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 2 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 2022
MEET THE PROFESSOR

ENDOCRINE
CASE MANAGEMENT
2055 L Street, NW, Suite 600
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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 2022

Bulent O. Yildiz, MD, PhD

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eISBN: 978-1-936704-11-8
 ENDO 2022
CONTENTS

ADIPOSE TISSUE, APPETITE, AND OBESITY

Hypothalamic Obesity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Ashley H. Shoemaker, MD, MSCI

Electronic Tools to Help Patients During Their Weight-Loss Journey. . . . . . . . . . . . . . . . . . . . .8

Manpreet S. Mundi, MD

Update on the Medical Management of Obesity.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15

David A. D’Alessio, MD, and Jonathan E. Campbell, PhD

Long-Term Follow-Up of Bariatric Surgery in Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . .22

Ilene Fennoy, MD, MPH

ADRENAL
Glucocorticoid-Induced Adrenal Insufficiency.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30
Alessandro Prete, MD, and Wiebke Arlt, MD, DSc

Advances in the Treatment of Congenital Adrenal Hyperplasia. . . . . . . . . . . . . . . . . . . . . . . .38

Adina F. Turcu, MD, MS

Hypercortisolism: A Challenging Disease to Diagnose and Manage . . . . . . . . . . . . . . . . . . . .46

Ricardo R. Correa, MD, EdD, and Katherine A. Araque, MD, MSCR

Pheochromocytoma and Paraganglioma: Diagnosis and Perisurgical Management . . . . . .54

Annika M. A. Berends, MD, and Michiel N. Kerstens, MD, PhD

Below the Tip of the Iceberg: Just How Much Aldosterone Is Out There?.. . . . . . . . . . . . . . . .68
Martin Reincke, MD

BONE AND MINERAL METABOLISM

Denosumab Discontinuation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78
Bente L. Langdahl, MD, PhD, DMSc

Using the Best Available Evidence to Personalize Osteoporosis Treatment . . . . . . . . . . . . . .85

E. Michael Lewiecki, MD, and Micol S. Rothman, MD

ENDO 2022 • Contents  iii

CARDIOVASCULAR ENDOCRINOLOGY
Choosing Cholesterol-Lowering Medications in Patients With Liver Disease. . . . . . . . . . . . .92
Savitha Subramanian, MD

Update on Genetic Causes of Hypercholesterolemia: What’s New in the Evaluation

and Treatment of These Hard-to-Treat Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .98
Marc-Andre Cornier, MD

PCSK9 Inhibitors: Basic Biology to Clinical Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

Connie B. Newman, MD, MACP

DIABETES MELLITUS AND GLUCOSE METABOLISM

Disparities in Diabetes Care and Evidence-Based Programs to Address Them .. . . . . . . . 116
Rocio I. Pereira, MD

Time in Range: The New Hemoglobin A1c?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Jane E. B. Reusch, MD

Closed-Loop Insulin Delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

Sue A. Brown, MD

NEUROENDOCRINOLOGY AND PITUITARY

Perioperative Management of Pituitary Adenomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Ismat Shafiq, MD

Shifting Fluids: Syndrome of Inappropriate Antidiuretic Hormone Secretion

and Diabetes Insipidus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Julia Kharlip, MD

Multiple Endocrine Neoplasia Type 1 Across the Lifespan . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

Maria Luisa Brandi, MD, PhD

Aggressive Pituitary Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

Nienke Biermasz, MD

Controversies in the Field of Acromegaly.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

Elena V. Varlamov, MD, and Maria Fleseriu, MD

Management of Nonsecretory Pituitary Tumors When Surgery Fails . . . . . . . . . . . . . . . . . 180

Mark Gurnell, MD, PhD

iv  ENDO 2022 • Endocrine Case Management

PEDIATRIC ENDOCRINOLOGY
Precocious Puberty: Evidence-Based Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
Maria G. Vogiatzi, MD

Dilemmas in Diabetes Mellitus in Youth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

Philip S. Zeitler, MD, PhD

Novel Therapies in the Treatment of Congenital Hyperinsulinism. . . . . . . . . . . . . . . . . . . . . 205

Diva D. De Leon-Crutchlow, MD, MSCE

Approach to Pediatric Lipid Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Ambika P. Ashraf, MD

Approach to Fractures in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

Rachel I. Gafni, MD

REPRODUCTIVE ENDOCRINOLOGY
Polycystic Ovary Syndrome Across the Lifespan .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
Melanie Cree Green, MD, PhD, and Kathleen M. Hoeger, MD, MPH

Beginner’s Guide to Gender-Affirming Hormone Therapy

for Transgender and Gender-Diverse Adults. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Caroline J. Davidge-Pitts, MB, BCh, and Sean J. Iwamoto, MD

Diagnosis and Treatment of Male Hypogonadism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

Channa N. Jayasena, PhD

Management Strategies for Primary Ovarian Insufficiency

in Adolescence: Protecting Long-Term Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Lawrence C. Layman, MD

THYROID
Molecular Diagnosis of Indeterminate Thyroid Nodules. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
Bryan R. Haugen, MD, and Sarah E. Mayson, MD

What’s Wrong With This Picture? Challenging Cases in Thyroid Ultrasonography . . . . . 272
Jennifer A. Sipos, MD

Unmet Needs in Hypothyroidism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277

Elizabeth A. McAninch, MD

Management of Hereditary Medullary Thyroid Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

Uriel Clemente-Gutierrez, MD, Bernice L. Huang, MD, Danica M. Vodopivec, MD, and Nancy D. Perrier, MD

What’s New in the Treatment of Differentiated Thyroid Cancer?. . . . . . . . . . . . . . . . . . . . . 294

Benjamin J. Gigliotti, MD

ENDO 2022 • Contents  v

MISCELLANEOUS
Doping With Androgens: Abuse of Androgenic Performance-Enhancing Drugs. . . . . . . . 306
Bradley D. Anawalt, MD

E-Consults: An Evolving Area of Endocrine Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

David Saxon, MD, and Varsha Vimalananda, MD

vi  ENDO 2022 • Endocrine Case Management

ENDO 2022
FACULTY

2022 Endocrine Case Management: Meet the Professor Faculty

Bradley Anawalt, MD Diva Del Carmen De Leon- Lawrence Clarke Layman, BS, MD
University of Washington Crutchlow, MD, MSCE Medical College of Georgia
Children’s Hospital of Philadelphia at Augusta University
Wiebke Arlt, MD, DSc,
FRCP, FMedSci Ilene Fennoy, MD, MPH Mike Lewiecki, MD
University of Birmingham Columbia University New Mexico Clinical Research
& Osteoporosis Center
Ambika Ashraf, MD Maria Fleseriu, MD
Children’s Hospital/University Oregon Health & Science University Sarah Mayson, MD
of Alabama at Birmingham University of Colorado
Rachel Gafni, MD School of Medicine
Annika M. A. Berends, MD NIH
University Medical Center Groningen Elizabeth McAninch, MD
Benjamin Gigliotti, MD Stanford University
Nienke Biermasz, MD University of Rochester School of Medicine
Leiden University Medical Center School of Medicine & Dentistry
Manpreet Mundi, MD
Maria Brandi, MD, PhD Mark Gurnell, MD, PhD Mayo Clinic
FIRMO Foundation University of Cambridge, Wellcome
Trust-MRC Institute of Metabolic Connie Baum Newman, MD, MACP
Sue Brown, MD Science & School of Clinical Medicine New York University
University of Virginia School of Medicine
Bryan Haugen, MD
Jonathan Campbell, PhD University of Colorado Rocio Pereira, MD
Duke University Denver Medical Campus Denver Health Medical Center

Uriel Clemente-Gutierrez, MD Kathleen Hoeger, MD, MPH Nancy Perrier, MD

University of Texas University of Rochester University of Texas
MD Anderson Cancer Center MD Anderson Cancer Center
Bernice L. Huang, MD
Marc-Andre Cornier, MD University of Texas Alessandro Prete, MD
Medical University of South Carolina MD Anderson Cancer Center University of Birmingham

Ricardo Correa, MD, EdD Sean Iwamoto, MD Martin Reincke, MD

University of Arizona College University of Colorado Medizinische Klinik und Poliklinik IV
of Medicine Phoenix School of Medicine & Rocky Mountain
Regional VA Medical Center Jane Reusch, MD
Melanie Cree-Green, MD, PhD Rocky Mountain Regional
University of Colorado and Channa Jayasena, MD VA Medical Center
Children’s Hospital Colorado Imperial College London
Micol Rothman, MD
David D’Alessio, MD Michiel Kerstens, MD, PhD University of Colorado
Duke University School of Medicine University Medical Center Groningen School of Medicine

Caroline Davidge-Pitts, MD, MBBCH Julia Kharlip, MD David Saxon, MD

Mayo Clinic University of Pennsylvania University of Colorado &
Rocky Mountain Regional
Bente Langdahl, MD, PhD, DMSc VA Medical Center
Aarhus University Hospital

ENDO 2022 • Faculty  vii

 Ismat Shafiq, MD Savitha Subramanian, MD Danica M. Vodopivec, MD
University of Rochester University of Washington University of Texas
MD Anderson Cancer Center
Ashley Shoemaker, MD Adina Turcu, MD, MS
Vanderbilt University Medical Center University of Michigan Maria Vogiatzi, MD
Children’s Hospital of Philadelphia
Jennifer Sipos, MD Varsha Vimalananda, MD, MPH
Ohio State University Center for Healthcare Organization Philip Zeitler, MD, PhD
and Implementation Research Children’s Hospital Colorado/
University of Colorado

Annual Meeting Steering Committee (AMSC)

Stephen Hammes, PhD, Bulent O. Yildiz, MD, PhD – Lauren Fishbein, MD, PhD
MD – AMSC Chair Clinical Practice Chair – Clinical Science Chair
University of Rochester Hacettepe University University of Colorado
School of Medicine School of Medicine

Annual Meeting Steering Committee Clinical Peer Reviewers

Andrew Bauer, MD Stephanie Fish, MD Robin Peeters, MD, PhD
Ernesto Bernal-Mizrachi, MD Lauren Fishbein, MD, PhD Margareta Pisarska, MD
Antonio Bianco, MD, PhD Matthew Freeby, MD Philipp Scherer, PhD
Kristien Boelaert, MD, PhD Adda Grimberg, MD Jennifer Sherr, MD, PhD
Massimiliano Caprio, MD, PhD Niki Karavitaki, FRCP, PhD Robert Wermers, MD
Bart Clarke, MD Marta Korbonits, MD, PhD Selma Witchel, MD
Dawn Davis, MD, PhD Maria Veronica Mericq, MD Bulent O. Yildiz, MD
Daniel Dumesic, MD Gabrielle Page-Wilson, MD Maria-Christina Zennaro, MD, PhD

viii  ENDO 2022 • Endocrine Case Management

ENDO 2022
XXXXXXXXXXXX
OVERVIEW

OVERVIEW  TARGET AUDIENCE 

Endocrine Case Management: Meet the Professor is designed Endocrine Case Management: Meet the Professor provides
to provide physicians with a concise and high-quality case-based education to clinicians interested in
review of more than 35 common and rare endocrine improving patient care.  
disorders to help you keep your practice current. It
consists of case-based clinical vignettes and rationales by
STATEMENT OF INDEPENDENCE 
experts in all areas of endocrinology, diabetes, and
As a provider of CME accredited by the Accreditation
metabolism.
Council for Continuing Medical Education, the
Endocrine Society has a policy of ensuring that the
ACCREDITATION STATEMENT  content and quality of this educational activity are
The Endocrine Society is accredited by balanced, independent, objective, and scientifically
the Accreditation Council for rigorous. The scientific content of this activity was
Continuing Medical Education to developed under the supervision of the Endocrine
provide continuing medical education Society’s Annual Meeting Steering Committee.  
for physicians. The Endocrine Society has received
Accreditation with Commendation. 
DISCLOSURE POLICY
The Endocrine Society designates this enduring material The faculty, committee members, and staff who are in
for a maximum of 30.0 AMA PRA Category 1 Credits™. position to control the content of this activity are
Physicians should claim only the credit commensurate required to disclose to the Endocrine Society and to
with the extent of their participation in the activity.  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)
LEARNING OBJECTIVES  whose products or services are related to the content.
Endocrine Case Management: Meet the Professor will allow Financial relationships are defined by remuneration in
learners to assess their knowledge of all aspects of any amount from the commercial interest(s) in the form
endocrinology, diabetes, and metabolism.  of grants; research support; consulting fees; salary;
ownership interest (e.g., stocks, stock options, or
Upon completion of this educational activity, learners ownership interest excluding diversified mutual funds);
will be able to:  honoraria or other payments for participation in
speakers’ bureaus, advisory boards, or boards of
• Recognize clinical manifestations of endocrine and directors; or other financial benefits. The intent of this
metabolic disorders and select among current disclosure is not to prevent planners with relevant
options for diagnosis, management, and therapy.  financial relationships from planning or delivery of
• Identify risk factors for endocrine and metabolic content, but rather to provide learners with information
disorders and develop strategies for prevention.  that allows them to make their own judgments of
whether these financial relationships may have
• Evaluate endocrine and metabolic manifestations of influenced the educational activity with regard to
systemic disorders.  exposition or conclusion. The Endocrine Society has
reviewed all disclosures and resolved or managed all
• Use existing resources pertaining to clinical
identified conflicts of interest, as applicable.
guidelines and treatment recommendations for
endocrine and related metabolic disorders to guide
diagnosis and treatment. 

