and hypoglycemia. Hypoglycemia Eversense CGM requires a small surgical
can be particularly dangerous for elderly patients procedure for sensor implantation and removal,
due to their increased vulnerability and the more wearing a transmitter on top of the sensor, and
severe consequences it can have on their health. sensor calibration with fingerstick blood glucose
Studies have shown that CGM improves glycemic measurement. Therefore, it would be considered
outcomes in older patients with type 1 diabetes.13 as the second choice for this patient. A blinded
This patient has hypoglycemia unawareness. She professional CGM (Answer E) would not provide
would benefit from using a CGM with glucose immediate glucose feedback and low glucose alerts.
alerts to reduce the risk of severe hypoglycemia.
Choosing the right CGM for a particular patient Case 3
requires an individualized approach, balancing
A 45-year-old man with type 1 diabetes is
ease of use, accuracy, and compatibility with an
scheduled to have a brain MRI for evaluation of
individual’s lifestyle and health care needs.
frequent headache. He has been using Abbott’s
Hydroxyurea is known to interfere with
CGM. He asks whether he should remove his
Medtronic’s disposable CGM and Dexcom
CGM sensor before the MRI or continue to wear
CGM sensors, can cause falsely higher CGM
it throughout the procedure.
glucose readings, which could result in missed
hypoglycemia alerts or errors in diabetes
management, such as administering too much
insulin due to falsely high sensor glucose values.14
Therefore, this patient should not use those
CGMs, although she would benefit from using
a Medtronic automatic insulin delivery system
integrated with Medtronic CGM if she were not
on hydroxyurea. A very high platelet count might
contribute to local clotting or inflammation at
the sensor site, potentially leading to inaccurate

ENDO 2025 • Diabetes and Vascular Disease 119

Which of the following is the for MRI, CT, and x-rays and reapplied after the
best recommendation? procedure. Glucose data return within 10 minutes
A. Remove it before MRI, replace with a new of reconnecting the transmitter.
sensor right after the procedure is completed, Abbott states their Libre CGM readings
and call the sensor company to ask for free may not be accurate during MRI, although
sensor replacement “uncompromised” readings will usually return after
B. Remove it before MRI, but do not replace it 1 hour. Users are advised to have their glucose
with a new sensor until the scheduled time for monitored closely during and after MRI using a
a new sensor, as her insurance might not cover glucose meter, until it is confirmed that the sensor
replacement of the one removed for MRI is still providing proper readings after MRI (thus,
Answer D is correct and Answer E is incorrect).
C. Remove it before MRI, self-pay for a new
The sensor does not need to be removed in
sensor, and start the new sensor right after the
advance of MRI (Answers A, B, and C).
procedure is completed
D. Continue wearing it throughout the
procedure, but monitor blood glucose closely Key Learning Points
with a glucose meter during and until at least 1
hour after the procedure to confirm the sensor • HbA1c and CGM monitoring have advantages
is still providing proper readings and pitfalls. Clinicians must be aware of the
conditions that can affect HbA1c and CGM
E. Continue wearing it throughout the
accuracy and interpret the results with the
procedure; no additional steps are required
clinical context in mind.
Answer: D) Continue wearing it throughout • CGM can be a valuable tool to evaluate
the procedure, but monitor blood glucose closely discordance of HbA1c and fingerstick blood
with a glucose meter during and until at glucose values, and to guide subsequent
least 1 hour after the procedure to confirm the diabetes management. Clinicians should
sensor is still providing proper readings consider using CGM to investigate the
accuracy of HbA1c and the reliability of
Electromagnetic interference can affect CGM
fingerstick blood glucose, and to identify
performance. Some sensors contain metal
potential causes of glucose monitoring
components that can interfere with MRI. In
discrepancies.
November 2024, Abbott’s CGM systems were
cleared by the FDA to stay on during MRI, CT, • Managing CGM requires a personalized
and x-ray procedures. Medtronic’s and Dexcom’s approach; sufficient knowledge of different
current guidance still state their sensors should features of various CGMs; skills on CGM
be removed for MRI and CT. For Eversense problem-solving; and extensive training
CGM, the sensor that is implanted under the skin on CGM ordering for different patient
is safe, but the transmitter should be removed populations, data analysis, and management.

References
1. Nathan DM, Kuenen J, Borg R, et al. Translating the A1C assay into 3. Rodbard D. Continuous glucose monitoring: a review of recent studies
estimated average glucose values. Diabetes Care. 2008;31(8):1473-1478. PMID: demonstrating improved glycemic outcomes. Diabetes Technol Ther.
18540046 2017;19(Suppl 3):S25-S37. PMID: 28585879
2. Radin MS. Pitfalls in hemoglobin A1c measurement: when results may be 4. Bellido V, Freckman G, Perez A, et al. Accuracy and potential interferences
misleading. J Gen Intern Med. 2014;29(2):388-394. PMID: 24002631 of continuous glucose monitoring sensors in the hospital. Endocr Pract.
2023;29(11):919-927. PMID: 37369291

120 ENDO 2025 • Endocrine Case Management

5. Wright LA-C, Hirsch IB. The challenge of the use of glycemic biomarkers 11. Wright JJ, Hu IR, Shajani-Yi Z, Bao S. Use of continuous glucose monitoring
in diabetes: reflecting on hemoglobin A1C, 1, 5-anhydroglucitol, and the leads to diagnosis of hemoglobin C trait in a patient with discrepant
glycated proteins fructosamine and glycated albumin. Diabetes spectrum. 2012; hemoglobin A1C and self-monitored blood glucose. AACE Clin Case Rep.
25(3):141-148. 2019;5(1):e31-e34. PMID: 31966996
6. Little RR, Roberts WL. A review of variant hemoglobins interfering with 12. Lorenzo-Medina M, De-La-Iglesia S, Ropero P, Nogueira-Salgueiro P,
hemoglobin A1c measurement. J Diabetes Sci Technol. 2009;3(3):446-451. Santana-Benitez J. Effects of hemoglobin variants on hemoglobin a1c values
PMID: 20144281 measured using a high-performance liquid chromatography method. J
7. Lenters-Westra E, Slingerland RJ. Three of 7 hemoglobin A1c point-of-care Diabetes Sci Technol. 2014;8(6):1168-1176. PMID: 25355712
instruments do not meet generally accepted analytical performance criteria. 13. Pratley RE, Kanapka LG, Rickels MR, et al; Wireless Innovation for Seniors
Clin Chem. 2014;60(8):1062-1072. PMID: 24865164 with Diabetes Mellitus (WISDM) Study Group. Effect of continuous
8. American Diabetes Association Professional Practice Committee. Summary glucose monitoring on hypoglycemia in older adults with type 1 diabetes: a
of revisions: standards of care in diabetes-2025. Diabetes Care. 2025;48(Suppl randomized clinical trial. JAMA. 2020;323(23):2397-2406. PMID: 32543682
1). PMID: 39651984 14. Szmullowicz ED, Aleppo G. Interferent effect of hydroxyurea on continuous
9. Klonoff DC, Nguyen KT, Xu NY, et al. Use of continuous glucose monitors glucose monitoring. Diabetes Care. 2021;44(5):e89-e90. PMID: 33653823
by people without diabetes: an idea whose time has come? J Diabetes Sci 15. Heinemann L. Interference with CGM systems: practical relevance? J Diabetes
Technol. 2023;17(6):1686-1697. PMID: 35856435 Sci Technol. 2021;16(2):271-274. PMID: 34911382
10. Sundaram RC, Selvaraj N, Vijayan G, Bobby Z, Hamide A, Dasse NR. 16. Lorenz C, Sandoval W, Mortllaro M. Interference assessment of various
Increased plasma malondialdehyde and fructosamine in iron deficiency endogenous and exogenous substances on the performance of the Eversense
anemia: effect of treatment. Biomed Pharmacother. 2007;61(10):682-685. long-term implantable continuous glucose monitoring system. Diabetes
PMID: 17698317 Technol Ther. 2018;20(5):344-352. PMID: 29600877

ENDO 2025 • Diabetes and Vascular Disease 121

SGLT-2 Inhibitor Therapy
in Type 2 Diabetes:
Advantages and Pitfalls
Aidar R. Gosmanov, MD, DMSc. Division of Endocrinology, Albany Medical College and
Section of Endocrinology, Stratton VAMC, Albany, NY; Email: [email protected]

Educational Objectives placebo-controlled trials, canagliflozin,

dapagliflozin, and empagliflozin—but not
After reviewing this chapter, learners should be
ertugliflozin—were shown to significantly reduce
able to:
CV death, heart failure hospitalizations, and
• Identify the clinical benefits and most kidney end points.2-5 A recent meta-analysis of
frequently observed adverse effects that occur SGLT-2 inhibitor effects on major adverse CV
in people with type 2 diabetes (T2D) after events clearly demonstrates that the therapeutic
initiation of SGLT-2 inhibitors. effects are driven by a reduction in CV death,
which in turn is explained by reductions in heart
• Identify approaches to effectively diagnose and
failure death and sudden cardiac death.6 In the
manage adverse effects of SGLT-2 inhibitors.
T2D trials with prespecified primary kidney
• Develop patient-centric strategies to reduce end points, SGLT-2 inhibitors consistently and
the risk of SGLT-2 inhibitor–associated significantly reduced the risk of kidney disease
adverse effects. progression in patients, regardless of baseline
estimated glomerular filtration rate.7
Despite the initial enthusiasm in the field,
prescription of SGLT-2 inhibitors in clinical
Significance of the practice remains lower than expected, placing
Clinical Problem a large number of patients who could have
benefitted from this class of medication at a
The landscape of diabetes pharmacotherapy has
disadvantage.8 While therapeutic inertia can
been revolutionized following FDA approval in
frequently explain delay in implementation of
2013 of the first SGLT-2 inhibitor, canagliflozin,
novel treatment modalities in the management of
for glycemic management in people with T2D.
chronic diseases, this notion by itself is unlikely to
In general, SGLT-2 inhibitors lead to modest
explain the persistently low prescription rate more
hemoglobin A1c reduction by 0.5% to 1.0%
than 10 years since approval of the first SGLT-2
depending on whether they were initiated in
inhibitor. We believe that unique and sometimes
drug-naïve patients or in patients already taking
serious, yet poorly predictable, adverse effects
metformin.1 The subsequent increase of SGLT-2
associated with the use of gliflozins make some
inhibitor use in clinical practice was, however,
providers cautious to initiate these agents. In this
driven not by their glycemic effects but rather by
chapter, the most frequently observed adverse
clear evidence of cardiovascular (CV) and kidney
effects associated with SGLT-2 inhibitors are
benefits that occur independent of their impact
discussed, as well as current knowledge in their
on glycemic control. In prospective, randomized
evaluation and management and challenges in

122 ENDO 2025 • Endocrine Case Management

predicting patient populations prone to develop infections (UTIs). The most serious yet rare
these adverse effects. adverse effect reported in these trials was the
development of diabetic ketoacidosis (DKA).
Finally, with the landmark trials demonstrating
Practice Gaps consistent placebo-adjusted increases in
hematocrit in those treated with SGLT-2
• The possibility of SGLT-2 inhibitor–
inhibitors,9 recent postmarketing observations
induced adverse effects in clinical practice is
revealed that some patients with T2D who are
overshadowed by the default assumption that
treated with SGLT-2 inhibitors develop new-
the risk–benefit profile favors therapeutic
onset erythrocytosis.10,11
efficacy over the risk of adverse effects.
• Providers may not be fully aware of the
previous and evolving body of evidence Genitourinary Infections
demonstrating that prescription of SGLT-2 There was no meaningful excess in UTI risk with
inhibitors can first lead to the development SGLT-2 inhibitor exposure compared with risk
of serious adverse effects that can negatively in the placebo arm.12 Nevertheless, in 2015, the
affect patients’ health in the short-term before FDA issued a black box warning to the labels
expected clinical benefits are attained. of all SGLT-2 inhibitors regarding the risk for
• While there is clear agreement on when severe UTIs following reports of severe sepsis
and how to prescribe SGLT-2 inhibitors for and pyelonephritis in patients treated with
optimization of T2D management, there is less gliflozins.13 This was downgraded to a warning
agreement on how to predict, diagnose, and in 2023. Glycosuria from uncontrolled diabetes
manage on-treatment adverse effects following or SGLT-2 inhibition can create a favorable
the initiation of SGLT-2 inhibitors. environment for the growth of Candida species in
the lower genitourinary tract. Candida organisms
can adhere to genitalia more extensively in the
Discussion presence of glycosuria and via attachment to
The very first landmark trials that demonstrated the host cells, which in turn can result in local
cardiovascular and kidney benefits of different yeast infection signs and symptoms, such as pain,
SGLT-2 inhibitors in T2D have consistently redness, swelling, and/or pruritis. Therefore, it is
reported clinically important safety events (Table). not surprising to see a 3-fold higher risk of GMIs
Use of SGLT-2 inhibitors increases risk of genital in large SGLT-2 inhibitor trials (Table), as well as
mycotic infections (GMIs) but not urinary tract in real-world practice.14 The clinical presentation
can range from balanitis in males and vulvovaginal

Table. Adverse Events and Off-Target Biological Effects Observed in Landmark

Randomized Placebo-Controlled SGLT-2 Inhibitor Trials

Genitourinary infections
Hematocrit
SGLT-2 inhibitor vs placebo, DKA
% incidence Placebo-adjusted
SGLT-2 inhibitor vs placebo, absolute change,
Type 2 diabetes trial / SGLT-2 inhibitor GMI UTI new cases/total participants %

EMPA-REG OUTCOME / empagliflozin5 6.4 vs 1.8 18.1 vs 18.0 4/4687 vs 1/2333 + 2.6%

DECLARE-TIMI 58 / dapagliflozin 4
0.9 vs 0.1 1.5 vs 1.6 27/8574 vs 12/8569 + 2.6%

CREDENCE / canagliflozin3 2.3 vs 0.6 11.1 vs 10.1 11/2200 vs 1/2197 + 2.4%

VERTIS CV / ertugliflozin2 5.4 vs 1.5 12 vs 10 19/5493 vs 2/2745 + 2.1%

ENDO 2025 • Diabetes and Vascular Disease 123

candidiasis in females to Fournier gangrene in SGLT-2 inhibitor–triggered erythrocytosis,
advanced cases. GMIs usually occur within the including studies in men receiving testosterone
first 6 months after SGLT-2 inhibitor initiation. replacement therapy. The absolute erythrocytosis
Other risk factors for GMIs in T2D include female incidence can reach up to 10%.10,11 It was shown
sex, uncircumcised males, obesity, and history of that SGLT-2 inhibitors increase erythropoiesis
recurrent GMIs. via stimulation of erythropoietin production
and inhibition of hepcidin synthesis.19,20 SGLT-2
inhibitor–induced erythrocytosis is a clinically
Diabetic Ketoacidosis
relevant finding, as a more pronounced rise
The initial warning that SGLT-2 inhibitors can in hematocrit could potentially increase blood
cause DKA in people with diabetes came within viscosity and, hence, reduce blood flow,
first 2 years following the approval of the first-in- resulting in tissue ischemia. It is unclear why
class agent, canagliflozin.15 Since then, DKA risk only a small fraction of patients develop de novo
has become a theme of multiple publications.16 erythrocytosis following the initiation of SGLT-
The absolute risk of DKA is less than 0.1%, and 2 inhibitors. It could be that some patients have
relative risk is about 2-fold higher than that of a genetic predisposition to excessive red blood
people with T2D treated with other hypoglycemic cell production and initiation of an SGLT-2
agents. These risks collectively translate to 1 to 2 inhibitor unmasks propensity towards unregulated
additional cases of DKA per 1000 patients with erythropoiesis.21 Until more information becomes
T2D who are treated with an SGLT-2 inhibitor available, prescribers should consider following
over 1 year.7 The mechanisms that predispose to hematocrit trends in people with T2D treated with
SGLT-2 inhibitor–induced DKA include a decrease SGLT-2 inhibitors regardless of the presence of
in insulin and an increase in glucagon production background testosterone replacement. In those
and an increase in blood concentration of ketone who develop marked rise in hematocrit meeting
bodies, which, in settings of volume depletion, criteria for erythrocytosis, blood donation should
caloric deprivation, reduction or discontinuation be strongly considered pending results of ancillary
of insulin therapy, alcohol intake, and/or laboratory assessments for other causes of new-
infection, can lead to ketoacidosis.15,16 SGLT- onset erythrocytosis following initiation of SGLT-
2 inhibitor–induced DKA can present initially 2 inhibitor therapy.
without hyperglycemia (ie, euglycemic DKA)
or classically with hyperglycemia.16,17 It should
be highlighted that in the landmark T2D trials, Clinical Case Vignettes
patients with a hemoglobin A1c value above 10.0% Case 1
(>86 mmol/mol)2,5 or 12.0% (>108 mmol/mol)3,4
A 69-year-old woman with a 15-year history
were excluded from study participation. Indeed,
of T2D returns to clinic for regular follow-up.
severe hyperglycemia in people with non–insulin-
The patient also has osteoporosis, dyslipidemia,
treated T2D already results in β-cell dysfunction
nephrolithiasis, history of total hysterectomy,
and insulinopenia.18 This clearly argues against
and diabetic kidney disease. She is intolerant
initiation of SGLT-2 inhibitors in patients who
of metformin and alogliptin due to abdominal
have a hemoglobin A1c value greater than 10% to
discomfort. Her T2D is currently diet-controlled.
12% (86-108 mmol/mol).
On physical examination, her BMI is
27.8 kg/m2 and blood pressure is normal.
Erythrocytosis Her hemoglobin A1c level has increased from
As SGLT-2 inhibitors can lead to hematocrit 6.9% (52 mmol/mol) at the last visit to 7.5%
elevation (Table), of particular interest are recent (58 mmol/mol) today. Other laboratory studies
studies that demonstrate an increased risk of are significant for an estimated glomerular

124 ENDO 2025 • Endocrine Case Management

filtration rate of 70 mL/min per m2 and spot urine inhibitor therapy can be resumed after providing
albumin-to-creatinine ratio of 200 mg/g (normal appropriate counseling.
<30 mg/g).
Based on the above data, dapagliflozin, 10 mg Case 1, Continued
daily, is initiated. One month later, she calls the
clinic and describes a 1-week history of itching in The patient returns for regular follow-up 3
her labia and vagina. She has no fever/chills and months later. The GMI episode reported at
no urinary symptoms. She had a similar episode the last encounter resolved following a short
about 10 years ago. course of fluconazole. Her hemoglobin A1c level
has improved to 7.1% (54 mmol/mol) while on
Which of the following is the best next dapagliflozin. Today, she reports that for the last 2
step in this patient’s management? weeks she has had new-onset intermittent urinary
A. Initiate nitrofurantoin frequency and hesitancy, which she attributes to
possible recurrent kidney stones. She does not
B. Hold dapagliflozin and start fluconazole,
report passing any stones. She has no fever/chills,
150 mg daily × 3 days
back pain, vaginal itching, or hematuria. Preclinic
C. Recommend no changes blood work shows no abnormalities of serum
D. Continue dapagliflozin and start fluconazole, biochemical parameters, and preclinic urinalysis
150 mg daily × 3 days performed 3 days ago demonstrates following:
E. Obtain urinalysis Glucose = >1000 mg/dL (SI: >55.5 mmol/L)
Ketones, negative
Answer: B) Hold dapagliflozin and start Small blood
fluconazole, 150 mg daily × 3 days Trace protein
Nitrite, negative
This patient likely has vulvovaginal candidiasis Leukocyte esterase, moderate
without systemic manifestations and is unlikely White blood cell count = 11-25 per high-power field
to have a bacterial infection. Thus, initiating (normal, 0-2)
nitrofurantoin (Answer A) or obtaining urinalysis Red blood cell count = 3-5 per high-power field
(normal, 0-2)
(Answer E) is not the best next step. There are Squamous epithelial cells = 11-25 (normal, 0-5)
no outcome studies to guide whether to advise Trace bacteria
holding or continuing an SGLT-2 inhibitor in
this situation. As patient safety is the utmost
During the clinic visit, the patient asks for advice
concern and her glycemic control is near-optimal,
to help manage her urinary symptoms.
her metabolic health would not be compromised
by holding dapagliflozin to reduce glucosuria Which of the following is the best next
for several days (thus, Answers C and D are step in this patient’s management?
incorrect). Holding dapagliflozin for several days
A. Repeat urinalysis in 1 week
and administering topical or oral antifungal agents
(Answer B) should address her GMI. In discussing B. Discontinue dapagliflozin
long-term plans regarding whether an SGLT-2 C. Obtain urine culture
inhibitor could be safely continued after an initial D. Discontinue dapagliflozin and start
episode of GMI, preventive strategies should be nitrofurantoin, 100 mg twice daily × 7 days
discussed, including advice on adequate hydration, E. Refer to urology clinic
maintenance of personal hygiene, emptying the
bladder regularly, and wearing loose-fitting cotton Answer: D) Discontinue dapagliflozin and start
underwear. In patients with an initial episode of nitrofurantoin, 100 mg twice daily × 7 days
successfully treated, uncomplicated GMI, SGLT-2

ENDO 2025 • Diabetes and Vascular Disease 125

She has likely developed cystitis in the background He takes 15 prescription medications. T2D
of SGLT-2 inhibitor therapy and history of kidney is treated with metformin, 1 g twice daily;
stones. Interestingly, recent reports suggested empagliflozin, 25 mg daily; semaglutide, 2 mg
that dapagliflozin increases UTI risk in a dose- subcutaneously weekly; and insulin glargine, 40
dependent manner. Given the risk of complicated units daily. Brief medical record review reveals
UTI, she should be started on an antibacterial his hemoglobin A1c level 2 months ago was 7.8%
regimen. Experts advise a 3- to 5-day course of (62 mmol/mol). Insulin was added to his treatment
cotrimoxazole or nitrofurantoin for treatment of regimen about 2 years ago, and empagliflozin was
the first episode of bacterial cystitis.22 Therefore, started 6 months ago.
stopping the SGLT-2 inhibitor as the only
strategy (Answer B) may not be sufficient, while Laboratory test results:
holding the SGLT-2 inhibitor and starting an Sodium = 137 mEq/L (SI: 137 mmol/L)
antibacterial agent (Answer D) that can attain high Chloride = 102 mEq/L (SI: 102 mmol/L)
concentrations in the urine is most appropriate. Bicarbonate = 16 mEq/L (22-32 mEq/L)
(SI: 16 mmol/L [22-32 mmol/L])
Obtaining urine culture (Answer C), repeating Potassium = 4.5 mEq/L (4.5 mmol/L)
urinalysis later (Answer A), or referring to urology Glucose = 141 mg/dL (SI: 7.8 mmol/L)
clinic (Answer E) could be suggested, but none of Lactic acid, normal
these options addresses the core problem, which White blood cell count, normal
is high suspicion for urinary bacterial infection Troponin, normal
Kidney function, normal
in a person with complicated genitourinary Chest x-ray, normal
history. If left untreated, a bacterial infection
in this setting could lead to more severe UTI. Urinalysis:
Previous uncomplicated UTI is currently not a
Glucose = >1000 mg/dL (>55.5 mmol/L)
contraindication to SGLT-2 inhibitor therapy. Ketones = >150 mg/dL
There are no clear clinical guidelines on whether Large leukocyte esterase
SGLT-2 inhibitors can be resumed in patients White blood cell count = >50 per high-power field
after an initial UTI. Until then, it might be a safe Few bacteria
practice not to continue SGLT-2 inhibitors in Few yeasts
patients whose first UTI was severe or if there The emergency department provider consults
is known accompanying genitourinary history, endocrinology in light of recent reports of SGLT-2
including structural abnormalities, benign prostate inhibitor–induced euglycemic DKA.
hyperplasia, presence of indwelling Foley catheter,
nephrolithiasis, and/or kidney cysts. Which of the following is the best next
step in this patient’s management?
Case 2 A. Measure β-hydroxybutyrate in blood
A 76-year-old man with a 20-year history of T2D B. Obtain arterial blood gases
is evaluated in the emergency department for C. Repeat biochemistries, as the blood glucose
confusion. He also has obesity (BMI = 38 kg/m2), value of 141 mg/dL is likely an error
atrial fibrillation, hypertension, depression, and D. Begin intravenous infusion of insulin and
frailty. His home-based primary care provider was dextrose-containing fluids
repeatedly unable to contact the patient who lives
E. Start fluconazole
alone. The provider requested a wellness check by
local police who found the patient to be confused. Answer: D) Begin intravenous infusion of
In the emergency department, he was afebrile insulin and dextrose-containing fluids
and hemodynamically stable and had generalized
nonfocal weakness.

126 ENDO 2025 • Endocrine Case Management

This patient has euglycemic DKA. Following In preparation for discharge, which
recent recommendations on the evaluation of of the following is the best next step
patients with suspected DKA,18 the diagnosis in this patient’s management?
here is made based on history of T2D, significant A. Measure serum fasting C-peptide
ketonuria, and bicarbonate value less than B. Stop empagliflozin and emphasize that insulin
18 mEq/L (<18 mmol/L). Therefore, additional glargine should be administered daily as
studies to prove he has ketosis (Answer A) prescribed
or acidosis (Answer B) are only confirmatory
C. Measure glutamic acid decarboxylase 65
and they would only delay initiation of DKA
antibody titer
therapy. Nevertheless, the admitting team
measured serum ketones before insulin D. Resume all home medications
was initiated (β-hydroxybutyrate assay was E. Resume all home medications and advise use
not available), which later was reported as of fluconazole if he develops genitourinary
“moderately” positive (equivalent to 2+ grade symptoms
[~ 30-40 mg/dL] ketonemia). The patient is
Answer: B) Stop empagliflozin and
clearly adherent to SGLT-2 inhibitor therapy
emphasize that insulin glargine should
given significant glucosuria in the setting of
be administered daily as prescribed
euglycemia. Therefore, there is no indication
to repeat biochemistries (Answer C). Although The main task in this case is to reduce risk of
the urinalysis results may suggest he has UTI recurrent DKA. The factor that likely precipitated
or GMI (Answer E), the priority at this time is euglycemic DKA is omission of insulin in the
to commence comprehensive therapy of DKA setting of concomitant SGLT-2 inhibitor use in a
consisting of intravenous infusion of insulin and person with longstanding T2D who already has
fluids (Answer D). The fact that he is euglycemic significantly diminished capacity for endogenous
necessitates use of dextrose-containing fluids insulin production. Immediately following the
to prevent hypoglycemia in the background of DKA episode, endogenous insulin production,
insulin infusion. A recent report highlighted that judged by C-peptide level (Answer A), will be low.
resolution of SGLT-2 inhibitor–induced DKA A subset of patients with T2D may have latent
can, in some cases, take up to 20 days, and this is autoimmune diabetes in adults (LADA), which is
likely commensurate with the degree of acidosis characterized by progressive loss of β-cell function
on presentation and/or prolonged elimination of requiring early introduction of insulin therapy to
SGLT-2 inhibitors from the circulation.23 aid glycemic control. In this case, the presence of
longstanding diabetes and only recent initiation
Case 2, Continued of basal insulin would suggest testing for glutamic
acid decarboxylase 65 antibodies (Answer C) is
Follow-up conversation with the patient revealed
unnecessary.
that 1 to 2 weeks before this admission, he self-
Reassurance that resuming home medications
discontinued insulin because he was tired of taking
(Answer D), including empagliflozin, will not
multiple medications. Four days after admission,
put him at risk for another DKA episode is not
the primary team informs the endocrinology
substantiated by systematic evidence. In addition,
consulting team that the patient will be discharged
there are no studies to suggest that empiric
home soon.
treatment for suspected GUI (Answer E) while
being treated with SGLT-2 inhibitors in the
outpatient setting can reduce DKA risk.
Therefore, at this time, the safest approach
would be discontinuation of empagliflozin

ENDO 2025 • Diabetes and Vascular Disease 127

and patient reeducation on the importance of cohort studies provided early evidence that men
adherence to a diabetes treatment regimen, with T2D commencing SGLT-2 inhibitors have a
including basal insulin (Answer B). higher risk of developing erythrocytosis.10,11 Such
risk is particularly evident in hypogonadal men
receiving concurrent testosterone replacement
Case 3
therapy.24 In this case, the patient has experienced
A 67-year-old White man with a history of T2D, erythrocytosis, which likely led to blood pressure
ischemic stroke, hypertension, and dyslipidemia elevation; thus, prompt action to correct
comes for a 6-month follow-up appointment for erythrocytosis is indicated.
hypogonadism management. He is clinically and Referring to a hematologist (Answer B),
biochemically eugonadal while on testosterone commencing aspirin (Answer D), or increasing the
cypionate, 200 mg intramuscularly every 10 lisinopril dosage (Answer E) could be considered,
days for past the 7 years. He has no history of but they do not address the core of his present
tobacco use or sleep apnea. His BMI is 33.1 kg/m2. problem.
Four months ago, his primary provider added He successfully lost weight and reduced his
empagliflozin, 10 mg daily, to his regimen of hemoglobin A1c level after empagliflozin initiation.
metformin and sitagliptin. One month ago, he Therefore, discontinuing the SGLT-2 inhibitor
was in the emergency department for evaluation (Answer C) is not warranted.
of progressive headaches. At that time, extensive Although his current testosterone regimen
clinical, biochemical, and radiological evaluation resulted in optimal management of his
revealed presence of hypertensive urgency and hypogonadism over years, holding it (Answer
elevated hematocrit of 53.5% (normal, 32%-50%). A) would offer the fastest short-term solution to
An antihypertensive medication, amlodipine, was lower his hematocrit and prothrombotic risk and
added. His hematocrit and hemoglobin A1c values improve blood pressure.
before empagliflozin initiation were 49.2% and
7.0% (53 mmol/mol), respectively.
In clinic, his blood pressure is 145/90 mm Hg Case 3, Continued
while on lisinopril, 20 mg daily, and amlodipine, Four weeks later, the patient returns because he
5 mg daily. He reports a 10-lb (4.5-kg) weight loss is experiencing hypogonadal symptoms while
since starting the SGLT-2 inhibitor. His current off testosterone injections and asks to resume
hemoglobin A1c value is 6.4% (46 mmol/mol), and treatment. He is willing to continue empagliflozin
repeat hematocrit remains elevated at 56%. given its proven health benefits in patients with
T2D. His hematocrit is now normal at 45%.
Which of the following is the best next Testosterone is resumed at a lower dosage.
step in this patient’s management?
A. Hold testosterone replacement therapy Which of the following assessments would
B. Refer to a hematologist help determine whether the patient
remains at risk for erythrocytosis?
C. Discontinue the SGLT-2 inhibitor
A. HFE (human iron homeostatic protein) genetic
D. Begin low-dosage aspirin testing
E. Increase the lisinopril dosage to 40 mg daily B. JAK2 genetic testing
Answer: A) Hold testosterone replacement therapy C. Polysomnography
D. Iron measurement
This patient developed secondary erythrocytosis
defined as a hematocrit value greater than 50% E. Bone marrow biopsy
following the initiation of empagliflozin. Recent

128 ENDO 2025 • Endocrine Case Management

Answer: A) HFE (human iron homeostatic Key Learning Points
protein) genetic testing
• SGLT-2 inhibitors offer numerous health
When screening for hemochromatosis, iron
benefits to people with T2D.
measurement by itself (Answer D) has no value.
Also, SGLT-2 inhibitors increase erythropoiesis • Initiation of SGLT-2 inhibitors may, however,
and inhibit the hepcidin pathway19; thus, increase risk of GUI, DKA, and new-onset
interpretation of iron metabolism in this patient erythrocytosis.
may be challenging. • Timely identification of patients who are at
The prevalence of JAK2 pathogenic variants risk for serious adverse effects is critical before
(Answer B) that predispose to polycythemia vera initiation of SGLT-2 inhibitor therapy.
in the general population and in patients with
• Although early reports can help to shape
secondary erythrocytosis, as in this case, is very low.
initial approaches to enhance safety of
The patient did not report snoring, and he
SGLT-2 inhibitor prescription, prediction,
experienced weight loss after initiation of SGLT-
diagnosis, and management of adverse effects
2 inhibitor therapy, so screening for sleep apnea
can be challenging due to lack of systematic
(Answer C) is not warranted.
postmarketing data reporting and consensus
Knowing that up to 20% of US non-Hispanic
among content experts.
White persons may be asymptomatic carriers of a
hemochromatosis gene allele,25 we requested HFE • As SGLT-2 inhibitors are frequently
genetic analysis (Answer A), which revealed that prescribed by nonendocrinology providers,
the patient’s genotype was C282Y –/– (he was the role of endocrinologists and diabetologists
heterozygous for the H63D pathogenic variant). in educating trainees and primary care,
In one case series describing White men who cardiology, and nephrology specialists on
developed erythrocytosis while on combined avoiding these adverse effects must be
testosterone and SGLT-2 inhibitor therapy, revitalized, which, in turn, should enhance
there was high prevalence of newly diagnosed confidence of practitioners in initiating SGLT-
heterozygosity in one HFE allele.21 2 inhibitor therapy.
Finally, bone marrow biopsy (Answer E) is an • When initiating SGLT-2 inhibitors to improve
invasive procedure and is unlikely to help in the care for people with diabetes, providers should
evaluation of secondary erythrocytosis. always discuss the spectrum of adverse effects,
The patient`s sexual symptoms improved reassess clinical and laboratory parameters at
while on a less-intense testosterone regimen each follow-up visit, and advise the patient to
of 150 mg every 2 weeks. Repeat hematocrit contact the clinic any time an adverse reaction
measurements were consistently below 50%, develops.
which allowed for safe continuation of his
endocrine treatments with plans to closely
monitor hematocrit trends.

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high anion-gap metabolic acidosis in patients receiving SGLT-2 inhibitors erythropoietin levels, iron stores, and red blood cell morphology in patients
for diabetes management. J Diabetes Complications. 2017;31(3):611-614. PMID: with type 2 diabetes mellitus and coronary artery disease. Circulation.
27913012 2020;141(8):704-707. PMID: 31707794
18. Umpierrez GE, Davis GM, ElSayed NA, et al. Hyperglycemic crises in adults • Gangat N, Szuber N, Alkhateeb H, Al-Kali A, Pardanani A, Tefferi A. JAK2
with diabetes: a consensus report. Diabetes Care. 2024;47(8):1257-1275. wild-type erythrocytosis associated with sodium-glucose cotransporter 2
PMID: 39052901 inhibitor therapy. Blood. 2021;138(26):2886-2889. PMID: 34653249
19. Ghanim H, Abuaysheh S, Hejna J, et al. Dapagliflozin suppresses hepcidin and • Pishdad R, Auwaerter PG, Kalyani RR. Diabetes, SGLT-2 inhibitors, and
increases erythropoiesis. J Clin Endocrinol Metab. 2020;105(4):dgaa057. PMID: urinary tract infection: a review. Curr Diab Rep. 2024;24(5):108-117. PMID:
32044999 38427314
20. Sano M, Goto S. Possible mechanism of hematocrit elevation by sodium • Poitout V, Robertson RP. Glucolipotoxicity: fuel excess and beta-cell
glucose cotransporter 2 inhibitors and associated beneficial renal and dysfunction. Endocr Rev. 2008;29(3):351-366. PMID: 18048763
cardiovascular effects. Circulation. 2019;139(17):1985-1987. PMID: 31009585

130 ENDO 2025 • Endocrine Case Management

Optimal Use of Diabetes
Technology in the Clinical
Management of Diabetes
Rayhan Lal, MD. Divisions of Endocrinology, Departments of Medicine and Pediatrics,
Stanford University, Stanford, CA; Email: [email protected]

Educational Objectives Practice Gaps

After reviewing this chapter, learners should be
able to: • Keeping up-to-date with new diabetes
technology.
• Describe components of an automated • Ensuring access to all available tools.
insulin dosing (AID) system and the current
regulatory framework. • Being provided full details of algorithm
operation.
• Explain who can benefit from an AID system.
• Understanding what, if any, effect adjustments
• Provide optimizations for people using an have on system operation.
AID system.

Discussion
Every commercial insulin pump manufacturer
Significance of the in the United States offers an AID system. The
Clinical Problem US FDA has cleared 5 such systems (Tandem
Control-IQ, iLet Bionic Pancreas, OmniPod 5,
More than 2 million Americans with absolute
twiist with Tidepool Loop, CamAPS) as class II
insulinopenia require insulin replacement therapy.
medical devices and approved the MiniMed 780G
Network meta-analysis demonstrates that among
as a class III medical device. Under the class II
studied diabetes technologies, AID results in the
designations are 3 components: the glucose sensor
most significant improvements in time-in-range,
or integrated continuous glucose monitor (iCGM),
hemoglobin A1c, and severe hypoglycemia.1,2 The
alternate controller enabled (ACE) insulin pump,
2025 American Diabetes Association Standards
and algorithm dubbed iAGC (interoperable
of Care now recommend continuous glucose
automated glycemic controller). While it may
monitors (CGMs) for all people with diabetes and
appear that these regulatory precedents guarantee
AID for people requiring insulin when it can be
interoperability (plug-and-play operation of any
used safely.3 Keeping up-to-date with the latest
pump, CGM, and algorithm), pairing components
technology, understanding how it works, ensuring
requires commercial business agreements between
access, and integrating this technology into life
manufacturers. In addition, these commercial
can pose barriers for people with diabetes and the
options require announcement of meals and
providers caring for them.4
exercise to achieve optimal glycemic outcomes.
Many commercial AID options do not
have full descriptions of how they automate

ENDO 2025 • Diabetes and Vascular Disease 131

glucose control (also known as closed source), Which of the following is the
as these mechanisms are held as trade secrets by best advice for this patient?
manufacturers. There are 2 popular open-source A. Weaken the carbohydrate-to-insulin ratio
AID (OS-AID) algorithms: the FDA-cleared B. Weaken basal insulin and instruct her on basal
Loop algorithm and the randomized controlled insulin titration and timely CGM replacement
trial–validated OpenAPS algorithm.5 The Loop
C. Weaken the insulin sensitivity factor
algorithm is implemented in the iOS Loop app,
while the OpenAPS algorithm can run on iOS D. Instruct her to always have a bedtime snack
(iAPS, Trio), Android (AndroidAPS), or Linux E. Counsel on the risk of dead-in-bed syndrome
(OpenAPS). These algorithms are compatible
with multiple sensors and pumps. The OpenAPS Answer: B) Weaken basal insulin and instruct her on
algorithm is the only current control software basal insulin titration and timely CGM replacement
designed and tested for unannounced meals.6 The In general, AID systems reduce basal insulin
2025 American Diabetes Association Standards of delivery in anticipation of hypoglycemia. This
Care encourage providers to support people with may make providers feel that basal rates do not
diabetes using OS-AID.3 really matter. However, in this case, without
With all the available options, it is CGM input, the system fell back to the scheduled
theoretically possible for most people with type basal rate, resulting in hypoglycemia. The young
1 diabetes to achieve glycemic targets even with woman had an overly aggressive basal rate relative
unannounced meals. Unfortunately, access to to her other therapy settings. After reducing the
diabetes technology is not equitable7 and is basal insulin dosage, it may be useful for her to
driven by profit-based motives. As providers, it titrate basal insulin (potentially even with closed
is critical to remain up-to-date and consistently loop turned off) (Answer B).
offer diabetes technology to any person with Based on the timeline, her last meal was
type 1 diabetes. around 6 PM and most of her prandial insulin
effect would have dissipated. In addition, her
Clinical Case Vignettes 9 PM glucose value was 100 mg/dL (5.6 mmol/L),
so it is unlikely that any corrective insulin doses
Case 1 would have been at play. Therefore, weakening
A 17-year-old girl with 12-year history of type the carbohydrate-to-insulin ratio (Answer A) or
1 diabetes recently started using an AID system insulin sensitivity factor (Answer C) would be
and reports that 1 night ago when her sensor unlikely to affect this overnight hypoglycemia.
expired, she woke up 8 hours after her last meal Consuming extra calories from carbohydrates
feeling hungry, shaky, and tired. The glucose value (Answer D) to counter nonphysiologic settings
before the sensor cut off at 9 PM was recorded would not be appropriate.
as 100 mg/dL (5.6 mmol/L), and a fingerstick It is important to reassure this young woman
value when she woke up at 2 AM was 45 mg/dL that while she did have a low glucose value, she
(2.5 mmol/L). She consumed carbohydrates woke up and treated hypoglycemia appropriately.
appropriately to treat the hypoglycemia, replaced Instilling fear of fatal overnight hypoglycemia
her sensor, and returned to sleep. Her estimated (Answer E) is unlikely to result in any positive
total daily dose over the last 2 weeks was 50 units. behavioral changes and could result in maladaptive
Her current therapy settings include a basal rate behaviors.
of 1.5 units/h, insulin-to-carbohydrate ratio of
8 g, and insulin sensitivity factor of 40 mg/dL
(2.2 mmol/L).

132 ENDO 2025 • Endocrine Case Management

Case 2 Case 3
A 22-year-old man with a 10-year history of type A 39-year-old woman with a 14-year history of
1 diabetes on a commercial AID seeks help to type 1 diabetes (using Loop) seeks assistance with
better control his postprandial blood glucose. He insulin resistance occurring 1 week per menstrual
reports diminished satiety and substantial weight cycle. During these weeks, her time-in-range
gain over the years, culminating in class 1 obesity drops to around 60%, but it is 80% at other times
(height, 71 in [180 cm]; weight, 216 lb [98 kg] without significant time-below-range.
[BMI = 30.1 kg/m2]) and an increase in insulin
needs to 120 units daily. Which of the following is the
Physical examination findings are notable for best recommendation?
hypertension and acanthosis nigricans on the neck A. Make all therapy settings uniformly more
and axillae. aggressive
A point-of-care hemoglobin A1c value is 6.9% B. Change the glucose target
(52 mmol/mol).
C. Make all therapy settings uniformly weaker
Which of the following is the best next step D. Set up a custom preset to manage periods of
to improve this patient’s overall health? insulin resistance or offer a monophasic oral
A. Start a GLP-1 receptor agonist contraceptive pill
B. Strengthen the carbohydrate-to-insulin ratio E. Change the glucose safety limit
C. Strengthen basal insulin Answer: D) Set up a custom preset to manage
D. Strengthen the insulin sensitivity factor periods of insulin resistance or offer a
E. Discontinue AID monophasic oral contraceptive pill

Answer: A) Start a GLP-1 receptor agonist Altered hormone levels during the menstrual
cycle can affect insulin sensitivity. For example,
This man has reasonable glycemic control but elevated progesterone levels in the luteal phase
is dealing with obesity and type 2 diabetes on (10-14 days before a period) may induce insulin
top of his known type 1 diabetes. It is important resistance. This can make type 1 diabetes more
to realize that in this scenario, GLP-1 receptor difficult to manage in those with menstrual
agonist therapy (Answer A) is entirely on label periods. Loop offers override presets that can
(both for obesity and type 2 diabetes). Presently, uniformly intensify therapy settings by a fixed
obesity and insulin resistance are his primary percentage for a duration of the user’s choosing. It
health problems. may, for example, be useful to set up a 110% preset
Increasing the aggressiveness of his therapy for when this woman is experiencing insulin
settings (Answers B, C, and D) would only lead to resistance (Answer D). This preset can be activated
further weight gain and would not substantially and deactivated when she feels it is appropriate.
improve health outcomes, even if there is a further Alternatively, a monophasic oral contraceptive
hemoglobin A1c reduction. pill could eliminate the hormonal fluctuations and
Discontinuing AID (Answer E) would likely reduce these changes over the course of a cycle.
increase the workload of diabetes and would not Changing the glucose target (Answer B)
be appropriate at this time. Indeed, following or uniformly strengthening or weakening the
the initiation of a GLP-1 receptor agonist, and settings at all times (Answers A and C) would be a
especially as weight loss progresses, insulin nuisance given that she is maintaining target time-
modulation will be important to reduce the risk of in-range most of the time.
hypoglycemia. The glucose safety limit is a feature of Loop;
in the case of an actual or predicted glucose value

ENDO 2025 • Diabetes and Vascular Disease 133

below the glucose safety limit, Loop will suspend would not increase insulin delivery during times of
all insulin delivery. Changing the value (Answer E) resistance.

References
1. Pease A, Clement L, Earnest, Kiriakova V, Liew D, Zoungas S. Time in range uptake, onboarding, and continued use. J Diabetes Sci Technol. 2025;19(1):47-
for multiple technologies in type 1 diabetes: a systematic review and network 53. PMID: 39212371
meta-analysis. Diabetes Care. 2020;43(8):1967-1975. PMID: 32669412 5. Braune K, Hussain S, Lal R. The first regulatory clearance of an open-source
2. Pease A, Clement L, Earnest A, Kiriakova, Liew D, Zoungas S. The efficacy automated insulin delivery algorithm. J Diabetes Sci Technol. 2023;17(5):1139-
of technology in type 1 diabetes: a systematic review, network meta-analysis, 1141. PMID: 37051947
and narrative Synthesis. Diabetes Technol Ther. 2020;22(5):411-421. PMID: 6. Petruzelkova L, Neuman V, Plachy L, et al. First use of open-source
31904262 automated insulin delivery AndroidAPS in full closed-loop scenario:
3. American Diabetes Association Professional Practice Committee. 7. Pancreas4ALL Randomized Pilot Study. Diabetes Technol Ther.
Diabetes technology: standards of care in diabetes-2025. Diabetes Care. 2023;25(5):315-323. PMID: 36826996
2025;48(Suppl_1):S146-S166. PMID: 39651978 7. Burckhardt M-A. Addala A, and de Bock M. Editorial: equity in type 1
4. Tanenbaum ML, Commissariat PV, Wilmot EG, Lange K. Navigating the diabetes technology and beyond: where are we in 2022? Front Endocrinol
unique challenges of automated insulin delivery systems to facilitate effective (Lausanne). 2024;15:1400240. PMID: 38596223

134 ENDO 2025 • Endocrine Case Management

Addressing Racial Health
and Health Care Inequities
in Diabetes
Alyson K. Myers, MD. Department of Medicine, Montefiore Einstein, Bronx, NY; Email:
[email protected]

Educational Objectives 1930s, when involuntary sterilization was being

imposed in Germany to prevent continuation of
After reviewing this chapter, learners should be
conditions such as epilepsy or manic depression,
able to:
diabetes was considered but not selected.2 In
• Describe the role of systemic racism and bias current times, diabetes disproportionately affects
in health outcomes. persons who identify as non-Hispanic Black,
Hispanic/Latino, American Indian Alaskan Native,
• Identify racial/ethnic disparities in diabetes
or Pacific Islander compared with non-Hispanic
diagnosis, complications, and management.
White persons.
• Illustrate methods for improving gaps in Disparities in both diagnosis and management
diabetes care. have led to increased rates of diabetes
complications, such as end-stage kidney disease,
blindness, or amputations, among people from
these communities. Identifying the root causes
Significance of the of these disparities—discrimination, racism, bias,
Clinical Problem social determinants of health—is necessary to close
these disparity gaps.3
Race is social construct that has been used to
categorize people by phenotype and ancestry.
Unfortunately, race has also been used as a tool Practice Gaps
to discriminate against certain groups of people—
racism. In a study of medical students at the • There is a lack of provider awareness about the
University of Virginia, those who held a greater need to consider the unique needs of racial and
number of false beliefs about the differences ethnic minorities who are living with diabetes.
between White and Black patients (eg, Black • It is imperative for providers to consider
people have thicker skin than White people) were how implicit bias, discrimination, and social
more likely to incorrectly assess or treat the pain determinants of health can affect patient care.
of Black patients.1
Such discriminatory theories have also • There is a gap in understanding how
extended to diabetes, which was known in the individuals, health systems, and insurance
late 1800s as Judenkrankheit—the Jewish malady— organizations can improve health outcomes
because doctors found that those who were Jewish for people with diabetes from marginalized
were 2 to 6 times more likely to die of diabetes populations.
than those who were not Jewish.2 During the

ENDO 2025 • Diabetes and Vascular Disease 135

Discussion Diabetes Management
Diabetes affects 38.4 million people or roughly Diabetes is best managed with a patient-centered
12% of the population, but the rates and approach. It is important to consider medication
complications are more prevalent in communities cost, insurance status, comorbidities, lifestyle,
of color. People from racial and ethnic minoritized housing and food security/insecurity when
groups bear the extra burden of patient-provider devising a treatment plan for a patient. For
discordance, discrimination, and the downstream example, a patient who is undomiciled may
effects of historical injustice (ie, slavery, redlining, not be able to store their unused insulin in the
Jim Crow laws). Such factors affect trust and refrigerator. Alternatively, a patient with blindness
access to care and ultimately create a system of from retinopathy may need help in organizing
inequitable care. their pills or giving injections. Also, patients with
a high deductible may not be able to afford newer
diabetes medications until the middle or end of the
Diabetes Screening and Diagnosis
year when that deductible has been reached.
Diabetes screening should be done in people Disparities in health insurance also
older than 40 years, as well as in people who are can interfere with screening for diabetes
sedentary and/or have overweight or obesity. For complications. The National Health Interview
persons of Asian descent, different BMI cutoffs Survey of persons recently diagnosed with diabetes
are used to diagnose both overweight and obesity found that Hispanic patients were less likely to
(23 kg/m2 vs 25 kg/m2 and 28 kg/m2 vs 30 kg/m2, be insured when compared with Black or White
respectively).4 In several studies, those who participants.8 As a result, Hispanic participants
identify as Japanese American were diagnosed were less likely to have lipid, blood pressure, or
with diabetes at a BMI as low as 22 kg/m2.4 As a retinal screening.8
result, it has been suggested that waist‐to‐height Insurance is not the sole barrier for screenings.
ratio of 0.5 or greater may be a better predictor In a review of the barriers of retinal screening
than BMI for Chinese patients.5 for racial/ethnic minoritized populations, there
Diabetes can be diagnosed with a fasting were numerous social determinants of health
serum glucose measurement (or random glucose that were highlighted as impeding care, including
concentration >200 mg/dL [>10.0 mmol/L]), transportation issues, language barriers, cost, and
hemoglobin A1c (HbA1c) measurement, or low level of education.9
oral glucose tolerance test (OGTT). HbA1c Unfortunately, provider bias may also impede
can be falsely elevated or lowered in some a successful treatment plan. Studies in both the
populations due to the presence of anemia or pediatric and adult literature have shown increased
hemoglobinopathies (eg, thalassemia, sickle awareness and use of diabetes technology in White
cell anemia).6 In addition, in some racial/ethnic patients when compared with those who identify
groups, postprandial hyperglycemia is the problem as Black or Hispanic.10-12 Another study found
as opposed to impaired fasting glucose, so using that there was also favoritism when prescribing
fasting glucose alone could potentially lead to an diabetes technology to those with English names
incorrect diagnosis. The Diabetes Epidemiology or private insurance.13
Collaborative Analysis of Diagnostic Criteria in
Asia (DECODA) Study Group found that using
both fasting glucose and OGTT identified more Diabetes Complications
persons with diabetes than simply using fasting Racial and ethnic minority patients are also more
serum glucose alone.7 likely to have diabetes complications, including
blindness, end-stage kidney disease, peripheral
arterial disease, and skin infections.6 Persons with

136 ENDO 2025 • Endocrine Case Management

diabetes have a 25% lifetime chance of developing the patient-provider relationship becomes one
a diabetic foot ulcer, and nearly 20% of those with of mistrust and can lead to nonadherence. Lastly,
a diabetic foot ulcer will need a lower-extremity we must continue to support research efforts to
amputation.14 Lower-extremity amputations are further close these diabetes disparity gaps and
associated with a 5-year mortality of 50%, which make diabetes care equitable.
is greater than the 5-year mortality of either colon
or breast cancer.15 Risk factors for amputation
include male sex, age younger than 70 years,
Clinical Case Vignettes
Black/Hispanic/Native American race/ethnicity, Case 1
living in a rural area, depression, and tobacco use. A 78-year-old Chinese woman with stage
Comorbid neuropathy and peripheral arterial 3 chronic kidney disease, hearing loss, and
disease in the setting of poor glycemic control polyneuropathy of the feet has been living
can also increase the risk of lower-extremity with type 2 diabetes for the past 10 years. She
amputation.14 The use of the SGLT-2 inhibitor also has hepatic steatosis, hypertension, and
canagliflozin has not been consistently shown to hyperlipidemia. She lives with her husband who is
lead to lower-extremity amputation. As a result, a retired maintenance worker at a bank. Her HbA1c
it is important to counsel patients on daily foot is 6.8% (51 mmol/mol) on basal insulin, 14 units
exams, proper footwear, and cigarette smoking subcutaneously once daily at bedtime; metformin,
cessation. Studies have shown that Hispanic 1000 mg twice daily; and an GLP-1 receptor
patients are less likely than White patients to agonist delivered subcutaneously at maximal
receive smoking cessation advice. Factors that dosage weekly. On review of her continuous
contribute to these disparities include language, glucose monitoring report, her time in range is
insurance status, frequency of doctor’s visits, 75%, with a coefficient of variation of 28%, and
provider bias, and access to care.16 Counseling there is no hypoglycemia.
and medication can be used together to most At today’s visit, she laments that her son has
effectively help a patient quit smoking.17 been helping her pay for her GLP-1 receptor
agonist therapy, as it costs $400 per month. On
Closing Disparity Gaps review of her insurance, she has a high deductible
that she will not meet until the end of the year.
To close the disparity gaps that exist for racial/
ethnic minoritized groups, it is important to
Which of the following is the best
first start at the level of the provider. Providers
strategy in this patient’s diabetes care?
must stay up-to-date with diabetes diagnosis and
management. In addition, we need to transition A. Continue current therapy
from the paternalistic approach to care to that of a A. Switch from subcutaneous to oral GLP-1
patient-centered model. This requires a discussion receptor agonist
with patients about their goals for care and B. Increase the metformin dosage
difficulties and ensuring that they understand their C. Add bolus insulin
treatment plan. Using the teach-back method at
D. Discontinue the GLP-1 receptor agonist and
the end of the visit is a great way to assess whether
start pioglitazone
patients understand what was communicated.
We also must acknowledge and explore our Answer: E) Discontinue the GLP-1 receptor
biases to ensure that we are providing patients agonist and start pioglitazone
with the best care. In doing so, we must validate
the feelings of discrimination and racism that our GLP-1 receptor agonists and thiazolidinediones
patients have endured. By ignoring such feelings, both can improve steatohepatitis and potentially
prevent worsening of fibrosis.18 If the cost of

ENDO 2025 • Diabetes and Vascular Disease 137

the GLP-1 receptor agonist is too high, then Case 2
switching to a less expensive agent would be
best (Answer E). Oral GLP-1 receptor agonists Patient 1
(Answer B) are also costly, so that would not help A 64-year-old retired city transit worker who
her financial issue. Her metformin is at maximal immigrated from the Dominican Republic 30
dosage, so increasing it (Answer C) would not be years ago presents for a well visit. She lives with
recommended. Her HbA1c goal is less than 7.5% her husband of 40 years and her 2 adult sons in a
(<58 mmol/mol) based on her age, so adding bolus community where the median annual income is
insulin (Answer D) is not needed now. $48,700.20 She has hypertension, type 2 diabetes,
dyslipidemia, and kidney stones. Her HbA1c
level is 8.5% (69 mmol/mol). She is currently on
Case 1, Continued metformin, 1000 mg twice daily, and glipizide,
The patient is bilingual in English and Cantonese. 10 mg daily. She has been minimally active since
retiring 3 years ago.
After adjusting her medications, what
would be the best way to decide whether Patient 2
she understands her medication changes? A 60-year-old public school high school principal
A. Give her a paper handout with her medication lives with his 2 dogs in a community where
list in her preferred language the median annual income is $79,190.20 Three
B. Read her the medication list months ago, during an annual exam, he was
diagnosed with type 2 diabetes (HbA1c = 9.0%
C. Perform a teach-back
[75 mmol/mol]). Semaglutide and metformin
D. Call her pharmacy were initiated. At his follow-up visit today, he has
E. Schedule an appointment with the certified lost 8 lb (3.6 kg), and his HbA1c level has decreased
diabetes care and education specialist to 6.9% (52 mmol/mol). He works out at the gym
at his job 3 to 4 times per week.
Answer: C) Perform a teach-back
This patient’s hearing loss may compromise The 2 patients are treated by the same
what she processes through listening, so the only physician but are managed differently.
way to know if she heard what was said is to use What could be the reason?
the teach-back method (Answer C), as it would A. Ageism
require her to explain what she was taught in her B. Implicit bias
own words.19 Paper handouts (Answer A), reading C. Imposter syndrome
her the medication list (Answer B), and calling
D. Intersectionality
the pharmacy (Answer D) would not help the
provider to determine if the patient understands E. Stereotype threat
the information. Although working with a Answer: B) Implicit bias
certified diabetes care and education specialist
(Answer D) has been shown to improve health Implicit bias (Answer B) is an unconscious bias
outcomes,17 it is important for the patient to adjust that we all have as human beings, which can lead
her medications at the time of her appointment, to prescribing differences between patients. These
not at a future date. 2 patients are similar in age, so ageism (Answer
A) is not an issue. Intersectionality (Answer D)
is a term used to recognize a person’s multiple
identities, such as race, ethnicity, gender, sexual
orientation, and immigrant status as opposed to

138 ENDO 2025 • Endocrine Case Management

focusing on only one. The imposter syndrome use (tobacco, marijuana, and cocaine). At home,
(Answer C) occurs when one undervalues their he takes insulin glargine, 20 units subcutaneously
own work while praising the work of others. daily at bedtime, and insulin lispro, 8 units
Stereotype threat (Answer E) occurs when subcutaneously 3 times a day before meals.
an individual purposely avoids behaving in a His vital signs are stable, and his glucose sensor
manner that is stereotypical of the group to which shows a sideways arrow with a blood glucose value
they belong.21 of 150 mg/dL (8.3 mmol/L).
On physical examination, he has an ulcer with
an overlying callus. There is neither erythema nor
Case 2, Continued
pus expressed, but there is concern for an infection
On review of his medical records, the 60-year- underneath the callus. His monofilament testing
old male patient in part 1 of this vignette has a shows decreased sensation in the first metatarsal,
mean corpuscular volume of 78 µm3 (78 fL) with and his pulses are 2+ in both the dorsal pedis and
normal measurements of ferritin, transferrin, and posterior tibialis pulses.
reticulocyte count.
Which of the following factors increases
How does this finding affect his risk for having an amputation in
glycemic control measurements? patients with diabetic foot ulcers?
A. His HbA1c is unaffected A. Female sex
B. His HbA1c may be falsely elevated B. Age >70 years
C. His HbA1c may be falsely low C. Tobacco use
D. His fructosamine may be falsely elevated D. 20/20 vision
E. His fructosamine may be falsely low E. Type 1 diabetes
Answer: C) His HbA1c may be falsely low Answer: C) Tobacco use
This patient’s laboratory findings suggest Male sex, age younger than 70 years, and poor
a presence of a hemoglobinopathy, such as vision are all associated with increased risk of
thalassemia trait, which can falsely lower HbA1c amputation (thus, Answers A, B, and D are
(Answer C). Glycation of red blood cells occurs incorrect).22,23 There are more people with type 2
with mature cells, so conditions with high red diabetes than type 1 diabetes, so the rate of diabetic
blood cell turnover lead to a lower HbA1c level.6 foot ulcer in those with type 2 diabetes is greater
Fructosamine involves glycation of albumin, so a than that of type 1 diabetes (thus, Answer E is
hemoglobinopathy would not be an issue. incorrect).14 Tobacco use (Answer C) increases
risk for amputation in patients with diabetic
Case 3 foot ulcers.
A 28-year-old unemployed Hispanic/Latino man
with uncontrolled type 1 diabetes (HbA1c = 12.0% Case 3, Continued
[108 mmol/mol]) presents to diabetes clinic for The patient has been smoking 1 pack of cigarettes
follow-up care. He was hospitalized 2 months ago per day for about 10 years. He wants to quit
with a right fifth metatarsal ulcer and was told smoking cold turkey, starting today. He has tried
to follow-up with podiatry in 2 weeks, but no several times in the past but has not been able
appointment was made. to quit for more than a couple of weeks, as he
He has been living with type 1 diabetes for 12 develops problems with sleep, anxiety, worsening
years and has associated neuropathy. He also has a
history of depression, anxiety, and polysubstance

ENDO 2025 • Diabetes and Vascular Disease 139

depression, and poor concentration. He does not Answer: E) Nicotine patch and counseling
have headaches or dizziness.
In patients with diabetes who are trying to quit
Which of the following is his diagnosis smoking, medical therapy with counseling is the
as it relates to tobacco use? best choice, so the nicotine patch paired with
counseling (Answer E) would be a better option
A. Tobacco use disorder
than the nicotine patch (Answer C), varenicline
B. Tobacco dependence disorder (Answer A), or bupropion (Answer B) alone.17
C. Tobacco abuse Bupropion should also be avoided, as it can
D. Tobacco overuse disorder worsen anxiety in people with an anxiety disorder.
E. Tobacco withdrawal E-cigarettes (Answer D) are neither recommended
nor FDA-approved for smoking cessation.17
Answer: B) Tobacco dependence disorder
The diagnosis of tobacco dependence (Answer B) Key Learning Points
is based on his withdrawal symptoms (tolerance),
his multiple attempts to quit, and his continued • Race is a social, NOT a biological, construct.
use of nicotine despite worsening depression.24 • Discrimination, racism, and implicit bias
can lead to misdiagnosis, mismanagement,
Case 3, Continued and worse health outcomes for patients with
diabetes. Acknowledging biases can help
Which of the following is the best providers deliver equitable care.
management for his tobacco diagnosis?
• Systemic racist policies, such as redlining
A. Varenicline or segregation, have been implicated in
B. Bupropion poorer health outcomes for marginalized
C. Nicotine patch communities.
D. E-cigarettes • Assessing the social determinants of health
E. Nicotine patch and counseling allows health care providers to bridge the
disparity gaps for marginalized communities.

References
1. Hoffman KM, Trawalter S, Axt JR, Oliver MN. Racial bias in pain assessment 7. Qiao Q, Nakagami T, Tuomilehto J, et al; DECODA Study Group.
and treatment recommendations, and false beliefs about biological differences Comparison of the fasting and the 2-h glucose criteria for diabetes in different
between blacks and whites. Proc Natl Acad Sci U S A. 2016;113(16):4296-4301. Asian cohorts. Diabetologia. 2000;43(12):1470-1475. PMID: 11151755
PMID: 27044069 8. Marcondes FO, Cheng D, Alegria M, Haas JS. Are racial/ethnic minorities
2. Tuchman AM. Diabetes: A History of Race and Disease. Yale University Press; recently diagnosed with diabetes less likely than white individuals to
2020. receive guideline-directed diabetes preventive care? BMC Health Serv Res.
3. Golden SH, Joseph JJ, Hill-Briggs F. Casting a health equity lens on 2021;21(1):1150. PMID: 34689778
endocrinology and diabetes. J Clin Endocrinol Metab. 2021;106(4):e1909-e1916. 9. Fathy C, Patel S, Sternberg Jr. P, Kohanim S. Disparities in adherence
PMID: 33496788 to screening guidelines for diabetic retinopathy in the United States: a
4. Hsu WC, Araneta MRG, Kanaya AM, Chiang JL, Fujimoto W. BMI cut comprehensive review and guide for future directions. Semin Ophthalmol.
points to identify at-risk Asian Americans for type 2 diabetes screening. 2016;31(4):364-377. PMID: 27116205
Diabetes Care. 2015;38(1):150-158. PMID: 25538311 10. Agarwal S, Schechter C, Gonzalez J, Long JA. Racial-ethnic disparities in
5. Xu Z, Qi X, Dahl AK, Xu W. Waist-to-height ratio is the best indicator diabetes technology use among young adults with type 1 diabetes. Diabetes
for undiagnosed type 2 diabetes. Diabet Med. 2013;30(6):e201-e207. PMID: Technol Ther. 2021;23(4):306-313. PMID: 33155826
23444984 11. Lai CW, Lipman TH, Willi SM, Hawkes CP. Racial and ethnic disparities in
6. Young C, Myers AK. Racial and ethnic disparities in diabetes clinical care and rates of continuous glucose monitor initiation and continued use in children
management: a narrative review. Endocr Pract. 2023;29(4):295-300. PMID: with type 1 diabetes. Diabetes Care. 2020;44(1):255-257. PMID: 33177169
36464131

140 ENDO 2025 • Endocrine Case Management

12. Ye Y, Acevedo Mendez BA, Izard S, Myers AK. Demographic variables 19. Hong YR, Jo A, Cardel M, Huo J, Mainous AG. Patient-provider
associated with diabetes technology awareness or use in adults with type 2 communication with teach-back, patient-centered diabetes care, and diabetes
diabetes. Diabetes Spectr. 2023;37(1):60-64. PMID: 38385093 care education. Patient Educ Couns. 2020;103(12):2443-2450. PMID: 32507589
13. Odugbesan O, Addala A, Nelson G, et al. Implicit racial-ethnic and insurance- 20. CoreData.nyc. Accessed January 24, 2025. http://coredata.nyc
mediated bias to recommending diabetes technology: insights from T1D 21. Williams M. Elevating the Voices of Women of Color in the Workplace. IGI
exchange multicenter pediatric and adult diabetes provider cohort. Diabetes Global; 2024.
Technol Ther. 2022;24(9):619-627. PMID: 35604789 22. Boyko EJ, Zelnick LR, Braffett BH, et al. Risk of foot ulcer and lower-
14. Gallagher KA, Mills JL, Armstrong DG, et al; American Heart Association extremity amputation among participants in the diabetes control and
Council on Peripheral Vascular Disease; Council on Cardiovascular and complications trial/epidemiology of diabetes interventions and complications
Stroke Nursing; Council on Clinical Cardiology; and Council on Lifestyle and study. Diabetes Care. 2022;45(2):357-364. PMID: 35007329
Cardiometabolic Health. Current status and principles for the treatment and 23. Lin C, Liu J, Sun H. Risk factors for lower extremity amputation in patients
prevention of diabetic foot ulcers in the cardiovascular patient population: with diabetic foot ulcers: a meta-analysis. PLOS ONE. 2020;15(9):e0239236.
a scientific statement from the American Heart Association. Circulation. PMID: 32936828
2024;149(4):e232-e253. PMID: 38095068 24. Baker TB, Breslau N, Covey L, Shiffman S. DSM criteria for tobacco use
15. Armstrong DG, Swerdlow MA, Armstrong AA, Conte MS, Padula WV, disorder and tobacco withdrawal: a critique and proposed revisions for DSM-
Bus SA. Five year mortality and direct costs of care for people with diabetic 5. Addiction. 2012;107(2):263-275. PMID: 21919989
foot complications are comparable to cancer. J Foot Ankle Res. 2020;13(1):16.
PMID: 32209136
16. Babb S, Malarcher A, Asman K, et al. Disparities in cessation behaviors
between Hispanic and non-Hispanic White adult cigarette smokers in the
Recommended Reading
United States, 2000-2015. PMID: 31999539 • Blackstock U. Legacy: A Black Physician Reckons With Racism in Medicine.
17. American Diabetes Association Professional Practice Committee. 5. Viking; 2024.
Facilitating positive health behaviors and well-being to improve health • Tuchman AM. Diabetes: A History of Race and Disease. Yale University Press;
outcomes: standards of care in diabetes-2025. Diabetes Care. 2025;48(Suppl 2020.
1):S86-S127. PMID: 39651983 • Washington HA. Medical Apartheid: The Dark History of Medical
18. Castera L, Cusi K. Diabetes and cirrhosis: current concepts on diagnosis and Experimentation on Black Americans From Colonial Times to the Present.
management. Hepatology. 2023;77(6):2128-2146. PMID: 36631005 Doubleday Books; 2006.

ENDO 2025 • Diabetes and Vascular Disease 141

Management of Cystic
Fibrosis–Related Diabetes
Melissa Putman, MD. Harvard Medical School, Diabetes Research Center, Massachusetts
General Hospital; Email: [email protected]

Educational Objectives Up to 20% of adolescents and 30% to 50% of

adults with CF develop CFRD,1 making this one of
After reviewing this chapter, learners should be
the most common nonpulmonary complications of
able to:
CF. The etiology of CFRD is likely multifactorial
• Describe the prevalence, pathogenesis, and and is not fully understood, but the primary
clinical significance of cystic fibrosis–related driver is a progressive insulin secretory defect
diabetes (CFRD). caused by β-cell dysfunction.2 There is also a
component of insulin resistance that occurs in
• Highlight current approaches to screening,
CFRD, likely related to significant illness and
diagnosis, and management of CFRD.
inflammation, which can fluctuate over time based
• Discuss the role of diabetes technologies and on clinical status. Risk factors for CFRD include
alternative therapies in the management of pancreatic exocrine insufficiency, older age, severe
CFRD. lung disease, CF-related liver disease, and lung
transplantation.3 The diagnosis of CFRD has been
associated with clinical decline in those with CF,
including worsening lung function and nutritional
Significance of the status, as well as earlier mortality.4
Clinical Problem
Cystic fibrosis (CF) is an autosomal recessive Practice Gaps
disorder affecting roughly 40,000 people in the
United States and more than 100,000 worldwide. • Diabetes screening tools for people with CF
Defective function of the CF transmembrane are limited, and new approaches are needed for
conductance regulator (CFTR) protein leads to screening and diagnosing CFRD.
exocrine pancreatic insufficiency and progressive • Diabetes-related tasks can add substantial
pulmonary decline, which is the primary cause treatment burden to a patient population that
of mortality in this patient population. Due to already carries a large medical burden related
improved care and treatments available to people to lung disease and other comorbidities.
with CF, the median predicted survival has
increased substantially over the past 3 decades, • Nutritional needs are changing in the
from 30 years of age for people born between postmodulator era with the rising prevalence
1989 and 1993 to the current 61 years for those of obesity in people with CF.
born between 2019 and 2023.1 As people with CF • As life expectancy continues to improve in
live longer, nonpulmonary complications of CF people with CF, new complications of aging
are becoming more prevalent and add significant will likely arise, including increasing rates of
morbidity and treatment burden. microvascular and macrovascular disease.

142 ENDO 2025 • Endocrine Case Management

Discussion an exaggerated second-phase insulin release. A
key priority identified by the CFF-NIH Workshop
Given the often insidious onset of CFRD with
is to develop approaches to improve diabetes
the gradual development of brief prandial
management and reduce treatment burden for
hyperglycemia with normal fasting glucose
people with CFRD.8
levels and no apparent symptoms, screening is
Since the introduction of ETI (elexacaftor/
important. Oral glucose tolerance testing (OGTT)
tezacaftor/ivacaftor) in 2019, there has been
is recommended for annual CFRD screening
a significant increase in the prevalence of
in all people with CF older than 10 years.4
overweight and obesity in adults with CF in the
OGTT is the screening test of choice because
United States, with most recent estimates from
the diagnosis of CFRD by this test has been
the Cystic Fibrosis Foundation Patient Registry
correlated with important CF-specific outcomes,
reporting 13% with a BMI in the obesity range
including pulmonary function and nutritional
above 30 kg/m2 and 28.4% with a BMI in the
status. However, rates of screening with OGTT
overweight range of 25 to 29.9 kg/m2.1 Moreover,
have been suboptimal over the past 20 years,
data suggest that normal-weight obesity, defined
and just over 30% of adults with CF underwent
as a normal BMI with elevated fat mass, has been
annual screening OGTT in 2023.1 New screening
reported to occur with a prevalence of more
approaches are urgently needed.
than 30% in this patient population.9 Although
Insulin is the only recommended treatment
data are limited, complications of obesity are
for CFRD because this is the only therapy that
being increasingly reported in the aging CF
has been shown to improve CF-specific clinical
population, including hypertension, hepatic
outcomes.4 Recommended glycemic targets are
steatosis (which can exacerbate underlying
the same as they are for type 1 and 2 diabetes;
CF-related liver disease), and cardiovascular
however, these targets were established based on
disease.10-12 Insulin resistance related to obesity
the development of microvascular complications,
may exacerbate β-cell dysfunction and further
and there are no data guiding whether CF-specific
complicate diabetes management. CFRD-metabolic
targets are needed for optimizing lung function
syndrome is terminology currently being used
and nutritional status. Diabetes tasks can add
to describe patients with CF who have diabetes
significant burden to an already burdensome
and also have evidence of insulin resistance and
disease, affecting quality of life in addition to
underlying type 2 diabetes phenotype. Whether
CF-specific clinical outcomes.5,6 In addition,
noninsulin therapies will be safe and effective in
there are other unique aspects of CFRD that
treating obesity and insulin resistance this patient
can make management challenging7: (a) variable
population is currently being investigated.
degree of endogenous insulin production, such
Historically, microvascular complications of
that some patients may need small doses of only
diabetes were relatively rare occurrences in people
rapid-acting insulin with meals, whereas others
with CFRD, primarily because the limited life
may require a more typical basal-bolus insulin
expectancy meant that people were more likely
regimen; (b) fluctuating insulin requirements
to die of lung disease before developing these
based on clinical status, with much more insulin
complications. However, this is changing in the
needed when sick or receiving glucocorticoid
postmodulator era, and further studies are needed
treatment and much less required while healthy;
to understand the best approach to screening,
(c) high calorie nutritional requirements to
prevention, and management of diabetes
attain optimal BMI and nutritional status for
complications in people with CFRD.
optimizing lung function, which can often
involve high carbohydrate intake; and (d) risk
of spontaneous reactive hypoglycemia related to
delayed first-phase insulin secretion followed by

ENDO 2025 • Diabetes and Vascular Disease 143

Clinical Case Vignettes risk of CFRD who may not need OGTT in an
effort to improve overall screening rates.15-17
Case 1 The Canadian CF guidelines have recently
A 17-year-old young man has a history of CF, incorporated a tiered screening approach, such
pancreatic insufficiency, and malnutrition that those with hemoglobin A1c values below 5.5%
requiring a gastrotomy tube with overnight (<37 mmol/mol) do not require further CFRD
formula feeds. His BMI is low at the 10th screening with OGTT.18
percentile, but his pulmonary function is excellent
with forced expiratory volume in 1 second (FEV1)
Case 1, Continued
percent predicted at 99%. He has had no recent
pulmonary exacerbations, hospitalizations, or The patient declines a repeat OGTT to confirm
glucocorticoid treatment. Results of annual CFRD the diagnosis.
screening with OGTT are shown in the Table.
Which of the following should be
Why is hemoglobin A1c falsely recommended next for this patient?
low in patients with CF? A. Check fingerstick glucose before meals and 2
A. Accelerated red blood cell turnover hours after meals to collect more data
B. Chronic hypoxia B. Initiate continuous glucose monitoring to
collect more data
C. Laboratory error
C. Start insulin glargine, 0.1 units/kg per day
D. It’s not falsely low
D. Start insulin lispro with a carbohydrate ratio of
Answer: D) It’s not falsely low 1:30 with meals
Hemoglobin A1c has been shown to correlate Answer: B) Initiate continuous glucose
strongly with average glucose values in adults with monitoring to collect more data
CF, and this relationship is the same as in other
diabetes populations.13,14 However, hemoglobin Although in the past we relied on fingerstick
A1c does not perform well as a screening test for glucose checks to determine the next steps in
CFRD because average glucose is often normal treatment, intermittent glucose checks can easily
in early CFRD, which is marked by brief prandial miss glycemic variability in early CFRD, which
excursions with episodes of reactive hypoglycemia is characterized by brief glycemic excursion
and normal glucose levels overnight. Recent after meals often lasting less than 2 to 3 hours
studies suggest that hemoglobin A1c can be used with normal fasting and premeal glucose levels.
as an initial test to identify those at very low Continuous glucose monitoring (CGM) has
significantly changed our approach to CFRD

Year Fasting glucose 2-Hour glucose Hemoglobin A1c* Glycemic category

Year 1 108 mg/dL 78 mg/dL 5.0% Impaired fasting glucose

(SI: 6.0 mmol/L) (SI: 4.3 mmol/L) (31 mmol/mol)

Year 2 111 mg/dL 110 mg/dL 4.9% Impaired fasting glucose

(SI: 6.2 mmol/L) (SI: 6.1 mmol/L) (30 mmol/mol)

Year 3 114 mg/dL 149 mg/dL 5.0% Impaired fasting glucose/

(SI: 6.3 mmol/L) (SI: 8.3 mmol/L) (31 mmol/mol) impaired glucose tolerance

Year 4 102 mg/dL 203 mg/dL 5.0% CFRD

(SI: 5.7 mmol/L) (SI: 11.3 mmol/L) (31 mmol/mol)

*Despite the diagnosis of CFRD based on OGTT, his hemoglobin A1c values have remained overall stable and well within the normal range.