ENDO 2022 • Overview  ix

 The Endocrine Society has reviewed these relationships Maria Brandi, MD, PhD; Uriel Clemente-Gutierrez,
to determine which are relevant to the content of this MD; Ricardo Correa, MD, EdD; Melanie Cree-
activity and resolved any identified conflicts of interest Green, MD, PhD; Caroline Davidge-Pitts, MD,
for these individuals. MBBCH; Ilene Fennoy, MD, MPH; Rachel Gafni,
MD; Benjamin Gigliotti, MD; Mark Gurnell, MD,
The faculty reported the following relevant financial PhD; Bryan Haugen, MD; Kathleen Hoeger, MD,
relationship(s) during the content development process for this MPH; Bernice L. Huang, MD; Sean Iwamoto, MD;
activity: Sue Brown, MD, Grant Recipient: Dexcom, Michiel Kerstens, MD, PhD; Julia Kharlip, MD;
Tandem Diabetes Care, Insulet Corporation. Jonathan Lawrence Clarke Layman, BS, MD; Sarah Mayson,
Campbell, PhD, Advisory Board Member: ShouTi; MD; Manpreet Mundi, MD; Connie Baum
Grant Recipient: Eli Lilly & Company, Novo Nordisk, Newman, MD, MACP; Rocio Pereira, MD; Nancy
Proteostasis; Speaker: Eli Lilly & Company. Marc- Perrier, MD; Alessandro Prete, MD; Martin
Andre Cornier, MD, Advisory Board Member: Reincke, MD; Jane Reusch, MD; Micol Rothman,
Regeneron Pharmaceuticals; Grant Recipient: Novartis MD; David Saxon, MD; Ismat Shafiq, MD; Jennifer
Pharmaceuticals. David D’Alessio, MD, Advisory Sipos, MD; Varsha Vimalananda, MD, MPH; Danica
Board Member: Eli Lilly & Company; Grant Recipient: M. Vodopivec, MD; and Maria Vogiatzi, MD
Merck & Co., Applied Therapeutics, Inc., Boehringer
Ingelheim, Eli Lilly & Company, Genentech, Inc., The following AMSC peer reviewers reported relevant
Hanmi, Janssen Research & Development Company, financial relationships: Andrew Bauer, MD, Speaker:
Metacrine, Novartis Pharmaceuticals, Novo Nordisk, Hexal, AG. Antonio Bianco, MD, PhD, Consulting
Oramed, Pfizer, Inc., REMD Biotherapeutics Inc., Fee: Allergan, BLA Technology, IBSA Foundation,
Sanofi, VTV Therapeutics. Research Investigator. Diva Synthonics. Kristien Boelaert, MD, PhD, Advisory
Del Carmen De Leon-Crutchlow, MD, MSCE, Board: Pfizer, EISAI. Massimiliano Caprio, MD, PhD,
Consulting Fee: Ultragenyx, Zealand Pharma, Hanmi Grant Recipient: Bayer AG. Bart Clarke, MD, Advisory
Pharmaceuticals, Heptares Therapeutics, Eiger Pharma, Board: Bristol-Myers Squibb; Consulting Fee: Shire/
Crinetics Pharmaceuticals; Grant Recipient: Twist Takeda, Inc., Calcilytix, Inc., Amolyt, Inc. Dawn Davis,
Pharma, Crinetics Pharmaceuticals; Stock Owner: MD, PhD, Employee: Department of Veterans Affairs;
Merck & Co. Maria Fleseriu, MD, Consulting Fee: Grant Recipient: Department of Veterans Affairs, NIH.
Ionis Pharmaceuticals Inc., Ipsen, Pfizer Global R&D, Daniel Dumesic, MD, Advisory Board: Spruce
Crinetics, Amryt, Recordati; Grant Recipient: Ionis BioSciences Inc.; Grant Recipient: NIH. Lauren
Pharmaceuticals Inc., Crinetics, Recordati. Channa Fishbein, MD, PhD, Advisory Board: PheoPara
Jayasena, MD, Grant Recipient: Logixx Pharma Ltd. Alliance; Consulting Fee: Lantheus/Azedra. Matthew
Bente Langdahl, MD, PhD, DMSc, Advisory Board Freeby, MD, Grant Recipient: Novo Nordisk, Abbott
Member: Amgen, UCB, Gedeon-Richter; Grant Diabetes. Adda Grimberg, MD, Advisory Board:
Recipient: Novo Nordisk, Amgen; Speaker: Amgen, Pfizer; Consulting Fee: Sandoz; Grant Recipient: Eunice
UCB, Gedeon-Richter, Astra-Zenica, Astellas. Mike Kennedy Shriver National Institute of Child Health and
Lewiecki, MD, Consulting Fee: Amgen Inc; Speaker: Human Development. Niki Karavitaki, FRCP, PhD,
Amgen Inc. Elizabeth McAninch, MD, Owner/ Advisory Board: Recordati Rare Diseases, Pfizer, Ipsen;
Co-Owner: Equilibrate Therapeutics. Ashley Speaker: HRA Pharma, Pfizer, Ipsen. Marta Korbonits,
Shoemaker, MD, Advisory Board Member: Radius MD, PhD, Consultant Fee: ONO, Novo Nordisk,
Health Inc, Saniona, Rhythm Pharmaceuticals. Savitha Corcept; Speaker: Pfizer, Ipsen. Maria Veronica
Subramanian, MD, Advisory Board Member: Abbott Mericq, MD, Advisory Board: Pfizer, Sandoz, Merck,
Laboratories, Akcea Therapeutics, Amarin. Adina Novo Nordisk; Consultant Fee: Novartis/Sandoz; Grant
Turcu, MD, MS, Advisory Board Member: Novartis; Recipient: Merck. Gabrielle Page-Wilson, MD,
Consulting Fee: CinCor, PhaseBio. Philip Zeitler, MD, Advisory Board: Strongbridge Biopharma, Recordati
PhD, Consulting Fee: Boehringer Ingelheim, Daiichi Rare Diseases, Inc. Robin Peeters, MD, PhD, Advisory
Sankyo, Eli Lilly & Company, Janssen Research & Board: Sanofi Genzyme, Bayer; Speaker: Berlin-Chemie,
Development Company, Merck. Goodlife Fertility BV, Institut Biochimique SA (IBSA),
Sanofi Genzyme, Bayer, EISAI. Jennifer Sherr, MD,
The following faculty reported no relevant financial PhD, Advisory Board: Bigfoot Biomedical, Lilly, Insulet,
relationships: Bradley Anawalt, MD; Wiebke Arlt, Cecelia Health; Consultant Fee: Medtronic Diabetes,
MD, DSc, FRCP, FMedSci; Ambika Ashraf, MD; Sanofi; Grant Recipient: JDRF
Annika M. A. Berends, MD; Nienke Biermasz, MD;

x  ENDO 2022 • Endocrine Case Management

The following AMSC peer reviewers reported no relevant PRIVACY AND CONFIDENTIALITY
financial relationships: Ernesto Bernal-Mizrachi, MD; STATEMENT
Stephanie Fish, MD; Margareta Pisarska, MD; The Endocrine Society will record learner’s personal
Philipp Scherer, PhD; Robert Wermers, MD; Selma information as provided on CME evaluations to allow
Witchel, MD; Bulent O. Yildiz, MD, PhD; and for issuance and tracking of CME certificates. The
Maria-Christina Zennaro, MD, PhD Endocrine Society may also track aggregate responses to
questions in activities and evaluations and use these data
The Endocrine Society staff associated with the to inform the ongoing evaluation and improvement of
development of content for this activity reported no its CME program. No individual performance data or
relevant financial relationships. any other personal information collected from
evaluations will be shared with third parties.
DISCLAIMERS
The information presented in this activity represents ACKNOWLEDGMENT OF
the opinion of the faculty and is not necessarily the COMMERCIAL SUPPORT
official position of the Endocrine Society. This activity is not supported by educational grant(s) or
other funds from any commercial supporter.
USE OF PROFESSIONAL JUDGMENT:
The educational content in this enduring activity relates
to basic principles of diagnosis and therapy and does not AMA PRA CATEGORY 1 CREDIT
substitute for individual patient assessment based on the (CME) INFORMATION
health care provider’s examination of the patient and To receive a maximum of 30.0 AMA PRA Category 1
consideration of laboratory data and other factors Credits™, participants must complete the online
unique to the patient. Standards in medicine change as interactive module and activity evaluation located at
new data become available. https://education.endocrine.org/MTP2022.
Participants must achieve a minimum score of 70% to
DRUGS AND DOSAGES: claim CME credit. After initially completing the module,
When prescribing medications, the physician is advised if participants do not achieve a minimum score of 70%,
to check the product information sheet accompanying they have the option to change their answers and make
each drug to verify conditions of use and to identify any additional attempts to achieve a passing score. Learners
changes in drug dosage schedule or contraindications. also have the option to clear all answers and start over.

POLICY ON UNLABELED/OFF-LABEL USE METHOD OF PARTICIPATION

The Endocrine Society has determined that disclosure of This enduring material is presented online and in print
unlabeled/off-label or investigational use of commercial format. The estimated time to complete this activity,
product(s) is informative for audiences and therefore including review of material, is 30 hours. Participants
requires this information to be disclosed to the learners must achieve a minimum score of 70% to claim CME
at the beginning of the presentation. Uses of specific credit. After initially completing the module, if
therapeutic agents, devices, and other products discussed participants do not achieve a minimum score of 70%, they
in this educational activity may not be the same as those have the option to change their answers and make
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requires that any discussions of such “off-label” use be
based on scientific research that conforms to generally
SYSTEM REQUIREMENTS
accepted standards of experimental design, data
To complete this activity, participants must have access
collection, and data analysis. Before recommending or
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prescribing any therapeutic agent or device, learners
connection and use an up to date version of any major
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precautions, and adverse events.
and Javascript must be enabled in the browser’s options.

LAST REVIEW DATE: April 2022

ENDO 2022 • Overview  xi

 ACTIVITY RELEASE DATE: June 9, 2022 For questions about content or obtaining CME credit,
please contact the Endocrine Society at
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COMMON ABBREVIATIONS

ACTH = corticotropin FSH = follicle-stimulating hormone NPH insulin = neutral protamine

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

BMI = body mass index peptide 1 receptor agonist PSA = prostate-specific antigen
GnRH = gonadotropin-releasing PTH = parathyroid hormone
CNS = central nervous system
hormone PTHrP = parathyroid hormone–related
CT = computed tomography
hCG = human chorionic gonadotropin protein
DHEA = dehydroepiandrosterone
HDL = high-density lipoprotein SGLT-2 inhibitor = sodium-glucose
DHEA-S = dehydroepiandrosterone cotransporter 2 inhibitor
sulfate HIV = human immunodeficiency virus
SHBG = sex hormone–binding globulin
DNA = deoxyribonucleic acid HMG-CoA reductase inhibitor =
3-hydroxy-3-methylglutaryl coenzyme A T3 = triiodothyronine
DPP-4 inhibitor = dipeptidyl-peptidase
reductase inhibitor T4 = thyroxine
4 inhibitor
IGF-1 = insulinlike growth factor 1 TPO antibodies = thyroperoxidase
DXA = dual-energy x-ray
LDL = low-density lipoprotein antibodies
absorptiometry
LH = luteinizing hormone TRH = thyrotropin-releasing hormone
FDA = Food and Drug Administration
MCV = mean corpuscular volume TRAb = thyrotropin-receptor antibodies
FGF-23 = fibroblast growth factor 23
MIBG = meta-iodobenzylguanidine TSH = thyrotropin
FNA = fine-needle aspiration
MRI = magnetic resonance imaging VLDL = very low-density lipoprotein

xii  ENDO 2022 • Endocrine Case Management

ADIPOSE TISSUE,
APPETITE, AND OBESITY
Hypothalamic Obesity
Ashley H. Shoemaker, MD, MSCI. Department of Pediatrics, Endocrinology, and Diabetes,
Vanderbilt University Medical Center, Nashville, TN; E-mail: [email protected]

Learning Objectives Significance of the

As a result of participating in this session, learners Clinical Problem
should be able to: Hypothalamic obesity occurs in up to 60%
• Identify signs and symptoms of hypothalamic of patients with tumors in the hypothalamic
obesity. region, most commonly craniopharyngiomas.
Hypothalamic dysfunction can be due to
• Explain the risks and benefits of available tumor infiltration or be a consequence of
treatment options for hypothalamic obesity. surgery or radiation therapy. Survival rates for
craniopharyngiomas are excellent with an overall
5-year survival rate of 80%, but survivors still
face a 5-times greater overall mortality rate and
Main Conclusions a 3-times greater cardiovascular mortality rate
Hypothalamic obesity is a common complication compared with rates in the general population.1
of tumors in the hypothalamic region. It is Those who develop hypothalamic obesity have
characterized by rapid weight gain and is often even greater morbidity and mortality than normal-
accompanied by hypopituitarism. Risk factors weight survivors.2 Prevention and treatment of
for development of hypothalamic obesity obesity in this population is vital to decrease the
include large tumor size, damage to the posterior morbidity and mortality from diabetes, stroke, and
hypothalamus, hypopituitarism, pretreatment myocardial infarction.
obesity, and younger age. Hypothalamic obesity
is refractory to treatment and is highlighted by
Barriers to Optimal Practice
variable hyperphagia, reduced energy expenditure,
and hyperinsulinemia. Lifestyle modifications Multiple abnormalities in energy balance
including a reduced calorie, low-carbohydrate diet, lead to hypothalamic obesity. Patients with
and regular physical activity are recommended craniopharyngioma who have obesity may have
but are unlikely to lead to significant weight loss. decreased resting energy expenditure compared
Medications such as GLP-1 receptor agonists with control patients who have obesity, most likely
have shown potential to mitigate weight gain due to decreased sympathetic tone,3 although this
in patients with hypothalamic obesity, although has not been a consistent finding. Resting energy
weight loss is still difficult. Bariatric surgery can expenditure represents approximately two-thirds
be a safe and effective option for long-term weight of daily energy expenditure, with physical activity
loss and weight-loss maintenance. and other nonexercise activities accounting for the
remaining one-third. Patients with hypothalamic
obesity typically have a decreased daily activity
level. Patients with craniopharyngioma have
decreased movement counts as measured by
accelerometry and rate their physical capabilities
lower than those of healthy control participants.2

2  ENDO 2022 • Endocrine Case Management

We used accelerometry to measure physical YY, and to our knowledge there are no studies
activity over a 1-year period in 31 children and evaluating glucagon, adiponectin, or GLP-1 levels
young adults with hypothalamic obesity enrolled compared with those of control participants.
in a clinical trial.4 Overall, patients spent the most There are conflicting data on hyperleptinemia in
of the time in sedentary activity and low-intensity patients with hypothalamic obesity.5,7 One concern
activity with an average of only 24 minutes per is that 2 of the studies that found hyperleptinemia
day of moderate or vigorous activity—well below in patients with hypothalamic obesity correlated
the recommendation of 60 minutes per day. Other leptin levels with BMI, not fat mass.7 We suspect
studies have also shown decreased quality of life a role of hyperleptinemia due to both the lack
scores in the areas of physical mobility, fatigue, of hypothalamic feedback and the stimulation
and energy. of leptin production from adipocytes in chronic
Along with the reduction in daily energy hyperinsulinemia.
expenditure, there is a failure to reduce food
intake. While some patients with hypothalamic
obesity have significant hyperphagia, most patients
Strategies for Diagnosis,
do not report extreme hunger or food-seeking Therapy, and/or Management
behaviors.3,5 Hyperphagia questionnaire scores are Patients may present with hypothalamic obesity
similar to those of patients with common obesity.5 at the time of brain tumor diagnosis. If a patient
Patients with hypothalamic obesity struggle with has obesity at diagnosis, they are at high risk of
accurate food recall, underreporting caloric intake hypothalamic obesity. While obesity is common
by an average of 26%.5 It is possible that the long- in the United States population, the presence of
term cognitive effects of brain tumors and their obesity at diagnosis may also signal abnormal
treatment make food recall particularly difficult weight gain over the preceding months. Most
for patients with hypothalamic obesity, although patients develop hypothalamic obesity as a result
underreporting is common in patients with all of treatment, typically surgery or radiation.2
forms of obesity. Surgical effects are seen immediately while
Hypothalamic obesity is associated with radiation effects can take months to present.
increased risk of metabolic syndrome.6 Even Presence of hypopituitarism is another risk factor
children with hypothalamic obesity have been for hypothalamic obesity, most likely due to the
found to have impaired fasting glucose and most correlation with extensive hypothalamic damage.
children with hypothalamic obesity meet criteria Posterior hypothalamic damage can be a marker
for metabolic syndrome. These patients often have for hypothalamic obesity risk. While not yet
insulin resistance and decreased insulin sensitivity. routinely used in clinical care, there is a published
A consistent finding is increased insulin secretion, MRI scoring system that may help identify patients
particularly an exaggerated first-phase response. at high risk of developing hypothalamic obesity.
In animal models, lesions of the ventromedial The hallmark of hypothalamic obesity is rapid
hypothalamus cause obesity and hyperinsulinemia weight gain leading to a notable change in weight
that is ameliorated by vagotomy. The increased trajectory. The most rapid weight gain is typically
vagal efferent activity in hypothalamic obesity seen in the first 6 months, highlighting the need for
may directly stimulate insulin secretion from the early diagnosis and intervention, as prevention of
pancreas. With the exception of bariatric surgery, weight gain can be more successful than weight loss.
currently available medical treatments have not Medical treatments have not been very
been shown to improve glucose intolerance or successful in treating hypothalamic obesity.8
metabolic syndrome in hypothalamic obesity.4 Octreotide, a somatostatin analogue that decreases
Changes in other gut hormones are not clear; insulin secretion, was one of the first medications
there are conflicting studies on ghrelin and peptide tried for hypothalamic obesity, but its use in a

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  3

randomized controlled trial failed to cause weight dexamphetamine in patients with hypothalamic
loss. Additional studies have used metformin alone obesity. Another stimulant, phentermine, is approved
or in combination but did not result in significant for short-term treatment of obesity in adults and a
weight loss, although metformin may help slow phentermine/topiramate combination is approved
the rate of weight gain. Perhaps due to its safety for long-term treatment of obesity. The mechanism
profile and the prevalence of metabolic syndrome/ of action is not well understood, but most likely
prediabetes, metformin is commonly prescribed involves the hypothalamus. Since the degree of
to patients with hypothalamic obesity; 31% of hypothalamic damage is variable in hypothalamic
patients (27 of 87) in the International Registry obesity, it is possible that some patients will respond
of Hypothalamic Obesity Disorders reported use to phentermine/topiramate, but studies are needed.
of metformin for weight loss.8 Low-carbohydrate Oxytocin is synthesized in the hypothalamus
diets are often recommended in clinical practice and secreted through the posterior pituitary. Unlike
despite a lack of robust supporting evidence.9 other pituitary hormones, oxytocin is not routinely
GLP-1 is an incretin that enhances release of replaced. This neuropeptide has been shown to
insulin in response to hyperglycemia, decreases reduce appetite and increase energy expenditure.
the rate of gastric emptying, and increases satiety. Oxytocin is not approved for treatment of obesity
At pharmacologic dosages, GLP-1 crosses the or hypopituitarism. It is typically given intranasally,
blood brain barrier and has direct effects on and an effective dosage regimen is not yet defined.
GLP-1 receptors in the brain. GLP-1 receptors In Prader-Willi syndrome, a genetic obesity
are expressed in numerous brain regions outside disorder with hypothalamic dysfunction, oxytocin
of the hypothalamus, particularly the brainstem. has had variable effects on hyperphagia. An
GLP-1 receptor agonists are increasingly used oxytocin analogue, carbetocin, was evaluated by
for treatment of obesity; the US FDA has granted the US FDA in 2021 for treatment of hyperphagia
approval for liraglutide (2020) and semaglutide but was not approved due to concerns about
(2021) for chronic weight management. Due to efficacy. It is recommended that oxytocin not be
the extrahypothalamic actions of GLP-1 receptor used outside of clinical trials.
agonists, they are a potential pharmacotherapy for Bariatric surgery may be successful in
hypothalamic obesity. A randomized controlled patients with hypothalamic obesity.8,10 A recent
clinical trial in children and young adults showed retrospective, case-control study from the
evidence that GLP-1 receptor agonists may slow Netherlands showed a mean weight loss of 22%
the rate of weight gain and decrease fat mass in at 5 years in patients with hypothalamic obesity.10
patients with hypothalamic obesity.4 Unfortunately, While this was significantly less than weight loss
patients treated with GLP-1 receptor agonists also in control patients, it is still clinically significant
showed a significant reduction in total daily energy weight loss. Sleeve gastrectomy performed better
expenditure despite simply slowing their rate of than Roux-en-Y gastric bypass.10 The International
weight gain and not having significant weight loss. Registry of Hypothalamic Obesity Disorders
Central nervous system stimulants may be found that only 8% of patients underwent
helpful in treating patients with hypothalamic bariatric surgery but it was most effective with a
obesity.9 Dexamphetamine and methylphenidate median 8.2 kg/m2 decrease in BMI.8 Patients with
are most commonly used in attention-deficit hypothalamic obesity who underwent gastric
disorder and can have a side effect of decreased bypass also reported decreased hunger and cravings.
appetite. Many pediatric patients with hypothalamic
obesity also have attention and/or executive
function deficits, warranting consideration of a
stimulant. There are reports of weight stabilization
and increased daytime wakefulness from

4  ENDO 2022 • Endocrine Case Management

Clinical Case Vignettes Which of the following is the most
likely reason for this patient’s
Case 1 postoperative weight gain?
A 9.5-year-old girl presents to her pediatrician with A. Fluid retention due to diabetes insipidus
headaches that have been worsening for 10 days. B. Hypothalamic obesity due to tissue damage
She has decreased height velocity with steady weight from tumor extension
gain along the 50th percentile. Head imaging shows
C. Increased appetite due to postoperative
a complex mixed cystic and solid suprasellar mass
dexamethasone
(3 × 3 × 3.4 cm) that extends superiorly, effacing
the third ventricle and resulting in obstructive D. Postoperative hypothalamic obesity
hydrocephalus. She is admitted to the hospital, Answer: D) Postoperative hypothalamic obesity
and the tumor is resected surgically. Pathology
findings are consistent with a craniopharyngioma. This patient demonstrates the classic weight gain
She is discharged on hormone replacement for pattern of hypothalamic obesity due to tumor
panhypopituitarism, including diabetes insipidus, treatment with a sharp inflection point in the rate
and a 2-week course of dexamethasone for of weight gain from prediagnosis to posttreatment.
postoperative swelling. One month later, she Complete resection of a large tumor may increase
returns to the endocrine clinic for follow-up. Her the risk of postoperative hypothalamic obesity
parents report that she has experienced increased (Answer D). Other risk factors for hypothalamic
swelling and weight gain since coming home from obesity include her young age and evidence
the hospital. Her clothing size has increased from of endocrine dysfunction at diagnosis (poor
7 to 12. She has increased hunger and is craving of growth rate). She did not have the risk factor of
sweet foods/junk foods that she never ate before. preoperative obesity.
She snacks frequently throughout the day and is Dexamethasone can increase appetite and
hungry again immediately after mealtimes. Her weight gain, but the effects do not continue after
growth chart is shown (see Figure). the medication is discontinued (thus, Answer C
is incorrect).
Hypothalamic obesity due to tumor extension
is often more gradual in onset and the increased
weight gain is evident pretreatment. In this
patient, the rate of weight gain was steady until
the time of diagnosis and intervention (thus,
Answer B is incorrect).
While a small amount of weight gain caused
by fluid retention is possible due to overtreatment
of diabetes insipidus, a weight gain of 10 kg in
6 months cannot be explained by hypervolemia
(thus Answer A is incorrect).
Early recognition of hypothalamic
obesity allows for environmental and dietary
interventions to decrease caloric intake and slow
the rate of weight gain. A visit with a registered
dietitian can help families implement daily caloric
maximums and parent-guided portion sizes. This
patient shows symptoms of hyperphagia such as
increased interest in food and decreased satiety.