144 ENDO 2025 • Endocrine Case Management

management by providing comprehensive with treatment in those with 1 copy of delF508
glycemic data that can be used to inform or other responsive variant.19 There was an
treatment. For example, if glucose levels overnight immediate and rapid uptake in treatment in the
are within the normal range and postprandial United States upon approval in 2019, and at
reactive hypoglycemia is occurring, then starting present more than 75% of the CF population is
long-acting insulin may lead to significant currently on CFTR modulator therapy.1 There
hypoglycemia. Similarly, if the patient is having are now emerging studies providing insight into
prandial hyperglycemia with glucose values in the how CFTR modulator therapy affects CFRD.
range of 200 to 300 mg/dL (11.1-16.7 mmol/L) Early studies using CGM reported improvement
lasting 3 hours or more, this may indicate that in measures of hyperglycemia and glycemic
rapid-acting insulin with meals can be started variability without an effect on hypoglycemia after
to improve dysglycemia. Although there are initiation of modulator therapy.20 The largest study
currently no accepted CGM thresholds to diagnose to date was the PROMISE Endocrine substudy,
CFRD, one study found that CGM measures of a multicenter longitudinal observational study
hyperglycemia could reliably distinguish between following children and adults with CF starting
those with and without diabetes,13 laying the treatment with ETI at 12 to 18 months and again
groundwork for future prospective longitudinal at 24 to 30 months. This study found a small
studies investigating CGM as a diagnostic tool. but significant improvement in hemoglobin
Future studies are needed to determine CGM A1c from 5.7% to 5.5% over 2 years. However,
measures that correlate with long-term CF- glycemic categories as defined by OGTT (normal
specific outcomes, such as pulmonary function glucose tolerance, early glucose intolerance,
and nutritional status. However, CGM may still impaired glucose tolerance, and CFRD) did not
be very helpful for deciding the best treatment significantly change.21 Overall, these data suggest
approach for those with abnormal OGTT results. that this treatment may lead to small improvement
in glycemia but may not prevent the development or
progression of abnormal glucose tolerance or CFRD.
Case 1, Continued
He had started treatment with ETI in between
his OGTTs in years 3 and 4 and is concerned that Case 2
CFTR modulator therapy may have affected his A 32-year-old man has CF, pancreatic
glycemic control. insufficiency, and moderate lung disease and
was diagnosed with CFRD at age 20 years based
How does CFTR modulator therapy on OGTT. His CFRD has been managed with a
affect glycemia in people with CF? basal-bolus insulin regimen of glargine and lispro
A. Makes it much better for many years. However, he acknowledges that
B. Makes it a little better diabetes management has always been one of
his greatest challenges. Consistent with this, his
C. Makes it much worse
hemoglobin A1c level is 12.2% (110 mmol/mol).
D. Makes it a little worse He has had frequent admissions to the hospital
E. Does not have an effect for treatment of CF exacerbations and has
intermittently required high-dosage prednisone
Answer: B) Makes it a little better
tapers over the past year. His BMI is 19 kg/m2,
CFTR modulator therapy has transformed the and his pulmonary function tests show a predicted
landscape of CF. Studies have shown an estimated FEV1 of 50%.
14% sustained improvement in FEV1 and Despite counseling, education, and
significant reduction in pulmonary exacerbations adjustments to his insulin regimen in attempt to

ENDO 2025 • Diabetes and Vascular Disease 145

optimize glycemic control, his hemoglobin A1c There is a temporary improvement in his glycemic
ranges from 11% to 12% (97-108 mmol/mol) over control. However, a series of medical stressors take
the next year, primarily because he rarely checks his attention away from diabetes management,
fingerstick glucose and frequently misses short- and his hemoglobin A1c returns to 11.6%
and long-acting insulin injections. (103 mmol/mol) 6 months later. At a telehealth
appointment, the option of starting an AID device
Which of the following is the best in conjunction with CGM is discussed.
recommendation now to help this
patient with diabetes management? Which of the following is true about the
A. Metformin use of AID devices in people with CFRD?
B. Repaglinide A. There are no randomized trials investigating
C. Semaglutide or tirzepatide the use of AID devices in the CF population
D. CGM B. Observational studies suggest that AID devices
do not increase the percentage of time in the
E. Automated insulin delivery device
target range for people with CFRD
Answer: D) CGM C. People with CFRD spend a greater percentage
of time in hypoglycemic ranges with AID
In this patient with a BMI below the devices than people with type 1 diabetes
recommended goal of 23 kg/m2 and significant
D. There are no FDA-approved AID devices for
lung disease, medications that may result in
CFRD
further weight loss should be avoided, such as
metformin (Answer A) or GLP-1 receptor agonists Answer: D) There are no FDA-approved
(Answer C). In a clinical trial comparing insulin AID devices for CFRD
or repaglinide (Answer B) vs placebo, repaglinide
led to transient weight increase, but only insulin There are limited data on the use of AID devices
was associated with sustained weight gain in CFRD. Two retrospective studies investigating
over the course of the year-long study.22 CGM the Tandem TslimX2 with Control IQ25 and
(Answer D) has been validated in patients with the Omnipod 526 reported improvement in
CF.23 Although there are no randomized clinical the percentage of time in target range of 70 to
trials investigating CGM in the management of 180 mg/dL (3.0-10.0 mmol/L) and percentage
CFRD, a recent meta-analysis and systematic of time in the hyperglycemic range without a
review found that use of CGM over at least 6 significant change in the percentage of time
weeks was associated with a 0.4% improvement in the hypoglycemic range after initiation of
in hemoglobin A1c compared with fingerstick each of these devices. Another nonrandomized
glucose monitoring.24 Automated insulin delivery longitudinal study compared people on multiple
(AID) systems (Answer E) have also been studied daily injection regimens with those who switched
in the management of CFRD. However, it would to either sensor-augmented pump or AID
be prudent to first initiate CGM before moving devices (Medtronic 670G or 780G, Omnipod,
forward with an AID device. Tandem TslimX2, or Accu-Chek) and reported
improvement in hemoglobin A1c over 2 years.27
In a random-order cross-over design clinical trial,
Case 2, Continued the iLet Bionic Pancreas led to improvement in
Although the patient is initially reluctant to be average glucose and percentage of time in the
“attached to something all the time,” he starts using target range with no change in the percentage
CGM, which he finds very helpful for glucose of time in the hypoglycemic range over 4
monitoring and reminding him to take his insulin. weeks in 20 adults with CFRD.28 A multicenter

146 ENDO 2025 • Endocrine Case Management

randomized clinical trial investigating the iLet is to measure hemoglobin A1c again (Answer C).
ongoing in the United States (NCT06449677), CGM could also be used, but because there are no
and another randomized clinical trial is ongoing universally accepted thresholds for confirming the
in the United Kingdom with the CamAPS system diagnosis of CFRD, this tends to be more helpful
(NCT05562492). Overall, the decision to trial for deciding if and how insulin should be started.
AID devices requires education and discussion
of potential risks and benefits, tailored to Case 3, Continued
each individual.
Which of the following should be
Case 3 recommended next to manage this
A 42-year-old woman has CF and pancreatic patient’s obesity and CFRD?
insufficiency. As a child, she was underweight A. Diet and exercise
and had difficulty gaining weight gain and B. Insulin glargine, 0.1 units/kg per day
maintaining a goal BMI at the 50th percentile,
C. Insulin lispro with a carbohydrate ratio of 1:30
but this improved by young adulthood. After
with meals
starting ETI in 2019, her lung function improved
to over 90% predicted, but she gained a substantial D. Repaglinide
amount of weight, bringing her current BMI E. Semaglutide or tirzepatide
to 38 kg/m2. Despite efforts at diet and exercise
Answer: E) Semaglutide or tirzepatide
over the past year, she has not been able to lose
weight; she finds her current appearance very As illustrated in this case, there has been
frustrating and distressing. Annual screening a significant increase in the prevalence of
labs show a hemoglobin A1c value of 6.7% overweight and obesity since the introduction and
(50 mmol/mol), increased from 5.9% to 6.3% (41 rapid uptake of ETI in 2019.1 Although insulin is
to 45 mmol/mol) over the past 2 years. She has not the recommended treatment for CFRD, starting
had a recent OGTT. insulin would likely exacerbate her weight gain.
Moreover, her pulmonary function is excellent,
Which of the following is the best suggesting that insulin is not required to improve
next step for further evaluation? her lung disease. Diet and exercise are key aspects
A. OGTT of obesity management, but they have not worked
B. Pancreatic antibodies for her, with worsening hemoglobin A1c despite
C. Repeat hemoglobin A1c measurement attempts at lifestyle changes. Repaglinide may
also worsen weight gain. Recent studies suggest
D. CGM
that GLP-1 receptor agonist therapy (Answer
E. No need for further testing E) may be effective for weight loss and diabetes
Answer: C) Repeat hemoglobin A1c measurement management in people with CF,29 and this
would a reasonable option to try for this patient.
Similar to the diagnosis of type 2 diabetes, at However, there are important considerations
least 2 tests are needed to confirm the diagnosis for the use of these medications in this specific
of CFRD.4 Although hemoglobin A1c is not a patient population. Many people with CF have a
sensitive test for CFRD screening, a value of 6.5% history of gastroesophageal reflux disease, delayed
or above (≥48 mmol/mol) is consistent with the gastric emptying, and gastroparesis, which can
diagnosis of diabetes. In this case, it would be be exacerbated by this therapy. Moreover, some
challenging to have the patient come in for an patients with CF require frequent procedures
OGTT, and an easier confirmatory test would be (bronchoscopy and colonoscopy) and should be

ENDO 2025 • Diabetes and Vascular Disease 147

counseled on holding treatment in advance of Key Learning Points
needing anesthesia. People with CF are at risk for
distal intestinal obstruction syndrome. Although • CFRD is common and is associated with
not reported with GLP-1 receptor agonist use, it decline in pulmonary function, compromised
is conceivable that slowed gastrointestinal motility nutritional status, and earlier mortality.
and worsening constipation could predispose to
• The recommended screening test for CFRD is
this complication, and constipation should be
OGTT, although national screening rates are
aggressively managed. Pancreatitis occurs more
very low and new approaches are needed.
commonly in people with certain CFTR pathogenic
variants, particularly in individuals with pancreatic • Insulin is the only recommended treatment
sufficiency. Excessive weight loss to a BMI for CFRD, and it has been shown to improve
below the recommended goal of 22 kg/m2 in clinical status.
women and 23 kg/m2 in men should be avoided. • Diabetes technology may help to improve
Ongoing clinical trials are investigating noninsulin glycemic management and reduce treatment
therapies, including semaglutide (NCT05788965) burden in people with CFRD.
and SGLT-2 inhibitors (NCT 06149793) in the • Rising rates of obesity and metabolic syndrome
management of CFRD. In the meantime, GLP-1 raise the possibility for other treatment
receptor agonists may be a reasonable option for options (GLP-1 receptor agonists, SGLT-2
treating CFRD and obesity in carefully selected inhibitors, etc) for CFRD.
patients, with comprehensive counseling on
potential risks and adverse effects.

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19. Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor-tezacaftor- cystic fibrosis related diabetes: a systematic review and meta-analysis. J Cyst
ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. Fibros. 2023;22(1):39-49. PMID: 35906171
2019;381(19):1809-1819. PMID: 31697873 25. Scully KJ, Palani G, Zheng H, Moheet A, Putman MS. The effect of Control
20. Scully KJ, Marchetti P, Sawicki GS, et al. The effect of elexacaftor/tezacaftor/ IQ hybrid closed loop technology on glycemic control in adolescents
ivacaftor (ETI) on glycemia in adults with cystic fibrosis. J Cyst Fibros. and adults with cystic fibrosis-related diabetes. Diabetes Technol Ther.
2022;21(2):258-263. PMID: 34531155 2022;24(6):446-452. PMID: 35020476
21. Chan CL, Shirley Bezerra M, Stefanovski D, et al. Glycemia and insulin 26. Scully KJ, Palani G, Zheng H, Moheet A, Putman MS. Effect of hybrid closed
secretion in cystic fibrosis two years after elexacaftor/tezacaftor/ivacaftor: loop insulin delivery on glycemic control in adolescents and adults with cystic
PROMISE-ENDO. J Clin Endocrinol Metab. 2024:dgae857. PMID: 39657947 fibrosis-related diabetes. Diabetes Technol Ther. 2022;24(6):446-452. PMID:
22. Moran A, Pekow P, Grover P, et al; Cystic Fibrosis Related Diabetes Therapy 35020476
Study G. Insulin therapy to improve BMI in cystic fibrosis-related diabetes 27. Grancini V, Alicandro G, Porcaro LL, et al. Effects of insulin therapy
without fasting hyperglycemia: results of the cystic fibrosis related diabetes optimization with sensor augmented pumps on glycemic control and body
therapy trial. Diabetes Care. 2009;32(10):1783-1788. PMID: 19592632 composition in people with cystic fibrosis-related diabetes. Front Endocrinol
23. O’Riordan SM, Hindmarsh P, Hill NR, et al. Validation of continuous glucose (Lausanne). 2023;14:1228153. PMID: 37720540
monitoring in children and adolescents with cystic fibrosis: a prospective 28. Sherwood JS, Castellanos LE, O’Connor MY, et al. Randomized trial of the
cohort study. Diabetes Care. 2009;32(6):1020-1022. PMID: 19279304 insulin-only iLet Bionic Pancreas for the treatment of cystic fibrosis-related
24. Kumar S, Soldatos G, Ranasinha S, Teede H, Pallin M. Continuous glucose diabetes. Diabetes Care. 2024;47(1):101-108. PMID: 37874987
monitoring versus self-monitoring of blood glucose in the management of 29. Park S, Jain R, Mirfakhraee S. Glucagon-like-peptide-1 agonist therapy in
adults with cystic fibrosis. J Cyst Fibros. 2025;24(1):40-46. PMID: 39214747

ENDO 2025 • Diabetes and Vascular Disease 149

Optimizing Health After
Gestational Diabetes:
What’s Next?
Ellen W. Seely, MD. Endocrinology, Diabetes and Hypertension Division, Brigham and
Women’s Hospital/Mass General Brigham, Boston, MA; Email: [email protected]

Educational Objectives women with GDM have increased risk of future

GDM with subsequent pregnancies,3,4 as well as
After reviewing this chapter, learners should be
future T2D5-8 and CVD.9-12 However, most women
able to:
with previous GDM do not receive counseling or
• Determine the risk of type 2 diabetes (T2D) referral to programs to decrease future risks.
following gestational diabetes mellitus (GDM).
• Institute prevention of T2D after GDM. Practice Gaps
• Identify and manage risk for cardiovascular
disease (CVD) after GDM. • Despite the well-recognized risk of T2D
following GDM, most providers do not solicit
a pregnancy history of GDM.
When caring for patients with previous GDM,
health care providers should implement: • Women with previous GDM should receive
regular screening for T2D.
• T2D screening. • Women with previous GDM should receive
• T2D prevention with either an intensive advice about lifestyle modification and referral
lifestyle program or metformin (not FDA to a National Diabetes Prevention Program
approved for this indication but recommended (DPP), or similar program, to prevent T2D or
by the American Diabetes Association). be prescribed metformin.
• CVD risk factor screening and prevention. • Women with previous GDM should receive
counseling about CVD prevention.

Significance of the Discussion

The American Diabetes Association defines GDM
Clinical Problem
as diabetes first diagnosed during pregnancy after
GDM (diabetes first diagnosed in pregnancy after the first trimester.13 GDM is diagnosed by oral
the first trimester) affects 7% to 8% of pregnancies glucose tolerance testing (OGTT), usually at weeks
in the United States and approximately 14% of 24 to 28 of gestation by either the 2-step test (50-
pregnancies globally.1,2 GDM is associated with g glucose load followed by 100-g OGTT using
risk during pregnancy both to the mother and to Carpenter Coustan criteria) or 1-step test (75-g
the fetus/neonate, and these risks are attenuated OGTT using the International Association of the
by diagnosis and treatment of GDM. Although Diabetes and Pregnancy Study Groups [IAPDSG]
GDM resolves with delivery of the pregnancy, criteria).13 There is debate as to which, if either,

150 ENDO 2025 • Endocrine Case Management

of these criteria are superior. Mothers with GDM T2D Prevention After GDM
have increased risk for hypertensive disorders of
The good news is that we have known since
pregnancy and cesarean delivery, and the fetus/
2008 that diabetes can be prevented or delayed in
neonate is at increased risk for macrosomia,
women with previous GDM. A post hoc analysis
shoulder dystocia, birth trauma, and neonatal
of 350 parous women who participated in the
hypoglycemia. Two large randomized controlled
DPP and who self-reported GDM revealed that
trials have demonstrated that diagnosis and
intensive lifestyle modification reduced rates of
treatment of GDM decreases adverse pregnancy
diabetes by 53% and metformin reduced rates of
outcomes.14,15
diabetes by 50%.19 The study also confirmed the
magnification of risk for T2D in women with a
T2D After GDM history of GDM, as the rates of T2D were 71%
Since the 1980s,5 it has been known that women higher in women with previous GDM than in
with prior GDM have an increased risk of future parous women without this history.
T2D. This risk has been supported by many The Diabetes Prevention Program
subsequent studies. Data support that up to 50% Observational Study, which followed DPP
of women with previous GDM develop T2D, participants for 10 years, demonstrated persistent
with many developing the condition within 5 protection against the development of T2D in
years of the GDM pregnancy.6 A meta-analysis the population who received intensive lifestyle
demonstrated that women with previous GDM modification or metformin.20 Even 10 years
were 7 to 8 times more likely to develop T2D later, women with a history of GDM had a
than those without previous GDM.7,8 Within the 35% reduction in diabetes progression with
population of women with a history of GDM, intensive lifestyle modification, and those who
Hispanic and non-Hispanic, non-White women had received metformin had a 40% reduction.
are more likely to develop T2D than non-Hispanic Interestingly, in women with no history of GDM,
White women.16 Another meta-analysis confirmed intensive lifestyle modification demonstrated an
the magnification of conversion rate, finding overall reduction of diabetes by 30%, whereas no
a relative risk of 8.3 (95% CI, 6.5-10.6) among reduction was seen in the group who had received
more than 300,000 women with a history of metformin. These studies were performed in
GDM.8 Because of the high risk of T2D associated women remote from their GDM pregnancy (age
with a history of GDM, the American Diabetes 43 ± 7.6 years).
Association13 recommends OGTT 4 to 12 weeks Weight gain subsequent to a GDM pregnancy
post partum to determine whether the woman has appears to modify future risk of T2D. A
T2D at that time. If she does not have T2D but prospective population-based analysis from the
has impaired fasting glucose (IFG) or impaired Nurses’ Health Study II showed that in women
glucose tolerance (IGT), the recommendation is with previous GDM, each 1 kg/m2 increase in
to screen annually. If the OGTT result is normal, BMI was associated with a 16% increase in risk
the recommendation is to screen every 3 years. of developing diabetes.21 More proximate to
Unfortunately, many women do not return for the pregnancy, a longitudinal study that followed
6-week postpartum OGTT (<50%),17 and many participants with previous GDM for 4 years post
women do not receive the recommended long- partum showed that the group with a decrease
term screening.18 Thus, there is lost opportunity in BMI of –1.8 kg/m2 had an 8.6% incidence of
for early detection, prevention, and early diabetes, while the group with an increase in BMI
treatment of diabetes in this high-risk population. of +1.6 kg/m2 had a 16.9% incidence of diabetes.22
Therefore, loss of pregnancy weight gain may be
an opportunity to decrease future risk of diabetes.

ENDO 2025 • Diabetes and Vascular Disease 151

 There has been interest in targeting FDA-approved indication for this purpose.. In the
postpartum weight retention as an opportunity original DPP study,19 metformin therapy reduced
to decrease progression to diabetes, as weight diabetes incidence in women with previous GDM
retained at 6 months post delivery is predictive of by 50%, a similar reduction rate as that associated
long-term weight gain.23 Several studies have been with intensive lifestyle modification. In the DPP
designed to decrease postpartum weight retention Outcomes Study,20 metformin at a dosage of
in women with recent GDM, and some have been 850 mg twice daily reduced progression to diabetes
successful in that regard.24,25 Whether this will by 40% compared with placebo in women with
translate into diabetes prevention is not known. a history of GDM, similar to intensive lifestyle
modification, which reduced diabetes progression
by 35% over 10 years. Some argue that in the real
Intensive Lifestyle Programs
world, metformin is more effective than intensive
Many lifestyle programs are available that are lifestyle modification for diabetes prevention
based on the DPP. The most prominent, and because it may be easier for individuals to take a
endorsed by the Centers for Disease Control, are medication than to be adherent to lifestyle change.
the National Diabetes Prevention Programs.26
These programs are available nationwide in the
United States and are commonly covered by History of GDM and Future CVD
insurance. They are based on the DPP curriculum Women with previous GDM who develop T2D
and are available both in-person and online. are at increased risk for CVD, as diabetes is an
A history of GDM is a qualifying diagnosis important risk factor for CVD. Several studies
for entry into a National Diabetes Prevention have demonstrated that even after accounting
Program. Women with previous GDM appear to for the future development of T2D, women
benefit from participation in a National Diabetes with previous GDM have increased CVD
Prevention Program, with a study27 showing that risk. A meta-analysis and systematic review of
younger women (age <40 years) with previous women with previous GDM demonstrated an
GDM who attended at least 1 session had greater almost 2-fold increased risk for cardiovascular
weight loss (3.04% ± 0.59 vs 1.49% ± 0.11, P = events (fatal/nonfatal ischemic heart disease and
.010) in covariate-adjusted models than other cerebrovascular events) compared with risk of
participants. Despite this promise, younger women without previous GDM.9 Women with
women with previous GDM are about 50% less previous GDM who had not developed T2D
likely to enroll in a National Diabetes Prevention demonstrated a relative risk for CVD events of
Program than women without GDM.28 Other 1.56 (95% CI, 1.04-2.32) compared with the risk of
countries have DPP programs similar to the women without previous GDM. In a study using
National Diabetes Prevention Program, such as a large United Kingdom biobank, the hazard ratio
the United Kingdom’s National Health System for developing a cardiovascular outcome (coronary
Diabetes Prevention Programme and Australia’s artery disease, peripheral artery disease, heart
Diabetes Australia, which are free of charge. failure, mitral regurgitation, and atrial fibrillation)
was 1.36 (1.18-1.55) in women with previous
GDM compared with women without previous
Metformin
GDM, even after adjusting for the development
The DPP demonstrated that metformin, 850 mg of T2D, further supporting a direct pathway from
orally twice daily, was as effective as intensive GDM to CVD.10 Because of this and other data, in
lifestyle modification in reducing rates of diabetes 2011, the American Heart Association designated
in women with previous GDM.19 It is important GDM as a major risk factor for CVD.11 As opposed
to note that although metformin is widely used to the studies that support prevention of diabetes
for diabetes prevention, it does not have an

152 ENDO 2025 • Endocrine Case Management

following GDM, there are no data specific to the was associated with a 21% lower odds of GDM
prevention of CVD in this population. However, recurrence. In some other studies of weight loss
it makes sense to recognize this group of women before pregnancy, no benefit in the rate of GDM
as being at increased risk for CVD and address was observed, perhaps because those assigned to
CVD risk factor reduction with them,12 have the weight-loss intervention counteracted this
a lower threshold for prescribing medications benefit by gaining more weight during pregnancy.
that decrease CVD risk, such as statins and
antihypertensive agents. Risk factor reduction
should include weight management, physical
Clinical Case Vignettes
activity, and smoking cessation. Hemoglobin Case 1
A1c and blood pressure should be monitored.12 A 32-year-old woman (G1, P1) with Hashimoto
Whether women with previous GDM should thyroid disease (treated with levothyroxine,
receive more intensive lipid screening is not 100 mcg daily) presents for a return visit. She is
well established. having regular menses.
On physical examination, her blood pressure
Previous GDM and GDM Recurrence is 130/80 mm Hg, pulse rate is 72 beats/min, and
in Subsequent Pregnancy BMI is 32 kg/m2. The rest of the examination
findings are normal, including a normal thyroid
Women with GDM have a high risk of being gland and no hirsutism.
diagnosed with GDM in a subsequent pregnancy. At the end of the visit, she says, “I hope that
In a meta-analysis and systematic review, the when I see you next year, I will have had another
pooled GDM recurrence rate was 48% (95% CI, baby.” You realize you had never obtained a
41%-54%).3 These numbers may be inflated in that pregnancy history. She had GDM in her first
many women with previous GDM start doing pregnancy 3 years ago and required insulin.
fingerstick glucose measurement using their home
glucose meters from a prior pregnancy and report In addition to measuring TSH, which of the
elevated glucose values to their provider, thus following assessments should be ordered?
bypassing formal screening for GDM. Whether
A. Testosterone measurement
weight loss between pregnancies reduces recurrent
GDM is unclear. In observational studies, women B. LH measurement
who enter a subsequent pregnancy at a lower C. Ovarian ultrasonography
weight than they did for their previous GDM D. Antimullerian hormone measurement
pregnancy have lower rates of subsequent GDM.4 E. Hemoglobin A1c measurement
In cross-sectional data, women who were at lower
body weights at the time of their subsequent Answer: E) Hemoglobin A1c measurement
pregnancy were at lower risk of recurrent GDM.
She is having regular menses and has no hirsutism
A randomized controlled trial29 that compared
on exam, so there is no suggestion of polycystic
lifestyle intervention with decreased weight
ovary syndrome. With her regular menses and
preconception in women with previous GDM
a recent pregnancy, there is no reason to expect
was successful at reducing weight, but it did not
premature ovarian insufficiency.
reduce rates of recurrent GDM compared with
It is crucial to screen women with a history
rates in the control group, perhaps due to reduced
of GDM for T2D, as many such women develop
power, as there were 50% fewer pregnancies than
T2D, with the highest relative risk in the first
had been planned for. However, regardless of
5 years after pregnancy. Even if this patient
group assignment, greater weight loss between
had been screened 4 to 12 weeks after delivery,
study entry and last weight before pregnancy

ENDO 2025 • Diabetes and Vascular Disease 153

she should have screening now based on the What is her chance of developing T2D?
American Diabetes Association recommendation A. 10%
to screen all women with previous GDM every B. 20%
3 years if testing is normal. If test results indicate
prediabetes, she should be screened yearly. C. 50%
The most sensitive test is OGTT, but patients D. 100%
generally dislike the test, it is time consuming, and E. 0% (her 6-week postpartum OGTT results in
it cannot usually be done on the day of the visit the electronic medical record confirm she did
because it must be done in the fasting state. Thus, not have T2D at that time)
hemoglobin A1c measurement (Answer E) is the
most practical test at this point. Answer: C) 50%
Family planning should be discussed with Women with previous GDM have a 50% chance
all women with previous GDM, so they are of developing T2D (Answer C) with the increase
aware of the importance of screening for T2D in relative risk being the highest in the first 5
(hemoglobin A1c, fasting blood glucose, or years following the GDM pregnancy. Because her
OGTT) when planning a pregnancy. If test results risk is so high and because the DPP appeared to
confirm T2D, the patient will need counseling be effective in women with previous GDM, you
to achieve a hemoglobin A1c level less than discuss referral to a National Diabetes Prevention
6.5% (48 mmol/mol) before conception. Unless Program and use of metformin.
screening for T2D in patients with previous GDM
is routine, the patient in this scenario could have
presented while pregnant and with T2D and less- Case 1, Continued
than-optimal glycemic control. That evening when you are completing your
notes, her hemoglobin A1c has come back at 5.8%
(40 mmol/mol). You remember that you only
Case 1, Continued
counseled her about future risk of T2D and forgot
You ask the patient to step back into your office, other important counseling.
reminding yourself you should have discussed
family planning and future risk of T2D during the You enter a reminder in the electronic
visit. You discuss the high recurrence rate of GDM medical record to talk to her about which
and ask if she had been counseled about future of the following at her next visit?
long-term risks following GDM. She replies, “I A. She has a very high risk of premature ovarian
was told that my diabetes would go away when insufficiency because she has thyroid disease
I delivered.” You counsel her about future T2D and had GDM
risk and the need for regular diabetes screening
B. She will not need adjustment of her
every 3 years if testing is normal and yearly if she
levothyroxine dosage during her planned
has impaired fasting glucose, impaired glucose
pregnancy because her recent TSH value was
tolerance, or prediabetes according to hemoglobin
normal
A1c measurement. She is planning a pregnancy,
which prompts you to order hemoglobin A1c C. She only needs to worry about future CVD if
measurement that day. she develops future T2D
D. She has an increased risk for CVD independent
of the development of future T2D
E. Her risk of recurrent GDM is low because it is
most common in a first pregnancy

154 ENDO 2025 • Endocrine Case Management

Answer: D) She has an increased risk for CVD Key Learning Points
independent of the development of future T2D
• A pregnancy history of GDM should be
Women with a history of GDM have an increased
obtained from all parous women.
risk for future CVD independent of the future
development of T2D (Answer D). The American • Women with a history of GDM should be
Heart Association has endorsed GDM as a major screened regularly for T2D to allow to early
risk factor for CVD. Recommendations are to diagnosis and treatment of diabetes and its
screen women with previous GDM for other comorbidities.
CVD risk factors. She does not have high risk • Women with previous gestational diabetes
of premature ovarian insufficiency with only should be referred to a National Diabetes
Hashimoto thyroiditis. The GDM recurrence rate Prevention Program or similar program or
is very high. be prescribed metformin to help prevent or
delay diabetes. Of note, metformin is not FDA
approved for this indication but is endorsed by
many organizations, including the American
Diabetes Association.

References
1. Gregory EC, Ely DM. Trends and characteristics in gestational diabetes: 12. Parikh NI, Gonzalez JM, Anderson CAM, et al. Adverse pregnancy outcomes
United States, 2016-2020. Natl Vital Stat Rep. 2022;71(3):1-15. PMID: and cardiovascular disease risk: unique opportunities for cardiovascular
35877134 disease prevention in women: a scientific statement from the American Heart
2. Wang H, Li N, Chivese T, et al; IDF Diabetes Atlas Committee Association. Circulation. 2021;143(18):e902-e916. PMID: 33779213
Hyperglycaemia in Pregnancy Special Interest Group. IDF Diabetes Atlas: 13. Management of diabetes in pregnancy: standards of care in diabetes-2025.
estimation of global and regional gestational diabetes mellitus prevalence for Diabetes Care. 2025;48(Suppl 1):S306-S320. PMID: 39651985
2021 by International Association of Diabetes in Pregnancy Study Group’s 14. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS.
Criteria. Diabetes Res Clin Pract. 2022;183:109050. PMID: 34883186 Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N
3. Schwartz N, Nachum Z, Green MS. The prevalence of gestational diabetes Engl J Med. 2005;352(24):2477-2486. PMID: 15951574
mellitus recurrence--effect of ethnicity and parity: a metaanalysis. Am J Obstet 15. Landon MB, Spong CY, Thom E, et al; Eunice Kennedy Shriver National
Gynecol. 2015;213(3):310-317. PMID: 25757637 Institute of Child Health and Human Development Maternal-Fetal Medicine
4. Sorbye LM, Cnattingius S, Skjaerven R, et al. Interpregnancy weight change Units Network. A multicenter, randomized trial of treatment for mild
and recurrence of gestational diabetes mellitus: a population-based cohort gestational diabetes. N Engl J Med. 2009;361(14):1339-1348. PMID: 19797280
study. BJOG. 2020;127(13):1608-1616. PMID: 32534460 16. Bower JK, Butler BN, Bose-Brill S, Kue J, Wassel CL. Racial/ethnic
5. O’Sullivan JB. Diabetes mellitus after GDM. Diabetes. 1991;40(Suppl 2):131- differences in diabetes screening and hyperglycemia among US women after
135. PMID: 1748242 gestational diabetes. Prev Chronic Dis. 2019;16:E145. PMID: 31651379
6. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of 17. Brown SD, Hedderson MM, Zhu Y, et al. Uptake of guideline-recommended
type 2 diabetes: a systematic review. Diabetes Care. 2002;25(10):1862-1868. postpartum diabetes screening among diverse women with gestational
PMID: 12351492 diabetes: associations with patient factors in an integrated health system in
7. Bellamy L, Casas JP, Hingorani AD, Williams D. Type 2 diabetes mellitus USA. BMJ Open Diabetes Res Care. 2022;10(3):e002726. PMID: 35725017
after gestational diabetes: a systematic review and meta-analysis. Lancet. 18. Zera CA, Bates DW, Stuebe AM, Ecker JL, Seely EW. Diabetes screening
2009;373(9677):1773-1779. PMID: 19465232 reminder for women with prior gestational diabetes: a randomized controlled
8. Dennison RA, Chen ES, Green ME, et al. The absolute and relative risk of trial. Obstet Gynecol. 2015;126(1):109-114. PMID: 26241263
type 2 diabetes after gestational diabetes: A systematic review and meta- 19. Ratner RE, Christophi CA, Metzger BE, et al. Prevention of diabetes in
analysis of 129 studies. Diabetes Res Clin Pract. 2021;171:108625. PMID: women with a history of gestational diabetes: effects of metformin and
33333204 lifestyle interventions. J Clin Endocrinol Metab. 2008;93(12):4774-4779. PMID:
9. Kramer CK, Campbell S, Retnakaran R. Gestational diabetes and the risk 18826999
of cardiovascular disease in women: a systematic review and meta-analysis. 20. Aroda VR, Christophi CA, Edelstein SL, et al. The effect of lifestyle
Diabetologia. 2019;62(6):905-914. PMID: 30843102 intervention and metformin on preventing or delaying diabetes among
10. Lee SM, Shivakumar M, Park JW, et al. Long-term cardiovascular outcomes women with and without gestational diabetes: the Diabetes Prevention
of gestational diabetes mellitus: a prospective UK Biobank study. Cardiovasc Program outcomes study 10-year follow-up. J Clin Endocrinol Metab.
Diabetol. 2022;21(1):221. PMID: 36309714 2015;100(4):1646-1653. PMID: 25706240
11. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the 21. Bao W, Yeung E, Tobias DK, et al. Long-term risk of type 2 diabetes
prevention of cardiovascular disease in women--2011 update: a guideline mellitus in relation to BMI and weight change among women with a history
from the American Heart Association. Circulation. 2011;123(11):1243-1262. of gestational diabetes mellitus: a prospective cohort study. Diabetologia.
PMID: 21325087 2015;58(6):1212-1219. PMID: 25796371

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22. Moon JH, Kwak SH, Jung HS, et al. Weight gain and progression to type 26. Centers for Disease Control. National Diabetes Prevention Program. 2025.
2 diabetes in women with a history of gestational diabetes mellitus. J Clin https://www.cdc.gov/diabetes-prevention/index.html
Endocrinol Metab. 2015;100(9):3548-3555. PMID: 26171796 27. Ritchie ND, Seely EW, Nicklas JM, Levkoff SE. Effectiveness of the National
23. Rooney BL, Schauberger CW. Excess pregnancy weight gain and long- Diabetes Prevention Program After Gestational Diabetes. Am J Prev Med.
term obesity: one decade later. Obstet Gynecol. 2002;100(2):245-252. PMID: 2023;65(2):317-321. PMID: 36918133
12151145 28. Ritchie ND, Sauder KA, Fabbri S. Reach and effectiveness of the National
24. Nicklas JM, Zera CA, England LJ, et al. A web-based lifestyle intervention Diabetes Prevention Program for Young Women. Am J Prev Med.
for women with recent gestational diabetes mellitus: a randomized controlled 2017;53(5):714-718. PMID: 28928038
trial. Obstet Gynecol. 2014;124(3):563-570. PMID: 25162257 29. Phelan S, Jelalian E, Coustan D, et al. Randomized controlled trial of
25. Ferrara A, Hedderson MM, Brown SD, et al. The comparative effectiveness prepregnancy lifestyle intervention to reduce recurrence of gestational
of diabetes prevention strategies to reduce postpartum weight retention in diabetes mellitus. Am J Obstet Gynecol. 2023;229(2):158.e1-158.e14. PMID:
women with gestational diabetes mellitus: the Gestational Diabetes’ Effects 36758710
on Moms (GEM) Cluster Randomized Controlled Trial. Diabetes Care.
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156 ENDO 2025 • Endocrine Case Management

Integrating Quality
Improvement into
Inpatient Diabetes Care
Sonali Thosani, MD. Department of Endocrine Neoplasia and Hormonal Disorders,
MD Anderson Cancer Center, Houston, TX. Email: [email protected]

Educational Objectives due to inappropriate insulin dosing or disruption

of meal or tube feeds.
After reviewing this chapter, learners should be
able to:
Practice Gaps
• Outline the steps to follow to implement a
successful quality improvement (QI) initiative. • Lack of awareness of standardized protocols/
• Discuss the different types of QI tools that are policies for inpatient diabetes management.
available. • Lack of knowledge on how to initiate and
• Identify the types of metrics that can be used sustain QI initiatives.
for tracking improvement in inpatient care for
patients with diabetes.
Discussion
There are some key steps to developing a successful
glycemic control initiative for inpatient diabetes
Significance of the care. The Glycemic Control Online Toolkit is an
excellent resource that is based on this guide and
Clinical Problem provides step-by-step methodology on how to
Caring for hospitalized patients with diabetes is a improve inpatient glycemic control as recommended
complex process with many opportunities for QI in the Society of Hospital Medicine guide.1
to ensure that care delivery meets the 6 Institute
of Medicine aims: safe, effective, timely, patient-
centered, equitable, and efficient. Patients with
Step 1: Gain support and
diabetes often need significant change to their priority for the initiative from
outpatient regimen upon admission and dynamic institutional leadership
monitoring to ensure that their treatment plan Stakeholder engagement is the first and most
is tailored to their ongoing inpatient clinical important step for any QI initiative. Stakeholder
situation. Without appropriate safeguards in place, engagement requires a clear understanding of who
certain vulnerable patients, such as those who your audience is and what matters to them. If your
are postoperative or on high-dosage steroids, can project is based in a single unit or affecting just
develop hyperglycemic emergency during their a few areas, then focusing on length of stay and
hospital stay, which is considered a preventable discharge-related metrics might be a good way
adverse event. Furthermore, patients can also be at to get stakeholder buy-in. If it is a larger project
risk of hypoglycemia and its related adverse events involving all inpatient diabetes care, then engaging

ENDO 2025 • Diabetes and Vascular Disease 157

C-suite leaders will likely require more buy-in Step 3: Assess the current
through review of preventable adverse events and state of glycemic management
discussion of how current practice compares with
in your facility through use of
benchmark standards for glycemic care.
QI tools and methodology
Using QI Tools
Step 2: Create a multidisciplinary
The QI Essentials Toolkit from the Institute
team that focuses on for Healthcare Improvement2 provides a great
reaching glycemic targets summary of various tools that can be used for QI
For any QI project, it is very important to identify work (Table 1).
a leader or co-leaders for an initiative with diverse
representation from various frontline members Step 4: Develop specific aims,
in the multidisciplinary team. Any effective
or goals, that are time-defined,
inpatient diabetes QI project will likely involve
representatives from nursing, pharmacy, diabetes measurable, and achievable
educators, patient care technicians or medical Every QI initiative should have an aim statement
assistants, clinical providers, informatics, and data that is Specific, Measurable, Attainable, Relevant,
analyst team. Input from various perspectives and Time bound (SMART). This statement is a
in developing the project and planning the clear summary of the magnitude of change that
intervention is key to ensuring that all facets the intervention hopes to achieve in a specified
of the problem have been considered and that amount of time and ensures ongoing stakeholder
intervention does not disrupt the workflow of any and team engagement. Aim statements can reflect
team members. 1 of the 2 types of measures that are used in health
care analytics3:
• Process measures: These measures focus
on the processes and systems that directly
contribute to the desired outcomes. Example:

Table 1. QI Essentials Toolkit From the Institute for Healthcare Improvement

QI tool Description Utility in QI work

Process mapping Flowchart outlining a complex process Allows for shared understanding of workflow and can
help identify bottleneck areas

Prioritization matrix 4 × 4 matrix that can help prioritize Helps teams focus on “quick wins” (low-effort, high-
solutions/interventions based on effort and impact) tasks, while setting aside time for high-effort/
impact high-impact tasks

Pareto chart According to Pareto principle, 80% of the Helps teams concentrate their improvement areas on
effect comes from 20% of the causes; tool factors that will likely have the greatest impact
can identify which factors are contributing
more often to problem

Ishikawa (fishbone) diagram Cause-and-effect diagram that looks Helpful in identifying all the factors contributing to a
at the people, environment, materials, problem
methods, and equipment related issues
that are contributing to the problem

Staff and patient surveys Questionnaires completed by staff and Provides information on subjective effectiveness of the
patients to gather more information of intervention and identifies challenges faced by frontline
qualitative impact of initiative teams or impact of intervention on patient experience

158 ENDO 2025 • Endocrine Case Management

 measuring use of a new order set implemented study of variation in data over time, which can
to increase use of basal-bolus insulin therapy. help identify causes of variation, such as special
• Outcome measures: These measures reflect and common cause variation.
the impact on the patient and identify the Some standardized metrics are available, such
result of improvement work. Example: as the electronic quality measures (eCQM) for
measuring average glucose levels for hyperglycemia and hypoglycemia as developed
patients on new order set compared with the by Centers for Medicare and Medicaid Services.4
benchmark target. Another practical resource is glucometrics
developed by the Society of Hospital Medicine
Task Force (Glycemic Control eQUIPS program).5
Step 5: Develop and track metrics that Metrics can be in any of the following categories:
are relevant to your aim statement measurements of safety, measurements of glycemic
There are many factors to consider when control, measurements of insulin use, or other
developing metrics related to inpatient diabetes process measures as summarized in Table 2.6
care at any given institution, including ease of
availability of data and access to a data analytics Step 6: Use Plan-Do-Study-Act
team and other resources to build a glycemic model to pilot interventions
management dashboard. Metrics can focus on
patient-days or on percentage of glucose values The most common type of QI model is the Plan-
that meet a specified threshold. Metrics should be Do-Study-Act (PDSA) model (Figure, following
tracked over time with a control chart to allow page).7 In the “plan” stage, teams must determine
what data to collect, clarify the aim statement, and

Table 2. Practical Recommendations for Glucometrics in the Hospital

Adapted from Schnipper JL et al. J Hosp Med, 2008; 3(5 Suppl): 66-75. © Society of Hospital Medicine. Published by Wiley InterScience.

ENDO 2025 • Diabetes and Vascular Disease 159

develop a clear plan to test the change. In the “do” or new issues. If you can sustain the change in
stage, the test is carried out at a small scale, with your area and want to work towards developing
documentation of any obstacles and/or unexpected an institutional glycemic management program
observations. In the “study” stage, data are analyzed that meets best practice standards, you can
and compared with assumed predictions with consider working towards a disease state–specific
reflection on what is learned. In the “act” stage, certification through The Joint Commission for
stakeholders review results and plan for the next advanced inpatient diabetes management. This
step based on what was learned from this test. The is a comprehensive program that is founded on
cycle is repeated multiple times for a QI initiative the American Diabetes Association’s Clinical
until the aim is achieved. Practice Recommendations and is linked to The
Joint Commission standards. This certification
Figure. Plan-Do-Study-Act Cycle represents a clinical program of excellence that can
help improve care processes, care delivery, patient
safety, and patient experience.8
Plan Do
Clinical Case Vignettes
Case 1
Act Study A 55-year-old woman with pancreatic cancer
underwent the Whipple procedure 4 days ago.
She has been initiated on tube feed therapy and
is receiving a calorically dense formula, 1.5 Cal
at 30 cc/h. She has been started on NPH insulin/
regular insulin 70/30 every 6 hours along with
Reprinted from Barr E. & Brannan, GD. Quality Improvement Methods
(LEAN, PDSA, SIX SIGMA), in StatPearls. 2025: Treasure Island (FL). ©
correctional regular insulin via sliding scale every
StatPearls Publishing LLC. 6 hours. The patient’s nurse administers 70/30
[Color—Print (Color Gallery page CG10) or web & ePub editions] insulin at 6 PM and advances the feed to 40 cc/h.
One hour later, the patient is vomiting and unable
to tolerate feeds. Imaging shows that the tube has
Step 7: Change and maintain a
been dislodged and cannot be used until evaluation
new culture of improvement the next morning. The patient describes shakiness
Although this is mentioned as the last step, it is the and dizziness around 10 PM, and a fingerstick
most challenging and requires continuous ongoing glucose value is 40 mg/dL (2.2 mmol/L).
effort. At any institution, there are changing Based on review of the safety event system,
priorities as time progresses, and key partnerships the team identifies that there have been at least
with chief quality and patient safety officers can 15 other similar cases of hypoglycemia in patients
ensure ongoing project success. Maintaining receiving tube feeds.
ongoing, long-term stakeholder engagement can
be very difficult. To plan for this, it is important Which QI tool would be best to analyze
to ensure that each area has a few champions who the most common contributing factors
will continue to advocate for the needed changes. that led to hypoglycemia in these events?
Project leaders should meet with the champions A. Pareto chart
on a routine basis to ensure engagement. A safety B. Ishikawa diagram
reporting system and root causes analysis of
C. Process mapping
high-harm events are also important in sustaining
change, as it ensures identification of ongoing D. Staff survey

160 ENDO 2025 • Endocrine Case Management

Answer: A) Pareto chart Answer: C) Process mapping
A Pareto chart (Answer A) would be a good tool to In this case, process mapping (Answer C) could
determine which factors are leading to hypoglycemia be used to break down the complex process into
in patients receiving tube feeds and to identify the simple steps to identify what did not happen
most common cause. Ishikawa diagram (Answer correctly in this situation.
B) is great at identifying all of the factors that may
have a role in hypoglycemia development, but it Case 2, Continued
cannot determine if one cause is more frequent than
another. Process mapping (Answer C) can outline Based on the event above, which of
the workflow to prevent hypoglycemia in patients the following interventions would be
receiving tube feeds, but it is not able to determine most effective in preventing a similar
the cause. Staff surveys (Answer D) may be helpful, event from happening again?
but they are not objective measures to determine the A. Development of periprocedural pump
most common cause. management protocol
B. Education of staff in diagnostic imaging
Case 2 C. Education of staff in nursing unit
A 40-year-old man with known type 1 diabetes is D. Safety alert within electronic health record to
admitted to the hospital with pyelonephritis. He alert nursing staff to ensure that pumps are
has had significant nausea and vomiting in the connected and functioning in patients who
last 24 hours and has not been able to eat much. have had procedures requiring temporary
At admission, electrolytes show no evidence of pump removal
metabolic acidosis. Glucose values range from Answer: D) Safety alert within electronic health
90 to 120 mg/dL (5.0-6.7 mmol/L). He is treated record to alert nursing staff to ensure that pumps are
with intravenous antibiotics. At home, the patient connected and functioning in patients who have had
has been on insulin pump therapy and notes that procedures requiring temporary pump removal
his pump has been running in auto mode. The
primary team orders CT for further evaluation, Creating a safety alert within electronic health
and the pump is removed before imaging. Due to record (Answer D) is likely the best way to prevent
unforeseen delay, the CT takes 2 to 3 hours longer similar events from happening, as it is an alert that
than anticipated, and patient returns to his room fires to remind any nurse who is in the patient’s
at midnight and falls asleep without reconnecting chart to ensure the insulin pump is connected and
his pump. The following morning, his glucose functioning after procedure. The other options
level is 425 mg/dL (23.6 mmol/L) with elevated could be helpful, but they unfortunately cannot
anion gap, consistent with diabetic ketoacidosis. guarantee that the teams will remember the
education or protocol that applies to this patient’s
Which of the following QI tools would particular scenario.
be best to help us understand what
steps should take place for a patient
with an insulin pump who will be
Case 2, Continued
undergoing a diagnostic imaging study? The team develops a project with an aim statement
A. Fishbone diagram of “Increasing reconnection of insulin pump
post diagnostic imaging by 50% from baseline by
B. Prioritization matrix
July 2025.”
C. Process mapping
D. Staff and patient surveys

ENDO 2025 • Diabetes and Vascular Disease 161

What type of measure is this aim statement? This patient likely has underlying latent
A. Balance measure autoimmune diabetes (Answer B) given his
B. Outcome measure positive antibody status and the history of needing
insulin therapy within 1 year of diagnosis. He
C. Process measure was assumed to have type 2 diabetes; however,
Answer: C) Process measure the presence of diabetic ketoacidosis and low
C-peptide concentration suggests that he likely has
This is a process measure (Answer C), as latent autoimmune diabetes. While ketosis-prone
reconnecting the insulin pump is a process that can diabetes could be considered, the presentation is
help reduce the outcome of diabetic ketoacidosis typically different and it does not happen in the
that can result when insulin therapy is disrupted. postoperative setting. Steroid-induced diabetes
A balance measure is typically looking for how one is unlikely, as the patient has not received
change impacts something downstream, which any steroids.
is not applicable here. Reconnecting the insulin
pump is not an outcome measure.
Case 3, Continued
Which of the following is the best
Case 3 QI tool to evaluate factors that
A 63-year-old man has a history of type 2 diabetes contributed to this safety event?
diagnosed at age 55 years and is admitted to the A. Ishikawa diagram
hospital for cholecystectomy. He does not have a
B. Prioritization matrix
strong family history of diabetes and was surprised
that he required insulin therapy within 1 year of C. Process mapping
diabetes diagnosis. His BMI is 23 kg/m2. His home D. Develop a new policy
regimen consists of insulin glargine and insulin
Answer: A) Ishikawa diagram
lispro with recent hemoglobin A1c measurement
of 6.9% (52 mmol/mol). After surgery, he is placed Many factors likely contributed to this safety
on sliding-scale insulin therapy. On postoperative event, and developing an Ishikawa diagram
day 1, he has poor appetite, and his glucose levels (Answer A) would be a helpful way to examine
range from 150 to 180 mg/dL (8.3-10.0 mmol/L). the various factors. A prioritization matrix is used
On postoperative day 2, his laboratory test results to identify the best solutions. Process mapping
show development of mild metabolic acidosis with is helpful for determining a current workflow
worsening hyperglycemia. Other results: and may not help with identifying the cause of
C-peptide = 0.2 ng/mL (0.07 nmol/L) this safety event. Policy creation is helpful after
Glucose = 225 mg/dL (SI: 13.0 mmol/L) factors leading to the safety event are identified,
Glutamic acid decarboxylase 65 antibodies, positive and in the scenario of a gap being found between
recommended standards and actual practice.
Which of the following is this patient’s
most likely underlying diagnosis?
Case 3, Continued
A. Type 2 diabetes
A project is developed based on this safety event.
B. Latent autoimmune diabetes
C. Ketosis prone diabetes Which of the following would be an
D. Steroid-induced diabetes appropriate aim statement for this project?
A. Reduce inpatient diabetic ketoacidosis
Answer: B) Latent autoimmune diabetes
B. Increase basal insulin use in patients with type
2 diabetes by 50%

162 ENDO 2025 • Endocrine Case Management

C. Improve glycemic management in limited because they are missing all the elements of
postoperative patients by May 2026 a SMART aim statement.
D. Decrease inpatient diabetic ketoacidosis in
postoperative patients with type 2 diabetes by Key Learning Points
10% from baseline by May 2026
Answer: D) Decrease inpatient diabetic • QI projects require a methodical step-by-step
ketoacidosis in postoperative patients with type approach to have impact and sustain change.
2 diabetes by 10% from baseline by May 2026 • Many useful QI tools are available to help
identify the best methodology with which to
The aim statement in Answer D fulfills all the approach a QI initiative.
criteria of a SMART aim statement, which is
specific, measurable, achievable, realistic, and • All QI projects need to have a SMART aim
timely. Answer A is partially correct but not statement to ensure that there is a finite goal in
time bound or specific. Answers B and C are also mind that is agreed upon by all stakeholders.

References
1. Maynard G, Berg K, Kulasa K, O’Malley C, Rogers KM, eds. The Glycemic 7. Barr E, Brannan GD. Quality improvement methods (LEAN, PDSA, SIX
Control Implementation Guide. Society of Hospital Medicine; 2015. SIGMA). 2024. Treasure Island (FL). StatPearls Publishing. PMID: 38261708
2. Institute for Healthcare Improvement. QI Essentials Toolkit. Institute for 8. Arnold P, Scheurer D, Dake AW, et al. Hospital guidelines for diabetes
Healthcare Improvement; 2017. management and the Joint Commission-American Diabetes Association
3. Preston K. Types of improvement measures in healthcare. LifeQI Blog. Inpatient Diabetes Certification. Am J Med Sci. 2016;351(4):333-341. PMID:
March 2020.https://blog.lifeqisystem.com/types-of-improvement-measures. 27079338
4. Khan SA, Zilbermint M. Centers for Medicare & Medicaid services’ hospital
harm measures for severe hypoglycemia and hyperglycemia: is your hospital
ready? Diabetes Spectr. 2022;35(4):391-397. PMID: 36561656
5. Maynard G, Ramos P, Kulasa K, Rogers KM, Messler J, Schnipper JL. How
Recommended Reading
sweet is it? The use of benchmarking to optimize inpatient glycemic control. • The Joint Commission. Disease Specific Care Core and Advanced Certification
Diabetes Spectr. 2014;27(3):212-217. PMID: 26246782 Programs: Review Process Guide for Advanced Inpatient Diabetes. The Joint
6. Schnipper JL, Magee M, Larsen K, Inzucchi SE, Maynard G, Society of Commission; 2024.
Hospital Medicine Glycemic Control Task Force. Society of Hospital • Institute of Medicine (US) Committee on Quality of Health Care in America.
Medicine Glycemic Control Task Force summary: practical recommendations Crossing the Quality Chasm: A New Health System for 21st Century. National
for assessing the impact of glycemic control efforts. J Hosp Med. 2008;3(Suppl Academies Press (US); 2001.
5):66-75. PMID: 18951387

ENDO 2025 • Diabetes and Vascular Disease 163

GENERAL
ENDOCRINOLOGY
Complications of Novel
Nonimmunotherapy
Cancer Treatments
Afreen Shariff, MD. Division of Endocrinology, Metabolism, and Nutrition, Duke University
School of Medicine and Duke Cancer Institute, Durham, NC; Email: [email protected]

Randol Kennedy, MD. Division of Endocrinology, Metabolism, and Nutrition, Duke

University School of Medicine, Durham, NC

Educational Objectives life-saving therapies. As new treatments emerge,

endocrinologists are stepping into a pivotal role by
After reviewing this chapter, learners should be
supporting both patients and oncologists to ensure
able to:
safer, uninterrupted cancer care.
• Identify mechanisms of endocrine
complications associated with novel Practice Gaps
nonimmunotherapy-based cancer treatments.
• Recommend management and treatment • There is lack of awareness of emerging cancer
options while considering the impact of therapies and their impact on the endocrine
treating endocrine complications of cancer system.
therapies and vice versa. • There are training and education gaps on
• Describe and manage long-term emerging toxicities and identification and
sequalae of endocrine complications of management of endocrine toxicities.
nonimmunotherapy-based cancer treatments. • There are notable challenges with
comanagement, evidence gaps, and
coordinated care when working with
complex, high-acuity oncology patients in
Significance of the the survivorship phase who continue to have
Clinical Problem persistent long-term endocrine complications.
Every 15 seconds, someone is diagnosed with
cancer. Endocrine complications of cancer Discussion
therapy are common and affect 10% of patients
In 2024 alone, the US FDA granted approval for
during treatment and up to 60% of survivors.1,2
immunotherapy, combination immunotherapy,
With cancer therapies rapidly evolving beyond
chemotherapy, and other agents for 62 new
traditional chemotherapy, radiation, and surgery,
indications. While we continue to learn about
more than 80% of patients now face treatment-
endocrine immune-related adverse events,
related adverse effects, some of them life-
endocrinologists globally are being challenged
threatening. Early, effective management of these
with keeping abreast of the rapid adoption of
toxicities is critical to allow patients to continue
novel cancer therapies, which is occurring at

166 ENDO 2025 • Endocrine Case Management

a much faster pace than evidence and expert hyperglycemia when cancer treatment affects the
guidelines can be generated to inform practice insulin-signaling pathway.
for these endocrine toxicities. In this chapter, The PI3K/Akt/mTOR signaling pathway is a
we discuss novel cancer therapies targeting the highly conserved signal transduction network in
insulin-signaling pathway, the cortisol synthesis eukaryotic cells that promotes cell survival, cell
pathway, and novel cancer delivery systems that growth, and cell-cycle progression.4 Regarding
are being adopted by oncologists globally. its role in gluconeogenesis, the mTOR pathway
is also a modulator of insulin-mediated glucose
metabolism and glycogen synthesis (Figure 1).5,6
Nonimmunotherapy Treatments
Deregulation of this pathway is a common and
Inhibitors of the Phosphoinositide 3-Kinase/ well-established mechanism for cancer growth.
Serine-Threonine Protein Kinase Akt/ For example, pathogenic variants in the genes
Mammalian Target of Rapamycin (PI3K/ encoding PI3K/Akt/mTOR are the most frequent
Akt/mTOR) Signaling Pathway pathways of breast cancer tumorigenesis.7
The interplay of metabolic disease, diabetes, and This, therefore, has led to evolution of cancer
obesity strongly correlates with a greater risk for at therapies, with more than 40 agents targeting this
least 13 different cancer types.3 It is not surprising mechanism.8,9 However, with the increased use
that patients can develop treatment-induced of these therapies, there is an expectant increase
in the number of hyperglycemia-related adverse

Figure 1. Simplified Schematic of the Intracellular Mechanism of the PI3K/Akt/mTOR Pathway

Insulin binding initiates autophosphorylation and activation of the tyrosine kinase component of the β domain. The activated tyrosine kinase phosphorylates
IRS1, which, when triggered, activates PI3K that generates PIP3 from PIP2. PIP3 phosphorylates Akt/protein kinase B, which when activated, either
indirectly affects mTORC1 through TSC2 or directly through PRAS40 (proline-rich Akt substrate of 40 kDa), leads to regulation of cellular metabolism and
growth/proliferation. Activation is shown by arrowhead lines, whereas inhibition is indicated by ‘T’-shaped lines. Abbreviations: AMPK, AMP-activated
protein kinase; IRS1/2, insulin receptor substrate 1 and 2; mTORC1/2, mechanistic target of rapamycin complex 1 and 2; PI3K, phosphatidylinositide-3
kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; Rheb, Ras homolog enriched in brain; TSC1/2, tuberous
sclerosis protein complex 1 and 2.
[Color—Print (Color Gallery page CG10) or web & ePub editions]

ENDO 2025 • General Endocrinology 167

events. One drug class that will not be covered idelalisib, umbralisib) have not been associated
in this discussion because of its familiarity, but with significant hyperglycemia.6
should be briefly mentioned in this context, is Hyperglycemia is the most frequent adverse
mTOR inhibitors (eg, sirolimus [rapamycin], event and the one of the most common reasons
temsirolimus, everolimus). Hyperglycemia is a for PI3K inhibitor discontinuation.10,11 While
relatively frequent adverse event associated with hyperglycemia with copanlisib infusion is usually
mTOR inhibitors, with reports that it affects as transient (occurring within hours of infusion and
many as 50% of treated patients.6 Less familiar but resolving within 24 to 48 hours after infusion12),
evolving targeted cancer therapies of the PI3K/ hyperglycemia with alpelisib is of slower onset,
Akt/mTOR signaling pathway include inhibitors occurring days after drug initiation (Table 1).11
of Akt and PI3K. Therefore, management of copanlisib-induced
hyperglycemia may be brief, with fluid hydration
PI3K Inhibitors during infusion and oral hypoglycemic agents or
Since the FDA approved idelalisib for chronic short-acting insulin as needed. Treatment with
lymphocytic leukemia in 2014, there has been long-acting insulins is generally avoided due to
an upsurge in clinical trials and the use of PI3K risk of hypoglycemia. Hyperglycemia with alpelisib
inhibitors in cancer therapy. Currently, there are 5 is generally approached with oral hypoglycemic
FDA-approved drugs on the market (Table 1) with agents as first-line treatment (metformin being
other clinical trials ongoing. PI3K inhibitors can the first agent of choice), with insulin regimens
be broadly characterized as pan-PI3K inhibitors reserved for patients with severe hyperglycemia
(copanlisib), isoform selective (alpelisib, α isoform (Figure 2, following page).6 Diabetic ketoacidosis has
selective; idelalisib, δ isoform selective), and dual also been reported as a rare severe complication of
selective (duvelisib, δ and γ isoforms). Umbralisib alpelisib use.13
is a unique dual inhibitor of the PI3K δ isoform There is concern about the use insulin
and casein kinase-1ε. Interestingly, PI3K inhibitors and sulfonylureas as part of hyperglycemia
with which the α isoform is spared (duvelisib, management in patients with PI3K-mediated
cancer tumors, as this could potentially stimulate

Table 1. Incidence and Mechanism of Action of Hyperglycemia Associated With Cancer Therapies

Mechanism of Reported
Median onset/resolution development of incidence of
Drug category Drug name of hyperglycemia hyperglycemia hyperglycemia

Phosphatidylinositol IDE-1 Idelalisib Alpelisib Blocking PI3K interferes 28% to 30%

kinase (PI3K) inhibitors with insulin signaling,
Duvelisib Onset 15 days; resolution: 4-7 days 11
resulting in insulin
Copanlisib Copanlisib resistance
Alpelisib Onset, 5 hours after infusion;
resolution: 24-48 hours after infusion
Umbralisib

Akt or protein kinase B Capivasertib Onset, 15 days15 • Reduces hepatic 2.3%

inhibitors glycogen synthesis
• Induces hepatic
glycogenolysis
• Blocks insulin
signaling, resulting in
insulin resistance

Antibody drug conjugates Enfortumab Onset, 19 days22 Unknown 14%

vedotin

168 ENDO 2025 • Endocrine Case Management

Figure 2. Algorithm for the Management of PI3K/Akt/mTOR–Induced Hyperglycemia

Abbreviations: DKA, diabetic ketoacidosis; ED, emergency department; eGFR, glomerular filtration rate; HCO3, bicarbonate; HHS, hyperglycemic hyperosmolar
syndrome; IVF, intravenous fluids; MF, metformin; PCP, primary care provider; Na, serum sodium; TZD, thiazolidinediones; BUN, serum urea nitrogen.6
Reprinted from Cheung YM et al. Curr Probl Cancer, 2022; 46(1): 100776. © Elsevier Inc.
[Color—Print (Color Gallery page CG11) or web & ePub editions]

ENDO 2025 • General Endocrinology 169

tumorigenesis through PI3K activation, based on before administration (to deplete liver glycogen
the mechanism proposed above. However, this stores), as well as by a low-carbohydrate diet.
hypothesis remains speculative, with no evidence Interestingly, oral antidiabetes agents such as
highlighting an association of cancer progression metformin, pioglitazone, and DPP-4 inhibitors did
with high endogenous insulin use in these patients. not completely attenuate prandial hyperglycemia,
However, there is a growing body of evidence unlike the scenario with PI3K inhibitors. Despite
supporting the role of hyperinsulinemic states in these aberrancies in the response shown in vivo
tumorigenesis.6 As insulin is the most effective of oral hypoglycemic agents with Akt inhibitor–
pharmacotherapy for severe hyperglycemia, induced hyperglycemia, the approach to managing
especially in oncologic patients, exogenous insulin Akt inhibitor–induced hyperglycemia in clinical
should also be used when clinically indicated. practice is similar to that of other forms of
Sulfonylureas, however, should be discouraged in cancer therapy–induced insulin resistance. Oral
patients undergoing chemotherapy with PI3K/ hypoglycemic agents are first-line treatment, with
Akt/mTOR inhibitors.6 or without insulin therapy (Figure 2, preceding
page).6 Hyperglycemia is usually reversible, with
Akt Inhibitors resolution after therapy discontinuation. Diabetic
In November 2023, capivasertib became the ketoacidosis has also been reported as a rare severe
first FDA-approved Akt inhibitor to be used complication of Akt inhibitor use.18
in combination with fulvestrant (an estrogen
receptor antagonist) in the treatment of breast Antibody Drug Conjugates
cancer with biomarkers to Akt or the catalytic Targeted chemotherapies using monoclonal
α-subunit on phosphoinositide 3-kinase antibodies as a vector were introduced in the
(PI3KCA).8 In the phase 3 trial leading to FDA 1970s. By specifically binding an antigen on a
approval, hyperglycemia of any grade occurred cancerous cell, it was theorized that monoclonal
in 16.3% of patients (2.3% grade 3 or higher) in antibodies could reduce nonspecific toxicities,
comparison with 3.7% of patients on placebo + target tumor cells, and either alter their signaling
fulvestrant (0.3% grade 3 or higher).14 The median patterns towards a therapeutic outcome or direct
onset of hyperglycemia was 15 days, ranging from an immune response toward the tumor cell.19
1 to 51 days.15 Although these incidences appear Therefore, there is no surprise that this medium
to be lower than that related to PI3K inhibitors, of cancer therapy has become more common,
the authors did consider the intermittent use of with approximately 13 antibody drug conjugates
capivasertib in the study as a contributing factor. that are FDA approved for cancer therapy in the
Therefore, an increased incidence in clinical United Sates and more than 100 ongoing clinical
practice with more routine use of agents similar to trials.20 However, in attempts to deliver the
PI3K inhibitors is a reasonable assumption. maximum dose for anticancer efficacy, antibody
Akt inhibition and its role in obesity and drug conjugates have been associated with
hyperglycemia has already been investigated unwarranted adverse events, leading to frequent
in previous studies. For example, Cho et al therapy discontinuation.
demonstrated significant fasting hyperglycemia,
as well as near 4-fold increase in islet mass Enfortumab Vedotin
consistent with β-cell compensation to insulin Enfortumab vedotin is an antibody targeting
resistance.16 Crouthamel et al also demonstrated a the cell adhesion molecule nectin-4 linked to a
similar mechanism of hyperglycemia in vivo when microtubule inhibitor conjugate. This antibody
GSK690693, a pan-AKT kinase inhibitor, was drug conjugate was first granted accelerated FDA
given to mice.17 This Akt-induced hyperglycemia approval in 2019 for the treatment of urothelial
was demonstrated to be attenuated by fasting carcinoma based on a phase 1 clinical trial.21

170 ENDO 2025 • Endocrine Case Management

Pertinent to this discussion, severe hyperglycemia prolonging the exposure time of metastases to
occurred in 5% of patients, and it was the only chemotherapy and decreasing systemic toxicity.25
grade 3 or higher adverse event occurring in High-dosage intra-arterial dexamethasone
5% or more of patients. In December 2023, commonly accompanies chemotherapy to reduce
enfortumab vedotin coupled with pembrolizumab systemic toxicity.24,25 Although clinical trials have
(an inhibitor of programmed cell death protein-1/ not reported iatrogenic Cushing syndrome as a
PD-1) was also FDA approved for the treatment of common adverse event of HIAP therapy, a few
urothelial carcinoma. cases have been reported, suggesting a possible
In further clinical trials, hyperglycemia of consequence of prolonged steroid exposure, as
any grade occurred in 14% of patients treated with other forms of high-dosage glucocorticoid
with enfortumab vedotin, with 7% of patients steroid therapy.
developing grade 3 to 4 hyperglycemia.20,22 Median
time of hyperglycemia onset was 19 days.22 Future Directions
Hyperglycemia also occurred more frequently
in patients with baseline hyperglycemia or Emerging cancer therapies continue to be more
BMI of 30 kg/m2 or higher.22 The mechanism enhanced, personalized, and targeted, with several
of enfortumab-induced hyperglycemia is still drugs in the pipeline for approval in the coming
unknown. Diabetic ketoacidosis has also been months to years. Importantly, these approvals
reported as a severe complication with high are both as monotherapy and combination
mortality.23 Therefore, the FDA has issued therapy that integrate radiation, chemotherapy,
guidelines related to monitoring for hyperglycemia immunotherapy, and newer targeted therapies that
while enfortumab is being used, with advice to can include vaccine therapies, bispecific agents,
hold enfortumab if the glucose concentration is etc. Given the growth of oncology portfolio
greater than 250 mg/dL (>13.9 mmol/L). of therapies, treatments are being approved
to manage early-stage cancers. This further
Hepatic Intra-Arterial Chemotherapy expands the pool of individuals with cancer
Lastly, hepatic intra-arterial chemotherapy was who are eligible to receive these treatments.
introduced in the early 1970s to deliver localized The intertwined relationship of new endocrine
chemotherapy to the liver via the hepatic artery toxicities and preexisting comorbidities, such as
in an attempt to circumvent the toxic effects of obesity, diabetes, and cancer, underscores the need
systemic chemotherapy. The liver’s dual blood to stay up to date with this intersecting field of
supply preferentially delivers high doses of oncology and endocrinology.
chemotherapeutic agents to the hepatic artery, and
because the liver metabolizes the chemotherapy Clinical Case Vignettes
(first-pass effect), intra-arterial delivery
diminishes the systemic toxic effects.24 Cancers Case 1
that could be treated using this medium includes A 73-year-old woman presents to the emergency
hepatocellular carcinoma, metastatic colon cancer, department with a 3-week history of worsening
and cholangiocarcinoma. Hepatic artery intra- fatigue, nausea, vomiting, increased thirst, and
arterial pump (HIAP) chemotherapy has become urination. She has no history of diabetes or no
more frequently used as an option in treating other notable endocrine issues. She does, however,
unresectable disease. have an oncologic history of ER/PR-positive,
HIAPs are implanted at specialized centers. HER-2/neu-negative invasive ductal carcinoma of
Chemotherapy is instilled into the pump using the left breast diagnosed 20 years ago. Treatment
infusion needles every 2 to 3 weeks, allowing for consisted of mastectomy, 4 cycles of dose-dense
continuous rather than bolus infusions, thereby doxorubicin + cyclophosphamide with paclitaxel

ENDO 2025 • General Endocrinology 171

chemotherapy, radiation therapy, and 10 years of Which of the following is the most
endocrine therapy (exemestane, then switched to likely mechanism explaining this
letrozole therapy). After completion of endocrine patient’s new-onset diabetes?
therapy, she was found to have bone and lung A. Autoantibody-mediated destruction of
metastases when she presented to the hospital pancreatic β cells
for weight loss and dyspnea. Chemotherapy was B. Autoreactive T cell–mediated destruction of
reinitiated. Due to persistent disease, a liquid pancreatic β cells
biopsy for tumor DNA analysis was performed,
C. Acquired adipolysis leading to hypoleptinemia
which identified pathogenic variants in the
and increased insulin resistance
genes encoding PI3K and the estrogen receptor 1
(ESR1). She was therefore started on capivasertib D. Insulin resistance through direct inhibition of
and fulvestrant therapy 1 month before her the insulin receptor–signaling pathway
current hospital presentation. E. Pathogenic variant in hepatocyte nuclear
On physical examination, she appears ill. Her factor 1α leading to abnormal insulin secretion
temperature is 98.9°F (37.2°C), blood pressure
Answer: D) Insulin resistance through direct inhibition
is 125/58 mm Hg, pulse rate is 94 beats/min,
of the insulin receptor–signaling pathway
and oxygen saturation is 97% on room air. Her
weight is 149.7 lb (67.9 kg) (BMI = 25.68 kg/m²). This patient presented with symptoms concerning
Mucous membranes are moist. Fine bibasilar for diabetic ketoacidosis (polydipsia, polyurea,
crackles are audible and consistent with atelectasis. nausea, vomiting) with significant hyperglycemia.
Examination findings are otherwise normal. Although her biochemistry panel shows a mildly
elevated anion gap, β-hydroxybutyrate and
Laboratory test results:
bicarbonate levels are normal, thereby ruling
Sodium = 126 mEq/L (135-145 mEq/L) out diabetic ketoacidosis as a complication of
(SI: 126 mmol/L [135-145 mmol/L]) severe hyperglycemia. She therefore likely has
Potassium = 4.5 mEq/L (3.5-5.0 mEq/L)
(SI: 4.5 mmol/L [3.5-5.0 mmol/L])
some preserved pancreatic β-cell function.
Chloride = 87 mEq/L (98-108 mEq/L) Factors leading to pancreatic β-cell dysfunction
(SI: 87 mmol/L [98-108 mmol/L]) are less likely to be the cause of this patient’s
Bicarbonate = 24 mEq/L (21-30 mEq/L) new-onset diabetes. Type 1 diabetes is caused
(SI: 24 mmol/L [21-30 mmol/L]) by autoantibody-mediated pancreatic β-cell
Creatinine = 1.7 mg/dL (0.6-1.3 mg/dL)
(SI: 150.3 μmol/L [53.0-114.9 μmol/L])
destruction (Answer A), whereas the main
Serum urea nitrogen = 37 mg/dL (7-20 mg/dL) proposed mechanism of immune checkpoint
(SI: 13.2 mmol/L [2.5-7.1 mmol/L]) inhibitor–related diabetes is T cell–mediated
Glucose = 758 mg/dL (70-140 mg/dL) destruction (Answer B). In both etiologies,
(SI: 42.1 mmol/L [3.9-7.8 mmol/L]) diabetic ketoacidosis is a common presenting
Anion gap = 15 mEq/L (3-12 mEq/L) (SI: 15 mmol/L
[3-12 mmol/L])
feature. Acquired generalized lipodystrophy
β-Hydroxybutyrate = 0.4 mmol/L (<0.4 mmol/L) is another rare cause of immune checkpoint
(SI: 400 μmol/L [<400 μmol/L]) inhibitors leading to hypertriglyceridemia and
Hemoglobin A1c = 5.5% (<5.7%) (37 mmol/mol insulin resistance (Answer C). This patient is not
[<39 mmol/mol]) on an immune checkpoint inhibitor, but rather
a protein kinase B/Akt inhibitor (capivasertib),
thereby leading to impaired insulin signaling
through the PI3K/Akt/mTOR pathway (Answer
D). This causes hyperglycemia with a median
onset of 15 days. First-line treatments include oral
hypoglycemic agents, such as metformin, unless

172 ENDO 2025 • Endocrine Case Management

there is a question of severe hyperglycemia. She Which of the following is the most appropriate
was acutely managed with insulin and fluids with next step in this patient’s management?
rapid improvement of glycemic control while A. Order a basic metabolic panel and measure
capivasertib was briefly interrupted. Maturity- plasma renin and aldosterone
onset diabetes in the young (MODY), as its name B. Order a cosyntropin-stimulation test
implies, occurs in patients younger than 30 years
C. Initiate hydrocortisone, 20 mg in the morning
who usually have a strong family history due to
and 10 mg in the afternoon
its autosomal dominant transmission (Answer E),
which is not the case in this vignette. D. Measure 21-hydroxylase antibodies
E. Order a dexamethasone-suppression test
Case 2 Answer: C) Start hydrocortisone, 20 mg in
A 50-year-old man is referred for endocrinology the morning and 10 mg in the afternoon
consultation for 2 weeks of worsening fatigue.
This patient has symptoms and signs of cortisol
He has an oncologic history of colorectal
excess/Cushing syndrome related to HIAP
adenocarcinoma with liver metastases diagnosed
dexamethasone infusion (weight gain, central
2 years ago. Treatment consisted of folinic
obesity, proximal muscle wasting, purple striae,
acid, fluorouracil, and oxaplatin (FOLFOX)-
new-onset diabetes) and is now demonstrating
based chemotherapy and bevacizumab for 5
central adrenal insufficiency because of abrupt
months, after which he underwent primary liver
discontinuation of intrahepatic dexamethasone
resection and placement of a HIAP with infusions
infusion. Therefore, a diagnostic workup for
of floxuridine (FUDR) and dexamethasone,
20 mg every 2 to 3 weeks, for 64 weeks. During
treatment, the patient reported a 30-lb (14-kg) Figure 3.
weight gain over 3 to 6 months. A random point-
of-care glucose value of 500 mg/dL (27.8 mmol/L)
during an outpatient follow-up visit prompted
commencement of metformin and empagliflozin
to address the new diagnosis of diabetes. HIAP
therapy was discontinued 4 weeks before
consultation whereby random point-of-care
fingerstick glucose readings improved to 130 to
150 mg/dL (7.2-8.3 mmol/L).
On physical examination, his temperature is
98.9°F (37.2°C), blood pressure is 110/58 mm Hg,
pulse rate is 80 beats/min, and oxygen saturation
is 97% on room air. His weight is 219.8 lb
(99.7 kg) (BMI = 34 kg/m²). Central obesity is
noted with visible purple striae on the lower
abdomen (Figure 3). Proximal muscle wasting is
also noted in the extremities. Comparison staging
CT of the abdomen and pelvis is shown (Figure 4,
following page). Physical exam findings include a dorsocervical fat pad (“buffalo hump”)
(Panel A), purple abdominal striae on the abdomen (Panel B) and under
the armpit (Panel C), and truncal obesity 2 years after starting HIAP with
dexamethasone, pictured here roughly 30 months after therapy initiation.25
Reprinted from Ferreira MS & Shariff AI. Current Problems in Cancer: Case
Reports, 2022; 7(1): 100177. © The Authors. Published by Elsevier Inc.
[Color—Print (Color Gallery page CG12) or web & ePub editions]

ENDO 2025 • General Endocrinology 173

Figure 4. enough to forego further diagnostic laboratory
workup. In cases of ambiguity, measurement of
morning serum cortisol and ACTH would be the
initial step, not a cosyntropin-stimulation test
(Answer B), as this could be misleadingly normal
in the setting of secondary adrenal insufficiency
(if the adrenal cortex has not yet atrophied in the
presence of prolonged steroid exposure). In this
patient, the adrenal glands showed evidence of
atrophy on interval imaging.

Key Learning Points

• Novel cancer therapies beyond
immunotherapy—especially PI3K, Akt
inhibitors, and antibody drug conjugates—are
increasingly associated with serious endocrine
toxicities, particularly hyperglycemia.
• Hyperglycemia is the most common and
clinically significant endocrine adverse event
associated with PI3K/Akt/mTOR inhibitors.
Contrast-enhanced abdominal CT of normal adrenal glands before
initiation of floxuridine (FUDR) via HIAP (Panel A), and significant
Management requires tailored strategies based
adrenal atrophy approximately 64 weeks after receiving 20 mg HIAP on the specific agents.
dexamethasone every 2 to 3 weeks (Panel B).
Reprinted from Ferreira MS & Shariff AI. Current Problems in Cancer: Case • Emerging treatments, such as HIAP
Reports, 2022; 7(1): 100177. © The Authors. Published by Elsevier Inc.
chemotherapy, can lead to steroid-induced
[Color—Print (Color Gallery page CG12) or web & ePub editions]
Cushing syndrome and secondary adrenal
insufficiency, emphasizing the need for
primary adrenal insufficiency (Answers A and proactive monitoring and early intervention.
D) should not be considered in this clinical • Endocrinologists have a critical role in
scenario. Also, due to the patient’s compelling identifying, managing, and educating patients
signs and symptoms related to exogenous steroid and clinicians about endocrine complications
use, a dexamethasone-suppression test (Answer of cancer therapies to bridge gaps in
E) is unnecessary. Although proof of adrenal survivorship care and help patients stay on
insufficiency can be considered with laboratory life-saving treatments.
testing, this patient’s clinical scenario is convincing

References
1. Hattersley R, Nana M, Lansdown AJ. Endocrine complications of 3. Berrington de Gonzalez A, Hartge P, Cerhan JR, et al. Body-mass index and
immunotherapies: a review. Clin Med (Lond). 2021;21(2):e212-e222. PMID: mortality among 1.46 million white adults. N Engl J Med. 2010;363(23):2211-
33762389 2219. PMID: 21121834
2. Gebauer J, Higham C, Langer T, Denzer C, Brabant G. Long-term endocrine 4. Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling
and metabolic consequences of cancer treatment: a systematic review. Endocr transduction pathway and targeted therapies in cancer. Mol Cancer.
Rev. 2019;40(3):711-767. PMID: 30476004 2023;22(1):138. PMID: 37596643
5. Tremblay F, Gagnon A, Veilleux A, Sorisky A, Marette A. Activation of the
mammalian target of rapamycin pathway acutely inhibits insulin signaling to

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 Akt and glucose transport in 3T3-L1 and human adipocytes. Endocrinology. 16. Cho H, Mu J, Kim JK, et al. Insulin resistance and a diabetes mellitus-like
2005;146(3):1328-1337. PMID: 15576463 syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science.
6. Cheung YM, McDonnell M, Hamnvik OR. A targeted approach to 2001;292(5522):1728-1731. PMID: 11387480
phosphoinositide-3-kinase/Akt/mammalian target of rapamycin-induced 17. Crouthamel MC, Kahana JA, Korenchuk S, et al. Mechanism and
hyperglycemia. Curr Probl Cancer. 2022;46(1):100776. PMID: 34376311 management of AKT inhibitor-induced hyperglycemia. Clin Cancer Res.
7. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast 2009;15(1):217-225. PMID: 19118049
tumours. Nature. 2012;490(7418):61-70. PMID: 23000897 18. Rodriguez YE, Batra R, Patel K, Martinez S. Capivasertib-induced diabetic
8. Mullard A. FDA approves first-in-class AKT inhibitor. Nat Rev Drug Discov. ketoacidosis in a patient with estrogen receptor-positive/human epidermal
2024;23(1):9. PMID: 38049466 growth factor receptor 2-negative (ER+/HER2-) metastatic breast cancer and
9. Sirico M, D’Angelo A, Gianni C, Casadei C, Merloni F, De Giorgi U. Current no prior history of diabetes mellitus: a case report. Cureus. 2024;16(7):e63710.
state and future challenges for PI3K inhibitors in cancer therapy. Cancers PMID: 39099917
(Basel). 2023;15(3):703. PMID: 36765661 19. Chau CH, Steeg PS, Figg WD. Antibody-drug conjugates for cancer. Lancet.
10. Panayiotidis P, Follows GA, Mollica L, et al. Efficacy and safety of copanlisib 2019;394(10200):793-804. PMID: 31478503
in patients with relapsed or refractory marginal zone lymphoma. Blood Adv. 20. Nguyen TD, Bordeau BM, Balthasar JP. Mechanisms of ADC toxicity and
2021;5(3):823-828. PMID: 2021;5(3):823-828. PMID: 33560394 strategies to increase ADC tolerability. Cancers (Basel). 2023;15(3):713. PMID:
11. Rugo HS, Andre F, Yamashita T, et al. Time course and management of key 36765668
adverse events during the randomized phase III SOLAR-1 study of PI3K 21. Rosenberg J, Sridhar SS, Zhang J, et al. EV-101: a phase I study of single-
inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced agent enfortumab vedotin in patients with nectin-4-positive solid tumors,
breast cancer. Ann Oncol. 2020;31(8):1001-1010. PMID: 32416251 including metastatic urothelial carcinoma. J Clin Oncol. 2020;38(10):1041-
12. Patnaik A, Appleman LJ, Tolcher AW, et al. First-in-human phase I study of 1049. PMID: 32031899
copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 22. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin
3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s in previously treated advanced urothelial carcinoma. N Engl J Med.
lymphomas. Ann Oncol. 2016;27(10):1928-1940. PMID: 27672108 2021;384(12):1125-1135. PMID: 38446675
13. Farah SJ, Masri N, Ghanem H, Azar M. Diabetic ketoacidosis associated 23. Atemnkeng F, Aguilar F, Gupta S, Chugh S, Klein M. Diabetic ketoacidosis
with alpelisib treatment of metastatic breast cancer. AACE Clin Case Rep. and acute kidney injury associated with enfortumab vedotin for urothelial
2020;6(6):e349-e351. PMID: 33244501 carcinoma: a case report. Kidney Med. 2023;5(12):100737. PMID: 38028029
14. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor- 24. Franssen S, Soares KC, Jolissaint JS, et al. Comparison of hepatic arterial
positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. infusion pump chemotherapy vs resection for patients with multifocal
PMID: 37256976 intrahepatic cholangiocarcinoma. JAMA Surg. 2022;157(7):590-596. PMID:
15. Rugo HS, Oliveira M, Howell SJ, et al. Capivasertib and fulvestrant 35544131
for patients with hormone receptor-positive advanced breast cancer: 25. Ferreira MS. Iatrogenic Cushing’s syndrome presenting with adrenal
characterization, time course, and management of frequent adverse events insufficiency in 2 patients receiving dexamethasone for metastatic colorectal
from the phase III CAPItello-291 study. ESMO Open. 2024;9(9):103697. cancer through an intrahepatic arterial infusion pump. Current Problems in
PMID: 39241495 Cancer: Case Reports. 2022;7:100177.