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  5

Hyperphagic symptoms should be systematically C. Lifestyle modifications such as a reduced
evaluated at each clinic visit to assess efficacy of calorie diet and increased exercise
interventions. Similar to patients with Prader- D. Reduction in his hydrocortisone dosage to
Willi syndrome, patients with hypothalamic 5 mg/m2 daily
obesity and hyperphagia may benefit from
scheduled meals/snacks. A regular meal/snack Answer: A) Antidiabetes medication with weight-
schedule can help with anxiety around food and loss effects such as a GLP-1 receptor agonist
minimize food-seeking behaviors. For patients
This patient demonstrates evidence of
with food-seeking behaviors such as sneaking food
hypothalamic obesity due to radiation adverse
and nighttime eating, environmental modification
effects. Radiation can be used as adjunctive or
such as locking the pantry/refrigerator and
primary therapy for craniopharyngiomas. Proton
not leaving food and drinks on counters can
radiotherapy provides precise delivery of radiation
be effective. Since hyperinsulinism is common
due to a lower entrance dose and elimination
in hypothalamic obesity, a lower carbohydrate
of the exit dose compared with photon-beam
diet can be beneficial. While this has not been
radiotherapy. While proton radiotherapy is more
evaluated in a well-controlled study, several case
targeted, treatment of suprasellar tumors still
reports demonstrate benefit, typically starting at
confers a risk of postradiation hypopituitarism
less than 50 g of carbohydrates per day.
and hypothalamic obesity. Children are more
sensitive to radiation adverse effects, with about
Case 2 50% of children demonstrating at least 1 pituitary
A 52-year-old man is diagnosed with a hormone deficiency 4 years after treatment.
craniopharyngioma after presenting to his Hypothalamic obesity is most commonly seen
primary care physician with concerns of decreased in patients who receive 51 Gy or more to the
peripheral vision. He is treated with proton hypothalamic region.
radiotherapy. Six months after radiation therapy, Hypothalamic obesity is refractory to
he develops central hypothyroidism and adrenal treatment and aggressive therapy is recommended
insufficiency, managed with levothyroxine and to prevent further weight gain. Lifestyle
hydrocortisone, 8 mg/m2 daily. He does not report modifications (Answer C) are important, but
symptoms of hyperphagia but does describe a 50-lb success is more likely when paired with an
(22.6-kg) weight gain over the past 6 months. His antiobesity medication. Since this patient has
BMI has increased from 26 kg/m2 pretreatment evidence of hyperglycemia, medications such as
to 34 kg/m2 posttreatment. A close diet history GLP-1 receptor agonists (Answer A) and SGLT-2
reveals some increased snacking and decreased inhibitors have the potential to lower his
ability to feel full; for example, he often finishes hemoglobin A1c and support weight loss. While
his children’s leftovers when cleaning up the no medications are approved for treatment of
kitchen. Screening labs are notable for mild mixed hypothalamic obesity, GLP-1 receptor agonists
hyperlipidemia and a hemoglobin A1c value of 6.7% have shown some benefit in a phase 2 clinical
(50 mmol/mol). trial, and they are approved for treatment of
type 2 diabetes and general obesity. SGLT-2
Which of the following would be inhibitors have not been trialed in patients with
the best management strategy for hypothalamic obesity, but their mechanism of
this patient’s weight gain? action, increased glucosuria, is preserved in
A. Antidiabetes medication with weight-loss hypothalamic obesity. These medication classes
effects such as a GLP-1 receptor agonist have extrahypothalamic mechanisms of action and
therefore potential for efficacy in patients with
B. Bariatric surgery
hypothalamic obesity. Antidiabetes medications

6  ENDO 2022 • Endocrine Case Management

that increase weight gain, such as insulin and weight management is recommended as first-
sulfonylureas, should be avoided. line therapy. A tertiary medical center can be
There is no evidence that appropriate necessary for patients with panhypopituitarism
glucocorticoid replacement causes or and hypothalamic obesity due to the increased
worsens hypothalamic obesity, so reducing operative and postoperative complexity of adrenal
his hydrocortisone dosage (Answer D) is not insufficiency and diabetes insipidus. We also
indicated. encourage patients to follow clinicaltrials.gov, as
Bariatric surgery (Answer D) can be effective there are several investigational drugs targeting
in treating hypothalamic obesity, but medical hypothalamic obesity.

References
1. Bulow B, Attewell R, Hagmar L, Malmstrom P, Nordstrom CH, Erfurth EM. 6. Srinivasan S, Ogle GD, Garnett SP, Briody JN, Lee JW, Cowell CT. Features
Postoperative prognosis in craniopharyngioma with respect to cardiovascular of the metabolic syndrome after childhood craniopharyngioma. J Clin
mortality, survival, and tumor recurrence. J Clin Endocrinol Metab. Endocrinol Metab. 2004;89(1):81-86. PMID: 14715831
1998;83(11):3897-3904. PMID: 9814465 7. Roth C, Wilken B, Hanefeld F, Schroter W, Leonhardt U. Hyperphagia in
2. Muller HL, Bueb K, Bartels U, et al. Obesity after childhood children with craniopharyngioma is associated with hyperleptinaemia and a
craniopharyngioma--German multicenter study on pre-operative risk factors failure in the downregulation of appetite. Eur J Endocrinol. 1998;138(1):89-91.
and quality of life. Klin Padiatr. 2001;213(4):244-249. PMID: 11528558 PMID: 9461323
3. Holmer H, Pozarek G, Wirfalt E, et al. Reduced energy expenditure and 8. Rose SR, Horne VE, Bingham N, Jenkins T, Black J, Inge T. Hypothalamic
impaired feeding-related signals but not high energy intake reinforces obesity: 4 years of the International Registry of Hypothalamic Obesity
hypothalamic obesity in adults with childhood onset craniopharyngioma. J Disorders. Obesity (Silver Spring). 2018;26(11):1727-1732. PMID: 30296362
Clin Endocrinol Metab. 2010;95(12):5395-5402. PMID: 20826582 9. Abuzzahab MJ, Roth CL, Shoemaker AH. Hypothalamic obesity: prologue
4. Roth CL, Perez FA, Whitlock KB, et al. A phase 3 randomized clinical and promise. Horm Res Paediatr. 2019;91(2):128-136. PMID: 30884490
trial using a once-weekly glucagon-like peptide-1 receptor agonist in 10. van Santen SS, Wolf P, Kremenevski N, et al. Bariatric surgery
adolescents and young adults with hypothalamic obesity. Diabetes Obes Metab. for hypothalamic obesity in craniopharyngioma patients: a
2021;23(2):363-373. PMID: 33026160 retrospective, matched case-control study. J Clin Endocrinol Metab.
5. Shoemaker AH, Silver HJ, Buchowski M, et al. Energy balance in 2021;106(11):e4734-e4745. PMID: 34265053
hypothalamic obesity in response to treatment with a once-weekly GLP-1
receptor agonist. Int J Obes (Lond). 2022;46(3):623-629. PMID: 34975146

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  7

Electronic Tools to Help
Patients During Their
Weight-Loss Journey
Manpreet S. Mundi, MD. Division of Endocrinology, Diabetes, Metabolism, and Nutrition,
Mayo Clinic, Rochester, MN; E-mail: [email protected]

Learning Objectives where feasible and beneficial. These aids, such as

smartphone applications, can be used to improve
As a result of participating in this session, learners
capture of dietary intake, which is sometimes
should be able to:
significantly underreported through typical dietary
• Discuss the use of electronic tools to assist in recall conducted in the clinical setting. Similarly,
improving dietary capture. patients often overreport their physical activity
levels, and accuracy is improved significantly with
• Review the benefits of devices such as
the use of devices with built-in accelerometers.
smartwatches in terms of physical activity.
Technological aids such as virtual visits,
smartphone applications, and web-based programs
can be used to augment standard cognitive
behavioral therapy in an effort to improve results
Main Conclusions while reducing the time allocated by providers per
The prevalence of obesity continues to rise, with patient.
some estimates predicting that 1 in 2 adults in
the United States will have obesity by 2030. The
association of obesity with higher prevalence
of medical conditions such as diabetes mellitus,
Significance of the
hyperlipidemia, hypertension, obstructive Clinical Problem
sleep apnea, and cancer will have devastating Despite significant efforts to raise awareness and
implications for health care resources. Although develop novel treatment options, the prevalence
we have a plethora of treatment options for of obesity continues to rise. Without significant
managing obesity, including state-of-the art changes in these trends, it is estimated that by
lifestyle modification programs, medications, 2030, close to 1 in 2 adult Americans will have
endoscopic procedures, and bariatric surgery, obesity or have a BMI of 30 kg/m2 or greater
implementation of these strategies can be with the prevalence being higher than 50% in
quite resource-intensive. Additionally, patient 29 states.1 More alarming is the projection that
adherence can be low, leading to suboptimal close to 1 in 4 adults will have severe obesity or a
results, especially for programs that include BMI of 35 kg/m2 or greater. This has devastating
intensive lifestyle modifications. To manage the implications for health care, as obesity is associated
high volume of patients in a cost- and resource- with more than 60 comorbid medical conditions
effective manner, we must dramatically change and increases the risk of at least 12 different types
the way in which we deliver care to patients of cancer.2 Fortunately, we have a plethora of
with obesity with the use of technological aids treatment options available, including several

8  ENDO 2022 • Endocrine Case Management

medications approved by the US FDA with programs. Unfortunately, studies have noted
indications for weight loss, endoscopic procedures, that self-reported questionnaires are largely
and bariatric surgeries. Despite the availability dependent on an individual’s recall and perception
of these modalities, we would all agree that their of their quantity and intensity of physical activity
success is dependent on a strong foundation of and are thus prone to errors from recall bias,
lifestyle modification. Several large randomized, misinterpretation, and social desirability, which
prospective trials have demonstrated that a can be worse in patients with a higher BMI.
combination of caloric restriction, increased Slootmaker et al noted that 301 adults reported a
activity, energy expenditure, and intensive median of 340 minutes of moderate- and vigorous-
cognitive behavior therapy can result in 5% to 7% intensity activity per week while the accelerometer
weight loss, with some individuals achieving much only captured 144 minutes, an overreporting
better results. of 58%.4 Other studies with similar design have
Unfortunately, even though the curriculum also noted overreporting, especially of vigorous-
from these large trials, such as the Diabetes intensity activity, in many cases by as much as
Prevention Program and the Look AHEAD trial, is double of what was actually performed.5
widely available and free to use, implementation in Cognitive behavioral therapy and structured
clinical practice has proven difficult because of lifestyle interventions (which often use frequent
several factors. The biggest limiting factors are the group or individual visits that provide nutrition
resources needed to effectively implement and physical activity education) that rely on
intensive lifestyle modification programs, which behavior change techniques, motivational
often require touch points with a frequency of interviewing, self-monitoring, and accountability,
close to once weekly for the initial weight-loss have been noted to increase physical activity,
period of 3 to 6 months, followed by less frequent reduce sedentary behavior, and improve adherence
visits in weight maintenance periods.3 to dietary interventions, resulting in significant
Additionally, successful reduction in caloric intake weight loss. As an example, the Look AHEAD trial
requires accurate capture of dietary intake and used weekly group and individual counseling
accurate assessment of the caloric content and sessions targeting a caloric goal of 1200 to
portion size of meals. Often, capture of dietary 1800 kcal daily, along with 175 minutes of
intake is conducted through self-reported recall at moderate-intensity activity per week for 6 months
the time of office visits, which depends on the followed by less frequent visits for the next
patient’s ability to remember and willingness to 6 months to achieve an average weight loss of
report. When compared with more accurate 8.6% at 1 year. Unfortunately, these programs
markers such as doubly labeled water, self- can be quite labor- and resource-intensive with
reported dietary intake can be underreported by limited reimbursement, making them difficult to
as much as 37%. Improving the accuracy of dietary implement for most clinical practices.
recall may require ongoing interviews with trained
personnel, patient education, and more accurate
assessment of macronutrient composition and
Barriers to Optimal Practice
volume. These strategies can be quite time
• Accurate dietary and activity capture.
consuming and cost prohibitive for most clinical
practices and may not overcome social and • Patient adherence to lifestyle modification.
psychological determinants of underreporting. • Cost- and resource-prohibitive intensity
Similarly, difficulty with assessing intensity of therapy needed to achieve significant
of activity level can make it difficult for patients weight loss.
to achieve the 150 minutes of moderate- to • Reimbursement for weight-loss programs.
vigorous-intensity activity recommended by most

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  9

Strategies for Diagnosis, wide-angle camera around their neck capturing
an image approximately every 20 seconds.7
Therapy, and/or Management
The use of ongoing image capture reduced
As the prevalence of obesity continues to increase, underreporting of dietary intake to 9% in men
we must innovate and dramatically change the way and 7% in women. Most of this improvement
in which we deliver care for patients with obesity, occurred through capture of unreported food
including implementation of lifestyle modifications intake and misreporting errors. These previous
and intensive cognitive behavioral therapy. This techniques have involved the use of a trained
change initially starts with data capture, especially member of the team to analyze the captured
of dietary intake, activity level, and monitoring images to assess portion sizes and percentage
body weight. Transitioning away from self- consumed, again requiring significant resources
reported dietary intake to point-of-consumption to implement outside of clinical trials. Advances
dietary capture can improve accuracy. Tooze et al in artificial intelligence are allowing for the
evaluated the accuracy of dietary recall with food- development of platforms that can detect the
frequency questionnaires and 24-hour dietary amount of food consumed with similar accuracy
entry compared with doubly labeled water and to that of a dietitian analyzing images and is good
noted that food-frequency questionnaires were to excellent when compared with the weight of
associated with average underreporting of 34% in the tray. Currently, these applications are being
women and 30% in men.6 Use of 24-hour entry tested in the hospital setting where artificial
decreased the underreporting to 17% for women intelligence is used to analyze before and after
and 11% for men. The authors also found that images to capture consumption, and they rely on
social desirability, fear of a negative evaluation, knowledge of the caloric content of the meal.8 As
BMI, eating frequency, and variability of meals per artificial intelligence continues to evolve, we see
day were factors associated with underreporting. advancements being made towards the application
This and other similar trials have demonstrated of this technology to assess dietary intake for food
that although point-of-consumption dietary entry whose caloric content has not been prespecified.
can improve accuracy, it is still dependent on the With physical activity, advancements
patient measuring portion sizes accurately and in wearable device technology combining
entering all of their food intake, which can be accelerometers with sensors continue to add the
biased significantly by a number of factors ranging ability to monitor steps taken, distances traveled,
from education level and nutritional knowledge to heart rate, and energy expenditure. Additional
social desirability, especially the concept that their sensors, including those that measure oxygen
current weight is associated with their intake. As saturation, blood glucose, and the presence
such, we must continue to evaluate technological of arrhythmias, have the potential to increase
improvements such as imaging technology that safe activity for those with significant medical
can improve accuracy of dietary capture. comorbidities. A recent trial that enrolled 40
Imaging technology has been used in clinical patients with known cardiovascular disease
trials in some capacity since the 1980s to better assessed the accuracy of a consumer-grade
define portion sizes and caloric content of meals. smartwatch in measuring heart rate and energy
Many of these studies have used a handheld device expenditure.9 They noted that across variable
to manually capture a patient’s dietary intake. activity levels, the standard deviation of difference
More recently, use of wearable camera-assisted for energy expenditure was within the acceptable
dietary assessment has sought to eliminate the range for clinical practice at 17.5 kcal and the
error associated with manual image capture smartwatch tended to measure a higher value for
and further improve accuracy. In one trial, 40 energy expenditure by approximately 30.47 kcal.
ambulatory participants were asked to wear a Heart rate accuracy was much better. In addition