ENDO 2025 • General Endocrinology 175

NEUROENDOCRINOLOGY
AND PITUITARY
Challenging Cases of
Hyponatremia
Mirjam Christ-Crain, MD, PhD. Department of Endocrinology, University hospital Basel,
University of Basel, Switzerland; Email: [email protected]

Educational Objectives increased intracranial pressure, which manifests

as headaches, restlessness, and confusion. Brain
After reviewing this chapter, learners should be
herniation and death can occur if hyponatremia
able to:
is not treated immediately. However, if
• Describe the clinical symptoms of acute and hyponatremia develops over several days, sodium,
chronic hyponatremia. followed by organic solutes, is extruded from
the brain, decreasing intracerebral osmolality
• Construct the differential diagnosis of
and preventing the development of cerebral
hyponatremia and distinguish various
edema. Due to this adaptive mechanism, chronic
causes of chronic syndrome of inappropriate
hyponatremia is often clinically asymptomatic.
antidiuresis (SIAD).
A growing body of evidence has shown that
• Recommend treatment options for chronic hyponatremia is associated with increased
acute severe hyponatremia and chronic mortality and morbidity. A meta-analysis found
hyponatremia. that hyponatremia is significantly associated with
overall mortality2; an increased risk of falling,
osteoporosis, and fractures3; and attention deficit.4
Multimorbid patients generally have a worse
Significance of the prognosis. However, it remains unclear whether
Clinical Problem these observations represent causality or are
purely associations.
The prevalence of hyponatremia depends on
the nature of the patient population studied
(eg, hospitalized patients or outpatients) and Practice Gaps
the criteria used to define hyponatremia.
Using a definition of hyponatremia of a • Challenges in properly diagnosing the various
sodium concentration less than 135 mEq/L etiologies of hyponatremia.
(<135 mmol/L), it is the most common • Difficulty choosing the correct treatment for
electrolyte disorder and affects more than 15% of chronic hyponatremia.
hospitalized patients.1 The prevalence rate is even
higher (up to 30%) in acutely and chronically ill • Challenges meeting the need to immediately
hospitalized patients.1 The most common cause of treat patients with acute hyponatremia and
hyponatremia is SIAD. severe symptoms.
In acute hyponatremia (<48 hours), the
brain’s ability to compensate for the increased
osmotic gradient across the blood-brain barrier
is exceeded; water is osmotically shifted into the
brain, and cerebral edema occurs. This can lead to

178 ENDO 2025 • Endocrine Case Management

Discussion guidelines recommend intravenous infusion of
150 mL 3% hypertonic saline over 20 minutes
Diagnosis of Hyponatremia followed by a second administration of 150 mL
Appropriate differential diagnosis is essential while checking plasma sodium, with the goal
in hyponatremic patients because the treatment of reaching a 5 mmol increase and symptom
depends on the etiology. Once hypotonic improvement.5
hyponatremia is confirmed, urine osmolality In the management of chronic hyponatremia
should be measured, as it reflects arginine in patients with SIAD, fluid restriction is still
vasopressin (AVP) activity. Levels less than the first-line therapy currently recommended
100 mOsm/kg are indicative of suppressed by European Union and US hyponatremia
AVP, such as in primary polydipsia, low solute guidelines.5,7 Recommended fluid restrictions
intake, or beer potomania. Conversely, urine generally range from 500 to 1000 mL.8 In patients
osmolality greater than 100 to 200 mOsm/kg with persistent SIAD not responding to fluid
reflects increased AVP activity, which can be restriction, second-line therapy is required,
nonosmotically triggered by cortisol deficiency such as urea (recommended as a second-line
or low effective arterial volume resulting from treatment after fluid restriction in both the
hypovolemia, heart insufficiency, or cirrhosis. European hyponatremia guidelines and the US
However, AVP release can also be inappropriate expert panel recommendations).5,7 Another
with respect to plasma osmolality and second-line treatment option is vasopressin
hemodynamics as seen in SIAD.5 antagonists. Tolvaptan is an oral vasopressin
The clinical criteria necessary to diagnose V2-receptor antagonist that blocks AVP action
SIAD go back to the definition by Schwartz and in the kidneys, inducing water diuresis to raise
Bartter in 1967.6 SIAD is considered a diagnosis of serum sodium levels. The efficacy of tolvaptan vs
exclusion and is based on the evaluation of urine placebo was established in the SALT-1 and SALT-
and serum osmolality and sodium in the setting of 2 trials in patients with chronic euvolemic and
clinical euvolemia (Box 1). hypervolemic hyponatremia.9 The results showed
SIAD has a variety of underlying causes (Box 2). better improvement in serum sodium area under
the curve with tolvaptan by day 4. The initial
Treatment of Hyponatremia tolvaptan dosage was 15 mg daily. Based on this
study, tolvaptan was approved by the US FDA in
Acute symptomatic hyponatremia is an emergency
and must be treated immediately with hypertonic
saline. American guidelines recommend
Box 2. Etiologies of SIAD
intravenous infusion of 100 mL 3% hypertonic
saline over 10 minutes up to 3 times.7 European • Malignancy: solid organ (particularly chest and
nasopharyngeal), lymphoma
• Medications: antidepressants (eg, serotonin selective
reuptake inhibitors), anticonvulsants, and antipsychotic
Box 1. Diagnostic Criteria for SIAD agents
• Pulmonary disorders: infection, asthma, cystic fibrosis,
• Plasma osmolality <275 mOsmol/kg H20 respiratory failure
• Urine osmolality >100 mOsmol/kg H20 • Central nervous system disorders: infection, hemorrhage,
thrombosis, trauma, tumor, hydrocephalus, autoimmune
• Clinical euvolemia
(multiple sclerosis/Guillain-Barre syndrome), multiple
• Urinary sodium excretion >30 mmol/L with normal salt system atrophy, delirium tremens)
and water intake
• Transient stimuli (secondary to nausea, pain, stress,
• Exclusion of cortisol deficiency prolonged endurance exercise, general anesthesia)
• Normal kidney function • Idiopathic
• Absence of diuretic use • Hereditary (eg, nephrogenic SIAD)

ENDO 2025 • Neuroendocrinology and Pituitary 179

2009 to treat clinically significant hypervolemic or Glucose = 115.3 mg/dL (70.3-100.9 mg/dL)
euvolemic hyponatremia. (SI: 6.4 mmol/L [3.9-5.6 mmol/L])
Urine osmolality = 298 mOsm/kg (200-1200 mOsm/kg)
Evidence supporting use of loop diuretics
(SI: 298 mmol/kg [200-1200 mmol/kg])
and salt tablets is limited. A recent randomized Urinary sodium = 94 mmol/L (60-140 mmol/L)
controlled trial comparing the effect of fluid
restriction alone vs fluid restriction plus loop Which of the following
diuretics vs fluid restriction plus loop diuretics laboratory parameters is the most
plus salt tablets did not show a significant additive important to measure now?
effect of loop diuretics or salt tablets.8 A. TSH
SGLT-2 inhibitors are approved for use
B. Cortisol
in diabetes and heart failure.10,11 Because their
mechanism of action leads to glycosuria and C. Uric acid
osmotic diuresis, they have also been investigated D. Fractional excretion of urea
in euvolemic hyponatremia due to SIAD in E. B-type natriuretic peptide
hospitalized patients, but also in outpatients in
whom 4 weeks of treatment with empagliflozin, Answer: B) Cortisol
25 mg daily, increased sodium levels from a
baseline of 131 mEq/L to 134 mEq/L (131 mmol/L Case 1, Continued
to 134 mmol/L), corresponding to a serum sodium
Which of the following is the best
increase of 4.1 mEq/L (4.1 mmol/L), whereas no
treatment for this patient?
increase was seen with placebo.12 Lastly, protein
supplementation (90 g daily) increases plasma A. Urea, 15 g daily
sodium by 3 mEq/L (3 mmol/L), while oral urea B. Fluid restriction, <1 L per day
(30 g daily) increases plasma sodium by 2 mEq/L C. Vaptan, 7.5 mg daily
(2 mmol/L), thus pointing to a comparable effect D. 3% saline, 100 mL bolus
of protein supplementation and urea.13
E. Hydrocortisone, 100 mg intravenously
Answer: D) 3% saline, 100 mL bolus, and/or
Clinical Case Vignettes
E) Hydrocortisone, 100 mg intravenously
Case 1
This patient has acute onset of severe symptoms
A 47-year-old man is referred to the emergency of hyponatremia. The laboratory parameters
department due to acute onset of headache, are consistent with SIAD. However, SIAD is
vomiting, and vertigo. He is otherwise healthy a diagnosis of exclusion, and measurement of
and takes no medications. In the first laboratory serum cortisol is important to exclude adrenal
assessment, his sodium concentration is 112 mEq/L insufficiency. In one study, adrenal insufficiency
(SI: 112 mmol/L). His volume status is euvolemic. was the underlying cause in 3.8% patients with
Baseline laboratory test results: euvolemic hyponatremia who were initially
thought to have SIAD. A diagnostic cortisol cutoff
Sodium = 112 mEq/L (136-145 mEq/L) value greater than 10.9 µg/dL (SI: >300 nmol/L)
(SI: 112 mmol/L [136-145 mmol/L])
Serum osmolality = 238 mOsm/kg (280-300 mOsm/kg)
is recommended to exclude adrenal insufficiency.14
(SI: 238 mmol/kg [280-300 mmol/kg]) There is only limited evidence that
Hemoglobin = 14.2 g/dL (14.0-18.0 g/dL) hypothyroidism contributes significantly to
(SI: 142 g/L [140-180 g/L]) hyponatremia. Hyponatremia occurring in the
Creatinine = 0.84 mg/dL (0.67-1.18 mg/dL) setting of profound hypothyroidism may be
(SI: 74 µmol/L [59-104 µmol/L])
Urea = 1.7 mmol/L (3.2-7.3 mmol/L)
a consequence of myxedema, cardiac failure,
and systemic hypotension. An important study

180 ENDO 2025 • Endocrine Case Management

compared the serum sodium concentration of 999 concentration to a maximum of 129 mEq/L
patients with newly diagnosed hypothyroidism (SI: 129 mmol/L). He poorly tolerates fluid
with that of 4875 euthyroid control participants. restriction below 1.5 L per day.
While there was a correlation, it amounted
to a tiny 0.14 mEq/L (0.14 mmol/L) decrease Which of the following is the best next
in sodium levels for every 10 mIU/L rise in step in this patient’s treatment?
TSH, supporting the conclusion that there A. No further treatment, as this hyponatremia is
was no clinically relevant association between not relevant
hypothyroidism and hyponatremia.15 B. Urea, 30 g daily
This patient’s serum cortisol value was
C. A vaptan, 7.5 mg daily
0.76 µg/dL (SI: 21 nmol/L) (reference range, 6.0-
18.4 µg/dL [SI: 166-507 nmol/L]) and ACTH value D. Salt tablets, 3 to 6 daily
was 7.8 pg/mL (SI: 1.7 pmol/L) (reference range, E. Loop diuretics
<60.5 pg/mL [SI: <13.3 pmol/L]), thus confirming
Answer: B) Urea, 30 g daily or C)
the diagnosis of secondary adrenal insufficiency.
A vaptan, 7.5 mg daily
Before cortisol levels were available from the lab,
the patient was already transferred to the intensive This patient has chronic hyponatremia due to
care unit and treated with 3% saline infusion, which SIAD. SIAD has multiple causes (Box 2), and
increased his sodium level from 112 mEq/L to one important cause is medication induced.
116 mEq/L (SI: 112 to 116 mmol/L) within the Different medications can cause SIAD by
first 24 hours, thus significantly improving clinical stimulating AVP release (eg, antidepressant or
symptoms. As soon as adrenal insufficiency was antipsychotic agents), either by potentiating
diagnosed, he received hydrocortisone (initially its action or by being a direct AVP analogue.16
150 mg daily). CT showed a pituitary macroadenoma Thiazide diuretics are one of the most common
(15 × 1 5 × 27 mm), and further laboratory assessment causes of hyponatremia that can mimic SIAD.
revealed secondary hypogonadism and secondary Anticonvulsant treatment in patients with epilepsy
hypothyroidism in addition to secondary adrenal is another common cause of SIAD. Because
insufficiency. Treatment with levothyroxine and of the association between hyponatremia and
testosterone was started, and hydrocortisone was seizures, it is important to normalize sodium
tapered as soon as his symptoms improved. Elective levels. Fluid restriction is the first-line treatment
surgery was planned. in SIAD. The efficacy of 1000-mL daily fluid
restriction has been evaluated in a randomized
Case 2 trial in 46 patients, which showed a modest rise
in serum sodium of 3 mEq/L (SI: 3 mmol/L) in
A 32-year-old man is referred from a neurologist fluid-restricted patients compared with 1 mEq/L
colleague. The patient has had epilepsy for several (1 mmol/L) with no treatment. However, in
years and is treated with carbamazepine. While on this study, 39% of patients randomly assigned to
this treatment, he developed chronic hyponatremia, fluid restriction did not respond to treatment.17
with sodium values fluctuating between 123 Similarly, fluid restriction was unsuccessful in
and 127 mEq/L (SI: 123-127 mmol/L). Serum up to 50% of patients in larger observational
osmolality ranges between 250 to 260 mmol/kg, trials and registries. Importantly, a high urine
urine osmolality is 437 mmol/kg, and urinary osmolality or high urine sodium level was shown
sodium is 120 mEq/L (SI: 120 mmol/L). His cortisol to predict nonresponse to fluid restriction with
concentration is 19.9 µg/dL (SI: 549 nmol/L), thus high accuracy. In addition, fluid restriction is often
excluding adrenal insufficiency. Fluid restriction poorly tolerated, as in this patient. Urea (Answer
has been started, which increases his sodium B) is a cheap alternative treatment option. It is

ENDO 2025 • Neuroendocrinology and Pituitary 181

a product of hepatic nitrogen metabolism that urinary frequency. Other concerns raised about
is renally excreted, exerting an osmotic effect tolvaptan include cost and risk of liver function
and resulting in increased electrolyte-free water derangement seen with sustained higher dosages
clearance. A recent systematic review, including for other indications (eg, autosomal dominant
23 studies of 462 patients with SIAD treated with polycystic kidney disease). Alternative treatment
urea, showed that urea treatment increased sodium options (Figure), which were not chosen for this
levels by a mean of 9.6 mEq/L (SI: 9.6 mmol/L) patient, are SGLT-2 inhibitors (only off-label or
within a median treatment duration of 5 days. The in patients with concomitant diabetes type 2) and
mean increase in serum sodium after 24 hours was a high-protein diet. Evidence for loop diuretics
4.9 mEq/L (4.9 mmol/L). Adverse events were (Answer E) and/or salt tablets (Answer D) is weak.
few and mainly consisted of distaste or dysgeusia,
and no instances of osmotic demyelination were Figure. Treatment Options for SIAD
reported.18 The main limitations of urea are its
limited availability and low palatability due to
its bitter taste. Adherence can be improved by
combining it with orange juice, citric acid, sucrose,
and bicarbonate. Urea therapy increases the serum
urea concentration and blood urea nitrogen,
usually double baseline values, but this does not
represent deterioration in kidney function or
hypovolemia.19 After failure of fluid restriction in
this patient, urea was started at a dosage of 30 g
[Color—Print (Color Gallery page CG13) or web & ePub editions]
daily, which increased sodium levels to 132 mEq/L
(132 mmol/L). However, after a few days, the
patient refused to continue treatment because the
Case 3
bitter taste of urea was causing nausea. A 47-year-old woman undergoes craniotomy
The patient’s treatment was then transitioned to treat tuberculum sellae meningioma with
to a vaptan, with a starting dosage of 7.5 mg visual field deficits. Her postoperative course is
daily, which was increased to 15 mg daily. The unremarkable, with sodium measured every day:
vaptan corrected the sodium level to 141 mEq/L Date Serum sodium
(SI: 141 mmol/L). Vaptans are an efficient
Day of surgery 140 mEq/L
treatment option for chronic SIAD, but they (SI: 140 mmol/L)
are associated with risk for overcorrection and
Day 1 141 mEq/L
are expensive. While the SALT trials reported (SI: 141 mmol/L)
excessively rapid correction of hyponatremia in
Day 3 138 mEq/L
1.7% of tolvaptan-treated patients, observational (SI: 138 mmol/L)
studies of tolvaptan have reported highly variable
Day 4 139 mEq/L
rates of overcorrection, ranging from 0% to (SI: 139 mmol/L)
30%. Importantly, discontinuing fluid restriction Day 4 Discharge
when vaptans are started, initiating treatment in
Day 8 123 mEq/L
the hospital, and regularly monitoring sodium (SI: 123 mmol/L)
limits the risk for overcorrection. A lower initial
Day 9 128 mEq/L
dosage of tolvaptan, 7.5 mg daily, which has been (SI: 128 mmol/L)
associated with lower rates of overcorrection,
Day 11 140 mEq/L
should also be considered. Common adverse (SI: 140 mmol/L)
effects of tolvaptan include dry mouth, thirst, and

182 ENDO 2025 • Endocrine Case Management

On postoperative day 8, she develops nausea, pituitary surgery. As most patients are discharged
vomiting, and gait problems and is brought to the before SIAD develops, they must be educated
emergency department. to recognize symptoms of hyponatremia (eg,
confusion, headaches, or nausea) and seek prompt
Laboratory test results: medical attention if these symptoms develop. In
Serum sodium = 123 mEq/L (SI: 123 mmol/L) recent years, preventive strategies have focused
Serum osmolality = 258 mOsm/kg (SI: 258 mmol/kg) on implementing fluid-restriction protocols to
Urine osmolality = 713 mOsm/kg (SI: 713 mmol/kg) mitigate the risk. Fluid restriction volumes and
Urinary sodium = 224 mmol/L
durations vary across studies, typically ranging
Cortisol, normal
from 1000 to 2500 mL/day for 1 to 2 weeks
She is treated with 3% NaCl bolus therapy postoperatively. Matsuyama et al reported a
(total of 2 boluses), which increases her sodium reduction in SIAD incidence from 38% to 14%
concentration to 128 mEq/L (128 mmol/L) with fluid restriction of 1800 mL/day,21 while
within 24 hours, followed by fluid restriction and another study observed a decrease in hospital
normalization of her sodium concentration to readmissions from 8% to 2% using a 1500 mL/day
140 mEq/L (140 mmol/L). She is discharged after restriction.22 In addition, a study from 2021
3 days of hospitalization, on no treatment. demonstrated that a 7-day, 1000 mL/day fluid
restriction reduced hyponatremia from 5% to 1%.23
Which of the following is the best way to A meta-analysis including 1382 patients revealed
reduce the incidence of postoperative SIAD in a significant reduction in hyponatremia risk, with
patients who have undergone neurosurgery? an odds ratio of 5.0 (95% CI, 2.2-11.7), favoring
A. Hospitalization until the 10th postoperative day fluid restriction.24 Despite these findings, no
B. Fluid restriction from hospital discharge until prospective randomized trials have established the
day 10 optimal protocol.
C. Vaptan, 7.5 mg daily, in all patients
D. No specific recommendation, as SIAD Key Learning Points
postoperatively is very rare
• Adrenal insufficiency must be excluded before
E. Informing patients about possible symptoms of
SIAD is diagnosed.
hyponatremia and instructing to drink to thirst
• Acute, severe symptoms of hyponatremia are a
Answer: B) Fluid restriction from hospital medical emergency due to cerebral edema, and
discharge until day 10 and E) Informing patients immediate treatment is needed, usually with
about possible symptoms of hyponatremia hypertonic saline and/or with hydrocortisone
and instructing to drink to thirst in case of adrenal insufficiency. One should be
This patient has SIAD after pituitary surgery. In careful to avoid overcorrection!
a recent meta-analysis,20 delayed symptomatic • There are several treatment options of
hyponatremia was observed in 5.6% of patients chronic SIAD. Fluid restriction is the first-
who had undergone neurosurgery. Milder forms line treatment, but it has a high rate of
of postoperative SIAD can be found in up to 30% nonresponse. Main second-line treatment
of patients. Hyponatremia typically develops options are urea or vaptans.
between postsurgical days 4 and 14, peaking • SIAD after pituitary surgery is often delayed.
around day 7. While hyponatremia is generally It is important to instruct patients about
mild and self-limiting, severe cases can arise, symptoms of hyponatremia and to drink to
with symptomatic hyponatremia being one of thirst. Preventive fluid restriction has been
the leading causes of hospital readmission after shown to reduce postoperative hyponatremia.

ENDO 2025 • Neuroendocrinology and Pituitary 183

References
1. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of monocentric, open-label, proof-of-concept study-the TREASURE study. Eur
hyponatremia. Am J Med. 2006;119(7 Suppl 1):S30-S35. PMID: 16843082 J Endocrinol. 2023;189(2):252-261. PMID: 37540987
2. Corona G, Giulianai C, Parenti G, et al. Moderate hyponatremia is associated 14. Cuesta M, Garrahy A, Slattery D, et al. The contribution of undiagnosed
with increased risk of mortality: evidence from a meta-analysis. PLoS One. adrenal insufficiency to euvolaemic hyponatraemia: results of a large
2013;8(12):e80451. PMID: 24367479 prospective single-centre study. Clin Endocrinol (Oxf). 2016;85(6):836-844.
3. Upala S, Sanguankeo A. Association between hyponatremia, osteoporosis, PMID: 27271953
and fracture: a systematic review and meta-analysis. J Clin Endocrinol Metab. 15. Warner MH, Holding S, Kilpatrick ES. The effect of newly diagnosed
2016;101(4):1880-1886. PMID: 26913635 hypothyroidism on serum sodium concentrations: a retrospective study. Clin
4. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild Endocrinol (Oxf). 2006;64(5):598-599. PMID: 16649984
chronic hyponatremia is associated with falls, unsteadiness, and attention 16. Warren AM, Grossmann M, Christ-Crain M, Russell N. Syndrome of
deficits. Am J Med. 2006;119(1):71.e71-e78. PMID: 16431193 inappropriate antidiuresis: from pathophysiology to management. Endocr Rev.
5. Spasovski G, Vanholder R, Allolio B, et al. Clinical practice guideline on 2023;44(5):819-861. PMID: 36974717
diagnosis and treatment of hyponatraemia. Eur J Endocrinol. 2014;170(3):G1- 17. Garrahy A, Galloway I, Hannon AM, et al. Fluid restriction therapy for
47. PMID: 24569125 chronic SIAD; results of a prospective randomized controlled trial. J Clin
6. Bartter FC, Schwartz WB. The syndrome of inappropriate secretion of Endocrinol Metab. 2020;105(12):dgaa619. PMID: 32879954
antidiuretic hormone. Am J Med. 1967;42(5):790-806. PMID: 5337379 18. Wendt R, Fenves AZ, Geisler BP. Use of urea for the syndrome of
7. Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and inappropriate secretion of antidiuretic hormone: a systematic review. JAMA
treatment of hyponatremia: expert panel recommendations. Am J Med. Netw Open. 2023;6(10):e2340313. PMID: 37902751
2013;126(10 Suppl 1):S1-S42. PMID: 24074529 19. Rondon-Berrios, H. et al. Urea for the Treatment of Hyponatremia. Clin J Am
8. Krisanapan P, Vongsanim S, Pin-On P, Ruengorn C, Noppakun K. Soc Nephrol. 2018;13(11):1627-1632. PMID: 30181129
Efficacy of furosemide, oral sodium chloride, and fluid restriction for 20. Yu S, Taghvaei M, Reyes M, et al. Delayed symptomatic hyponatremia
treatment of syndrome of inappropriate antidiuresis (SIAD): an open-label in transsphenoidal surgery: systematic review and meta-analysis of its
randomized controlled study (The EFFUSE-FLUID Trial). Am J Kidney Dis. incidence and prevention with water restriction. Clin Neurol Neurosurg.
2020;76(2):203-212. PMID: 32199708 2022;214:107166. PMID: 35158166
9. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral 21. Matsuyama J, Ikeda H, Sato S, Yamamoto K, Ohashi G, Watanabe K. Early
vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. water intake restriction to prevent inappropriate antidiuretic hormone
2006;355(20):2099-2112. PMID: 17105757 secretion following transsphenoidal surgery: low BMI predicts postoperative
10. Zinman B, Wanner C. Lachin JM, et al. Empagliflozin, cardiovascular SIADH. Eur J Endocrinol. 2014;171(6):711-716. PMID: 25227132
outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117- 22. Deaver KE, Catel CP, Lillehei KO, Wierman ME, Kerr JM. Strategies to
2128. PMID: 26378978 reduce readmissions for hyponatremia after transsphenoidal surgery for
11. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of pituitary adenomas. Endocrine. 2018;62(2):333-339. PMID: 29961198
kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323-334. PMID: 23. Snyder MH, Asuzu DT, Shaver DE, Vance ML, Jane JA. Routine
27299675 postoperative fluid restriction to prevent syndrome of inappropriate
12. Refardt J, Imber C, Nobbenhuis R, et al. Treatment effect of the SGLT2 antidiuretic hormone secretion after transsphenoidal resection of pituitary
inhibitor empagliflozin on chronic dyndrome of inappropriate antidiuresis: adenoma. J Neurosurg. 2021;136(2):405-412. PMID: 34330096
results of a randomized, double-blind, placebo-controlled, crossover trial. J 24. Castle-Kirszbaum M, Goldschlager T, Shi MDY, Kam J, Fuller PJ.
Am Soc Nephrol. 2023;34(2):322-332. PMID: 36396331 Postoperative fluid restriction to prevent hyponatremia after transsphenoidal
13. Monnerat S, Atila C, Baur F, et al. Effect of protein supplementation on pituitary surgery: an updated meta-analysis and critique. J Clin Neurosci.
plasma sodium levels in the syndrome of inappropriate antidiuresis: a 2022;106:180-184. PMID: 36369079

184 ENDO 2025 • Endocrine Case Management

Stalk Lesions of the
Pituitary Gland
Dana Erickson, MD. Division of Endocrinology, Metabolism, and Nutrition, Mayo College of
Medicine, Rochester, MN; Email: [email protected]

Educational Objectives Practice Gaps

After reviewing this chapter, learners should be
able to: • PSLs have many etiologies, and rare causes are
often overlooked.
• Identify the spectrum of etiologies • The initial working diagnosis in patients with
contributing to imaging findings of pituitary PSLs may be incorrect, and awareness of this
stalk lesions (PSLs). phenomenon is important in clinical practice.
• Facilitate a logical and comprehensive • Available data in the literature suggest that a
diagnostic workup of etiologies and hormonal significant proportion of patients with PSLs
abnormalities in the setting of a PSL and do not undergo comprehensive pituitary
recognize possible treatment pitfalls. hormonal assessment in clinical practice (full
• Generate an effective management strategy, assessment is reported in 48%-91%).1
including conservative or necessary • The rationale for tissue biopsy for PSL should
neurosurgical intervention. be assessed on a case-by-case basis because it
has the potential to cause new-onset pituitary
hormonal deficiencies.
• There is no consensus on the recommended
Significance of the
intervals for surveillance MRI.
Clinical Problem
PSLs present a conundrum of challenges for
clinicians from both diagnostic and therapeutic
Discussion
standpoints. They are sometimes discovered The prevalence of PSLs is difficult to estimate,
incidentally because advanced imaging techniques, but they are reported to be present in 0.1% to
such as MRI, are frequently used in clinical practice 0.2% of head MRI studies. In a retrospective study
for the evaluation of chronic headaches or other from Mayo Clinic (1987-2006) of 150,000 MRI
issues. PSLs may also be identified during the studies, authors reviewed 2700 reports, and 152
evaluation of new-onset symptoms reflecting patients harbored PSLs.2 A study from Shanghai,
endocrinopathies or mass effect via optic chiasmal China, identified 325 PSLs among 143,000 MRI
compression. The spectrum of clinical presentation studies (2012-2018).1 The mean age of adults at
varies by the extent of pituitary gland involvement, presentation is 44 years, but large studies from
whether it is purely stalk or combination with Asia report an average of 30.5 years with a slight
extensive involvement of the hypothalamus and female predominance.3 Interestingly, in males,
or other pituitary gland areas. Clinical context and there are 2 age peaks: age 6 to 18 years and 42 to
the consideration of possible known or unknown 48 years.
systemic disorders are important.

ENDO 2025 • Neuroendocrinology and Pituitary 185

 The mode of incidental discovery varies, but evaluated in detail in many studies in adults with
up to 30% of PSLs are reported to be diagnosed PSLs. Hyperprolactinemia occurs in 30% to 40% of
incidentally.1 Upon detailed further endocrine patients. When AVP deficiency is documented, up
hormonal evaluation, 25% of patients with to 94% of patients have additional anterior pituitary
incidentally discovered PSLs have endocrine insufficiency, thus underscoring the necessity of
dysfunction. This underscores the necessity of testing.1 Importantly, because patients with PSL
a detailed workup and highlights the delicate are not always evaluated by an endocrinologist,
location of the pituitary stalk and its importance hormonal evaluation might not be comprehensive
from an anatomical and physiological standpoint. (eg, in the Mayo cohort, 20% of patients lacked any
When symptoms are present, they can include hormonal evaluation).
headache (22%), visual field deficiencies (11%- In the setting of PSL, the frequency of
25%), lethargy (14%), seizures or altered mental hypopituitarism is associated with the extent
state (13%), poor appetite (8.3%), weight loss of the lesion: 30% in pure stalk lesions, 73% in
(14%), dizziness (11%), and others.4 hypothalamic extension, 50% in sellar extension,
Documentation of hypopituitarism varies and 100% when all sites are involved.2 In a cohort
from cohort to cohort of patients with PSLs. The from Shanghai, the degree of stalk thickening was
prevalence of arginine vasopressin (AVP) deficiency associated with a higher incidence of hormone
ranges from 28% of a Mayo Clinic cohort to 69% in deficiencies (eg, for every 1 mm increase of
cohort from China3 to 72% in a recent meta-analysis pituitary stalk thickness in the group of patients
by Kim et al.4 Anterior pituitary dysfunction is with AVP deficiency, there was a 2.28-fold
common when evaluated: 32% patients have a increase in the risk of anterior pituitary deficits),
deficit in at least 1 hormonal axis and 21% of and stalk thickening greater than 4.5 mm was
patients have a deficiency in 2 hormonal axes. associated with the presence of AVP deficiency.1
Secondary hypogonadism can be present in up to The possible etiologies of PSL typically
29% cases, secondary adrenal insufficiency in 15% fall into 3 broad categories: (1) inflammatory/
to 25% of cases, and secondary hypothyroidism in infiltrative processes; (2) neoplastic processes; and
6.8% to 21% of cases. GH deficiency has not been (3) congenital conditions (Table 1). In smaller cases

Table 1. Etiology of PSL Reported in Large Studies

Author Year Total, No. Neoplastic, No. Inflammatory*, No. Congenital, No. Unknown, No.

Hamilton et al 2007 44 16 19 9 Not included

Turcu et al 2013 152 49 30 13 60

Catford et al 2016 75 19 51 3 2

Sbardella et al 2016 26 3 8 4 11

Lee et al 2017 158 130** 28**

Donec et al 2018 53 9 9 25 10

Zhou et al 2019 230 45 35 15 135

Ling et al 2019 325 56 14 Unknown 255

Devuyst et al 2020 38 11 27 0 0

Mean 30% 20% 6% 42%

Modified from Hana V et al. Neuroendocrinology, 2020; 110(9-10): 809-821. © S. Karger AG, Basel.
* Some authors include Langerhans cell histiocytosis in neoplastic group.
** Author provided diagnosis in some cases without tissue biopsy but based on follow-up.

186 ENDO 2025 • Endocrine Case Management

series, neoplastic causes account for 29% of cases, insertion on gland.5 The most common cut off for
while in larger series, 56% are reported to have a abnormal size in a meta-analysis was greater than
neoplastic etiology. The classification of Langerhans 3 mm.4 The posterior pituitary is visible in 95% of
histiocytosis as a neoplastic process in some studies the healthy population.
and as an inflammatory process in others obscures Turcu et al analyzed the various shapes of
the data. A recent meta-analysis by Kim et al of pituitary lesions on MRI (Figure 1), and the
1368 patients confirmed the heterogeneity of this strongest association following gadolinium
phenomenon with a pooled proportion of neoplasm enhancement was seen in congenital lesions
of 45% (germ-cell tumors [14%], Langerhans (round, presence of ectopic neurohypophysis),
histiocytosis [10%], metastasis [4.6%]).4 while neurosarcoidosis had a uniformly thickened
In most cohorts, only a proportion of patients stalk and xanthoma disseminatum had a pyramidal
undergo tissue biopsy of the stalk lesion (21%- shape. Among neoplastic lesions, lymphomas had
46%). A working diagnosis is achieved when a V-shaped pattern of PSL, while metastatic solid
systemic condition is established in a different cancers had a V-shaped or round characteristic;
locality, the patient is treated with empiric however, there was overlap across the various
glucocorticoids for a presumed inflammatory etiologies. An interesting recent study used a
etiology and lesion responds, or there is model of recursive partitioning logistic regression
spontaneous regression of the lesion.1-3 analysis in 158 patients with PSL (and further
Diagnostic clues have been explored by various validation in 63 patients) and described: (1) lack
investigators in several publications. While certain of extrasellar involvement; (2) stalk thickness
imaging features are more obvious and helpful less than 5.3 mm; and (3) presence of AVP
to elucidate a particular disease process, others deficiency as suggestive of nonneoplastic etiology
can be incredibly challenging. The average size (AUC 0.813).6 Cystic changes, high T1 signal,
of a normal pituitary stalk (transverse diameter) presence of a diffusely thickened stalk, and gland
as seen on pituitary MRI is 2.4 to 3.25 mm at involvement were of less discriminatory value.
the level of the optic chiasm and 1.91 mm at the In contrast, in a smaller cohort,7 the presence of

Figure 1. Illustration of Imaging Phenotypes of PSLs on MRI

Reprinted with permission from Turcu AF et al. J Clin Endocrinol Metab, 2013; 98(5): 1812–1818. © 2013 by The Endocrine Society.

ENDO 2025 • Neuroendocrinology and Pituitary 187

AVP deficiency was more common in neoplastic developed new AVP deficiency. Among those
etiologies along with texture heterogeneity on with at least 1 hormonal deficiency at baseline,
MRI. Ling et al developed a classifier model that 55% developed a new hormone deficiency. Finally,
considered important indicators differentiating among 22 patients without preexisting AVP
neoplastic from inflammatory causes with deficiency, new deficit of antidiuretic hormone
variables, including sex, neutrophilic granulocytes developed in 9 (46%). While the diagnostic yield
percentage, serum sodium concentration, presence in this study was 100%, other series reported 10%
of AVP deficiency, and pituitary stalk, with nondiagnostic biopsies. Cerebrospinal fluid leak
patterns of thickening of stalk.1 A study from and infection can occur.11
Belgium and France suggested that higher degree As outlined in Table 2, the etiology of PSL
of prolactin elevation might be associated with is broad. Suggested workup and management
a neoplastic process (1.25 × upper normal limit; are described in Figure 2 (following page).8
sensitivity, 95%; specificity, 67%).8 Importantly, Constitutional symptoms (night sweats) should
young patients tend to have intracranial germ-cell raise the possibility of hematologic malignancy or
tumors and histiocytosis as leading causes of this an infectious process. Concomitant autoimmune
clinical scenario. diseases or recent pregnancy point toward
Timing and necessity of tissue biopsy/surgical autoimmune hypophysitis. Hepatosplenomegaly
resection are challenging clinical dilemmas, and and enlargement of lymph nodes can be seen in
input from a multidisciplinary tumor board is the Langerhans histiocytosis or Erdheim-Chester
best approach for individual patients. In smaller disease. IgG4 disease serum titers should
lesions without severe endocrinopathies, tissue be measured in the setting of autoimmune
biopsy/surgical resection should be pursued pancreatitis and chronic sinusitis. A few tips
only if it would change the course of treatment. include erythema nodosum skin lesions in
For example, in a case series from Mayo Clinic, sarcoidosis and concomitant pineal lesions in cases
biopsy was necessary in 24% of patients, while it of germinoma. Serum α-fetoprotein and hCG
was performed in 40% to 65% of patients in other are positive in a minority of patients harboring
series.6,9 The safety of this procedure has been a germinoma, but hCG might be positive in
recently analyzed in an elegant study by Kang et two-thirds of such patients when analyzed in
al10 in 39 patients who underwent an endoscopic cerebrospinal fluid.8 FDG-PET is important when
endonasal approach after multidisciplinary team evaluating infiltrative disorders and malignancies.
recommendation (the most common pathological Treatment of PSLs can be surgical
diagnosis was germinoma [46%]). In patients (craniopharyngioma, adenoma) or systemic
without preoperative hypopituitarism, 30% (neoplasm, histiocytosis, neurosarcoidosis).

Table 2. Detailed Etiologies of PSL

Neoplastic Inflammatory Congenital

Germinoma Hypophysitis (all types) Ectopic neurohypophysis

Craniopharyngioma Langerhans histiocytosis Rathke cleft cyst
Metastases (breast, lung, kidney, Neurosarcoidosis Pituitary stalk interruption syndrome
melanoma, prostate, leukemia)
Erdheim- Chester disease Vascular lesion
Astrocytoma, glioblastoma
Tuberculosis Duplication of stalk
Primary CNS lymphoma
Behcet disease
Meningioma
Abscess
Pituitary neuroendocrine tumor
Whipple disease, lupus
Pituicytoma
Granulomatosis with polyangiitis

188 ENDO 2025 • Endocrine Case Management

Autoimmune hypophysitis can be observed or Clinical Case Vignettes
treated with systemic glucocorticoids when mass
effect or AVP deficiency effect is present. Other Case 1
immunomodulating agents may be indicated Three months after delivering a healthy baby, a
if further progression occurs. Germinoma can 30-year-old woman presents with symptoms of
be treated effectively with radiotherapy or increased thirst, craving for water, fluid intake
chemoradiation. of 4 L per day, and frequent urination every 40
The natural history of stalk lesions is to 60 minutes (including at night). Menstrual
underreported. Therefore, MRI at a short interval cycles were initially normal until an intrauterine
of 3 to 6 months is recommended, with further progesterone-containing device was inserted. She
longitudinal follow-up depending on initial changes. chose to nurse for 1 month.
Of 106 patients with clinically indeterminate There has been no unusual weight loss or
PSL pooled from 4 studies with a median weight gain. She has a normal appetite and blood
follow-up of 3 to 7.6 years, 18.5% demonstrated pressure. There is no cold intolerance or skin
progression (mean time to progression, 0.7-1.8 dryness. She notes that she has frequent headaches.
years), while 61% showed spontaneous regression There is no history of recent head trauma. Mucous
of PSL.4 membranes and skin turgor are normal.
Hormonal function must be assessed Initial laboratory evaluation reveals a normal
longitudinally. Among patients with Langerhans serum sodium concentration. After a 6-hour
cell histiocytosis, most develop at least 1 new fast, the following laboratory test results are
hormonal dysfunction over 11 years of follow-up. documented:
However, normalization, especially of anterior
Serum sodium = 146 mEq/L (SI: 146 mmol/L)
pituitary function, has been reported in patients Serum osmolality = 315 mOsm/kg (SI: 315 mmol/kg)
with lymphocytic hypophysitis.12 Urine osmolality = 106 mOsm/kg (SI: 106 mmol/kg)
Arginine vasopressin = <0.5 pg/mL
Urine output = 150 cc/h

Figure 2. Suggested Stepwise Workup of PSLs or Pituitary Stalk Tumors

Modified from Devuyst F et al. Eur J Endocrinol, 2020; 181(3): 95-105. © European Society of Endocrinology.

ENDO 2025 • Neuroendocrinology and Pituitary 189

Urine osmolality increases more than 100% Central AVP deficiency was diagnosed, and
following DDAVP administration. DDAVP, 0.1 tablet at night, was initiated and
uptitrated as needed to 3 tablets daily. A presumed
Anterior pituitary function testing: diagnosis of autoimmune hypophysitis was
Thyroid function tests, normal established. A trial of prednisone, 40 mg over
Cortisol (8 AM) = 13 µg/dL (SI: 358.6 nmol/L) 3 weeks downtitrating, was also initiated, but
DHEA-S = 100 µg/dL (SI: 2.71 μmol/L) she had no changes in her headache or degree of
ACTH = 26 pg/mL (SI: 5.72 pmol/L)
polyuria. She requested to discontinue prednisone
IGF-1 = 103 ng/mL (SI: 13.5 nmol/L)
Estradiol = 93 pg/mL (SI: 341.4 pmol/L) given the adverse effects she was experiencing.
Prolactin, normal Findings on follow-up MRI 4 months later were
unchanged. One year later, there was a slight
The initial diagnosis is isolated central AVP decrease in stalk thickening, and 2 years later, a
deficiency. further decrease was observed (Figure 4). AVP
Findings on MRI of the pituitary gland (Figure deficiency persisted. There were no new hormonal
3) are consistent with stalk thickening of a globular deficiencies.
shape, but the pituitary gland is not diffusely
enlarged. Figure 4.

Figure 3.

There is no evidence of other autoimmune In this clinical situation, extensive workup for
disorders. Measurements of α-fetoprotein, hCG, various causes of PSL was performed without a
and ACE are normal. Myeloperoxidase antibodies definitive secondary cause identified. Given the
and proteinase 3 antibodies are negative. Findings clinical scenario of postpartum presentation,
on bone scan are negative. her young age, and lack of other systemic
involvement, the presumed diagnosis was
Which of the following is the best next step? lymphocytic hypophysitis. Unfortunately, we do
A. Start replacement therapy with DDAVP only not have clinically available pituitary antibodies,
B. Start replacement therapy with DDAVP and some studies reported limitations.13 In the setting
initiate a course of prednisone of significant headaches and a small prospective
C. Initiate rituximab study suggestive of improvement in possible
D. Perform biopsy endocrinopathies and metanalysis of mostly
retrospective data, a trial of glucocorticoids was
Answer: B) Start replacement therapy with initiated, but it was not well tolerated because of
DDAVP and initiate a course of prednisone adverse effects.12,14

190 ENDO 2025 • Endocrine Case Management

 Critical follow-up imaging showed improvement replacement therapy is initiated: hydrocortisone,
of the degree of PSL, which indirectly confirmed the 10 mg in the morning; levothyroxine, 100 mcg
diagnosis of autoimmune or inflammatory origin. daily; testosterone gel; and DDAVP, 0.1 mg as
Given the clinical stability of the patient, needed at night. The patient reports feeling much
improvement in headaches, lack of PSL better on this regimen.
progression, and absence of other pituitary MRI of the sella shows an enlarged gland with
hormonal deficits, biopsy of this lesion was significant stalk thickening (Figure 5). Visual fields
not justified as it could be associated with are normal.
complications. Rituximab is second-line treatment
in refractory cases. Although DDAVP would help Figure 5.
with symptoms of polyuria, it would not help
with symptoms of headaches from mass effect,
although other medications for pain control could
be considered.

Case 2
A 22-year-old man with a history of obstructive
sleep apnea presents with concerns decreased
libido, fatigue, poor appetite, nausea, vomiting,
and weight loss (30 lb [13.6 kg] over the last 4
months). He has no headaches. Frequency of
urination is increased (2 to 3 times per night). He Additional laboratory test results:
notes increased thirst and fluid intake.
Serum α-fetoprotein, normal
On physical examination, his BMI is 24 kg/m2.
β-hCG, normal
Vital signs are normal, and visual fields are normal C-reactive protein, normal
to confrontation. Physical findings are normal, TPO antibodies, negative
including the skin and genitalia. ACE = 28 U/L (normal)
Calcium, normal
Laboratory test results: QuantiFERON for tuberculosis, negative
Syphilis, negative
LH = <0.3 mIU/mL (SI: <0.3 IU/L) Antineutrophil cytoplasmic antibodies, negative
Testosterone = <7 ng/dL (SI: 0.24 nmol/L) Antinuclear antibodies, negative
Prolactin = 89 ng/dL (SI: 3.9 nmol/L) Flow cytometry, negative for lymphoma
Cortisol (8 AM) = 9.2 µg/dL (SI: 253.8 nmol/L) IgG4 = 78 mg/dL (normal)
ACTH = 44 pg/mL (SI: 9.7 pmol/L) Cytokine profile, negative
Free T4 = 0.8 ng/dL (SI: 10.30 pmol/L)
TSH = 2.9 mIU/L Cerebrospinal fluid analysis is negative for hCG
IGF-1 = 75 ng/mL (SI: 9.8 nmol/L) and α-fetoprotein. There is a mild protein increase
DHEA-S = 95 μg/dL (SI: 2.57 μmol/L)
and nucleated cells.
No abnormal findings are identified on bone
Laboratory test results after 8 hours of fasting: scan or whole-body PET. Biopsy via endoscopic
Urine osmolality = 414 mOsm/kg (SI: 414 mmol/kg) endonasal approach is nondiagnostic. Three weeks
Serum sodium = 151 mEq/L (SI: 151 mmol/L) later, a repeat biopsy documented the following
Serum osmolality = 302 mOsm/kg (SI: 302 mmol/kg) pathology results: focal posterior pituitary tissue
and anterior pituitary shows robust chronic
Results of formal visual field testing are normal.
inflammation, including multinucleated giant cells
Panhypopituitarism is diagnosed, including
most consistent with granulomatous hypophysitis.
partial AVP deficiency. Treatment with hormone

ENDO 2025 • Neuroendocrinology and Pituitary 191

There is no evidence of lymphoma or other Answer: C) Repeat biopsy
malignancies. GMS and AFB stains are negative.
Treatment is initiated with prednisone, 60 The patient was started on high-dosage
mg daily, with a slow taper. Three months later, prednisone, 1000 mg for 5 days, and then 40
there is slight improvement on imaging .The plan mg daily thereafter, and infliximab, 500 mg
is to continue prednisone at the dosage of 15 to 20 intravenously monthly. There was continued
mg daily for 12 months. Six months later, there is progression and new visual field defects. Twelve
evidence of progression while on the lower dosage months since the previous biopsies, the patient
of prednisone, 15 mg daily (Figure 6). underwent subtotal resection via an endoscopic
endonasal approach (high-grade cerebrospinal
Figure 6.
fluid leak, repaired). Pathology documented a
germ-cell tumor with T- and B-cell infiltrate in
the background. Proton-beam radiation, 2340 cGY
in 25 fractions, was administered to the area of
lesion. Additional radiation was administered to
the spine, 1620 GY in 9 fractions.
If a patient does not respond to standard
therapies based on initial pathology, sampling
error must be considered and eventually the
biopsy should be repeated to confirm the correct
tissue diagnosis.15 Clinicians must recognize
when the working diagnosis might be incorrect
despite detailed investigation, including tissue
There are no clear-cut vision problems. The
biopsy. For this young man, germinoma should
prednisone dosage is increased to 30 mg daily.
have been very high on the differential diagnosis
Nine months after the initial biopsies, there
list. Approximately 2.9% to 4.2% of intracranial
is further progression of visual concerns
germinomas could be masked by unspecific
(documented on visual field testing) (Figure 7).
pathological findings of lymphocyte infiltration,
fibrous tissue, and even granulomatous reaction,
Figure 7.
which are thought to reflect the host immune
response to the neoplasm.15 Thus, close follow-
up is warranted when unspecified pathology is
seen, and a second biopsy might be indicated, as
highlighted in this case.

Key Learning Points

• PSLs can be discovered incidentally or after
evaluation of new-onset symptoms reflective
Which of the following should be done next? of endocrinopathies and/or local mass effect.
A. Initiate very high-dosage methyprednisolone • Detailed hormonal workup of anterior and
B. Start other immunomodulators posterior pituitary function is necessary
even for incidental lesions. AVP deficiency
C. Repeat biopsy
is reported to be present in 28% to 72% of
D. Administer radiation therapy patients with PSLs.

192 ENDO 2025 • Endocrine Case Management

• Etiologies of PSLs include inflammatory/ etiology: immunomodulating agents for
infiltrative processes, neoplastic processes, or severe inflammatory processes, surgical
congenital causes. decompression and/or radiation therapy,
• Biopsy of PSLs should only be performed and chemotherapy for neoplastic processes.
if extensive noninvasive testing does not Observation might be an option for patients
reveal an etiology. Risks and benefits of this with certain nonneoplastic diagnoses
procedure must be weighed carefully. (eg, congenital condition, autoimmune
hypophysitis).
• Treatment of PSLs includes
hormonal replacement in the setting • PSLs are best managed by a multidisciplinary
of hypopituitarism. Other systemic team.
therapies are indicated depending on the

References
1. Ling SY, Zhao ZY, Tao B, et al. Pituitary stalk thickening in a large cohort: 9. Hamilton BE, Salzman KL, Osborn AG. Anatomic and pathologic
toward more accurate predictors of pituitary dysfunction and etiology. Endocr spectrum of pituitary infundibulum lesions. AJR Am J Roentgeno.,
Pract. 2019;25(6):534-544. PMID: 30865546 2007;188(3):W223-W232. PMID: 17312027
2. Turcu AF, Erickson BJ, Lin E, et al. Pituitary stalk lesions: the Mayo Clinic 10. Kang H, Kim KM, Kim MS, Kim JH, Park CK, Kim YH. Safety of endoscopic
experience. J Clin Endocrinol Metab. 2013;98(5):1812-1818. PMID: 23533231 endonasal biopsy for the pituitary stalk-hypothalamic lesions. Pituitary.
3. Zhou X, Zhu H, Yao Y, et al. Etiological spectrum and pattern of change in 2022;25(1):143-151. PMID: 34471994
pituitary stalk thickening: experience in 321 patients. J Clin Endocrinol Metab. 11. Catford S, Wang YY, Wong R. Pituitary stalk lesions: systematic review and
2019;104(8):3419-3427. PMID: 30892632 clinical guidance. Clin Endocrinol (Oxf). 2016;85(4):507-521. PMID: 26950774
4. Kim DY, Kim PH, Jung AY, et al. Neoplastic etiology and natural course of 12. Donegan, D., et al., Outcomes of initial management strategies in patients
pituitary stalk thickening. J Clin Endocrinol Metab. 2021;107(2):563-574. with autoimmune lymphocytic hypophysitis: a systematic review and meta-
PMID: 34614160 analysis. J Clin Endocrinol Metab. 2022;107(4):1170-1190. PMID: 35137155
5. Hana V, Salenave S, Chanson P. Pituitary stalk enlargement in adults. 13. Chiloiro S, Capoluongo ED, Angelini F, et al. Autoantibody reactivity profile
Neuroendocrinology. 2020;110(9-10):809-821. PMID: 32074610 of primary autoimmune hypophysitis patients: preliminary results. Endocrine.
6. Lee JY, Park JE, Shim WH, et al. Joint approach based on clinical and imaging 2022;76(1):224-227. PMID: 34797510
features to distinguish non-neoplastic from neoplastic pituitary stalk lesions. 14. Chiloiro S, Tartaglione T, Capoluongo ED, et al., Hypophysitis outcome and
PLoS One. 2017;12(11):e0187989. PMID: 29140989 factors predicting responsiveness to glucocorticoid therapy: a prospective and
7. Sbardella E, Joseph RN, Jafar-Mohammadi B, Isidori Am, Cudlip S, Grossman double-arm study. J Clin Endocrinol Metab. 2018;103(10):3877-3889.
AB. Pituitary stalk thickening: the role of an innovative MRI imaging analysis 15. Pal R, Rai A, Vaiphei K, et al. Intracranial germinoma masquerading as
which may assist in determining clinical management. Eur J Endocrinol. secondary granulomatous hypophysitis: a case report and review of literature.
2016;175(4):255-263. PMID: 27418059 Neuroendocrinology. 2020;110(5):422-429. PMID: 31269501
8. Devuyst F, Kazakou P, Baleriaux D, et al. Central diabetes insipidus and
pituitary stalk thickening in adults: distinction of neoplastic from non-
neoplastic lesions. Eur J Endocrinol. 2020;181(3):95-105. PMID: 32530258

ENDO 2025 • Neuroendocrinology and Pituitary 193

Management of Pituitary
Tumors During Pregnancy
Andrea Glezer, MD, PhD. Neuroendocrine Unit, Division of Endocrinology and
Metabolism, University of São Paulo Medical School Hospital, São Paulo, Brazil; Email:
[email protected]

Educational Objectives guidelines, before pregnancy. In some cases,

hypogonadism is irreversible, and assisted
After reviewing this chapter, learners should be
reproductive treatments are necessary.
able to:
The pituitary gland’s function and size change
• Recognize that pituitary tumors can impair during pregnancy. Pituitary volume increases due
fertility and identify specific treatments for to normal lactotroph hyperplasia and hypertrophy
each type of tumor to be undertaken before with resultant hyperprolactinemia. Prolactinomas
pregnancy. can grow during pregnancy because of estrogen
stimulation, although symptoms related to mass
• Individualize the follow-up during pregnancy,
effect usually occur in individuals with large
depending on the type of pituitary tumor,
prolactinomas. Therefore, tumor volume control
tumor dimensions, and the patient’s
is recommended before pregnancy in patients with
comorbidities.
macroprolactinomas.
• Reevaluate tumor status after delivery and Physiological hormonal changes during
individualize recommendations regarding pregnancy make the diagnosis of GH and ACTH
breastfeeding, especially if clinical treatment is hypersecretion challenging. GH and ACTH
recommended. hypersecretion increases adverse maternal-
fetal outcomes such as arterial hypertension,
diabetes mellitus, and spontaneous abortion rates.
Hormonal hypersecretion should be controlled
Significance of the before and during pregnancy. Patients with
Clinical Problem tumor mass effect symptoms and/or severe
repercussions of GH and ACTH secretion should
Pituitary tumors can cause hypogonadism and
be managed by an expert multidisciplinary team to
infertility. Hypogonadism can be caused by
individualize treatment, labor, and breastfeeding
hyperprolactinemia (secondary to autonomous
recommendations.
secretion or pituitary stalk effect), pituitary
stalk disconnection, GH hypersecretion,
hypercortisolism, pituitary damage due to Practice Gaps
direct tumor compression, neurosurgery, and/
or radiotherapy. In women of childbearing age, • Patients harboring pituitary tumors should be
prolactinomas are the most common pituitary interviewed regarding fertility plans during
tumor, followed by tumors causing acromegaly routine follow-up appointments and, when
and rarely Cushing disease and nonfunctioning indicated, should be treated before pregnancy,
pituitary adenomas. Specific treatment for according to guidelines for the specific
each pituitary tumor type is recommended, per tumor type.

194 ENDO 2025 • Endocrine Case Management

• Assisted reproductive techniques should suprasellar expansion that do not shrink with
be considered for patients with permanent clinical treatment.2
hypogonadism. High estrogen levels during pregnancy increase
• In patients with pituitary tumors, pregnancy serum prolactin and the size of the pituitary gland
can be safe and maternal-fetal outcomes are due to lactotroph hyperplasia and hypertrophy.
similar to those of the general population if Also, hyperestrogenism can increase prolactinoma
hormonal hypersecretion and tumor volume volume. In microprolactinomas, symptomatic
are controlled before pregnancy. tumor growth occurs in less than 5% of cases,
while in macroprolactinomas it is reported in 20%
• In patients with well-controlled disease, clinical of cases.3 Therefore, tumor size reduction before
treatment is typically withdrawn during pregnancy is indicated for macroprolactinomas.
pregnancy, and its maintenance should be For microprolactinomas and intrasellar
discussed with a multidisciplinary care team. macroprolactinomas, treatment with dopamine
agonists, at the lowest effective dosage, is
Discussion recommended. However, treatment should be
withdrawn after pregnancy confirmation to
Pituitary tumors can cause hypogonadotropic
reduce fetal exposure to the drug.4 Although
hypogonadism and affect fertility. Fertility
there are more robust data with bromocriptine
plans should be discussed routinely as part of
regarding pregnancy induction, there were no
follow-up for women of childbearing age with
significant fetal and maternal adverse outcomes
pituitary tumors. Treatment aimed at achieving
in the approximately 1000 pregnancies induced
hormonal and tumoral control should be offered
by cabergoline.1,5,6 During pregnancy, patients
before pregnancy. Hormonal deficiencies should
with microprolactinomas should be followed
be properly replaced and monitored during
up clinically in each trimester, whereas patients
pregnancy. Pregnancy also influences normal
with expansive macroprolactinomas should be
pituitary size and function, which could lead to
followed up monthly. Routine serum prolactin
an increase in tumor dimension in some cases
measurement is not indicated. In the presence
and add complexity to managing acromegaly and
of mass effect symptoms, sellar MRI without
Cushing disease. This chapter reviews each type
contrast and a neuro-ophthalmological evaluation
of pituitary tumor and their specific management
should be performed. If, after evaluation, the
during pregnancy.
symptoms are confirmed to be related to tumor
size increase, dopamine agonist therapy must be
Prolactinomas reintroduced. Surgery should be performed in
Prolactinomas are the most common type of patients with significant vision deficiency despite
pituitary tumor, and they most often affect dopamine agonist treatment, preferentially
women in their third to fourth decades of life. during the second trimester. If pregnancy is near
Hyperprolactinemia can impair GnRH secretion term, possible delivery should be discussed with
and pulsatility, via kisspeptin reduction, causing the multidisciplinary care team. After labor,
hypogonadism, anovulation, and infertility. breastfeeding is recommended, except in women
Dopamine agonists, mainly cabergoline, are the for whom dopamine agonist therapy was necessary
criterion standard treatment due to their efficacy to control tumor volume during pregnancy.
in reducing tumor volume, promoting normal Prolactinoma status should be evaluated after
prolactin concentrations, and restoring gonadal delivery, as remission can occur. Dopamine
axis.1 Neurosurgery should be reserved for patients agonist therapy should be reintroduced after
with dopamine agonist intolerance, dopamine labor (after breastfeeding cessation) in patients
agonist resistance, or expansive tumors with without remission.7,8

ENDO 2025 • Neuroendocrinology and Pituitary 195

Acromegaly delivery because rebound of disease activity can
occur.4 Breastfeeding should be discussed with the
Acromegaly is usually caused by
patient if medical treatment is indicated.
somatotropinomas and mostly affects individuals
in their fourth and fifth decades of life.
Uncontrolled acromegaly can cause infertility due Cushing Disease
to hypogonadism, hyperprolactinemia, insulin Pregnancy is rare in women with Cushing
resistance, and polycystic ovary syndrome.9 syndrome, and it is more likely to occur in
Additionally, GH hypersecretion before pregnancy women with adrenal tumors than in women with
is associated with arterial hypertension and Cushing disease. In Cushing disease, infertility
hyperglycemia, which could impact maternal and can be secondary to hypogonadism caused
fetal outcomes.10 Consequently, neurosurgery is by hypercortisolism, hyperandrogenism, and
recommended as first-line therapy for women hyperprolactinemia.14 Pregnancy in patients with
with active acromegaly who desire pregnancy. Cushing disease is associated with maternal and
When surgery is not an option, medical treatment fetal morbidities such as preeclampsia, gestational
with ligand somatostatin receptors or cabergoline diabetes, cardiac failure, poor wound healing
can be used until pregnancy is confirmed.4 after cesarean delivery, abortion, premature
During pregnancy, the placenta secretes a GH labor, intrauterine growth restriction, and
variant that stimulates IGF-1 secretion. IGF-1 perinatal death.15 Therefore, patients with active
levels usually do not increase in pregnant women Cushing disease desiring pregnancy should be
with untreated acromegaly, probably because of treated, preferentially with neurosurgery, before
hyperestrogenism and the resistance that it can attempting pregnancy.4 For women with medically
cause in hepatic IGF-1 production.11 Mass effect treated Cushing disease who would like to become
symptoms are rare in pregnant women with pregnant, management by a multidisciplinary
acromegaly. team, including those with expertise in high-risk
In patients with adequate hormonal and pregnancy, is recommended.16 Hypercortisolism
tumoral control, cessation of medical treatment diagnosis and evaluation during pregnancy is
should be considered before or right after challenging because of placental corticotropin-
pregnancy confirmation. Routine GH and IGF- releasing hormone production, physiological
1 measurement is not recommended during activation of the hypothalamic-pituitary-adrenal
pregnancy.4,12 Maternal outcomes such as diabetes axis, and increased corticosteroid-binding globulin
and arterial hypertension can worsen or appear for levels. Prophylactic anticoagulation should be
the first time in pregnancy13; nevertheless, with considered, as hypercortisolism and pregnancy
recommended screening and treatment, there is increase venous thrombosis risk. Transsphenoidal
no increase in maternal and fetal mortality.10 In surgery, preferably during the second trimester,
patients with expansive macroadenomas near the should be reserved for patients with severe disease
optic chiasm, periodic neuro-ophthalmological that does not improve with medical treatment.17
evaluation should be performed, and sellar MRI Tumor status should be reevaluated after delivery.4
without contrast should be requested if mass
effects symptoms are present. Clinical treatment
should be initiated (or reinitiated) if the patient Nonfunctioning Pituitary Adenomas
has neurological symptoms or severe clinical Nonfunctioning pituitary adenomas are rarely seen
symptoms related to acromegaly. Neurosurgery, in the context of pregnancy. These tumors usually
preferably during the second trimester, is indicated affect older individuals, and fertility is usually
in patients with significant neurological symptoms only impaired in patients with macroadenomas
and suboptimal response to medical treatment.4 (which can cause hypogonadism, with or
Acromegaly status should be reevaluated after without hyperprolactinemia). Patients with

196 ENDO 2025 • Endocrine Case Management

macroadenomas should be treated surgically before Figure 1.
attempting pregnancy.4 Almost 30 cases were
reported in the literature and approximately one-
third were diagnosed before pregnancy.18, During
pregnancy, the normal pituitary gland can grow
due to hyperestrogenism, potentially leading to
mass effect symptoms. In the literature, 8 patients
presented with mass effect symptoms, and most
of them were successfully treated with dopamine
agonist therapy.18,19 However, if visual impairment
does not improve, neurosurgery, preferably in the
second trimester, or delivery if gestation is near
term, should be discussed with a multidisciplinary
care team.4

Clinical Case Vignettes

Case 1
A 29-year-old woman presents with 6 months of
amenorrhea after stopping an oral contraceptive
pill. She has no galactorrhea, comorbidities, or Sellar MRI, T1 coronal views, without contrast (Panel A) and with contrast
(Panel B), showing a pituitary macroadenoma on the left with suprasellar
history of drug use. expansion, not reaching the optical chiasma and in contact with the left
cavernous sinus.
Laboratory test results: [Color—Print (Color Gallery page CG13) or web & ePub editions]

FSH = 8.0 mIU/mL (2.4-10.2 mIU/mL) (SI: 8.0 IU/L

[2.4-10.2 IU/L]) If the patient desires pregnancy,
LH = 3.5 mIU/mL (1.9-12.5 mIU/mL) (SI: 3.5 IU/L which of the following is correct?
[1.9-12.5 IU/L])
Estradiol = 5.2 pg/mL (5.3-39.3 pg/mL)
A. Neurosurgery is the treatment of choice
(SI: 19.0 pmol/L [19.5-144.2 pmol/L]) B. Dopamine agonist therapy is the gold
Prolactin = 217 ng/mL (4.2-24.2 ng/mL) standard treatment and should be withdrawn
(SI: 9.44 nmol/L [0.18-1.05 nmol/L]) after prolactin normalization, even before
TSH = 2.57 mIU/L (0.27-4.20 mIU/L)
Free T4 = 1.08 ng/dL (0.93-1.70 ng/dL) pregnancy, to avoid exposure during
(SI: 13.90 pmol/L [11.97-21.88 pmol/L]) pregnancy
IGF-1 = 243 ng/mL (83-259 ng/mL) (SI: 31.8 nmol/L C. Radiotherapy is the treatment of choice
[10.9-33.9 nmol/L])
Cortisol = 14.1 μg/dL (5.3-22.5 μg/dL) D. Pregnancy is not recommended for a patient
(SI: 389.0 nmol/L [146.2-620.7 nmol/L]) with macroprolactinoma
E. Dopamine agonist therapy is the gold standard
Sellar MRI identifies a macroadenoma (Figure 1),
treatment, and barrier contraception is
and macroprolactinoma is diagnosed.
recommended until normoprolactinemia and
tumor reduction are achieved
Answer: E) Dopamine agonist therapy is the gold
standard treatment, and barrier contraception
is recommended until normoprolactinemia
and tumor reduction are achieved

ENDO 2025 • Neuroendocrinology and Pituitary 197

Prolactinomas can cause a range of problems, Figure 2.
from infertility to hypogonadism secondary
to impairment of GnRH secretion. Fertility
is usually restored after prolactin normalizes.
Clinical treatment with dopamine agonists is the
gold standard for both microprolactinomas and
macroprolactinomas. In the setting of expansive
macroprolactinomas, barrier contraception
should be used until normoprolactinemia is
achieved and tumor volume is reduced (Answer
E). Although scarce, data show that dopamine
agonist treatment for 12 to 24 months can reduce
the risk of symptomatic tumor growth in patients
with macroprolactinomas. Dopamine agonist
therapy should be used at the lowest effective
dosage and should be withdrawn after pregnancy
confirmation. Surgery is reserved for patients
who are intolerant of medical therapy or have
treatment-resistant disease. Radiotherapy is
Sellar MRI, T1 coronal views without contrast (Panel A) and with contrast
contraindicated for patients desiring pregnancy in (Panel B), showing reduction of tumor dimensions and no suprasellar
expansion.
the next few months.
[Color—Print (Color Gallery page CG13) or web & ePub editions]

Case 1, Continued
Once normoprolactinemia is achieved and
After 4 months of cabergoline, 0.5 mg weekly, the macroprolactinoma volume is reduced to
and subsequent normoprolactinemia and regular within sellar boundaries, dopamine agonist
menses, pregnancy is confirmed. On sellar MRI therapy should be withdrawn after pregnancy
performed just before pregnancy confirmation, confirmation (Answer A). The patient should
the tumor volume had decreased to within sellar be followed up clinically each trimester, and
boundaries (Figure 2). if neurological symptoms develop, sellar MRI
without contrast and neuro-ophthalmological
Which of the following is the best evaluation must be done.
management after pregnancy confirmation?
A. Stop cabergoline
Case 1, Continued
B. Switch cabergoline to bromocriptine
During the 12th week of gestation, the patient
C. Follow-up during pregnancy with sellar MRI
starts experiencing severe headaches. Sellar MRI
without contrast
without contrast shows an increase in tumor
D. Follow-up during pregnancy with serum volume (Figure 3, following page). Findings on
prolactin evaluation each trimester neuro-ophthalmological evaluation are normal.
E. No follow-up is necessary during pregnancy;
the risk of symptomatic tumor growth is less Which of the following is the best
than 5% next step in management?
A. Refer for neurosurgery
Answer: A) Stop cabergoline
B. Start bromocriptine
C. Reintroduce cabergoline

198 ENDO 2025 • Endocrine Case Management

Figure 3. Case 2
Ten years ago, a 28-year-old woman presented
with headache and diplopia. Cranial MRI
showed a pituitary adenoma (4 cm in maximum
diameter), with suprasellar expansion and right
parasellar invasion (Knosp 4). She underwent
transsphenoidal operations 10 years ago and 6
years ago, with partial debulking. Acromegaly
was diagnosed 4 years ago. Lanreotide, 120 mg
every 28 days, was initiated, but IGF-1 levels
did not decrease. Cabergoline, 3.5 mg weekly,
was added. There was no hormonal control or
significant tumor volume reduction. Another
neurosurgical operation was indicated. However,
due to the COVID-19 pandemic, the procedure
was postponed. Pegvisomant and pasireotide were
not available.
The patient, now 38 years old, desires
pregnancy. She takes levothyroxine to treat central
hypothyroidism. There are no other hormone
deficiencies. She does not have diabetes or arterial
Sellar MRI, T1 coronal view without contrast (Panel A) and T2 coronal
hypertension.
view (Panel B) showing an increase in tumor dimensions, with suprasellar
expansion. Current laboratory test results:
GH = 5.67 ng/mL (SI: 5.67 µg/L)
D. No specific management is necessary since IGF-1 = 477 ng/mL (69-227 ng/mL) (SI: 62.5 nmol/L
there is no visual impairment [9.0-29.7 nmol/L])
Prolactin = <1.5 ng/mL (SI: <0.07 nmol/L)
E. Evaluate for fetal maturity in anticipation of
labor induction Current sellar MRI shows a pituitary tumor
(3.4 cm in maximum diameter), with suprasellar
Answer: C) Reintroduce cabergoline
extension and parasellar invasion.
In the presence of neurological symptoms due
to an increase in tumor volume, the dopamine In the context of the patient’s desire for
agonist should be reintroduced (Answer C) at pregnancy, which of the following is correct?
the dosage that promoted tumor control before A. Arterial blood pressure and glycemic
pregnancy—in this case, cabergoline, 0.5 mg parameters should be monitored to identify
weekly. Neurosurgery should be performed if preeclampsia and gestational diabetes
there is visual impairment that does not improve B. Radiotherapy is indicated due to debulking
with clinical treatment, preferentially during the difficulties of the parasellar tumor remnant
second trimester. If the pregnancy is near term, C. GH and IGF-1 should be periodically assessed
and there has been no success with a dopamine during pregnancy
agonist, delivery induction can be considered after
D. Neuro-ophthalmological evaluation is not
assessment of fetal maturity and evaluation by a
necessary during pregnancy
multidisciplinary team.
E. Pregnancy is contraindicated for this patient

ENDO 2025 • Neuroendocrinology and Pituitary 199

Answer: A) Arterial blood pressure and glycemic C. If she develops neurological symptoms,
parameters should be monitored to identify neurosurgery should be performed, regardless
preeclampsia and gestational diabetes of trimester
D. Clinical treatment is contraindicated during
During pregnancy, evaluation of arterial blood
pregnancy
pressure and assessment for hyperglycemia
(Answer A) should be done periodically under the E. Levothyroxine replacement should be
guidance of an obstetric team. maintained, and dosage adjustments may be
For patients with acromegaly desiring necessary throughout pregnancy
pregnancy, neurosurgery is the first treatment Answer: E) Levothyroxine replacement should
to be offered, and radiotherapy (Answer B) is be maintained, and dosage adjustments may
contraindicated. be necessary throughout pregnancy
Once pregnancy is confirmed, routine
GH and IGF-1 evaluations (Answer C) are During pregnancy, hypopituitarism should
not recommended and, in most cases, there is be treated with hormone replacement. The
no increase in IGF-1 levels even after clinical levothyroxine dosage should be adjusted according
treatment withdrawal. to free T4 levels (Answer E).
For patients with large and invasive adenomas, If there are neurological symptoms due
especially those close to the optic chiasm, regular to tumor growth during pregnancy, clinical
neuro-ophthalmologic evaluation is required treatment can be tried, with first-generation
and, if necessary, pituitary MRI without contrast somatostatin receptor ligands with or without
should be performed (thus, Answer D is incorrect). cabergoline (thus, Answer D is incorrect).
Pregnancy is not contraindicated (Answer E); Although use of pegvisomant has been
however, fertility should be assessed to evaluate reported in pregnancy, it does not act on tumor
whether assisted reproduction technology may be volume (thus, Answer A is incorrect).
needed to achieve pregnancy. If clinical treatment fails, neurosurgery should
Another important issue is that clinical be performed, preferentially during the second
treatment does not control GH hypersecretion trimester (thus, Answer C is incorrect).
and does not decrease tumor dimensions. If the Breastfeeding is not contraindicated in
tumor increases during pregnancy and causes this setting, but recommendations should be
neurological symptoms, clinical treatment may individualized based on disease activity and
or may not be effective, and neurosurgery during drug treatment maintenance (thus, Answer B is
pregnancy may be indicated. incorrect).

Case 2, Continued Case 3

The patient schedules a follow-up appointment A 35-year-old woman presents with facial
after a positive home pregnancy test. plethora, rounded face, violaceous striae, lower
limb weakness, and amenorrhea.
Which of the following statements is correct? Laboratory evaluation documents ACTH-
A. If there is tumor growth during pregnancy dependent hypercortisolism.
accompanied by neurological symptoms,
Laboratory test results:
pegvisomant should be prescribed
B. Breastfeeding is contraindicated 24-Hour urinary free cortisol = 85.6 µg/24 h (1750 mL),
83.4 µg/24 h (200 mL), and 697.9 µg/24 h
(1700 mL) (reference range 3-43 µg/24 h)

200 ENDO 2025 • Endocrine Case Management

 Serum cortisol = 24.5 µg/dL (6.7-22.6 µg/dL) activation of the pituitary-adrenal gland, mostly
(SI: 675.9 nmol/L [184.8-623.5 nmol/L]) due to corticotropin-releasing hormone placental
Late-night salivary cortisol = 0.87 µg/dL (<0.2 µg/dL)
secretion. Urinary free cortisol and late-night
(SI: 24.0 nmol/L [<5.5 nmol/L])
ACTH = 87.0 pg/mL (7.2-63.3 pg/mL) salivary cortisol increase throughout normal
(SI: 19.1 pmol/L [1.6-13.9 pmol/L]) pregnancy. Cushing syndrome is indicated by a
urinary free cortisol value more than 2 to 3 times
Sellar MRI reveals an 0.8-cm microadenoma, and the upper normal limit and a late-night salivary
she undergoes transsphenoidal neurosurgery. cortisol value 1.4 times the upper normal limit
Postoperatively, she experiences clinical and in the second trimester and 2 times the upper
hormonal remission, and sellar imaging 3 months normal limit in the third trimester. Corticotropin-
later shows no tumor. Menses are regular, and she releasing hormone testing is a high-cost test that
becomes pregnant 7 months after surgery, while is not available in many countries. In this case, the
on no medications. During the eighth week of late-night salivary cortisol value 3 times higher
gestation, she presents with signs and symptoms of than the upper normal limit in the first trimester
hypercortisolism. suggests hypercortisolism recurrence.
Laboratory test results:
Urinary free cortisol = 231 µg/24 h (28.5-
Case 3, Continued
213.7 µg/24 h) (1.08 times the upper normal When hypercortisolism recurrence
limit) (SI: 637.6 nmol/d [78.7-589.8 nmol/d]) is diagnosed in pregnancy, which
Late-night salivary cortisol = 0.61 µg/dL (<0.2 µg/dL) of the following is correct?
(3 times the upper normal limit) (SI: 16.8 nmol/L
[<5.5 nmol/L]) A. Neurosurgery is the first choice of treatment,
especially during the second trimester
Which of the following is B. Clinical treatment can be used without
correct regarding the diagnosis of reservations during pregnancy
hypercortisolism during pregnancy?
C. Mifepristone is the gold standard treatment
A. Low-dosage dexamethasone-suppression test for women with gestational diabetes related to
(1 mg) is the method of choice hypercortisolism
B. Late-night salivary cortisol increases early in D. Mild hypercortisolism can be followed with
the timeline of hypercortisolism recurrence obstetric care aiming to control comorbidities
C. Urinary free cortisol is very sensitive, and E. Bilateral adrenalectomy should be performed
slight increases are diagnostic of Cushing in patients with severe hypercortisolism,
syndrome especially in the first trimester
D. Serum cortisol is a good method for diagnosis
during pregnancy Answer: D) Mild hypercortisolism can be followed
with obstetric care aiming to control comorbidities
E. Corticotropin-releasing hormone testing is
easy and widely available Patients with mild hypercortisolism can be
followed up with supportive medical and obstetric
Answer: B) Late-night salivary cortisol increases
care (Answer D). In patients with moderate
early in the timeline of hypercortisolism recurrence
hypercortisolism, a multidisciplinary team
During pregnancy, hyperestrogenism increases should discuss recommendations for clinical
cortisol-binding globulin levels, leading to treatment or neurosurgery. In patients with
inaccuracy in dexamethasone-suppression severe hypercortisolism and in those for whom
testing and random serum cortisol measurement. clinical treatment fails or those who experience
Additionally, in pregnancy, there is a physiological intolerance, neurosurgery should be performed,

ENDO 2025 • Neuroendocrinology and Pituitary 201

preferentially during the second trimester. tumors to plan specific treatment for each type
Although clinical treatment is not approved for of tumor.
use in pregnancy, an expert team can individualize • Clinicians should properly replace hormonal
treatment. Mifepristone is abortive and absolutely deficiencies before and during pregnancy,
contraindicated in pregnancy. while considering the physiological
modifications in this setting.
Key Learning Points • In most patients with tumor control before
gestation, clinical treatment can be withdrawn
• Clinicians should be comfortable discussing after pregnancy confirmation. Follow-up
routine fertility and pregnancy issues with during pregnancy is important, and patients
women of childbearing age harboring pituitary should be reevaluated after delivery.

References
1. Petersenn S, Fleseriu M, Casanueva FF, et al. Diagnosis and management 10. Bandeira DB, Olivatti TOF, Bolfi F, Boguszewski CL, Dos Santos Nunes-
of prolactin-secreting pituitary adenomas: a Pituitary Society international Nogueira V. Acromegaly and pregnancy: a systematic review and meta-
consensus statement. Nat Rev Endocrinol. 2023;19(12):722-740. PMID: analysis. Pituitary. 2022;25(3):352-362. PMID: 35098440
37670148 11. Bronstein MD, Paraiba DB, Jallad RS. Management of pituitary tumors in
2. Glezer ABM. Prolactinomas and disorders of prolactin secretion. In: pregnancy. Nat Rev Endocrinol. 2011;7(5):301-310. PMID: 21403665
Robertson RP, ed. DeGroot’s Endocrinology: Basic Science and Clinical Practice. 12. Abucham J, Bronstein MD, Dias ML. Management of endocrine disease:
8th ed. Elsevier; 2022. Acromegaly and pregnancy: a contemporary review. Eur J Endocrinol.
3. Huang W, Molitch ME. Pituitary tumors in pregnancy. Endocrinol Metab Clin 2017;177(1):R1-R12. PMID: 28292926
North Am. 2019;48(3):569-581. PMID: 31345524 13. Jallad RS, Shimon I, Fraenkel M, et al. Outcome of pregnancies in a large
4. Luger A, Broersen LHA, Biermasz NR, et al. ESE clinical practice guideline cohort of women with acromegaly. Clin Endocrinol (Oxf). 2018;88(6):896-907.
on functioning and nonfunctioning pituitary adenomas in pregnancy. Eur J PMID: 29574986
Endocrinol. 2021;185(3):G1-G33. PMID: 34425558 14. Castinetti F, Brue T. Impact of Cushing’s syndrome on fertility and
5. Sant’ Anna BG, Musolino NRC, Gadelha MR, et al. A Brazilian multicentre pregnancy. Ann Endocrinol (Paris). 2022;83(3):188-190. PMID: 35443159
study evaluating pregnancies induced by cabergoline in patients harboring 15. Machado MC, Fragoso MCBV, Bronstein MD. Pregnancy in patients with
prolactinomas. Pituitary. 2020;23(2):120-128. PMID: 31728906 Cushing’s syndrome. Endocrinol Metab Clin North Am. 2018;47(2):441-449.
6. Bandeira DB, Alves LS, Glezer A, Boguszewski CL, Dos Santos Nunes- PMID: 29754643
Nogueira V. Disease activity and maternal-fetal outcomes in pregnant women 16. Gheorghiu ML, Fleseriu M. Conundrums of diagnosis and management
with prolactinoma: a systematic review and meta-analysis. J Clin Endocrinol of Cushing’s syndrome in pregnancy. Endocrinol Metab Clin North Am.
Metab. 2024;110(4):e1241-e1251 2024;53(3):421-435. PMID: 39084817
7. Glezer A, Bronstein MD. Prolactinomas in pregnancy: considerations before 17. Hamblin R, Coulden A, Fountas A, Karavitaki N. The diagnosis and
conception and during pregnancy. Pituitary. 2020;23(1):65-69. PMID: management of Cushing’s syndrome in pregnancy. J Neuroendocrinol.
31792668 2022;34(8):e13118. PMID: 35491087
8. Zhang CD, Ioachimescu AG. Prolactinomas: preconception and 18. Jallad RS GA, Machado MC, Bronstein MD. Pituitary disorders during
duringpPregnancy. Endocrinol Metab Clin North Am. 2024;53(3):409-419. pregnancy and lactation. In: Maternal-Fetal and Neonatal Endocrinology
PMID: 390848816 Physiology, Pathophysiology, and Clinical Management. Elsevier; 2020: 259-286.
9. Pirchio R, Auriemma RS, Grasso LFS, et al. Fertility in acromegaly: a single- 19. Rosmino J, Tkatch J, Di Paolo MV, Berner S, Lescano S, Guitelman M. Non-
center experience of female patients during active disease and after disease functioning pituitary adenomas and pregnancy: one-center experience and
remission. J Clin Endocrinol Metab. 2023;108(8):e583-e593. PMID: 36790068 review of the literature. Arch Endocrinol Metab. 2021;64(5):614-622. PMID:
34033303

202 ENDO 2025 • Endocrine Case Management

Craniopharyngiomas in Adults:
Modern Management and
Changes in the Paradigm
Emmanuel Jouanneau, MD, PhD. Pituitary Center, Neurological Department, Groupement
Hospital Est, Hospices Civils de Lyon, Lyon, France; Claude Bernard University, Lyon,
France; Cancer Research Center of Lyon, Lyon, France; Email: emmanuel.jouanneau@chu-
lyon.fr

Gerald Raverot, MD, PhD. Claude Bernard University, Lyon, France; Cancer Research
Center of Lyon, Lyon, France; Endocrinology Department, Reference Center for Rare
Pituitary Diseases HYPO, “Groupement Hospitalier Est” Hospices Civils de Lyon, Bron,
France; Email: [email protected]

Educational Objectives survival, with significantly lower recurrence rates

than those associated with subtotal resection
After reading this chapter, readers should be able to:
(0%-50% vs 50%-100% at 10 years).2 When
• Describe the overexpressed oncogenic the craniopharyngioma has invaded the third
pathways in craniopharyngiomas in adults and ventricle or the visual pathway, surgery should be
pathogenic variants based on histopathology. subtotal, sparing the hypothalamus and favoring a
combined strategy with radiotherapy. Numerous
• Explain the possibility of targeted therapy for
studies have demonstrated that adjuvant
craniopharyngiomas and data from recent
radiotherapy significantly improves long-term
reports and studies.
tumor control and overall survival rates after
• Describe the concept of neoadjuvant therapy subtotal removal at 10 years when compared with
for craniopharyngiomas. subtotal resection alone, with results similar to
those of gross total removal.3
The main issue with such tumors remains
the hypothalamic involvement found in type C
Significance of the (suprasellar-pseudoventricular craniopharyngioma)
Clinical Problem and type D (infundibulo-tuberal
craniopharyngioma) (Prieto classification) tumors,
Craniopharyngiomas are rare, accounting for 1.2%
with the high posttherapeutic morbidity.4 In these
to 4.6% of intracranial tumors in adults and up to
cases, even subtotal removal may be damaging,
11% in children. There are 2 craniopharyngioma
resulting in a low quality of life. In such cases or
subtypes: adamantinomatous craniopharyngioma
in the case of recurrence after surgery or failure of
(ACP), which is the only subtype found in
radiotherapy, there is a need for medical treatment
children, and the papillary form (PCP), which
to avoid invasive surgery. Recently, Brastianos et
represents 20% of craniopharyngiomas in adults.1
al identified the BRAF V600E pathogenic variant
When feasible, gross total removal gives
in PCPs.5 Additionally, overexpression of IL6 and
the best recurrence-free survival and overall

ENDO 2025 • Neuroendocrinology and Pituitary 203

VEGF has been identified in ACPs. These findings radiotherapy), and palliative (recurrence after
have given rise to targeted therapies, such as anti- surgery and radiotherapy). All groups showed
BRAF in PCP and anti-IL6/VEGF in ACP and an identical response. In the neoadjuvant group,
have prompted neuro-oncological concepts for the tumor reduction was impressive and rapid
managing craniopharyngioma.6-8 (decompressive results in 3 months, maximum
reached at around 6 months) and patients were
referred thereafter for radiotherapy. In a phase 2
Practice Gaps trial, in a similar cohort, the efficacy and adverse
effects of the combined therapy were exactly
• Clinicians typically consider only surgery and
the same.13 Interestingly, 6 of 7 patients who
radiotherapy for craniopharyngiomas.
discontinued targeted therapy had no evidence
• Hypothalamic morbidity remains the main of recurrence after 23 months of follow-up. In
concern of the disease. these 2 cohorts, the cystic components responded
• All clinicians caring for patients should be more slowly to therapy, but showed an equivalent
aware of recent advances in targeted therapy response in the solid tumor components by the
and the possibility of a neoadjuvant approach end of treatment.
with such therapies. These results have given rise to a new
paradigm: for invasive unresectable hypothalamic
craniopharyngiomas, surgery should be replaced
Discussion by simple biopsy with neoadjuvant anti-BRAF
Despite improvements in surgery in the endoscopic debulking in the case of PCPs, with the goal
era and in radiotherapy, clinicians still face the of avoiding ineffective surgery and decreasing
problem of craniopharyngioma recurrence.9,10 hypothalamic morbidity.14 Biopsy continues to
Surgery must spare the hypothalamus to remain mandatory, as imaging or liquid biopsy
maintain patients’ quality of life. In types C and cannot currently ensure an accurate diagnosis.
D craniopharyngioma Prieto subtypes, surgery is However, in most published cases, combined
therefore mainly partial and risky. anti-MEK and anti-BRAF have been used to
Since the first description of results with maximize efficacy and reduce toxicity. However,
anti-BRAF in PCPs carrying the BRAF pathogenic numerous questions remain, and further trials
variant, strong evidence has accumulated showing are required to determine the optimal treatment
the efficacy of such therapy in recurrent or newly duration in cases of recurrence and in newly
diagnosed PCPs. The BRAF V600E pathogenic diagnosed craniopharyngiomas, the benefits
variant is present in approximately 95% of PCPs.5,11 of upfront vs delayed radiotherapy using a
Recently, in 15 of 16 patients treated with neoadjuvant approach, and the final target of
anti-MEK and anti-BRAF combined therapy radiotherapy (initial tumoral volume or the final
in a French national cohort, a tumor volume contrast enhancement). Studies are also needed
reduction of nearly 90% was reported.12 to determine the recurrence rate when targeted
Morbidity was acceptable, but it led to treatment therapy is stopped, and the efficacy of such therapy
discontinuation in 3 patients, mainly for a when it is resumed due to recurrence.
combination of fever/pneumopathy or fever, In ACPs, the pathogenic variants in the
fatigue, headache, rash, or diarrhea. Liver enzyme CTNNB1 gene are typical (occurring in 96% of
elevation led to transient discontinuation in 2 ACPs), which drives accumulation of β-catenin in
patients. Targeted therapy was used in 3 separate cells and inactivates the proteasomal degradation
groups: neoadjuvant (biopsy-only followed by pathway.5,15 There is currently no targeted
targeted therapy), adjuvant (recurrence after therapy available for disease associated with
surgery followed by targeted therapy before CTNNB1 pathogenic variants. However, in ACPs,

204 ENDO 2025 • Endocrine Case Management

overexpression of growth factors, including EGFR, Clinical Case Vignettes
VEGF, and the proinflammatory cytokine IL6,
have been found, with the latter growth factors Case 1
being in the liquid or wall of cysts. Notably, in a A 56-year-old man is referred with a 2-month
recent case report of recurrent ACP, anti-VEGF history of total pituitary insufficiency. In the last
therapy showed a 50% tumor reduction and visual several months, he experienced weight gain of
improvement before radiotherapy.16 In 2 other 22 lb (10 kg). He has no visual symptoms. MRI
studies, combined systemic therapy with anti- reveals a type D craniopharyngioma (infundibulo-
VEGF and anti-IL6 was used with encouraging tuberal Prieto classification).
results and dramatic cyst reduction.17,18
Oncological medical treatments are emerging Is the best next step surgery to remove
for both craniopharyngioma subtypes. The field the tumor or a simple biopsy to
is clearly moving towards a neuro-oncological further characterize the diagnosis?
paradigm to address aggressive pituitary Since a PCP was suspected, a simple biopsy was
neuroendocrine tumors and craniopharyngiomas. performed and a neoadjuvant anti-BRAF agent
This is exemplified by the concept of pituitary (dabrafenib, 150 mg twice daily) and an anti-MEK
tumor centers of excellence, which rely on strong agent (trametinib, 2 mg once daily) were started.
collaboration with oncologists.8,19 Three years ago, The solid part of the tumor decreased quickly over
following these recent developments in France, 2 months, while the cystic part continued to grow
a monthly national multidisciplinary team was during the next 4 months and was managed by
established to discuss craniopharyngiomas for transventricular marsupialization into the third
which targeted therapy could be used. ventricle. Radiotherapy was finally initiated to
treat the remaining contrast enhancement, and the
tumor was optimally controlled at the last follow-
up (2 years after diagnosis). Figure 1 summarizes
the tumor’s evolution during the treatment course.

Figure 1.

Reprinted from De Rosa A et al. Annales d'Endocrinologie, 2023; 84(6):727–733. © Elsevier Masson SAS.
[Color—Print (Color Gallery page CG14) or web & ePub editions]

ENDO 2025 • Neuroendocrinology and Pituitary 205

Case 2 Figure 2.

A 68-year-old man is being monitored for

multilocular sclerosis with an infundibulo-
tuberal tumor (type D, Prieto and Pascal
classification) discovered 3 years ago. The tumor
has continued to grow over the last year. The
occurrence of bitemporal hemianopsia prompts a
treatment decision.

Considering the hypothalamus invasion,

is the best next step surgery to remove the
tumor or a simple biopsy with the aim
of recommending targeted neoadjuvant
therapy if a PCP is confirmed?
Considering the fast and effective tumor reduction
achieved with anti-BRAF therapy, a simple biopsy
should be chosen to avoid additional morbidity.
Once the diagnosis was confirmed, combined
anti-BRAF and anti-MEK therapy (the same
protocol used in the preceding case) was
introduced, with visual improvement in 3 weeks,
normalization in 3 months, and a 90% decrease in
tumor volume in 3 months (Figure 2). Reprinted from De Rosa A et al. Annales d'Endocrinologie, 2023;
84(6):727–733. © Elsevier Masson SAS.
After a multidisciplinary meeting, the patient
was referred to radiotherapy with optimal tumor
control observed 1 year after treatment initiation.
The patient had no hypothalamic symptoms. patient was able to resume reading. He eventually
had excellent visual recovery in 3 months in the
Case 3 right eye. Both the cystic and solid parts of the
tumor shrank by 50% (Figure 3, following page).
An 84-year-old man with poor clinical Radiotherapy was administered with subsequent
status presents with suspected recurrence of good tumor control at 1 year follow-up.
craniopharyngioma (the biopsy results from initial
diagnosis are unavailable) and visual impairment.
A transsphenoidal biopsy is performed, which Key Learning Points
confirms a final diagnosis of ACP.
• Craniopharyngiomas are benign tumors that
Is the best therapeutic strategy to propose can cause hypothalamic symptoms when
decompressive surgery or radiotherapy alone? invasive.
The patient’s clinical status was poor, and • All craniopharyngiomas in children are the
he was not a candidate for decompressive adamantinomatous subtype; the papillary
surgery, so radiotherapy was proposed. The subtype represents 20% of craniopharyngiomas
patient was almost blind within 4 weeks. After in adults.
a multidisciplinary team meeting, anti-VEGF
• Ninety-five percent of PCPs have the V600E
treatment was initiated, which had excellent
BRAF pathogenic variant and respond rapidly
clinical tolerance. After 4 weeks of treatment, the
to combined anti-bRAF and anti-MEK therapy

206 ENDO 2025 • Endocrine Case Management

Figure 3.

Reprinted from De Rosa A et al. Annales d'Endocrinologie, 2023; 84(6):727–733. © Elsevier Masson SAS.

in phase 2 and historical cohort studies (90% tumoral debulking in the hope of decreasing
tumor volume reduction in a median time of final morbidity and improving oncological
6 months). control.
• Overexpression of IL6 and/or VEGF in • Multicentric trials are needed to answer
ACPs can be targeted by systemic therapy, as questions about long-term outcomes and the
supported by encouraging findings published exact role of targeted therapy.
in case reports. • More pituitary centers of excellence are needed
• Neoadjuvant targeted therapy for to treat these patients and incorporate neuro-
hypothalamic PCPs may replace surgery for oncological concepts into management.

References
1. Vasiljevic A, Villa. Histopathology and molecular pathology of 5. Brastianos PK, Taylor-Weiner A, Manley PE, et al. Exome sequencing
craniopharyngioma in adults. In: Jouanneau E, Raverot G, eds. Adult identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet.
Craniopharyngiomas: Differences and Lessons From Paediatrics. Springer; 2020:1-17. 2014;46(2):161-165. PMID: 24413733
2. Mortini P, Gagliardi F, Boari N, Losa M. Surgical strategies and modern 6. Martinez-Gutierrez JC, D’Andrea MR, Cahill DP, Santagata S, Barker FG,
therapeutic options in the treatment of craniopharyngiomas. Crit Rev Oncol Brastianos PK. Diagnosis and management of craniopharyngiomas in the
Hematol. 2013;88:514-529. PMID: 23932582 era of genomics and targeted therapy. Neurosurg Focus. 2016;41:E2. PMID:
3. Dandurand C, Sepehry AA, Asadi Lari MH, Akagami R, Gooderham P. 24413733
Adult craniopharyngioma: case series, systematic review, and meta-analysis. 7. Stec NE, Barker FG, Brastianos PK. Targeted treatment for
Neurosurgery. 2018;83:631-641. PMID: 29267973 craniopharyngioma. J Neurooncol. 2025;172(3):503-513. PMID: PMID:
4. Prieto R, Pascual JM, Barrios L. Topographic diagnosis of 39951179
craniopharyngiomas: the accuracy of MRI findings observed on conventional 8. Jouanneau E, Calvanese F, Ducray F, Raverot G. Pituitary tumor centers of
T1 and T2 images. AJNR Am J Neuroradiol. 2017;38(11):2073-2080. PMID: excellence (PTCOE) should now include neuro-oncologic input. Pituitary.
28935625 2023;26(5):642-643. PMID: 37676531

ENDO 2025 • Neuroendocrinology and Pituitary 207

9. Ghosh S, Goda JS, Chatterjee A, et al. Patterns of care in craniopharyngioma: 15. Malgulwar PB, Nambirajan A, Pathak P, et al. Study of β-catenin and
clinical outcomes after surgery and radiation therapy in a real-world setting. BRAF alterations in adamantinomatous and papillary craniopharyngiomas:
World Neurosurg. 2024;181:e809e819. PMID: 37923012 mutation analysis with immunohistochemical correlation in 54 cases. J
10. Cappabianca P, Cavallo LM, Esposito F, De Divitiis E. Craniopharyngiomas. J Neurooncol. 2017;133(3):487-495. PMID: 28500561
Neurosurg. 2008;109(1):1-3. PMID: 18590426 16. De Rosa A, Calvanese F, Ducray F, et al. First evidence of anti-VEGF efficacy
11. Brastianos PK, Shankar GM, Gill CM, et al. Dramatic response of BRAF in an adult case of adamantinomatous craniopharyngioma: case report
V600E mutant papillary craniopharyngioma to targeted therapy. J Natl Cancer and illustrative review. Ann Endocrinol (Paris). 2023;84(6):727-733. PMID:
Inst. 2016;108:djv310. PMID: 26498373 37865272
12. De Alcubierre D, Gkasdaris G, Mordrel M, et al. BRAF and MEK inhibitor 17. Grob S, Mirsky DM, Donson AM, et al. Targeting IL-6 Is a potential
targeted therapy in papillary craniopharyngiomas: a cohort study. Eur J treatment for primary cystic Craniopharyngioma. Front Oncol. 2019;9:791.
Endocrinol. 2024;191(2):251-261. PMID: 39158090 PMID: 31497533
13. Brastianos PK, Twohy E, Geyer S, et al. BRAF-MEK Inhibition in newly 18. Webb LM, Okuno SH, Ransom RC, et al. Recurrent adamantinomatous
diagnosed papillary craniopharyngiomas. N Engl J Med. 2023;389(2):118-126. craniopharyngioma stabilized with tocilizumab and bevacizumab: illustrative
PMID: 37437144 case. J Neurosurg Case Lessons. 2025;9(2):CASE24410. PMID: 39805108
14. Calvanese F, Jacquesson T, Manet R, et al. Neoadjuvant B-RAF and MEK 19. Giustina A, Uygur MM, Frara S, et al. Pilot study to define criteria for
inhibitor targeted therapy for adult papillary craniopharyngiomas: a new Pituitary Tumors Centers of Excellence (PTCOE): results of an audit of
treatment paradigm. Front Endocrinol (Lausanne). 2022;13:882381. PMID: leading international centers. Pituitary. 2023;26(5):583-596. PMID: 37640885
35757402

208 ENDO 2025 • Endocrine Case Management

Therapeutic Use Exemption
in Elite Sport: The
Endocrinologist as the
Expert for Hormonal Drugs
Alan D. Rogol, MD, PhD. Department of Pediatrics, University of Virginia, Charlottesville,
VA; Email: [email protected]

Educational Objectives [Comment to Article 4.2(a): The Use of the

Prohibited Substance or Prohibited Method may
After reviewing this chapter, learners should be
be part of a necessary diagnostic investigation
able to:
rather than a treatment per se.]
• Determine whether a patient/athlete requires
4.2b The Therapeutic Use of the Prohibited
a therapeutic use exemption (TUE) to compete
Substance or Prohibited Method will not, on the
in elite organized sport.
balance of probabilities, produce any additional
• Provide the appropriate medical information to enhancement of performance beyond what
the TUE Committee to permit them to concur might be anticipated by a return to the
with the medical diagnosis and issues a TUE. Athlete’s normal state of health following the
treatment of the medical condition.
[Comment to Article 4.2(b): An Athlete’s
Significance of the normal state of health will need to be
determined on an individual basis. A normal
Clinical Problem state of health for a specific Athlete is their
This Meet the Professor chapter is not about a state of health but for the medical condition
specific disease and how to diagnose and manage for which the Athlete is seeking a TUE.]
it. It is about a process to help elite athletes/
patients who have endocrine conditions that 4.2c The Prohibited Substance or Prohibited
require a World Anti-Doping Agency (WADA)- Method is an indicated treatment for the
banned drug obtain a TUE to compete. This medical condition, and there is no reasonable
means that the physician/endocrinologist should permitted Therapeutic alternative.
provide enough information to ensure that the [Comment to Article 4.2(c): The physician
athlete can obtain an exemption, specifically by must explain why the treatment chosen was
meeting the following criteria of section 4.2 of the the most appropriate, eg, based on experience,
WADA code: side-effect profiles, or other medical
4.2a The Prohibited Substance or Prohibited justifications, including, where applicable,
Method in question is needed to treat a geographically specific medical practice,
diagnosed medical condition supported by and the ability to access the medication.
relevant clinical evidence. Further, it is not always necessary to try and

ENDO 2025 • Neuroendocrinology and Pituitary 209

 fail alternatives before using the Prohibited published by WADA covering multiple topics of
Substance or Prohibited Method.] prohibited substances, including Therapeutic Use
Exemptions,” the topic of this chapter.
4.2d The necessity for the Use of the Prohibited
Substance or Prohibited Method is not a
consequence, wholly or in part, of the prior TUE Guidelines
Use (without a TUE) of a substance or method Introduction
which was prohibited at the time of such Use. The International Standard for Therapeutic Use
[Comment to Article 4.2: The WADA Exemptions (ISTUE) was created to provide a
documents titled “TUE Physician Guidelines,” detailed, fair, and understandable process for
posted on WADA’s website, should be used athletes, anti-doping organizations, physicians,
to assist in the application of these criteria and athlete support personnel to follow when
in relation to particular medical conditions. situations arise where, due to illness or medical
The granting of a TUE is based solely on condition, an athlete may require the use of
consideration of the conditions set out in substances or methods that are specifically
Article 4.2. It does not consider whether the included in the WADA prohibited list (List).2,3 The
Prohibited Substance or Prohibited Method is the TUE application process provides athletes with
most clinically appropriate or safe, or whether an opportunity to apply for an exemption when
its use is legal in all jurisdictions.] medical treatment is required involving the use of
a prohibited substance or prohibited method. This
process promotes competition on a level playing
Practice Gaps field. If a TUE is granted, an athlete may continue,
or start to use, the otherwise prohibited substance
• Unfamiliarity with the TUE process. or method while competing without resulting
• Unfamiliarity with the list of banned drugs or in an Anti-Doping Rule Violation (ADRV) and
techniques. sanction, if applicable. An athlete applying for a
TUE must have a diagnosed medical condition,
confirmed by relevant medical data that meet
Discussion the ISTUE criteria for the granting of a TUE.2
The World Anti-Doping Agency (WADA; in This mandatory documentation, provided by the
French, Agence mondiale antidopage [AMA]) is athlete’s physician, here likely an internal medicine
an international organization founded by more or pediatric endocrinologist, must accompany
than 140 governments along with the International the TUE application. This information should be
Olympic Committee (IOC) with headquarters guided by the relevant TUE Physician Guideline
in Montreal, Canada. Its purpose is to promote, and Checklist.4 For our purposes today, these
coordinate, and monitor the use of drugs and illegal guidelines and checklists cover diabetes mellitus,
methods in sports. The agency’s remit includes male hypogonadism (testosterone deficiency), and
scientific research, education, development of anti- the use of GH for GH-deficient athletes, whether
doping capacities, and monitoring of the World adolescent or adult, and for some adolescents with
Anti-Doping Code (Code). non–GH-deficient short stature.
The Code is a document published by WADA
to which hundreds of sports organizations are “An Athlete may be granted a TUE if (and
signatories.1 This Code “harmonizes anti-doping only if) they can show, on the balance of
policies, rules, and regulations within sport probabilities, that each of the following
organizations and among public authorities” to conditions is met: a) The Prohibited Substance
“protect the athletes’ multiple international standards or Prohibited Method in question is needed
to treat a diagnosed medical condition

210 ENDO 2025 • Endocrine Case Management

supported by relevant clinical evidence. whether its use is legal in all jurisdictions.
[Comment to Article 4.2(a): The Use of When an International Federation or Major
the Prohibited Substance or Prohibited Event Organization TUEC is deciding whether
Method may be part of a necessary diagnostic or not to recognize a TUE granted by another
investigation rather than a treatment per se.] Anti-Doping Organization (see Article 7), and
b) The Therapeutic Use of the Prohibited when WADA is reviewing a decision to grant
Substance or Prohibited Method will not, (or not to grant) a TUE (see Article 8), the
on the balance of probabilities, produce any issue will be the same as it is for a TUEC that
additional enhancement of performance is considering an application for a TUE under
beyond what might be anticipated by a Article 6, i.e., has the athlete demonstrated on
return to the Athlete’s normal state of health the balance of probabilities that each of the
following the treatment of the medical conditions set out in Article 4.2 is met?].”2,3
condition. [Comment to Article 4.2(b): An
Athlete’s normal state of health will need to be Specific Endocrine Conditions
determined on an individual basis. A normal 1. Diabetes mellitus2-4
state of health for a specific Athlete is their a. Diabetes is diagnosed if the patient satisfies
state of health, but for the medical condition any 1 of the following criteria and, as in all
for which the Athlete is seeking a TUE.] cases of type 1 diabetes, treatment involves
c) The Prohibited Substance or Prohibited regular injections of insulin. TUE Physician
Method is an indicated treatment for the Guidelines Diabetes Mellitus:
medical condition, and there is no reasonable
permitted Therapeutic alternative. [Comment a. Fasting plasma glucose ≥126 mg/dL
to Article 4.2(c): The physician must explain (≥7.0 mmol/L); 2-hour plasma glucose
why the treatment chosen was the most ≥200 mg/dL (≥11.1 mmol/L) during oral
appropriate, eg, based on experience, side- glucose tolerance testing
effect profiles or other medical justifications, b. Hemoglobin A1c ≥6.5% (≥48 mmol/mol)
including, where applicable, geographically c. In a patient with classic symptoms of
specific medical practice, and the ability to hyperglycemia or hyperglycemic crisis, a
access the medication. Further, it is not always random plasma glucose value ≥200 mg/dL
necessary to try and fail alternatives before (≥11.1 mmol/L)
using the Prohibited Substance or Prohibited
b. The drug of choice is insulin, which may be
Method.] d) The necessity for the Use of the
administered in multiple ways with multiple
Prohibited Substance or Prohibited Method
forms of longer- or shorter-acting insulin
is not a consequence, wholly or in part, of
analogues.
the prior Use (without a TUE) of a substance
or method which was prohibited at the time c. Monitoring of blood glucose levels in real time
of such Use. [Comment to Article 4.2: The and over months is beyond the scope of this
WADA documents titled “TUE Physician discussion.
Guidelines”, posted on WADA’s website,
should be used to assist in the application of 2. Male hypogonadism2-4
these criteria in relation to particular medical a. Organic hypogonadism with testosterone
conditions. The granting of a TUE is based deficiency is the focus of this discussion.
solely on consideration of the conditions set Low circulating testosterone without a clear
out in Article 4.2. It does not consider whether pathological cause, in this context, is not
the prohibited substance or prohibited method considered to be hypogonadism. TUEs for
is the most clinically appropriate or safe, or

ENDO 2025 • Neuroendocrinology and Pituitary 211

 androgen (testosterone) deficiency should not Clinical Case Vignettes
be approved in women.
Case 1
b. Medical history: organic hypogonadism A 23-year-old paralympic track and field athlete
is usually long-lasting or permanent, who sustained a blast injury to his lower body
while functional reductions in circulating while deployed with the US Army in Iraq presents
testosterone are potentially reversible. for the diagnosis and treatment of potential
c. Primary hypogonadism may be due to: hypogonadism. He had 1 lower limb and both
testicles removed immediately following the
a. Genetic abnormalities injury. After several years of physical therapy
b. Developmental abnormalities and training, he has become an elite paralympic
c. Bilateral testicular trauma shot putter.
d. Bilateral testicular torsion Since he understands that a TUE is
e. Orchitis required, he asks for an evaluation and
treatment recommendations, specifically with
d. Secondary hypogonadism may be due to:
reference to testosterone therapy. He currently
a. Genetic abnormalities of pituitary and receives testosterone enanthate, 75 mg weekly
hypothalamus subcutaneously.
b. Pituitary or hypothalamic tumors On physical examination, he is a muscular
c. Other anatomical (structural), destructive, male with 1 leg missing and normal external
and infiltrative disorders of the pituitary or genitalia and pubic hair except for no palpable
hypothalamus. testicular tissue in a flat scrotum.
Previous laboratory data obtained before
3. Organic defects in androgen action or production
testosterone replacement confirm the diagnosis of
(differences in sex development [46,XY DSD])
primary hypogonadism:
a. 46,XY DSD due to androgen receptor defects
ranges from males with complete androgen Testosterone = 54 ng/dL (SI: 1.9 nmol/L)
insensitivity (CAIS, formerly known as LH = 50.0 mIU/mL (SI: 50.0 IU/L)
testicular feminization) who have a near- FSH = 91.0 mIUm/L (SI: 91.0 IU/L)
normal female phenotype to males with mild Twice-yearly laboratory data show the following
androgen insensitivity (MAIS) who have a average values:
near-normal male phenotype. Individuals
with partial androgen insensitivity syndrome Testosterone = 600 ng/dL (SI: 20.8 nmol/L)
LH = 8.0 mIU/mL (SI: 8.0 IU/L)
(PAIS) have an intermediate level of androgen
FSH = 23.0 mIU/mL (SI: 23.0 IU/L)
sensitivity and clinical phenotype.
b. 46,XY DSD due to 5α-reductase type 2 Should this athlete obtain a
deficiency (5ARD2) or 17β-hydroxysteroid TUE for testosterone?
dehydrogenase type 3 (17HSD3) in genetic This is a “yes” or “no” answer, and the rationale
males who have atypical genitalia at birth. involves the answers to the questions noted under
4.2a-d.
4. Constitutional delay of puberty is viewed as 4.2a. The athlete has met the criterion of a
a special category since TUE may be approved proper medical diagnosis of primary hypogonadism
for treatment with testosterone even if the based on the history of the injury, the surgical
etiology may be temporary and reversible. removal of the damaged testes, and low testosterone
levels with elevated gonadotropin levels.

212 ENDO 2025 • Endocrine Case Management

 4.2b. The issue of enhancement vs return to Should this athlete receive a TUE for
normal state of health can be met by longitudinal insulin given the diagnosis of T1D?
history relevant to adverse events and serial This is a “yes” or “no” answer, and the rationale
measurements of testosterone as part of the involves the answers to the questions noted under
athlete’s biological passport. 4.2a-d.
4.2c. Testosterone is the appropriate 4.2a. The athlete has met the criteria for the
therapy for this condition, and there is no other diagnosis of T1D as outlined by WADA. She has
non-banned drug since other anabolic steroid the appropriate history, severely elevated blood
hormones are not permitted for a TUE. glucose level, elevated hemoglobin A1c level, likely
4.2d. There is no evidence that prior anabolic mild ketoacidosis, and 2 of 5 positive antibodies
steroid therapy was responsible for this athlete’s (for T1D).
medical condition based on the history of injury 4.2b. The issue of enhancement vs return to
and the operative notes. state of normal health is easy for T1D because
excessive insulin therapy, which may clearly be
anabolic, causes hypoglycemia. Longitudinal
Case 2
monitoring, as is noted in multiple Endocrine
A 15-year-old elite tennis player presents to her Society guidelines, is key to the short-term and
pediatrician with a 1-month history of increasing long-term health of these athletes/patients,
fatigue and polyuria. She also has new-onset especially for children and adolescents with
nocturia and polydipsia. She and her coaches have decades of expected survival.
noted a drop-off in her usual energy level and 4.2c. There are no nonbanned primary
ability to train or play during matches. Since she drugs for T1D. Insulin in its many forms is
has a family history of type 1 diabetes (T1D), her the appropriate treatment, and the treatment
pediatrician measures capillary glucose, which regimen must account for rest, training, and
is documented to be 270 mg/dL (15.0 nmol/L). competition days to ensure optimal health without
She is referred to a pediatric endocrinologist hypoglycemia.
for precise diagnosis and therapy. The history 4.2d. This is usually not a problem with
obtained shows worsening symptoms over the last patients who have T1D.
week. She has lost 5 lb (2.3 kg), but she continues
to have regular menstrual cycles (menarche was at
age 12 years). Case 3
On physical examination, she is a slightly A 15-and-0/12-year-old national-level female
lethargic adolescent girl. Her height is at the 50th tennis player (and thus subject to anti-doping
percentile, and weight is at the 30th percentile. rules) with GH deficiency presents to discuss
Basal heart rate is 80 beats/min, and blood obtaining a TUE for testosterone. Menarche
pressure is 105/68 mm Hg. The rest of the findings was at age 13 and 0/12 years. She is otherwise
are within normal limits except for a mild decrease well except for seasonal allergies for which she
in skin turgor. takes an antihistamine. Her parents and only
sibling are at the 75th percentile for height, and
Laboratory test results: no other members of the extended family have
Glucose = 310 mg/dL (SI: 17.2 nmol/L) significant short stature. She is a good student and
β-Hydroxybutyrate = 2.1 nmol/L is considering international tennis competition.
Hemoglobin A1c = 7.1% (54 mmol/mol) She initially presented to a pediatric
Two of 5 antibodies related to T1D are positive. endocrinologist at age 9 and 6/12 years for short
stature and faltering growth, at which time
her height was –2.5 SD and weight was at the
10th percentile. She was prepubertal. Screening

ENDO 2025 • Neuroendocrinology and Pituitary 213

laboratory values were within normal limits. midparental height is biological evidence of GH
Her IGF-1 level was –1 SD for age. Bone age was deficiency.
interpreted to be 7 and 0/12 years. An arginine- 4.2b. The issue of enhancement vs return to
glucagon test for GH documented peaks at 4.5 and state of normal health involves absence of adverse
3.7 ng/mL (standard stimulation test for GH, since events, height velocity, IGF-1 levels within the
its normal levels are pulsatile [up and down], and upper normal range, and no rapid acceleration of
one must stimulate the pituitary gland to secrete bone age.
the already-made GH). 4.2c. Human GH is the appropriate therapy
GH deficiency was diagnosed, and treatment whether administered daily or with some of the
was initiated with recombinant human GH, newer longer-acting products. As noted above, its
30 mcg/kg daily. Catch-up growth was evident efficacy should be determined mainly by change in
after GH therapy was started. height velocity and IGF-1 concentration.
At today’s appointment, her height is at 4.2d. As is usual for children, most of the
the 60th percentile and weight is at the 50th diagnoses that fulfill the WADA requirements are
percentile. Examination findings are normal, with not the result of abuse of drugs or methods.
no dysmorphic features. Sexual development is
Tanner stage 5 at a chronologic age of 15 and 0/12
years, her bone age is mature, and her IGF-1 value
Key Learning Points
is +0.9 SD for age and sex.
• The TUE process is in place to permit athletes
with diagnosed conditions that require banned
Should this athlete obtain a TUE for GH?
drugs or methods to compete on a level
This is a yes or no answer, and the rationale
playing field with other athletes.
involves the answers to the questions noted under
4.2a-d. • The medical practitioner working with
4.2a. The athlete was short and slowly growing the athlete is required to present enough
at the time GH deficiency was diagnosed at 9 and information that a diagnosis can be made and
6/12 years. Her weight plotted slightly higher that there is a rationale for the prescription of
than her height at initial evaluation. The IGF-1 a banned substance.
value was –1 SD, and the response to provocative • The TUE committee (TUEC) reviewing the
stimuli was in the range of GH deficiency. In data does not examine the patient and thus it is
retrospect, she had marked catch-up growth when the sum of the history, physical examination,
she began GH therapy. GH deficiency in children and laboratory/imaging data that must be
is characterized by growth failure and (usually) consistent with the medical diagnosis and can
short stature. The diagnosis is based on the clinical convince a panel of experts in the field (TUEC)
history and auxology buttressed by biochemical that the diagnosis is correct.
data to rule out other diseases (eg, celiac disease or
• The TUEC does not practice medicine for
inflammatory bowel disease, kidney failure). The
the patient/athlete. While it may appear that
key data are those of the GH-IGF-1 axis, including
therapy is not optimal, the TUEC does not
GH responses to 2 provocative stimuli. Imaging
have all of the information that the physician
analysis includes bone age and brain MRI. More
has. The treatment needs to be reasonable (to
recently, genetic panels have become available
the TUEC) and meets the a-d requirements of
for some GH-related causes of short stature and,
section 4.2.
importantly, for the much more common causes
of short stature that do not involve the GH-IGF-1 • Embedded within the TUE process is therapy
axis, such as genetic disorders of the growth plate. monitoring, which can differ by condition and
Catch-up growth during GH therapy to nearly the age. For example, the long-term follow-up of
a patient with GH deficiency differs greatly

214 ENDO 2025 • Endocrine Case Management

 whether the patient is at adult height. In fact, • The transition from adolescent to adult
there are 3 separate WADA TUE physician care may require additional evaluation or
guidelines for human GH: children and change in therapy. For example, managing
adults with GH deficiency and a new one for GH deficiency when near-adult height is
children/adolescents with short stature, but attained or managing testosterone therapy for
who are not GH deficient. someone with transient hypogonadotropic
hypogonadism (usually constitutional delay of
growth and puberty).

References
1. World Anti-Doping Agency. The World Anti-Doping Code. https://www. 4. World Anti-Doping Agency. WADA Publishes Updated Therapeutic
wada-ama.org/en/what-we-do/world-anti-doping-code. Accessed November Use Exemption Physician Guidelines and Checklists Reflecting Changes
2024. Concerning Injectable Glucocorticoids. https://www.wada-ama.org/en/
2. World Anti-Doping Agency. International Standards. https://www.wada- news/wada-publishes-updated-therapeutic-use-exemption-physician-
ama.org/en/what-we-do/international-standards. Accessed November 2024. guidelines-and-checklists. Accessed November 2024.
3. World Anti-Doping Agency. Prohibited List. https://www.wada-ama.
org/en/resources/world-anti-doping-code-and-international-standards/
prohibited-list. Accessed November 2024.

ENDO 2025 • Neuroendocrinology and Pituitary 215

Perioperative Management
of Pituitary Tumors
Whitney W. Woodmansee, MD, MA. University of Florida Neuroendocrine/Pituitary
Program, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism,
University of Florida, Gainesville, FL; Email: [email protected]

Educational Objectives is needed for treatment planning and long-term

management. Evaluation involves assessing
After reviewing this chapter, learners should be
the extent of tumor burden and pituitary
able to:
hyperfunction or hypofunction and includes
• Recommend the preoperative evaluation that clinical exams, hormonal testing, visual testing,
should be performed before surgery for all and brain imaging. Many pituitary tumors are
patients with pituitary tumors. treated with surgical removal, and all require
preoperative, perioperative, and postoperative
• Manage immediate postoperative endocrine
management with long-term, ongoing follow-up
disorders.
for hormonal management and monitoring for
• Provide postoperative management tumor recurrence.
recommendations for ongoing care.

Practice Gaps
• Some clinicians see a low volume of patients
Significance of the
with pituitary tumors in their clinical practice
Clinical Problem and thus have minimal experience performing
Pituitary lesions are relatively common in the the necessary perioperative management.
general population with prevalence estimates • Many outpatient endocrine clinicians are
that 10% to 20% of the population have a visible unfamiliar with optimal management of
lesion on imaging.1 Although the differential inpatients’ acute postoperative endocrine
diagnosis of a sellar mass is broad, most lesions issues.
are benign pituitary adenomas (>90%).2 Patients
can present with a wide range of signs and • The importance of long-term follow-up for
symptoms depending on the size of the tumor assessment of endocrine function and tumor
and whether it is disrupting normal pituitary recurrence can be under-appreciated by
hormonal systems. Symptoms may be related to patients and clinicians.
mass effects, such as headaches, visual loss, or
cranial nerve abnormalities. Some individuals with Discussion
pituitary tumors are completely asymptomatic,
Pituitary lesions are the second most common
while others may present with symptoms related
intracranial tumor and represent approximately
to either hormonal excess or deficiency. The
18% of brain tumors reported in the recent
evaluation of patients with pituitary tumors
US Central Brain Tumor Registry analysis.3
can be quite complex, as many symptoms are
Although most sellar masses are benign pituitary
nonspecific. A multidisciplinary team approach

216 ENDO 2025 • Endocrine Case Management

adenomas, the differential diagnosis includes cystic Box 1. General Approach to Pituitary Disorders
lesions (Rathke cleft cyst, craniopharyngioma),
Approach to Pituitary Disorders
inflammatory lesions (hypophysitis, sarcoidosis, Evaluate:
amyloidosis), nonadenomatous neoplasms, • Mass effects
metastases, and vascular etiologies (apoplexy).1,2 • Pituitary hyperfunction
Pituitary lesions can present with mass effects • Baseline and “Suppression tests”
• Pituitary hypofunction
(headaches, visual loss, cranial nerve dysfunction) • Baseline and “Stimulation tests”
and pituitary hormonal hypersecretion or
deficiency (Box 1). Although medical therapy
is often considered first-line management for Box 2. Perioperative Management of Pituitary Adenomas
prolactinomas, surgery is generally considered
the treatment of choice for other endocrine- Preoperative Evaluation:
Assess for mass effect and pituitary
Postoperative Management:
• Patients typically evaluated 1, 6,
active pituitary adenomas (acromegaly, Cushing function:
• Brain imaging and visual assessment 12 weeks post operatively.

disease, and thyrotrope adenomas), as well as • Replace deficiencies as needed.

(thyroid & cortisol most important)
• MRI typically repeated at 8-12
weeks postoperatively to serve
clinically nonfunctioning adenomas, pituitary • Assess for pituitary hormonal
hyperfunction
as new baseline
• Annual follow-up recommended
apoplexy, Rathke cleft cysts, craniopharyngiomas, • Stress dosing glucocorticoids if
necessary for all or as dictated by clinic
status:
and other parasellar lesions causing mass effects. Early Perioperative Management: • Hormonal assessments
Assess for surgical complications:
The decision to proceed with neurosurgical • General: infection, DVT/PE
• Imaging - MRI
• Vision
• Neurologic: hemorrhage, visual, CSF leak
tumor resection can be quite complex and is best • Endocrine • Long-term assessment of
AVP deficiency hormonal status and tumor
considered in a multidisciplinary clinical setting.4 SIADH recurrence required

Once the decision has been made to proceed, Adrenal insufficiency

all patients require preoperative evaluation,

perioperative monitoring in an inpatient setting,
and long-term follow-up (Box 2 and Figure 1).

Figure 1. Perioperative Management Flowchart for Pituitary Adenomas

Preoperative Evaluation: Replace thyroid and adrenal hormones if insufficiency detected

Mass Effects
Hormonal Status:
Adrenal
Thyroid
Prolactin
Gonad
GH axis Transsphenoidal surgery
Posterior Pituitary Perioperative stress dose steroids if indicated
Glucocorticoids not universally required

Early Inpatient Monitoring Early Outpatient Assessment Long-Term Follow-Up

Assess: Week 1: Hormonal status evaluation annually or as

Potential complications General status, sodium dictated by clinical state. More frequent
Neurologic status Cortisol (if not on steroids) assessments required for patients with
Adrenal insufficiency hormonal deficiency or excess.
AVP deficiency
SIADH
Weeks 6-12: Assessment for tumor recurrence
General status and hormonal MRI / Vision assessment
assessment
Adrenal, thyroid, GH axis,
Prolactin as clinically indicated Monitoring for biochemical remission in
MRI – Baseline post op image hormonally active tumors

Adapted from Woodmansee WW et al. Endocr Pract, 2015; 21(7): 832-838. © Elsevier Inc.

ENDO 2025 • Neuroendocrinology and Pituitary 217

Preoperative Evaluation still recommend measurement of diluted prolactin
in the setting of large tumors with mild prolactin
A full preoperative evaluation should include a
elevation.8 Confirmation of prolactinoma is an
thorough medical history, physical examination,
important diagnostic step, as this significantly
laboratory testing, brain imaging, and neuro-
affects treatment decisions.
ophthalmologic assessment with formal visual
Although neurologic assessment is critical for
field testing if the lesion is close to the optic
preoperative planning, it is also vital to assess and
chiasm (Box 2 and Figure 1).5,6 Assessment should
manage hypopituitarism preoperatively to achieve
include evaluation for signs and symptoms
optimal outcomes. It is particularly important to
of pituitary hormonal deficiency or excess. It
identify deficiency of the adrenal and thyroid axes
is critical to determine preoperatively if the
before surgery and to initiate replacement therapy
lesion is a functional tumor (eg, prolactinoma,
preoperatively. Most patients with pituitary
acromegaly, Cushing disease, or the rarely
adenomas do not report signs or symptoms of
encountered thyrotropin-secreting tumor) or
arginine vasopressin (AVP) deficiency, but it is
if any degree of hypopituitarism is present.
important to screen for the condition by taking an
Baseline laboratory testing of pituitary function
appropriate history (ask about thirst, polydipsia,
should be performed in all patients. Typical
polyuria). Measurement of serum electrolytes and
preoperative baseline pituitary labs are listed in
urine specific gravity can also alert the clinician to
Box 3 and include assessment of adrenal, thyroid,
this condition. Patients with adrenal insufficiency,
GH, prolactin, and reproductive axes. If Cushing
hypothyroidism, and AVP deficiency should
disease or acromegaly is suspected, patients
all receive replacement therapy before surgery.
require more extensive confirmatory testing
Preoperative replacement of gonadal hormones
before consideration of surgical intervention.
and GH is not required and can be considered later
Prolactinomas are usually obvious based on
in the postoperative period.
prolactin levels, but sample dilution may be
All patients should also have their health
required in patients with large tumors and
optimized from a general medical standpoint
minimally elevated prolactin levels to rule out the
and should be evaluated for other potential
“hook effect” that can occur in some laboratory
comorbidities. Individuals with acromegaly
assays, leading to artificially low prolactin levels.7,8
and Cushing disease are particularly prone to
In a recent Pituitary Society Delphi survey,6 not all
associated conditions, such as hypertension,
participants supported this preoperative laboratory
cardiac dysfunction, hyperlipidemia, and
assessment, citing the fact that the “hook effect”
diabetes, and thus benefit from preoperative
is less commonly observed with the newer
medical management. It is recommended that
automated prolactin immunoassays. However, not
thromboprophylaxis be considered for patients
all clinicians have access to newer assays, so many
with Cushing disease.9,10 There is no current
consensus regarding preoperative disease-specific
Box 3. Standard Pituitary Laboratory Tests treatment of hyperfunctioning tumors to improve
surgical cure rates or outcomes, but optimization
Standard Pituitary Laboratory Tests
• Adrenal of medical therapy for associated comorbidities
• ACTH, Cortisol may reduce perioperative complications and
• Thyroid promote general postoperative recovery.6,11,12
• TSH, Free T4
• Reproductive
• Prolactin (with dilution if macroadenoma)
• FSH, LH, testosterone (men) or estradiol (women)
• GH Critical to assess prolactin prior proceeding to surgery
• IGF-I, GH Extra tests required if GH or ACTH excess or
deficiency is suspected.

218 ENDO 2025 • Endocrine Case Management

Perioperative Management The most important potential endocrine
complications in the immediate postoperative
All patients with preoperatively identified adrenal
period are fluid and electrolyte abnormalities and
insufficiency and hypothyroidism require hormone
acute adrenal insufficiency. AVP/antidiuretic
replacement therapy before surgery. Adrenal-
hormone insufficiency or excess (syndrome of
insufficient patients should receive stress-dosing
syndrome of inappropriate antidiuretic hormone
glucocorticoids on the day of surgery and taper
secretion [SIADH]) is not uncommon, and
postoperatively to presurgical home doses as clinical
patients require close monitoring of fluid intake,
status allows. For patients with normal preoperative
urine output, and volume status, along with serial
adrenal function, there is no clear consensus on
sodium and urine specific gravity or osmolality.17
administration of glucocorticoids perioperatively.
AVP deficiency most often develops within the
Perioperative steroids are a common component
first 48 hours after pituitary surgery and occurs
of pituitary surgical care with the goal to treat or
in up to 25% of patients.17 Fortunately, AVP
prevent potential iatrogenic adrenal insufficiency
deficiency is usually transient with only 2% to 5%
and they may reduce edema. However, many
of cases becoming permanent.18,19 It is thought to
centers follow a steroid-sparing protocol both
occur from manipulation, traction, or disruption
perioperatively and postoperatively to avoid
of the pituitary stalk during tumor removal
unnecessary glucocorticoid exposure. The literature
leading to interruption of AVP release. It is more
suggests that withholding perioperative steroids in
common in patients undergoing surgery for
patients with known intact hypothalamic-pituitary-
Rathke cleft cysts or craniopharyngiomas.19 AVP
adrenal function can be an acceptable approach with
deficiency can be managed with desmopressin
appropriate clinical monitoring.13,14
(DDAVP), and since this condition is usually
temporary, standing scheduled DDAVP doses
Postoperative Management are not recommended. Patients may also develop
Postoperative management occurs in 2 general isolated SIADH leading to symptomatic and
phases: the immediate inpatient postoperative delayed hyponatremia.20 It is recommended that
period and the longer-term outpatient follow-up sodium levels be checked every few days for 7 to
that includes the early outpatient evaluation and 10 days to avoid missing delayed hyponatremia
chronic disease management and monitoring for in the outpatient setting. Mild hyponatremia
recurrence. (ie, 130-135 mEq/L [130-135 mmol/L]) may be
managed by fluid restriction as an outpatient, but
Immediate Postoperative Management severe or symptomatic hyponatremia (sodium
Patients are generally monitored for immediate typically <125 mEq/L [<125 mmol/L]) requires
postoperative complications in an intensive care hospitalization for more aggressive management.
unit setting with close observation for potential Finally, the clinician should be aware of the
surgical or endocrine complications. Fortunately, critical need to monitor adrenal function and
serious complications following pituitary adenoma replace glucocorticoids if deficiency is detected.
surgery are relatively uncommon, particularly As previously noted, there is a lack of consensus
with an experienced surgical team.15,16 The most regarding glucocorticoid management in the
serious early surgical complications include sellar perioperative and postoperative timeframes,
hematoma, meningitis, CSF leakage, sinusitis, and ranging from glucocorticoid treatment at surgery
epistaxis. Patients should be monitored closely for with gradual tapering to steroid-sparing protocols
potential neurologic or ophthalmologic changes with careful observation. Some clinicians choose
and urgent imaging should be performed if to empirically treat all patients perioperatively
deterioration is detected. with glucocorticoids at stress doses and others
withhold glucocorticoids in patients with normal

ENDO 2025 • Neuroendocrinology and Pituitary 219

preoperative adrenal function. In the latter Box 4. Management of Hypopituitarism
scenario, it is recommended that serial morning
cortisol levels be monitored and glucocorticoids be Hypopituitarism
Management
initiated if the value is consistent with insufficiency.
• Treatment based on correcting hormonal deficiencies.
While measurement of basal morning cortisol is • Thyroid - levothyroxine (remember TSH cannot guide Rx, monitor free T4 levels)
only suggestive of and not diagnostic of adrenal • Adrenal – Hydrocortisone (preferred), prednisone. Use lowest dosage possible to
control symptoms, avoid over or under replacement

insufficiency, various cut points have been • Central AI patients rarely need mineralocorticoid replacement.
• Patients require education about stress dosing for illness

proposed, below which glucocorticoid replacement •

•
Gonad - Men often require testosterone, women may require HRT (OCP)
Growth hormone - Can treat with rhGH
should be considered. Proposed cut points for • Prolactin - no replacement available.
• Posterior pituitary – Desmopressin (DDAVP)
guidance in management are based on studies that • Patient educated to drink to thirst. DDAVP primarily controls polyuria if thirst mechanism is
intact. If thirst mechanism not functional, will need DDAVP and water intake recommendations

suggest a high likelihood of adrenal insufficiency

• Medical Alert Jewelry, especially if adrenal insufficiency
with a morning cortisol level less than 5 µg/dL
(<137.9 nmol/L) and low likelihood if the level is
above 10 to 15 µg/dL (275.9-413.8 nmol/L).21,22
Early Postoperative Management (1-12 weeks)
There is no best approach, and many factors
It is generally recommended that all patients
must be considered for an individual patient, but
undergo a repeat full evaluation of pituitary
minimizing unnecessary glucocorticoid exposure
function 6 to 12 weeks after surgery (Figure 1).
is generally desired. If glucocorticoids are initiated
As in the preoperative evaluation, all anterior
in the perioperative period based on morning
pituitary hormonal axes are generally reevaluated
cortisol levels dropping below a specified cut point,
to assess pituitary function integrity. Specifically,
then physiological replacement therapy should
thyroid, adrenal, gonadal, and GH axes should be
be maintained until further provocative testing
reassessed. Occasionally preoperative hormonal
(approximately 6 weeks postoperatively) can be
deficiencies recover after tumor resection.26
performed to assess long-term replacement needs.
Patients should be evaluated for hypothyroidism
Finally, in patients with functional tumors, it
6 to 8 weeks after surgery (timing based on the
is important to assess early biochemical remission
half-life of thyroid hormone). Adrenal function
following surgery.6 For patients with acromegaly,
should be evaluated in all patients. If a patient was
Cushing disease, and prolactinomas, morning
treated with glucocorticoids perioperatively, the
measurement of GH,23 cortisol,9,11 and prolactin,24
long-term need for replacement therapy should be
respectively, on postoperative days 1 and 2
reassessed. If the screening morning cortisol value
has been shown to be moderately predictive of
is not sufficient to rule out adrenal insufficiency
early and long-term remission. In patients with
(ie, >15 µg/dL [>413.8 nmol/L]), then dynamic
acromegaly, IGF-1 levels should be measured 6
endocrine testing for adrenal insufficiency should
weeks postoperatively, and, if elevated, should
be performed (usually cosyntropin-stimulation
be remeasured at 12 weeks before determining
test). Ongoing assessments are performed in
further interventions. After hospital discharge,
functional tumors to determine biochemical
patients are followed in the clinic and screened
remission persistence. GH and reproductive
for potential surgical complications. As follow-up
function are evaluated, and consideration for
progresses in the ensuing months, the most active
replacement therapy is performed at variable times
issues are usually related to pituitary function
after surgery. A postoperative MRI to serve as a
assessment and management (Box 2 and Figure 1)
new baseline image is typically obtained 8 to 12
with either hormonal replacement of deficiencies
weeks postoperatively to allow resolution of acute
(Box 4)25 or ongoing assessment for biochemical
postoperative changes.
remission in cases of hormonal excess.

220 ENDO 2025 • Endocrine Case Management

Long-Term Postoperative Management Clinical Case Vignettes
(Ongoing and Lifelong)
Periodic clinical assessment in the first year after Case 1
surgery is dictated by the clinical status of the A 69-year-old man with a history of hypertension,
patient and the need for titration of hormonal aortic stenosis, hyperlipidemia, nephrolithiasis,
replacement therapy or treatment of any persistent and prediabetes is referred for evaluation of a
pituitary hormonal hyperfunction (Box 4). large sellar mass. He initially presented with vision
Generally, all patients are followed at least on an loss and diplopia. He underwent cataract surgery
annual basis for evaluation of pituitary function. last year with suboptimal vision improvement.
Since most pituitary adenomas grow very slowly, He was seen by a retinal specialist who ordered
frequency of postoperative imaging must be MRI, revealing a large pituitary mass. He was then
tailored to the individual patient.27,28 Imaging referred for further evaluation.
timing is dictated by consideration of patient and He reports headaches in addition to vision
tumor characteristics, with larger, more aggressive loss and acknowledges cold intolerance, mild
tumors typically imaged at closer intervals constipation, and fatigue. He developed erectile
than smaller, more stable microadenomas. dysfunction 8 years ago, and a low testosterone
Pituitary imaging for patients with hormonally level was documented 2 years ago. He received
hyperfunctioning tumors depends on tumor testosterone replacement, but this was
type, biochemical parameters, and overall disease discontinued due to a rising PSA level. He has no
activity. The main point to impress upon patients symptoms of hypercortisolism or acromegaly. His
and clinicians is that all pituitary tumors, although medications are amlodipine and metformin.
usually benign, require long-term monitoring Physical examination is notable only for
for pituitary function and tumor progression or bilateral visual field deficits.
recurrence. Long-term follow-up is critical, and Pituitary MRI demonstrates a 1.6 × 2.4 ×
patients require an individualized multimodality 3.1-cm mass that compresses the optic chiasm
treatment program. and invades the right cavernous sinus (Figure 2).
Preoperative formal visual field testing confirms
bitemporal hemianopsia.

Figure 2.

T1 postcontrast MRI demonstrating a large lobulated sellar mass invading the right cavernous sinus and compressing the optic chiasm.
[Color—Print (Color Gallery page CG14) or web & ePub editions]

ENDO 2025 • Neuroendocrinology and Pituitary 221

Preoperative laboratory test results (sample drawn with serial dilution confirmed he did not have
while fasting at 8:00 AM): a prolactinoma.
GH can be measured preoperatively, but this
Comprehensive chemistry panel (including sodium,
kidney function, and liver function), normal is a pulsatile hormone and IGF-1 is the preferred
Complete blood cell count, normal hormone for assessing acromegaly preoperatively.
ACTH = 20.0 pg/mL (7.2-63.3 pg/mL) Oral glucose tolerance testing is not required in this
(SI: 4.4 pmol/L [1.6-13.9 pmol/L]) patient given that he already has a known diagnosis
Cortisol = 12.8 µg/dL (6.2-19.4 µg/dL)
of prediabetes. This test would also not be needed
(SI: 353.1 nmol/L [171.0-535.2 nmol/L])
TSH (third-generation assay) = 2.43 mIU/L to assess GH suppression following an oral glucose
(0.40-5.00 mIU/L) load given that his IGF-1 level was not elevated
Free T4 = 0.59 ng/dL (0.60-1.20 ng/dL) and clinically there was no concern for acromegaly.
(SI: 7.59 pmol/L [7.72-15.44 pmol/L]) Finally, α-subunit can be measured, but its clinical
Prolactin = 8.9 ng/mL (2.0-18.0 ng/mL)
utility does not add to this patient’s management.
(SI: 0.39 nmol/L [0.09-0.78 nmol/L])
FSH = 3.6 mIU/mL (1.0-19.0 mIU/mL) (SI: 3.8 IU/L
[1.0-19.0 IU/L]) Case 1, Continued
LH = 1.6 mIU/mL (1.2-8.6 mIU/mL) (SI: 1.6 IU/L
[1.2-8.6 IU/L]) Surgery is recommended for this patient due to
Testosterone = 82.0 ng/dL (230.0-800.0 ng/dL) large tumor size and his vision compromise. His
(SI: 2.8 nmol/L [8.0-27.8 nmol/L]) laboratory tests confirm central hypogonadism
IGF-1 = 81 ng/mL (40-225 ng/mL) (SI: 10.61 nmol/L
[5.24-29.48 nmol/L])
and hypothyroidism. He is preoperatively started
Hemoglobin A1c = 6.1% (<5.7%) (43 mmol/mol on levothyroxine replacement. His preoperative
[<39 mmol/mol]) cortisol level suggests that his adrenal axis is
functional, but he is started on preoperative
Surgical resection is recommended given the large empiric glucocorticoid replacement therapy to
tumor size and impact on his vision. prevent the possibility that treating his central
hypothyroidism will unmask adrenal insufficiency.
Which of the following laboratory
tests should be performed before Immediate postoperative inpatient
considering surgery in this patient? monitoring should include measurement
A. GH measurement of which of the following?
B. Oral glucose tolerance test A. Daily fasting morning cortisol
C. Diluted prolactin measurement B. Prolactin
D. α-Subunit measurement C. Testosterone
Answer: C) Diluted prolactin measurement D. Serial sodium and urine specific gravity
E. GH
Many endocrinologists recommend measuring
diluted prolactin (Answer C) in patients with Answer: D) Serial sodium and urine specific gravity
macroadenomas to rule out the “hook effect” that
Perioperative monitoring for sodium disorders,
can occur in some laboratory assays.6-8,27 The
including hypernatremia and hyponatremia, is
“hook effect” results when the prolactin in the
critical in the postoperative period. Patients can
patient’s serum is extremely high and in excess
develop AVP deficiency or SIADH in the early
to the assay antibodies used to measure levels in
postoperative period. Monitoring sodium levels
vitro, and it can lead to artificially lower prolactin
and urine specific gravity and/or urine osmolality
measurements. Accurate assessment of prolactin
and recording accurate oral fluid intake and urine
levels is imperative to help dictate treatment
output is recommended in the 24 to 72 hours
planning. This patient’s prolactin measured

222 ENDO 2025 • Endocrine Case Management

immediately after surgery. Exact duration of FSH = <0.7 mIU/mL (1.0-19.0 mIU/mL)
intense monitoring depends on the patient, but it (SI: <0.7 IU/L [1.0-19.0 IU/L])
LH = <0.2 mIU/mL (1.2-8.6 mIU/mL) (SI: <0.2 IU/L
should usually be done at least for the first 24 to
[1.2-8.6 IU/L])
48 hours and then periodically for the first 7 to 10 Testosterone = 85.0 ng/dL (230.0-800.0 ng/dL)
days after surgery. Most cases of AVP deficiency (SI: 2.9 nmol/L [8.0-27.8 nmol/L])
are transient and can be managed with on-demand IGF-1 = 55 ng/mL (41-279 ng/mL) (SI: 7.21 nmol/L
desmopressin. Standing desmopressin doses are [5.37-36.55 nmol/L])
Hemoglobin A1c = 6.8% (<5.7%) (51 mmol/mol
not recommended given the mostly transient
[<39 mmol/mol])
nature (>95%)19 of postoperative AVP deficiency.
Given this patient’s laboratory results
Case 2 and clinical presentation, what should be
the initial approach to assess recurrent
A 63-year-old man presents with concerns of
hypercortisolism after stopping prednisone?
progressive muscle weakness and fatigue. He was
successfully treated for Cushing disease at age A. Recheck cortisol and ACTH levels
35 years with transsphenoidal pituitary tumor B. Perform pituitary MRI
resection. He has been on hormonal replacement C. Perform 1 or more screening tests for
therapy for panhypopituitarism since surgery, hypercortisolism (eg, late-night salivary
including levothyroxine, testosterone, and cortisol, 1-mg overnight dexamethasone-
glucocorticoids (low-dosage prednisone). He notes suppression test, and/or 24-hour urinary free
having progressive weakness for the last several cortisol with creatinine)
years. Earlier evaluations revealed deficiencies of D. Perform inferior petrosal sinus sampling
vitamin B12 and vitamin D, but supplementation
E. Perform PET
did not significantly improve symptoms. He had 2
episodes of unprovoked deep venous thrombosis Answer: C) Perform 1 or more screening tests for
with pulmonary embolism and developed a left hypercortisolism (eg, late-night salivary cortisol,
biceps tear that required hospital admission. During 1-mg overnight dexamethasone-suppression test, and/
admission, his muscle weakness was exacerbated or 24-hour urinary free cortisol with creatinine)
by immobility, and he was subsequently referred to
endocrinology for consideration of steroid-induced One or more of the typical screening tests can be
myopathy. At today’s evaluation, he is able to performed to confirm hypercortisolism (Answer
ambulate with a walker but is unable to climb stairs C), and this should be the next step before other
or drive a car and requires assistance with activities laboratory tests or additional imaging. It would be
of daily living. His only other symptoms are fatigue reasonable to simultaneously perform pituitary MRI
and insomnia. since the patient has known history of confirmed
Cushing disease, but the best answer in this case
Laboratory test results after holding prednisone: is to evaluate for recurrent hypercortisolism to
ACTH = 128 pg/mL (6-50 pg/mL) (SI: 28.2 pmol/L determine the best treatment course.
[1.3-11.0 pmol/L])
Cortisol = 31.7 µg/dL (4.0-22.0 µg/dL)
(SI: 875.5 nmol/L [110.3-606.9 nmol/L])
Case 2, Continued
TSH (third-generation assay) = 0.01 mIU/L Prednisone is discontinued, and hypercortisolism
(0.40-5.00 mIU/L) is confirmed by a 1-mg overnight dexamethasone-
Free T4 = 1.5 ng/dL (0.80-1.80 ng/dL)
(SI: 19.3 pmol/L [10.30-23.17 pmol/L])
suppression test that demonstrates lack of
Prolactin = 4.9 ng/mL (2.0-18.0 ng/mL) appropriate cortisol suppression and elevated 24-
(SI: 0.21 nmol/L [0.09-0.78 nmol/L]) hour urinary free cortisol excretion. MRI confirms
recurrent tumor (1.2 × 0.8 × 1.3 cm) extending into

ENDO 2025 • Neuroendocrinology and Pituitary 223

the right cavernous sinus (Figure 3). The patient syndrome.11,29,30 Unfortunately, this patient
undergoes repeat transsphenoidal tumor resection, experienced a second recurrence 2 years later and
and pathology confirms recurrent corticotrope was treated with radiation and medical therapy.
adenoma. Postoperatively, he is in biochemical This case highlights that patients with Cushing
remission and there is no evidence of residual disease can have late recurrences and require long-
tumor on imaging. term monitoring for return of hypercortisolism,
even in cases of previous panhypopituitarism.
What is the most sensitive test to monitor
for recurrent hypercortisolism?
Key Learning Points
A. Fasting morning cortisol and ACTH
measurement • Pituitary adenomas are relatively common, and
B. 24-hour urinary free cortisol measurement diagnosis and treatment planning generally
C. 1-mg overnight dexamethasone-suppression require a multidisciplinary team approach.
test • All patients with pituitary tumors require
D. Late-night salivary cortisol level measurement full pituitary hormonal, visual, and brain
(2-3 samples) imaging evaluations to help determine the
best personalized treatment course. For many
Answer: D) Late-night salivary cortisol
patients, surgical removal is the treatment of
measurement (2-3 samples)
choice and, as such, they require care in the
All patients with pituitary tumors require long- preoperative, perioperative, and postoperative
term follow-up to monitor for recurrence or periods.
progression of residual disease. It is particularly • All patients with pituitary tumors require
important to follow patients with Cushing long-term follow-up for management and
syndrome, as recurrence is associated with monitoring of hormonal status and tumor
many comorbidities related to hypercortisolism. progression or recurrence.
Although there is heterogeneity in presentation,
it has been shown that late-night salivary cortisol
levels (Answer D) tend to become abnormal earlier
than other tests in cases of recurrent Cushing

Figure 3.

T1 postcontrast MRI demonstrating recurrent tumor invading the right cavernous sinus.
[Color—Print (Color Gallery page CG15) or web & ePub editions]

224 ENDO 2025 • Endocrine Case Management

References
1. Giraldi E, Allen JW, Ioachimescu AG. Pituitary incidentalomas: best practices 19. Burke WT, Cote DJ, Penn DL et al. Diabetes insipidus after endoscopic
and looking ahead. Endocr Pract. 2023;29(1):60-68. PMID: 36270609 transsphenoidal surgery. Neurosurgery. 2020;87(5):949-955. PMID: 32503055
2. Freda PU, Post KD. Differential diagnosis of sellar masses. Endocrinol Metab 20. Hensen J, Henig A, Fahlbusch R, Meyer M, Boehnert M, Buchfelder
Clin North Am. 1999;28(1):81-117. PMID: 10207686 M. Prevalence, predictors and patterns of postoperative polyuria and
3. Ostrom QT, Price M, Neff C, et al. CBTRUS statistical report: primary brain hyponatremia in the immediate course after transsphenoidal surgery for
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2015-2019. Neuro Oncol. 2022;24(Suppl 5):v1-v95. PMID: 36196752 10468901
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Neuroendocrine and Pituitary Scientific Committee. American Association 255. PMID: 20339931
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state clinical review: postoperative management following pituitary surgery. morning cortisol levels as predictors of short-term and long-term adrenal
Endocrine Practice, 2015;21(7):832-838. PMID: 26172128 function after endonasal transsphenoidal surgery for pituitary adenomas and
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Collaborative Group. Pituitary Society Delphi Survey: an international 23. Krieger MD, Couldwell WT, Weiss MH. Assessment of long-term remission
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transsphenoidal surgery for pituitary adenomas. Pituitary. 2022;25(1):64-73. 12691394
PMID: 34283370 24. Amar AP, Couldwell WT, Chen JC, Weiss MH. Predictive value of serum
7. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of prolactin levels measured immediately after transsphenoidal surgery. J
hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Neurosurg. 2002;97(2):307-314. PMID: 12186458
Endocrinol Metab. 2011;96(2):273-288. PMID: 21296991 25. Fleseriu M, Christ-Crain M, Langlois F, Gadelha M, Melmed S.
8. Mahmoud MM, Haj-Ahmad LM, Sweis NWG et al. Clinical features and Hypopituitarism. Lancet. 2024;403(10444):2632-2648. PMID: 38735295
hormonal profile of macroprolactinomas presenting with the hook effect: a 26. Laws ER, Iuliano SL, Cote DJ, Woodmansee WW, Hsu L, Cho CH. A
systematic review. Endocr Pract. 2025;31(2) 215-225. PMID: 39542401 benchmark for preservation of normal pituitary function after endoscopic
9. Varlamov EV, Vila G, Fleseriu M. Perioperative management of Cushing transsphenoidal surgery for pituitary macroadenomas. World Neurosurgery.
disease. J Endocr Soc. 2022;6(3):bvac010. PMID: 35178493 2016;91:371-375. PMID: 27113402
10. Isand K, Arima H, Bertherat J, et al. Delphi panel consensus on 27. Tritos NA, Miller KK. Diagnosis and management of pituitary adenomas: a
recommendations for thromboprophylaxis of venous thromboembolism review. JAMA. 2023;329(16):1386-1398. PMID: 37097352
in endogenous Cushing’s syndrome: a position statement. Eur J Endocrinol. 28. Constantinescua SM, Thierry Duprezb T, Bonnevillec JF, Maitera D. How
2025;192(3):R17-R27. PMID: 39973025 often should we perform magnetic resonance imaging (MRI) for the follow-
11. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and up of pituitary adenoma? Ann Endocrinol (Paris). 2024;85(4):300-307. PMID:
management of Cushing’s disease: a guideline update. Lancet Diabetes 38604408
Endocrinol. 202;9(12):847-875. PMID: 34687601 29. Amlashi FG, Swearingen B, Faje AT, et al. Accuracy of late-night salivary
12. Papaioannou C, Druce M. Preoperative medical treatments and surgical cortisol in evaluating postoperative remission and recurrence in Cushing’s
approaches for acromegaly: A systematic review. Clin Endocrinol (Oxf). disease. J Clin Endocrinol Metab. 2015;100(10):3770-3777. PMID: 26196950
2022;98(1):14-31. PMID: 35726150 30. Carroll TB, Javorsky BR, Findling JW. Postsurgical recurrent Cushing
13. Guo X, Zhang D, Pang H, et al; ZS-2608 Trial Team. Safety of withholding disease: clinical benefit of early intervention in patients with normal urinary
perioperative hydrocortisone for patients with pituitary adenomas with an free cortisol. Endocr Pract. 2016;22(10):1216-1223. PMID: 27409817
intact hypothalamus-pituitary-adrenal axis: a randomized clinical trial. JAMA
Netw Open. 2022;5(11):e2242221. PMID: 36383383
14. Batista S, Almeida JA, Koester S, et al. Safety of withholding perioperative
steroids for patients with pituitary resection with an intact hypothalamus-
Additional Reading
pituitary-adrenal axis: ameta-analysis of randomized clinical trials. Clin Neurol • Ezzat S, Asa SL, Couldwell WT, et al. The prevalence of pituitary adenomas:
Neurosurg. 2023;234:107974. PMID: 37797363 a systematic review. Cancer. 2004;101(3):613-619. PMID: 15274075
15. Barker FG 2nd, Klibanski A, Swearingen B. Transsphenoidal surgery for • Scangas GA, Laws ER Jr. Pituitary incidentalomas Pituitary. 2014;17(5):486-
pituitary tumors in the United States, 1996-2000: mortality, morbidity, 491. PMID: 240522242
and the effects of hospital and surgeon volume. J Clin Endocrinol Metab. • Melmed S. Pituitary-tumor endocrinopathies. N Engl J Med.
2003;88(10):4709-4719. PMID: 14557445 2020;382(10):937-950. PMID: 32130815
16. Shahlaie K, McLaughlin N, Kassam AB, Kelly DF. The role of outcomes data • Fleseriu M, Lee M, Pineyro MM, et al. Giant invasive pituitary prolactinoma
for assessing the expertise of a pituitary surgeon. Curr Opin Endocrinol Diabetes with falsely low serum prolactin: the significance of “hook effect.” J
Obes. 2010;17(4):369-376. PMID: 20453648 Neurooncol. 2006;79(1):41-43. PMID: 16598425
17. Loh JA, Verbalis JG. Diabetes insipidus as a complication after pituitary • Vilar L, Vilar CF, Lyra R et al. Pitfalls in the diagnostic evaluation of
surgery. Nat Clin Pract Endocrinol Metab. 2007;3(6):489-494. PMID: 17515893 hyperprolactinemia. Neuroendocrinology. 2019;109(1):7-19. PMID: 30889571
18. Nemergut EC, Zuo Z, Jane JA Jr, Laws ER Jr. Predictors of diabetes • Ben-Shlomo A, Melmed S. Clinical review 154: the role of pharmacotherapy
insipidus after transsphenoidal surgery: a review of 881 patients. J Neurosurg. in perioperative management of patients with acromegaly. J Clin Endocrinol
2005;103(3):448-454. PMID: 16235676 Metab. 2003;88(3):963-968. PMID: 12629068

ENDO 2025 • Neuroendocrinology and Pituitary 225

PEDIATRIC AND
ADOLESCENT
ENDOCRINOLOGY
Management of Patients With
Congenital Adrenal Hyperplasia
During Transition Care
Tânia Bachega, MD, PhD. School of Medicine, Sao Paulo University, Brazil; Email:
[email protected]

Educational Objectives simple virilizing form of CAH, some degree

of residual enzyme activity may be sufficient
After reviewing this chapter, learners should be
to maintain aldosterone production; however,
able to:
patients remain at risk of developing adrenal
• Highlight the importance of properly crises, particularly during stress conditions. The
organizing the transition care of patients with most severe cases of CAH are classified as the
congenital adrenal hyperplasia (CAH) in an salt-wasting form, depending on the presence of
individualized manner to ensure continuity of hyponatremic dehydration and/or shock in the
follow-up. neonatal period. The classic forms are the most
common cause of atypical genitalia in newborns
• Identify key points that should be evaluated
with a 46,XX karyotype and of primary adrenal
in the transition care process, including
insufficiency in childhood.1
glucocorticoid replacement therapy and
CAH is classified as a rare disease since it
comorbidities.
affects approximately 1:10,000 to 1:18,000 live
• Educate patients and their families about CAH, births.2 Therefore, in the absence of neonatal
emphasizing measures to prevent adrenal crisis. screening, most patients receive a delayed
diagnosis and have many comorbidities, especially
in developing countries,3 highlighting the need
for continuing education programs for health care
Significance of the professionals.
Clinical Problem The primary goal of CAH therapy is to
replace glucocorticoid and/or mineralocorticoid
CAH due to 21-hydroxylase deficiency is one of
to prevent adrenal insufficiency and to avoid
the most common autosomal recessive disorders
excessive secretion of adrenal androgens.
and is characterized by impaired cortisol secretion.
Hydrocortisone is the preferred glucocorticoid
Depending on the degree of 21-hydroxylase
therapy for pediatric patients, as the focus during
impairment, aldosterone secretion may also
childhood and adolescence is to optimize growth
be severely compromised, leading to adrenal
velocity and final height. In contrast, there is no
insufficiency and salt-wasting crisis in the first
consensus regarding the glucocorticoid regimen
weeks of life. In parallel, increased ACTH levels,
for adults, which varies significantly among
secondary to loss of negative feedback of cortisol,
centers.4 Individuals with the salt-wasting form
result in excessive androgen secretion. This leads
of CAH also require mineralocorticoid, typically
to prenatal external genital virilization in females
fludrocortisone, alongside appropriate sodium
and postnatal virilization in both sexes. In the
intake. Dosage adjustments are based on adrenal

228 ENDO 2025 • Endocrine Case Management

androgens and steroid precursor levels. However, • Deficiencies in communication and
significant variability in individual glucocorticoid coordination between pediatric and adult
and mineralocorticoid metabolism and peripheral teams may lead to loss of follow-up during the
sensitivity makes achieving optimal therapeutic transition of care.
balance particularly challenging. A fundamental • Inadequate long-term health monitoring
objective in managing CAH during transition care makes it difficult to systematically evaluate
is to restore hormonal balance, which is frequently treatment adherence and the adverse effects of
disrupted during puberty, by appropriately glucocorticoid therapy.
replacing glucocorticoids and mineralocorticoids,
thereby preventing adrenal crises while • Psychological support and quality of life
minimizing androgen excess.5 assessment are often overlooked during the
Adolescence presents significant challenges, transition to adult care.
including psychological issues and maintaining
treatment adherence. Additionally, this phase Discussion
involves changes in steroid hormone metabolism,
Collaboration between pediatric and adult
accompanied by the onset of gonadal sex steroid
endocrinology services is crucial to ensure
secretion. During transition care, support should
adequate transition care through the
be provided for monitoring and/or preventing
implementation of a structured transition
metabolic complications; however, it is also essential
program that incorporates joint consultations
to evaluate sexual function, provide guidance on
between pediatric and adult health care teams,
contraceptive methods, assess the functionality of
enabling a gradual shift of responsibility to the
the genitalia (in patients who have undergone or
patient and strengthening self-management skills.
not undergone feminizing genitoplasty), monitor
Young patients should acquire independence
menstrual patterns, and assess the risk of infertility
and autonomy. Therefore, the process should
(especially screening for the presence of testicular
start gradually, be individualized, and include a
adrenal rest tumors [TARTs]). A flowchart for the
multidisciplinary team.
multidisciplinary team can facilitate transition care
The transition period is an important time
by providing a clear, step-by-step visual guide to
to address the mental health of adolescents with
ensure a structured and efficient process. It helps
chronic diseases and/or trauma related to the
health care providers navigate critical steps, reducing
presence of genital atypia. In patients with CAH,
the risk of missed evaluations or delays. This process
anxiety, depression, and/or illicit drug use are not
should be carefully planned, beginning at the onset
uncommon,6 and therefore providing support to
of adolescence and extending into young adulthood
patients and caregivers is essential.
if necessary. The primary goals are to empower
young individuals through education, with open
discussions of their medical history, to ensure proper Clinical Case Vignettes
follow-up while maintaining treatment adherence, Case 1
and to facilitate access to multidisciplinary teams that
address their individual needs. A 19-year-old woman accompanied by her mother
presents with concerns of menstrual irregularity
and acne for the last year. Menarche occurred at
Practice Gaps age 12 years. She was diagnosed with salt-wasting
CAH as a neonate. Her current treatment regimen
• There is a lack of patient and family education is hydrocortisone, 25 mg daily (14 mg/m2 per
and training regarding the continuous need for day), divided into 3 doses, and fludrocortisone,
glucocorticoid replacement therapy and dosage 75 mcg daily.
adjustments during stress conditions.

ENDO 2025 • Pediatric and Adolescent Endocrinology 229

 Her height is 63.8 in (162 cm) (target height = dexamethasone has been associated with greater
65.4 in [166 cm]), and weight is 158.7 lb (72 kg) steroid suppression and increased weight gain.7
(BMI = 27.4 kg/m2). However, at our center, dexamethasone elixir is
available, allowing for dose titration with good
Laboratory test results: results.8 New glucocorticoid formulations, such
Serum 17-OHP = 10,502 ng/dL (follicular phase as modified-release hydrocortisone, appear to
<110 ng/dL) (SI: 318.2 nmol/L [<3.3 nmol/L) offer better hormonal control than conventional
Androstenedione = 358 ng/dL (25-220 ng/dL) glucocorticoid therapy, although they are not yet
(SI: 12.5 nmol/L [0.87-7.68 nmol/L])
widely available.6
Total testosterone = 90 ng/dL (<63 ng/dL)
(SI: 3.1 nmol/L [<2.2 nmol/L])
Plasma renin activity = 7.2 ng/mL per h Hormonal Control
(<5.8 ng/mL per h) Measurement of serum 17-OHP, androstenedione,
and testosterone levels are the most widely used
parameters to adjust glucocorticoid therapy.
Which of the following is the best next step
However, the optimal target levels of these
regarding her glucocorticoid regimen?
steroids to prevent adverse metabolic outcomes
A. Continue hydrocortisone regimen and remain unclear. According to the Endocrine
introduce low-dosage contraceptive pill Society guideline,2 androstenedione levels should
B. Continue hydrocortisone regimen and be referenced based on age- and sex-specific
evaluate for polycystic ovary syndrome reference ranges, while upper-normal to mildly
C. Switch hydrocortisone to long-acting elevated 17-OHP levels are considered acceptable.
corticosteroid to improve adherence Alternative target ranges, based on expert opinion,
D. Continue hydrocortisone regimen and increase suggest 3 to 36 nmol/L or 12 to 36 nmol/L for
fludrocortisone dosage 17-OHP, with the recommendation to normalize
androstenedione within the sex- and age-specific
E. Discuss with the patient her therapeutic
range. In our center, after the achievement of
preferences regarding corticosteroid regimen
final height, the primary goal is to normalize
and encourage lifestyle changes
androstenedione and testosterone within the
Answer: E) Discuss with the patient her sex- and age-specific reference ranges to minimize
therapeutic preferences regarding corticosteroid glucocorticoid exposure.8
regimen and encourage lifestyle changes Recent advancements have broadened the
understanding of androgen biosynthesis pathways,
Glucocorticoid Therapy and Its Objectives suggesting that 11-oxygenated androgens,
During transition care, once growth has originating from alternative androgen metabolites,
ceased, a key step is to review glucocorticoid may serve as more precise indicators of adequate
therapy with the patient, considering their hormonal regulation. However, they are not yet
expectations, adherence, and metabolic profile. widely incorporated into routine clinical practice.9
For adults, there is still no consensus on the The recommended hydrocortisone replacement
ideal glucocorticoid regimen. Some centers dosage typically ranges from 10 to 15 mg/m²
administer 2 glucocorticoid preparations, while per day. However, higher dosages, between 12
others provide the higher dosage either at night and 18 mg/m² per day, have also been used. It is
or in the morning.6 Hydrocortisone can be important to highlight that exceeding the dosage
given in 2 doses or as a single dose of a longer- of 15 to 20 mg/m² per day increases the risk of
acting glucocorticoid to improve adherence. adverse effects.10
Prednisolone is often preferred for young adults
due to its less frequent dosing requirements, while

230 ENDO 2025 • Endocrine Case Management

Case 2 Although glucocorticoid therapy has
significantly improved survival rates in people
A 17-year-old girl presents to the emergency
with CAH, the risk of acute adrenal insufficiency
department with a history of persistent vomiting,
remains a major concern, and life expectancy
lethargy, and poor feeding. She has the simple
remains lower than that of the general population.
virilizing form of CAH and is regularly taking
A Swedish nationwide CAH study identified
hydrocortisone, 20 mg daily, divided into 3 doses.
adrenal crises as the primary cause of death,11 and
She has been experiencing a cough and fever of
gastrointestinal infections are a frequent trigger.12
101.3°F (38.5°C) for the past 3 days, during which
Data from the I-CAH multicenter registry
she doubled her daily hydrocortisone dose, but
disclosed that the frequency of hospital admissions
without improvement in her lethargy. Earlier
was higher in individuals with the salt-wasting
this morning, her vomiting worsened, and she
form, and sick-day episodes were more prevalent
went to the emergency department where she
among toddlers and late adolescents receiving
was diagnosed with pneumonia. She showed
higher glucocorticoid dosages.12 Nonadherence
her emergency letter to the health care team
to treatment during adolescence may be a key
and received intravenous saline and was then
factor contributing to the increased occurrence
discharged. She now returns for further evaluation
of adverse events. Although patient-initiated
due to severe weakness and worsening vomiting.
stress dosing is a crucial intervention to prevent
Her height is 65.0 in (165 cm), and weight
adrenal crises, these events continue to occur
is 130.1 lb (59 kg). Her blood pressure is
at an elevated rate. Preventing adrenal crises
80/50 mm Hg, and pulse rate is 128 beats/min.
remains a top priority in CAH management.
Which of the following is the Discussions about sick-day management strategies
best course of action? should be prioritized at every clinical visit with
young patients and their families, emphasizing
A. Measure sodium and potassium levels to guide
the need to use bracelets or identification cards
therapy
for emergencies.13 Efforts should also be made
B. Triple the oral hydrocortisone dosage to promote continuing education for health
C. Evaluate for sepsis care professionals involved in emergency care
D. Administer intravenous saline and about the immediate use of glucocorticoids
hydrocortisone (50-100 mg/m2) in patients with adrenal insufficiency during
E. Exercise caution when administering stressful situations, even in infectious conditions.
corticosteroids due to the pulmonary infection Educational booklets and easy access to emergency
cards on medical and patient society websites may
Answer: D) Administer intravenous saline be useful (www.sbteim.org.br).
and hydrocortisone (50-100 mg/m2)
Outcomes for Assessment
Adrenal Crisis Body Mass Index
Transition care is important for educating patients Increased BMI and unfavorable body composition
on the prevention of adrenal crises and how to have been frequently reported in patients with
adjust glucocorticoid therapy during sick day CAH undergoing different glucocorticoid
episodes. During childhood, this knowledge is regimens4; however, it is not possible to conclude
usually under the caregivers’ domain, making it whether synthetic glucocorticoids contribute to a
essential to enhance the patient’s understanding higher frequency of obesity. In our cohort, which
and autonomy regarding their condition as they included 60 adults with CAH who were exclusively
transition to adulthood. treated with a low dosage of dexamethasone
after reaching their final height, the prevalence

ENDO 2025 • Pediatric and Adolescent Endocrinology 231

of obesity and overweight was 27% and 35%, levels, but also on clinical parameters, such as
respectively, which is higher than the prevalence blood pressure and serum electrolytes.17
in the general population. However, the mean
BMI standard deviation did not differ significantly Metabolic Profile and Cardiovascular Risk
between the time of dexamethasone initiation In a systematic review of 437 patients with CAH,
and the last evaluation, over an average follow-up there were no significant differences in fasting
period of 10 years.8 Although most studies report blood glucose and insulin levels compared with
a high prevalence of obesity in patients with CAH, values in control participants, but a higher
it is likely that weight gain begins in childhood as homeostatic model assessment of insulin resistance
a compensatory mechanism to mitigate androgen was observed in patients with CAH.18 Findings
excess and control the bone age advancement.14 on the lipid profile remain controversial; in
Body fat distribution also appears to be altered this systematic review, total cholesterol, LDL
in patients with CAH, with increased visceral and cholesterol, HDL cholesterol, and triglyceride
subcutaneous adipose tissue on CT reported in levels were comparable between patients and
a cohort of 28 adolescents and young adults.15 In control participants. However, higher carotid
addition to glucocorticoid type and dosage, genetic intima thickness was observed in patients with
factors modulating glucocorticoid metabolism CAH. A study focusing on young adults with
and peripheral sensitivity may contribute to the CAH19 also identified similar lipid profiles in
development of an adverse metabolic profile. comparison with control participants.
Measures to combat obesity should be routinely The introduction of glucocorticoid
assessed during follow-up, and healthy lifestyle replacement has improved the lifespan of people
habits should be encouraged. with CAH. As individuals with CAH are now
reaching adulthood, a higher frequency of
Blood Pressure cardiovascular risk factors has been observed
A normal resting and 24-hour blood pressure compared with the frequency in the reference
profile is generally observed in patients with population. It remains to be determined whether
CAH; however, a slight increase in diurnal and/or individuals with CAH have an increased frequency
nocturnal blood pressure has also been reported.4 of cardiovascular disease. Currently, it is difficult
An increased prevalence of hypertension was to reach a conclusion, as the studies comprise
observed in a cohort of 545 Swedish patients with heterogeneous young cohorts who are treated
CAH,16 with a higher frequency in women. As with different glucocorticoid regimens and have
expected, the high prevalence of obesity among different goals of hormonal control. However, in
people with CAH negatively affects blood pressure many studies, there is an evident effect of obesity
values. Variability in blood pressure outcomes on the development of cardiovascular risk factors.
across studies is likely influenced not only by Lifestyle modifications and attempts to adjust
cumulative glucocorticoid and mineralocorticoid glucocorticoid and mineralocorticoid dosages seem
dosages, but also by different hormonal control to be of great importance.4
strategies. Some centers aim to maintain renin in
the upper half of the reference range, while others Fertility in Women
prioritize normalizing blood pressure and serum During transition care, aspects related to sexual
sodium levels. Considering the great variability function and fertility become central. Increased
of renin levels according to posture, timing of adrenal androgen secretion contributes to
the last mineralocorticoid dose, adherence, and menstrual irregularities, often leading to a
concomitant medications, data from the I-CAH polycystic ovary-like phenotype. It is essential to
registry suggest that mineralocorticoid titration assess menstrual patterns in adolescents and young
should not be primarily based on serum renin adults with CAH during each clinical visit.