10  ENDO 2022 • Endocrine Case Management

to more accurate capture, what is more intriguing participants lost weight to some degree, while
is the ability of these devices to decrease sedentary 22.7% experienced more that 10% weight loss.12
behavior and increase activity. In a recent These investigators reported that frequency of
prospective trial, all participants were provided input of body weight, exercise, and dinner along
an activity tracker, with some participants being with baseline BMI were all positively correlated
blinded while others were able to monitor with the amount of weight reduction.
their step count.10 They also randomly assigned
individuals to receive brief feedback sessions to
increase activity. The combination of being able
Clinical Case Vignettes
to monitor their activity combined with brief Case 1
feedback sessions resulted in more than 10% A 44-year-old woman with depression and
increase in activity level. Another trial randomly obesity complicated by type 2 diabetes presents for
assigning individuals to both blinding and assistance with weight loss after recent diagnosis
unblinding of activity measured in a smartphone of diabetes.
app, as well as feedback through text messages, On physical examination, her height is 68.5 in
documented similar results. Patients who were (174 cm), and weight is 202 lb (92 kg) (BMI =
unblinded to their activity level increased their 30.4 kg/m2). She has central adiposity.
number of steps per day by 1024 compared with In her 20s, she reports being able to maintain
those who were blinded, while those who were her weight in the range of 120 to 140 lb (54-64 kg),
unblinded and received feedback through text although she was an avid runner at the time. In her
messages increased their steps by 2534. 30s, her activity level declined significantly because
Similar technological advancements are of knee injuries, rearing young children, and work,
being made in the implementation of cognitive and her weight stabilized in the range of 160 to
behavioral therapy to address many factors 180 lb (73-82 kg). In her 40s, she transitioned to
that lead to patient attrition. The use of virtual a consulting position that required significantly
meetings, which reduces the need to travel for more travel. Her weight gradually increased,
weekly meetings, has been greatly accelerated and depression and diabetes were diagnosed.
during the COVID-19 pandemic and shows Bupropion was prescribed for depression, and she
similar results to in-person sessions. Virtual reports that her mood has been stable for the last
meetings, however, do not reduce provider 3 years. Her diabetes is managed with metformin,
resources used, as equivalent time is needed for 500 mg twice daily, and her last hemoglobin A1c
in-person vs virtual sessions. Thus, there has measurement was 6.2% (44 mmol/mol).
been a movement to replicate many of the key She reports that although she does not capture
components of behavioral therapy and provide her dietary intake, she targets between 1200 and
them in an enhanced manner through initially 1500 calories per day. She describes being active at
web-based interface and now smartphone apps. work, as well as at home with household activities
In a clinical trial, the use of a mobile application such as gardening. She does not engage in any
that allows patients to enter dietary intake and formal exercise.
activity level combined with standard cognitive
behavioral therapy resulted in 3.1% more weight
loss than that achieved by standard therapy alone.11
Weight loss was even more significant in those
who used the application more, which is key
to efficacy of these approaches. A retrospective
analysis of more than 35,000 users of a popular
weight-loss smartphone app noted that 77.9% of

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  11

Which of the following is the again keeping in mind that most individuals tend
most appropriate next step in the to underreport caloric intake.
management of this patient’s obesity? Similarly, lifestyle modifications should be
A. Initiation of second-line therapy for diabetes attempted before adding a second-line agent for
B. Intensive lifestyle program with ongoing diabetes (Answer A) given her current hemoglobin
monitoring of dietary intake and activity level A1c level of 6.2% (44 mmol/mol). There are many
medications now approved for management of
C. Referral to psychiatry for transition to another
diabetes that are either weight neutral or have
therapy for depression
weight-loss properties. Some GLP-1 receptor
D. Very low-calorie diet targeting 600 to agonists also have separate indications for
800 calories per day weight loss and can be quite effective in reducing
Answer: B) Intensive lifestyle program with ongoing caloric intake.
monitoring of dietary intake and activity level
Case 2
In this case, the initial treatment option should
focus on lifestyle modification (Answer B). A 37-year-old woman with a history of bipolar
Patients often underreport caloric intake disorder, posttraumatic stress disorder, tobacco
and overreport activity level. Starting with use (1 pack per day), and obesity complicated by
ongoing capture of her dietary intake through a type 2 diabetes, hypertension, hyperlipidemia,
smartphone application would be ideal, not only to and obstructive sleep apnea seeks help with
ascertain her intake, but also to educate her about weight loss. She began to gain weight in high
the caloric content of the food she is consuming. school and weighed 210 lb (95.3 kg) by the time
Additionally, use of an activity tracking device she graduated. Soon after graduating, she became
can assist with not only more accurate capture but pregnant with her son and reports that she
also facilitate a gradual increase in activity. These gained 60 lb (27.2 kg) during her pregnancy, with
efforts should be combined with an intensive minimal weight loss afterwards. She estimates
lifestyle program that initially meets weekly gaining 20 to 30 lb (9.1 to 13.6 kg) with each of
or biweekly for 3 to 6 months followed by less her 2 subsequent pregnancies and weighed close
frequent meetings. to 300 lb (136 kg) by age 30 years. She tried to lose
Referral to psychiatry for transition to another weight through “countless” programs, including
therapy (Answer C) would not be best next step, as a commercial calorie-counting program, but
her depression is well controlled. Bupropion when her most successful effort was meal replacement
combined with naltrexone has been shown to be whereby she lost 50 lb (22.7 kg) over 6 months in
an effective weight-loss agent.13 her early 30s.
A caloric target of 600 to 800 calories per day On physical examination, her height is 66.1 in
(Answer D) may be too restrictive, especially in (168 cm) and weight is 317 lb (143.8 kg) (BMI =
the setting of underreporting of intake. Based on 51 kg/m2). She has increased neck circumference,
predictive equations such as the Harris-Benedict acanthosis nigricans, and central adiposity.
equation, her caloric needs at her current weight Her diabetes is currently managed
would be approximately 2300 kcal. Thus, it with metformin, 1000 mg twice daily, and
would be appropriate for her to target between liraglutide, 1.8 mg daily. Her last hemoglobin A1c
1600 to 1800 calories per day combined with measurement was 7.9% (63 mmol/mol). She is
increased activity for weight loss. If necessary, not able to tolerate continuous positive airway
further reduction in calories can be attempted if pressure because she feels claustrophobic. She has
inadequate weight loss is achieved with that target, longstanding posttraumatic stress disorder due to

12  ENDO 2022 • Endocrine Case Management

childhood trauma and feels that bipolar disorder is history of childhood trauma often report that
a misdiagnosis. weight issues began at an early age and are more
She currently eats most of her meals outside of likely to have weight-related comorbidities even
the home. She works 2 jobs. On the way to her after controlling for BMI. Victims of childhood
first job, she typically stops for breakfast at a trauma also report lower self-esteem, are more
fast-food restaurant. She then skips lunch, but likely to feel judged by their health care provider,
usually stops for a hot dog or pretzel at a and are less likely to feel they are treated with
convenience store on the way to her second job. respect. Thus, history of childhood trauma, whether
Her evening meal is usually picked up on the way it is physical or sexual abuse, can dramatically
home from her second job. She also reports affect how individuals interact with their health
snacking throughout the day. Her beverage of care providers, including seeking care and being
choice is soda. She does not engage in any formal forthcoming regarding their abuse. Weight can
exercise, but she reports being quite active also be protective, leading to increased failed
at work. attempts at weight loss. Therefore, in addressing
weight loss, it is important to create a
Which of the following is the best next nonjudgmental environment that allows the
step in this patient’s management? patient to openly discuss contributing factors to
A. Add an SGLT-2 inhibitor to improve weight gain. Providers should also solicit a history
glycemic control of trauma, especially in patients with weight gain
B. Initiate dietary restriction targeting 800 kcal at a young age, such as this patient. Patients should
per day be referred to a provider trained in the management
of trauma. Often, management will require
C. Refer her for bariatric surgery (Roux-en-Y
ongoing therapy that may start with addressing
gastric bypass)
mood disorders and trauma, followed by
D. Refer her to psychiatry for evaluation of introduction of concepts focused on weight loss.
posttraumatic stress disorder/bipolar disorder Dietary restriction (Answer B) or addition of a
followed by virtual cognitive behavioral therapy second-line agent for diabetes (Answer A) would
Answer: D) Refer her to psychiatry for evaluation not be the ideal next step in the setting of an
of posttraumatic stress disorder/bipolar disorder unaddressed mood disorder and trauma history.
followed by virtual cognitive behavioral therapy Bariatric surgery (Answer C) can be very
beneficial for patients with class III obesity,
This patient’s weight-loss journey should start by producing significant weight loss, as well as
addressing her childhood trauma (Answer D), as remission of many obesity-related comorbidities
that is most likely a major contributor to weight such as diabetes. However, it is essential to ensure
gain. A recent survey of overweight and obese that patients are medically optimized and that
individuals noted that 36.8% of participants with mood disorders are stable and well managed before
class III obesity (BMI ≥40 kg/m2) reported being a proceeding with surgery.
victim of childhood trauma.14 Persons with a

References
1. Ward ZJ, Bleich SN, Cradock AL, et al. Projected U.S. state-level prevalence 3. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline
of adult obesity and severe obesity. N Engl J Med. 2019;381(25):2440-2450. for the management of overweight and obesity in adults: a report of the
PMID: 31851800 American College of Cardiology/American Heart Association Task Force on
2. Hurt RT, Edakkanambeth Varayil J, Mundi MS, Martindale RG, Ebbert JO. practice guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63(25 Pt
Designation of obesity as a disease: lessons learned from alcohol and tobacco. B):2985-3023. PMID: 24239920
Curr Gastroenterol Rep. 2014;16(11):415. PMID: 25277042

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  13

4. Slootmaker SM, Schuit AJ, Chinapaw MJ, Seidell JC, van Mechelen W. 10. Nanda S, Hurt RT, Croghan IT, et al. Improving physical activity and body
Disagreement in physical activity assessed by accelerometer and self-report in composition in a medical workplace using brief goal setting. Mayo Clin Proc
subgroups of age, gender, education and weight status. Int J Behav Nutr Phys Innov Qual Outcomes. 2019;3(4):495-505. PMID: 31993569
Act. 2009;6:17. PMID: 19320985 11. Spring B, Duncan JM, Janke E, et al. Integrating technology into standard
5. Quinlan C, Rattray B, Pryor D, et al. The accuracy of self-reported physical weight loss treatment: a randomized controlled trial. JAMA Intern Med.
activity questionnaires varies with sex and body mass index. PLoS ONE. 2013;173(2):105-111. PMID: 23229890
2021;16(8):e0256008. PMID: 34379676 12. Chin SO, Keum C, Woo J, et al. Successful weight reduction and maintenance
6. Tooze JA, Subar AF, Thompson FE, Troiano R, Schatzkin A, Kipnis V. by using a smartphone application in those with overweight and obesity. Sci
Psychosocial predictors of energy underreporting in a large doubly labeled Rep. 2016;6:34563. PMID: 27819345
water study. Am J Clin Nutr. 2004;79(5):795-804. PMID: 15113717 13. Khera R, Murad MH, Chandar AK, et al. Association of pharmacological
7. Gemming L, Rush E, Maddison R, et al. Wearable cameras can reduce dietary treatments for obesity with weight loss and adverse events: a systematic
under-reporting: doubly labelled water validation of a camera-assisted 24 h review and meta-analysis. JAMA. 2016;315(22):2424-2434. PMID: 27299618
recall. Br J Nutr. 2015;113(2):284-291. PMID: 25430667 14. Mundi MS, Hurt RT, Phelan SM, et al. Associations between experience
8. Van Wymelbeke-Delannoy V, Juhel C, Bole H, et al. A cross-sectional of early childhood trauma and impact on obesity status, health, as well as
reproducibility study of a standard camera sensor using artificial intelligence perceptions of obesity-related health care. Mayo Clin Proc. 2021;96(2):408-
to assess food items: The FoodIntech Project. Nutrients. 2022;14(1):221. 419. PMID: 33549259
PMID: 35011096
9. Falter M, Budts W, Goetschalckx K, Cornelissen V, Buys R. Accuracy of
Apple Watch measurements for heart rate and energy expenditure in patients
with cardiovascular disease: cross-sectional study. JMIR MHealth UHealth.
2019;7(3):e11889. PMID: 30888332

14  ENDO 2022 • Endocrine Case Management

Update on the Medical
Management of Obesity
David A. D’Alessio, MD. Department of Medicine, Division of Endocrinology, Duke
University Medical Center, Durham, NC; E-mail: david.d’[email protected]

Jonathan E. Campbell, PhD. Department of Medicine, Division of Endocrinology, Duke

University Medical Center, Durham, NC; E-mail: [email protected]

Learning Objectives Significance of the

As a result of participating in this session, learners Clinical Problem
should be able to: Obesity is a worldwide health problem that is
• Identify the individual characteristics that linked to reduced life expectancy and multiple
determine the appropriate weight-loss comorbidities. While the causes of the obesity
intervention. epidemic are multifactorial, they involve some
combination of genetic predisposition with
• Develop a better understanding of the current environmental forces, which are immutable risk
and emerging pharmacological strategies for factors for most people. However, a desire to
weight loss. lose weight is one of the most common patient
concerns in clinical medicine. Excessive adiposity
leads to an increased risk of cardiometabolic
complications, including dyslipidemia,
Main Conclusions hypertension, nonalcoholic steatosis, insulin
resistance, and type 2 diabetes mellitus (T2DM).
• A range of drugs that can cause weight loss is The World Health Organization has reported
now available. a 3-fold increase in the prevalence of obesity in
• Most agents are only modestly effective adults in the last 50 years. Even more concerning
and meet the standard of clinical efficacy is that the rate of obesity in children has
(>5% placebo-corrected weight loss) in half increased nearly 5-fold during the same period,
of patients. foreshadowing how if left unchecked, the current
• Recently developed injectable GLP-1 receptor rates of obesity will continue to accelerate.
agonists show more promise, with average
placebo-corrected weight loss of 10% to 15%. Barriers to Optimal Practice
• Incretin-based drugs in development are likely
to be even more potent. • Lifestyle interventions, primarily diet and
exercise, can lead to clinically meaningful
weight loss in the short term, but success over
periods longer than 1 year is limited.
• Bariatric surgery is currently the most effective
mechanism to produce significant, long-term
weight loss and to reverse obesity-related

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  15

 comorbidities. However, surgery is limited by (40 mg/dL [0.45 mmol/L]), as well as increases
access, scalability, and expense. in HDL cholesterol (5 mg/dL [0.13 mmol/L]).3
• Until recently, available drugs for weight The improvement in these risks factors for
loss had only modest efficacy (~5% placebo- cardiovascular disease increases in proportion to
corrected weight loss). the degree of weight loss, demonstrating a linear
relationship between reductions in adiposity
and improvements in cardiometabolic health.
Moreover, weight reductions of approximately
Strategies for Diagnosis,
8% lower the risk of all obesity-related cancers
Therapy, and/or Management by 16%.4 Thus, even modest reductions in body
The Threat of Obesity weight of 5% (~10 to 15 lb [4.5 to 6.8 kg] in the
to Global Health majority of individuals with obesity) can have a
significant effect on clinical outcomes. However,
Obesity, defined as a BMI greater than 30 kg/m2, given the linear relationship between weight loss
now affects more than half the population of and improvements in health, a common target
the United States. Excess weight places an for weight loss proposed by various associations
enormous mechanical and psychological stress is 10%, with even greater losses in body weight
on individuals, leading to a number of daily associated with improved metabolic outcomes.
burdens, including osteoarthritis, joint and
musculoskeletal pain, impaired body image, low
self-esteem, and depression. These alone greatly Lifestyle Interventions
decrease the quality of life for individuals with Initial actions to combat obesity often start with
obesity. Also of great concern are the numerous lifestyle modifications, including reducing caloric
comorbidities associated with obesity that lead intake through diet modifications and enhancing
to an increased risk of death. It is generally energy expenditure through physical activity.
estimated that 75% to 86% of persons with Diet-alone interventions have the greatest
T2DM have obesity, with the increased adiposity effect on weight loss, with physical activity-
proposed to increase inflammation, cause insulin alone interventions often failing to produce a
resistance, and impair metabolic homeostasis. meaningful decrease in body weight in individuals
The combination of obesity and T2DM produces with obesity.5 The combination of diet and
dyslipidemia, hypertension, coagulation defects, exercise comprises most nonpharmacological
and atherosclerosis, greatly increasing the risk or nonsurgical interventions for the treatment
of cardiovascular disease.1 Finally, obesity has of obesity. Intense lifestyle modifications in the
been estimated to account for 10% to 20% of all setting of clinical trials, where participants often
cases of cancer.2 When considered as a whole, the receive weekly treatment sessions designed to
economic costs of chronic diseases driven by the modify both eating and activity habits, have
risk factor of obesity in the United States has been proven to be effective for weight loss. In this
estimated to be $1.72 trillion, or approximately 9% setting, patients often consume fewer calories
of the gross domestic product. Thus, addressing (1200 to 2000 kcal daily, low-fat diet) and engage
the rising prevalence of obesity is a pressing need. in 150 minutes per week of physical activity.6
Even modest reductions in body weight can These lifestyle interventions lead to 7% reductions
have significant impacts on both health and quality in body weight, sufficient to produce positive
of life. Compared with weight-stable individuals, effects on cardiometabolic outcomes. However,
patients who lose 5% to 10% of their body weight it is important to emphasize that these changes
show reductions in hemoglobin A1c (0.5%), are achieved with organized lifestyle modification
fasting glycemia (20 mg/dL [1.11 mmol/L]), programs that are biased by high attrition
blood pressure (5 mm Hg), and triglycerides

16  ENDO 2022 • Endocrine Case Management

rates and fail to set generalizable outcomes for effect on the obesity problem in the United States.
individuals attempting lifestyle modifications Approximately 250,000 metabolic surgeries are
on their own. This is highlighted by the limited performed annually in the United States, with
efficacy of the organized lifestyle modification about half being Roux-en-Y gastric bypass and
programs when examining the long-term effects. half being vertical sleeve gastrectomy. Given that
Individuals who lose 7% of their body weight more than 30 million American adults have a
while in the program have a high likelihood BMI of 40 kg/m2 or greater, performing bariatric
of rebounding when managing their lifestyle surgery in this population is currently not feasible.
independently, with most study participants This is without considering the population of
returning to their pretrial body weight within 1 the additional 100 million Americans with a BMI
to 2 years. Based on the results of clinical trials, it greater that 30 kg/m2 who qualify as candidates for
seems unlikely that most individuals with obesity metabolic surgery. Moreover, the surgery requires
can maintain a reduced body weight solely with a multidisciplinary team and comes with additional
lifestyle modifications. risks associated with an invasive procedure.
Therefore, while surgical intervention for obesity
Surgical Interventions is tremendously effective with proven durability,
it fails to be an option for most individuals with
Bariatric surgery is an intervention that provides obesity who require weight loss.
effective and sustainable weight loss. Longstanding
eligibility criteria for bariatric surgery are a BMI
greater than 40 kg/m2 or a BMI greater than Pharmacological Interventions
35 kg/m2 in the presence of comorbidities. These Pharmacotherapy for obesity provides a mechanism
criteria have been challenged in recent years with to augment weight loss for individuals who do not
the demonstration that patients with lower BMI reach clinical goals (>5% weight loss) with lifestyle
also benefit from surgery. For example, patients modification alone. Early medications that provided
with T2DM and a BMI of 30 to 35 kg/m2 have weight loss were also found to increase the risk
substantial improvements in glycemic control. of cardiovascular disease, ultimately conferring
Expected weight loss following bariatric surgery is more harm than good for overweight individuals.
between 20% to 30%, depending on starting BMI This led to stricter regulatory oversight, requiring
and the surgical procedure performed. A 10-year current medications to demonstrate significant
follow-up study of 573 patients undergoing efficacy and pass cardiovascular safety concerns.
Roux-en-Y gastric bypass averaged 21% weight Most antiobesity medications target appetite
loss 10 years following the surgery,7 and only 3% through neuronal networks that control food
of the participants regained to within 5% of their intake, which has proven to be an effective way to
preoperative weight 10 years after surgery. In a promote weight loss. A brief overview of current
randomized controlled trial of bariatric surgery obesity drugs is presented below.
compared with intensive lifestyle management,
patients with T2DM who had gastric bypass or Phentermine Plus Topiramate
sleeve gastrectomy lost approximately 25% of Approved in 2012, the combination of phentermine
starting body weight and had 2% reduction of plus topiramate is available for persons with a
hemoglobin A1c, results that were 5-fold greater BMI greater than 30 kg/m2 or a BMI greater than
than in the diet and exercise group.8 Whether 27 kg/m2 with at least 1 weight-related comorbidity.
these effects of bariatric surgery to improve The mechanism for phentermine involves
diabetes are due to mechanisms beyond weight increased norepinephrine activity in the CNS that
loss alone has been debated.9 However, bariatric drives a reduction in food intake. It may also act
surgery is not a realistic means to have a major as a sympathomimetic in the periphery to increase
energy expenditure. Topiramate decreases food

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  17

intake through induction of taste aversion. Maximal liraglutide (1.2/1.8 mg). It is a GLP-1 receptor
dosage (15 mg/92 mg daily) efficacy ranges between agonist that activates satiety centers in the CNS
8.7% and 9.3% placebo-subtracted weight loss in to reduce food intake. In a 56-week clinical trial,
clinical trials, with metabolic improvements in liraglutide 3.0 mg produced between 4% and 5.2%
hypertension, lipids, and fasting glycemia/insulin reductions in placebo-subtracted weight loss.
levels. Common adverse effects include paresthesias, Additional improvements in waist circumference,
dizziness, constipation, insomnia, and anxiety, lipids, hemoglobin A1c, and blood pressure were
which are possibly mitigated with dosage titration. also demonstrated in clinical trials. Liraglutide
3.0 mg has not undergone a cardiovascular
Bupropion and Naltrexone outcomes trial, but liraglutide at the lower dosages
Approved is 2014, the combination of bupropion (1.2/1.8 mg) has shown a 22% reduction in
and naltrexone is available for persons with a cardiovascular death and a 15% reduction in all-
BMI greater than 30 kg/m2 or a BMI greater than cause mortality and is approved for cardiovascular
27 kg/m2 with at least 1 weight-related comorbidity. prevention in adults with T2DM. In clinical
Bupropion inhibits the reuptake of dopamine and trials, liraglutide 3.0 mg produced meaningful
norepinephrine to increase activity in the CNS decreases in blood pressure, LDL cholesterol,
and promote satiety. Naltrexone is an antagonist and triglycerides, along with increases in HDL
of the opioid receptor that inhibits the feedback cholesterol, suggesting a similar effect on
loop on anorexigenic neurons that are activated cardiovascular outcomes. Adverse effects include
by bupropion, enhancing the efficacy. Maximal nausea, vomiting, and gastrointestinal distress that
dosage (360 mg/32 mg) efficacy was 4.8% placebo- can be potentially mitigated with dosage-titration.
subtracted weight loss in clinical trials, with significant
improvements in waist circumference, adiposity, Semaglutide 2.4 mg
and lipids. Common adverse effects include nausea, Approved in 2021, semaglutide 2.4 mg is available
constipation, headache, dizziness, and insomnia. for persons with a BMI greater than 30 kg/m2
or a BMI greater than 27 kg/m2 with at least
Orlistat 1 weight-related comorbidity. Semaglutide is a
Approved in 1999, orlistat is available for persons long-acting GLP-1 receptor agonist that is taken
with a BMI greater than 30 kg/m2 or a BMI greater weekly (liraglutide is taken daily). The mechanism
than 27 kg/m2 with at least 1 weight-related is similar to that of liraglutide 3.0 mg, where
comorbidity. It inhibits gastrointestinal lipase GLP-1 receptor agonism in the CNS promotes
activity, decreasing the absorption of dietary fat by reduction in food intake. Clinical trials showed
up to 30%. During a 2-year randomized, placebo- that semaglutide 2.4 mg produced a 10% to 15%
controlled trial, orlistat (120 mg, 3 times daily) reduction in placebo-subtracted weight loss when
produced 3.1% placebo-subtracted weight combined with behavioral therapy over a 68-week
loss and led to modest improvements in waist period.10 Semaglutide 2.4 mg produced significant
circumference and lipids. Significant adverse improvements in waist circumference, blood
effects include gastrointestinal events and pressure, lipids, and hemoglobin A1c. Cardiovascular
deficiency in fat-soluble vitamins. outcomes trials are ongoing for semaglutide
2.4 mg (expected completion in 2023); however,
Liraglutide 3.0 mg the diabetes drug semaglutide 1.0 mg produced
Approved in 2014, liraglutide 3.0 mg is available significant improvements in major adverse cardiac
for persons with a BMI greater than 30 kg/m2 events. Common adverse effects include nausea
or a BMI greater than 27 kg/m2 with at least and gastrointestinal distress that can be potentially
1 weight-related comorbidity. Liraglutide 3.0 mg mitigated with dosage-titration.
is the high-dosage option of the antidiabetes drug