232 ENDO 2025 • Endocrine Case Management

 In adolescent patients who have previously adulthood. Additionally, both patient and parental
undergone feminizing genitoplasty, transition satisfaction with the surgical outcomes was high,
care should include an assessment of whether with the majority preferring the procedure to be
the urogenital sinus opening and/or vagina performed during childhood.22 These results are
are adequate for sexual activity. In cases of consistent with previous studies.23 It is also worth
stenosis, acrylic mold dilations should only be highlighting the lack of long-term studies on
recommended when the patient expresses a desire the psychological aspects in adulthood of 46,XX
to initiate sexual activity, and surgical dilation is individuals who grew up with atypical genitalia.
reserved for more severe cases.20 The outcomes of delayed surgical intervention are
The routine practice of performing genital also unknown.
surgery within the first year of life for infants
with CAH and atypical genitalia has become Case 3
increasingly debated. Concerns regarding genital
sensitivity, potential long-term complications, and A 25-year-old man is referred due to primary
the frequency of reoperation in adulthood have infertility. At 4 years of age, he was diagnosed with
prompted some researchers to reassess the timing the simple virilizing form of CAH. Treatment
of surgical intervention. The guideline from the with hydrocortisone was started. The patient
Endocrine Society, along with a European expert developed normally until 19 years of age, when he
consensus, emphasizes that parents should be abandoned his treatment and was lost to follow-up
informed about surgical options, including the consultations. He and his wife have been unable
possibility of postponing surgery and allowing to achieve pregnancy after 2 years of trying. His
observation until the child reaches an age where height is 66 in (168 cm), and weight is 172 lb
they can participate in the decision-making (78 kg) (BMI = 27.8 kg/m²). He has small, soft
process.2,21 Extensive discussions regarding risks testicles compatible with testicular atrophy. Semen
and benefits, shared decision-making, review of analysis reveals azoospermia.
potential complications, and fully informed consent Laboratory test results are suggestive of testicular
need to occur before surgery. If surgery is delayed, failure:
the risk of hematocolpos should be assessed.
In recent decades, surgical techniques Very increased levels of serum ACTH, 17-OHP, LH
have been refined to reduce clitoral size while and FSH
Total testosterone = 320 ng/dL (240-816 ng/dL)
preserving sensitivity and enhancing both (SI: 11.1 nmol/L [8.3-28.3 nmol/L])
the cosmetic and functional aspects of female
genitalia.22 However, it is essential to emphasize Which of the following describes the
that these procedures should be performed only best initial approach for this patient?
in centers with experienced pediatric surgeons/ A. Perform bilateral testicular biopsy to evaluate
urologists, pediatric endocrinologists, pediatric for obstructive azoospermia
anesthesiologists, behavioral/mental health
professionals, and social work services.2 Despite B. Reintroduce glucocorticoid treatment and
these advancements, research on long-term request scrotal ultrasonography to screen for
patient satisfaction and functional outcomes TARTs
remains limited. In a cohort of 36 female C. Start testosterone replacement therapy
participants with CAH who underwent feminizing D. Start mineralocorticoid therapy
genitoplasty under the care of an interdisciplinary E. Perform analysis of sperm DNA integrity
team, the findings indicated that the procedure
did not negatively affect overall genital sensitivity Answer: B) Reintroduce glucocorticoid treatment and
compared with sensitivity in control groups in request scrotal ultrasonography to screen for TARTs

ENDO 2025 • Pediatric and Adolescent Endocrinology 233

Fertility in Men 3, enabled a significant reduction in glucocorticoid
Gonadal dysfunction is frequently identified dosages.25 Atumelnant is a potent, once-daily,
in male patients with CAH, either due to poor orally bioavailable, nonpeptide, first-in-class
hormonal control, leading to hypogonadotropic competitive and selective melanocortin type 2
hypogonadism, or the presence of TARTs.2,5 receptor antagonist. Results from a phase 2, open-
Excess ACTH is thought to be a key driver in label, dose-finding study (40 mg, 80 mg, or 120
the development of TARTs. Neonatal trophic mg) demonstrated rapid, substantial, and sustained
stimulation of testicular cells may even increase the reductions in serum androstendione and 17-OHP
pool of ACTH-sensitive cells, which could grow levels. Androstenedione levels were reduced from
into significantly sized TARTs during periods of baseline by 60%, 70%, and 80%, respectively.25 No
poor hormonal control. A delayed CAH diagnosis serious adverse events were reported with either
(more than 1 year after birth) has been associated crinecerfont or atumelnant.
with a higher risk of TART development. The
tumors’ mass effects may lead to testicular damage,
resulting in primary hypogonadism, impaired
Key Learning Points
fecundity, and infertility.24 Effective transition care should encompass
There is limited published guidance on the thorough education on CAH with the aims of:
prevention of TARTs. Regular screening should
• Empowering and educating young people to
begin in adolescence or as early as age 8 years,
take responsibility for their health condition.
with annual testicular ultrasonography, as the risk
of TARTs is higher in patients with poor disease • Emphasizing the importance of adhering to
control or a late diagnosis.5 Close surveillance glucocorticoid and mineralocorticoid therapies
of gonadal function, along with optimization to prevent adverse outcomes.
of hormonal control, is a key goal in managing • Providing patients with detailed guidance
classic forms of CAH in boys during adolescence. on stress dosing during illness or surgical
However, suppressing ACTH stimulation through procedures to reduce the risk of complications.
glucocorticoid therapy often leads to significant • Psychological support should be offered, as
weight gain and/or cushingoid features. Since adolescents with CAH often face issues with
infertility is a major risk for patients with TARTs, body image, concerns about genital appearance
appropriate counseling should be provided at a and/or functionality, and difficulties with
young age to improve treatment adherence, which social relationships.
may reduce the risk of further tumor growth.
When appropriate, semen analysis and storage • Regular assessment of metabolic indicators
should also be considered.6 is essential to fine-tune treatment plans and
swiftly detect emerging health issues.
New Therapies • Support and counseling should be provided for
Patients with CAH typically receive long- both patients and caregivers to assist with the
term treatment with supraphysiological doses process.
of glucocorticoid to reduce adrenal androgen • Evidence from studies of patients with
secretion, raising concerns about long-term other chronic medical conditions confirms
risks. Recently, new therapies have entered the that openness in the sharing of information
experimental phase, aiming to reduce stimulation is associated with enhanced psychosocial
of androgen production. Crinecerfont, an oral adaptation.26 Engaging patients/families as
corticotropin-releasing factor type 1 receptor effective partners in care management and
antagonist, lowered androstenedione levels in shared decision-making is vital to ensuring
patients with CAH in phase 2 trials and, in phase high-quality, appropriate care.

234 ENDO 2025 • Endocrine Case Management

Conflict of Interest pharmacokinetics of CRN04894 (Atumelnant) in
individuals with CAH.
Principal investigator for the phase 2 study
that evaluated the safety, efficacy, and

References
1. White PC, Bachega TA. Congenital adrenal hyperplasia due to 21 hydroxylase hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab.
deficiency: from birth to adulthood. Semin Reprod Med. 2012;30(5):400-409. 2015;100(8):E1153-E1159. PMID: 26062016
PMID: 23044877 16. Falhammar H, Frise´n L, Hirschberg AL, et al. Increased cardiovascular
2. Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due and metabolic morbidity in patients with 21-hydroxylase deficiency: a
to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice Swedish population-based national cohort study. J Clin Endocrinol Metab.
guideline. J Clin Endocrinol Metab. 2018;103(11):4043-4088. PMID: 30272171 2015;100(9):3520-3528. PMID: 26126207
3. Miranda MC, Haddad LBP, Madureira G, Mendonca BB, Bachega TASS. 17. Pofi R, Prete A, Thornton-Jones V, et al. Plasma renin measurements are
Adverse outcomes and economic burden of congenital adrenal hyperplasia late unrelated to mineralocorticoid replacement dose in patients with primary
diagnosis in the newborn screening absence. J Endocr Soc. 2019;4(2):bvz013. adrenal insufficiency. J Clin Endocrinol Metab. 2020;105(1):dgz055. PMID:
PMID: 32047870 26126207
4. Gomes LG, Bachega TASS, Mendonca BB. Classic congenital adrenal 18. Tamhane S, Rodriguez-Gutierrez R, Iqbal AM, et al. Cardiovascular and
hyperplasia and its impact on reproduction. Fertil Steril. 2019;111(1):7-12. metabolic outcomes in congenital adrenal hyperplasia: a systematic review
PMID: 30611420 and meta-analysis. J Clin Endocrinol Metab. 2018;103(11):4097-4103. PMID:
5. Balagamage C, Arshad A, Elhassan YS, et al. Management aspects of congenital 30272185
adrenal hyperplasia during adolescence and transition to adult care. Clin 19. Vijayan R, Bhavani N, Pavithran PV, et al. Metabolic profile, cardiovascular
Endocrinol (Oxf). 2024;101(4):332-345. PMID: 37964596 risk factors and health-related quality of life in children, adolescents and
6. Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-hydroxylase young adults with congenital adrenal hyperplasia. J Pediatr Endocrinol Metab.
deficiency. N Engl J Med. 2020;383(13):1248-1261. PMID: 32966723 2019;32(8):871-877. PMID: 31271560
7. Whittle E, Falhammar H. Glucocorticoid regimens in the treatment of 20. Sircili MHP, de Mendonca BB, Denes FT, Madureira G, Bachega TASS,
congenital adrenal hyperplasia: a systematic review and meta-analysis. J Endocr d Queiroz e Silva FA. Anatomical and functional outcomes of feminizing
Soc. 2019;3(6):1227-1245. genitoplasty for ambiguous genitalia in patients with virilizing congenital
8. Seraphim CE, Frassei JS, Pessoa BS, et al. Impact of long-term dexamethasone adrenal hyperplasia. Clinics (Sao Paulo). 2006;61(3):209-214. PMID: 16832553
therapy on the metabolic profile of patients with 21-hydroxylase deficiency. J 21. Cools M, Nordenström A, Robeva R, et al. Caring for individuals with
Endocr Soc. 2019;3(8):1574-1582. PMID: 31384718 a difference of sex development (DSD): a consensus statement. Nat Rev
9. Turcu AF, Mallappa A, Nella AA, et al. 24-Hour profiles of 11-oxygenated Endocrinol. 2018;14(7):415-429. PMID: 29769693
C19 steroids and Δ5-steroid sulfates during oral and continuous subcutaneous 22. Bag MJ, Inacio M, Bachega TASS, et al. Long-term outcomes of feminizing
glucocorticoids in 21-hydroxylase deficiency. Front Endocrinol (Lausanne). genitoplasty in DSD: genital morphology, sensitivity, sexual function, and
2021;12:751191. PMID: 34867794 satisfaction. J Endocr Soc. 2025;9(3):bvaf014. PMID: 39975957
10. Bacila I, Freeman N, Daniel E, et al. International practice of corticosteroid 23. Shalaby M, Chandran H, Elford S, Kirk J, McCarthy L. Recommendations
replacement therapy in congenital adrenal hyperplasia: data from the I-CAH of patients and families of girls with 46XX congenital adrenal hyperplasia
registry. Eur J Endocrinol. 2021;184(4):553-563. PMID: 33460392 in the United Kingdom regarding the timing of surgery. Pediatr Surg Int.
11. Falhammar H, Frisén L, Norrby C, et al. Increased mortality in patients 2021;37(1):137-143. PMID: 33230638
with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin 24. Schröder MAM, Neacşu M, Adriaansen BPH, et al. Hormonal control during
Endocrinol Metab. 2014;99(12):E2715-E2721. PMID: 25279502 infancy and testicular adrenal rest tumor development in males with congenital
12. Ali SR, Bryce J, Haghpanahan H, et al. Real-world estimates of adrenal adrenal hyperplasia: a retrospective multicenter cohort study. Eur J Endocrinol.
insufficiency-related adverse events in children with congenital adrenal 2023;189(4):460-468. PMID: 37837609
hyperplasia. J Clin Endocrinol Metab. 2021;106(1):e192-e203. PMID: 32995889 25. Auchus RJ, Hamidi O, Pivonello R, et al; CAHtalyst Adult Trial Investigators.
13. Lousada LM, Mendonca BB, Bachega TASS. Adrenal crisis and mortality rate Phase 3 trial of crinecerfont in adult congenital adrenal hyperplasia. N Engl J
in adrenal insufficiency and congenital adrenal hyperplasia. Arch Endocrinol Med. 2024;391(6):504-514. PMID: 38828955
Metab. 2021;65(4):488-494. PMID: 34283908 26. Richard A, Trainer P, Lucas KJ, et al; TouCAHn study investigators. Interim
14. Sarafoglou K, Forlenza GP, Yaw Addo O, et al. Obesity in children with Analysis From a 12-Week, Phase 2, Open-Label, Sequential Dose Cohort Study
congenital adrenal hyperplasia in the Minnesota cohort: importance of to Evaluate the Safety, Efficacy, and Pharmacokinetics of CRN04894 Treatment
adjusting body mass index for height-age. Clin Endocrinol (Oxf). 2017;86(5):708- in Participants with Classical Congenital Adrenal Hyperplasia (TouCAHn).
716. PMID: 28199739 Poster presentation at Endo 2024, June 1-4, Boston, MA.
15. Kim MS, Ryabets-Lienhard A, Dao-Tran A, et al. Increased abdominal
adiposity in adolescents and young adults with classical congenital adrenal

ENDO 2025 • Pediatric and Adolescent Endocrinology 235

How to Approach Children
With Short Stature Not
Responding to Growth
Hormone Treatment
Stefano Cianfarani, MD. Department of Systems Medicine, University of Rome ‘Tor
Vergata,’ Endocrinology and Diabetes Unit, ‘Bambino Gesù’ Children’s Hospital, IRCCS,
Rome, Italy; and Department of Women’s and Children’s Health, Karolinska Institute,
Stockholm, Sweden; Email: [email protected]

Educational Objectives Poor treatment response should prompt

the physician to discontinue GH treatment and
After reviewing this chapter, learners should be
determine the cause of the suboptimal response,
able to:
which may require challenging the initial
• Define a good response to GH treatment and diagnosis. In many cases, further investigations
describe the predictive variables. (mainly genetic) are needed to clarify the
underlying condition leading to growth failure
• Identify causes of poor response to GH
and nonresponse to GH treatment. Another pitfall
treatment.
in the evaluation of the response to GH therapy
• Select appropriate further evaluation and and, consequently, in the decision whether to
therapeutic strategies when patients do not continue treatment, is the value given to the
respond to GH treatment. first-year growth response. During the first year
of GH therapy, most short children, independent
of the diagnosis, show a satisfactory response that
is not sustained over time, resulting in an adult
Significance of the height far below their target (midparental) height.
Clinical Problem Finally, once a short child has been identified as a
nonresponder to GH, the choice of other growth-
GH therapy has been approved worldwide for
promoting medications to be used alone or in
treatment of children with different conditions
combination with GH is difficult due to the lack of
associated with short stature. However, the
robust evidence and specific guidelines.
individual response to GH treatment is variable,
especially in non–GH-deficient short children.
A high rate of poor or unsatisfactory response to Practice Gaps
GH therapy is commonly observed in the clinical
setting and, despite that, many physicians continue • GH therapy is often based on results of
GH treatment until adult height is achieved. Some laboratory tests or clinical characterization
children diagnosed as having GH deficiency may without a clear understanding of the
not respond to GH therapy, often due to incorrect underlying molecular mechanism.
diagnosis or poor adherence to therapy.

236 ENDO 2025 • Endocrine Case Management

• The definition of a good response to GH treatment and variably included in the equations
treatment is still arbitrary. of the different models are chronological age,
• The prediction of a good long-term response birth weight, height, height SDS minus target
to GH is challenging because the available height SDS, GH peak to provocative tests,
prediction models are based on the short-term and GH dosage. Prediction models derived
(first-year) response. from the large KIGS database (Kabi Pharmacia
International Growth Study, Pharmacia & Upjohn,
• There are no guidelines for genetic testing Inc., International Growth Database) explain
in short children who do not respond to GH approximately 60% of the variability of response
therapy. to GH therapy in patients with GH deficiency and
• There are no guidelines for alternative 40% in individuals with idiopathic short stature.4
treatments in short children who do not The addition of genomic markers may increase
respond to GH therapy. the accuracy of prediction models. For example, an
exon 3 deletion polymorphism in the GH receptor,
as well as a specific (-202 A) polymorphism in the
Discussion
IGFBP3 gene promoter, is associated with a better
Indications for GH Therapy therapeutic response.5,6 Recently, pretreatment
and Prediction of Response blood transcriptomics by next-generation RNA
GH therapy is licensed by the European Medicines sequencing has been proposed as a predictive
Agency (EMA) and the US FDA for treatment of tool for first-year growth and IGF-1 response
GH deficiency, Turner syndrome, short stature to GH therapy.7 The assumption of most
in children born small-for-gestational age and predictive models is that first-year response is
children who have Prader-Willi syndrome, predictive of long-term response to GH therapy.
SHOX deficiency, chronic kidney insufficiency, However, it is a common clinical experience to
or Noonan syndrome. In the United States, the observe a satisfactory response during the first
FDA has additionally approved GH therapy for year of treatment, which does not persist in the
idiopathic short stature. Children with severe following years.
GH deficiency are highly responsive to GH
replacement therapy, whereas children with the Definition of Good Response
other conditions for which GH therapy is licensed to GH Therapy
show a variable response.1-3 Individual variability
A univocal definition of responsiveness to GH is
in response to GH treatment may be secondary to
still lacking. A good response in the first year of
an incorrect diagnosis, underlying genetic cause
GH treatment may be defined by a height gain
of short stature making GH therapy ineffective,
of 0.5 or more SDS and/or an increase in height
poor adherence, suboptimal treatment dosage,
velocity of 3 cm or more per year and/or a height
or late initiation of treatment. Furthermore,
velocity of 1 or more SDS.8,9
individual genetic variants may affect the response
to GH therapy by influencing drug absorption,
distribution, metabolism, and excretion. Common Causes of Poor
The need to identify responders to therapy Response to GH Therapy
has led to the development of many prediction The diagnosis of childhood-onset short stature
models based on the response during the first is often challenging and should be based on
year of treatment in children with GH deficiency, a comprehensive clinical, anthropometric,
Turner syndrome, small-for-gestational-age, and biochemical, endocrine, radiological, and, in
idiopathic short stature. The main predictive selected cases, genetic approach. The lack of such a
factors of response to GH in the first year of comprehensive approach may lead to misdiagnosis

ENDO 2025 • Pediatric and Adolescent Endocrinology 237

and, consequently, ineffective therapies. A Table. Current Indications for GH Therapy
diagnosis of GH deficiency based only on the
Current
response to provocative tests may be misleading indications for Year of
due to the high false-positive rate of such tests. GH therapy approval Dosage

Therefore, a poor response to GH therapy GH deficiency 1985 Daily

should prompt the clinician to reconsider the • 23-43 mcg/kg per day (US)
initial diagnosis.10 The false-positive rate of GH- • 25-35 mcg/kg per day (EU)
provocative tests is even higher in children with • 0.16-0.24 mg/kg per week
delayed puberty. Sex steroids increase pituitary (EU and US)

GH release during puberty. Estrogens are the Weekly

effectors of such action on the pituitary gland in • Somatrogon: 0.66 mg/kg

per week (EU and US)
both sexes, as testosterone in males is converted
• Somapacitan: 0.16 mg/kg
into estrogens through androgen aromatization. per week (EU and US)
Estrogens stimulate GH secretion by (a) reducing • Lonapegsomatropin:
somatostatin receptor expression, (b) increasing 0.24 mg/kg per week (EU
and US)
the number of GHRH binding sites, and (c)
• Jintrolong: 0.2 mg/kg per
amplifying ghrelin-induced GH secretion.11 Due week (China)
to the crucial role played in GH secretion during • Eutropin-plus: 0.5 mg/kg
puberty, sex steroid priming before provocative per week (South Korea and
EU*)
tests should be considered in prepubertal boys
older than 11 years and in prepubertal girls Chronic kidney 1993 50 mcg/kg per day (US)
insufficiency 45-50 mcg/kg per day (EU)
older than 10 years, especially to distinguish GH
Turner syndrome 1997 47-67 mcg/kg per day (US)
deficiency from constitutional delay of growth and 45-50 mcg/kg per day (EU)
puberty (CDGP).12,13
Prader-Willi 2000 34 mcg/kg per day (US)
Idiopathic short stature and small-for- syndrome 35 mcg/kg per day (EU)
gestational-age are clinical definitions that imply
Small-for- 2001 67-69 mcg/kg per day (US)
many different underlying molecular defects gestational-age 35 mcg/kg per day (EU)
accounting for broad individual variability in without catch-up
growth
response to GH therapy.14-16
Rarely, an insufficient GH dosage is the cause Idiopathic short 2003** 43-67 mcg/kg per day (US)
stature
of a poor response. Depending on the patient’s
condition, the GH dosage varies from 25 mcg/kg SHOX gene 2006 50 mcg/kg per day (EU and
haploinsufficiency US)
per day to 67 mcg/kg per day (Table).
Noonan syndrome 2007 35-66 mcg/kg per day (EU
Distinguishing between nonresponsiveness to and US)
GH therapy and suboptimal response because of
poor adherence is often difficult, and a thorough Abbreviations: EU, European Union; US, United States.

investigation into the regularity of GH injections * Approved but not commercialized.

is needed to identify the cause of nonresponse. ** In US only.

Nonadherence to GH therapy is as high as 36%

to 66%,17,18 and it can be secondary to discomfort missing more than 1 GH dose each week can affect
(eg, associated with daily injections), long-term long-term efficacy.18 Measurement of IGF-1 may
treatment, complexity of treatment regimens, provide information about adherence, especially
age (eg, adolescence), and the patient’s or family’s when an unexpected drop in IGF-1 concentration
lack of understanding of treatment benefits and is observed. Strategies to reduce nonadherence
consequences of nonadherence. Poor adherence is include (a) educating the patient and family
associated with impaired growth outcome because on manage management; (b) emphasizing the

238 ENDO 2025 • Endocrine Case Management

importance of adherence at each outpatient visit; Figure. Algorithm for Evaluating Children
With Poor Response to GH Therapy
(c) addressing the choice of the injection device;
(d) facilitating inclusion in a patient support First-year poor response to GH therapy
program; and (e) use of electronic monitoring.19 Height gain <0.5 SDS
Height velocity increase <3 cm/year
The recent availability of long-acting GH Height velocity < +1 SDS

preparations, which decrease the frequency of

injections from daily to weekly, might improve
Confirm the appropriate Assess regimen
adherence to GH therapy and ultimately lead to GH dosage regimen adherence

better growth outcomes.20

The algorithm to be followed in case of
nonresponse or poor response starts with checking Adjust GH dosage

the appropriate dosage and assessing adherence to

GH therapy. In cases with confirmed adherence,
the therapy should be stopped, the diagnosis Poor adherence
Good adherence
should be challenged, and further tests (mainly (low IGF-1)

genetic) should be performed (Figure).

Alternative Growth-Promoting
Stop GH therapy Monitor adherence

Therapies in Short Children With

Poor Response to GH Treatment Questionnaires
Re-evaluate diagnosis Injection logbook
A poor response to GH treatment raises the Injection-recording devices

problem of choosing effective alternative

therapeutic strategies. Increasing the GH dosage Genetic testing*
is usually ineffective and is associated with the
challenge of maintaining IGF-1 levels in the
normal range, as well as high cost. The use of * Genetic testing includes karyotype analysis, comparative genomic
long-acting GH may improve adherence,20 but hybridization array, single-nucleotide polymorphism array, whole-exome
sequencing, whole-genome sequencing, and DNA methylation analysis.21
long-acting GH has been approved only for More than one-third of children diagnosed as being small-for-gestational
age or having idiopathic short stature have pathogenic variants, mainly
patients with GH deficiency. in genes involved in growth cartilage physiology, such as ACAN, COL2A1,
Another theoretical alternative is to combine FBN1, FGFR3, IHH, NPPC, NPR2, and SHOX.14,22,23 Some polymorphisms
located in GHR, IGFBP3, and SOCS2 reduce responsiveness to GH
GH with IGF-1 to treat patients who with poor treatment.24

response to GH therapy alone. IGF-1 has been [Color—Print (Color Gallery page CG15) or web & ePub editions]

approved for treating patients with primary

IGF-1 deficiency, but it has also been used in
combination with GH to treat children with Genetic characterization of children with
idiopathic short stature in a randomized clinical short stature can better personalize therapies.
trial.25 However, the response to combination For example, children with gain-of-function
therapy was modest and only seen in the first pathogenic variants in the gene encoding fibroblast
year. Moreover, as expected, children receiving growth factor receptor 3 (FGFR3), causing
combination treatment experienced dramatic hypochondroplasia and achondroplasia, respond
elevations in serum IGF-1.25 In addition, IGF- to C-type natriuretic peptide analogues (eg,
1 therapy requires a twice-daily regimen and vosoritide) administered via daily subcutaneous
is associated with a high rate of hypoglycemic injections.26-28 A multicenter phase 2 clinical
reactions (42%). trial with vosoritide in children with idiopathic
short stature is ongoing. Infigratinib is an oral
tyrosine kinase inhibitor that counteracts FGFR3

ENDO 2025 • Pediatric and Adolescent Endocrinology 239

hyperactivity by inhibiting its phosphorylation his first year of treatment, height gain was +0.3
and therefore downstream signaling. Promising SDS, height velocity was +0.2 SDS, and height
preliminary results have recently been reported in velocity increase was +2.0 cm/year. His mother
patients with achondroplasia.29 had menarche at age 14 years, and her height is
Another strategy to improve the growth –1.1 SDS. His father’s height is –0.8 SDS. The
outcome of short children who start GH therapy patient’s birth weight at 40 weeks’ gestation was
in puberty is to delay fusion of the growth plates 6 lb 6 oz (2900 g), and birth length was 19.7 in
either with GnRH analogues or aromatase (50 cm).
inhibitors.30 The use of GnRH analogues in On physical examination, he has no
combination with GH can promote growth in dysmorphic features, testicular volume is 3 cc, and
puberty in boys and girls with GH deficiency, pubertal development is Tanner stage 2.
small-for-gestational-age, and idiopathic short Bone age is 11.5 years. IGF-1 is +0.1 SDS.
stature.30 However, suppression of physiological Results of endocrine and biochemical tests are
puberty makes a pubertal child hypogonadal at a in the normal range. Adherence to therapy is
critical time of development. While treated with adequate according to his therapy logbook.
GnRH analogue therapy, the child will not only
be short, but also sexually infantile compared with Which of the following is the
his/her peers, and this may impair psychological best recommendation now?
well-being. The high cost of such therapy is A. Increase the GH dosage
another limiting factor. B. Continue GH therapy for another year
Aromatase inhibitors block estrogen and
C. Reassess the diagnosis of GH deficiency, stop
increase testosterone production, thus delaying
GH therapy, and repeat GH-provocative
growth plate fusion while GH promotes growth.
testing after sex steroid priming
Although safety and efficacy data of aromatase
inhibitors used alone or in combination with D. Continue GH therapy and add testosterone
GH in male children with GH deficiency and E. Continue GH therapy and add a GnRH
idiopathic short stature are promising, there is analogue
still little evidence because most reports are based
Answer: C) Reassess the diagnosis of GH
on predicted rather than actual adult height. The
deficiency, stop GH therapy, and repeat GH-
potential detrimental effects of estrogen depletion
provocative testing after sex steroid priming
and androgen increase on bone mineralization and
virilization (increase in musculature and acne), This boy has had a poor response to GH therapy.
respectively, should be closely monitored during Based on his family history, physical examination
aromatase inhibitor treatment. findings, delayed bone age, and normal IGF-
1 concentration, the most likely diagnosis is
Clinical Case Vignettes constitutional delay of growth and development.
Constitutional delay of growth and development is
Case 1 by far the most frequent cause of delayed puberty
A 14-year-old boy diagnosed with GH deficiency (absence of testis enlargement in boys at the age of
is referred for short stature (height, –2.2 SDS) 14 years or breast development in girls at the age
and poor response to GH therapy. He has been 13 years) and transient growth retardation in both
treated with GH for 1 year. The initial diagnosis sexes. For unknown reasons, it is more common in
of isolated idiopathic GH deficiency was based boys than in girls. Boys with constitutional delay
on subnormal peak GH responses to 2 different of growth and development are usually referred
GH-stimulation tests. No sex steroid priming was for short stature secondary to the delayed pubertal
performed before GH-provocative tests. During growth spurt, but their slow “tempo” of growth

240 ENDO 2025 • Endocrine Case Management

does not impair the achievement of a normal adult her birth weight was 4 lb 3 oz (1900 g), and length
height corresponding to their genetic growth was 17.3 in (44 cm).
potential (midparental height). The patient’s On physical examination, her BMI is +2.0 SDS.
subnormal GH responses to provocative tests were She is prepubertal and has no dysmorphic features.
misleading, suggesting impaired GH secretion. The
false-positive rate of GH-provocative testing is Which of the following is the best next
high in children with delayed puberty. Sex steroids step in this patient’s management?
increase pituitary GH release during puberty, and A. Increase the GH dosage
sex steroid priming before provocative tests should B. Stop GH therapy and wait to see of
be considered in prepubertal boys older than 11 spontaneous puberty occurs
years and in prepubertal girls older than 10 years
C. Continue GH therapy and add an aromatase
to discriminate constitutional delay of growth and
inhibitor
development from GH deficiency. Short courses
of low-dosage testosterone may be indicated in D. Continue GH therapy and add a GnRH
boys with constitutional delay of growth and analogue
development who have a prolonged infantile E. Reassess the diagnosis of GH deficiency, stop
phenotype to increase height velocity, accelerate GH therapy, and pursue further testing
sexual maturation, and improve psychosocial well-
Answer: E) Reassess the diagnosis of GH deficiency,
being without negative effects on bone maturation
stop GH therapy, and pursue further testing
and adult height. The usual testosterone regimen
is testosterone ester, 50 mg intramuscularly each The diagnosis of GH deficiency was based on
month for 3 to 4 months, which can be repeated the responses to provocative tests only, instead
for another 3 to 4 months. of a comprehensive clinical, anthropometric,
biochemical, endocrine, radiological, and genetic
Case 2 approach. A GH dosage of 25 mcg/kg per day
(0.18 mg/kg per week) is an adequate replacement
An 8-year-old girl diagnosed with isolated regimen in GH-deficient children, leading to
idiopathic GH deficiency is referred for short catch-up growth and achievement of adult height
stature (height, –3.2 SDS) and poor first-year consistent with genetic potential (midparental
response to GH therapy. During the first year height). A further increase in the GH dosage
of treatment, her height gain was +0.1 SDS, and would not be advised in this case because the
height velocity was +0.3 SDS (+1.1 cm/year). The selected therapeutic regimen is appropriate and
peak GH value in response to arginine-stimulation her IGF-1 concentration is in the upper normal
testing was 6.1 ng/mL (6.1 µg/L), and peak range. Poor response to GH therapy, normal/
GH value in response to clonidine-stimulation high IGF-1 values, and normal pituitary and
testing was 6.7 ng/mL (6.7 µg/L). Her IGF-1 hypothalamus on MRI should strongly challenge
concentration was +2.0 SDS. MRI showed a the diagnosis of GH deficiency. Moreover, the
normal hypothalamus and pituitary gland. Her GH patient’s obesity may account for the blunted
dosage regimen is consistent with the diagnosis of responses to GH-provocative tests. Her small
GH deficiency: 0.2 mg/kg per week, and adherence size at birth and the degree of her mother’s short
to her treatment regimen is adequate according to stature suggest a genetic cause. The high IGF-1
her therapy logbook. levels are consistent with a pathogenic variant in
There is no relevant family history. Her the IGF1R gene. Most individuals carrying IGF1R
mother’s height is –2.9 SDS, and her father’s variants are heterozygous with a single-nucleotide
height –1.6 SDS. At a gestational age of 39 weeks, variant or deletions encompassing IGF1R. Only
few patients with homozygous IGF1R variants or

ENDO 2025 • Pediatric and Adolescent Endocrinology 241

compound heterozygous IGF1R variants have been Answer: D) Explore the patient’s adherence to therapy
reported so far. In this case, the initial diagnosis
of GH deficiency should be reassessed, and genetic The patient’s anthropometry, responses to
tests (particularly focused on IGF1R variants) provocative testing, low IGF-1 concentrations,
should be undertaken to elucidate the underlying MRI findings, and the good response to GH
cause of her short stature. therapy in the first and second year of treatment
confirm the diagnosis of GH deficiency. The
GH dosage is appropriate, as demonstrated by
Case 3 the initial satisfactory response to therapy and
An 8-year-old boy diagnosed with isolated good response of IGF-1 levels. The sudden drop
idiopathic GH deficiency is referred for blunted in height velocity and IGF-1 concentrations
response to GH therapy during the third year in the third year of treatment strongly suggest
of therapy. His pretherapy GH responses to nonadherence to therapy.
provocative tests were 1.4 ng/mL (1.4 µg/L) to Nonadherence in pediatric patients on GH
arginine stimulation and 2.1 ng/mL (2.1 µg/L) therapy ranges from 36% to 66%. In general,
to clonidine stimulation. His IGF-1 value was adherence to therapy in patients with chronic
–2.1 SDS. Brain MRI showed ectopic posterior diseases decreases with longer treatment
pituitary, pituitary stalk agenesis, and anterior duration. Multiple factors affecting patients
pituitary hypoplasia. His pretherapy height was and their parents impair long-term adherence,
–3.5 SDS, and height velocity was –1.9 SDS. His such as poverty, low literacy, unemployment,
first-year response to GH therapy was satisfactory a weak social network, dysfunctional family
with a height gain of +1.1 SDS, height velocity relationships, unstable living conditions, cost of
of +1.8 SDS, and height velocity increase of medicines and transportation, and principles and
+4.5 cm/year. The good response was maintained beliefs regarding the disorder and its treatment.
during the second year of treatment. IGF-1 levels Assessment of adherence is difficult and may
in the first and second year of GH therapy were be based on indirect or direct methods. Indirect
+1.5 SDS and +1.2 SDS, respectively. Monitoring methods include the verbal checks of the regularity
of thyroid function before and during GH of injections at each visit, as well as asking
therapy yielded normal results. Now, in his third patients/families to fill in “ad hoc” questionnaires
year of treatment, he has had an unexpected or therapy logbooks. Injection-recording
drop in height velocity (–2.1 SDS), and IGF- devices represent direct methods to measure
1 concentration (–2.0 SDS). His GH dosage is therapy adherence, but even these methods can
appropriate for the diagnosis of GH deficiency be circumvented by fake injections. IGF-1 is
(0.2 mg/kg per week). The rest of endocrine and probably the best biomarker of adherence to GH
biochemical test results are in the normal range. therapy, as was the case in this patient who had
an initial increase of IGF-1 levels followed by a
Which of the following is the best next sudden drop. When interviewing his parents, it
step in this patient’s management? became apparent that there was a difficult parental
A. Increase the GH dosage separation in conjunction with the refusal to
B. Stop GH therapy and reassess the diagnosis of continue GH therapy.
GH deficiency Patient and parent education and
communication between the pediatric
C. Continue GH therapy and add an aromatase endocrinologist and families are the pillars to
inhibitor improve the adherence to GH therapy. The recent
D. Explore the patient’s adherence to therapy introduction of long-acting GH with weekly,
E. Continue GH therapy and add a GnRH rather than daily, injections is another potentially
analogue

242 ENDO 2025 • Endocrine Case Management

effective tool to at least partially circumvent affecting GH/IGF-1 axis function and growth
patient resistance to long-term GH therapy. plate physiology may account for poor
response to treatment
Key Learning Points • The use of long-acting GH preparations can
be helpful in GH-deficient children with poor
• GH is widely prescribed for children with therapy adherence. Ongoing clinical trials are
short stature who have a range of growth testing the efficacy and safety of long-acting
disorders. A high rate of poor or unsatisfactory GH preparations in children with Turner
response to GH therapy (ie, not leading to syndrome, small-for-gestational age, and
significant catch-up growth) in terms of height idiopathic short stature.
gain and height velocity increase is observed in • There are no valid alternatives to the use
children with approved indications. of daily or weekly GH for treating children
• A good response in the first year of GH with short stature (except for those with
treatment is defined by a height gain of 0.5 primary IGF-1 deficiency who can benefit
SDS or greater and/or height velocity increase from IGF-1 therapy). C-natriuretic peptide
of 3 cm/year or greater and/or a height analogue therapy, previously shown to be
velocity of 1 SDS or greater. effective in promoting growth in patients with
achondroplasia and hypochondroplasia, is being
• The main predictive factors of the response to
tested in children with idiopathic short stature.
GH therapy are chronological age, birth weight,
height, height SDS minus target height SDS, • When GH therapy is initiated in puberty, the
GH peak to provocative tests, and GH dosage. use of GnRH analogues to suppress puberty or
aromatase inhibitors to slow down growth plate
• A poor response to GH therapy should lead
maturation in association with GH may be an
clinicians to assess treatment adherence.
option to improve growth outcomes, but robust
Once good adherence is confirmed, the initial
evidence for the long-term efficacy and safety of
diagnosis should be reevaluated and further
such combination treatments is still lacking.
tests should be performed. Genetic variants

References
1. Carel JC, Chatelain P, Rochiccioli P, Chaussain JL. Improvement in adult patients with severe growth hormone deficiency. J Clin Endocrinol Metab.
height after growth hormone treatment in adolescents with short stature 2009;94(2):588-595. PMID: 18984657
born small for gestational age: results of a randomized controlled study. J Clin 7. Garner T, Clayton P, Højby M, Murray P, Stevens A. Gene expression
Endocrinol Metab. 2003;88(4):1587-1593. PMID: 12679443 signatures predict first-year response to somapacitan treatment in children
2. Maiorana A, Cianfarani S. Impact of growth hormone therapy on adult height with growth hormone deficiency. J Clin Endocrinol Metab. 2024;109(5):1214-
of children born small for gestational age. Pediatrics. 2009;124(3):e519-e531. 1221. PMID: 38066644
PMID: 19706577 8. Bang P, Ahmed SF, Argente J, et al. Identification and management of poor
3. Deodati A, Cianfarani S. Impact of growth hormone therapy on adult height response to growth-promoting therapy in children with short stature. Clin
of children with idiopathic short stature: systematic review. Bmj-British Endocrinol (Oxf). 2012;77(2):169-181. PMID: 22540980
Medical Journal. 2011;342:c7157. PMID: 21398350 9. Cohen P, Rogol AD, Deal CL, et al; 2007 ISS Consensus Workshop
4. Ranke MB, Lindberg A. Predicting growth in response to growth hormone Participants. Consensus statement on the diagnosis and treatment of children
treatment. Growth Horm IGF Res. 2009;19(1):1-11. PMID: 18824380 with idiopathic short stature: a summary of the Growth Hormone Research
5. Dos Santos C, Essioux L, Teinturier C, Tauber M, Goffin V, Bougnères P. A Society, the Lawson Wilkins Pediatric Endocrine Society, and the European
common polymorphism of the growth hormone receptor is associated with Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab.
increased responsiveness to growth hormone. Nat Genet. 2004;36(7):720-724. 2008;93(11):4210-4217. PMID: 18782877
PMID: 15208626 10. Bright GM, Morris PA, Rosenfeld RG. When is a positive test for pediatric
6. 6.Costalonga EF, Antonini SR, Guerra-Junior G, Mendonca BB, Arnhold IJ, growth hormone deficiency a true-positive test? Horm Res Paediatr.
Jorge AA. The -202 A allele of insulin-like growth factor binding protein-3 2021;94(11-12):399-405. PMID: 34856538
(IGFBP3) promoter polymorphism is associated with higher IGFBP-3 11. Partenope C, Galazzi E, Albanese A, Bellone S, Rabbone I, Persani L. Sex
serum levels and better growth response to growth hormone treatment in steroid priming in short stature children unresponsive to GH stimulation

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 tests: why, who, when and how. Front Endocrinol (Lausanne). 2022;13:1072271. 21. Collett-Solberg PF, Ambler G, Backeljauw PF, et al. Diagnosis, genetics,
PMID: 36523598 and therapy of short stature in children: a growth hormone research society
12. Duncan G, Kiff S, Mitchell RT. Sex steroid priming for growth hormone international perspective. Horm Res Paediatr. 2019;92(1):1-14. PMID:
stimulation testing in children and adolescents with short stature: A 31514194
systematic review. Clin Endocrinol (Oxf). 2023;98(4):527-535. PMID: 22. Inzaghi E, Reiter E, Cianfarani S. The challenge of defining and investigating
36515075 the causes of idiopathic short stature and finding an effective therapy. Horm
13. Grimberg A, DiVall SA, Polychronakos C, et al. Guidelines for growth Res Paediatr. 2019;92(2):71-83. PMID: 31578025
hormone and insulin-like growth factor-I treatment in children and 23. Jee YH, Baron J, Nilsson O. New developments in the genetic diagnosis of
adolescents: growth hormone deficiency, idiopathic short stature, and short stature. Curr Opin Pediatr. 2018;30(4):541-547. PMID: 29787394
primary insulin-like growth factor-I deficiency. Horm Res Paediatr. 24. Braz AF, Costalonga EF, Trarbach EB, et al. Genetic predictors of long-term
2016;86(6):361-397. PMID: 27884013 response to growth hormone (GH) therapy in children with GH deficiency
14. Hauer NN, Popp B, Schoeller E, et al. Clinical relevance of systematic and Turner syndrome: the influence of a SOCS2 polymorphism. J Clin
phenotyping and exome sequencing in patients with short stature. Genet Med. Endocrinol Metab. 2014;99(9):E1808-E1813. PMID: 24905066
2018;20(6):630-638. PMID: 29758562 25. Backeljauw PF, Miller BS, Dutailly P, et al. Recombinant human
15. Hokken-Koelega ACS, van der Steen M, Boguszewski MCS, et al. growth hormone plus recombinant human insulin-like growth factor-1
International consensus guideline on small for gestational age: etiology and coadministration therapy in short children with low insulin-like growth
management from infancy to early adulthood. Endocr Rev. 2023;44(3):539- factor-1 and growth hormone sufficiency: results from a randomized,
565. PMID: 36635911 multicenter, open-label, parallel-group, active treatment-controlled trial.
16. Cohen LE, Rogol AD. Children with idiopathic short stature: an expanding Horm Res Paediatr. 2015;83(4):268-279. PMID: 25765099
role for genetic investigation in their medical evaluation. Endocr Pract. 26. Galetaki D, Zhang A, Qi Y, et al. Phase 2 trial of vosoritide use in patients
2024;30(7):679-686. PMID: 38679385 with hypochondroplasia: a pharmacokinetic/pharmacodynamic analysis.
17. Haverkamp F, Johansson L, Dumas H, et al. Observations of nonadherence to Horm Res Paediatr. 2024:1-7. PMID: 39427650
recombinant human growth hormone therapy in clinical practice. Clin Ther. 27. Savarirayan R, Irving M, Bacino CA, et al. C-type natriuretic peptide
2008;30(2):307-316. PMID: 18343269 analogue therapy in children with achondroplasia. N Engl J Med.
18. Cutfield WS, Derraik JG, Gunn AJ, et al. Non-compliance with growth 2019;381(1):25-35. PMID: 31269546
hormone treatment in children is common and impairs linear growth. PLoS 28. Savarirayan R, Tofts L, Irving M, et al. Once-daily, subcutaneous vosoritide
One. 2011;6(1):e16223. PMID: 21305004 therapy in children with achondroplasia: a randomised, double-blind, phase
19. Wit JM, Deeb A, Bin-Abbas B, Al Mutair A, Koledova E, Savage MO. 3, placebo-controlled, multicentre trial. Lancet. 2020;396(10252):684-692.
Achieving optimal short- and long-term responses to paediatric growth PMID: 32891212
hormone therapy. J Clin Res Pediatr Endocrinol. 2019;11(4):329-340. PMID: 29. Savarirayan R, De Bergua JM, Arundel P, et al. Oral infigratinib therapy in
31284701 children with achondroplasia. N Engl J Med. 2025;392(9):865-874. PMID:
20. Pampanini V, Deodati A, Inzaghi E, Cianfarani S. Long-acting growth 39555818
hormone preparations and their use in children with growth hormone 30. Mauras N, Ross J, Mericq V. Management of growth disorders in puberty:
deficiency. Horm Res Paediatr. 2023;96(6):553-559. PMID: 35220308 GH, GnRHa, and aromatase inhibitors: a clinical review. Endocr Rev.
2023;44(1):1-13. PMID: 35639981

244 ENDO 2025 • Endocrine Case Management

State-of-the-Art Management
of Turner Syndrome
Claus H. Gravholt, MD, PhD. Department of Endocrinology and Department of Molecular
Medicine, Aarhus University Hospital, Aarhus, Denmark; Email: [email protected]

Educational Objectives than normally seen in the general population.3-5

This means that the clinician must be vigilant and
After reviewing this chapter, learners should be
expect the unexpected when dealing with patients
able to:
who have TS. Furthermore, the clinical diagnosis
• Identify and risk stratify patients with Turner of TS is often severely delayed,6 despite the fact
syndrome (TS) at all ages. that textbook depictions of girls with TS describe
a very distinct phenotypic presentation. However,
• Continuously follow-up and regularly screen
many girls with TS present with fewer stigmata
for relevant conditions occurring more
that may be easily overlooked, and the median age
frequently among patients with TS.
at diagnosis is 15 years.6 An estimated 15% of all
• Adequately treat comorbidities in patients individuals with TS are never diagnosed.
with TS.

Practice Gaps
• Diagnosis is delayed for many individuals
Significance of the
with TS.
Clinical Problem
• Individuals with Turner syndrome almost
Treatment with GH during childhood and always have comorbidities that often go
adolescence allows a considerable gain in adult undetected but should be diagnosed and
height. SHOX deficiency explains some of the treated. Known conditions, such as congenital
phenotypic characteristics in TS, principally short heart malformations, also need correct
stature. Puberty must be induced in most girls, and treatment, including surgery, when necessary.
female sex hormone replacement therapy (HRT)
should continue during the adult years. These • Appropriate HRT should be given to all
issues are normally dealt with by pediatricians, hypogonadal girls with TS starting around
but once a patient with TS enters adulthood, age 11 years to induce puberty and should
it is less clear who should be the primary care be continued at least until the normal age of
giver. Morbidity and mortality are increased, menopause (52-53 years), sometimes even
especially due to the risk of aortic dissection and longer. Some women with TS receive a
other cardiovascular diseases, type 2 diabetes, suboptimal dosage or no HRT at all.
hypertension, osteoporosis, thyroid disease, and • Cardiovascular issues are common in women
other diseases.1 The average loss of lifespan of with TS, and they often interfere with other
women with TS is considerable and amounts to treatments, such as the possibility of becoming
13 to 15 years.2 The comorbidities listed above pregnant via oocyte donation.
and other conditions occur much more frequently
in individuals with TS and also at a younger age

ENDO 2025 • Pediatric and Adolescent Endocrinology 245

Discussion Mosaic karyotypes are associated with a higher
likelihood of preserved ovarian function, as
Consensus documents concerning the optimal
determined by the frequency of spontaneous
treatment of Turner syndrome have been produced,
menarche. Women with TS are most often
but they are only fully implemented in a few
infertile, this being the greatest factor influencing
clinics around the world.3 Furthermore, a range of
their quality of life.11 Very few can become
outstanding issues and questions remain unanswered,
pregnant with their own oocytes. Most women
both when addressing problems relating to childhood
with TS are likely to experience premature ovarian
and adolescence, as well as adulthood.
insufficiency and are hence less likely to become
The 45,X karyotype is still the most common
pregnant. Spontaneous pregnancy occurs in 4.8%
karyotype identified among individuals with
to 7.6% of women with TS,12,13 and miscarriages
TS; however, during recent decades, the
are more frequent in such pregnancies.14
number of individuals diagnosed with mosaic
According to the international TS guidelines,1 it
TS (45,X/46,XX) has increased.6,7 Other
is recommended to initiate estrogen replacement
karyotypes exist, including ring X chromosomes,
when the patient is between 11 and 12 years of
iso chromosomes, deletions of part of the X
age, increasing to an adult dosage over 2 to 3
chromosome, or karyotypes including part
years. Low-dosage estradiol is recommended, and
of a Y chromosome. Only 30% to 85% of all
transdermal administration is preferred to oral use
individuals with TS are ever diagnosed, with a
because of fewer adverse effects. Once bleeding
wide range of age at diagnosis, from prenatally to
occurs, progesterone should be added. With
after postmenopausal age.6 There is no obvious
adequate hormone replacement, it is possible to
explanation for this lack of diagnosis, but new
stimulate uterine growth, which will then reach
avenues for better diagnostics, such as neonatal
adult size and thus potentially be ready for oocyte
screening programs using genome sequencing,
donation from a foreign donor. It is also clear that
should probably be put in place.1 The median age at
pregnancy after oocyte donation carries a higher
TS diagnosis is 15 years, although it is younger in
risk of pregnancy complications and spontaneous
those with a 45,X karyotype or a mosaic karyotype,
abortion than the rare spontaneous pregnancy
and older in those with other karyotypes.
among women with TS.15
TS is usually accompanied by
The risk of both type 1 and type 2 diabetes
hypergonadotropic hypogonadism, leading to
is increased in women with TS.5 Altered body
low levels of estrogens and, compared with
composition associated with TS includes increased
healthy girls, lower androgen levels.8 Ovarian
BMI, decreased muscle mass, and increased
insufficiency leads to pubertal delay, primary or
total fat mass and visceral fat mass.16 Relatively
secondary amenorrhea, poor development of
sedentary lifestyle and decreased physical fitness
secondary sex characteristics, impaired sexual
have also been demonstrated.17 In the face of
functioning, and in most cases infertility. The
widespread abnormalities of glucose homeostasis
phenotype differentiates depending on karyotype,
and increased risk of type 1 and type 2 diabetes,
as individuals with 45,X have more pronounced
there is a need for persistent attention to these
symptoms. Gonadal functioning in TS is
factors in clinical follow-up. Recommendations
extremely variable and dependent on karyotype.
for diagnosis and treatment of diabetes adhere
Approximately 20% of girls with monosomy X
to general population guidelines and annual
enter puberty spontaneously, compared with 70%
screening of fasting glucose and hemoglobin
of girls with mosaicism. About one-third of girls
A1c should be performed. Autoimmune thyroid
with TS have spontaneous breast development,
disease is common in TS, with hypothyroidism
which is positively associated with the circulating
occurring in up to 50% of women at age 50 years.18
antimullerian hormone concentration.9 Regular
Hyperthyroidism also occurs more frequently
menstrual cycles occur in 6% of girls with TS.10

246 ENDO 2025 • Endocrine Case Management

than among control patients. Treatment of with TS may have arterial hypertension.22-24 The
thyroid disease should follow clinical guidelines. cause of hypertension in TS is likely multifactorial.
In individuals with TS, the occurrence of all The high prevalence of overweight and obesity in
other autoimmune diseases is also increased in TS contributes significantly to the hypertension
comparison with the background population risk, disease burden and to the association with type 1
although the reason for this increase remains and type 2 diabetes.23
obscure.19 Therefore, the clinician should be
vigilant and examine women with TS if there
is the slightest suspicion. Currently, there are
Future Directions
recommendations for how a clinical care program Recently, new genes have been linked to TS.
should be tailored for adults with TS.1 Some Tissue inhibitor of matrix metalloproteinases 1
diseases, such as celiac disease, inflammatory (TIMP1) is an escape gene on Xp and is therefore
bowel disease, and rheumatoid disease, occur normally expressed in duplicate. Females with
frequently enough to warrant special attention. TS have haploinsufficiency for this gene. TIMP3
Peak bone mass depends on several factors, such is a gene with partially overlapping function on
as genetic background, nutrition, physical activity, chromosome 22 and haploinsufficiency of TIMP1
local growth factors, and a spectrum of hormones. and a certain risk single-nucleotide variant in
Estradiol secretion in TS is already deficient in TIMP3 predisposes to developing typical hallmark
childhood and adolescence, and children and signs of TS—aortic dilatation and bicuspid aortic
younger and middle-aged adult patients with TS valves. A decrease in TIMPs could lead to higher
have low bone mineral density. Studies show levels of MMP2 and MMP9, which are involved in
that the risk of fracture and frank osteoporosis the development of aortic dissection.25 Recently,
is increased in individuals with TS. Estrogen we showed increased levels of neutrophils and
substitution therapy is crucial to attain maximal increased neutrophil activation, which may
peak bone mass in adolescents and young adults. lead to neutrophil-driven inflammatory stress
Although cardiologists are the specialists in TS (submitted manuscript). The increase in
treating aortic disease that is often present in neutrophils was linked to increased expression
TS, endocrinologists must also have knowledge of the X-Y homologous gene TBL1X, suggesting
of cardiac conditions. In early adult life, aortic a genetic basis for the prevalence of neutrophil-
dilatation and eventually aortic dissection is driven chronic inflammatory diseases, such as
seen in significant numbers.20 In clear contrast, autoimmune disorders and metabolic conditions
aortic dissection is a disease mostly seen among in TS.5,19 Similarly, the SLC25A6 gene, also situated
elderly persons in the normal population. This is in the pseudoautosomal region of the X and
probably why aortic disease is misdiagnosed and Y chromosomes and normally expressed in 2
mistreated in young women with TS, in whom the copies, is associated with increased QT interval
significance of aortic dilatation is underestimated in individuals with TS, who have just 1 copy.26
and prophylactic surgery is often not offered in Such new studies are fascinating because they may
time. The presence of a bicuspid aortic valve is a direct future therapies in TS, and knowledge of
major determinant for aortic dilatation, as well these genes could be used preventively.
as for the presence of elevated diastolic blood
pressure and aortic arch anomalies.21 The current Clinical Case Vignettes
recommendation is to lower blood pressure with
an angiotensin II receptor, ACE inhibitor, or Case 1
β-adrenergic blocker. Hypertension is a common A 56-year-old woman has a complex medical
phenomenon in TS. The true prevalence is history. She had menarche at age 11 years and
uncertain, but up to 50% of an adult population regular menstruation until age 18 years. At age 23

ENDO 2025 • Pediatric and Adolescent Endocrinology 247

years, her primary care provider initiated HRT. years. Hypothyroidism was diagnosed at age 18
At age 29 years, she was reading a magazine story years. She had an uneventful early adulthood
about a woman with TS. She recognized herself and successfully worked fulltime and led an
in this story and asked her primary care provider active lifestyle. She received egg donation and
if she could be tested. The care provider told her had a healthy baby. She has always had delicate
that he had already tested her 5 years earlier with skin and psoriasis was diagnosed. She developed
a confirmed karyotype of 45,X. She developed type 2 diabetes (no positive autoantibodies for
hypothyroidism at age 30 years, underwent type 1 diabetes) at age 51 years. At that time,
hysterectomy at age 40 years because of profuse her weight was 127.9 lb (58 kg) and height
bleeding, and had a gall bladder operation at age was 57.1 in (145 cm) (BMI = 27.6 kg/m2). She
49 years, Hypertension was diagnosed at age 52 developed angina when jogging. Coronary
years. She retired early at age 54 years because of angiography showed constrictions of the left
depression and burn-out; neurocognitive evaluation anterior descending artery (second branch);
showed issues with executive functioning and however, it was not possible to place a stent.
multitasking. She recently had a knee replacement. She began treatment with metformin, statins,
Current medications are lisinopril, citalopram, and acetylsalicylic acid. She did not tolerate
levothyroxine, and estradiol. Her weight is 176.4 lb acetylsalicylic acid, so this was replaced with
(80 kg), and height is 58.7 in (149 cm) (BMI = clopidogrel. She developed severe exfoliative
36.0 kg/m2). dermatitis and was twice hospitalized, needing
Continued treatment with estradiol is planned high-dosage topical glucocorticoids. The psoriasis
until at least 60 years of age. diagnosis was revised to pityriasis rubra pilaris and
treated with methotrexate. She was determined to
Which of the following is the be probably likely allergic to statins, clopidogrel,
median age at diagnosis of TS? acetylsalicylic acid, and possibly other medications.
A. Age 1 year She developed hypertension at the age 52 years.
B. Age 5 years She is currently being treated with metformin, a
GLP-1 receptor agonist, methotrexate, bisoprolol,
C. Age 15 years
prasugrel (antithrombotic agent), topical steroids,
D. Age 27 years HRT, and levothyroxine. She has lost weight and
Answer: C) Age 15 years now weighs 119.1 lb (54 kg) (BMI = 25.7 kg/m2).

This vignette highlights problems with late diagnosis, Is metabolic syndrome more
which in this patient’s case is likely related to the common in individuals with TS
somewhat atypical normal menarche and ongoing than in the general population?
menstruation until age 18 years. However, many A. Less common
girls with TS undergo menarche. The median age at B. Same frequency
diagnosis of TS is 15 years (Answer C). In addition,
C. More common
the vignette also illustrates the increasing comorbidity
burden as women with TS age, and this necessitates D. Type 1 diabetes, but not type 2 diabetes, is
ongoing vigilance on behalf of the caring physician. more common
Answer: C) More common
Case 2
This vignette illustrates that metabolic syndrome
A woman was diagnosed with TS ((karyotype = sometimes develops with very slight weight
45,X) at age 10 years and subsequently received increases in women with TS. This case also
GH therapy. She did not have spontaneous illustrates that despite an uneventful early
menarche, so puberty was induced at age 14

248 ENDO 2025 • Endocrine Case Management

adulthood, this patient developed a host of issues should be viewed as preventable conditions
other comorbid conditions likely related to that should not lead to premature death.
metabolic syndrome. We speculate that low-grade
inflammation may be an integral part of TS.
Key Learning Points
Case 3 • TS is a chronic condition, often with
A 20-year-old woman with TS (karyotype = numerous comorbidities that develop as
45,X/46,XX) would like to know about her patients age. It is important to be vigilant
chances of fertility. She is on HRT to manage as the anchor physician and to diagnose
hypergonadotropic hypogonadism. She has such conditions during clinical follow-
bicuspid aortic valves and had an operation at up. Morbidity and mortality are elevated
age 4 months to address aortic valve stenosis. She in women with TS, and adulthood can be
is normotensive, but echocardiography shows complicated by a host of conditions, such as
moderate stenosis (30 mm Hg gradient), and osteoporosis, diabetes (both type 1 and 2),
subsequent MRI of the aorta shows a maximum hypothyroidism, obesity, and other endocrine
dilatation of the ascending aorta of 4.5 cm (indexed diseases. Prevention, intervention, and proper
aortic size is 2.58 cm/m2). She also has ectatic treatment are only just being recognized.
truncus brachiocephalicus. The size is larger than Hypertension is common and can be a
normative data.21 Her height is 60.6 in (154 cm), forerunner of cardiovascular disease. Aortic
and weight is 167.6 lb (76 kg) (BMI = 32.1 kg/m2). dilation and aortic dissection are frequently
seen at a compellingly young age.
Are congenital heart malformations • The proper HRT dosage with female sex
problematic for individuals with TS? steroids has not been established, and,
A. No, these malformations are usually likewise, benefits and/or drawbacks of HRT
asymptomatic have not been thoroughly evaluated. However,
B. Yes, they can be life-threatening, especially it is pivotal that patients with TS receive HRT
during pregnancy for at least 42 years, which is equivalent to the
normal length of time that women are exposed
C. Yes, they can be life-threatening and require
to endogenously produced estrogen.
lifelong monitoring
D. No, once they are identified and treated in • Fertility is an important issue for young
infancy, no additional heart problems usually adults, and many women with TS choose egg
arise donation. Based on the latest literature, egg
donation pregnancies may not be as risky as
Answers: B and C) Yes, they can be life-threatening, early reports suggested.
especially during pregnancy, and yes, they can be • The description of adult life with TS has
life-threatening and require lifelong monitoring been broadened, and medical, social, and
Cardiovascular issues are of great importance in psychological aspects are being added at a
the care of patients with TS, and they cause of compelling pace. Proper care during adulthood
50% of excess mortality. Lifelong surveillance is should be studied, and a framework for care
necessary because during adulthood patients often should be in place, since most morbidity is
develop issues with dilation of the aorta, bicuspid potentially amenable to intervention.
aortic valves, partial anomalous pulmonary
return, etc. Therefore, endocrinologists must
collaboration with knowledgeable cardiologists to
keep patients healthy. Today, these cardiovascular

ENDO 2025 • Pediatric and Adolescent Endocrinology 249

References
1. Gravholt CH, Andersen NH, Christin-Maitre S, et al. Clinical practice 14. Cauldwell M, Steer PJ, Adamson D, et al., Pregnancies in women with Turner
guidelines for the care of girls and women with Turner syndrome. Eur J syndrome: a retrospective multicentre UK study. BJOG. 2022;129(5):796-803.
Endocrinol. 2024;190(6):G53-G151. PMID: 38748847 PMID: 34800331
2. Schoemaker MJ, Swedlow AJ, Higgins CD, Wright AF, Jacobs PA; United 15. Chevalier N, Letur H, Lelannou D, et al; French Study Group for Oocyte
Kingdom Clinical Cytogenetics Group. Mortality in women with Turner Donation. Materno-fetal cardiovascular complications in Turner syndrome
syndrome in Great Britain: a national cohort study. J Clin Endocrinol Metab. after oocyte donation: insufficient prepregnancy screening and pregnancy
2008;93(12):4735-4742. PMID: 18812477 follow-up are associated with poor outcome. J Clin Endocrinol Metab.
3. Viuff MH, Stochholm K, Gronbaek H, Berglund A, Juul S, Gravholt CH. 2011;96(2):E260-E267. PMID: 21147890
Increased occurrence of liver and gastrointestinal diseases and anaemia 16. Gravholt CH, Eilersen Hjerrild B, Mosekilde L, et al., Body composition
in women with Turner syndrome - a nationwide cohort study. Aliment is distinctly altered in Turner syndrome: relations to glucose metabolism,
Pharmacol Ther. 2021;53(7):821-829. PMID: 33550624 circulating adipokines, and endothelial adhesion molecules. Eur J Endocrinol.
4. Viuff MH, Stochholm K, Juul S, Graveholt CH. Disorders of the eye, ear, skin, 2006;155(4)583-592. PMID: 16990658
and nervous system in women with Turner syndrome -a nationwide cohort 17. Santi M, Fluck CE, Hauschild M, Kuhlmann B, Kuehni CE, Sommer
study. Eur J Hum Genet. 2022;30(2):229-236. PMID: 34707298 G. Health behaviour of women with Turner syndrome. Acta Paediatr.
5. Viuff MH, Berglund A, Juul S, Andersen NH, Stochholm K, Graveholt 2021;110(8):2424-2429. PMID: 33615554
CH. Sex hormone replacement therapy in Turner Syndrome - impact on 18. Naessén S, Eliasson M, Berntorp K, et al. Autoimmune disease in Turner
morbidity and mortality. J Clin Endocrinol Metab. 2020;105(2):dgz039. PMID: syndrome in Sweden: an up to 25 years´ controlled follow-up study. J Clin
31545360 Endocrinol Metab. 2023;109(2):e602-e612. PMID: 37758506
6. Berglund A. Stochholm K, Gravholt CH. The epidemiology of sex 19. Jorgensen KT, Rostgaard K, Bache I, et al. Autoimmune diseases in women
chromosome abnormalities. Am J Med Genet C Semin Med Genet. with Turner’s syndrome. Arthritis Rheum. 2010;62(3):658-666. PMID:
2020;184(2):202-215. PMID: 32506765 20187158
7. Tuke MA, Ruth KS, Wood AR, et al. Mosaic Turner syndrome shows 20. Alam S, Claxton JS, Mortillo M, et al. Thirty-year survival after cardiac
reduced penetrance in an adult population study. Genet Med. 2019;21(4):877- surgery for patients with Turner syndrome. J Pediatr. 2021;239:187-192.e1.
886. PMID: 30181606 PMID: 34450123
8. Viuff MH, Just J, Brun S, et al. Women with Turner syndrome are both 21. Mortensen KH, Erlandsen M, Andersen NH, Gravholt CH. Prediction
estrogen and androgen deficient - the impact of hormone replacement of aortic dilation in Turner syndrome--enhancing the use of serial
therapy. J Clin Endocrinol Metab. 2022;107(7):1983-1993. PMID: 35302622 cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2013;15(1):47.
9. Hamza RT, Mira MF, Hamed A, Ezzat T, Sallam MT. Anti-müllerian PMID: 23742092
hormone levels in patients with turner syndrome: relation to karyotype, 22. De Groote K, Demulier L, De Backer J, et al. Arterial hypertension in Turner
spontaneous puberty, and replacement therapy. Am J Med Genet A. syndrome: a review of the literature and a practical approach for diagnosis
2018;176(9):1929-1934. and treatment. J Hypertens. 2015;33(7):1342-1351. PMID: 26039527
10. Dabrowski E, Jensen R, Johnson E, Habiby RL, Brickman WJ, Finlayson C. 23. Fiot E, Zenaty D, Boizeau P, Haignere J, Dos Santos S, Leger J; French
Turner syndrome systematic review: spontaneous thelarche and menarche Turner Syndrome Study Group. X chromosome gene dosage as a determinant
stratified by karyotype. Horm Res Paediatr. 2019;92;(3):143-149. PMID: of congenital malformations and of age-related comorbidity risk in patients
31918426 with Turner syndrome, from childhood to early adulthood. Eur J Endocrinol.
11. Sutton EJ, McInerney-Leo A, Bondy CA, Gollust SE, King D, Biesecker B. 2019;180(6):397-406. PMID: 30991358
Turner syndrome: four challenges across the lifespan. Am J Med Genet A. 24. K. Sandahl, J. Wen, M. Erlandsen, N. H. Andersen, C. H. Gravholt, Natural
2005;139A(2):57-66. PMID: 16252273 History of Hypertension in Turner Syndrome During a 12-Year Pragmatic
12. Bryman I, Sylven L, Berntorp K, et al. Pregnancy rate and outcome in Interventional Study. Hypertension. 2020;76(5):1608-1615. PMID: 32895020
Swedish women with Turner syndrome. Fertil Steril. 2011;95(8)2507-2510. 25. Corbitt H, Morris SH, Gravholt CH, et al; GenTAC Registry Investigators.
PMID: 21256486 TIMP3 and TIMP1 are risk genes for bicuspid aortic valve and aortopathy in
13. Bernard V, Donadille B, Zenaty D, et al. Spontaneous fertility and pregnancy Turner syndrome. PLoS Genet. 2018;14(10):e1007692. PMID: 30281655.
outcomes amongst 480 women with Turner syndrome. Hum Reprod. 26. Skakkebæk A, Kjæ-Sorensen K, Matchkov VV, et al. Dosage of the
2016;31(4)782-788. PMID: 26874361 pseudoautosomal gene SLC25A6 is implicated in QTc interval duration. Sci
Rep. 2023;13(1):12089. PMID: 37495650

250 ENDO 2025 • Endocrine Case Management

Pediatric Obesity:
Challenges and Solutions
Ashley Shoemaker, MD, MSCI. Pediatric Endocrinology, Vanderbilt University Medical
Center, Nashville, TN; Email: [email protected]

Educational Objectives in children, but physicians must be willing to

integrate pharmacotherapy into their treatment
After reviewing this chapter, learners should be
plans. Additionally, incorporating genetic testing
able to:
into diagnostic algorithms can further refine
• Recognize patterns of abnormal weight gain in treatment selection as there are now drugs
childhood. targeting leptin deficiency and MC4R pathway
defects. Additional drugs are under development
• Identify appropriate pharmacologic options for
for treatment of Prader-Willi syndrome. By
treatment of pediatric obesity.
adopting a multifaceted approach, we can improve
• Explain the role of genetic testing for the treatment efficacy and ultimately enhance the
diagnosis of pediatric obesity. quality of life of children living with obesity and its
associated complications.

Significance of the Practice Gaps

Clinical Problem • Many of the drugs used for treatment of
Pediatric obesity is an escalating problem, pediatric obesity have been approved in the
with a 2017-2020 prevalence of 19.7% among past 3 years; therefore, many physicians lack
children and adolescents in the United States training in pharmacotherapy options for
according to the Centers for Disease Control. pediatric obesity.
The implications are far-reaching, with obesity- • Inexpensive genetic obesity panels are now
related comorbidities such as sleep apnea, type 2 available, and physicians need additional
diabetes, and metabolic dysfunction-associated education to understand how to incorporate
steatotic liver disease, now prevalent among these tools into their practice.
children. Traditional lifestyle interventions,
including diet and exercise, have proven
insufficient in combating pediatric obesity, often Discussion
leading to frustration and a sense of hopelessness Pediatric obesity is a growing public health
for both families and health care providers. This concern, with significant implications for long-
underscores the urgent need for enhanced efforts term health outcomes. It is critical that primary
in obesity prevention and treatment. care physicians and subspecialists who manage
Recent advancements in medical treatments obesity comorbidities become more comfortable
offer promising solutions for pediatric obesity. with the diagnosis and treatment of pediatric
Bariatric surgery and pharmacotherapy obesity. Centers for Disease Control BMI growth
(particularly GLP-1 receptor agonists) have shown charts are commonly used for diagnosis:
effectiveness in managing and reducing obesity

ENDO 2025 • Pediatric and Adolescent Endocrinology 251

• Class 1 obesity: BMI ≥95th percentile obesity, emphasizing the importance of family
• Class 2 obesity: BMI ≥120% of the 95th involvement to support sustainable lifestyle
percentile changes.3,4 Despite their intensive nature, the
effectiveness of these programs can be modest. A
• Class 3 obesity: ≥140% of the 95th percentile review of 44 randomized controlled trials involving
There is a high correlation between pediatric and approximately 5000 adolescent participants found
adult obesity, particularly in patients with early that lifestyle interventions resulted in a mean
adiposity rebound.1,2 difference in BMI of only –1.18 kg/m².5 This
suggests that while lifestyle interventions are
beneficial, they often need to be supplemented with
Intensive Lifestyle Programs other treatments for clinically meaningful results.
Intensive lifestyle programs are a cornerstone
in the treatment of pediatric obesity. Intensive
Pharmacotherapy
programs are defined as including 26 or more hours
of face-to-face treatment over a period of 3 to 12 Pharmacotherapy is an important adjunct to
months. They focus on comprehensive behavioral lifestyle interventions for pediatric obesity.
interventions that include dietary changes, Numerous antiobesity medications are available
increased physical activity, and behavioral therapy. for adults (adult defined by the US FDA as 17
The American Academy of Pediatrics (AAP) years and older) and an increasing number are
and Endocrine Society guidelines recommend approved for use in children aged 12 years and
these programs for children and adolescents with older (Table). While medications such as orlistat

Table. FDA-Approved Antiobesity Medications

Age
Drug Approval date range, y Indication Mechanism

Phentermine 1959 ≥17 Obesity Sympathomimetic amine that decreases appetite,

approved for short-term (12 weeks) use only

Orlistat 1999 ≥12 Obesity Blocks intestinal lipase to reduce fat absorption

Phentermine/ 2012 adults ≥12 Obesity Sympathomimetic amine plus topiramate

topiramate (mechanism unknown)
2022 pediatrics

Naltrexone/bupropion 2014 ≥12 Obesity Blocks autoinhibitory feedback and stimulates

POMC neurons, possibly regulating reward
pathways

Liraglutide 2014 adults ≥12 Obesity GLP-1 receptor agonist, increases satiety and
decreases rate of gastric emptying
2020 pediatrics

Metreleptin 2014 All Congenital leptin deficiency Leptin analogue, stimulates leptin receptor

Lisdexamfeta-mine 2015 ≥17 Binge eating Noncatecholamine sympathomimetic amine

Semaglutide 2021 adults ≥12 Obesity GLP-1 receptor agonist, increases satiety and
decreases rate of gastric emptying
2023 pediatrics

Tirzepatide 2023 ≥17 Obesity GLP-1 and GIP dual receptor agonist, increases
satiety and decreases rate of gastric emptying

Setmelanotide 2020 ≥2 Genetic obesity (biallelic α-Melanocortin stimulating hormone analogue,

PCSK1/LEPR/POMC improves signaling through MC4R pathway
deficiency, Bardet-Biedl
syndrome)

252 ENDO 2025 • Endocrine Case Management

have been approved for decades, they were limited Genetic Obesity Syndromes
by lack of effectiveness and poor tolerability.6
More than 80 genes have been identified as
Incretin based therapies, such as GLP-1 receptor
contributing to obesity risk, and screening patients
agonists, have revolutionized pharmacotherapy
for genetic obesity may improve treatment
for obesity due to their dramatic improvement
decisions. The Endocrine Society guidelines
in efficacy. For example, 68 weeks of treatment
recommend considering genetic testing in patients
with semaglutide resulted in a 15% mean decrease
with obesity onset before 5 years of age who have
in BMI in adolescents.7 Dual and triple incretins
clinical features of genetic obesity syndromes,
may have even better efficacy; trials are ongoing
particularly extreme hyperphagia and/or a family
in children. The Endocrine Society guidelines
history of extreme obesity.3 It can be hard to
recommend pharmacotherapy for children 12
determine obesity onset if early growth chart data
years and older in children with obesity who have
are not available. At least 1 cohort found MC4R
not responded to lifestyle interventions.3 The 2023
variants in greater than 5% of children with onset of
American Academy of Pediatrics recommend use
severe obesity before 10 years old.11 While children
of pharmacotherapy for children 12 years and
with genetic obesity may have associated short
older with obesity and consideration of therapy for
stature, their linear growth rate is usually normal.
children 8 to 11 years old.4
Patients with syndromic obesity, such as
Prader-Willi syndrome, Bardet-Biedl syndrome,
Bariatric Surgery and pseudohypoparathyroidism typically
For adolescents with severe obesity, bariatric present with early-onset obesity, hyperphagia,
surgery is a viable and effective treatment option. developmental delays, and other congenital
Procedures such as gastric bypass and sleeve anomalies. Nonsyndromic obesity can present
gastrectomy have shown significant and sustained with childhood obesity alone. The most common
weight loss, along with improvements in obesity- cause of nonsyndromic obesity is due to deleterious
related comorbidities such as type 2 diabetes and variants in the MC4R gene, affecting approximately
hypertension. Compared with adults, adolescents 1 in 100 persons with obesity.12,13 When evaluating
have similar 5-year outcomes, with an average a patient with obesity, the severity of obesity
weight loss of 26%, but adolescents are more alone is not a reliable indicator of a genetic cause;
likely to have resolution of comorbidities (type 2 instead, a combination of early-onset and increased
diabetes, hypertension).8 Referral for consideration appetite should prompt genetic evaluation. The
of bariatric surgery is recommended by the AAP one exception is Prader-Willi syndrome, which has
for adolescents (13 years and older) with a BMI distinct nutritional phases, beginning with poor
greater than 120% of the 95th percentile/class 2 feeding and failure to thrive in infancy, not obesity.
obesity. Challenges of bariatric surgery include The classic extreme hyperphagia of Prader-Willi
access to pediatric bariatric surgery and insurance syndrome has an onset around 8 years old.14
coverage.9 Adolescents undergoing bariatric Emerging treatments targeting genetic
surgery need ongoing monitoring for nutritional syndromes include the melanocortin 4 receptor
deficiencies and long-term mental health support. (MC4R) agonist setmelanotide, which is approved
Depression is often a comorbid condition for treatment of biallelic POMC, LEPR, or PCSK1
with obesity. Mental health disorders are not a deficiency, as well as Bardet-Biedl syndrome.
contraindication to bariatric surgery, unless there Recombinant human leptin is available for
is active suicidality, active psychosis, or ongoing treatment of complete leptin deficiency.15 Several
substance abuse.10 drugs for Prader-Willi syndrome are in phase
3 clinical trials. Early genetic testing is crucial
for identifying these syndromes and initiating
appropriate interventions.