18  ENDO 2022 • Endocrine Case Management

The Future of Metabolic Cagrilintide Plus Semaglutide, Novo Nordisk
Pharmacology Cargrilintide is a long-acting amylin analogue,
given in combination with semaglutide 2.4 mg.
Tirzepatide, Eli Lilly Both are once-weekly subcutaneous injectables.
Tirzepatide is a multireceptor agonist for both In a phase 1b clinical trial, the combination of
the GLP-1 receptor and the glucose-dependent cargrilintide 2.4 mg and semaglutide 2.4 mg
insulinotropic polypeptide receptor (GIPR). The given for 20 weeks to overweight individuals
metabolic outcomes of tirzepatide were compared (BMI >27 kg/m2) produced a 17.1% reduction in
with those of semaglutide 1.0 mg in a 40-week, body weight, compared with a 9.8% reduction
phase-3 clinical trial in persons with T2DM.11 for semaglutide 2.4 mg alone.12 Native amylin
Semaglutide 1.0 mg produced 6.7% reductions in is cosecreted with insulin and has been shown
body weight, while tirzepatide produced 8.5%, to reduce gastric emptying, inhibit postprandial
11%, and 13.1% weight loss with 5-, 10-, and glucagon secretion, and suppress food intake
15-mg doses, respectively. This resulted in greater in the CNS. Amylin has also been proposed to
reductions in hemoglobin A1c, fasting glycemia, regulate food preferences in the CNS. Given
triglycerides, and VLDL cholesterol when alone to individuals with obesity, high dosages
comparing all doses of tirzepatide to semaglutide. of cargrilintide (4.5 mg) reduced body weight by
All dosages of tirzepatide also produced greater 10.8% over a 26-week period. The mechanism
reductions in waist circumference and BMI. A that drives the additive effects on weight loss
direct comparison to semaglutide 2.4 mg (the with the combination of cargrilintide and
dosage of semaglutide used for obesity alone) has semaglutide remains unknown, but likely stems
not been performed. Cardiovascular outcome from enhanced activation of food suppression in
trials are currently underway and are expected the CNS. There were increased reports of nausea
to be completed in 2024. The mechanism that and vomiting in the combination therapy group
drives weight loss in response to tirzepatide vs the semaglutide alone group, supporting the
remains unresolved. There is a reduction in food notion of additive effects on CNS activity. Overall,
intake, which has been largely attributed to GLP- adverse effects were modestly increased relative
1 receptor agonism. In preclinical models, GIPR to semaglutide 2.4, supporting further pursuit of
agonism has been proposed to engage separate this intervention.
CNS networks that limit the nausea in response
to GLP-1 receptor agonism. From this, it has Glucagon Agonism
been proposed that the combination of GIPR and Currently, the most effective pharmacological
GLP-1 receptor agonism may produce enhanced agents for obesity primarily target the CNS to
efficacy on food intake, but this has yet to be reduce food intake. The combination of reduced
tested in humans. Furthermore, GIPR agonism in food intake along with interventions that enhance
adipose tissue has been shown to enhance insulin energy expenditure may provide additional
sensitivity in a weight-independent manner, efficacy for weight loss. Multiple interests have
potentially increasing the efficacy of tirzepatide pursued glucagon receptor (GCGR) agonism to
on glycemia. Adverse effects are similar to those enhance energy expenditure. Glucagon drives
of GLP-1 receptor agonists, with nausea and numerous catabolic effects in hepatocytes,
gastrointestinal distress being predominant. including enhanced metabolism of carbohydrates,
Dosage escalation over a 12-week period has lipids, and amino acids. There is some evidence to
been shown to be effective in producing a more suggest that glucagon agonism may also enhance
favorable adverse effect profile. thermogenesis in adipose tissue. The notion
that GCGR agonism also enhances endogenous
glucose production is a concern for individuals

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  19

with obesity who are often hyperglycemic or complications. His current weight is 273 lb
present with T2DM. Thus, GCGR agonism has (BMI = 38 kg/m2). Since his wife died 2 years ago,
often been paired with GLP-1 receptor agonism he has been preparing his own meals but eats at
to mitigate the hyperglycemic effects, and in some restaurants half the time. To help him qualify for
cases, triple agonisms for the GCGR, the GLP-1 surgery quickly, you choose medical management.
receptor, and the GIPR are being investigated.
Glucagon/GLP-1 coagonism is often derived Which of the following options
from either engineered peptides with activity at is the best choice?
both receptors or derivatives of oxyntomodulin, A. Dulaglutide
a naturally occurring agonist for both receptors. B. Liraglutide
There are multiple ongoing clinical trials for
C. Semaglutide, injectable
the glucagon/GLP-1 coagonists, with only a
few published results. Many early combinations D. Semaglutide, oral
were discontinued due to unacceptable safety E. Whatever his health insurance will cover
profiles or lack of efficacy. However, some of
Answer: C) Semaglutide, injectable
these compounds have provided impressive
effects on weight loss. Analogue 17 (Altimmune) Injectable semaglutide (Answer C) is the most
is a balanced glucagon/GLP-1 compound that potent medical agent available for weight loss,
produced 10.3% reduction in body weight especially the 2.4 mg dosage. This man needs
over a 12-week period. Cotadutide, a separate aggressive treatment to help him meet his
balance glucagon/GLP-1 agonist, produced 5% surgeon’s criteria for knee replacement. Oral
reduction in body weight over a 52-week period, semaglutide (Answer D), dulaglutide (Answer
and LY3305677, an oxyntomodulin derivative, A), or liraglutide (Answer B) is unlikely to result
produced 6% reduction in body weight over in the 25-lb (11.3-kg) weight loss that it will take
a 12-week period. Thus, individual therapies to lower his BMI to 35 kg/m2. However, with
have varied outcome efficacy. Combinations injectable semaglutide, this degree of weight loss is
with GIPR agonism are also being pursued, with realistic. Unfortunately, GLP-1 receptor agonists
multiple companies investigating GLP-1/GIP/ are very expensive and for long-term treatment,
glucagon triagonists. This combination therapy cost concerns are an important consideration in
has yielded impressive effects on body weight in choosing drugs. However, for the 4 to 6 months
preclinical models, with phase 1 and 2 clinical that this man will require treatment, efficacy is
trials currently ongoing. Overall, the combination probably the deciding factor (thus, Answer E is
of GCGR agonism with GLP-1/GIP activity shows incorrect).
early promising effects on body weight and the
associated metabolic outcomes.
Case 2
A 55-year-old woman is referred for help with
Clinical Case Vignettes weight loss. Her BMI has been greater than
Case 1 30 kg/m2 since the birth of her third child 24 years
ago, and her weight has steadily increased. Her
A 67-year-old man presents for help with weight
current weight is 232 lb (105.2 kg). She has treated
loss. He has degenerative joint disease in both
hypertension and stage 3 chronic kidney disease
knees with limited ability to ambulate and pain
with an estimated glomerular filtration rate of 50
that disturbs his sleep. The orthopedic surgeon
to 60 mL/min per 1.73 m2, but no other major
who is caring for him wants him to achieve a
morbidities. She has tried multiple diets over the
BMI less than 35 kg/m2 because evidence suggests
years with varied success, but these have ultimately
this will decrease his risk for postoperative

20  ENDO 2022 • Endocrine Case Management

not changed her long-term weight trajectory. The most common adverse effects of GLP-1
You decide to treat her with a GLP-1 receptor receptor agonists are gastrointestinal: nausea,
agonist, and the preferred choice on her insurance vomiting, and diarrhea. Patients taking liraglutide
formulary is liraglutide. and semaglutide have also been reported to have
more cholelithiasis and episodes of clinical gall
Which of the following adverse effects bladder disease. GLP-1 receptor agonists are
is LEAST LIKELY to occur with a typically associated with an increase in heart
course of liraglutide, 3.0 mg daily? rate of 3 to 5 beats/min, but greater increases
A. Cholelithiasis have been reported. GLP-1 receptor agonists can
B. Diarrhea cause dehydration, mostly with initiation and
gastrointestinal adverse effects. This can be of a
C. Increased heart rate
sufficient magnitude to cause acute kidney injury,
D. Nephrolithiasis but increased rates of nephrolithiasis have not
E. Vomiting been reported (thus, Answer D is correct).
Answer: D) Nephrolithiasis

References
1. Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with 7. Maciejewski ML, Arterburn DE, Van Scoyoc L, et al. Bariatric surgery and
cardiovascular disease. Nature. 2006;444(7121):875-880. PMID: 17167476 long-term durability of weight loss. JAMA Surg. 2016;151(11):1046-1055.
2. Lauby-Secretan B, Scoccianti C, Loomis D, et al; International Agency for PMID: 27579793
Research on Cancer Handbook Working Group. Body fatness and cancer-- 8. Schauer PR, Bhatt DL, Kirwan JP, et al; STAMPEDE Investigators. Bariatric
viewpoint of the IARC Working Group. N Engl J Med. 2016;375(8):794-798. surgery versus intensive medical therapy for diabetes - 5-year outcomes. N
PMID: 27557308 Engl J Med. 2017;376(7):641-651. PMID: 28199805
3. Wing RR, Lang W, Wadden TA, et al; Look AHEAD Research Group. 9. Yoshino M, Kayser BD, Yoshino J, et al. Effects of diet versus gastric bypass
Benefits of modest weight loss in improving cardiovascular risk factors on metabolic function in diabetes. N Engl J Med. 2020;383(8):721-732. PMID:
in overweight and obese individuals with type 2 diabetes. Diabetes Care. 32813948
2011;34(7):1481-1486. PMID: 21593294 10. Wilding JPH, Batterham RL, Calanna S, et al; STEP 1 Study Group. Once-
4. Look AHEAD Research Group, Yeh H-C, Bantle JP, et al. Intensive weight weekly semaglutide in adults with overweight or obesity. N Engl J Med.
loss intervention and cancer risk in adults with type 2 diabetes: analysis 2021;384(11):989. PMID: 33567185
of the Look AHEAD Randomized Clinical Trial. Obesity (Silver Spring). 11. Frias JP, Davies MJ, Rosenstock J, et al; SURPASS-2 Investigators.
2020;28(9):1678-1686. PMID: 32841523 Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes.
5. Stephens SK, Cobiac LJ, Veerman JL. Improving diet and physical activity N Engl J Med. 2021;385(6):503-515. PMID: 34170647
to reduce population prevalence of overweight and obesity: an overview of 12. Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability,
current evidence. Prev Med. 2014;62:167-178. PMID: 24534460 pharmacokinetics, and pharmacodynamics of concomitant administration
6. Knowler WC, Barrett-Connor E, Fowler SE, et al; Diabetes Prevention of multiple doses of cagrilintide with semaglutide 2.4 mg for weight
Program Research Group. Reduction in the incidence of type 2 diabetes management: a randomised, controlled, phase 1b trial. Lancet.
with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403. 2021;397(10286):1736-1748. PMID: 33894838
PMID: 11832527

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  21

Long-Term Follow-Up
of Bariatric Surgery
in Adolescents
Ilene Fennoy, MD, MPH. Department of Pediatrics, Division of Pediatric Endocrinology,
Diabetes, and Metabolism, New York, NY; E-mail: [email protected]

Learning Objectives improvement in hepatic steatosis, and another has

demonstrated improvement in kidney function
As a result of participating in this session, learners
for patients with abnormalities at baseline.
should be able to:
Both pseudotumor cerebri and obstructive sleep
• Identify clinical implications for long-term apnea improve with weight loss after bariatric
health in adolescents with severe obesity. procedures in adolescents. Although health-
related quality of life (HRQoL) improvements are
• Identify the magnitude of BMI change
well documented, psychiatric disorders are more
expected from bariatric surgical procedures.
variable in their response and frequently require
• Identify the metabolic parameters shown to ongoing postsurgical treatment.
improve postbariatric interventions, as well as Nutritional deficiencies do occur, with low values
how psychopathology problems change. for vitamin B12, iron, and vitamin D frequently
• Identify key nutritional deficiencies known to identified, particularly after Roux-en-Y gastric
occur after bariatric surgery. bypass (RYGB).