ENDO 2025 • Pediatric and Adolescent Endocrinology 253

Conclusions Semaglutide is approved for pediatric use and one
of the more effective antiobesity medications and
The treatment of pediatric obesity requires a
approved for treatment of both type 2 diabetes
multifaceted approach that includes intensive
and obesity. Phentermine/topiramate is not
lifestyle programs, pharmacotherapy, and/or
recommended in a patient with a history of cardiac
bariatric surgery. While lifestyle interventions
arrythmias. Setmelanotide is indicated for treatment
form the foundation of treatment, their modest
of several genetic obesity syndromes but not
effectiveness highlights the need for additional
common obesity. Metformin is an excellent first-
therapeutic options. Pharmacotherapy and
line therapy for type 2 diabetes but has minimal
bariatric surgery offer significant benefits for
antiobesity effects. Orlistat is typically less effective
selected patients, and advances in genetic research
than semaglutide for treatment of adolescent obesity
hold promise for personalized treatment strategies.
and does not lower hemoglobin A1c.
Early identification and intervention are key to
improving outcomes for children and adolescents
with obesity. Case 1, Continued
The patient has some weight loss with semaglutide
Clinical Case Vignettes (BMI now 37 kg/m2) but requires addition of basal
insulin for persistent hyperglycemia. The family
Case 1 is interested in additional options for treatment of
A 15-year-old boy presents for evaluation of type obesity.
2 diabetes. He has been overweight for several
years, but reports gaining 30 lb (13.6 kg) over Which of the following would
summer break that he attributes to more snacking represent a contraindication to
while at home alone. At his well-child visit, his bariatric surgery in this patient?
BMI is 40 kg/m2 (class 3 obesity). The pediatrician A. Age
sent screening labs which were significant for a B. Class 2 obesity
hemoglobin A1c value 7.5% (58 mmol/mol), mild C. Depression with suicidality
mixed hyperlipidemia and elevated transaminases.
D. Insulin-requiring type 2 diabetes
There is a family history of obesity and type 2
diabetes in his father and maternal grandmother. Answer: C) Depression with suicidality
Medical history is significant for an episode of
supraventricular tachycardia and depression with The patient’s age and degree of obesity meet
a recent hospital admission for suicidality. He is criteria for referral for consideration of bariatric
asymptomatic without polyuria, polydipsia, or surgery. Type 2 diabetes, whether insulin
weight loss. dependent or not, and other obesity-related
comorbidities are further indications for bariatric
Which of the following antiobesity surgery. While a history of mental illness is not
medications would you recommend as a contraindication for bariatric surgery, active
first-line treatment for this patient? psychosis, suicidality, and current substance abuse
A. Semaglutide are reasons to delay referral.
B. Phentermine/topiramate
C. Setmelanotide Case 2
D. Metformin You are consulted for abnormal weight gain
E. Orlistat in an 8-year-old girl. Her weight is at the 99th
percentile, and height is tracking along the 50th
Answer: A) Semaglutide percentile. She has a history of developmental

254 ENDO 2025 • Endocrine Case Management

delays and a single kidney. She wears glasses and Answer: C) Setmelanotide
has some difficulty with night vision. Her parents
report onset of obesity in the toddler years. She Setmelanotide is approved for treatment of obesity
likes to snack and eats an adult portion at dinner. in patients 2 years and older with Bardet-Biedl
She participates in a Special Olympics softball syndrome. The other options are all antiobesity
program for exercise. There is no family history of medications, but they are not approved for a child
consanguinity. She has 2 older siblings; both are this young and not specifically indicated for her
healthy and do not have obesity. syndromic obesity.

Which of the following is the best laboratory Case 3

test to order now for this patient?
A child presents at 5 years old with class 3 obesity
A. Methylation testing of chromosome 15 (BMI = 145% of the 95th percentile). She had rapid
B. Thyroid hormone levels weight gain noted in early infancy, associated with
C. Targeted sequencing of GNAS severe hyperphagia. As an infant she would eat
D. Genetic obesity panel until she vomited. Now as a child she will sneak
food at night and is never satiated. She is doing
E. Midnight salivary cortisol level
well in school without any developmental delays
Answer: D) Genetic obesity panel or other chronic medical problems. Her height is
at the 95th percentile. She has acanthosis nigricans
This patient has clinical features of Bardet- on exam but no other clinically significant physical
Biedl syndrome, including early-onset obesity, or laboratory findings. The patient is adopted and
developmental delays, kidney anomalies, and night family history is unknown.
blindness (early sign of rod-cone dystrophy). A
genetic obesity panel is an appropriate next step, Which of the following genetic obesity
as there are more than 20 genes associated with disorders is most likely in this patient?
Bardet-Biedl syndrome. Methylation testing A. Prader-Willi syndrome
of chromosome 15 is used in the diagnosis of
B. Bardet-Biedl syndrome
Prader-Willi syndrome. Variants in GNAS can
cause pseudohypoparathyroidism. A decrease in C. MC4R deficiency
linear growth velocity would be expected from D. POMC deficiency
symptomatic hypothyroidism or hypercortisolism. E. Leptin deficiency
Answer: C) MC4R deficiency
Case 2, Continued
The child is found to have 2 likely pathogenic This patient has severe, early-onset obesity with
variants in the BBS2 gene. Ophthalmology hyperphagia, concerning for a genetic etiology.
consultation showed rod-cone dystrophy. MC4R deficiency is the most common cause
of nonsyndromic genetic obesity. Prader-Willi
Which of the following medications syndrome causes failure to thrive in infancy with
is indicated for treatment of hyperphagia onset later in childhood, as well as
obesity in this child? developmental delays. Bardet-Biedl syndrome is
associated with numerous congenital anomalies,
A. Semaglutide
such as polydactyly, genitourinary anomalies,
B. Phentermine/topiramate developmental delays, and rod-cone dystrophy.
C. Setmelanotide POMC deficiency is a rare autosomal recessive
D. Tirzepatide disorder associated with congenital adrenal
E. Orlistat insufficiency. Leptin deficiency is extremely rare,

ENDO 2025 • Pediatric and Adolescent Endocrinology 255

autosomal recessive, and often associated with • Several classes of antiobesity medications are
frequent infections in childhood. approved for use in children.
• Bariatric surgery is an option for adolescents
Key Learning Points with class 2 obesity.
• Genetic testing can help determine the
• Lifestyle modification is an important part of underlying cause of obesity.
obesity management but is rarely sufficient as
• Some genetic obesity disorders have available
monotherapy.
targeted pharmacotherapies.

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rebound and the risk of adult obesity. Pediatrics. 1998;101(3):E5. PMID: Interest Group. Trends in pediatric obesity management, a survey from the
9481024 Pediatric Endocrine Society Obesity Committee. J Pediatr Endocrinol Metab.
2. Serdula MK, Ivery D, Coates RJ, Freedman DS, Williamson DF, Byers T. 2020;33(4):469-472. PMID: 32069245
Do obese children become obese adults? A review of the literature. Prev Med. 10. Pratt JSA, Browne A, Browne NT, et al. ASMBS pediatric metabolic and
1993;22(2):167-77. PMID: 8483856 bariatric surgery guidelines, 2018. Surg Obes Relat Dis. 2018;14(7):882-901.
3. Styne DM, Arslanian SA, Connor EL, Farooqi IS, Murad MH, Silverstein PMID: 30077361
JH, Yanovski JA. Pediatric obesity-assessment, treatment, and prevention: 11. Farooqi IS, Keogh JM, Yeo GSH et al. Clinical spectrum of obesity
an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. and mutations in the melanocortin 4 receptor gene. N Engl J Med.
2017;102(3):709-757. PMID: 28359099 2003;348(12):1085-1095. PMID: 12646665
4. Hampl SE, Hassink SG, Skinner AC, et al. Clinical practice guideline for the 12. Lubrano-Berthelier C, Dubern B, Lacorte J-M, et al. Melanocortin 4 receptor
evaluation and treatment of children and adolescents with obesity. Pediatrics. mutations in a large cohort of severely obese adults: prevalence, functional
2023;151(2):e202206040. PMID: 366221115 classification, genotype-phenotype relationship, and lack of association with
5. Al-Khudairy L, Loveman E, Colquitt JL, et al. Diet, physical activity binge eating. J Clin Endocrinol Metab. 2006;91(5):1811-1818. PMID: 16507637
and behavioural interventions for the treatment of overweight or 13. Stutzmann F, Tan K, Vatin V, et al. Prevalence of melanocortin-4
obese adolescents aged 12 to 17 years. Cochrane Database Syst Rev. receptor deficiency in Europeans and their age-dependent penetrance
2017;6(6):CD012691. PMID: 28639320 in multigenerational pedigrees. Diabetes. 2008;57(9):2511-2518. PMID:
6. Sjostrom L, Rissanen A, Andersen T, et al. Randomised placebo- 185559663
controlled trial of orlistat for weight loss and prevention of weight regain 14. Miller JL, Lynn CH, Driscoll DC, et al. Nutritional phases in Prader-Willi
in obese patients. European Multicentre Orlistat Study Group. Lancet. syndrome. Am J Med Genet A. 2011;155A(5):1040-1049. PMID: 21465655
1998;352(9123):167-172. PMID: 9683204 15. Farooqi IS, Matarese G, Lord GM, et al. Beneficial effects of leptin on obesity,
7. Weghuber D, Barrett T, Barrientos-Perez M, et al; STEP TEENS T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of
Investigators. Once-weekly semaglutide in adolescents with obesity. N Engl J human congenital leptin deficiency. J Clin Invest. 200;110(8):1093-1103.
Med. 2022;387(24):2245-2257. PMID: 36322838 PMID: 12393845
8. Inge TH, Courcoulas AP, Helmrath MAet al., Five-year outcomes of
gastric bypass in adolescents as compared with adults. N Engl J Med.
2019;380(22):2136-2145. PMID: 31461610

256 ENDO 2025 • Endocrine Case Management

REPRODUCTIVE
ENDOCRINOLOGY
Hormone Management in
Aging Transgender Patients
Danit Ariel, MD, MS. Division of Endocrinology, Gerontology and Metabolism. Stanford
University School of Medicine, Stanford, CA; Email: [email protected]

Micol S. Rothman, MD. Endocrinology, Diabetes, and Metabolism University of Colorado

School of Medicine, Aurora; Email: [email protected]

Educational Objectives older adults. Moreover, despite guidelines for the

initiation and monitoring of GAHT, there are no
After reviewing this chapter, learners should be
formal recommendations to guide management of
able to:
GAHT for aging TGD individuals.
• Describe the effect that gender-affirming
hormone therapy (GAHT) may have on Practice Gaps
cardiovascular disease risk factors in older
transgender and gender-diverse (TGD) • No specific guidelines exist for the
individuals. management of GAHT for older TGD
• Implement osteoporosis screening individuals.
appropriately in older TGD individuals. • No specific gender-affirming care guidelines
• Explain the effect of GAHT on natural exist for the management of the menopausal
menopause in TGD patients designated female transition in older TGD individuals.
at birth.
Discussion
Gender-affirming care remains a crucial component
Significance of the of health care for aging TGD individuals,
necessitating a lifespan approach that incorporates
Clinical Problem both medical and psychosocial considerations.
The proportion of people identifying as TGD Long-term GAHT requires careful monitoring for
ranges from 0.5% to 3% globally.1-3 As the TGD potential effects on cardiovascular health, bone
population advances in age, health care systems density, and metabolic function.5 Feminizing GAHT
must evolve to accommodate their distinct has been associated with increased thrombotic
medical, psychosocial, and structural determinants risk and necessitates individualized cardiovascular
of health. The confluence of aging and gender screening protocols.6 Similarly, masculinizing
diversity necessitates a nuanced understanding of GAHT can influence lipid profiles, hematocrit
chronic disease burden, mental health trajectories, levels, and bone mineral density, warranting
social determinants, and legal protections continued endocrinological oversight.8
interwoven with GAHT.4 While there are not formal guidelines for
Despite the extensive number of studies cardiovascular screening or specific treatments for
focused on the health of TGD individuals in recent TGD people, studies have raised concerns about
years, there remains a lack of studies focused on the risk of cardiovascular disease in transgender

258 ENDO 2025 • Endocrine Case Management

women, although results have varied in their it is affected by one’s physical, psychological,
findings based on the comparator groups chosen. emotional, and cultural lens.
The STRONG study, which is the largest US In a study examining transgender women’s
study, found 2.9 myocardial infarctions per 1000 experience and belief about menopause, authors
patient-years in a cohort of 2842 transgender found that (1) menopause was generally not
women.6 This represented an increased risk considered to be particularly relevant in light of
compared with that of cisgender women (adjusted biological differences between transgender and
hazard ratio [aHR] = 1.8; 95% CI, 1.1-2.9) but not cisgender women; (2) most transgender women
cisgender men (aHR = 0.9; 95% CI, 0.6-1.5). expected to use GAHT indefinitely; and (3)
A recent meta-analysis that included 10 studies many expressed uncertainty regarding clinical
with 15,781 transgender women from both Europe management approaches at and beyond the
and the United States found a 1.2% incidence of “menopausal age,” largely because of clinicians’
myocardial infarction with a pooled relative risk inexperience with this clinical management.10
of 1.0 (95% CI, 0.8-1.2) compared with cisgender There are no studies evaluating transgender men’s
men.8 They found a higher incidence of stroke personal experiences, beliefs, and expectations of
(1.8%; 1.3 times higher than that of cisgender men menopause and GAHT.11 However, transgender
[95% CI, 1.0-1.8]) and venous thromboembolism men are likely to have different experiences from
(1.6%; 2.2 times higher than that of cisgender men those of transgender women depending on the
[95% CI, 1.1-4.5]). Comparison was not made level of their transitioning and history of gender-
to cisgender women in this cohort. Given the affirming surgery. For transgender women on
heterogeneity of these and other results, this is estrogen-based GAHT who reach menopausal age,
certainly an area that needs more study. The role of individualized shared decision-making is needed
minority stress and its impact on other risk factors to determine next steps in their GAHT treatment.
must be considered as well.9 Depending on gonadectomy status, some women
For transgender men, the data are generally may decrease their estradiol dosage to be more
reassuring. The STRONG study did not show in line with the steady decline of estradiol over
an increased risk of venous thromboembolism, a cisgender woman’s lifespan. In this case, we
ischemic stroke, or myocardial infraction for would recommend a gradual decrease to minimize
comparator groups of both cisgender men and potential vasomotor symptoms. In addition,
cisgender women.6 The previously mentioned switching to a transdermal route of estradiol
recent meta-analysis found the incidence of is recommended to reduce cardiovascular risk.
myocardial infarction was 0.6%, with a pooled Likewise, for transgender men on testosterone-
relative risk of 1.7 (95% CI, 0.8-3.6) in the based GAHT, it is important to consider the
transgender male group compared with cisgender patient’s personal goals and quality of life,
women.8 Some studies have shown small rises comorbidities, and medical risks that increase
in blood pressure, and testosterone is known to with age when addressing continued GAHT. For
decrease HDL cholesterol. Longer-term studies those achieving target levels of total testosterone
with older adults are needed to know how best to midcycle (400-700 ng/dL [13.9-24.3 nmol/L]),
counsel aging transgender men. we would not expect menopausal symptoms,
Cessation of ovarian function affects all such as vasomotor symptoms. No vasomotor
persons with ovaries and may be relevant to older symptoms are expected because there is a stable
transgender people assigned female at birth who exogenous source of sex hormones, so the
do not use GAHT. However, the term menopause decline in endogenous sex hormone production
is framed around cisgender women. Menopause is irrelevant. Additionally, elevated levels of total
in aging TGD individuals is a complex process testosterone have the potential to be aromatized to
at the intersection of gender identity and aging; estradiol, which would provide estrogen to protect

ENDO 2025 • Reproductive Endocrinology 259

against vasomotor symptoms. Lastly, osteoporosis levels before initiation of hormone therapy;
is also a disease impacted by age. Numerous (2) hypogonadism with no plan to take GAHT;
studies have shown that transgender girls and and (3) other International Society of Clinical
women frequently have lower bone mineral Densitometry indications for BMD testing, such
density (BMD) than their peers of the same sex as glucocorticoid use and hyperparathyroidism.16
assigned at birth, even before initiating GAHT.12 In our practice, we incorporate BMD data with
The etiology is not completely understood, but it a variety of risk factors to make decisions for
may be related to decreased physical activity, low individual patients regarding pharmacologic
vitamin D, and other factors. Transgender youth treatment options for low BMD.
who undergo treatment with GnRH agonists Potential discontinuation of hormone therapy
may have additional concerns for low peak bone in later life introduces additional complexities.
mass. BMD typically improves with initiation Some aging TGD individuals may face pressure to
of estrogen-based GAHT in adults, despite reduce or cease hormone therapy due to medical
suppression of testosterone, but this generally comorbidities, institutional policies in assisted
levels off after a few years of treatment.13 The only living or long-term care settings, or provider biases.
study with fracture data we have suggests that However, cessation of GAHT can lead to physical
older transgender women may have increased and psychological distress, including dysphoria,
fracture risk when compared with cisgender men decreased muscle mass, osteoporosis risk, and mood
of similar age, but there is no difference in fracture instability. Expert opinion holds that GAHT should
risk when compared with cisgender women of not be withheld solely based on age.5 Multiple
similar age.14 Transgender boys and men are factors should affect decisions on continued or
more likely to have baseline BMD similar to their dose-adjusted GAHT, including comorbidities,
cisgender peers, and addition of testosterone-based risks, and patient preferences and goals. Thus,
GAHT appears to maintain BMD despite relative an individualized, patient-centered approach is
suppression of estradiol. An exception to this may essential to ensure continued access to GAHT while
be in patients who undergo oophorectomy, but balancing overall health considerations.
more data are needed in this population.15
Regarding interpretation of DXA in TGD
people, the International Society of Clinical
Clinical Case Vignettes
Densitometry released a position statement in Case 1
2019 on “Bone Densitometry in Transgender and A 57-year-old transgender woman is seen in the clinic
Gender Non-Conforming (TGNC) Individuals.16 after hospital admission for myocardial infarction. At
When calculating the BMD Z-score in TGD the time of admission, she was on a GAHT regimen
individuals, they recommend “using the reference consisting of oral estradiol, 6 mg daily, and micronized
data (mean and standard deviation) of the gender progesterone, 100 mg daily. She underwent
conforming with the individual’s gender identity.” orchiectomy and vaginoplasty several years before this
Multiple guidelines suggest screening BMD at admission. She underwent coronary artery stenting
various ages for transgender women. Endocrine and has been prescribed appropriate lipid-lowering
Society guidelines suggest considering screening and blood pressure–lowering medications. Her
transgender women with DXA as a baseline for estradiol and micronized progesterone were held at
patients at age 60 years, if GAHT is stopped after the time of admission, and she was told not to restart
gonadectomy, or for those with other risk factors until seeing you. She is in no distress today and will be
for low BMD.17 International Society of Clinical beginning cardiac rehabilitation, but she shares that
Densitometry guidelines suggest baseline BMD she is experiencing hot flashes and fatigue.
testing for patients with (1) history of gonadectomy
or therapy that lowers endogenous gonadal steroid

260 ENDO 2025 • Endocrine Case Management

Which of the following is true? used cyproterone or medroxyprogesterone,
A. Standards of Care Version 8 guidelines suggest and some have questioned whether micronized
transgender women transition to injectable progesterone could be a better choice with fewer
estrogen at age 55 years adverse effects, but no data currently support this.
B. Micronized progesterone is the optimal choice Given this patient’s recent cardiac event, it would
if she restarts GAHT seem prudent to continue withholding micronized
progesterone at this time even if estrogen is
C. The antiandrogen spironolactone is the reinitiated via the transdermal route.
optimal choice if she restarts GAHT
D. Oral estrogen is the optimal choice if she
restarts GAHT Case 2
E. Standards of Care Version 8 guidelines suggest A 50-year-old healthy transgender man on
transgender women transition to transdermal masculinizing GAHT since age 30 years without
estrogen at age 45 years interruption presents with vasomotor symptoms
(hot flashes during the day and night sweats).
Answer: E) Standards of Care Version 8 He has not had removal of his uterus or ovaries.
guidelines suggest transgender women transition He reports no extraordinary social or economic
to transdermal estrogen at age 45 years stressors and states that these vasomotor
symptoms are affecting his concentration at
As cardiovascular disease is a disease of aging,
work and quality of sleep. His mother was
we are likely to encounter an increasing
50 years old when she went through natural
number of TGD patients who have had cardiac
menopause, and he wonders whether this is what
events. This is a challenging clinical scenario,
he is experiencing. He was taking testosterone
and careful discussion should be had with the
cypionate, 100 mg intramuscularly once weekly,
patient in conjunction with her cardiologist. If
and another gender care clinic provider increased
she is doing well with rehabilitation and is on
the dosage to 125 mg intramuscularly once weekly,
adequate antiplatelet and lipid-lowering therapy,
with no symptom improvement, but worsening
it may be reasonable to restart GAHT using
acne. The patient’s midcycle total testosterone
low-dosage transdermal estrogen. The World
concentration was 769 ng/dL (26.7 nmol/L).
Professional Association for Transgender Health
(WPATH) Standards of Care Version 8 guidelines Which of the following is true?
suggest transitioning all transgender women to
transdermal estrogen at age 45 years (thus, Answer A. His symptoms are likely related to natural
E is correct and Answers A and D are incorrect).5 menopausal
Spironolactone (Answer C) is an antiandrogen B. Low-dosage estradiol should be started to treat
that acts of the level of the testosterone receptor vasomotor symptoms
to block androgen action and also decrease C. Evaluation should be done for other possible
testosterone levels to some degree. As this patient endocrine causes of hot flashes
has already had an orchiectomy, it would not have D. Low-dosage progestogen should be started to
a role in her gender-affirming care at this time. treat vasomotor symptoms
Progesterone (Answer B) is not recommended E. Nonhormonal therapies, such as fezolinetant,
as part of standard GAHT.5 A recent systematic selective serotonin reuptake inhibitor,
review did not find evidence for improved quality serotonin and norepinephrine reuptake
of life or breast development and raised concerns inhibitor, or gabapentin should be started to
for increased risk of venous thromboembolism, treat vasomotor symptoms
as well as adverse effects on mood and decreased
HDL cholesterol.18 The studies reviewed typically

ENDO 2025 • Reproductive Endocrinology 261

Answer: C) Evaluation should be done for other She wonders whether she should have DXA to
possible endocrine causes of hot flashes assess her BMD.
Evaluation should be undertaken for other Which of the following is true?
possible endocrine causes of hot flashes,
A. Since she was assigned male at birth, DXA
including hyperthyroidism, hypoglycemia,
screening is not recommended at any age
pheochromocytoma, carcinoid syndrome, and
anxiety (Answer C). The patient has been on B. She should have DXA with Z-scores from the
longstanding and consistent masculinizing male reference database
GAHT with testosterone, without a lapse in use. C. She should have DXA with Z-scores from the
Therefore, we expect his endogenous estradiol female reference database
to be suppressed through suppression of his D. The FRAX calculator has an option to
hypothalamic-pituitary-ovarian axis. Moreover, calculate fracture risk outside the gender
laboratory studies demonstrate that he has binary
adequate levels of circulating total testosterone. E. Transgender women typically have better
Thus, assuming his symptoms are due to natural BMD than their cisgender peers before
menopause (Answer A) is incorrect, and his starting GAHT
vasomotor symptoms should not be treated with
estradiol, progestogen, or nonhormonal therapies Answer: C) She should have DXA with Z-scores
(Answers B, D, and E) given that their etiology is from the female reference database
likely another endocrine or nonendocrine cause.
There are concerns that transgender women have
In this patient’s case, his masculinizing
lower BMD than their cisgender peers (thus,
GAHT should be continued indefinitely with
Answer E is incorrect) and screening would be
consideration of his goals, comorbid conditions,
recommended (thus, Answer A is incorrect).
risks associated with GAHT, social or economic
Currently, the FRAX calculator does not have
issues, and gender-affirming surgeries. If he
options outside the gender binary (thus, Answer D
wanted to eventually stop masculinizing GAHT at
is incorrect). The International Society of Clinical
this age or beyond, no significant change would be
Densitometry suggests that BMD, and specifically
expected in masculine secondary sex characteristics
Z-scores, in people on GAHT be interpreted using
since endogenous estrogen production would
gender identity (thus, Answer C is correct and
remain low. In that case, GAHT should be
Answer B is incorrect). The T-score reference is
gradually weaned to avoid signs and symptoms of
typically female in all comers, so this would not be
sex hormone deficiency.
affected by gender identity.

Case 3
Key Learning Points
A 66-year-old transgender woman presents
for routine follow-up of GAHT. Her current • Long-term GAHT requires careful monitoring
medications include estradiol patch, 0.200 mg for potential effects on cardiovascular health,
changed twice weekly; spironolactone, 100 mg bone density, and metabolic function.
daily; metformin, 1000 mg twice daily; lisinopril,
• GAHT should not be withheld solely based
10 mg daily; and sertraline, 50 mg daily. She has
on age.
a history of tobacco use (but does not currently
smoke cigarettes). She exercises twice weekly and • The World Professional Association for
has never had a fracture. Transgender Health Standards of Care
She mentions that her 89-year-old mother Version 8 guidelines suggest transitioning all
recently died after complications of a hip fracture.

262 ENDO 2025 • Endocrine Case Management

 transgender women to transdermal estrogen at and shared-decision making must be used in
age 45 years. creating an individualized treatment plan.
• Menopause in aging TGD individuals is a • Older transgender women may have increased
complex process at the intersection of gender fracture risk when compared with risk of
identity and aging, impacted by one’s physical, similarly aged cisgender men, but there is no
psychological, emotional, and cultural lens, difference in fracture risk when compared
with cisgender women of similar age.

References
1. Herman J, Flores A, O’Neill K. How many adults and youth identify as 10. Mohamed S, Hunter MS. Transgender women’s experiences and beliefs about
transgender in the United States? [Internet]. UCLA School of Law Williams hormone therapy through and beyond mid-age: an exploratory UK study. Int J
Institute; 2022. Available from: https://williamsinstitute.law.ucla.edu/wp- Transgend. 2019;20(1):98-107. PMID: 32999597
content/uploads/Trans-Pop-Update-Jun-2022.pdf 11. Kelley C and Ariel D. A review of menopause in transgender and gender
2. Spizzirri G, Eufrásio R, Lima MCP, et al. Proportion of people identified as diverse individuals. Curr Opin Obstet Gynecol. 2025;37(2):83-96. PMID:
transgender and non-binary gender in Brazil. Sci Rep. 2021;11(1):2240. PMID: 39970047
33500432 12. Rothman MS, Iwamoto SJ. Bone health in the transgender population. Clin
3. Ipsos Global Advisor. LGBT+Pride 2023 Global Survey Report [Internet]. Rev Bone Miner Metab. 2019;17(2):77-85. PMID: 31452648
Ipsos; 2023. Available from: https://www.ipsos.com/sites/default/files/ 13. Wiepjes CM, de Jongh RT, de Blok CJ, et al. Bone safety during the first ten
ct/news/documents/2023-05/Ipsos%20LGBT%2B%20Pride%202023%20 years of gender-affirming hormonal treatment in transwomen and transmen.
Global%20Survey%20Report%20-%20rev.pdf J Bone Miner Res. 2019;34(3):447-454. PMID: 30537188
4. Witten TM, Eyler AE. Gay, Lesbian, Bisexual, and Transgender Aging: Challenges 14. Wiepjes CM, de Blok CJ, Staphorsius AS, et al. Fracture risk in trans women
in Research, Practice, and Policy. Johns Hopkins University Press, 2012. and trans men using long-term gender-affirming hormonal treatment: a
5. Coleman E, Radix AE, Bouman WP, et al. Standards of care for the health nationwide cohort study. J Bone Miner Res. 2020;35(1):64-70. PMID: 31487065
of transgender and gender diverse people, version 8. Int J Transgend Health. 15. Sanna E, Lami A, Giacomelli G, et al. Bone health in transgender assigned
2022;23(Suppl 1):S1-S259. PMID: 36238954 female at birth people: effects of gender-affirming hormone therapy and
6. Getahun D, Nash R, Flanders WD, et al. Cross-sex hormones and acute gonadectomy. Front Endocrinol (Lausanne). 2024;15:1416121. PMID: 39391880
cardiovascular events in transgender persons: a cohort study. Ann Intern Med. 16. Rosen HN, Hamnvik O-PR, Jaisamrarn U, et al. Bone densitometry in
2018;169(4):205-213. PMID: 29987313 transgender and gender non-conforming (TGNC) individuals: 2019 ISCD
7. Irwig MS. Testosterone therapy for transgender men. Lancet Diabetes Official Position. J Clin Densitom. 2019;22(4):544-553. PMID: 31327665
Endocrinol. 2017;5(4):301-311. PMID: 27084565 17. Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of
8. van Zijverden LM, Wiepjes CM, van Diemen JJK, Thijs A, den Heijer M. gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical
Cardiovascular disease in transgender people: a systematic review and meta- practice guideline. J Clin Endocrinol Metab. 2017;102(11):3869-3903. PMID:
analysis. Eur J Endocrinol. 2024;190(2):S13-S24. PMID: 38302717 28945902
9. Iwamoto SJ, Defreyne J, Kaoutzanis C, Davies RD, Moreau KL, Rothman 18. Patel KT, Adeel S, Rodrigues Miragaya J, Tangpricha V. Progestogen use
MS. Gender-affirming hormone therapy, mental health, and surgical in gender-affirming hormone therapy: a systematic review. Endocr Pract.
considerations for aging transgender and gender diverse adults. Ther Adv 2022;28(12):1244-1252. PMID: 36007714
Endocrinol Metab. 2023;14:20420188231166494. PMID: 37113210

ENDO 2025 • Reproductive Endocrinology 263

Amenorrhea Management
in Overweight and
Underweight Women
Daniel A. Dumesic, MD. Department of Obstetrics and Gynecology, David Geffen
School of Medicine at University of California Los Angeles, Los Angeles, CA; Email:
[email protected]

Educational Objectives amenorrhea. Hypothalamic amenorrhea

accompanies suppression of circulating
After reviewing this chapter, learners should be
gonadotropin and estradiol levels without a
able to:
central nervous system lesion and can occur in
• Outline the diagnostic and laboratory women who are underweight (<10% below ideal
assessment of women with hypothalamic body weight). These women often report weight
amenorrhea. loss, emotional strain, and excessive exercise
and can have an eating disorder, although no
• Describe the management of hypothalamic
precipitating event may be identified.2 Low
amenorrhea and its comorbidities.
bone mass from HPO suppression is a serious
• Distinguish amenorrhea due to obesity from long-term complication. With undernutrition,
that due to polycystic ovary syndrome (PCOS). anorexia nervosa (AN) can occur when weight
loss of greater than 15% for height accompanies an
altered body image and amenorrhea.
Conversely, obesity is now a global epidemic
Significance of the affecting 12% of the world’s adult population.
Clinical Problem Amenorrhea due to obesity also disrupts HPO
function through enhanced adipose aromatization
Nutrition is important in human reproduction,
of androgen to estrogen, altered adipokine
with body fat mass being a crucial permissive
production, and impaired ovarian function.
signal governing the hypothalamo-pituitary-
Hyperinsulinemia from adipose-dependent insulin
ovarian (HPO) axis.1,2 Both insufficient and
resistance increases androgen bioavailability
excessive body fat in women can disrupt
through decreased hepatic SHBG, which
metabolic-reproductive signaling and cause
can mimic or exaggerate PCOS expression.3
ovulatory dysfunction and amenorrhea, defined
Consequently, amenorrhea due to obesity can be
as absent menses for over a 6-month period or
easily confused with amenorrhea due to PCOS,
for at least 3 previous menstrual cycles (normal
with increased adiposity in both conditions
menstrual cycle duration: between 21 and 45
increasing the risks of metabolic syndrome,
days from 1 to <3 years post menarche; between
cancers, and subfertility.3,4
21 and 35 days from ≥3 years post menarche to
perimenopause).
Several mechanisms underlying nutrition,
body fat, stress, and exercise contribute to

264 ENDO 2025 • Endocrine Case Management

Practice Gaps nutritional and psychological support, exercise
modification, and hormone replacement.
• Lack of awareness exists regarding the Importantly, adipose serves as both energy
diagnosis of hypothalamic amenorrhea in storage and a dynamic endocrine organ.
young women. Subcutaneous adipose normally protects against
insulin resistance through fat storage, while
• Long-term adverse consequences of
intra-abdominal adipose has the opposite effect.
hypothalamic amenorrhea may be
Normally, the anorexigenic hormone leptin and
unrecognized.
the orexigenic hormone ghrelin contribute to
• Distinguishing amenorrhea due to obesity metabolism, energy homeostasis, and satiety,
from amenorrhea due to PCOS can be with contributions from enteroendocrine
challenging. cells and gastrointestinal flora that affect the
• Personalized amenorrhea management should gut-brain relationship.8 When energy intake
be established for overweight and underweight exceeds the capacity to safely store fat, ectopic
women. lipid accumulates in nonadipose tissue where it
induces oxidative/endoplasmic reticulum stress
linked with insulin resistance and inflammation
Discussion (ie, lipotoxicity). Disruption of HPO function
Functional hypothalamic amenorrhea (FHA) is a through increased adiposity can adversely affect
form of chronic anovulation associated with stress, puberty, fertility, menstrual cyclicity, endometrial
weight loss, and/or excessive exercise without an development, and metabolism in women with or
identifiable organic cause.2 Often accompanying without PCOS. Although medications, hormonal
an energy deficit below 30 kcals/kg (fat free mass), managements, and bariatric surgery can improve
FHA is a diagnosis of exclusion that requires some reproductive and metabolic consequences
assessment of systemic and endocrine etiologies. of obesity,4,9,10 questions remain regarding adverse
Women with FHA have a higher prevalence of effects of obesity on oocyte quality and endometrial
disordered eating patterns, stress, weight loss, or development in women wishing to conceive.
excess exercise, occasionally accompanied by an
underlying genetic disorder.5 Eating disorders
are common in adolescent girls; in a cross- Clinical Case Vignettes
sectional study of girls (mean age 15.0 years), 23% Case 1
had disordered eating and 4.1% had secondary A 17-year-old woman presents with secondary
amenorrhea.6 amenorrhea. She has no excess hair growth,
Adverse consequences of FHA involve galactorrhea, hot flashes, or headaches. Menarche
metabolism, neuroendocrine function, and occurred at age 11 years, and she had regular
reproduction. Significant risks include delayed monthly menses until 6 months ago, when she
puberty, amenorrhea, infertility, and long- lost more than 1 kg/week over 3 consecutive
term consequences of hypoestrogenism, with a weeks while exercising 5 to 6 days weekly with
significant long-term risk being bone loss and/or heavy weights and running 10 miles weekly. She
inability to obtain peak bone mass despite exercise. does not eat red meat, dairy, or eggs. She does
Prolonged FHA also has adverse effects on not take any medications and uses condoms for
metabolic, bone, cardiovascular, mental/cognitive, contraception. Her medical history is notable for
and reproductive health.5,7 Women who conceive an altered body image and depression.
with a history of FHA are at risk for preterm labor, On physical examination, she is afebrile,
fetal loss, small-for-gestational-age infants, and blood pressure is 80/40 mm Hg, and pulse rate
cesarean delivery. Multidisciplinary care includes

ENDO 2025 • Reproductive Endocrinology 265

is 39 beats/min. Her BMI is 17 kg/m2. She has and disordered eating habits. Hospitalization for
normal breast and pelvic development. the treatment of severe AN may be necessary (Table
1, following page).13 Approximately 50% of adults
Laboratory test results: with AN recover following behavioral, psychiatric,
LH = 1.5 mIU/mL (2.0-8.0 mIU/mL [follicular]) and medical therapies; 30% experience only partial
(SI: 1.5 IU/L [2.0-8.0 IU/L]) recovery; while the remaining have relapses or
FSH = 4.0 mIU/mL (3.0-10.0 mIU/mL [follicular]) chronic disease.11,12 Recovery can improve many,
(SI: 4.0 IU/L [3.0-10.0 IU/L])
but not all, hormonal changes, with deficits in bone
Estradiol = 20 pg/mL (20-400 pg/mL)
(SI: 73.4 pmol/L [73.4-1468.4 pmol/L]) mass accrual due to multiple adaptive endocrine
Hemoglobin = 8.5 g/dL (12.0-18.0 g/dL) (SI: 85 g/L and neuropsychiatric comorbidities.12,13
[120-180 g/L])
Sodium = 123 mEq/L (135-146 mEq/L)
(SI: 123 mmol/L [135-146 mmol/L]) Case 1, Continued
Serum urea nitrogen = 15 mg/dL (7-22 mg/dL) The patient is hospitalized, and cognitive
(SI: 5.4 mmol/L [2.5-7.9 mmol/L])
Potassium = 2.4 mEq/L (3.6-5.3 mEq/L) behavioral therapy is started. Serum vitamin D,
(SI: 2.4 mmol/L [3.6-5.3 mmol/L]) calcium, magnesium, and zinc concentrations are
normal. DXA shows osteopenia of the spine and
Findings on MRI of the head are normal. hip regions. You are consulted regarding hormone
replacement.
Which of the following endocrine changes
is most likely to exist in this patient? Which of the following therapies should
A. Decreased antidiuretic hormone be started to prevent bone loss?
B. Decreased cortisol A. Transdermal estradiol with cyclic progesterone
C. Decreased ghrelin B. Oral estrogen with cyclic progesterone
D. Increased GH C. Oral contraceptives
E. Increased total thyroxine D. Bisphosphate
E. Denosumab
Answer: D) Increased GH
Answer: A) Transdermal estradiol
AN is a condition of severe undernutrition
with cyclic progesterone
characterized by altered body image, persistent
food restriction, low body weight, and endocrine About 50% of girls with AN have a bone mineral
dysregulation.11 Accompanied by neuropsychiatric density Z-score less than –2, with the spine being
comorbidities, AN occurs in 1% of adolescent girls commonly affected. Transdermal estrogen can be
and young women.12 Individuals with AN have used in teenagers who have completed growth and
HPO suppression with sex steroid deficiency, have a significant history of fracture or low bone
GH resistance (ie, increased GH secretion and density Z-scores. Transdermal estradiol and cyclic
decreased systemic IGF-1), hypercortisolism, low progesterone replacement increases spine and hip
total T4 (from its increased peripheral deiodination bone mineral density in adolescents with anorexia,
to reverse T3), hyponatremia (from increased although catch-up growth may not occur because
antidiuretic hormone), decreased leptin and insulin, of persistent hormone abnormalities (eg, cortisol)
and increased ghrelin.11,12 These endocrine changes or frequent relapses. Oral estrogen administration
in hypothalamic hormones, adipokines, and is not effective in increasing bone density in these
appetite-regulating hormones can be in response women, perhaps because it lowers hepatic IGF-1
to chronic nutritional deprivation.11 Clinical effects levels as an important bone anabolic hormone.11,12
include hypothalamic amenorrhea, bone loss, The role of oral contraceptives in increasing
mood-affective symptoms, reduced fat/lean mass, bone density is controversial, likely for similar

266 ENDO 2025 • Endocrine Case Management

Table 1. Risk Factors for Severity of AN at 17 Years of Age

Risk factor Normal risk Moderate risk Severe risk

BMI percentile ≥fifth BMI percentile First-fourth BMI percentile <first BMI percentile

BMI ≥18.2 kg/m2 17.2-18.1 kg/m2 ≤17.1 kg/m2

Weight loss Stable 500 g to <1 kg/week for 3 weeks ≥1 kg/week for 3 weeks with <fifth
with <fifth BMI percentile BMI percentile

Fluid intake Little or no reduced fluid Markedly reduced fluid intake or Severe dehydration or cessation of
intake cessation of fluid intake for 12 to fluid intake for >24 h
24 h

Food cessation <12 h in a day 12-24 h >24 h

Heart rate Z-score > –1: Z-score –1 to –4: Z-score < –4:
>63 beats/min 40-62 beats/min <39 beats/min

Systolic blood pressure Z-score > –1 (106 mm Hg) Z-score –1 to –4 (85-105 mm Hg) Z-score < –4 (84 mm Hg)

Diastolic blood pressure Z-score > –1 (63 mm Hg) Z-score –1 to –4 (41-62 mm Hg) Z-score < –4 (42 mm Hg)

Electrocardiography, QTc <460 ms <460 ms >460 ms or electrocardiographic

change not related to QTc

Syncope No (pre)syncope Dizziness, presyncope, or 1 syncope Repeated syncopal episodes

Temperature >36.0°C <36.0°C to 35.5°C <35.5°C

Laboratory findings Normal phosphate, Deviations from normal values Hypophosphatemia (phosphate
sodium, potassium, still within the limits above severe <0.8 mmol/L)
albumin, glucose, values
Hyponatremia (sodium <125 nmol/L)
transaminases, leukocytes,
and hemoglobin Hypokalemia (potassium
<2.5 mmol/L)
Hypoalbuminemia (albumin <30 g/L)
Hypoglycemia (glucose <3 mmol/L)
Transaminases > 3 times normal
Leukocytes <2/nL
Hemoglobin <10 g/dL

Modified from Hebebrand J et al. Dtsch Arztebl Int, 2024; 121(5): 164-174. Published by Deutsches Ärzteblatt International.

effects on lowering IGF-1 and free testosterone Case 2

levels.14 Adequate calcium (1200-1500 mg daily)
A 38-year-old nulliparous woman with obesity
and vitamin D (400-1000 international units [10-
presents with a 4-month history of secondary
25 mcg]) intake is important,5 and vitamin D levels
amenorrhea that was preceded by irregular
should remain above 30 ng/mL (>74.9 nmol/L).
menstrual bleeding. Her medical history is notable
Bisphosphates are not approved for women of
for hypertension, hyperlipidemia, and migraine
childbearing age because they cross the placenta and
headaches with aura. She takes metformin,
can affect fetal development.11 Denosumab, a human
1000 mg orally daily, and uses condoms for
monoclonal antibody against receptor activator of
contraception.
nuclear factor-kB ligand, limits bone resorption by
On physical examination, she is afebrile,
inhibiting osteoclast maturation. It has not been
blood pressure is 135/85 mm Hg, and pulse rate
tested sufficiently in women with anorexia, and fetal
is 90 beats/min. BMI is 31.5 kg/m2. She has
exposure could potentially be teratogenic.2

ENDO 2025 • Reproductive Endocrinology 267

hirsutism and an abdominal circumference of Answer: B) Endometrial biopsy
35.4 in (90 cm).
Abnormal uterine bleeding (AUB) can occur due
Laboratory test results: to polyps, adenomyosis, leiomyoma, endometrial
hyperplasia/malignancy, coagulopathy, and
LH = 15.0 mIU/mL (2.0-8.0 mIU/mL [follicular])
(SI: 15.0 IU/L [2.0-8.0 IU/L]) anovulation associated with unopposed estrogen
FSH = 4.0 mIU/mL (3.0-10.0 mIU/mL [follicular]) stimulation of the endometrium. History,
(SI: 4.0 IU/L [3.0-10.0 IU/L]) examination, and testing in the context of
Testosterone = 72 ng/dL (9-55 ng/dL) age-related causes include pregnancy testing,
(SI: 2.5 nmol/L [0.3-1.9 nmol/L])
complete blood cell count, TSH measurement,
Free testosterone = 0.85 ng/dL (0.08-0.74 ng/dL)
(SI: 0.029 nmol/L [0.003-0.026 nmol/L]) cervical cancer screening, and coagulation
DHEA-S = 4000 ng/mL (400-3600 ng/mL) studies (ie, von Willebrand-ristocetin cofactor
(SI: 108.4 µmol/L [10.8-97.6 µmol/L]) activity, von Willebrand factor antigen, and
Estradiol = 70 pg/mL (20-400 pg/mL) factor VIII) if a bleeding disorder is suspected.
(SI: 257.0 pmol/L [73.4-1468.4 pmol/L])
Although many endometrial sampling
Progesterone = 0.5 ng/mL (2.6-21.5 ng/mL [luteal])
(SI: 1.6 nmol/L [8.3-68.4 nmol/L]) techniques can be used, endometrial biopsy is
Fasting glucose = 104 mg/dL (<100 mg/dL) generally the first-line procedure in women
(SI: 5.8 mmol/L [<5.6 mmol/L]) with AUB who are older than 45 years or who
Hemoglobin A1c = 5.8% (<5.7%) (40 mmol/mol are younger than 45 years with unopposed
[<39 mmol/mol])
estrogen exposure from obesity and/or PCOS.
Total cholesterol = 207 mg/dL (<200 mg/dL)
(SI: 5.36 mmol/L [<5.18 mmol/L]) This patient has PCOS by Rotterdam criteria
HDL cholesterol = 40 mg/dL (>50 mg/dL) with at least 2 of the following 3 features: (1)
(SI: 1.04 mmol/L [>1.30 mmol/L]) clinical/biochemical hyperandrogenism, (2)
LDL cholesterol = 124 mg/dL (<100 mg/dL) oligo-anovulation, and (3) polycystic ovaries,
(SI: 3.21 mmol/L [<2.59 mmol/L])
excluding other endocrinopathies.15 Given her
Non–HDL-cholesterol = 154 mg/dL (<130 mg/dL)
(SI: 3.99 mmol/L [<3.37 mmol/L]) metabolic dysfunction, she is at increased risk for
Triglycerides = 162 mg/dL (<150 mg/dL) endometrial hyperplasia and carcinoma,16 so an
(SI: 1.83 mmol/L [<1.70 mmol/L]) endometrial biopsy is indicated. With sufficient
Hemoglobin, normal tissue, endometrial biopsy can detect endometrial
Electrolytes, normal
disease throughout the uterine cavity but may
Complete metabolic panel, normal
Prolactin, normal not detect disease occupying less than 50% of the
17-Hydroxprogesterone, normal endometrial surface area.
Thyroid function, normal Persistent bleeding despite a benign
Overnight dexamethasone-suppression test, normal endometrial biopsy, or without sufficient
Pregnancy test, negative
tissue, requires further testing, including
Transvaginal ultrasonography shows a 9-mm sonohysterography, dilation and curettage, and/
endometrium, a normal right ovary, and a 12 or hysteroscopy to rule out isolated intrauterine
cc3 left ovary with 22 antral follicles. Results of a pathology. MRI is not a primary imaging modality
Papanicolaou test are normal. for AUB, although it may help guide treatment
of multiple leiomyomata. Laparoscopy is not
Which of the following is the best next step? indicated since transvaginal ultrasonography
A. Dilation and curettage shows a left polycystic ovary with no masses.15
B. Endometrial biopsy
C. Hysteroscopy Case 2, Continued
D. Laparoscopy with hysteroscopy Histological examination of the biopsy tissue
shows endometrial hyperplasia without atypia.
E. Sonohysterography

268 ENDO 2025 • Endocrine Case Management

Which of the following is the best next step? hysterectomy is not an option, an endometrial
A. Endometrial ablation biopsy should be supplemented with dilation and
B. Hysteroscopic-guided uterine sampling curettage and/or hysteroscopic-guided uterine
sampling to exclude malignancy. Relapse of
C. Levonorgestrel-releasing intrauterine device endometrial hyperplasia after initial regression
D. Micronized progesterone can occur. Long-term follow-up is advised, with
E. Oral contraceptives weight loss and glycemic control used to improve
overall health and decrease the risk of endometrial
Answer: D) Micronized progesterone carcinoma. Endometrial ablation is not used in
Endometrial hyperplasia is classified as benign women with unresolved endometrial hyperplasia
endometrial hyperplasia or atypical endometrial who may wish to conceive.
hyperplasia/endometrial intraepithelial neoplasia.17
Benign endometrial hyperplasia rarely progresses Case 2, Continued
to endometrial cancer, with a 20-year progression
The patient returns 1 year after weight loss.
risk of less than 5%. It often is a noninvasive
She wishes to conceive and has had unprotected
abnormal endometrial proliferation from chronic
intercourse for 3 months. Metabolic parameters
anovulatory unopposed estrogen exposure,
have improved, but she has menses every 2
although rare genetic factors exist. Women with
months. She has discontinued metformin.
PCOS are about 3 times more likely to develop
On physical examination, she is afebrile,
endometrial cancer.
blood pressure is 125/80 mm Hg, and pulse rate is
Benign endometrial hyperplasia in
90 beats/min. Her BMI is 27.5 kg/m2.
reproductive-aged women is usually managed
with progestins (ie, medroxyprogesterone Laboratory test results:
acetate, 10 to 20 mg daily; norethindrone acetate,
Testosterone = 58 ng/dL (9-55 ng/dL)
2.5 to 10 mg daily; micronized progesterone, (SI: 2.0 nmol/L [0.3-1.9 nmol/L])
100 mg 2 to 3 times daily; megestrol acetate, Free testosterone = 0.75 ng/dL (0.08-0.74 ng/dL)
40 to 200 daily) or a levonorgestrel-releasing (SI: 0.026 nmol/L [0.003-0.026 nmol/L])
intrauterine device to antagonize estrogen DHEA-S =3600 ng/mL (400-3600 ng/mL)
action on endometrial proliferation and induce (SI: 97.56 µmol/L [10.84-97.56 µmol/L])
Estradiol = 80 pg/mL (20-400 pg/mL)
atrophy. The levonorgestrel-releasing intrauterine (SI: 293.7 pmol/L [73.4-1468.4 pmol/L])
device has a 96% success rate of treating benign Progesterone = 0.7 ng/mL (2.6-21.5 ng/mL [luteal])
endometrial hyperplasia.18 Progestins used in a (SI: 2.2 nmol/L [8.3-68.4 nmol/L])
continuous manner over 3 to 6 months, however, Hemoglobin A1c = 5.7% (<5.7%) (39 mmol/mol
may be a better option than a levonorgestrel- [<39 mmol/mol])
Total cholesterol = 200 mg/dL (<200 mg/dL)
releasing intrauterine device for women who (SI: 5.18 mmol/L [<5.18 mmol/L])
wish to conceive, although their adverse effects HDL cholesterol = 50 mg/dL (>50 mg/dL)
include bloating, nausea, headaches, and mood (SI: 1.30 mmol/L [>1.30 mmol/L])
swings.17 Occasional bleeding may be more LDL cholesterol = 110 mg/dL (<100 mg/dL)
common with intrauterine devices, while nausea (SI: 2.85 mmol/L [<2.59 mmol/L])
Non–HDL-cholesterol = 140 mg/dL (<130 mg/dL)
may be more associated with oral progestins. (SI: 3.63 mmol/L [<3.37 mmol/L])
Oral contraceptives are avoided in women with Triglycerides = 149 mg/dL (<150 mg/dL)
migraines and aura. (SI: 1.68 mmol/L [<1.70 mmol/L])
The 20-year progression risk of endometrial Pregnancy test, negative
intraepithelial neoplasia to endometrial cancer is
about 28%. Although progestins can also be used
to treat endometrial intraepithelial neoplasia when

ENDO 2025 • Reproductive Endocrinology 269

Which of the following is the best next step? women with PCOS, children in the metformin
A. Continue lifestyle intervention group had a higher BMI Z-score at age 5 to 10
B. Order an oral glucose tolerance test years than those in the placebo group, suggesting a
potential risk of altered cardiometabolic health in
C. Restart metformin later life.21 Deciding whether to restart metformin
D. Start a GLP-1 receptor agonist in pregnancy should be considered in the context
E. Engage in timed intercourse for 3 more of oral glucose tolerance testing.
months Lifestyle interventions may increase natural
conception, improve ovulation induction, and
Answer: B) Order an oral glucose tolerance test reduce pregnancy morbidities in anovulatory
Obesity has serious adverse effects on maternal women with obesity.4,22 Lifestyle interventions’
and neonatal outcomes.4 The 2023 International effects, however, do not necessarily improve the
Evidence-Based Guideline for the Assessment live birth rate in ovulatory women or in women
and Management of Polycystic Ovary Syndrome requiring assisted reproductive technology.4 In a
recommends oral glucose tolerance testing in randomized controlled trial of infertile women
women with PCOS who do not have preexisting with obesity, 6-month lifestyle intervention
diabetes when planning pregnancy, given their preceding infertility treatment did not improve
increased risk of hyperglycemia and pregnancy the term singleton birth rate at 24 months vs the
comorbidities.15 GLP-1–based therapies enhance birth rate of women receiving prompt infertility
glucose-dependent insulin secretion, slow gastric treatment. Rather, it delayed the time to pregnancy
emptying, reduce postprandial glucagon, and by about 2 months, despite the increased frequency
decrease food intake. Use of a GLP-1 receptor of natural conception.23 Given the adverse effects
agonist with or without metformin in women of maternal age vs obesity on fecundity of this
with PCOS who are overweight or have obesity 39-year-old patient,24 (Table 2 , following page),
can improve both metabolism (ie, improve insulin continued lifestyle intervention would not be a
sensitivity, reduce weight central/visceral adipose better choice than ovulation induction if results
and liver fat, decrease total/LDL cholesterol and from oral glucose tolerance testing are normal.
triglycerides, lower blood pressure, and increase Timed intercourse alone is not recommended
SHBG) and reproductive parameters (ie, reduce since it is unclear whether this patient is ovulating.
ovarian/adrenal androgens, decrease ovarian Even if a serum progesterone value greater than
size, improve menstrual frequency and ovulation, 3 ng/mL (>9.5 nmol/L) confirms infrequent
and increase natural conception).9,10 Although ovulation,25 she remains oligo-ovulatory and
preliminary data suggest that these medications may should undergo ovulation induction.
not cause major congenital malformations, the small
number of exposed human pregnancies thus far does Case 2, Continued
not rule out an increased risk for malformations or
fetal growth abnormalities.19 Therefore, these drugs Which of the following is the best
should not be used in pregnancy. next step for ovulation induction?
Metformin, a biguanide that increases
A. Aromatase inhibitor
peripheral insulin sensitivity and inhibits hepatic
glucose production, is commonly used to treat B. Dopamine agonist
gestational diabetes. It can pass the placenta C. Human menopausal gonadotropins
and enter the fetus with potential long-term D. Recombinant FSH
consequences for offspring.4,20 In a double-blind E. Selective estrogen-receptor modulator
randomized controlled trial comparing metformin
(2000 mg daily) with placebo in 257 pregnant Answer: A) Aromatase inhibitor

270 ENDO 2025 • Endocrine Case Management

Table 2. Failure to Achieve an Intrauterine Pregnancy consider cost, expertise required, availability of
by Assisted Reproduction Based on Autologous
Oocytes From Women by Age and BMI*
ultrasonography for monitoring, and minimal
dosing to minimize a multiple pregnancy. Clinical
efficacy is similar for various gonadotropin
preparations.
The dopamine receptor 2 agonist
cabergoline is used in women undergoing
assisted reproduction who are at risk of
ovarian hyperstimulation syndrome with
increased vascular permeability from ovarian
hypersecretion of vascular endothelial growth
factor. In a prospective, randomized, double-blind
study of women at increased risk for ovarian
hyperstimulation syndrome undergoing assisted
reproduction, cabergoline prevented increased
* Overall clinical intrauterine pregnancy, 44% per embryo transfer. vascular permeability via inactivation of the
** Adjusted for women’s race, ethnicity, day/number of embryos vascular endothelial growth factor receptor 2.
transferred, and infertility diagnosis. Failure to achieve a clinical
intrauterine pregnancy increased with high BMI, but to a lesser extent in
older women due to impaired age-related oocyte quality. Woman’s age
effect (AOR [95% CI]): <30 y (1.00 [reference]), 30-34 y (1.03 [95% CI, Key Learning Points
0.91-1.18]), 35-39 y (1.48 [95% CI, 1.31-1.69]), 40-44 y (2.84 [95% CI,
2.40-3.36]), ≥45 y (7.19 [95% CI, 3.10-16.66]).
Modified with permission from Luke B et al. Hum Reprod, 2011; 26(1): • Amenorrhea related to altered body weight
245-52. © The Authors. Published by Oxford University Press on behalf of
the European Society of Human Reproduction and Embryology.
requires prompt diagnosis, examination,
and laboratory assessment to establish a
management plan for the health of the woman
Although used off-label in many countries, the and her future offspring.
aromatase inhibitor letrozole is now the first-
line pharmacological treatment for ovulation • Functional amenorrhea can accompany stress,
induction in infertile women with anovulatory weight loss, and/or excessive exercise without
PCOS (with no other infertility factors), since it is an identifiable organic cause, but can signal
more effective than clomiphene citrate (a selective anorexia in a woman with altered nutrition
estrogen-receptor modulator).15,25 In a double- and body image.
blind randomized controlled trial of letrozole vs • Functional amenorrhea accompanying AN
clomiphene citrate for ovulation induction in requires a prompt multidisciplinary plan
women with PCOS, cumulative live births over with nutritional consultation, psychological
5 cycles (letrozole, 27.5%; clomiphene citrate, support, exercise modification, and sex steroid
19.1% [P = .007]), ovulation rate/cycle (letrozole, replacement.
61.7%; clomiphene citrate, 48.3% [P < .001]), • Amenorrhea associated with obesity can
and ovulation rate/patient (letrozole, 88.5%; mimic or exaggerate PCOS expression with
clomiphene citrate, 76.6% [P < .001) were higher adverse effects on endometrial development,
for letrozole than for clomiphene citrate.25 Unless metabolic-reproductive function, and fertility.
other factors exist (ie, male-factor infertility, other
• In amenorrheic women with obesity, fertility
reproductive or genetic diseases), gonadotropins
strategies should balance postponing ovulation
are generally second-line pharmacological
induction to improve metabolic health
therapy for women with PCOS for whom first-
with delaying conception, as maternal-fetal
line ovulation induction has been unsuccessful.
complications increase with age.
The decision to use gonadotropins should

ENDO 2025 • Reproductive Endocrinology 271

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Recommended Reading
• Nass R, Evans WS. Physiological and pathophysiological alterations of • Pape J, Herbison AE, Leeners B. Recovery of menses after functional
the neuroendocrine components of the reproductive axis. In: Yen and hypothalamic amenorrhoea: if, when and why. Hum Reprod Update.
Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology and Clinical 2021;27(1):130-153. PMID: 33067637
Management, Ninth Edition. Strauss JF III, Barbieri RL, Dokras A, Williams CJ, • McLaughlin T, Lamendola C, Liu A, Abbasi F. Preferential fat deposition in
Williams SZ (eds). Elsevier Saunders, Philadelphia, 2024, pgs. 475-515. subcutaneous versus visceral depots is associated with insulin sensitivity. J
• Misra M, Katzman D, Miller KK, et al. Physiologic estrogen replacement Clin Endocrinol Metab. 2011;96(11) E1756-E1760. PMID: 21865361
increases bone density in adolescent girls with anorexia nervosa. J Bone Miner • Cui H, López M, Rahmouni K. The cellular and molecular bases of leptin and
Res. 2011;26(10):2430-2438. PMID: 21698665 ghrelin resistance in obesity. Nat Rev Endocrinol. 2017;13(6):338-351. PMID:
• GBD 2015 Obesity Collaborators; Afshin A, Forouzanfar MH, et al. Health 28232667
effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. • Papaetis GS, Kyriacou A. GLP-1 receptor agonists, polycystic ovary syndrome
2017;377(1):13-27. PMID: 28604169 and reproductive dysfunction: current research and future horizons. Adv Clin
• Brennan KM, Kroener LL, Chazenbalk GD, Dumesic DA. Polycystic ovary Exp Med. 2022;31(11):1265-1274. PMID: 35951627
syndrome: impact of lipotoxicity on metabolic and reproductive health. Obstet • Chittenden BG, Fullerton G, Maheshwari A, Bhattacharya S. Polycystic ovary
Gynecol Surv. 2019;74(4) 223-231. PMID: 31344250. syndrome and the risk of gynaecological cancer: a systematic review. Reprod
• Li S, Ma S, Yao X, Liu P. Effects of metabolic syndrome on pregnancy Biomed Online. 2009;19(3):398-405. PMID: 19778486
outcomes in women without polycystic ovary syndrome. J Endocr Soc.
2024;8(10):bvae143. PMID: 39224458

272 ENDO 2025 • Endocrine Case Management

THYROID BIOLOGY
AND CANCER
Management of
Hyperthyroidism-
Related Complications
Grigoris Effraimidis, MD, PhD. School of Health Sciences, University of Thessaly, Larissa,
Greece; Department of Endocrinology and Metabolic Diseases, University General Hospital
of Larissa, Larissa, Greece; E-mail: [email protected]

Educational Objectives Atrial fibrillation is the most common

cardiac complication, occurring in 5% to 15% of
After reviewing this chapter, learners should be
hyperthyroid patients, compared with 1% to 3%
able to:
in the general population, and it may be the initial
• Identify the cardiac, electrolyte, and presentation of hyperthyroidism.2
muscular complications associated with Thyrotoxic periodic paralysis is a rare
hyperthyroidism, including atrial fibrillation, but potentially life-threatening complication
thyrotoxic periodic paralysis, and thyroid characterized by hypokalemia and muscle
storm. weakness that predominantly affects young
Asian males. Without prompt recognition and
• Diagnose hyperthyroidism-related
treatment, thyrotoxic periodic paralysis can lead to
complications using clinical features,
cardiac arrhythmias and respiratory failure.
laboratory findings, and diagnostic scoring
Similarly, thyroid storm represents a critical
systems.
endocrine emergency with a high mortality rate,
• Manage hyperthyroidism-related atrial requiring immediate and aggressive intervention
fibrillation, thyrotoxic periodic paralysis, to prevent fatal outcomes.
and thyroid storm through targeted These complications highlight the need for
pharmacological and supportive therapies. enhanced clinical awareness, prompt diagnosis,
• Explain the role of anticoagulation in and effective management strategies to mitigate
hyperthyroidism-related atrial fibrillation the risks.
and the risks and benefits of direct oral
anticoagulants vs warfarin. Practice Gaps
• The optimal anticoagulation strategy for
patients with hyperthyroid-related atrial
Significance of the fibrillation remains an area requiring further
Clinical Problem investigation.
Hyperthyroidism is common, with an estimated • There is limited awareness and recognition
global prevalence of 0.2% to 1.3% in its overt form of thyrotoxic periodic paralysis, resulting
and 0.7% to 1.8% in its subclinical form among in delayed diagnosis and treatment, which
iodine-sufficient populations.1 It is a disorder increases the risk of cardiac arrhythmias or
affecting multiple organ systems. respiratory failure.

274 ENDO 2025 • Endocrine Case Management

• Diagnosis can be challenging due to A holistic approach, similar to the
the inability of thyroid function tests to management of atrial fibrillation in the general
distinguish thyroid storm from uncomplicated population, is recommended for hyperthyroidism-
thyrotoxicosis, as well as inadequate use related atrial fibrillation. This approach is based
of diagnostic scoring systems (eg, Burch- on controlling rate and rhythm, avoiding stroke/
Wartofsky score) and standardized treatment thromboembolism, and managing cardiovascular
protocols, which contributes to suboptimal risk factors and comorbidities, recognizing that
management and higher mortality rates. hyperthyroidism is a modifiable risk factor for
atrial fibrillation. Rate control with β-adrenergic
blockers is central to the management of
Discussion hyperthyroidism-related atrial fibrillation, by
Hyperthyroidism is associated with significant optimizing the ventricular response (optimal
complications, including atrial fibrillation, target <110 beats/min), relieving symptoms, and
thyrotoxic periodic paralysis, and thyroid storm, preventing cardiomyopathy. Rhythm control is
leading to increased morbidity and mortality if generally reserved for hemodynamically unstable
not promptly diagnosed and managed. Herein, patients, or those in whom atrial fibrillation
we discuss the clinical manifestations, diagnostic is persistent or recurrent after restoration of
approaches, and management strategies for these euthyroidism. The stroke and systemic embolism
hyperthyroidism-related complications. risk in hyperthyroidism-related atrial fibrillation
remains a controversial topic. Decisions about
Atrial Fibrillation anticoagulation should follow the general atrial
fibrillation guidelines by using the CHA2DS2-VASc
Atrial fibrillation is the most common cardiac
and HAS-BLED scores, although these scores may
complication of hyperthyroidism and can be the
not fully account for hyperthyroidism-related
first manifestation of hyperthyroidism, making
atrial fibrillation–specific risks, as data are thus
routine thyroid function testing a significant
far inconclusive. Recent evidence suggests that
diagnostic consideration in the evaluation of
both warfarin and direct oral anticoagulants are
patients with new-onset atrial fibrillation.
equally effective, but direct oral anticoagulants
Individuals with Graves hyperthyroidism have a
may potentially offer a lower bleeding risk. Finally,
doubled risk of atrial fibrillation compared with
optimizing comorbidities (eg, hypertension,
risk of population controls.3 Risk factors for atrial
diabetes, obesity) and addressing modifiable risk
fibrillation in hyperthyroid patients do not differ
factors, such as cigarette smoking and alcohol, is
from those in the general population (ie, age,
required (Figure, following page).
male sex, ischemic heart disease, heart failure, and
valvular heart disease). In addition, it has been
found that subclinical hyperthyroidism, as well Thyrotoxic Periodic Paralysis
as free T4 in the high-normal range, significantly Thyrotoxic periodic paralysis is a rare endocrine
increases atrial fibrillation risk. emergency characterized by acute, reversible,
Hyperthyroidism is a reversible cause of atrial painless muscle weakness and hypokalemia,
fibrillation, with most patients spontaneously predominantly affecting Asian individuals with
reverting to sinus rhythm within 4 to 6 months thyrotoxicosis, with a reported incidence of
of achieving thyroid control, often even before 2% (compared with 0.1% to 0.2% in non-Asian
full euthyroidism is reached. Therefore, control of individuals with thyrotoxicosis). More than 95%
thyroid hormone levels is the most important step of thyrotoxic periodic paralysis cases occur in men,
in the management of hyperthyroidism-related typically in those aged 20 to 40 years. Often, events
atrial fibrillation, and euthyroidism should be
achieved as soon as possible.

ENDO 2025 • Thyroid Biology and Cancer 275

Figure. Management of Hyperthyroidism-Related Atrial Fibrillation

Reprinted from Kostopoulos G & Effraimidis G. Eur Thyroid J, 2024; 13(2): e230254. © The Authors. Published by Bioscientifica Ltd. on behalf of The
European Thyroid Association.

276 ENDO 2025 • Endocrine Case Management

such as heavy exercise or high-carbohydrate meals The diagnosis of thyroid storm is clinical, as
precede the thyrotoxic periodic paralysis episodes. thyroid function tests alone cannot distinguish
Thyrotoxic periodic paralysis results from thyroid storm from uncomplicated thyrotoxicosis,
intracellular potassium movement, leading to although free T4 and free T3 levels may be slightly
hypokalemia, but the total body potassium is higher in thyroid storm.6 Scoring systems, such as
preserved. Episodes can range from mild muscle the Burch-Wartofsky score and a Japanese system,
weakness to flaccid paralysis, primarily affecting assist in diagnosis, but clinical judgment is essential
proximal leg muscles, and occur only during (Table, following page).7,8 Symptoms include
thyrotoxicosis. Symptoms of thyrotoxicosis may high fever, severe tachycardia, gastrointestinal
precede, coincide with, or follow the onset of manifestations (nausea, vomiting, diarrhea), and
thyrotoxic periodic paralysis.4 During attacks, CNS disorders (irritability, confusion, coma).
serum potassium levels often drop below 3 mEq/L Treatment of thyrotoxicosis in thyroid storm
(<3 mmol/L), and sometimes less than 1.5 mEq/L involves high-dosage antithyroid drugs to decrease
(<1.5 mmol/L), risking cardiac arrhythmias or production and secretion of thyroid hormones
respiratory failure and making prompt diagnosis (propylthiouracil is preferred due to its inhibition
and treatment critical. Potassium chloride (10- of T4 to T3 conversion), β-adrenergic blockers
200 mmol) should be administered cautiously to ameliorate manifestations of thyroid storm
to avoid rebound hyperkalemia. High-dosage (particularly the cardiac ones), iodine to block
nonselective β-adrenergic blockers, such as thyroid hormone release, and glucocorticoids
propranolol, are used in the treatment of to inhibit extrathyroidal conversion of Τ4 to
thyrotoxic periodic paralysis due to their ability Τ3.9 Supportive care should include cooling,
to suppress β2-adrenergic activity and inhibit fluids, intensive care unit monitoring, and
insulin secretion, as hyperadrenergic activity appropriate treatment (eg, antibiotics) of the
and hyperinsulinemia are implicated in the underlying precipitating factor. In refractory cases,
pathogenesis of thyrotoxic periodic paralysis. plasmapheresis, hemoperfusion, or emergency
Further attacks can be prevented by managing thyroidectomy may be required. Early and
the underlying cause of thyrotoxicosis (typically aggressive treatment is crucial to reduce mortality.
Graves hyperthyroidism), prescribing nonselective
β-adrenergic blockers, and avoiding known
precipitating factors.
Clinical Case Vignettes
Case 1
Thyroid Storm A 46-year-old man with no relevant medical
history, aside from a history of smoking cessation,
Thyroid storm is a rare, life-threatening condition
presents to his primary care physician with
characterized by severe thyrotoxicosis and high
concerns of palpitations and fatigue following
mortality rates. It is twelve times more likely
a 3-day viral illness characterized by fever,
to be fatal than uncomplicated thyrotoxicosis,
arthralgia, myalgia, and paroxysmal cough. On
and it typically results from untreated or poorly
physical examination, an irregular heartbeat
managed thyrotoxicosis, often triggered by
is noted, prompting referral to a cardiologist.
factors such as infections, surgery, trauma, or
The cardiologist diagnoses atrial fibrillation and
iodine excess. All causes of thyrotoxicosis have
admits the patient to the cardiology department.
been associated with thyroid storm, with Graves
Treatment with a β-adrenergic blocker
disease and multinodular goiter being the most
(bisoprolol, 10 mg daily) and anticoagulation
common. Thyroid storm has also been reported as
(apixaban) is initiated.
a complication of immune checkpoint inhibitor–
mediated thyrotoxicosis.5

ENDO 2025 • Thyroid Biology and Cancer 277

Table. Scoring Systems to Diagnose Thyroid Storm

278 ENDO 2025 • Endocrine Case Management

Thyroid function test results indicate autoimmune patient characteristics. Decisions regarding
hyperthyroidism: anticoagulation should follow general atrial
fibrillation guidelines, using established stroke and
TSH = <0.01 mIU/L
Free T3 = 15.6 pg/mL (1.6-3.9 pg/mL) bleeding risk assessment tools (CHA2DS2-VASc
(SI: 24.0 pmol/L[2.4-6.0 pmol/L]) and HAS-BLED scores) (Answer C).
Free T4 = 2.9 ng/dL (0.7-1.5 ng/dL) (SI: 37.2 pmol/L Since hyperthyroidism-related atrial fibrillation
[9.0–19.0 pmol/L]) often resolves with control of hyperthyroidism,
TPO antibodies = 1050 IU/L
and patients experience a spontaneous return to
TRAb = 36.0 IU/L (<1.75 IU/L)
sinus rhythm, recommendations for long-term
The cardiology team decides that cardioversion anticoagulation follow those for the general
will be deferred until stabilization of thyroid population with atrial fibrillation.
function and consults an endocrinologist who Warfarin use in hyperthyroidism-related
starts methimazole, 10 mg twice daily, to manage atrial fibrillation requires careful monitoring and
hyperthyroidism. regular dosage adjustments due to the increased
breakdown of vitamin K-dependent clotting
Which of the following is the factors in hyperthyroidism. This results in lower
best recommendation? warfarin dosage requirements to maintain a
A. Initiate anticoagulation as soon as possible due therapeutic INR.
to high risk of embolism The novel direct oral anticoagulants are
B. Use warfarin only, as direct oral anticoagulants not contraindicated in hyperthyroidism. Data
are contraindicated in hyperthyroidism on the comparison of direct oral anticoagulants
with warfarin in hyperthyroidism-related atrial
C. Follow standard atrial fibrillation guidelines
fibrillation suggests that direct oral anticoagulants
using CHA2DS2-VASc and HAS-BLED scores
are at least as beneficial as warfarin in this
to assess stroke and bleeding risk
population but have a potential lower bleeding risk.
D. Initiate aspirin instead of anticoagulation for Aspirin is inferior to anticoagulants for
stroke prevention stroke prevention in atrial fibrillation and is not
E. Use long-term anticoagulation even after recommended.
thyroid function normalizes This patient became euthyroid 18 days after
methimazole initiation (free T4 = 1.4 ng/dL
Answer: C) Follow standard atrial fibrillation [17.8 pmol/L]) and experienced a spontaneous
guidelines using CHA2DS2-VASc and HAS- return to sinus rhythm at that time. His
BLED scores to assess stroke and bleeding risk cardiologist had started apixaban at the time
Hyperthyroidism is associated with a of atrial fibrillation diagnosis, which was not
hypercoagulable state, as elevated levels of absolutely necessary given the CHA2DS2-VASc
different clotting factors have been found in score of 0, indicating a stroke risk similar to that of
individuals with hyperthyroidism. However, persons without atrial fibrillation.
epidemiological data on the association between
hyperthyroidism, stroke, and thrombosis are Case 2
inconclusive. Some studies suggest increased
A 42-year-old man of Chinese ancestry with a
stroke risk in hyperthyroidism-related atrial
1-year history of Graves disease presents to the
fibrillation, while other studies show no increased
emergency department with progressive weakness
risk, and sometimes even decreased risk, compared
in his arms and legs. Thyroid tests 6 months earlier
with risk in people with atrial fibrillation without
showed euthyroidism on methimazole, 5 mg
hyperthyroidism.10-12 These discrepancies may
daily. Symptoms began 2 weeks ago with episodic
emerge from differences in study design and

ENDO 2025 • Thyroid Biology and Cancer 279

morning leg weakness that resolved spontaneously 20 to 40 years of age. The patient’s demographic
during the day. On the day of admission, the patient profile aligns with the typical thyrotoxic periodic
woke up with severe leg weakness, preventing him paralysis epidemiological pattern (Answer A).
from getting out of bed. As the morning progressed, Nevertheless, it should be highlighted that
weakness extended to his arms, although less thyrotoxic periodic paralysis can also occur in
pronounced than in the legs. other ethnic groups. Raising awareness outside
On physical examination, muscle strength is Asian populations is important to prevent delayed
1-2/5 on knee flexion and extension, hip flexion, diagnosis.
ankle dorsiflexion, and plantar flexion; 2/5 on Biochemical confirmation of thyrotoxicosis is
abduction and on flexion of both shoulders; essential for thyrotoxic periodic paralysis diagnosis,
and 4/5 on extension of the elbows, wrists, and as paralysis only occurs in the thyrotoxic state.
fingers. Muscle tone and deep tendon reflexes are Thyrotoxic periodic paralysis is an acquired
normal. Sensation to light touch, pinprick, and disorder resulting in increased Na+/K+–ATPase
temperature is intact. sensitivity. Multiple susceptibility loci have been
Laboratory test results show severe associated with thyrotoxic periodic paralysis,
hypokalemia (1.7 mEq/L [1.7 mmol/L]) and including a loss-of-function or dominant-
thyrotoxicosis. Electrocardiography reveals normal negative variants in the gene encoding the skeletal
sinus rhythm. muscle potassium channel Kir2.6 and variants
in the KCNJ2 gene that encodes the skeletal
Which of the following statements is correct? muscle potassium channel Kir2.1.13 However,
A. The patient’s Asian ethnicity and male sex are genetic testing is not required for diagnosis,
consistent with the typical epidemiology of which is primarily clinical. The hallmark is
thyrotoxic periodic paralysis hypokalemia accompanied by thyrotoxicosis,
B. The patient’s thyrotoxic state is unrelated to triggered by conditions such as heavy exercise,
thyrotoxic periodic paralysis, as thyrotoxic high-carbohydrate meals, and, less often, trauma,
periodic paralysis only occurs in euthyroid respiratory infections, high salt intake, stress,
individuals alcohol, or medication. In this case, the patient
reported no precipitating factors.14
C. Genetic testing for variants in the gene
Potassium correction is the primary treatment
encoding the Kir2.6 potassium channel is
for acute thyrotoxic periodic paralysis episodes,
required to confirm the diagnosis of thyrotoxic
while nonselective β-adrenergic blockers, such as
periodic paralysis
propranolol, can be used at high dosages during
D. Immediate first-line treatment is nonselective acute episodes and at lower dosages to prevent
β-adrenergic blockers to correct hypokalemia recurrence.
and prevent paralysis Routine prophylactic potassium
E. Prophylactic potassium supplementation is supplementation is not recommended, as there is
recommended to prevent future episodes no evidence supporting effectiveness in preventing
of thyrotoxic periodic paralysis, even after thyrotoxic periodic paralysis episodes.
achieving euthyroidism The patient was admitted for potassium
correction, with a remarkable recovery following
Answer: A) The patient’s Asian ethnicity
normalization of potassium levels (3.7 mEq/L
and male sex are consistent with the typical
[3.7 mmol/L]) 9 hours later. Strength fully
epidemiology of thyrotoxic periodic paralysis
returned to grade 5 in all extremities.
Thyrotoxic periodic paralysis predominantly
affects Asian men, with a male-to-female ratio of
30:1, and 80% of first episodes present between

280 ENDO 2025 • Endocrine Case Management

Case 3 Answer: D) Effective treatment requires high-
dosage propylthiouracil,β-adrenergic blockers,
A 47-year-old woman presents in a comatose
iodine, glucocorticoids, supportive measures,
state with tachycardia, hypertension, and pyrexia
and intensive care unit monitoring
following a 5-day history of headache, cough,
shortness of breath, nasal congestion, myalgias, Treatment guidelines recommend this
and chills. Upon arrival at the hospital, tracheal comprehensive approach: high-dosage
intubation is required, and she is admitted propylthiouracil, β-adrenergic blockers,
to the intensive care unit with suspected iodine, glucocorticoids, supportive care, and
meningoencephalitis. Initial hypertension progresses treatment of the precipitating or underlying
to hypotension, requiring noradrenaline infusion. condition (Answer D). Thionamide antithyroid
Despite intervention, tachycardia and hyperpyrexia drugs are used to block new thyroid hormone
persist. The SARS-CoV-2 rapid nasal swab returns synthesis, administered in high doses orally or
positive, and cerebrospinal fluid analysis is normal via nasogastric tube, or, in selected patients,
except for elevated lactate. Thyroid function tests rectally as a suppository. Propylthiouracil is
reveal elevated free T4 and free T3 levels with theoretically preferred to methimazole due to its
undetectable TSH. A large goiter with bruit and additional inhibitory effect on peripheral T4 to
positive TPO antibodies and TRAb support the T3 conversion. Iodide (Lugol solution or SSKI)
autoimmune origin of hyperthyroidism. The Burch- is given to inhibit hormone release and must be
Wartofsky score is 85, confirming the diagnosis of administered an hour after the thionamide. Other
thyroid storm secondary to Graves hyperthyroidism. treatment options include radiographic contrast
The patient is treated with propylthiouracil, 200 agents (no longer available in the United States),
mg 4 times daily; propranolol, 40 mg 3 times daily; lithium as an alternative to iodide in iodine-
Lugol solution, 5 drops 4 times daily (60 minutes allergic patients or those with previous severe
after administration of propylthiouracil); intravenous reactions to thionamides, cholestyramine (which
hydrocortisone, 200 mg bolus followed by 8 mg/h works by decreasing reabsorption of thyroid
infusion; and cholestyramine, 3 g 3 times daily. hormone from the enterohepatic circulation),
hemoperfusion and plasmapheresis in exceptional
Which of the following statements is correct? cases, and finally thyroidectomy, which is rarely
A. Thyroid storm’s pathogenesis primarily involves performed during active thyroid storm as it is too
increased serum catecholamine levels, making risky before thyrotoxicosis is controlled.
β-adrenergic blockers unnecessary in treatment The pathogenesis of thyroid storm is unclear,
B. Diagnosis is based solely on elevated thyroid and very high thyroid hormone levels alone are
hormone levels (free T4 and free T3) and insufficient to explain the condition. Decreased
suppressed TSH, distinguishing thyroid storm protein binding of thyroid hormones, resulting
from uncomplicated hyperthyroidism in higher free hormone levels, and increased
C. Infections, including SARS-CoV-2 infection, peripheral tissue sensitivity to thyroid hormones
do not act as a trigger, exacerbating thyroid can possibly be exacerbated by the precipitating
hormone activity or underlying conditions. Although symptoms
resemble catecholamine excess, catecholamine
D. Effective treatment requires high-dosage
levels are typically normal. However, drugs,
propylthiouracil, β-adrenergic blockers, iodine,
such as propranolol, can dramatically improve
glucocorticoids, supportive measures, and
symptoms, suggesting the involvement of the
intensive care unit monitoring
sympathetic nervous system.
E. Plasmapheresis is the standard first-line Thyroid function tests in thyroid storm are
treatment for patients with thyroid storm often not different than those of uncomplicated
resistant to medical therapy hyperthyroidism. Diagnosis of thyroid storm relies

ENDO 2025 • Thyroid Biology and Cancer 281

primarily on recognizing the severity of thyrotoxic Rate control with β-adrenergic blockers is
symptoms and signs, and it must be highlighted the mainstay of initial symptomatic treatment
that the thyroid storm diagnosis should be based while rhythm-control is reserved in cases
on clinical judgment, with the scoring systems of hemodynamically unstable, persistent, or
being ancillary (Burch-Wartofsky score, Japanese recurrent atrial fibrillation. Anticoagulation
Thyroid Association Criteria) (Table). decisions should follow standard atrial
Thyroid storm can be triggered by an fibrillation guidelines (CHA2DS2-VASc
intercurrent illness or injury that worsens existing and HAS-BLED scores), with direct oral
thyrotoxicosis. An acute event causing a sudden anticoagulants potentially offering a lower
surge in thyroid hormone secretion, such as bleeding risk compared with that of warfarin.
thyroidectomy or radioiodine therapy can (rarely) Further research is needed to optimize
trigger thyroid storm. Infections are the most anticoagulation strategies in hyperthyroidism-
common trigger, but other illnesses, trauma related atrial fibrillation.
(including surgery), and even certain toxins can • Thyrotoxic periodic paralysis is a rare but
also precipitate thyroid storm in individuals with life-threatening condition characterized by
underlying thyrotoxicosis. Distinguishing between acute hypokalemia and muscle weakness,
symptoms of infection and impending thyroid predominantly affecting young Asian males.
storm can be challenging, but a disproportionately Diagnosis is based on clinical presentation,
high fever and sweating may help to lead to the hypokalemia, and thyrotoxicosis. Immediate
diagnosis. potassium correction is critical, with
As previously mentioned, hemoperfusion cautious administration to avoid rebound
and plasmapheresis may be considered in hyperkalemia. Achieving euthyroidism is
exceptional cases. essential to prevent further episodes. Increased
This patient’s tachycardia and pyrexia resolved awareness of thyrotoxic periodic paralysis
within hours, and vasopressor support was outside Asian populations is crucial to prevent
discontinued. She was successfully extubated the delayed diagnosis.
following day and transferred to a general medical
ward in stable condition. • Thyroid storm is a critical endocrine
emergency with high mortality, requiring
aggressive treatment. Diagnosis relies on
Key Learning Points clinical judgment and scoring systems (eg,
Burch-Wartofsky score), as thyroid function
• Hyperthyroidism can lead to severe tests alone cannot distinguish thyroid storm
complications, such as atrial fibrillation, from uncomplicated hyperthyroidism.
thyrotoxic periodic paralysis, and thyroid Treatment involves high-dosage antithyroid
storm, which require prompt recognition drugs (propylthiouracil preferred),
and management to prevent morbidity and β-adrenergic blockers, iodine, glucocorticoids,
mortality. and supportive care (eg, cooling, fluids,
• Hyperthyroidism is a reversible cause of intensive care unit monitoring).
atrial fibrillation. Achieving euthyroidism is
the most crucial step in the management of
hyperthyroidism-related atrial fibrillation.

282 ENDO 2025 • Endocrine Case Management

References
1. Wiersinga WM, Poppe KG, Effraimidis G. Hyperthyroidism: aetiology, 11. Friberg L, Rosenqvist M, Lip GYH. Evaluation of risk stratification schemes
pathogenesis, diagnosis, management, complications, and prognosis. Lancet for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation:
Diabetes Endocrinol. 2023;11(4):282-298. PMID: 36848916 the Swedish Atrial Fibrillation cohort study. Eur Heart J. 2012;33(12):1500-
2. Kostopoulos G, Effraimidis G. Epidemiology, prognosis, and challenges in 1510. PMID: 22246443
the management of hyperthyroidism-related atrial fibrillation. Eur Thyroid J. 12. Lin YS, Tsai HY, Lin CY, et al. Risk of Thromboembolism in Non-Valvular
2024;13(2):e230254. PMID: 38377675 Atrial Fibrillation With or Without Clinical Hyperthyroidism. Glob Heart.
3. Okosieme OE, Taylor PN, Evans C, et al. Primary therapy of Graves’ disease 2021;16(1):45. PMID: 34211831
and cardiovascular morbidity and mortality: a linked-record cohort study. 13. Allegretti AS, Czawlytko CL, Stathatos N, Sadow PM. Case 13-2024: a
Lancet Diabetes Endocrinol. 2019;7(4):278-287. PMID: 30827829 27-year-old man with leg weakness. N Engl J Med. 2024;390(16):1514-1522.
4. Chang CC, Cheng CJ, Sung CC, et al. A 10-year analysis of thyrotoxic PMID: 38657248
periodic paralysis in 135 patients: focus on symptomatology and precipitants. 14. Garvey LF, Bergmann NC, Worm D, Effraimidis G. Muscle weakness
Eur J Endocrinol. 2013;169(5):529-536. PMID: 23939916 in the extremities in a man with Graves’ disease. Ugeskr Laeger.
5. Iwama S, Kobayashi T, Arima H. Management, biomarkers and prognosis 2022;184(18):V12210931. PMID: 35506625
in people developing endocrinopathies associated with immune checkpoint
inhibitors. Nat Rev Endocrinol. PMID: 39779950
6. Brooks MH, Waldstein SS. Free thyroxine concentrations in thyroid storm.
Ann Intern Med. 1980;93(5):694-697. PMID: 7212477
Recommended Reading
7. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. • Wiersinga WM, Poppe KG, Effraimidis G. Hyperthyroidism: aetiology,
Endocrinol Metab Clin North Am. 1993;22(2):263-277. PMID: 17127140 pathogenesis, diagnosis, management, complications, and prognosis. Lancet
8. Satoh T, Isozaki O, Suzuki A, et al. 2016 Guidelines for the management of Diabetes Endocrinol. 2023;11(4):282-298. PMID: 36848916
thyroid storm from The Japan Thyroid Association and Japan Endocrine • Kostopoulos G, Effraimidis G. Epidemiology, prognosis, and challenges in
Society (First edition). Endocr J. 2016;63(12):1025-1064. PMID: 27746415 the management of hyperthyroidism-related atrial fibrillation. Eur Thyroid J.
9. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association 2024;13(2):e230254. PMID: 38377675
guidelines for diagnosis and management of hyperthyroidism and other • Vanderpump M. Thyrotoxic periodic paralysis. In: Matfin G, ed. Endocrine
causes of thyrotoxicosis. Thyroid. 2016;26(10):1343-1421. PMID: 27521067 and Metabolic Medical Emergencies: A Clinician’s Guide. John Wiley & Sons Ltd;
10. Siu CW, Pong V, Zhang X, et al. Risk of ischemic stroke after new- 2018:296-304.
onset atrial fibrillation in patients with hyperthyroidism. Heart Rhythm. • Angell TE, Lechner MG, Nguyen CT, Salvato VL, Nicoloff JT, LoPresti JS.
2009;6(2):169-173. PMID: 19187905 Clinical features and hospital outcomes in thyroid storm: a retrospective
cohort study. J Clin Endocrinol Metab. 2015;100(2):451-459. PMID: 25343237

ENDO 2025 • Thyroid Biology and Cancer 283

Update on the Management
of Nonhereditary Medullary
Thyroid Carcinoma
Rossella Elisei, MD. Endocrine Unit, University Hospital of Pisa and University of Pisa, Pisa,
Italy; Email: [email protected]

Educational Objectives sporadic disease2 and by genetic screening for RET

pathogenic variants in the case hereditary disease.3
After reviewing this chapter, learners should be
The frequency of MTC in the general
able to:
population is unknown, but it represents
• Identify patients with sporadic medullary approximately 5% of all thyroid tumors and
thyroid carcinoma (MTC) early, when the 0.4% to 1.4% of all thyroid nodules. Unlike
tumor is still intrathyroidal. differentiated thyroid carcinomas that are more
common in women, MTC is not associated with
• Distinguish sporadic from hereditary forms of
a difference in distribution between the 2 sexes.
MTC by RET genetic screening.
The average age at diagnosis for the sporadic
• Recommend appropriate follow-up and choose form is in the fourth and fifth decades, whereas
the right drug at the right time in patients with the hereditary form has a wider range of age
metastatic disease that will be treated with at diagnosis. Only the hereditary form affects
systemic therapy. children. Generally, the more aggressive the RET
germline pathogenic variant responsible for the
disease, the earlier MTC manifests.
To date, the risk factors that affect MTC
Significance of the development are unknown. However, its
Clinical Problem pathogenesis is very well understood, and it is due,
in most cases, to activation of the RET oncogene
MTC is a well-differentiated thyroid tumor
by a pathogenic variant that constitutively
derived from parafollicular or calcitonin-
activates the membrane tyrosine kinase receptor.4
producing C cells. Its neuroendocrine origin
The RET pathogenic variant is present at the
makes it a separate entity from other differentiated
somatic level in 50% to 60% of sporadic cases
thyroid carcinomas. MTC is a unique model in
and at the germline level in 98% of hereditary
that there is both a sporadic form (75%) and a
cases. The prevalence of RET somatic pathogenic
hereditary form (25%). Regardless of whether it
variants increases in more aggressive cases. The
is sporadic or hereditary, the biological behavior
biological behavior of MTC is less favorable
of MTC is similar, and definitive cure essentially
than that of the other well-differentiated thyroid
depends on early diagnosis when the tumor is
carcinomas, but it is more favorable than that
still intrathyroidal.1 Early diagnosis is achieved
of anaplastic carcinoma. Several series have
by measuring circulating calcitonin at the time
reported a 10-year survival of approximately 50%
of thyroid nodule diagnosis in the setting of
in patients with MTC. Cure rate and survival of

284 ENDO 2025 • Endocrine Case Management

patients with MTC are positively affected by an of serum calcitonin in all patients with thyroid
early diagnosis.1 nodules is still controversial8 despite evidence
that this approach allows for early diagnosis and
treatment of MTC, which significantly improves
Practice Gaps the outcome of this potentially lethal disease.2
• The diagnosis of MTC is often late, and
Figure 1.
diagnosis may even occasionally occur after
surgery performed for another indication, as
serum calcitonin is not always measured in the
workup of thyroid nodules.
• It is crucial that clinicians know how to
interpret serum calcitonin values, especially
when these values are between 20 and
50 pg/mL (5.8-14.6 pmol/L).
• There is a lack of awareness of the relevance
of RET germline genetic analysis to distinguish
sporadic from hereditary forms of MTC.
• Ideally, all patients with MTC at an advanced
disease stage at diagnosis should rapidly have
genetic testing to assess for the presence of
somatic RET pathogenic variants.
Patient with advanced MTC and flushing syndrome.

Discussion [Color—Print (Color Gallery page CG16) or web & ePub editions]

Clinical Presentation and Diagnosis

Sporadic MTC usually manifests as an isolated
Surgical Treatment
thyroid nodule or within a multinodular goiter. According to current American Thyroid
Except for the presence of diarrhea and/or Association guidelines,9 the elective intervention
flushing syndrome (Figure 1) (which is, however, in the case of a presurgical MTC diagnosis is
rare and usually present only in advanced and total thyroidectomy and central lymph node
metastatic cases), affected patients usually do not dissection. A bilateral or ipsilateral lateral
have specific symptoms. Neck ultrasonography is cervical lymphadenectomy is indicated if neck
unable to identify or suggest the medullary origin ultrasonography shows the presence of metastatic
of the nodule, and sonographic features of MTC lymph nodes. Thus, before the operation, it is
are highly suspicious for malignancy in less than necessary to perform accurate ultrasonography
half of cases.5 Thyroid scintigraphy, if performed, of the neck with evaluation of the lateral cervical
shows a “cold” nodule as is the case for most of lymph node compartments.
thyroid malignancies. Cytologic examination of Recently, the scientific community has begun
aspirate material from FNA of the nodule provides to consider the possibility of treating some selected
a diagnosis of MTC in only 50% of cases.6 Since patients with lobectomy and removal of the central
1994, numerous studies have demonstrated that lymph node hemicompartment.10 This approach
the routine measurement of serum calcitonin is seems to be feasible in patients with sporadic
the most accurate diagnostic tool for the correct MTC who have a single nodule, mildly elevated
diagnosis of MTC in patients with thyroid calcitonin values, and neck ultrasonography that is
nodules.7 Nevertheless, routine measurement negative for extrathyroidal disease extension.

ENDO 2025 • Thyroid Biology and Cancer 285

Postoperative Management significant findings, it is best to perform second-
and Follow-Up level imaging. In this regard, it is important to
remember that for circulating calcitonin values
Initial evaluation should be done approximately lower than 150 pg/mL (<43.8 pmol/L), it is very
3 months after surgery to assess circulating unlikely that even very sensitive imaging can
calcitonin and perform neck ultrasonography. identify the metastatic site.9 Recently, 18F-DOPA
The same response to therapy classification that has been demonstrated to discover small metastatic
has been applied to differentiated thyroid cancer lesions not detected by other imaging, indicating
can be also applied to MTC and used to guide that its sensitivity and specificity are much higher
clinical management during follow-up.11 Patients (Figure 2).13 Patients with incomplete removal of
with an excellent response must be followed for structural disease must be followed up given the
a few years with basal measurement of calcitonin risk that their disease will progress and require
and neck ultrasonography; action is only taken other therapies. In these cases, in addition to
if calcitonin becomes detectable. Patients with calcitonin measurement, it is advisable to measure
biochemically persistent disease have a relatively carcinoembryonic antigen (CEA), which, although
high risk of developing structural disease over the not specific for MTC, is strongly correlated with
years (30%-40%).12 Thus, these patients must be the tumor burden. The doubling time of both
followed with annual biochemical and imaging markers is important.14
assessments. If calcitonin values remain stable,
there is no need to perform imaging beyond
neck ultrasonography. If calcitonin increases
and neck ultrasonography does not show

Figure 2.

DOPA PET showing a left latero-cervical lymph node (Panel A) and lesion in the anterior border of L4 (Panel B) and their CT coregistrations (Panels A1 and
18

B1). Neither lesion had been previously identified on other imaging.

[Color—Print (Color Gallery page CG16) or web & ePub editions]

286 ENDO 2025 • Endocrine Case Management

Therapies for Advanced the only specific RET inhibitor that can be used in
and Progressive MTC clinical practice.
Advanced and progressive metastatic MTC can
be treated with targeted therapies. The first-line Genetic Testing in the Era
drugs currently available are multikinase inhibitors, of Precision Therapy
such as vandetanib15 and cabozantinib,16 and The use of selective RET inhibitors in clinical
RET-specific inhibitors, such as selpercatinb17 and practice raises the issue of genetic analysis; in
pralsetinib.18 Multikinase inhibitors inhibit various particular, when and for whom it should be
tyrosine kinase receptors involved in tumor cell performed. Genetic screening on constitutive
growth and angiogenesis. They are essentially DNA is a standard test that must be performed
cytostatic drugs and are therefore able to inhibit in all patients of MTC, both in those who have
tumor growth and stabilize disease, even for a long hereditary disease and in those who have sporadic
time. However, they are also strong antiangiogenic disease. Of those with sporadic disease, 7% to 8%
drugs, and their main target is the vascular of these cases may in fact be hereditary.19 Still
growth factor receptor. Their efficacy has been unresolved is the question of whether to perform
well demonstrated in 2 international randomized the search for somatic variants in all sporadic cases
phase 3 clinical trials,15,16 which show significantly or only in selected cases. Given the high frequency
better progression-free survival in patients treated of RET somatic pathogenic variants in patients
with the drugs than in those receiving placebo. with sporadic disease and a worse prognosis,20
However, because of their antiangiogenic action, genetic testing for somatic RET variants is
the use of both multikinase inhibitors is burdened
by numerous and varied adverse effects, which
represent the main reason for the reduction or Figure 3.

suspension of therapy over time.

The selective RET inhibitors selpercatinib and
pralsetinib show great efficacy (Figure 3) and low
toxicity as demonstrated in phase 1 and 2 clinical
trials. Both selpercatinib and pralsetinib are very
selective RET inhibitors that act on wild-type
RET, RET fusions, and point variants and are also
active against “gatekeeper” variants (eg, V804L,
V804M) that induce resistance to vandetanib in in
vitro studies.
Based on the results of the phase 1/2 trial,
a randomized phase 3 study (LIBRETTO-531)
was initiated comparing the efficacy and safety
of selpercatinib vs standard therapy (vandetanib/
cabozantinib) in the first-line treatment of
patients with progressive RET variant–associated
advanced MTC. Compared with standard therapy,
selpercatinib demonstrated greater efficacy
and better safety profile, and the drug has been
approved in both first- and second-line treatment
of advanced and progressive MTC. Manufacturers
of pralsetinib subsequently decided to discontinue
Large hilar lymph node metastasis before (upper panel) and 3 months
drug development, so selpercatinib is currently after (lower panel) treatment with selpercatinib.

ENDO 2025 • Thyroid Biology and Cancer 287

useful in patients with advanced and metastatic histological type of thyroid carcinoma, high
disease from the onset and in those patients not levels of calcitonin have been demonstrated to be
definitively cured by surgery who have risk factors present both in the tumoral tissue and serum of
for progression.21 patients with MTC. Elevated basal levels of serum
calcitonin, with few exceptions, are diagnostic
of MTC. Mildly elevated calcitonin values in the
Clinical Case Vignettes presence of small thyroid nodules should represent
Case 1 an alert for the possibility of MTC, and additional
A 35-year-old woman presents for evaluation should be performed, such as a calcium-
persistently elevated serum calcitonin values stimulation test, measurement of calcitonin in
(35 pg/mL [10.2 pmol/L]) 3 months after total the washout of the needle used for the cytology,
thyroidectomy. She had a 1-cm thyroid nodule and immunocytochemistry for calcitonin. If the
diagnosed 5 years earlier and was followed up serum calcitonin values are less than 50 pg/mL
over time without further investigations. After 5 (<14.6 pmol/L) and the thyroid nodule is small,
years, the nodule had grown to 2.5 cm. On neck follow-up in 6 months could be recommended to
ultrasonography, the nodule was isoechoic, had a ensure a definitive diagnosis.
well-defined border, had no microcalcifications, Routine measurement of serum calcitonin in
and, although fundamentally solid, had some nodular thyroid diseases allows for preoperative
anechoic areas. It was classified as EUTIRADS 3, diagnosis of unsuspected sporadic MTC.
which means low risk of malignancy. Although Calcitonin screening allows for early diagnosis of
not fully recommended, FNA was performed MTC, usually when the tumor is still at stage 1,
because of the increasing volume, and findings on thus favoring successful surgical treatment. In this
cytological examination were classified as Bethesda patient’s case, it is very likely that if the calcitonin
III. She chose to undergo total thyroidectomy. had been measured when the nodule was first
Histology showed that the nodule was malignant identified, even if centimetric, the MTC diagnosis
in nature (MTC), and several perithyroidal lymph could have been anticipated and the surgery
nodes were already metastatic. could have been curative. Unfortunately, not all
guidelines suggest screening patients with thyroid
Which of the following diagnostic tools was nodules with serum calcitonin measurement, but
missing in the workup of this nodule that it remains undisputed that both ultrasonography
could have led to a presurgical diagnosis and FNA with cytological examination have low
of MTC and therefore to a more radical sensitivity for finding MTC and may miss the
and likely curative intervention? correct diagnosis in many cases.
A. A second FNA
B. Elastosonography Case 2
C. Measurement of serum calcitonin A 47-year-old man with MTC who underwent
D. Thyroid scintigraphy surgical treatment 3 years ago is concerned
E. Doppler ultrasonography because his postoperative calcitonin values have
remained elevated in the absence of evidence of
Answer: C) Measurement of serum calcitonin structural disease, as assessed by total-body CT. He
asks what tests could be done to identify the source
Calcitonin is the most specific and sensitive MTC of calcitonin production. The calcitonin values,
marker, both before and after thyroidectomy. although elevated, have remained mostly stable
It is a small polypeptide hormone of 32 amino (~60 pg/mL [17.5 pmol/L]). CEA has also had a
acids produced almost exclusively by C cells. Ten similar trend with mean values of 7.5 ng/mL.
years after the recognition of MTC as a distinct

288 ENDO 2025 • Endocrine Case Management

Which additional diagnostic tool Case 3
could be used to look for the source
Five years after initial diagnosis of MTC, a
of calcitonin production?
62-year-old man presents with progressive
A. Nuclear magnetic resonance metastatic disease at the lung and bone level.
B. 18FDG The doubling time of calcitonin and CEA is 8 to
C. Bone scintigraphy 9 months, and the dimensional increase of the
D. 18F-DOPA lung lesions is greater than 20%. These findings,
therefore, represent a disease in progression
E. Octreotide scan
according to the RECIST (Response Evaluation
Answer: D) 18F-DOPA Criteria in Solid Tumors). Systemic therapy
is recommended. No information is available
About 50% of patients with MTC who have regarding the RET status of the primary tumor,
persistently elevated serum levels of either basal but the patient is trying to recover the paraffin-
or stimulated calcitonin after surgery have no embedded tissues at the hospital where he
evidence of metastatic disease when assessed underwent thyroidectomy.
with traditional imaging techniques. In the
case of “biochemical disease” without evidence Which of the following drugs would
of metastatic lesions, the most widely accepted be best to treat this patient now?
follow-up strategy is “wait and see.” Detectable A. Vandetanib
serum calcitonin is in fact compatible with long-
B. Cabozantinib
term survival, as calcitonin may remain stable with
time or slowly increase. The average time after C. Selpercatinib
which metastatic disease is detected is about 3 to D. Either vandetanib or cabozantinib
4 years. Typically, recurrence is in the neck, but E. Either vandetanib or selpercatinib
it can also be distant. With very few exceptions,
clinical manifestations of the disease correlate Answer: D) Either vandetanib or cabozantinib
with the increase in serum markers (calcitonin Without knowing the molecular profile of the
and CEA) and, therefore, as long as they remain tumor or, in particular, the mutational status of
stable, it is very unlikely that the disease has RET, it is not possible to prescribe selpercatinib,
manifested itself. In this regard, the doubling time which is a selective inhibitor of RET. To prescribe
of both calcitonin and CEA is very important: selpercatinib, one must demonstrate the presence
the shorter the doubling time, the faster the of a RET pathogenic variant, either at the somatic
disease progression. Various studies suggest that or germline level. Therefore, in this patient’s case,
if the serum calcitonin concentration is less than it would be necessary to start with a multikinase
150 pg/mL (<43.8 pmol/L), it is unlikely that inhibitor, such as vandetanib or cabozantinb.
second-level imaging techniques can identify Recently, a randomized phase 3 study
the source of calcitonin production. However, (LIBRETTO-531) comparing the efficacy and
18
F-DOPA has shown a higher sensitivity and safety of selpercatinib vs standard therapy
specificity than all other imaging techniques, (vandetanib/cabozantinib) in the first-line
especially in cases with detectable calcitonin treatment setting in patients with progressive
and CEA values but in a medium-low range. RET-mutated advanced MTC clearly demonstrated
Therefore, in this patient’s case, PET 18F-DOPA higher efficacy and lower toxicity of selpercatinib.
could be useful, but if findings are normal, no A total of 291 patients were included (selpercatinib
more second-level imaging should be performed to vandetanib/cabozantinib ratio of 2:1). At 12
unless calcitonin and CEA concentrations months, the progression-free interval was 86.8%
rapidly double. in the selpercatinib group and 65.7% in the control

ENDO 2025 • Thyroid Biology and Cancer 289

group. The objective response rate was 69.4% in experienced in the management of both the drug
the selpercatinib group and 38.8% in the control and the disease.
group. Adverse events led to dosage reduction in
38.9% of participants in the selpercatinib group
and in 77.3% of participants in the control group
Key Learning Points
and led to treatment discontinuation in 4.7%
• MTC is a rare thyroid tumor that should be
of participants in the selpercatinib group and
diagnosed as early as possible (when it is still
in 26.8% of participants in the control group.
intrathyroidal) for the best chance of complete
Based on this study, selpercatinib has been
cure. To diagnose MTC early, serum calcitonin
approved as first-line treatment (it was already
should be measured in all patients with thyroid
approved as second-line treatment) of advanced
nodules. Although MTC’s frequency is only
and progressive MTC. While selpercatinib
1 in 200 to 250 nodules, it has been very well
represents an important opportunity for patients,
demonstrated that screening is cost-effective.
its prescription, as already mentioned, requires
the presence of a RET pathogenic variant. If the • MTC can be either sporadic (in most cases)
patient is able to locate the paraffin-embedded or hereditary. Since some cases appear to be
material and molecular analysis demonstrates the sporadic but are actually hereditary (7%-8%
presence of a RET pathogenic variant, switching of all sporadic forms), genetic testing for RET
from the multikinase inhibitor to selpercatinib pathogenic variants should be performed in all
could be considered, especially if the patient were newly diagnosed patients.
experiencing adverse effects during the treatment • Patients with MTC who are not cured
with the multikinase inhibitor. If, however, a RET completely by surgery but who have no
pathogenic variant is not identified, the patient obvious structural disease (ie, “biochemically
would continue therapy with the multikinase persistent” disease) should have follow-up
inhibitor already started. If there is disease based on calcitonin and CEA values and their
progression, the patient could switch to the other doubling time. As long as calcitonin levels
multikinase inhibitor. remain less than 150 pg/mL (<43.8 pmol/L),
Therapeutic efficacy of the therapy should identifying the source of production is very
initially be monitored every 3 months with difficult. Performing 18F-DOPA can be helpful.
measurement of calcitonin and CEA and total- • Patients with metastatic and progressive
body CT with intravenous contrast medium. MTC can now be treated with molecularly
Both the medical staff and the patient must pay targeted drugs, such as selpercatinib, which is
particular attention to the development of adverse very effective and has few adverse effects. If
events, so they can be treated immediately to the pathogenic variant is not known or if no
ensure that it does not become so severe that pathogenic variant is identified, the patient
treatment is interrupted. These patients should can be treated with 1 of the 2 multikinase
be followed in tertiary care centers that are inhibitors, vandetanib or cabozantinib.

References
1. Gharib H, McConahey WM, Tiegs RD, et al. Medullary thyroid carcinoma: experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol
clinicopathologic features and long-term follow-up of 65 patients treated Metab. 2004;89:163-168. PMID: 14715844
during 1946 through 1970. Mayo Clin Proc. 1992;67(10):934-940, PMID: 3. Wells SA Jr, Baylin SB, Leight GS, Dale JK, Dilley WG, Farndon JR. The
1434853 importance of early diagnosis in patients with hereditary medullary thyroid
2. Elisei R, Bottici V, Luchetti F, et al. Impact of routine measurement of carcinoma. Ann Surg. 1982;195(5):595-599. PMID: 7073356
serum calcitonin on the diagnosis and outcome of medullary thyroid cancer:

290 ENDO 2025 • Endocrine Case Management

4. Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the 13. Beheshti M, Pocher S, Vali R, et al. The value of 18F-DOPA PET-CT in
RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. patients with medullary thyroid carcinoma: comparison with 18F-FDG PET-
1993;363(6428):458-460. PMID: 8099202 CT. Eur Radiol. 2009;19(6):1425-1434. PMID: 19156423
5. Matrone A, Gambale C, Biagini M, Prete A, Vitti P. Ultrasound features 14. Laure Giraudet A, Al Ghulzan A, Auperin A, et al. Progression of medullary
and risk stratification systems to identify medullary thyroid carcinoma. Eur J thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen
Endocrinol. 2021;185(2):193-200. PMID: 34010144 doubling times. Eur J Endocrinol. 2008;158(2):239-246. PMID: 18230832
6. Essig GF Jr, Porter K, Schneider D, et al. Fine needle aspiration and 15. Wells SA, Jr., Robinson BG, Gagel RF, et al. Vandetanib in patients with
medullary thyroid carcinoma: the risk of inadequate preoperative evaluation locally advanced or metastatic medullary thyroid cancer: a randomized,
and initial surgery when relying upon FNAB cytology alone. Endocr Pract. double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141. PMID: 22025146
2013;19:920-927. PMID: 23757627 16. Elisei R, Schlumberger MJ, Muller SP, et al. Cabozantinib in progressive
7. Pacini F, Fontanelli M, Fugazzola L, et al. Routine measurement of serum medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639-3646. PMID:
calcitonin in nodular thyroid diseases allows the preoperative diagnosis of 24002501
unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab. 17. Hadoux J, Elisei R, Brose MS, et al; LIBRETTO-531 Trial Investigators.
1994;78(4):826-829. PMID: 8157706 Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid
8. Deftos LJ. Should serum calcitonin be routinely measured in patients with cancer. N Engl J Med. 2023;389(20):1851-1861. PMID: 37870969
thyroid nodules--will the law answer before endocrinologists do? J Clin 18. Subbiah V, Hu MI, Wirth LJ, et al. Pralsetinib for patients with advanced
Endocrinol Metab. 2004;89(9):4768-4769. PMID: 15356093 or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-
9. Wells SA Jr, Asa SL, Dralle H, et al; American Thyroid Association label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol. 2021;9(8):491-
Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American 501. PMID: 34118198
Thyroid Association guidelines for the management of medullary thyroid 19. Romei C, Cosci B, Renzini G, et al. RET genetic screening of sporadic
carcinoma. Thyroid. 2015;25(6):567-610. PMID: 25810047 medullary thyroid cancer (MTC) allows the preclinical diagnosis of
10. Liang W, Shi J, Zhang H, et al: Total thyroidectomy vs thyroid lobectomy for unsuspected gene carriers and the identification of a relevant percentage of
localized medullary thyroid cancer in adults: a propensity-matched survival hidden familial MTC (FMTC). Clin Endocrinol (Oxf). 2011;74(2):241-247.
analysis. Surgery. 2022;172(5):1385-1391.PMID: 35995619 PMID: 21054478
11. Tuttle RM, Ganly I. Risk stratification in medullary thyroid cancer: moving 20. Elisei R, Cosci B, Romei C, et al. Prognostic significance of somatic RET
beyond static anatomic staging. Oral Oncol. 2013;49(7):695-701. PMID: oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-
23601563 up study. J Clin Endocrinol Metab. 2008;93(3):682-687. PMID: 18073307
12. Prete A, Gambale C, Torregrossa L, et al. Clinical evolution of sporadic 21. Matrone A, Prete A, Gambale C, et al. Timing and ideal patient for an
medullary thyroid carcinoma with biochemical incomplete response after appropriate search for somatic RET mutation in medullary thyroid cancer.
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36722192

ENDO 2025 • Thyroid Biology and Cancer 291

Oncocytic Thyroid Cancer
Ian Ganly, MD, MS, PhD. Department of Head and Neck Surgery, Memorial Sloan Kettering
Cancer Center, New York, NY; Email: [email protected]

Educational Objectives hallmarks that set it apart from other differentiated

thyroid cancers (DTCs).2,3
After reviewing this chapter, learners should be
Despite accounting for only about 5% of all
able to:
thyroid cancers, OTC poses significant clinical
• Describe the unique molecular, challenges due to its aggressive potential and
clinicopathologic, and genetic characteristics relatively poor iodine avidity, which limits the
that differentiate oncocytic thyroid cancer efficacy of traditional radioactive iodine (RAI)
(OTC) from other thyroid malignancies, therapy. The disease predominantly affects older
including its classification as a distinct clinical individuals and can present with both locoregional
entity by the World Health Organization. and distant metastases, often at a more advanced
stage compared with other DTCs.4-8 These
• Identify the clinical features, preoperative
characteristics, coupled with the scarcity of specific
investigations, and limitations in diagnosing
epidemiologic and clinical data, highlight the need
OTC, including its typical presentation,
for a deeper understanding of OTC to optimize its
imaging modalities, and cytological challenges.
diagnosis, treatment, and prognosis. This review
• Analyze the current management options, synthesizes current literature on the molecular
including surgical approaches, systemic underpinnings, pathologic classifications, and
therapies, and the challenges posed by poor clinical management of OTC.
iodine avidity, while understanding the
prognostic factors influencing disease-specific
survival and recurrence. Practice Gaps
• There is limited preoperative diagnostic
accuracy for OTC. FNA cannot reliably
distinguish between benign and malignant
Significance of the
oncocytic thyroid neoplasms, as the diagnosis
Clinical Problem of OTC requires confirmation of capsular and/
OTC, formerly known as Hürthle cell carcinoma, or vascular invasion. Additionally, current
represents a rare but distinct type of thyroid molecular testing methods, while improved, still
malignancy. In recent years, the World Health face challenges in distinguishing benign from
Organization reclassified OTC as a separate malignant oncocytic tumors. This diagnostic
clinical entity due to its unique molecular uncertainty complicates preoperative planning
and clinicopathologic features.1 Previously and management strategies.
grouped with follicular thyroid carcinoma • There is a lack of tailored treatment guidelines
(FTC), OTC exhibits distinct genetic profiles, for OTC. Despite its distinct molecular profile,
biological behavior, and clinical outcomes that clinical behavior, and poor iodine avidity, OTC
necessitate tailored management strategies. is often managed using the same guidelines as
This differentiation underscores the growing other DTCs. This approach fails to account for
recognition of its specific pathologic and molecular its unique characteristics, such as its limited

292 ENDO 2025 • Endocrine Case Management

 response to RAI therapy and differences in critically needed to inform evidence-based
surgical and systemic treatment efficacy. management of advanced and metastatic OTC.
• There are insufficient clinical trial data specific
to OTC. Most clinical trials group OTC with Discussion
other DTCs, leading to a lack of specific
OTC is a distinct entity, previously classified under
evidence regarding treatment efficacy for
FTC, that is now recognized separately due to
OTC. As a result, current systemic treatment
unique molecular, histopathologic, and clinical
options, including tyrosine kinase inhibitors,
characteristics.1-3
are extrapolated from broader DTC data and
are limited by substantial adverse effects and
suboptimal outcomes. Dedicated research is

Figure 1.

Panel A, Electron microscopy showing nucleus of cell surrounded by abundant mitochondria. Panel B, Hematoxylin and eosin slide showing vascular
invasion in vessels surrounding a widely invasive OTC.
[Color—Print (Color Gallery page CG17) or web & ePub editions]

Figure 2.

1-3 invasive foci: Minimally invasive (Low risk) 1 VI ≠ 6 VI

> 4 foci of vascular invasion: Widely invasive (High risk)

Min invasive Widely invasive
HCC HCC

Overall survival Locoregional recurrence Distant recurrence

Panel A, Classification of OTC into minimally invasive and widely invasive by extent of vascular invasion. Panel B, Outcomes stratified by extent of vascular
invasion showing poorer outcome with widely invasive carcinoma.
[Color—Print (Color Gallery page CG17) or web & ePub editions]

ENDO 2025 • Thyroid Biology and Cancer 293

Table. Mutation Rate of Key Drivers in Clinically, OTC often presents at an advanced
Differentiated
Table. MutationThyroid Cancers
Cancers
Rate of Key Drivers in Differentiated Thyroid stage, spreading via hematogenous or lymphatic
Gene PTC FTC HCC routes. Compared with FTC, OTC has a higher
9 18 22 frequency of vascular invasion, increasing
TERT promoter
0 0 13 recurrence risk.9
ERCC5
2 18 11
EIF1AX
ERBB2
0 0 11 Molecular Basis of OTC
8 21 9
NRAS OTC has a distinct genetic profile, differing
1 4 9 from papillary thyroid carcinoma (PTC) and
NF1
0 0 9 FTC (Table).2,3,10-13 Whole-exome sequencing
HLA-A
1 0 7 has identified pathogenic variants in EIF1AX,
TSC1/2
1 10 7 MADCAM1, OR4L1, ATXN1, UBXN11, NRAS, and
TP53 other genes. Unlike FTC and PTC, OTC rarely
0 0 7
ALKBH7 harbors BRAF, NRAS, HRAS, KRAS, PIK3CA, or
0 0 7
FAT1 RET pathogenic variants or PAX8-PPARG fusions.
0 0 7
NBPF1 OTC is characterized by a high somatic
0 1 5 mutational burden affecting the RAS/RAF/MAPK
CREBBP
1 1 5 and PIK3CA/AKT/mTOR pathways (Figure 3,
ATM
0 0 5 following page).
XPC
1 4 4 We identified RTK pathogenic variants (ERBB2
KRAS in 11%), RAS pathogenic variants (15%), and
4 7 2
HRAS tumor suppressor gene pathogenic variants in NF1
62 2 0
BRAF (9%), PTEN (4%), and TSC1/2 (6%). Chromosomal
7 0 0
RET fusions amplifications in RICTOR and BRAF contribute
PPARɣ Fusions
1 27 0 to oncogenesis. EIF1AX (11%) and EIF3B
1 6 0 (overexpressed due to chromosome 7 duplication)
PIK3CA
influence translation dysregulation. OTC exhibits
Table based on following manuscripts 2, 10-13
mitochondrial DNA pathogenic variants, including
large deletions affecting the electron transport
system (Figure 4, following page).2,3 These variants
Pathologic and Clinical Features disrupt oxidative phosphorylation, increasing
OTC consists of at least 75% oncocytic cells, reactive oxygen species and shifting metabolism to
characterized by eosinophilic granular cytoplasm aerobic glycolysis (Figure 5, following pages).14
due to mitochondrial proliferation (Figure 1A, Metabolite quantification (Figure 6, following
preceding page). Malignancy is determined by pages) confirms this metabolic shift.15 This explains
capsular or vascular invasion (Figure 1B, preceding why OTCs are hypermetabolic on PET scans
page). OTC was previously classified by extent of (Figure 7, following pages).
vascular invasion as widely invasive (>4 foci) and A unique OTC feature is genomic
minimally invasive (<4 foci) (Figure 2A, preceding chromosomal loss of heterozygosity leading
page). Biological behavior is determined by the to chromosomal instability.2,3 OTC has 3
extent of vascular invasion (Figure 2B, preceding page). phenotypes: diploid (minimally invasive),
The 2022 World Health Organization classification haploid, and polysomic (aggressive). Fluorescent
refines OTC into 3 prognostic subtypes.9 Unlike in situ hybridization illustrates haploid and
FTC, OTC requires histological examination for polysomic OTC (Figure 8A and 8B, following
diagnosis, as FNA alone is insufficient. pages). Chromosome 7 preservation, housing

294 ENDO 2025 • Endocrine Case Management

Figure 3.

RTK/PIK3/RAS Pathway showing alterations in 60% of cancers

[Color—Print (Color Gallery page CG18) or web & ePub editions]

Figure 4.

Panel A, Types of mitochondrial pathogenic variants observed in 56 OTCs.2 Panel B, Mitochondrial variants categorized by electron transport complexes.
[Color—Print (Color Gallery page CG18) or web & ePub editions]

ENDO 2025 • Thyroid Biology and Cancer 295

Figure 5.

Electron transport chain showing interaction of complexes with Krebs cycle. The arrow indicates complex I is the first site of electron transport chain.
Pathogenic variants in complex I disrupt electron transport chain, which in turn disrupts the TCA cycle.
[Color—Print (Color Gallery page CG19) or web & ePub editions]

key oncogenes EGFR and BRAF, may drive CT is preferred over whole-body iodine scans.
progression. Genomic chromosomal loss of Systemic therapy options are limited. Tyrosine
heterozygosity is linked to reduced immune kinase inhibitors (TKIs), such as sorafenib and
infiltration, aiding immune evasion.16 Targeting lenvatinib, improve progression-free survival
the mTOR pathway shows promise in (DECISION, SELECT trials),19,20 but overall
preclinical studies.17 survival benefits remain unclear. Ongoing trials
targeting mTOR and immune checkpoints
(nivolumab, ipilimumab) offer potential.21,22
Management Challenges
The ALLIANCE study showed improved
OTC is iodine-refractory, limiting RAI efficacy.18 survival with sorafenib and everolimus (Figure 9,
Total thyroidectomy is standard for advanced following pages).23
cases, while lobectomy suffices for minimally
invasive tumors. Lymph node dissection is
performed if metastases are present. Even when
RAI uptake is detected, responses are rare. PET/

296 ENDO 2025 • Endocrine Case Management

Figure 6.

Metabolic alterations in 40 OTCs. Metabolites with less abundance to normal are shown in blue and those greater than normal are shown in red. The blue
circle indicates the large decrease in citrate in the TCA cycle. The red circle indicates the increase in lactate due to increased aerobic glycolysis.
[Color—Print (Color Gallery page CG20) or web & ePub editions]

Prognosis and Future Directions therapies. OTC’s distinct molecular and clinical
features demand tailored management strategies.
Prognosis varies based on invasiveness. Minimally
Advances in molecular characterization and
invasive OTC has a 10-year disease-specific
targeted therapies offer hope for improved
survival of ~100%, compared with ~70% for
outcomes. Future research should focus on
widely invasive cases. Iodine refractoriness in
refining diagnostics and developing effective
recurrent or metastatic OTC necessitates new
systemic treatments.

ENDO 2025 • Thyroid Biology and Cancer 297

Figure 7.

OTCs are hypermetabolic on FDG PET due to increased aerobic glycolysis. Imaging shows a large left thyroid lobe mass on CT and PET. The patient has
multiple hypermetabolic lung metastases.
[Color—Print (Color Gallery page CG21) or web & ePub editions]

Figure 8.

Panel A, Fluorescent in situ hybridization (FISH) staining of a haploid cancer showing 1 copy of chromosome 2 and 2 copies of chromosome 5 and 7. Panel
B, FISH staining of a polysomic cancer showing 2 copies of chromosome 2 and 4 copies of chromosome 5 and 7. Panel C, Loss of chromosomes results in a
global loss of heterozygosity (LOH). Cancers with global LOH have a poorer outcome as shown by the Kaplan Meier plot.
[Color—Print (Color Gallery page CG21) or web & ePub editions]

298 ENDO 2025 • Endocrine Case Management

 Figure 9. Which of the following best characterizes
A. the differential
B.
diagnosis?
A. Oncocytic adenoma or oncocytic carcinoma
100
Sorafenib(400mg bid) B. Follicular adenoma or follicular carcinoma

Progression-Free Survival
Sorafenib/Everolimus
R Everolimus(5mg daily) 80 Sorafenib
A C. Papillary thyroid carcinoma Everolimus
N 60
RAI refractory D D. Follicular adenoma or oncocytic adenoma
O Target N= 30 40
OTC M E. Follicular
20
adenoma, oncocytic adenoma,
I
Z oncocytic carcinoma, or follicular carcinoma
0
E 0 12 24 36
Sorafenib alone(400mg bid Answer: E) Follicular adenoma,
Months oncocytic adenoma,
B.
oncocytic carcinoma, or follicular carcinoma

100 Both benign and malignant oncocytic neoplasms

Progression-Free Survival

Sorafenib/Everolimus
80 Sorafenib
could be reported as oncocytic follicular
60
Everolimus neoplasms. Oncocytic cells can also be present in
40
follicular adenomas and carcinomas.
Figure 9. A. Clinical phase II trial of patients with RAI refractory OTC randomizing patients to sorafenib alone versus sorafenib/everolimus. B. Patients treated with sorafenib/everolimus had
20 progression free survival.
increased
0
0 12 24 36
Case 1, Continued
id Months
If this were an oncocytic neoplasm, what
Panel A, Clinical phase 2 trial of patients with RAI-refractory OTC would be the expected results with Thyroseq?
randomly assigning patients to sorafenib alone vs sorafenib/everolimus.
Panel B, Patients treated with sorafenib/everolimus had increased A. V600E BRAF positive
progression-free survival.
[Color—Print (Color Gallery page CG22) or web & ePub editions] B. PPARG-PARP fusion positive
C. Amplification of chromosome 1q
patients to sorafenib alone versus sorafenib/everolimus. B. Patients treated with sorafenib/everolimus had D. Widespread copy-number alterations with
amplification of chromosomes 5, 7, 12, 20
E. No pathogenic variants or copy-number
Clinical Case Vignettes alterations
Case 1
Answer: D) Widespread copy-number alterations
A 67-year-old woman with no notable medical with amplification of chromosomes 5, 7, 12, 20
history is referred for evaluation of a 2.8-cm
thyroid nodule incidentally discovered during Oncocytic neoplasms can display distinct copy-
routine carotid ultrasonography. Physical number alterations characterized by amplification
examination reveals a palpable, nontender thyroid of chromosomes 5, 7, 12, and 20 and uniparental
nodule without cervical lymphadenopathy. disomy of remaining chromosomes. These
Thyroid ultrasonography shows an encapsulated alterations are most pronounced in aggressive
3-cm thyroid nodule with increased vascularity. forms of oncocytic cancers, but they can also
There are no nodules in the contralateral lobe. occur in more indolent forms. If copy-number
There are no suspicious lymph nodes. FNA alterations are absent, oncocytic neoplasms may
cytology is consistent with an oncocytic follicular have pathogenic variants in NRAS, EIF1AX, PTEN,
neoplasm (Bethesda IV). A sample is sent for TSC1, TSC2, and mTOR. BRAF pathogenic variants
Thyroseq testing. do not occur in OTC. Similarly, PPARG-PARP
fusions occur in follicular neoplasms but not in
oncocytic neoplasms.

ENDO 2025 • Thyroid Biology and Cancer 299

Case 1, Continued C. Contrast CT of the neck
Diagnostic lobectomy is performed, and D. Contrast CT of the neck and chest
histopathology reveals a minimally invasive OTC E. None
with capsular invasion but no vascular invasion.
Answer: B) PET and contrast CT of the neck
Which of the following treatments Oncocytic neoplasms are very FDG-avid due to an
should be offered now? extreme Warburg effect with a shift in metabolism
A. None from the Krebs cycle to aerobic glycolysis.
B. Completion thyroidectomy Therefore, PET is a very effective method of
C. Completion thyroidectomy with ipsilateral detecting regional and distant metastatic spread. The
central neck dissection presence of vocal cord paralysis and extrathyroidal
extension on ultrasonography suggest invasion of
D. Completion thyroidectomy with ipsilateral
the left recurrent laryngeal nerve, as well as possible
central neck dissection and RAI
involvement of the trachea and esophagus. A
E. Completion thyroidectomy with bilateral detailed contrast neck CT is required to evaluate the
central neck dissection and RAI degree of extrathyroidal extension in this patient.
Answer: A) None PET is not sufficient to give this level of detail. Neck
CT will also give more anatomical detail of regional
Given the absence of high-risk features, lymph node spread and relationship to carotid artery
completion thyroidectomy is not indicated. and internal jugular vein. Thus, the best additional
Minimally invasive oncocytic carcinomas rarely imaging for this patient is PET and contrast CT of
metastasize to lymph nodes. This patient was the neck (Answer B).
monitored with periodic neck ultrasonography
and serum thyroglobulin measurement, which
Case 2, Continued
remained undetectable over 3 years of follow-up.
Imaging shows a large vascular left thyroid mass
but no invasion of the trachea or esophagus.
Case 2 Multiple lymph nodes are present in the
A 72-year-old man presents with a 3-month ipsilateral central neck, as well as in levels 2, 3,
history of progressive dysphagia and hoarseness. and 4 of the lateral neck. PET shows several small
Ultrasonography reveals a 5.5-cm hypoechoic hypermetabolic subcentimeter pulmonary nodules
left thyroid mass with extrathyroidal extension suggestive of metastatic disease.
and suspicious cervical lymph nodes. Flexible
laryngoscopy shows a paralyzed left vocal cord. Which of the following treatments
FNA cytology suggests an oncocytic neoplasm, and should be recommended now?
subsequent core biopsy confirms widely invasive A. None; the patient should now be on
OTC with vascular invasion. Molecular testing palliative care
reveals TERT and mTOR pathogenic variants, as B. High-dose RAI
well as widespread copy-number alterations of
C. Surgery with left thyroid lobectomy and
chromosomes 5, 7, 12, and 20.
central and lateral neck dissection; observation
Which of the following radiological of pulmonary metastases
tests should be done now? D. Surgery with total thyroidectomy and central
A. PET and detailed ultrasound lymph node and lateral neck dissection; treatment of
mapping of the neck pulmonary metastases with lenvatinib
B. PET and contrast CT of the neck E. Lenvatinib alone

300 ENDO 2025 • Endocrine Case Management

Answer: C) Surgery with left thyroid lobectomy tumor deposits due to vascular and lymphatic
and central and lateral neck dissection; permeation of the soft tissues. Metastases to lung
observation of pulmonary metastases and bone are common. Genomic analysis has
shown upregulation of the mTOR pathway in 60%
As in all types of locally advanced thyroid cancer, of widely invasive OTCs.2 A randomized phase 2
the initial goal is to control the central neck to trial has shown increased efficacy and prolonged
prevent airway compromise and asphyxiation. progression-free survival with sorafenib
The presence of left vocal cord paralysis indicates in combination with the mTOR inhibitor
extrathyroidal extension to the recurrent laryngeal everolimus.23 There are no data to suggest that
nerve. Left thyroid lobectomy (Answer C) with OTCs are sensitive to immune checkpoint
central neck dissection would help control the inhibitor therapy. Recent research shows OTCs
central neck. Removal of lateral neck nodes can be are immune-depleted tumors with increased
done in the same operation. Total thyroidectomy immunosuppression in the more aggressive forms
is not required since widely invasive OTC are of OTC. Therefore, the use of immunotherapy
not RAI-avid. This also reduces the chance of alone is unlikely to have any activity. Thus, the
any inadvertent injury to the contralateral right best recommendation for this patient is lenvatinib
recurrent laryngeal nerve. The presence of and everolimus (Answer C).
multiple subcentimeter FDG-avid pulmonary
nodules is not an indication for treatment at this
stage. As in other forms of thyroid cancer, an Case 3
initial period of observation with serial chest CT A 55-year-old woman undergoes total
should be done to assess nodule growth. Distant thyroidectomy for a presumed benign multinodular
metastatic disease can be treated with a tyrosine goiter. Pathology unexpectedly reveals a 5-cm,
kinase inhibitor such as lenvatinib, which has widely invasive OTC with vascular invasion.
strong VEGF inhibitor activity.
Which of the following histological features
are diagnostic of widely invasive OTC?
Case 2, Continued
A. Abundant eosinophilic granular cytoplasm,
Observation of the pulmonary nodules over 12
encapsulated neoplasm, presence of vascular
months shows rapid growth in both lungs. The
invasion (2 foci)
patient also develops subcutaneous FDG-avid
nodules in the operated neck 6 months after B. Abundant eosinophilic granular cytoplasm,
surgery. encapsulated neoplasm, and presence of
vascular invasion (5 foci)
Which of the following treatments C. Abundant eosinophilic granular cytoplasm,
should be offered now? presence of vascular invasion (2 foci),
A. None; the patient should be on palliative care extrathyroidal extension
B. Lenvatinib alone D. Abundant eosinophilic granular cytoplasm,
presence of vascular invasion (5 foci),
C. Lenvatinib and everolimus
extrathyroidal extension
D. Everolimus alone
E. Encapsulated neoplasm, presence of vascular
E. Lenvatinib and pembrolizumab invasion (5 foci)
Answer: C) Lenvatinib and everolimus Answer: D) Abundant eosinophilic granular
The clinical and radiological findings show cytoplasm, presence of vascular invasion
widespread distant metastases. OTCs, which (5 foci), extrathyroidal extension
are widely invasive, can recur as subcutaneous

ENDO 2025 • Thyroid Biology and Cancer 301

Oncocytic neoplasms have granular eosinophilic D. Yes; give 100 mCi since thyroglobulin is
cytoplasm due to the presence of 1000s of detectable
abnormal mitochondria. OTCs show invasion of E. Yes because it helps to reduce the incidence of
the capsule +/- vascular invasion. The presence distant metastases
of fewer than 4 foci of vascular invasion occurs in
encapsulated angioinvasive OTC. The presence Answer: B) No because widely invasive
of more than 4 foci with extrathyroidal extension OTCs are not RAI-avid
occurs in the most aggressive OTC (widely
As OTCs become more aggressive, they lose
invasive OTC) (Answer D).
expression of the thyroid differentiation genes,
including the sodium-iodide symporter gene (NIS).
Case 3, Continued As a result, the widely invasive forms of OTC are
Postoperative ultrasonography shows no obvious not RAI-avid (Answer B). This is in contrast to
metastatic lymph nodes. minimally invasive OTC, which retains expression
of the NIS gene and are RAI-avid. There is no
Which of the following is the best way to evidence to suggest that RAI reduces the risk of
manage the central neck and lateral neck? distant metastases.
A. Ipsilateral central neck dissection
B. Bilateral central neck dissection Key Learning Points
C. Ipsilateral central neck dissection and
ipsilateral lateral neck dissection • OTC, formerly treated as a subtype of
FTC, has been recognized by the World
D. Bilateral central and lateral neck dissection
Health Organization as a distinct thyroid
E. Observation malignancy due to its unique molecular and
Answer: E) Observation clinicopathologic features. This change reflects
advances in understanding OTC’s genetic basis
Metastatic spread of cancer to regional lymph and distinct clinical behavior.
nodes rarely occurs in minimally invasive OTC. • OTC exhibits a unique genomic profile,
However, it does occur in the more aggressive including pathogenic variants in the genes
forms of OTC, particularly widely invasive involved in the RAS/RAF/MAPK and
cancers with extrathyroidal extension and vascular PIK/AKT/MTOR pathways and in genes
invasion. If present on lymph node mapping on controlling telomere elongation. Additionally,
ultrasonography or on contrast neck CT, regional mitochondrial DNA pathogenic variants and
lymph node dissection should be done of all genomic chromosomal loss of heterozygosity
involved lymph node levels. are hallmarks, with implications for tumor
progression and therapeutic resistance.
Case 3, Continued • OTC typically presents at more advanced stages
Should postoperative RAI treatment be given? than other DTCs and is associated with worse
A. No because the postoperative thyroglobulin is survival outcomes. Diagnosis is challenging due
undetectable to the inability of FNA to confirm capsular/
vascular invasion. Furthermore, OTC is
B. No because widely invasive OTCs are not
often iodine-refractory, limiting the efficacy
RAI-avid
of standard RAI therapy and necessitating
C. Yes; give low-dose 30 mCi since thyroglobulin alternative treatment strategies.
is undetectable

302 ENDO 2025 • Endocrine Case Management

• Prognosis varies widely based on therapies, such as mTOR inhibitors and
histopathologic features, with minimally combination systemic treatments, show
invasive OTC showing excellent outcomes promise in managing advanced or metastatic
and widely invasive cases associated with OTC but are constrained by limited data and
significantly worse survival. Emerging substantial adverse effects.

References
1. Baloch ZW, Asa SL, Barletta JA, et al. Overview of the 2022 WHO molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab.
classification of thyroid neoplasms. Endocr Pathol. 2022;33(1):27-63. PMID: 2003;88(5):2318-2326. PMID: 12727991
35288841 14. Frank AR, Li V, Shelton SD, et al. Mitochondrial-encoded complex I
2. Ganly I, Makarov V, Deraje S, et al. Integrated genomic analysis of Hürthle impairment induces a targetable dependency on aerobic fermentation in
cell cancer reveals oncogenic drivers, recurrent mitochondrial mutations, and Hurthle cell carcinoma of the thyroid. Cancer Discov. 2023;13(8):1884-1903.
unique chromosomal landscapes. Cancer Cell. 2018;34(2):256-70.e5. PMID: PMID: 37262072
30107176 15. Ganly I, Liu EM, Kuo F, et al. Mitonuclear genotype remodels the metabolic
3. Gopal RK, Kübler K, Calvo SE, et al. Widespread chromosomal losses and and microenvironmental landscape of Hürthle cell carcinoma. Sci Adv.
mitochondrial DNA alterations as genetic drivers in Hürthle cell carcinoma. 2022;8(25):eabn9699. PMID: 35731870
Cancer Cell. 2018;34(2):242-55.e5. PMID: 30107175 16. Ganly I, Kuo F, Makarov V, et al. Characterizing the immune
4. Máximo V, Lima J, Prazeres H, Soares P, Sobrinho-Simões M. The biology microenvironment and neoantigen landscape of Hürthle cell carcinoma
and the genetics of Hürthle cell tumors of the thyroid. Endocr Relat Cancer. to identify potential immunologic vulnerabilities. Cancer Res Commun.
2016;23(12):X2. PMID: 27807063 2023;3(7):1409-1422. PMID: 37529400
5. Ghossein RA, Hiltzik DH, Carlson DL, et al. Prognostic factors of recurrence 17. Dong Y, Gong Y, Kuo F, et al. Targeting the mTOR pathway in Hurthle
in encapsulated Hurthle cell carcinoma of the thyroid gland: a clinicopathologic cell carcinoma results in potent antitumor activity. Mol Cancer Ther.
study of 50 cases. Cancer. 2006;106(8):1669-1676. PMID: 16534796 2022;21(2):382-394. PMID: 34789562
6. Shaha AR, Shah JP, Loree TR. Patterns of nodal and distant metastasis based 18. Bischoff LA, Ganly I, Fugazzola L, et al. Molecular alterations and
on histologic varieties in differentiated carcinoma of the thyroid. Am J Surg. comprehensive clinical management of oncocytic thyroid carcinoma: a
1996;172(6):692-694. PMID: 8988680 review and multidisciplinary 2023 update. JAMA Otolaryngol Head Neck Surg.
7. Grossman RF, Clark OH. Hurthle cell carcinoma. Cancer Control. 2024;150(3):265-272. PMID: 38206595
1997;4(1):13-17. PMID: 10762998. 19. Brose MS, Robinson B, Sherman SI, et al. Cabozantinib for radioiodine-
8. Lopez-Penabad L, Chiu AC, Hoff AO, et al. Prognostic factors in patients refractory differentiated thyroid cancer (COSMIC-311): a randomised,
with Hurthle cell neoplasms of the thyroid. Cancer. 2003;97(5):1186-1194. double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(8):1126-
PMID: 12599224. 1138. PMID: 34237250
9. Matsuura D, Yuan A, Wang LY, et al. Follicular and Hurthle cell carcinoma: 20. Brose MS, Nutting CM, Jarzab B, et al; DECISION investigators. Sorafenib
comparison of clinicopathological features and clinical outcomes. Thyroid. in radioactive iodine-refractory, locally advanced or metastatic differentiated
2022. PMID: 35078345 thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet.
10. Cancer Genome Atlas Research Network. Integrated genomic 2014;384(9940):319-328. PMID: 24768112
characterization of papillary thyroid carcinoma. Cell. 2014;159(3):676-690. 21. Lorch JH, Barletta JB, Nehs M, et al. A phase II study of nivolumab (N) plus
PMID: 25417114 ipilimumab (I) in radioiodine refractory differentiated thyroid cancer (RAIR
11. Park H, Shin HC, Yang H, et al. Molecular classification of follicular thyroid DTC) with exploratory cohorts in anaplastic (ATC) and medullary thyroid
carcinoma based on TERT promoter mutations. Mod Pathol. 2022;35(2):186- cancer (MTC). J Clin Oncol. 2020;38(15):6513-6513.
192. PMID: 34497362 22. Sherman EJ, Dunn LA, Ho AL, et al. Phase 2 study evaluating the combination
12. Marques AR, Espadinha C, Catarino AL, et al. Expression of PAX8- of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory
PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and thyroid cancer. Cancer. 2017;123(21):4114-4121. PMID: 28662274
adenomas. J Clin Endocrinol Metab. 2002;87(8):3947-3952. PMID: 12161538 23. Sherman EJ, Foster NR, Su YB, et al. Randomized phase II study of sorafenib
13. Nikiforova MN, Lynch RA, Biddinger PW, et al. RAS point mutations and with or without everolimus in patients with radioactive iodine refractory
PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct Hurthle cell thyroid cancer. J Clin Oncol. 2021;39(15):6076-6076.

ENDO 2025 • Thyroid Biology and Cancer 303

Special Diets for Thyroid
Health: Fact or Fiction?
Angela M. Leung, MD, MSc. Division of Endocrinology, Diabetes, and Metabolism,
Department of Medicine, University of California Los Angeles David Geffen School of
Medicine, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California;
Email: [email protected]

Educational Objectives understanding of the benefits, potential harms,

and uncertainties of various nonprescription
After reviewing this chapter, learners should be
supplements and diets is important when caring
able to:
for patients with thyroid disease.
• Describe the current understanding of
trace mineral supplements use, thyroid Practice Gaps
autoimmunity, and thyroid dysfunction risk.
• Define the effects of various popular diets • There is a need for physicians to become
on thyroid autoimmunity and thyroid more familiar with the literature addressing
dysfunction. nonprescription supplements and diets that
• Summarize the associations between dietary patients may be taking in an effort to improve
patterns, risk of malignant thyroid nodules, or maintain normal thyroid health.
and thyroid cancer behavior. • Increased recognition of popular supplements
and diets touted for thyroid health is an
important component of shared decision-
making between patients and clinicians.
Significance of the • Discussion of the data gaps regarding the
Clinical Problem thyroidal benefits and potential harms of
Dietary supplements and restricted diets have dietary supplements and interventions is an
become increasingly popular in recent years, with important component of managing thyroid
52% of the US general adult population reporting issues.
use of a supplement in 2011-20121 and 17.1% of
US adults 20 years or older reporting adherence Discussion
to a specific diet in 2015-2018.2 In particular,
dietary supplements and dietary interventions Dietary Supplements Commonly
aimed at improving thyroid health are becoming Used to Improve Thyroid Health
increasingly popular. Patients may be taking Autoimmune thyroid disease, also termed
supplements or adhering to special diets, possibly Hashimoto thyroiditis or chronic lymphocytic
in combination with prescribed thyroid or thyroiditis, and defined as the presence of serum
antithyroid medications, in an effort to maintain thyroid autoantibodies, affects approximately
or decrease thyroid autoimmunity, preserve 15% of individuals.3 It is more common in
normal thyroid function, or mitigate the risks persons with other autoimmune conditions,
of thyroid nodules and thyroid cancer. A greater such as celiac disease, vitiligo, type 1 diabetes,

304 ENDO 2025 • Endocrine Case Management

and pernicious anemia. Women with thyroid and other items (including calories) have been
autoimmunity have an approximately 2% per studied for their effects on the thyroid. The data
year risk of hypothyroidism compared with unfortunately remain sparse, and there are no
individuals without thyroid-antibody positivity.4 consistent data supporting that such any specific
It is not uncommon for patients with Hashimoto type of elimination diets significantly reduces the
thyroiditis to inquire how they may mitigate risk of thyroid autoimmunity.10
the risk of developing hypothyroidism. Many Finally, there is some evidence suggesting
supplements in this setting have been studied, that overweight and obesity may be independent
including iodine, selenium, iron, magnesium, risk factors for cancer development. Mechanisms
vitamin D, vitamin B12, and others. underlying the higher risk of malignancy may
Iodine is a micronutrient required for thyroid be related to an inflamed white adipose tissue
hormone production that comes from dietary microenvironment, in which elevated insulin
sources (eg, iodized salt and other foods) and and IGF-1 can activate the PI3K/Akt/mTOR and
iodine-containing supplements. Adequate iodine Ras/Raf/MAPK pathways that stimulate tumor
intake is particularly important in women during growth.11 Although leptin is best understood as
the preconception period, pregnancy, and the a signal of satiety, it can also stimulate TSH, and
postpartum period because of the increased thus potentially represent a thyroidal growth
thyroid hormone requirements of the developing factor.12 In the United States, analysis of the NIH-
fetus during gestation. The World Health AARP Diet and Health Study dataset suggests
Organization recommends 150 mcg iodine daily that higher BMI is a risk factor for both low- and
in nonpregnant, nonlactating adults and 250 mcg high-risk thyroid cancers.13 These findings are
iodine daily in pregnant women.5 To help achieve consistent with an animal study showing that mice
this, pregnant women who may have risk of fed a high-fat diet had higher mortality, larger
insufficient dietary iodine (ie, if they are following thyroid tumors, and more histologic anaplastic
a restricted diet) should be advised to take a daily changes compared with those fed a low-fat diet.14
iodine supplement containing 150 mcg.6,7 Patients There is general understanding that a healthy,
should also be educated about the risk of thyroid balanced diet rich in fruits and vegetables, whole
dysfunction in the setting of iodine excess and grains, and lean proteins may diminish cancer risk.
advised to avoid supplements containing more A survey study reported an inverse association
than 500 mcg iodine.8 between self-report of a Mediterranean-based diet
and sonographically suspicious thyroid nodules,15
while a large multicenter European study reported
Special Diets Commonly Used
that consuming inflammatory foods was weakly
to Improve Thyroid Health positive for differentiated thyroid cancer risk.16
There is increasing recognition that the
composition of intestinal microbiota is related to
health and disease, with some evidence suggesting Clinical Case Vignettes
that its alteration (ie, intestinal dysbiosis), bacterial Case 1
overgrowth, and increased intestinal permeability A 32-year-old woman has a 10-year history
may favor the development of thyroid of Hashimoto thyroiditis. Celiac disease was
autoimmunity.9 Thus, the concept of addressing diagnosed 5 years ago, and she has since been
“leaky gut syndrome” has been proposed, in which strictly adherent to a gluten-free diet. She takes
diets that eliminate certain foods or food groups is no medications. Her mother has hypothyroidism
thought to alter the risk of Hashimoto thyroiditis associated with Hashimoto thyroiditis and is
and potentially hypothyroidism. Elimination diets taking levothyroxine, 100 mcg once daily. The
that omit or reduce gluten, lactose, dairy, grains, patient is interested in learning about supplements

ENDO 2025 • Thyroid Biology and Cancer 305

she could take to reduce her risk of, or at least effect on thyroid function.17,18 These negative
delay, developing hypothyroidism. She would findings thus do not support routine selenium
like to avoid the need for future thyroid hormone supplementation for the purpose of improving
replacement. thyroid health, outside of its selected use in some
individuals with Graves ophthalmopathy.19 This
Which of the following is the best patient could be counseled that although sparse
advice to provide this patient? data suggest selenium supplementation may
A. Start selenium, 200 mcg by mouth once daily decrease some aspects of thyroid autoimmunity in
B. Start ferrous sulfate, 325 mg by mouth once the short term, its long-term benefits of altering
daily the risk of thyroid dysfunction remain unknown,
and it would not be recommended for this purpose
C. Start magnesium, 250 mg by mouth once daily
(Answer A).
D. Start vitamin D, 25 mcg (1000 units) by mouth Iron is an important component of the thyroid
once daily synthesis pathway, as the heme-containing enzyme
E. Measure TSH measurement if she develops TPO is critical for thyroid hormone production,
any signs or symptoms of thyroid dysfunction and deiodinase activity is altered in iron
deficiency.20 However, the evidence for an adverse
Answer: E) Measure TSH measurement if she develops
thyroid impact resulting from iron deficiency is
any signs or symptoms of thyroid dysfunction
limited, and associations between iron deficiency,
This patient has 2 autoimmune conditions: serum TPO-antibody and thyroglobulin-antibody
Hashimoto thyroiditis and celiac disease. She is positivity, higher TSH levels, and lower free T4
thus at risk for developing additional autoimmune levels are inconsistent.21 As such, the thyroidal
conditions. The diagnosis of Hashimoto thyroiditis benefits of iron supplementation (Answer B)
confers an up to 2% per year added risk of are not clear, and its routine use is not currently
developing hypothyroidism, compared with risk recommended for the purpose of supporting
of individuals who do not have thyroid-antibody thyroid health.
positivity.4 Patients with Hashimoto thyroiditis Magnesium (Answer C) is thought have
often inquire how they may mitigate the risk of antiinflammatory properties, and low serum
developing hypothyroidism. magnesium levels have been associated with
Selenium (Answer A) is thought to have markers of thyroid autoimmunity and an increased
antiinflammatory properties that may protect risk of hypothyroidism.10 One Chinese study
against oxidative damage important for general reported an up to 5-fold risk of hypothyroidism
health, and some selenoproteins (eg, glutathione with severe magnesium deficiency, and limited
peroxidase and iodothyronine deiodinases) have data also show high magnesium levels may
crucial roles in thyroid hormone metabolism. The improve Graves disease.10 However, supporting
US recommended daily allowance of selenium evidence is inconsistent, and thus routine
is 55 mcg daily in nonpregnant, nonlactating magnesium supplementation is not recommended
adults, with a tolerable upper limit set at 400 mcg for its potential thyroid benefits.
daily.6 Selenium-rich foods include seafood, organ Vitamin D (Answer D) has important
meats, and mushrooms, with lower amounts roles in cell proliferation, differentiation, and
found in breads, grains, meat, poultry, fish, and immunomodulation, and limited data suggest that
eggs. Although there are limited data showing compared with healthy individuals, persons with
that selenium supplementation (200 mcg daily) Hashimoto thyroiditis have increased cytokines
in small prospective cohorts of short duration secreted by proinflammatory Th1 and Th17 cells
(3-6 months) may decrease TPO-antibody and/or (IFN-gamma and IL-17).22 However, the specific
thyroglobulin-antibody levels, there is no known benefit of vitamin D supplementation to alter

306 ENDO 2025 • Endocrine Case Management

thyroid autoimmunity remains unclear, and it is between energy expenditure, metabolism, and
thus not recommended. the thyroid gland are complex. Only scarce
This patient may be advised that although evidence supports a predictable pattern of weight
she has a slightly higher risk of developing changes in the setting of thyroid dysfunction.25
hypothyroidism4 compared with individuals who Compared with individuals who do not have
do not have Hashimoto thyroiditis (and potentially thyroid-antibody positivity, women with
an even higher risk given that she has coexisting thyroid autoimmunity have an up to 2% per year
celiac disease),23 the benefit of supplements to additional risk of developing hypothyroidism.4
mitigate this risk is unknown and they are not The risk of hypothyroidism may be independently
recommended. Serum TSH should be measured associated with markers of obesity, such as waist
if she develops signs or symptoms of thyroid circumference.26
dysfunction (Answer E). Autoimmune thyroid disease commonly
coexists with other autoimmune conditions. A
systematic literature review and meta-analysis
Case 2
showed a greater than 3-fold risk of thyroid
A 49-year-old woman with no relevant medical disease in persons with celiac disease. Mechanisms
history is seen for weight gain that she has noticed explaining the potential overlap between thyroid
over the past 4 years. She reports that maintaining and celiac disease are not fully understood, but
a normal weight is a constant struggle, despite shared genetic factors are likely. HLA DQ2 and
adhering to healthy, low-fat, low-carbohydrate DQ8 are weakly associated with Hashimoto
diet and a regular exercise regimen. She has thyroiditis, and the haplotypes are overexpressed
heard about the connection between a “leaky in celiac disease.23 Furthermore, CTLA-4 is
gut” and autoimmune thyroid disease, which associated with both autoimmune thyroid and
she is interested in preventing. Her serum TSH celiac disease.23 A small, prospective, blinded
concentration is normal (1.4 mIU/L), and she has interventional study showed that selenium
undetectable TPO antibodies. Her height is 62 in supplementation given for 3 months significantly
(157.5 cm), and weight is 130 lb (60.0 kg) (BMI = decreased serum TPO-antibody concentrations,
23.8 kg/m2). but not thyroglobulin antibodies, compared with a
placebo group.17
Which of the following is the best In summary, there are no consistent data
advice to provide this patient? demonstrating that adoption of a specific type
A. Eliminate gluten from her diet of elimination diet is useful in this setting. The
B. Reduce dietary intake by 500 calories per day omission of gluten (Answer A), lactose (Answer
C. Avoid lactose-rich foods C), and grains and dairy (Answer D) has not
D. Eat a paleo-style diet (ie, avoid grains and dairy shown sustained benefits in individuals with
products) autoimmune thyroid disease. Additionally,
calorie reduction (Answer B) may be helpful
E. Reassure her that she has a normal BMI and in maintaining a net neutral energy balance
recommend routine monitoring depending on her level of daily physical activity,
Answer: E) Reassure her that she has a normal but it is not expected to, by itself, decrease her
BMI and recommend routine monitoring risk of developing autoimmune thyroid disease.
This patient should be counseled that her weight
Obesity is a worsening epidemic, with is characterized as normal according to BMI
approximately 42% of all US adults meeting definitions and routine screening with annual BMI
criteria for obesity in 2016 (projected to assessment is recommended (Answer E).
increase to 50% by 2030).24 The relationships

ENDO 2025 • Thyroid Biology and Cancer 307

Case 3 D) (ie, those belonging to the Brassica genus)
contain goitrogenic compounds that decrease the
A 69-year-old man with no relevant medical
availability of iodine to the thyroid and thereby
history was diagnosed with papillary thyroid
may pose a risk of hypothyroidism in individuals
cancer 1 year ago. Surgical pathology was
who ingest high amounts. However, consumption
consistent with low-risk disease, and he was
of cruciferous vegetables is not known to be
counseled that there is an estimated 5% risk
associated with thyroid cancer, and in fact,
of disease recurrence. He takes levothyroxine,
may even decrease malignancy risk due to their
125 mcg once daily, and a multivitamin. His height
antioxidant properties.
is 70 in (177.8 cm), and weight is 168 lb (76.2 kg)
(BMI = 24.1 kg/m2). He is interested in learning
about foods and dietary patterns that may be Key Learning Points
helpful in decreasing his risk of thyroid cancer
recurrence. • Although thyroid autoimmunity is associated
with an approximately 2% per year increased
Which of the following is the best risk of developing hypothyroidism, the
advice to provide this patient? potential long-term benefits of various
A. Maintain a normal BMI through diet and supplements, including iron, magnesium, and
exercise vitamin D, in altering thyroid autoimmunity
B. Start a Mediterranean-based diet and thyroid function remain unknown, and
supplements are not recommended for this
C. Minimize intake of sugary foods
purpose.
D. Avoid consuming cruciferous vegetables
• In small prospective cohorts of short duration,
E. Start a ketogenic high-fat, low-carbohydrate selenium supplementation has been shown to
diet decrease TPO-antibody and/or thyroglobulin-
Answer: A) Maintain a normal BMI through diet antibody levels, but there are no effects on
and exercise thyroid function. Current data do not support
routine selenium supplementation for the
The best advice is to encourage this patient to prevention of thyroid dysfunction.
maintain a normal BMI through diet and exercise
• The gut microbiome is important in health and
(Answer A), as there are some data showing a
disease. However, there are no consistent data
higher risk of malignancies among individuals
that elimination diets (including the omission
with overweight or obesity due to the adverse
or reduction of gluten, lactose, dairy, grains,
metabolic and tumoral effects of an inflamed
and caloric intake) significantly and durably
white adipose tissue microenvironment.11
reduce the risk of thyroid autoimmunity.
Evidence supporting that a specific diet, such as
Mediterranean (Answer B), low-sugar (Answer • Maintaining a normal BMI should be
C), or ketogenic (Answer E), confers a significantly advised because overweight and obesity are
decreased thyroid cancer risk is extremely limited independent risk factors for the development
or absent. Cruciferous vegetables (Answer of some cancers, including thyroid cancer.

References
1. Kantor ED, Rehm CD, Du M, White E, Giovannucci EL. Trends in dietary 2. Stierman B, Ansai N, Mishra S, Hales C. Special diets among adults: United
supplement use among US adults trom 1999-2012. JAMA. 2016;316(14):1464- States, 2015-2018. NCHS Data Brief, no 389 Hyattsville, MD: National Center
1474. PMID: 27727382 for Health Statistics. 2020.

308 ENDO 2025 • Endocrine Case Management

3. Hollowell JG, Staehling NW, Hannon WH, et al. Iodine nutrition in the 16. Lecuyer L, Laouali N, Dossus L, et al. Inflammatory potential of the diet
United States. Trends and public health implications: iodine excretion data and association with risk of differentiated thyroid cancer in the European
from National Health and Nutrition Examination Surveys I and III (1971- Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Eur J
1974 and 1988-1994). J Clin Endocrinol Metab. 1998;83(10):3401-3408. PMID: Nutr. 2022;61(7):3625-3635. PMID: 35635567
9768638 17. Gartner R, Gasnier BC, Dietrich JW, Krebs B, Angstwurm MW. Selenium
4. Prummel MF, Wiersinga WM. Thyroid peroxidase autoantibodies in supplementation in patients with autoimmune thyroiditis decreases
euthyroid subjects. Best Pract Res Clin Endocrinol Metab. 2005;19(1):1-15. thyroid peroxidase antibodies concentrations. J Clin Endocrinol Metab.
PMID: 15826919 2002;87(4):1687-1691. PMID: 11932302
5. World Health Organization (WHO), United Nations International Children’s 18. Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H.
Emergency Fund (UNICEF), and International Council for the Control of Levothyroxine treatment in euthyroid pregnant women with autoimmune
Iodine Deficiency Disorders (ICCIDD). Assessment of the iodine deficiency thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab.
disorders and monitoring their elimination. Geneva: World Health 2006;91(7):2587-2591. PMID: 16621910
Organization; 2007. Report No.: WHO/NHD/01.1. 19. Burch HB, Perros P, Bednarczuk T, et al. Management of thyroid eye
6. Food and Nutrition Board, U.S. Institute of Medicine. Dietary reference disease: a consensus statement by the American Thyroid Association and
intakes. National Academy Press; 2006: 320. the European Thyroid Association. Thyroid. 2022;32(12):1439-1470. PMID:
7. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American 36480280
Thyroid Association for the diagnosis and management of thyroid disease 20. Beard JL, Brigham DE, Kelley SK, Green MH. Plasma thyroid hormone
during pregnancy and the postpartum. Thyroid. 2017;27(3):315-389. PMID: kinetics are altered in iron-deficient rats. J Nutr. 1998;128(8):1401-1408.
28056690 PMID: 9687562
8. Sohn SY, Inoue K, Rhee CM, Leung AM. Risks of iodine excess. Endocr Rev. 21. Garofalo V, Condorelli RA, Cannarella R, Aversa A, Calogero AE, La Vignera
2024;45(6):858-879. PMID: 38870258 S. Relationship between iron deficiency and thyroid function: a systematic
9. Cayres LCF, de Salis LVV, Rodrigues GSP, et al. Detection of alterations in review and meta-analysis. Nutrients. 2023;15(22):4790. PMID: 38004184
the gut microbiota and intestinal permeability in patients with Hashimoto 22. Mikulska AA, Karazniewicz-Lada M, Filipowicz D, Ruchala M, Glowka FK.
thyroiditis. Front Immunol. 2021;12:579140. PMID: 33746942 Metabolic characteristics of Hashimoto’s thyroiditis patients and the role of
10. Larsen D, Singh S, Brito M. Thyroid, diet, and alternative approaches. J Clin microelements and diet in the disease management-an overview. Int J Mol Sci.
Endocrinol Metab. 2022;107(11):2973-2981. PMID: 35952387 2022;23(12):6580. PMID: 35743024
11. Iyengar NM, Gucalp A, Dannenberg AJ, Hudis CA. Obesity and cancer 23. Sun X, Lu L, Yang R, Li Y, Shan L, Wang Y. Increased incidence of thyroid
mechanisms: tumor microenvironment and inflammation. J Clin Oncol. disease in patients with celiac disease: a systematic review and meta-analysis.
2016;34(35):4270-4276. PMID: 27903155 PLoS One. 2016;11(12):e0168708. PMID: 28030626
12. Flier JS, Harris M, Hollenberg AN. Leptin, nutrition, and the thyroid: the 24. Ward ZJ, Bleich SN, Cradock AL, et al. Projected U.S. state-level prevalence
why, the wherefore, and the wiring. J Clin Invest. 2000;105(7):859-861. PMID: of adult obesity and severe obesity. N Engl J Med. 2019;381(25):2440-2450.
10749565 PMID: 31851800
13. La Greca A, Grau L, Arbet J, et al. Anthropometric, dietary, and lifestyle 25. Roa Duenas OH, Xu Y, Ikram MA, Peeters RP, Visser E, Chaker L. Thyroid
factors and risk of advanced thyroid cancer: the NIH-AARP diet and health function and anthropometric measures: a systematic review and meta-
cohort study. Clin Endocrinol (Oxf). 2023;99(6):586-597. PMID: 37694684 analysis. Endocr Pract. 2025;31(2):198-207. PMID: 39631665
14. Kim WG, Park JW, Willingham MC, Cheng SY. Diet-induced obesity 26. Wen X, Mao Y, Li Z, Chen G, Zhou S. Association between weight-adjusted
increases tumor growth and promotes anaplastic change in thyroid cancer in waist index and Hashimoto’s thyroiditis: insights from NHANES 2007-2012.
a mouse model. Endocrinology. 2013;154(8):2936-2947. PMID: 23748362 Front Nutr. 2024;11:1520440. PMID: 39834468
15. Barrea L, Muscogiuri G, de Alteriis G, et al. Adherence to the Mediterranean
diet as a modifiable risk factor for thyroid nodular disease and thyroid cancer:
results from a pilot study. Front Nutr. 2022;9:944200. PMID: 35782938

ENDO 2025 • Thyroid Biology and Cancer 309

The Unhappy Patient
With Hypothyroidism
Marco Medici, MD, PhD, MSc. Erasmus Medical Center, Rotterdam, Netherlands; Email:
[email protected]

Maria Papaleontiou, MD. Division of Metabolism, Endocrinology, and Diabetes, University

of Michigan, Ann Arbor, MI; Email: [email protected]

Educational Objectives results in stable serum levels of thyroid hormones.

It has generally been assumed that the peripheral
After reviewing this chapter, learners should be
conversion of LT4 into T3 makes it unnecessary to
able to:
add LT3 to the treatment regimen.
• Describe the prevalence and potential causes Despite normalized TSH levels that indicate
of persistent symptoms despite biochemical biochemical euthyroidism, a substantial group
euthyroidism in levothyroxine (LT4)-treated of patients with hypothyroidism (~10%-15%)
patients with hypothyroidism. are “unhappy” because they do not feel well and
report dissatisfaction with and reduced quality
• Describe the evidence regarding LT4/
of life on LT4 monotherapy. These patients
liothyronine (LT3) combination therapy
often exhibit persistent debilitating hypothyroid
and desiccated thyroid extract (DTE) use
symptoms, including fatigue and weight gain, but
in patients with hypothyroidism who have
also impaired neurocognitive function (brain fog),
persistent symptoms.
impaired psychological well-being, depression
• Discuss the utility of addressing patient or anxiety, or other somatic hypothyroid
requests to assess unconventional clinical symptoms.2,3 As a uniform approach to these
thyroid parameters (eg, reverse T3) or genetic patients is still lacking, this clinical problem places
variants. a high burden on daily clinical practice, leads to
patient dissatisfaction, and may challenge the
relationship between patients and clinicians.

Significance of the
Practice Gaps
Clinical Problem
Hypothyroidism has a prevalence of 3% to • There is lack of knowledge on the prevalence
8% in the general population, with thyroid and potential causes of persistent symptoms
autoimmunity being the cause for most despite biochemical euthyroidism in patients
patients. Hypothyroidism increases the risk of with hypothyroidism who are treated with
cardiovascular, metabolic, depressive, and anxiety LT4.
disorders if it remains untreated.1 Since the 1970s, • There is lack of knowledge on the benefits and
synthetic LT4 has been the standard of care for limitations of existing LT4/LT3 combination
thyroid hormone replacement in patients with therapy and DTE for patients with
hypothyroidism. This is because LT4 is cheap, has hypothyroidism, leading to heterogeneity in
a long half-life allowing for once-daily dosing, and their use among clinicians in clinical practice.

310 ENDO 2025 • Endocrine Case Management

• It is crucial that clinicians can reassure patients symptoms, well-being, or quality of life compared
and adequately address patient requests to test with targeting a TSH concentration in the upper
for nonconventional clinical thyroid parameters reference range. Another study by Samuels et al
(eg, reverse T3) or genetic variants. randomly assigned 138 LT4-treated individuals
with normal baseline serum TSH to receive
an unchanged, higher, or lower LT4 dosage in
Discussion double-blind fashion, targeting a TSH range of
Excluding Concomitant Diseases 0.34 to 2.50 mIU/L, 2.51 to 5.60 mIU/L, or 5.61
The most common cause of primary to 12.0 mIU/L.6 Participants had their LT4 dosage
hypothyroidism is chronic autoimmune thyroiditis adjusted every 6 weeks. After 6 months, there
(Hashimoto disease). Up to 15% of patients with were no significant differences in health status,
hypothyroidism have at least 1 concomitant mood, memory, or executive function between the
autoimmune disease, including rheumatoid 3 treatment arms. However, even though patients
arthritis (up to 30%), type 1 diabetes (6%-24%), and could not ascertain how their LT4 dosages were
celiac disease (3%), among others, and it can be a adjusted, they preferred LT4 dosages that they
part of a polyglandular autoimmune syndrome. perceived to be higher. These studies provide some
Concomitant autoimmune diseases in patients with preliminary data on the topic; however, they were
hypothyroidism who are biochemically euthyroid limited by small sample sizes. In addition, these
may lead to persistent nonspecific symptoms data do not address the possibility that differences
and should be excluded. It is important to note in individual TSH setpoints may exist, such that
that symptoms related to other nonautoimmune the TSH concentration needed to achieve similar
conditions, such as perimenopausal status, circulating thyroid hormone concentrations may
obstructive sleep apnea, and depression, may differ between individuals and may lead to patients
also overlap with hypothyroid symptoms, and with similar TSH concentrations responding
these should be considered when evaluating these differently to treatment.
patients. In addition, a recent study has shown
a high prevalence of somatic symptom disorder Synthetic LT4/LT3 Combination Therapy
among patients with hypothyroidism.4 Studies have shown that with LT4 monotherapy,
normalization of serum T3 and TSH levels can only
Levothyroxine Dosage Adjustments be achieved at the expense of higher-than-normal
Within the Euthyroid Range free T4 levels, leading to higher T4 to T3 ratios than
Anecdotal evidence has previously suggested that those observed in healthy persons.7,8 Therefore,
the well-being of patients with hypothyroidism the limitation of LT4 monotherapy is that it fails
may be improved by fine adjustments of the LT4 to mimic the physiological serum T4 to T3 ratio,
dosage, aiming for a serum TSH concentration in which could be a plausible cause of the persisting
the lower end of the reference range. Walsh et al hypothyroid symptoms. Animal studies have
conducted a double-blind randomized controlled provided specific insights into the consequences of
trial with a crossover design where 56 patients LT4 monotherapy on T4 and T3 concentrations in
received 3 different LT4 dosages in 8-week courses peripheral tissues. Escobar-Morreale et al showed
(high, middle, and low in 25 mcg increments) in that LT4 monotherapy in thyroidectomized rats did
random order, aimed to achieve target TSH levels not, at any dose, result in normal T4 and T3 levels
less than 0.30 mIU/L, 0.30 to 1.99 mIU/L, and 2.0 simultaneously in all tissues.9 However, LT4/LT3
to 4.8 mIU/L, respectively.5 Small changes in the combination therapy was able to normalize T4 and
LT4 dosage to achieve serum TSH concentrations T3 concentrations in plasma, as well as in all tissues,
in the lower reference range or slightly below did while also normalizing plasma TSH concentrations.
not lead to measurable changes in hypothyroidism

ENDO 2025 • Thyroid Biology and Cancer 311

 For these reasons, 19 clinical trials have be particularly sensitive to the relatively low T3
investigated whether LT4/LT3 combination levels inherent to LT4 monotherapy. While the
therapy has benefit over LT4 monotherapy in dosing and stability are less of an issue nowadays,
the treatment of patients with hypothyroidism. the largest concern with DTE remains its
These studies show conflicting results with several supraphysiological T3 content, which might lead
meta-analyses showing no beneficial effects on to transient thyrotoxicosis, with potential harmful
various complaints.1,10 However, several sources of effects on cardiovascular and skeletal tissues. The
heterogeneity in these trials must be considered. few small randomized controlled trials that have
First, the largest limitation common to all studies been performed do not support beneficial effects
was the lack of clear selection of patients with of DTE.1 Its use is therefore not recommended
the highest potential benefit (ie, patients with by international guidelines, while it is frequently
persistent symptoms despite LT4 monotherapy). requested by patients due to social media attention.
Second, many of the studies used LT4 to LT3
ratios ranging between 10:1 and 5:1. However, Nonconventional Thyroid
the average daily production of T4 and T3 by the Parameters and Genetic Variants
thyroid is 56 and 3 µg/day/m2, corresponding Patient dissatisfaction with hypothyroidism
to a physiological T4 to T3 ratio of 16:1, which is management due to reduced QoL may lead to patient
therefore also the recommended ratio endorsed requests for nonconventional tests and treatments.12
by various international guidelines.11 Third, these Even though some patients who feel unwell on LT4
studies used different nonthyroid-specific quality- monotherapy may have low serum T3 levels, thyroid
of-life (QoL) questionnaires, while none used hormone treatment adjustments based on serum
the well-validated and internationally accepted total or free T3 levels are not currently routinely
thyroid-specific ThyPRO QoL questionnaire. recommended.13 Similarly, no indications exist for
Finally, other sources of heterogeneity include the measurement of reverse T3 levels, a metabolically
short duration of follow-up and large differences inactive byproduct of thyroid hormone metabolism,
in sample sizes. However, when pooling the in the management of patients with hypothyroidism.13
results of those studies that reported on treatment The fact that the interindividual variation
preference, 25% of the participants expressed no in serum thyroid parameters is larger than
preference, 27% preferred LT4 monotherapy, and intraindividual variation suggests that every
48% preferred LT4/LT3 combination therapy.11 individual may have a unique hypothalamic-
Given these conflicting results, international pituitary-thyroid axis setpoint. Studies have
guidelines recommend against the routine use of estimated that most of this interindividual
LT4/LT3 combination therapy, but state that a variation is determined by genetic factors.14 While
trial can be considered in select patients. over the last 25 years many genetic variants
have been identified, including variants in the
Desiccated Thyroid Extract gene encoding type 2 deiodinase (among others
DTE was the standard of treatment for responsible for converting T4 to T3), these variants
hypothyroidism until the mid 1970s, after which do not yet have a proven role in the management
it was replaced by LT4. DTE is derived from the of patients with hypothyroidism.14
porcine or bovine thyroid gland and is commonly
prescribed in grains, in which 1 grain typically
Clinical Case Vignettes
contains approximately 38 mcg of T4 and 9 mcg of
T3.1 As for LT4/LT3 combination therapy, DTE Case 1
is of potential interest in LT4-treated patients A 35-year-old woman on LT4, 100 mcg daily,
with persistent symptoms despite biochemical seeks help to manage persistent symptoms of
euthyroidism, as this patient population might fatigue and brain fog. While discussing her

312 ENDO 2025 • Endocrine Case Management

symptoms, she states that she is sometimes so the LT4 dosage to suppress TSH would be
tired she has a hard time getting out of bed in inappropriate and should be avoided, as iatrogenic
the morning. In addition, she feels that she has hyperthyroidism has been associated with adverse
not been able to think clearly for the past several cardiovascular and skeletal effects.15
months and often feels sluggish and is unable to
focus. She has been unable to lose weight despite Case 2
changing her diet and adhering to a regular
exercise regimen. She has no other relevant A 40-year-old man with hypothyroidism due to
medical history. Thyroid function tests in the past Hashimoto thyroiditis is referred by his primary
year have repeatedly shown serum TSH and free care provider for persistent, severe tiredness
T4 values in the reference range. heavily affecting his work productivity and
social life. He has been on a stable dosage of LT4,
Most recent laboratory test results: 125 mcg daily, for years, and he is biochemically
TSH = 2.70 mIU/L euthyroid (also confirmed in the endocrine
Free T4 = 1.7 ng/dL (SI: 21.9 pmol/L) outpatient clinic). His primary care provider
already tried multiple small adjustments in the
She is upset and tearful. She asks if adjusting her LT4 dosage without any success in relieving the
LT4 dosage may help with her symptoms. patient’s symptoms. An extensive evaluation
excluded other causes of tiredness. The patient’s
Which of the following is the best initial wife is a renowned endocrinologist who frequently
step in addressing this patient’s concerns? attends the annual meeting of the Endocrine
A. Rule out other possible etiologies of Society and has listened to various debates on the
symptoms, including other autoimmune use of synthetic LT4/LT3 combination therapy
diseases and DTE. The patient would like to try one of
B. Increase the LT4 dosage while maintaining these treatments.
euthyroidism
C. Increase the LT4 dosage to suppress TSH Which of the following is an appropriate
response to this patient’s request?
D. Consider switching to LT4/LT3 combination
therapy A. Neither synthetic LT4/LT3 combination
therapy nor DTE should be prescribed
E. Consider switching to DTE
B. Synthetic LT4/LT3 combination therapy
Answer: A) Rule out other possible etiologies of should not be prescribed; DTE could be
symptoms, including other autoimmune diseases considered, starting with 1 grain daily
C. Synthetic LT4/LT3 combination therapy
This patient is biochemically euthyroid with several
should not be prescribed; DTE could be
persistent symptoms. After acknowledging the
considered, starting with 2 grains daily
patient’s symptoms, the first step is to exclude other
possible etiologies, including other autoimmune D. Synthetic LT4/LT3 combination therapy could
diseases, depression, etc (Answer A). If additional be considered, starting with a 5:1 ratio; DTE
etiologies of the persistent symptoms are ruled should not be prescribed
out, optimizing health habits, such as sleep, E. Synthetic LT4/LT3 combination therapy could
exercise, and nutrition, is also imperative before be considered, starting with a 16:1 ratio; DTE
considering thyroid hormone regimen adjustments. should not be prescribed
Subsequently, small adjustments to the LT4 dosage
Answer: E) Synthetic LT4/LT3 combination
may be attempted to see if the patient feels better
therapy could be considered, starting with a
at a different TSH concentration in the normal
16:1 ratio; DTE should not be prescribed
range (possible individual setpoint). Increasing

ENDO 2025 • Thyroid Biology and Cancer 313

Two randomized controlled trials have evaluated she read on social media that some people do not
the efficacy of DTE and did not find any appropriately convert T4 to T3, and she would like
improvements in QoL or symptom scores.16,17 to be tested for this to see if it is contributing to
However, as these studies have various limitations, her symptoms.
such as limited sample size and no targeted
inclusion of patients with persistent symptoms, Which of the following is an appropriate
these results should be interpreted with caution, response to this patient’s request?
and future large studies are needed to provide a A. Measure reverse T3
definitive answer as to whether DTE is effective B. Measure serum free T3 and adjust the LT4
in the management of hypothyroidism. For these dosage accordingly
reasons, DTE is not endorsed by international
C. Repeat TSH and free T4 measurements
guidelines for the management of hypothyroidism,
including in select cases. D. No further testing is necessary
As randomized controlled trials of synthetic E. Evaluate for genetic variations in genes
LT4/LT3 combination therapy show conflicting involved in thyroid hormone metabolism (eg,
results and have important limitations (see above), in DIO2)
international guidelines recommend against the
Answer: D) No further testing is necessary
routine use of synthetic LT4/LT3 combination
therapy, but state that a trial could be considered This patient has been biochemically euthyroid
in select patients who are adherent to their on LT4 replacement for years, confirmed by
regimen and are biochemically well-controlled, but recent TSH and free T4 measurements. Therefore,
have persistent symptoms despite LT4 treatment repeating TSH and free T4 measurements would
and after ruling out other etiologies for symptoms. not be useful. Furthermore, there is no proven
This 3-month trial should be discontinued if the role for titrating LT4 based on serum T3 or
patient does not experience clinical improvement.1 reverse T3 levels. For example, it has been shown
The European Thyroid Association guideline that in LT4-treated thyroidectomized patients,
on combination therapy provides guidance for there is no relation between thyroid hormone
clinicians when calculating the combined LT4/ parameters (including serum T3 and reverse T3)
LT3 dosing regimen.11 Although systematically and QoL.13 Genetic variation in type 2 deiodinase
collected long-term safety data are needed, had been shown to impair T4 to T3 conversion.
retrospective data analyses suggest that there is no Various clinical studies have therefore investigated
increased risk of long-term adverse effects as long these variants in LT4-treated patients and found
as physiological LT4 to LT3 ratios are used and conflicting results regarding their relationship
TSH is kept within the reference range.18 with QoL and benefit from LT4/LT3 combination
therapy.1,14 This is likely because these studies had
Case 3 several limitations, including small sample sizes and
heterogeneity in methodology. Instead of focusing
A 47-year-old woman with longstanding on a single genetic variant, Kus et al tested a panel
hypothyroidism due to Hashimoto thyroiditis of genetic variants (polygenic score), showing
presents with significant fatigue and hair loss. that this panel was able to provide personalized
These symptoms are causing substantial distress, TSH reference ranges, with substantial effects on
and she describes feeling very unhappy. She has diagnosis reclassification and LT4 prescription
been on a stable LT4 dosage, 75 mcg daily. Weight behavior.19 However, such panels need to be
is stable. Her TSH and free T4 levels have been in further refined and tested clinically before
the reference range for the past several years (most considering their routine use in clinical practice.
recent measurement 2 weeks ago). She states that

314 ENDO 2025 • Endocrine Case Management

Key Learning Points high-normal TSH levels on a population level,
it remains to be determined whether such
• Clinicians should acknowledge hypothyroid adjustments may be beneficial on an individual
patients’ report of continued symptoms patient level.
despite biochemical euthyroidism and further • A trial of combination synthetic LT4/LT3
investigate for possible etiologies. therapy may be cautiously considered in select
• While studies have shown no benefit of patients.
LT4 dosage adjustments to low-normal or

References
1. Taylor PN, Medici MM, Hubalewska-Dydejczyk A, Boelaert K. thyroid versus T4 monotherapy in hypothyroidism: a systematic review and
Hypothyroidism. Lancet. 2024;404(10460):1347-1364. PMID: 39368843 meta-analysis. BMC Endocr Disord. 2024;24(1):90. PMID: 38877429
2. Peterson SJ, Cappola AR, Castro MR, et al. An online survey of hypothyroid 11. Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MPJ. 2012
patients demonstrates prominent dissatisfaction. Thyroid. 2018;28(6):707- ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism.
721. PMID: 29620972 Eur Thyroid J. 2012;1(2):55-71. PMID: 24782999
3. Wiersinga WM. Paradigm shifts in thyroid hormone replacement therapies 12. Esfandiari NH, Reyes-Gastelum D, Hawley ST, Haymart MR, Papaleontiou
for hypothyroidism. Nat Rev Endocrinol. 2014;10(3):164-174. PMID: 24419358 M. Patient requests for tests and treatments impact physician management of
4. Perros P, Nagy EV, Papini E, et al. Hypothyroidism and somatization: results hypothyroidism. Thyroid. 2019;29(11):1536-1544. PMID: 31436135
from E-mode patient self-assessment of thyroid therapy, a cross-sectional, 13. Massolt ET, van der Windt M, Korevaar TIM, et al. Thyroid hormone and its
international online patient survey. Thyroid. 2023;33(8):927-939. PMID: metabolites in relation to quality of life in patients treated for differentiated
37134204 thyroid cancer. Endocrinol (Oxf). 2016;85(5):781-788. PMID: 27175823
5. Walsh JP, Ward LC, Burke V, et al. Small changes in thyroxine dosage do not 14. Kus A, Chaker L, Teurner A, Peeters RP, Medici M. The genetic basis of
produce measurable changes in hypothyroid symptoms, well-being, or quality thyroid function: novel findings and new approaches. J Clin Endocrinol Metab.
of life: results of a double-blind, randomized clinical trial. J Clin Endocrinol 2020;105(6):dgz225. PMID: 32271924
Metab. 2006;91(7):2624-2630. PMID: 16670161 15. Evron JM, Hummel SL, Reyes-Gastelum D, Haymart MR, Banerjee M,
6. Samuels MH, Kolobova I, Niederhausen M, Janowsky JS, Schuff KG. Effects Papaleontiou M. Association of thyroid hormone treatment intensity
of altering levothyroxine (L-T4) doses on quality of life, mood, and cognition with cardiovascular mortality among US veterans. JAMA Netw Open.
in L-T4 treated subjects. J Clin Endocrinol Metab. 2018;103(5):1997-2008. 2022;5(5):e2211863. PMID: 35552725
PMID: 29509918 16. Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MKM. Desiccated thyroid
7. Fish LH, Schwartz HL, Cavanaugh J, Steffes MW, Bantle JP, Oppenheimer extract compared with levothyroxine in the treatment of hypothyroidism:
JH. Replacement dose, metabolism, and bioavailability of levothyroxine in a randomized, double-blind, crossover study. J Clin Endocrinol Metab.
the treatment of hypothyroidism. The role of triiodothyronine in pituitary 2013;98(5):1982-1990. PMID: 23539727
feedback in humans. N Engl J Med. 1987;316(13):764-770. PMID: 3821822 17. Shakir MKM, Brooks DI, McAninch EA, et al. Comparative effectiveness of
8. Jonklaas J, Davidson B, Bhagat S, Soldin SJ. Triiodothyronine levels in levothyroxine, desiccated thyroid extract, and levothyroxine+liothyronine in
athyreotic individuals during levothyroxine therapy. JAMA. 2008;299(7):769- hypothyroidism. J Clin Endocrinol Metab. 2021;106(11):e4400-e4413. PMID:
777. PMID: 18285588 34185829
9. Escobar-Morrelae, del Rey FE, Obregon MJ, de Escobar GM. Only 18. Gottwald-Hostalek U, Tayrouz Y. A review of the safety of triiodothyronine
the combined treatment with thyroxine and triiodothyronine ensures in combination with levothyroxine for the management of hypothyroidism.
euthyroidism in all tissues of the thyroidectomized rat. Endocrinology. Curr Med Res Opin. 2024;40(12):2109-2116. PMID: 39625345
1996;137(6):2490-2502. PMID: 8641203 19. Kus A, Sterenborg RBTM, Haug EB, et al. Towards personalized TSH
10. Nassar M, Hassan A, Ramadan S, Desouki MT, Hassan MA, Chaudhuri A. reference ranges: a genetic and population-based approach in three
Evaluating the effectiveness of combined T4 and T3 therapy or desiccated independent cohorts. Thyroid. 2024;34(8):969-979. PMID: 38919119

ENDO 2025 • Thyroid Biology and Cancer 315

Navigating Thyroid Eye Disease:
From Diagnosis to Management
Marius N. Stan, MD. Division of Endocrinology, Mayo Clinic, Rochester, MN; Email:
[email protected]

Educational Objectives • Medical management of TED requires skills

that are the domain of endocrinology, but care
After reviewing this chapter, learners should be
for patients with this condition is typically
able to:
provided by ophthalmologists.
• Identify the important elements needed for
Corollary: Endocrinologists would be ideal
thyroid eye disease (TED) evaluation.
partners to ophthalmologists in guiding medical
• Identify TED activity and severity status. management of TED, if they would familiarize
• Recommend appropriate TED medical themselves with TED evaluation.
management choices.
Clinical Case Vignettes
and Discussion
Case 1
Significance of the
A 48-year-old woman develops palpitations
Clinical Problem associated with weight loss and increased
TED is present in 25% to 40% of individuals with sweatiness over the last month. She also has
Graves disease, and its management requires a difficulty sleeping and notes a sense of discomfort
combination of medical and surgical therapy. over her eyes. Her eyes are watering more and
Medical management of this condition has been are irritated and red. Her primary care physician
dominated by steroids for many years, but recently diagnoses Graves disease, prescribes a β-adrenergic
an IGF-1 receptor blocker, teprotumumab, has blocker, and refers her to an endocrinologist.
significantly changed the field. Both of these
therapies, and others less commonly used (eg, Laboratory test results:
tocilizumab, rituximab, mycophenolate), are TSH = <0.01 mIU/L
generating many systemic health implications and Free T4 = 3.8 ng/dL (SI: 48.9 pmol/L)
adverse effects that should be carefully considered. Total T3 = 430 ng/dL (SI: 6.6 nmol/L)
These therapies would best be carried out in a Thyrotropin antibodies = 7 IU/L (<1.75 IU/L)
White blood cell count, normal
multidisciplinary TED clinic, yet that approach Liver function tests, normal
rarely materializes.
On physical examination, she has an enlarged
thyroid gland (about 25 g) and slight tachycardia
Practice Gaps (92 beats/min). Overall, she is feeling better
since starting propranolol. Her eyes have injected
• Endocrinologists are insufficiently familiar
conjunctiva and mild lid edema but no other
with the evaluation of TED.
abnormalities. Extremities, nails included, are
unremarkable.

316 ENDO 2025 • Endocrine Case Management

 The diagnosis of Graves disease is confirmed, Disease Stage and Severity
and she is informed that the eye changes are To determine disease stage, or disease activity,
consistent with TED. After a conversation it is still useful to consider the Rundle curve3
about antithyroid drugs, radioactive iodine, and and evaluate the clinical activity score (CAS)4.
surgery, she concludes that she would like to start This assessment guides the provider toward the
methimazole, 10 mg twice daily, and continue appropriate set of therapeutic options. Disease
propranolol. severity is most important for deciding on the
aggressiveness of potential therapies from the
Which of the following elements subset of choices based on the disease stage
in the patient’s history is NOT identified earlier (ie, after disease activity was
necessary for TED evaluation? established). The main symptoms and signs useful
A. Cigarette smoking status for evaluating inflammation and severity are the
B. Thyroid hormone levels following:
C. TED recent progression • Diplopia
D. Her main concern about TED • Pain in primary vision and pain with
E. Selenium levels extraocular movements
Answer: E) Selenium levels • Changes in clarity and accuracy of vision
• Changes in color perception (reds and blues)
Cigarette smoking (Answer A) is associated with
a higher likelihood of TED progression and poor • Assess conjunctiva: edema (ie, what is
response to most therapies.1 Thyroid hormone chemosis?), injection
levels (Answer B) are important to determine, as • Assess globe position (ie, what is proptosis?)
dysthyroidism has a negative impact on TED.2 • Assess lids: edema, erythema, closure (ie, what
Progression in eye changes over the last 3 months is lagophthalmos?)
(Answer C) likely reflects ongoing inflammation
and possible responsiveness to medical therapy. • Assess caruncles
Knowing which TED element the patient • Changes in quality of life
considers most troublesome (Answer D) is useful
to understand when determining the main goal of Diplopia is the presence of double vision, and it
management/therapy. Selenium levels (Answer typically relates to dysfunction of the extraocular
E) are not known to affect TED disease course, muscles. Muscles that are inflamed or enlarged
and the data on the benefits of selenium therapy by infiltration with glycosaminoglycans lack
are not based on serum levels.7 Thus, knowing the normal mobility and, consequently, they no longer
patient’s selenium levels is not necessary in her synchronize their action with the corresponding
TED evaluation. muscles in the pair eye. This results in the brain
receiving 2 separate images. When the images
Case Follow-Up are relatively close, the brain can still fuse them
The patient has smoked 10 cigarettes per day and restore single vision (with an effort). When
for 15 years. We know she has elevated thyroid the images are far apart, the brain can ignore 1
hormone levels, but her TED has been stable over image and attain single vision. The problem is
recent weeks and months, and her main concern most challenging when the images are in between
is local discomfort (pain, redness, and swelling). these scenarios and the optical cortex continues to
She is counseled regarding the negative impact of struggle with 2 images and is unable to perceive
smoking on TED. reality clearly and safely. This is when patients
give up driving and are unable to operate various

ENDO 2025 • Thyroid Biology and Cancer 317

appliances/machines, which may require them to Answer: A) Establishing potential benefit of medical therapy
change jobs or alter their day-to-day activities.
Diplopia should resolve when patient closes Disease Activity and Severity
one eye (binocular diplopia), given the mechanism Clinical Activity Score
described earlier. If diplopia persists in that Disease activity is meant to reflect the presence
case (monocular diplopia) then the problem or absence of orbital inflammation as opposed to
is one of corneal surface and not extraocular fibrosis. This distinction is based on the Rundle
muscle dysfunction. This is best addressed by an curve3 combined with the work of the Amsterdam
ophthalmologist. group,4,5 which deemed that the first phase of
The change in vision clarity is usually due TED is one of inflammatory changes (dolor,
to corneal dryness (increased palpebral aperture rubor, tumor, calor) and thus they quantified it
with increased dryness). In that situation, vision through an instrument called the Clinical Activity
should become clearer with repeated blinking, Score (CAS). At the first encounter, this score
and this can be proactively aided by aggressive can take a value between 0 and 7 (Box), and at
eye lubrication. If these steps do not improve subsequent visits, the score can be between 0 and
vision clarity, then there should be a concern 10, adding the assessment of changes in severity
about optic nerve dysfunction. An early sign of measures to the evaluation of inflammation. This
this is the inability to distinguish various hues of instrument has been found useful in identifying
red and blue. Testing for optic nerve dysfunction patients with high probability of responding
is certainly the domain of ophthalmology, but to glucocorticoids if they have a CAS score of
a quick assessment for the presence of relative 3 or higher. Unfortunately, the use of CAS has
afferent pupillary defect is helpful to ascertain expanded and it has been used as a trial outcome,
likely optic nerve compression and can be with improvement in CAS value below 3 deemed
performed in the endocrinology office. to reflect a good overall result. This approach
Pain could be a sign of inflammation in TED has been taken by many clinical trials, without
and should be inquired about both in primary validation of its significance from the perspective
gaze (“straight out”) when pain reflects increased of patients.
intraorbital pressure, as well as in the patient
looking at different angles (pain with extraocular Box. Clinical Activity Score
muscles movements) when pain likely indicates
1. Spontaneous retrobulbar pain
inflammation of the muscles that are being stretched.
2. Pain with eye movement
3. Redness of the eyelids
Case 1, Continued 4. Redness of the conjunctiva

Which of the following best 5. Swelling of the eyelids

describes the benefit of defining the 6. Inflammation of the caruncle

patient’s clinical activity score? 7. Conjunctival edema

A. Establishing potential benefit of medical Clinical activity score = sum of all items present in each eye (1 point/item
therapy present); score might be different for left vs right; use highest score for
decision-making.
B. Indicating need for medical therapy
Therefore, the CAS is useful to indicate
C. Understanding risk of adverse effects from whether medical therapy could help to control
medical therapy inflammation (if CAS >2) (Answer A), but it
D. Understanding the complications of surgical will not determine the need for such therapy
therapy (Answer B) or which specific agent to use (Answer
E. Defining which medical therapy would be best E). That decision derives from TED severity
and TED dominant features. CAS will also not

318 ENDO 2025 • Endocrine Case Management

give any information on the potential adverse This is particularly challenging when the patient is
effects of medical therapy (Answer C) or provide not hyperthyroid (eg, remote history of radioactive
information on potential surgical complications iodine therapy or thyroidectomy, euthyroid
(Answer D). TED, or TED with Hashimoto thyroiditis).
Documenting thyroid autoimmunity markers
Assessing Disease Severity (thyrotropin receptor antibodies—TRAb and/
Disease severity has been practically defined by or thyroid-stimulating immunoglobulins) and
the European Group on Graves Orbitopathy imaging the orbit is necessary in these cases.
(EUGOGO) into 3 categories: mild, moderate-to Rarely, biopsy from the extraocular muscles is
severe, and sight-threatening disease.6 needed to clarify the diagnosis.
Sight-threatening disease is more obvious
to identify and is characterized by the presence TED Management—Mild Disease
of TED complications that can, as the name General Measures
implies, lead to rapid loss of vision if untreated: For all patients, normal thyroid hormone levels
dysthyroid optic neuropathy, globe subluxation should be pursued, along with smoking cessation
(the displacement of the eyeball in front of the lids, (including eliminating secondary smoking) and
which are thus unable to protect it anymore), and adequate lubrication of the cornea (artificial tears
corneal ulceration with potential infection (globe during the day and gel or ointment at night).
infection is extremely difficult to eradicate). The Additional measures can include the use of
distinction between mild and moderate-to-severe wraparound glasses or glasses with lateral shield
(a name I dislike for its length and difficulty in that limit draft in front of the eyes, sleeping
using in conversation with patients and colleagues) with the head of the bed elevated (decreasing lid
is based on extent of eye parameter changes (eg, edema), cold compresses (beneficial for pain),
degree of diplopia, proptosis, soft-tissue changes) and minimizing stress (expected to minimize
and the impact TED has on patients’ daily autoimmune response). The more specific TED
activities. The information presented in the Table approach taken beyond these basic measures
can be used as a guide for severity assessment. depends on disease activity and severity.
Potential Differential Diagnosis Mild TED
TED is, in most cases, the obvious diagnosis when The patient in this vignette has mild disease
there is symmetric inflammation and proptosis and therefore general measures will represent
in patients with an ongoing history of Graves the bulk of therapy. Additionally, there are data
disease. However, asymmetric presentation should that selenium (200 mcg daily for 6 months) can
raise the question of a possible intraorbital mass improve local discomfort in mild TED, with
masquerading as TED (eg, orbital lymphoma, persistent effect up to 6 months.7
meningioma, arteriovenous fistula/aneurysm).

Table. TED Severity per EUGOGO Guidelines

Lid Soft-tissue Cornea Globe prolapse/

Degree of severity retraction involvement Proptosis Diplopia exposure Optic nerve status subluxation

Mild (≥1) <2 mm Mild <3 mm Absent or Absent Normal Absent

Intermittent

Moderate-to-severe ≥2 mm Moderate or ≥3 mm Inconstant Mild Normal Absent

(≥1) severe or constant

Sight-threatening N/A N/A N/A N/A Ulcer Affected Present

(≥1)

ENDO 2025 • Thyroid Biology and Cancer 319

Case Follow-Up (Answer E) nor surgical management (Answer D)
Despite normalization of thyroid hormone levels, is appropriate. Medical choices that can mitigate
the patient describes progressive pain associated inflammation include teprotumumab (Answer
with more eye bulging and double vision upon B) and steroids. However, teprotumumab can
looking to the sides (worse when looking up and significantly improve proptosis and potentially
to the right). She has been consuming Brazil nuts improve diplopia, which are features unlikely
(rich in selenium) for past 2 months without to change significantly with intravenous steroid
benefit. Upon reevaluation, her CAS is determined therapy (Answer A). Therefore, I would endorse
to be 5 with excess proptosis of 4 mm in the right teprotumumab if no significant contraindications
eye and 2 mm in the left eye. Diplopia is indeed were present.
inducible at the angle described.
Medical Management
The most common therapeutic approach used
Case 1, Continued
to be steroids for inflammation control. This
Which of the following is the best is still a favored therapy if other agents are not
recommendation in this patient’s available. Steroids have proved their efficacy in
management at this stage? a number of trials, with intravenous steroids
A. Intravenous steroids being superior to oral steroids regarding efficacy
B. Teprotumumab (a composite index of eye parameters) and safety
C. Orbital decompression (better tolerated regarding the gastrointestinal
tract and bone health to name a few).8 Many
D. Strabismus surgery (for diplopia)
other agents have been tried over the years
E. Observation (including somatostatin analogues, B-cell
Answer: B) Teprotumumab depleter [eg, rituximab], interleukin-6 blockers,
azathioprine, mycophenolate, TNF-α blockers)
TED Management—Moderate-to-Severe Disease with inconsistent or minimal efficacy.9 However,
The patient now has moderate-to-severe the agent that has been introduced most recently,
disease, and consultation with ophthalmology teprotumumab, an IGF-1 receptor blocker, is likely
is mandatory. Understanding the perspective to be most effective. The data available about this
of ophthalmologists on eye health is essential agent reveal significant improvement in proptosis
to confirm the active disease stage and to (primary outcome in 2 randomized controlled
rule out sight-threatening elements. At our trials), CAS/inflammation and quality of life, while
multidisciplinary TED clinic, patients are seen diplopia responded less consistently.10 The benefit
same morning by endocrinology, ophthalmology, on proptosis was about 3 mm on average, which
and otolaryngology. Cases are discussed at the is equivalent to the expected result of orbital
noon conference by all these teams, and a joint decompression surgery targeting 1 orbital wall
decision is made about therapy. That decision (implicitly, more aggressive reduction in proptosis
is communicated to the patient in a brief recap can be achieved with more aggressive surgery).
visit in early afternoon performed jointly by If the patient in this vignette had struggled with
the endocrinologist and ophthalmologist. For only inflammatory features (without significant
the patient in this vignette, we concluded that proptosis or diplopia), steroids would be a very
she has active disease of moderate severity with reasonable choice. Notably, no head-to-head trial
no sight-threatening elements. This is best has compared teprotumumab with steroids, either
managed with medical therapy, mostly with intravenous or oral. In this patient’s case, however,
immunomodulatory action. As the disease has I would consider teprotumumab as the best agent
progressed and is still active, neither observation to achieve a good result with respect to proptosis

320 ENDO 2025 • Endocrine Case Management

and inflammation and, possibly, improvement overview of the benefits and risks associated with
in double vision as well. To proceed with different medical treatments, see the American
therapy, it is important to review the logistics of Thyroid Association consensus statement on
treatment (8 intravenous infusions every 3 weeks, TED.12 She patient achieves a decrease in CAS to
administered at an infusion therapy center) and a score of 1 (conjunctival injection persisted), but
the patient’s comorbidities to understand if there has no changes in proptosis or diplopia.
are any contraindications or potential conditions At this point, it is important to understand
that could be aggravated by teprotumumab. I the patient’s perception of these results. She is
am particularly interested in patients’ hearing still affected on a functional level by diplopia
acuity and discuss with them their concerns/ and on a social level by significant proptosis. Her
perspective on potential local ear discomfort evaluation with ophthalmology is again important
(eg, tinnitus, fullness, autophonia) and possible to establish the new baseline and rule out
sensorineural hearing loss. I obtain a baseline (consistently, at every visit) the possibility of sight-
audiogram since occasionally preexisting hearing threatening disease. The findings arere confirmed,
loss might not have been apparent to the patient, and a discussion takes place about the potential
and it is important to establish a baseline for later benefit of rehabilitative surgery. This entails the
assessing the impact of therapy. I also discuss spectrum of orbital decompression (removing
contraindications regarding inflammatory bowel retro-orbital fat, as well as some of the orbital
disease and uncontrolled diabetes. If patients bone, to create space for globe recession into the
have diabetes, then a hemoglobin A1c value less orbit), strabismus surgery (extraocular muscle
than 8.0% (64 mmol/mol) should be pursued. adjustments to synchronize the globe movements
Furthermore, it is important to ensure that these and ensure single vision in primary gaze—main
aspects are monitored during therapy. For patients goal), and lid surgery to repair excess retraction
with diabetes, I request a glucose measurement and troublesome globe exposure. The sequence of
after the first 2 infusions, and I repeat audiography these interventions must start with decompression
after the fourth infusion. That is also the time if proptosis is significant, followed by strabismus
when we reassess the TED response to therapy surgery (if diplopia is present up-front or induced
with the knowledge that most patients have a very by orbital decompression [15%-25% of cases]),
rapid response, usually noticeable after the first 2 and conclude with lid adjustments, if needed.
infusions. Several other adverse effects of therapy, These procedures are only performed after
including amenorrhea, should be considered when there is evidence of stability for a minimum of 3
discussing teprotumumab. Multiple review articles months, ideally 6 months. The experience of the
are available for those seeking a more thorough ophthalmologist in performing these interventions
review of teprotumumab’s adverse effects, their should be considered a primordial factor for
putative mechanism, and their management.11 success. The role as endocrinologists at this stage
is to ensure that thyroid parameters remain stable,
Case Follow-Up cigarette smoking is eliminated if possible, and
Due to concerns for hearing loss related to other comorbidities are well controlled.
teprotumumab, the patient elects therapy with Alternative scenario: had the patient selected
intravenous glucocorticoids. The patient initiates therapy with teprotumumab, my expectation is
the EUGOGO regimen of methylprednisone, 500 that we would have achieved good improvement
mg weekly for 6 weeks, followed by a dosage of in proptosis and inflammation but probably not
250 mg weekly for another 6 weeks. In this case, complete resolution of diplopia. I also expect
close monitoring of glucose and blood pressure that we would have encountered prediabetes
is required, and other adverse effects should be (around 60% general risk), which I tackle early
considered during follow-up. For an extensive with metformin. This issue is rarely a significant

ENDO 2025 • Thyroid Biology and Cancer 321

problem and after completion of therapy, we up with the strabismus experts for planned
are often able to discontinue metformin. There further interventions.
are frequent complaints of muscle cramps,
which I target with aggressive hydration, daily Future Directions to Share With Patients
multivitamins and minerals, and occasionally TED is an area of active research, and, fortunately
muscle relaxants. Muscle cramps tend to resolve for many patients, there is no urgency for
within couple months after therapy. Ear-related immediate intervention. Multiple agents are
changes are common, and a variety of symptoms currently being developed, targeting the IGF-1
are encountered: ear pain, pressure, autophonia, receptor, interleukin-6 and interleukin-6 receptor,
and occasionally diminished hearing from sensory- TRAb (through neonatal Fc receptor targeting),
neural injury, manifesting itself as hearing loss at TSH receptor, and a few others that have different
high frequencies. While most of the non–hearing targets. Some of these agents are already in phase
loss symptoms are reversible, it seems that 2/3 of evaluation, and I expect our therapeutic
sensory-neural hearing loss is a persistent problem choices will likely include some of them in the
and may sometimes lead to the use of hearing aids. coming years. Their potential benefits could be
Can the disease progress despite therapy? improved efficacy in comparison with available
Development of sight-threatening disease drugs, simultaneous targeting of TED and
is quite rare. Compressive optic neuropathy hyperthyroidism (if present), and a better adverse
(dysthyroid optic neuropathy) occurs in 3% to effect profile, allowing us to more effectively
5% of persons with TED and is initially treated individualize TED therapy.
with intravenous glucocorticoids (my preferred
regimen is 1g-0.5g-0.5 g for 3 consecutive Key Learning Points
days, repeated 2 weeks later, and reevaluated
in another 1 to 2 weeks). If no improvement • For all patients with Graves disease, risk
is noted, then emergent orbital decompression factors for TED development/progression
should be pursued. The other 2 sight-threatening should be identified (eg, cigarette smoking,
complications—orbital subluxation and corneal radioactive iodine, dysthyroidism) with the
ulceration—are ophthalmological emergencies and aim to minimize them.
should be entirely the prerogative of that specialty.
• When TED is present, the patient’s CAS
Additional Case Follow-Up and disease severity should be defined as a
The patient undergoes bilateral orbital necessary step toward therapy selection.
decompression and achieves nice improvement • In general, the inflammatory phase of TED
in proptosis. Unfortunately, her diplopia remains should be addressed with medical therapy and
clinically significant, and she is following the chronic, inactive phase should be addressed
with surgical management.

References
1. Bartalena L, Marcocci C, Tanda ML, et al. Cigarette smoking and treatment 4. Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity
outcomes in Graves ophthalmopathy. Ann Intern Med. 1998;129(8):632-635. score as a guide in the management of patients with Graves’ ophthalmopathy.
PMID: 9786811 Clin Endocrinol. 1997;47(1):9-14. PMID: 9302365
2. Prummel MF, Wiersinga WM, Mourits MP, Koornneef L, Berghout A, van 5. Prummel MF, Mourits MP, Berghout A, et al. Prednisone and cyclosporine
der Gaag R. Effect of abnormal thyroid function on the severity of Graves’ in the treatment of severe Graves’ ophthalmopathy. N Engl J Med.
ophthalmopathy. Arch Int Med. 1990;150(5):1098-1101. PMID: 1691908 1989;321(20):1353-1359. PMID: 2519530
3. Rundle FF, Wilson CW. Development and course of exophthalmos and 6. Bartalena L, Kahaly GJ, Baldeschi L, et al. The 2021 European Group on
ophthalmoplegia in Graves’ disease with special reference to the effect of Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical
thyroidectomy. Clin Sci. 1945;5(3-4):177-194. PMID: 21011937

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 management of Graves’ orbitopathy. Eur J Endocrinol. 2021;185(4):G43-G67. 10. Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the treatment
PMID: 34297684 of active thyroid eye disease. N Engl J Med. 2020;382(4):341-352. PMID:
7. Marcocci C, Kahaly GJ, Krassas GE, et al. Selenium and the course of mild 31971679
Graves’ orbitopathy. N Engl J Med. 2011;364(20):1920-1931. PMID: 21591944 11. Stan MN, Krieger CC. The adverse effects profile of teprotumumab. J Clin
8. Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, single blind trial of Endocrinol Metab. 2023;108(9):e654-e662. PMID: 37071658
intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin 12. Burch HB, Perros P, Bednarczuk T, et al. Management of thyroid eye
Endocrinol Metab. 2005;90(9):5234-5240. PMID: 15998777 disease: a consensus statement by the American Thyroid Association and
9. Stan MN, Salvi M. Management of endocrine disease: rituximab therapy for the European Thyroid Association. Thyroid. 2022;32(12):1439-1470. PMID:
Graves’ orbitopathy - lessons from randomized control trials. Eur J Endocrinol. 36480280
2017;176(2):R101-R109. PMID: 27760790

ENDO 2025 • Thyroid Biology and Cancer 323

TUMOR BIOLOGY
Landscape of Genetic Alterations
in Well-Differentiated Thyroid
Cancer in Pediatric Patients
Andrew J. Bauer, MD. The Thyroid Center, Division of Endocrinology and Diabetes,
Children’s Hospital of Philadelphia and Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA; Email: [email protected]

Educational Objectives for malignancy carries over in the cytological

interpretation of FNA reflected by the broad
After reviewing this chapter, learners should be
risk of malignancy within the indeterminate
able to:
categories of The Bethesda System for Reporting
• Describe the oncogenic drivers associated with Thyroid Cytopathology (TBSRTC): 0% to 50%
thyroid cancer and recognize the spectrum for atypia of undetermined significance; 20% to
of invasive disease associated with each 100% for follicular neoplasm; and 40% to 100%
oncogenic driver. for suspicious for malignancy. There is a higher
surgical resection rate for benign nodules in
• Describe the opportunities to incorporate
children than in adults, and there are a substantial
oncogenic drivers into stratifying and
number of patients with metastatic thyroid
optimizing surgical and medical management
carcinoma who require additional surgery for
of thyroid nodules and thyroid carcinoma.
persistent disease after initial tumor resection.
• Apply new knowledge to create an evaluation
process for thyroid nodules in children and
adolescents that optimizes outcomes. Practice Gaps
• There is a lack of training and experience
in completing and interpreting thyroid
Significance of the ultrasonography with reduced stratification of
Clinical Problem nodules selected for FNA.
Thyroid nodules in pediatric patients carry a • There is an increased risk of malignancy
higher risk for thyroid carcinoma, and the risk in nodules with TBSRTC indeterminate
of malignancy in indeterminate thyroid nodules categories with a broader risk range for
is higher in children than in adults. Thyroid children compared with adults within the same
ultrasonography is recommended as the best categories.
radiological exam for evaluation of thyroid
• It is critical to train providers involved in
nodules. However, there is less experience within
the evaluation and management of pediatric
pediatrics with a high degree of interobserver
patients with thyroid nodules.
and intraobserver variability in interpretation
of malignant sonographic features, as well as
incomplete evaluation for cervical neck lymph
node metastasis. The variability in interpretation

326 ENDO 2025 • Endocrine Case Management

Discussion low-risk to indeterminate sonographic features
(solid or complex composition with smooth
Thyroid tumorigenesis is driven by well-described
margins and no punctate echogenic foci) and
oncogenic driver alterations. In 2014, The
harbor oncogenic alterations associated with a
Cancer Genome Atlas Program published the
low risk for invasive behavior (RAS, DICER1,
“integrated genomic characterization of papillary
PTEN, non-V600E BRAF pathogenic variants or
thyroid carcinoma” in adults, which suggests
fusions involving PAX8::PPARG). For patients
that compared with traditional histopathological
with these features who are undergoing surgical
classification, reclassification of thyroid
intervention, lobectomy without prophylactic
cancers into molecular subtypes better reflects
central neck lymph node dissection may be
differentiation and invasive potential. Similar data
considered with additional surgical intervention
in pediatrics have been accumulating over the last
based on histological features. In contrast,
decade, supporting incorporation of oncogenic
nodules with TBSRTC category V (suspicious
drivers to increase the accuracy of identifying
for malignancy) or VI (malignant) cytology
thyroid malignancy in nodules with indeterminate
typically have sonographic features suspicious
cytology, and, potentially, to optimize stratification
for malignancy (solid composition, hypoechoic
of surgery. With the availability of FDA-approved
echogenicity, irregular, lobulated or infiltrative
oncogene specific inhibitors, there is also more
margin, and punctate echogenic foci) and harbor
research evaluating how to incorporate these oral
oncogenic alterations associated with intermediate
chemotherapeutic agents in both the neoadjuvant
or high risk for invasive behavior (BRAF V600E
and adjuvant settings. This chapter provides an
pathogenic variant or RET-like kinase fusions).
update on current research focusing on the use of
Total thyroidectomy with prophylactic central
somatic oncogenic driver alterations in an effort to
neck lymph node dissection is recommended for
improve stratification of care in pediatric patients
most patients harboring a thyroid nodule/lesion
with thyroid nodules and differentiated thyroid
with these features, with lobectomy and ipsilateral
carcinoma.
prophylactic central neck lymph node dissection
Compared with papillary thyroid carcinoma
considered in select patients with no evidence
(PTC) in adults, PTC in children has a higher
of lymph node metastasis on preoperative
prevalence of kinase fusions, especially in patients
ultrasonography (AJCC N0b).1
10 years or younger. The presence of a fusion
After total thyroidectomy, the decision to
oncogene involving RET, NTRK, ALK, or BRAF
use radioiodine (RAI) therapy is based on the
(most common; RET-like) is associated with
extent of extrathyroidal disease. For patients
an increased risk for extrathyroidal invasion
with distant metastasis, most commonly to the
and distant metastasis in children compared
lungs, a significant percentage develop persistent,
with disease associated with RAS-like variants
stable disease with a smaller number of patients
or the BRAF V600E pathogenic variant. Since
developing structurally progressive disease
the publication of the 2015 American Thyroid
despite single or repeated RAI treatments. Recent
Association pediatric guidelines, there are
advances in molecular profiling and clinical
accumulating data on the potential utility of
use of next-generation sequencing have led to
integrating ultrasound features with cytology
increasing recognition of targetable oncogenic
to increase the accuracy of predicting thyroid
drivers in pediatric thyroid carcinoma. In parallel,
malignancy with the addition of somatic oncogene
multiple molecularly targeted therapies for the
analysis, which ultimately provides objective
treatment of thyroid carcinoma have been studied,
data to help stratify the surgical approach.
primarily in adult patients, and have received
Most nodules with the designation TBSRTC
FDA approval. Approval for some of these agents
category III (atypia of unknown significance)
now extends into the pediatric age range. With
and IV (follicular neoplasm) cytology have

ENDO 2025 • Tumor Biology 327

molecular therapy for pediatric thyroid carcinoma American Thyroid Association pediatric low-risk
in its nascency, questions remain regarding the category for persistent postinitial surgical disease.
timing for initiation of these agents (neoadjuvant, Postoperative thyroid function testing 6 weeks
adjuvant), indications (disease not amenable to after surgery revealed a TSH value in the low-
surgery/radiation, systemic disease, differentiation mid reference range. Thyroid ultrasonography
therapy for increasing RAI efficacy), durability surveillance 1 year postoperatively showed
of response and duration of treatment, and a normal left thyroid lobe without evidence
combination with other agents or modalities of persistent/recurrent disease in the right
(especially RAI and surgery).2 thyroid bed.
Thyroid nodules with smooth margins are
typically encapsulated tumors associated with a
Clinical Case Vignettes higher likelihood of benign cytology (adenoma
Case 1 or noninvasive follicular thyroid neoplasm
A 15-year-old girl is found to have a right neck with papillary-like nuclear features [NIFTP])
swelling during routine physical examination. or a carcinoma with a lower-risk for metastasis
Ultrasonography confirms a 3.5-cm solid, (invasive encapsulated follicular variant PTC
hypoechoic intrathyroidal nodule with a wider- or minimally invasive FTC). Based on this,
than-tall shape, smooth margins, and no punctate total thyroidectomy (Answers A and C) and
echogenic foci. No abnormal lymph nodes are prophylactic central neck lymph node dissection
identified in the central or right lateral neck. (Answers C and D) are not necessary to achieve
Findings from FNA of the left thyroid nodule are remission. After lobectomy, if the lesion displays
compatible with TBSRTC atypia of unknown low or no mitotic activity, no extrathyroidal
significance. Somatic oncogene testing reveals an extension, and either no evidence of capsular
NRAS pathogenic variant (Q61R [c.182A>G]). angioinvasion or invasion in fewer than 3
blood vessels, lobectomy should be adequate to
Which of the following is the best surgical achieve remission. If histology reveals extensive
option associated with the highest angioinvasion or high-grade histological features,
likelihood of remission and lowest risk of completion thyroidectomy should be considered
potential complications for this patient? to provide an opportunity to evaluate and initiate
A. Total thyroidectomy surveillance for distant metastasis that may be
present at the time of initial surgery or present
B. Right lobectomy
5 to 10 years after initial diagnosis. Because of
C. Total thyroidectomy with ipsilateral central the paucity of data on angioinvasive FTC in the
neck lymph node dissection pediatric population, the flow diagram (Figure,
D. Right lobectomy with ipsilateral central neck following page) suggests more than 2 vessels to
lymph node dissection raise consideration and discussion regarding
the benefit of completion thyroidectomy. High-
Answer: B) Right lobectomy
grade histologic features include solid, trabecular,
This patient underwent right thyroid lobectomy or insular growth patterns, mitotic index of 3
(Answer B) with an uneventful recovery. or more per 10 high-power field, necrosis, and
Histopathologic examination revealed a unifocal, convoluted nuclei.1
minimally invasive follicular thyroid carcinoma
(FTC) measuring 3.6 cm. Two lymph nodes were
incidentally removed from right level VI (central)
and were negative for malignancy. TNM staging
was T2N0aM0(clinical), placing the patient in the

328 ENDO 2025 • Endocrine Case Management

Figure. Integrative Analysis of a Thyroid Nodule

Incorporation of preoperative oncogene data across the 3-tiered pediatric risk of invasive behavior of differentiated thyroid carcinoma to stratify surgical
management of a thyroid nodule. High-grade histologic features include solid, trabecular, or insular growth patterns, mitotic index ≥3 per 10 high power
fields, necrosis, and convoluted nuclei.
Reprinted from Lai STT & Bauer AJ. JCEM, 2025; Published online ahead of print: 1–14. © The Authors. Published by Oxford University Press on behalf of the
Endocrine Society
[Color—Print (Color Gallery page CG22) or web & ePub editions]

Case 2 Which of the following is the best surgical

option associated with the highest
A 16-year-old previously girl is noted to have a left
likelihood of remission and lowest risk of
neck swelling. Thyroid ultrasonography identifies
potential complications for this patient?
a 4-cm, solid, very hypoechoic infiltrative lesion
with wider-than-tall shape, irregular margins, and A. Total thyroidectomy
punctate echogenic foci in the left lobe. Multiple B. Left lobectomy
enlarged, round hypoechoic cervical lymph nodes C. Total thyroidectomy with ipsilateral central
with peripheral blood flow are identified in the neck lymph node dissection
right central neck (levels VI and VII). There are D. Left lobectomy with ipsilateral central neck
no abnormal lymph nodes in the lateral neck lymph node dissection
(levels 2, 3, 4, or 5). FNA of the thyroid nodule is
compatible with TBSRTC category VI (malignant) Answer: C) Total thyroidectomy with ipsilateral
cytology. central neck lymph node dissection

ENDO 2025 • Tumor Biology 329

This patient underwent total thyroidectomy with sufficient to achieve remission in patients with
left-sided central neck dissection (Answer C). unilateral disease and tumors smaller than 4 cm
Pathology revealed a 4.2-cm classic PTC without and without lateral neck lymph node involvement
extrathyroidal extension but with lymphatic on preoperative ultrasonography. Prophylactic
invasion, including intrathyroidal psammomatous central neck dissection is recommended for all
metastasis in the right lobe (primary tumor patients harboring a BRAF V600E pathogenic
in the left lobe). PTC was present in 9 of 25 variant or RET-like fusion oncogenic alteration
central lymph nodes. AJCC TNM staging was secondary to the increased risk of central neck
pT2N1aM0, and she was at pediatric intermediate lymph node metastasis (thus, Answers A and B
risk for persistent postinitial surgical disease are incorrect). In patients who undergo lobectomy
by American Thyroid Association criteria. A as the initial surgical approach, completion
diagnostic whole-body scan revealed residual thyroidectomy should be considered if histology
activity in the thyroid bed; single-photon emission reveals multifocal disease or 5 or more positive
computed tomography (SPECT)/CT was not central neck lymph nodes are identified on
sensitive enough to determine whether the activity prophylactic central neck lymph node dissection.
was thyroid remnant and/or residual lymph Based on the tumor size, total thyroidectomy
node metastasis. The patient received 131I therapy would be recommended rather than lobectomy
(1 mCi/kg) with an excellent response at 1 and 3 (Answer D). Last, the data on tumor size are
years after initial therapy. Although there was no limited3 and until additional data are available,
clinical indication for somatic oncogene testing lobectomy should only be considered in patients
(ie, the patient did not have progressive disease with unifocal tumors smaller than 1 cm with no
where systemic therapy was being considered), preoperative evidence of lymph node disease
a research-based somatic next-generation (AJCC N0b).4
sequencing panel was performed and was positive
for a BRAF V600E pathogenic variant. Case 3
The sonographic features of PTC associated
with a BRAF V600E pathogenic variant and RET- A 12-year-old girl with a history of radiation
like kinase fusion oncogenic alterations are similar, exposure presents with cervical neck
including solid composition, hypoechoic to very lymphadenopathy. Ultrasonography reveals an
hypoechoic echogenicity, irregular margin or infiltrative lesion occupying both lobes with
infiltrative pattern, increased rate of extrathyroidal bilateral lateral neck lymph node metastases. FNA
extension, and punctate echogenic foci. Central is positive for malignancy (TBSRTC category
and lateral neck lymphadenopathy are common, VI) to include a lymph node from both right
so pre-FNA ultrasonography must include and left levels 2 and 4. Totally thyroidectomy
sonographic assessment of the central neck (below with central and bilateral lateral dissection is
the thyroid and above the clavicle; levels 6 and 7), performed. Histology confirms diffuse sclerosing
as well as the lateral neck (levels 2, 3, 4, and 5) to PTC with extensive angioinvasion and lymphatic
optimize the surgical plan. Cytology is typically invasion with 33 of 82 positive lymph nodes
TBSRTC category V or VI. In the presence of (AJCC T3aN1b). A therapeutic dose of RAI is
bilateral disease and/or lateral neck involvement, administered, and the posttreatment whole-
total thyroidectomy with therapeutic central body scan shows uptake in the neck, lungs, and
neck dissection is warranted with the extent of skull (M1). Over the next 18 months, serial
the lateral neck dissection based on preoperative chest CT shows structural progression of diffuse
ultrasonography and FNA confirmation of lateral micronodular metastasis, and the patient begins to
neck compartment metastasis. Conversely, a more develop mild shortness of breath during aerobic
conservative surgical approach with lobectomy activities.
and prophylactic central neck dissection may be

330 ENDO 2025 • Endocrine Case Management

Which of the following is the best option oncogene-specific inhibitors have a lower adverse
for this patient based on the current data? effect profile.
A. Continued surveillance with serial laboratory For this patient, somatic oncogene testing
tests and imaging every 6 months identified a NCOA4::RET alteration (RET/
B. Repeated 131I therapy PTC3). Based on these findings, selpercatinib
was initiated. Subsequent chest CT showed near-
C. Multityrosine kinase inhibitor therapy with
complete structural response after 6 months on
lenvatinib
systemic therapy. Under a multicenter, prospective
D. Oncogene-specific inhibitor therapy protocol, a second treatment with RAI was
Answer: D) Oncogene-specific inhibitor therapy administered, and selpercatinib was stopped 5
days later. Chest CT 1 year later displayed near-
Most pediatric patients with structural PTC lung complete structural response in the lungs. While
metastasis do not achieve complete remission this single case highlights the potential benefit of
(excellent response), even with repeated RAI oncogene-specific inhibitory therapy, prospective,
therapy (Answer B). While many have stable, multicenter clinical trials are needed to better
persistent disease (the PTC metastasis does not define the use of systemic therapy in pediatric
progress, remaining present in a dormant state), patients, including those with RAI-refractory
a percentage of patients develop progressive disease and those who present with morbidly
disease with an increasing number and size of invasive regional disease (neoadjuvant therapy).2
PTC lesions detected on serial, noncontrast chest
CT. Structural progression with or without RAI
Key Learning Points
avidity is one of several forms of RAI-refractory
disease and may be associated with up to 10% • Over the past 2 decades, significant progress
disease-specific mortality in pediatric patients.2 has been made in the understanding the
Continued surveillance (Answer A) may be molecular landscape of thyroid neoplasms.
considered based on the extent of pulmonary
disease, as structural progression occurs slowly • The incorporation of an integrated,
(months to years). However, patients may develop multimodal approach to the evaluation of
signs and symptoms, most commonly during high- pediatric thyroid nodules into clinical practice,
effort aerobic activity or associated with an acute including the use of somatic oncogene testing,
respiratory illness. If the somatic oncogene can be has the potential to improve the diagnostic
identified, oncogene-specific inhibitory therapy accuracy and reliability of preoperative
(Answer D) is preferred over multityrosine evaluation to optimize the surgical approach.
kinase inhibitor therapy (Answer C), as the drugs • Knowledge of the somatic oncogene provides
result in both tumor regression and increased opportunities to incorporate oncogene-
expression of the sodium-iodide symporter, specific inhibitor therapy both in adjuvant and
raising the possibility for additional RAI therapy. neoadjuvant settings.
Compared with multityrosine kinase inhibitors,

References
1. Lai S-TT, Bauer AJ. Approach to the pediatric patient with thyroid nodules. J 3. Sugino K, Nagahama M, Kitagawa W, et al. Risk stratification of pediatric
Clin Endocrinol Metab. 2025 [Online ahead of print]. PMID: 39943817 patients with differentiated thyroid cancer: is total thyroidectomy necessary
2. Yang AT, Lai S-TT, Laetsch TW, et al. Molecular landscape and therapeutic for patients at any risk? Thyroid. 2020;30(4):548-556. PMID: 31910105
strategies in pediatric differentiated thyroid carcinoma. Endocr Rev. 2025 4. Sudoko CK, Jenks CM, Bauer AJ, et al. Thyroid lobectomy for T1 papillary
[Online ahead of print]. PMID: 39921216 thyroid carcinoma in pediatric patients. JAMA Otolaryngol Head Neck Surg.
2021;147(11):943-950. PMID: 34554217

ENDO 2025 • Tumor Biology 331

 ENDO 2025
MEET THE
COLOR PROFESSOR
GALLERY CONTENTS

ADIPOSE TISSUE, APPETITE, OBESITY, AND LIPIDS

Weight-Loss Pharmacotherapy in the Spectrum of Obesity Care. . . . . . . . . . . . . . . . . . . . . CG3
José O. Alemán, MD, PhD

Metabolic Dysfunction-Associated Steatotic Liver Disease: Tips for Endocrinologists. . . CG3

Eveline Bruinstroop, MD, PhD, and A. G. (Onno) Holleboom, MD, PhD

Atypical and Secondary Etiologies of Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CG4

Andrew T. Kraftson, MD

ADRENAL
How to Manage Bilateral Adrenal Masses.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CG6
Jérôme Bertherat, MD, PhD

Evaluation and Management of Postmenopausal Androgen Excess . . . . . . . . . . . . . . . . . . CG7

Michael W. O’Reilly, MD, PhD, and Wiebke Arlt, MD, DSc

BONE AND MINERAL METABOLISM

Long-Term Complications of Mild Asymptomatic Primary Hyperparathyroidism:
To Treat or Not to Treat?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CG8
Ghada El-Hajj Fuleihan, MD, MPH

Complex Cases in Hypophosphatemia: Navigating Diagnostic and

Treatment Challenges of Low Phosphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CG9
Eva S. Liu, MD

DIABETES AND VASCULAR DISEASE

Monitoring Diabetes Control Using Hemoglobin A1c and Continuous
Glucose Monitoring: Advantages and Pitfalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CG9
Shichun Bao, MD, PhD

Integrating Quality Improvement into Inpatient Diabetes Care.. . . . . . . . . . . . . . . . . . . . . CG10

Sonali Thosani, MD

ENDO 2025 • Color Gallery Contents CG1

GENERAL ENDOCRINOLOGY
Complications of Novel Nonimmunotherapy Cancer Treatments . . . . . . . . . . . . . . . . . . . . CG10
Afreen Shariff, MD, and Randol Kennedy, MD

NEUROENDOCRINOLOGY AND PITUITARY

Challenging Cases of Hyponatremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CG13
Mirjam Christ-Crain, MD

Management of Pituitary Tumors During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CG13

Andrea Glezer, MD, PhD

Craniopharyngiomas in Adults: Modern Management and Changes in the Paradigm. . CG14

Emmanuel Jouanneau, MD, PhD, and Gerald Raverot, MD, PhD

Perioperative Management of Pituitary Tumors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CG14

Whitney W. Woodmansee, MD, MA

PEDIATRIC AND ADOLESCENT ENDOCRINOLOGY

How to Approach Children With Short Stature Not Responding
to Growth Hormone Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CG15
Stefano Cianfarani, MD

THYROID BIOLOGY AND CANCER

Update on the Management of Nonhereditary Medullary Thyroid Carcinoma. . . . . . . . . CG16
Rossella Elisei, MD

Oncocytic Thyroid Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CG17

Ian Ganly, MD, MS, PhD

TUMOR BIOLOGY
Landscape of Genetic Alterations in Well-Differentiated Thyroid Cancer
in Pediatric Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CG22
Andrew J. Bauer, MD

CG2 ENDO 2025 • Endocrine Case Management

 ENDO 2025
MEET THE
COLOR GALLERY
PROFESSOR

ADIPOSE TISSUE, APPETITE, OBESITY, AND LIPIDS

Weight-Loss Pharmacotherapy in the Spectrum of Obesity Care
José O. Alemán, MD, PhD

Figure. Spectrum of Care for Obesity According to BMI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Future AOMs
BMI 25 30 35 40 >40
(kg/m2)
Lifestyle AOMs Bariatric Bariatric
Treatment -1st Gen: Endoscopy Surgery
Options >27 with orlistat,
comorbidities phentermine/ 2nd Gen AOMs
-AOMs topiramate,
bupropion/ >35 with
naltrexone, comorbidities:
liraglutide Bariatric
Surgery
-2nd Gen:
semaglutide,
tirzepatide

The spectrum of care for obesity by BMI reflects increasing overlap between AOMs and procedures, including bariatric endoscopy and bariatric surgery.

Metabolic Dysfunction-Associated Steatotic Liver Disease: Tips for Endocrinologists

Eveline Bruinstroop, MD, PhD, and A. G. (Onno) Holleboom, MD, PhD

Figure. Screening Strategy for MASLD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Screening strategy for MASLD, formerly known as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The strategy is based
on a 2-tier testing approach starting with FIB-4 and, when necessary, vibration-controlled transient elastography (VCTE). Patients with high suspicion of
advanced fibrosis should be referred to a specialized liver clinic for further evaluation.10
Reprinted with permission from Vieira Barbosa J &, Lai M. Hepatol Commun, 2020; 5(2): 158-167. © The Authors. Published by Wiley Periodicals LLC on
behalf of American Association for the Study of Liver Diseases.

ENDO 2025 • Color Gallery CG3

Atypical and Secondary Etiologies of Obesity
Andrew T. Kraftson, MD

Figure 1. Atypical and Secondary Etiologies of Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Figure 2. Various Weight Trends. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

CG4 ENDO 2025 • Endocrine Case Management

Figure 3. Screening for Atypical and Secondary Forms of Obesity.5,7,12,18-24. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

ENDO 2025 • Color Gallery CG5

ADRENAL
How to Manage Bilateral Adrenal Masses
Jérôme Bertherat, MD, PhD

Figure 1.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Figure 2.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Figure 3.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

CG6 ENDO 2025 • Endocrine Case Management

Figure 4.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Evaluation and Management of Postmenopausal Androgen Excess

Michael W. O’Reilly, MD, PhD, and Wiebke Arlt, MD, DSc

Figure. Clinical Algorithm for Evaluation and Management of Androgen Excess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Reprinted from Elhassan YS et al. Clinical Endocrinology, 2025, 1-27. https://doi.org/10.1111/cen.15265 © The Authors. Clinical Endocrinology is published by
John Wiley & Sons Ltd.

ENDO 2025 • Color Gallery CG7

BONE AND MINERAL METABOLISM
Long-Term Complications of Mild Asymptomatic Primary Hyperparathyroidism:
To Treat or Not to Treat?
Ghada El-Hajj Fuleihan, MD, MPH

Figure. Symptoms and Organ Involvement in Patients With PHPT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Symptoms and complications depend on disease severity. Causality is implied from evidence by reversal with surgery or from mechanistic studies. Causal in
is red, and association in green.
*Moderate to severe hypercalcemia may cause changes in mental status or cognitive function that are often reversible with correction of the serum calcium.
Reprinted from El-Hajj Fuleihan G et al. J Bone Miner Res, 2022; 37(11): 2330-2350. © The Authors. Published by Wiley Periodicals LLC on behalf of
American Society for Bone and Mineral Research

CG8 ENDO 2025 • Endocrine Case Management

Complex Cases in Hypophosphatemia: Navigating Diagnostic
and Treatment Challenges of Low Phosphate
Eva S. Liu, MD

Figure. Regulation of Phosphate Homeostasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

Dietary phosphate is absorbed in the gut by sodium phosphate transporter (NPT) 2b (NPT2b) and filtered by the kidneys. In the small intestine, phosphate
transport is predominantly regulated by NPT2b. 1,25-dihydroxyvitamin D (1,25[OH]2D) increases Pit-2 expression in the small intestine, which also leads to
phosphate absorption. PTH binds to the PTHR1 to reduce NPT2a and NPT2c protein levels, resulting increased renal loss of phosphate. FGF-23 is predominantly
expressed in bone and binds to the FGFR with α-Klotho (KL) as coreceptor in the kidneys. Urinary phosphate excretion increases with decreased renal proximal
tubule expression of NPT2a and NPT2c. FGF-23 also stimulates 24-hydroxlase expression, and it reduces 1α-hydroxylase. The combined net effects of the
actions of FGF-23 in the proximal renal tubules are decreased serum levels of phosphate and 1,25-(OH)2D. FGF-23 expression is reduced by PHEX, DMP1,
ENPP1, and FAM20C. Consequently, lack of these negative regulators leads to increased secretion of biologically active FGF-23, resulting in hypophosphatemia.
GALNT3 glycosylates and thus stabilizes FGF-23; lack of this enzyme enhances FGF-23 degradation, thereby reducing urinary phosphate excretion.
Reprinted from Liu ES and Juppner H “Chapter 20: Disorders of Phosphate Homeostasis” in Radovich S and Misra M, Eds. Pediatric Endocrinology, 4th
Edition: Springer 2024; 499-526.

DIABETES AND VASCULAR DISEASE

Monitoring Diabetes Control Using Hemoglobin A1c and Continuous
Glucose Monitoring: Advantages and Pitfalls
Shichun Bao, MD, PhD

Figure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

LibreView daily patterns report shows ambulatory glucose profile with average sensor glucose of 165 mg/dL (9.2 mmol/L), 73% readings within the target
range of 70 to 180 mg/dL (3.9-10.0 mmol/L), and an estimated HbA1c of 7.4% (57 mmol/mol). Dark and light shading shows 25th-75th and 10th-90th
percentiles, respectively.

ENDO 2025 • Color Gallery CG9

Integrating Quality Improvement into Inpatient Diabetes Care
Sonali Thosani, MD

Figure. Plan-Do-Study-Act Cycle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

Plan Do

Act Study

Reprinted from Barr E. & Brannan, GD. Quality Improvement Methods (LEAN, PDSA, SIX SIGMA), in StatPearls. 2025: Treasure Island (FL). © StatPearls
Publishing LLC.

GENERAL ENDOCRINOLOGY
Complications of Novel Nonimmunotherapy Cancer Treatments
Afreen Shariff, MD, and Randol Kennedy, MD

Figure 1. Simplified Schematic of the Intracellular Mechanism of the PI3K/Akt/mTOR Pathway. . . . . . . . . . . . . . . . . . . 167

Insulin binding initiates autophosphorylation and activation of the tyrosine kinase component of the β domain. The activated tyrosine kinase phosphorylates
IRS1, which, when triggered, activates PI3K that generates PIP3 from PIP2. PIP3 phosphorylates Akt/protein kinase B, which when activated, either
indirectly affects mTORC1 through TSC2 or directly through PRAS40 (proline-rich Akt substrate of 40 kDa), leads to regulation of cellular metabolism and
growth/proliferation. Activation is shown by arrowhead lines, whereas inhibition is indicated by ‘T’-shaped lines. Abbreviations: AMPK, AMP-activated
protein kinase; IRS1/2, insulin receptor substrate 1 and 2; mTORC1/2, mechanistic target of rapamycin complex 1 and 2; PI3K, phosphatidylinositide-3
kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; Rheb, Ras homolog enriched in brain; TSC1/2, tuberous
sclerosis protein complex 1 and 2.

CG10 ENDO 2025 • Endocrine Case Management

Figure 2. Algorithm for the Management of PI3K/Akt/mTOR–Induced Hyperglycemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

Abbreviations: DKA, diabetic ketoacidosis; ED, emergency department; eGFR, glomerular filtration rate; HCO3, bicarbonate; HHS, hyperglycemic hyperosmolar
syndrome; IVF, intravenous fluids; MF, metformin; PCP, primary care provider; Na, serum sodium; TZD, thiazolidinediones; BUN, serum urea nitrogen.6
Reprinted from Cheung YM et al. Curr Probl Cancer, 2022; 46(1): 100776. © Elsevier Inc.

ENDO 2025 • Color Gallery CG11

Figure 3.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

Physical exam findings include a dorsocervical fat pad (“buffalo hump”) (Panel A), purple abdominal striae on the abdomen (Panel B) and under the armpit
(Panel C), and truncal obesity 2 years after starting HIAP with dexamethasone, pictured here roughly 30 months after therapy initiation.25
Reprinted from Ferreira MS & Shariff AI. Current Problems in Cancer: Case Reports, 2022; 7(1): 100177. © The Authors. Published by Elsevier Inc.

Figure 4.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

Contrast-enhanced abdominal CT of normal adrenal glands before initiation of floxuridine (FUDR) via HIAP (Panel A), and significant adrenal atrophy
approximately 64 weeks after receiving 20 mg HIAP dexamethasone every 2 to 3 weeks (Panel B).
Reprinted from Ferreira MS & Shariff AI. Current Problems in Cancer: Case Reports, 2022; 7(1): 100177. © The Authors. Published by Elsevier Inc.

CG12 ENDO 2025 • Endocrine Case Management

NEUROENDOCRINOLOGY AND PITUITARY
Challenging Cases of Hyponatremia
Mirjam Christ-Crain, MD

Figure. Treatment Options for SIAD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

Management of Pituitary Tumors During Pregnancy

Andrea Glezer, MD, PhD

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

Sellar MRI, T1 coronal views, without contrast (Panel A) and with contrast (Panel B), showing a pituitary macroadenoma on the left with suprasellar
expansion, not reaching the optical chiasma and in contact with the left cavernous sinus.

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

Sellar MRI, T1 coronal views without contrast (Panel A) and with contrast (Panel B), showing reduction of tumor dimensions and no suprasellar expansion.

ENDO 2025 • Color Gallery CG13

Craniopharyngiomas in Adults: Modern Management and Changes in the Paradigm
Emmanuel Jouanneau, MD, PhD, and Gerald Raverot, MD, PhD

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

Reprinted from De Rosa A et al. Annales d'Endocrinologie, 2023; 84(6):727–733. © Elsevier Masson SAS.

Perioperative Management of Pituitary Tumors

Whitney W. Woodmansee, MD, MA

Figure 2.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

T1 postcontrast MRI demonstrating a large lobulated sellar mass invading the right cavernous sinus and compressing the optic chiasm.

CG14 ENDO 2025 • Endocrine Case Management

Figure 3.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

T1 postcontrast MRI demonstrating recurrent tumor invading the right cavernous sinus.

PEDIATRIC AND ADOLESCENT ENDOCRINOLOGY

How to Approach Children With Short Stature Not Responding to Growth Hormone Treatment
Stefano Cianfarani, MD

Figure. Algorithm for Evaluating Children With Poor Response to GH Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

First-year poor response to GH therapy

Height gain <0.5 SDS
Height velocity increase <3 cm/year
Height velocity < +1 SDS

Confirm the appropriate Assess regimen

GH dosage regimen adherence

Adjust GH dosage

Poor adherence
Good adherence
(low IGF-1)

Stop GH therapy Monitor adherence

Questionnaires
Re-evaluate diagnosis Injection logbook
Injection-recording devices

Genetic testing*

* Genetic testing includes karyotype analysis, comparative genomic hybridization array, single-nucleotide polymorphism array, whole-exome sequencing,
whole-genome sequencing, and DNA methylation analysis.21 More than one-third of children diagnosed as being small-for-gestational age or having
idiopathic short stature have pathogenic variants, mainly in genes involved in growth cartilage physiology, such as ACAN, COL2A1, FBN1, FGFR3, IHH,
NPPC, NPR2, and SHOX.14,22,23 Some polymorphisms located in GHR, IGFBP3, and SOCS2 reduce responsiveness to GH treatment.24

ENDO 2025 • Color Gallery CG15

THYROID BIOLOGY AND CANCER
Update on the Management of Nonhereditary Medullary Thyroid Carcinoma
Rossella Elisei, MD

Figure 1.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

Patient with advanced MTC and flushing syndrome.

Figure 2.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

DOPA PET showing a left latero-cervical lymph node (Panel A) and lesion in the anterior border of L4 (Panel B) and their CT coregistrations (Panels A1 and
18

B1). Neither lesion had been previously identified on other imaging.

CG16 ENDO 2025 • Endocrine Case Management

Oncocytic Thyroid Cancer
Ian Ganly, MD, MS, PhD

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

Panel A, Electron microscopy showing nucleus of cell surrounded by abundant mitochondria. Panel B, Hematoxylin and eosin slide showing vascular
invasion in vessels surrounding a widely invasive OTC.

Figure 2.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

1-3 invasive foci: Minimally invasive (Low risk) 1 VI ≠ 6 VI

> 4 foci of vascular invasion: Widely invasive (High risk)

Min invasive Widely invasive
HCC HCC

Overall survival Locoregional recurrence Distant recurrence

Panel A, Classification of OTC into minimally invasive and widely invasive by extent of vascular invasion. Panel B, Outcomes stratified by extent of vascular
invasion showing poorer outcome with widely invasive carcinoma.

ENDO 2025 • Color Gallery CG17

Figure 3.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

ERBB2 EGFR PDGFR TSHR MET RET

11% 2% 2% 4% 4% 4%

KRAS HRAS NRAS NF1

4% 2% 9% 9%

PTEN PIK3 BRAF Chr 7 amplification

4% 2% 12% mRNA overexpression

TSC1 TSC2
ERK
2% 4%

Chr 7 amplification RHEB p90S6K

mRNA overexpression 18% 2%

Chr 5 amplification RICTOR p70S6K

mTOR EIF4B EIF4B EIF1AX
mRNA overexpression 20% 2%
EIF4A 11%

EIF4G EIF1,2,3
EIF4H 9%
p70S6K
VEGF 4EBP1/EIF4E EIF4E EIF4E
2%
4EBP1
Translation Translation
Angiogenesis Off On

RTK/PIK3/RAS Pathway showing alterations in 60% of cancers

Figure 4.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

Panel A, Types of mitochondrial pathogenic variants observed in 56 OTCs.2 Panel B, Mitochondrial variants categorized by electron transport complexes.

CG18 ENDO 2025 • Endocrine Case Management

Figure 5.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296

Electron transport chain showing interaction of complexes with Krebs cycle. The arrow indicates complex I is the first site of electron transport chain.
Pathogenic variants in complex I disrupt electron transport chain, which in turn disrupts the TCA cycle.

ENDO 2025 • Color Gallery CG19

Figure 6.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

Metabolic alterations in 40 OTCs. Metabolites with less abundance to normal are shown in blue and those greater than normal are shown in red. The blue
circle indicates the large decrease in citrate in the TCA cycle. The red circle indicates the increase in lactate due to increased aerobic glycolysis.

CG20 ENDO 2025 • Endocrine Case Management

Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

CT neck PET/CT neck PET/CT lung metastases

OTCs are hypermetabolic on FDG PET due to increased aerobic glycolysis. Imaging shows a large left thyroid lobe mass on CT and PET. The patient has
multiple hypermetabolic lung metastases.

Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

A. B. C.
Haploid phenotype Polysomic phenotype
A B Global LOH

1.0
No LOH (UPD or haploidy)
0.9

0.8

0.7
Proportion Surviving

0.6
LOH (UPD or haploidy)
0.5

0.4 5yr PFS%

Chr 2 haploid ( 1 copy arrowed) Chr 2 diploid 0.3
LOH 66%
No LOH 100%
Chr 5 diploid Chr 5 WCD ( 4 copies per cell) p=0.02
0.2
Chr 7 diploid Chr 7 WCD (>4 copies per cell)
0.1

0.0
0 10 20 30 40 50 60
•chr2 •chr5 •chr7 Progression free survival(months)

Panel A, Fluorescent in situ hybridization (FISH) staining of a haploid cancer showing 1 copy of chromosome 2 and 2 copies of chromosome 5 and 7. Panel
B, FISH staining of a polysomic cancer showing 2 copies of chromosome 2 and 4 copies of chromosome 5 and 7. Panel C, Loss of chromosomes results in a
global loss of heterozygosity (LOH). Cancers with global LOH have a poorer outcome as shown by the Kaplan Meier plot.

ENDO 2025 • Color Gallery CG21

Figure 9.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

A. B.

100
Sorafenib(400mg bid)

Progression-Free Survival
Sorafenib/Everolimus
R Everolimus(5mg daily) 80 Sorafenib
A
Everolimus
N 60
RAI refractory D
O Target N= 30 40
OTC M
20
I
Z
0
E 0 12 24 36
Sorafenib alone(400mg bid Months
Panel A, Clinical phase 2 trial of patients with RAI-refractory OTC randomly assigning patients to sorafenib alone vs sorafenib/everolimus. Panel B, Patients
treated with sorafenib/everolimus had increased progression-free survival.

TUMOR BIOLOGY
Landscape ofII trial
Figure 9. A. Clinical phase Genetic Alterations
of patients with in Well-Differentiated
RAI refractory OTC randomizing patients to sorafenib alone versusThyroid Cancer
sorafenib/everolimus. intreated
B. Patients Pediatric Patients
with sorafenib/everolimus had
Andrew J. Bauer, MD
increased progression free survival.

Figure. Integrative Analysis of a Thyroid Nodule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329

Incorporation of preoperative oncogene data across the 3-tiered pediatric risk of invasive behavior of differentiated thyroid carcinoma to stratify surgical
management of a thyroid nodule. High-grade histologic features include solid, trabecular, or insular growth patterns, mitotic index ≥3 per 10 high power
fields, necrosis, and convoluted nuclei.
Reprinted from Lai STT & Bauer AJ. JCEM, 2025; Published online ahead of print: 1–14. © The Authors. Published by Oxford University Press on behalf of the
Endocrine Society

CG22 ENDO 2025 • Endocrine Case Management

 2025 Endocrine Case Management: Meet the Professor is your
source for the latest updates in the diagnosis and management of
a wide range of endocrine disorders. This valuable resource allows
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Features of 2025 Endocrine Case Management:

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