Significance of the
Main Conclusions Clinical Problem
Severe obesity in adolescents is associated with
Obesity, defined as a BMI ≥95th percentile, and
comorbidities that increase in prevalence as the
severe obesity, defined as a BMI ≥120% of the 95th
severity of the obesity increases. Bariatric surgery
percentile, has continued to increase among children
results in variable changes in BMI dependent on
aged 2 to 19 years, with recent data demonstrating
the specific surgical procedure performed, but it
an increase from 13.9% between 1999 and 2000 to
leads to an overall average decrease of –13.5 kg/m2
19.3% between 2017 and 2018. The prevalence of
(95% CI, –15.1 to -11.9 kg/m2) 1 year after the
severe obesity increased from 3.6% to 6.1% during
procedure. Weight regain often occurs after
this same period.1 As of 2015/2016, obesity was
bariatric surgery, but patients remain, on average,
present in 20.6% of 12- to 19-year-olds, and severe
significantly below their presurgical weight.
obesity was present in 7.7% of this age group.2
Inconsistency exists in the reporting of
Bariatric surgery in adolescence has become an
comorbidities. Improvements have been shown
expanding intervention to address this rise in
across studies evaluating prediabetes, diabetes,
severe obesity, particularly as recent studies now
dyslipidemia, and hypertension. Additionally,
demonstrate that patients with severe obesity are
at least 1 report has documented biopsy-proven
not always successful with lifestyle interventions.3

22  ENDO 2022 • Endocrine Case Management

 Guidelines from the American Society of baseline BMIs of 52.4, 49.6, and 49.6 kg/m2 for
Metabolic and Bariatric Surgery4 and the American patients undergoing RYGB, adjustable gastric
Academy of Pediatrics5,6 support bariatric surgery banding (AGB), and SG, respectively.12 Four of
as appropriate for adolescents based on the the 23 articles had follow-up of 24 to 36 months,
definition of severe obesity as ≥120% of the 95th but the remaining studies had follow-up limited
percentile in a patient with comorbidities or to approximately 12 months. Mean BMI change
≥140% of the 95th percentile in a patient without at 12 months for all procedures was –13.5 kg/m2
comorbidities. These comorbidities include type (95% CI, –15.1 to –11.9 kg/m2). Mean BMI
2 diabetes, obstructive sleep apnea, nonalcoholic change was –17.2 kg/m2 (95% CI, –20.1 to
fatty liver disease, idiopathic intracranial –14.3 kg/m2) for RYGB; –14.1 kg/m2 (95% CI,
hypertension, orthopedic disease (particularly –17.3 to –11.7 kg/m2) for SG; and –10.5 kg/m2
slipped capital femoral epiphysis and Blount (95% CI, –11.8 to –9.1 kg/m2) for AGB.12 This
disease), gastroesophageal reflux, and hypertension. early meta-analysis described inconsistency
Prevalence of these comorbidities has been shown in reporting of comorbidity definitions and
to increase as the severity of obesity increases.7 resolution in the various studies, and only 1
Adolescents with severe obesity also report low study reported on significant numbers of patients
HRQoL; mental health disturbances; and disordered with comorbidities in which dyslipidemia was
eating encompassing loss-of-control eating, binge moderately improved.
eating, bulimia, and night eating syndrome.4,5 More recently, Pedroso et al provided a
In the adolescent population, frequency of systematic literature review and meta-analysis
surgical procedures, however, has slowly increased through 2016 of weight-loss outcomes in
from 0.8 per 100,000 in 2000 to 2.4 per 100,000 in adolescents and adults younger than 21 years
2009,8 and recently more rapidly to 22.7 per 100,000 from 24 studies spanning follow-up periods of
in 2017.9 Sleeve gastrectomy (SG) has become the 6, 12, 24, and 36 months postoperatively.13 This
most common bariatric procedure in the United study reviewed 1928 patients, of whom 1010
States10 and in adolescents in New York state.11 had AGB, 139 had SG, and 779 had RYGB. The
Outcomes have been described both in terms of observed mean change in BMI at 6 months was
weight loss and resolution of comorbidities over –5.4 kg/m2 (95% CI, –3.0 to –7.8 kg/m2) for
varied periods. AGB, –11.5 kg/m2 (95% CI, –8.8 to –14.2 kg/m2)
for SG, and –18.8 kg/m2 (95% CI, –10.9 to
–26.6 kg/m2) for RYGB. At 24 months, nadir
Barriers to Optimal Practice BMI was –11.69 kg/m2 (95% CI, –10.33 to
–13.04 kg/m2) for AGB and –27.63 kg/m2
• Limited availability of comprehensive
(95% CI, –21.56 to –33.70 kg/m2) for RYGB,
adolescent bariatric surgery programs.
with patients in both groups showing weight
• Poor reimbursement for obesity care. regain by 36 months such that BMI change
• Incomplete long-term follow-up data. from baseline was –10.34 kg/m2 (95% CI, –6.95
to –13.94 kg/m2) for AGB and –15.00 kg/m2
(95% CI, –13.50 to –16.50 kg/m2) for RYGB.
Strategies for Diagnosis, No data were reported for SG at 24 months, but
12-month and 36-month data were similar, with
Therapy, and/or Management
mean BMI change of –13.05 kg/m2 (95% CI,
Outcomes –9.68 to –16.42 kg/m2) for SG at 12 months and
Black et al conducted a meta-analysis in 2013 –13.00 kg/m2 (95% CI, –11.00 to –15.00 kg/m2) at
that evaluated 23 studies including a total of 36 months. Comorbidities were not addressed in
637 patients, ages 12 to 19 years, with reported this review.

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  23

 One author has published 1-year biopsy Inge et al reported 3-year outcomes of RYGB
outcome data on the effect of bariatric surgery in and SG in 242 adolescents from 5 centers in
nonalcoholic steatohepatitis and hepatic fibrosis. the United States.20 Mean BMI was 53 kg/m2
In this study, 20 participants had SG with baseline with a mean decrease of –15 kg/m2 (95% CI,
liver biopsy and repeated biopsy at 12 months.14 –16 to –13 kg/m2) overall at 3 years. The mean
Using histological criteria for grading steatosis, BMI decrease was –15 kg/m2 (95% CI, –17 to
inflammation and portal inflammation, ballooning, –14 kg/m2) in the RYGB group and –13 kg/m2
and fibrosis, the authors were able to demonstrate (95% CI, –15 to –11 kg/m2) in the SG group. At
improvement in all markers of nonalcoholic liver 3 years, only 26% of the patients still had obesity.
disease in association with the SG procedure However, 2% of those undergoing RYGB and
compared with a similar number of patients 4% of those undergoing SG had regained above
undergoing treatment with intragastric weight-loss baseline weight at 3 years. Comorbidities also
devices and 53 nonsurgical weight-loss patients. demonstrated improvement. Of the 96 patients
Only patients who underwent SG experienced with hypertension, 74% had resolution by
significant weight loss, with a decline in weight and 3 years and only 4 incident cases occurred among
BMI of 21.5% and 20.6%, respectively, at 12 months. the 98 patients with normal blood pressure at
Several authors have evaluated pediatric baseline. Of 171 patients with dyslipidemia,
patients with pseudotumor cerebri who 66% had resolution by 3 years without lipid-
underwent bariatric surgery. Follow-up was of 6 lowering medications and only 3 incident cases
to 18 months’ duration with a very small number occurred among the 39 patients without lipid
of patients reported as case reports. Sugerman abnormalities at baseline. Nineteen of 20 patients
et al described 3 adolescents who underwent with type 2 diabetes demonstrated remission
gastroplasty or gastric bypass with resolution at 3 years with a mean hemoglobin A1c value of
of pseudotumor cerebri 1 year after surgery.15 5.3% (34 mmol/mol) and fasting blood glucose
Chandra et al described 1 patient with resolution of concentration of 88 mg/dL (4.9 mmol/L).
6 months after RYGB associated with 43% excess Prediabetes, defined as a hemoglobin A1c value
weight loss16 and Hoang et al described 3 patients, of 5.7% or greater (≥39 mmol/mol) and less than
2 of whom had resolution 18 months after SG.17 6.5% (<48 mmol/mol) or fasting blood glucose
Bariatric surgery has also been reported to concentration of 100 mg/dL or greater (≥5.6 mmol/L)
relieve obstructive sleep apnea in adolescents. Kaar and less than 126 mg/dL (<7.0 mmol/L) occurred
et al identified 81 patients (mean age 16.9 years), in 19 patients at baseline. Prediabetes resolved in
of whom 54% had obstructive sleep apnea based 76% of these patients at 3 years with 1 incident
on an apnea hypopnea index of 5 or greater.18 Only case occurring. Thirty-six of 212 patients (17%)
23 were available for follow-up, of whom 66% had abnormal kidney function at baseline, with 19
had remission 5 months after surgery. Resolution of 22 patients demonstrating resolution at 3 years.
of sleep apnea was not associated with amount Ferritin concentrations were low at baseline in 11
of weight loss during the first year after surgery, of 225 patients (5%) and were low at 3 years in 98
but it was associated with lower presurgical of 171 patients (57%), with a significant increase
weight. Similar results were found by Kalra et al in low concentrations in patients who underwent
in reviewing data of adolescents who underwent either RYGB or SG. Vitamin B12 showed a similar
RYGB with a mean decrease in BMI of 19 kg/m2 significant trend, with 1 of 222 patients (<1%)
6 months after surgery.19 All 10 patients evaluated having low values at baseline and 13 of 160 patients
postoperatively demonstrated improvement or (8%) having low values at 3 years. Low albumin,
resolution of obstructive sleep apnea. folate, and vitamin D at baseline demonstrated no
Data have accumulated regarding 3-year significant change at 3 years. Prevalence of high
outcomes for both RYGB and SG. In 2015, transferrin concentrations at baseline significantly

24  ENDO 2022 • Endocrine Case Management

increased in patients undergoing RYGB but not in Nutritional disorders of vitamin B12, iron deficiency,
patients undergoing SG. and vitamin D insufficiency increased in the
In a nationwide Swedish study of adolescents surgical group compared with the control group.
aged 13 to 18 years who underwent bariatric HRQoL was also evaluated in this Swedish
surgery (RYGB), 81 patients were matched study using the SF-36 short form and the Obesity
against a control group receiving conventional Related Problem Scale.21 The physical summary
therapy and against adults aged 35 to 45 years component of the SF-36 showed improvement
undergoing RYGB.21 Patients were evaluated among adolescents in the domains of physical role
5 years after surgery. Control patients entered the functioning, general health-related perceptions
conventional weight-loss program within 1 month and physical functioning. The physical role
of the bariatric surgery date and were evaluated functioning domain was better in the surgical
5 years later. Baseline BMI was greater in both group than in the control group. Surgical
adolescent and adult surgical patients compared patients also had improvement in weight-related
with BMI in the control group. At 5 years, mean psychosocial problems. Further exploration of
BMI was –13.1 kg/m2 (95% CI, –14.5 to –11.8) in mental health issues in this cohort has demonstrated
adolescents, –12.7 kg/m2 (95% CI, –13.7 to –10.9) similar proportions of patients prescribed
in adults, and +3.3 kg/m2 (95% CI, +1.1 to +4.8) in psychiatric drugs before and after surgery
the control group. Seventy-two percent and 76% compared with the control group.22 Although
of adolescent and adult surgical patients, respectively, treatment for mental health and behavioral
reached a BMI less than 35 kg/m2. Only 7% of the disorders did not differ before surgery, the surgical
control group achieved a BMI less than 35 kg/m2. group received more specialized therapy for a
Thirty-seven percent of adolescents and 40% of mental health disorder after surgery compared
adults no longer had obesity, with only 3% of with the control group. Self-esteem and binge-
the control group achieving this status. Most eating improved in surgical patients, whereas
surgical patients achieved 20% or greater weight mood did not. Binge eating was not related to
loss (69% of adolescents and 85% of adults) while degree of weight loss.22 Zeller reported similar
69% of control patients gained weight. Nadir findings in a cohort of 14 adolescents undergoing
weight occurred at 2 years with similar weight RYGB with improvements in HRQoL overall, but
regain by 5 years in both adolescents and adults, with similar proportions remitting or requiring
approximating a 10% rise over nadir BMI. ongoing psychiatric support 6 years after surgery.23
This Swedish study reported improvement in A systematic review of bariatric surgery
multiple metabolic parameters.21 Measurements procedures in adolescents documented consistent
of glucose homeostasis at 5 years in the surgical improvement in HRQoL at 2 years across multiple
group demonstrated remission of type 2 diabetes studies irrespective of surgical procedure.24
at 5 years in all patients who had diabetes at study Physical functioning most consistently improved,
initiation. At baseline, 27% of the surgical groups with less effectiveness demonstrated for emotional
had prediabetes, which resolved in 86% at 5 years, and mental health functioning. Depressive
and 2 new cases developed. The control group symptoms were most improved at 6 to 9 months
demonstrated a 5-year prevalence of prediabetes with some deterioration thereafter.24
of 16% with 1 new case reported. Dyslipidemia Loss-of-control eating is reported to be more
prevalence decreased in surgical patients from common in obese and overweight adolescents,25
69% to 15%, while the control group manifested with eating disorders being prevalent among
a 5-year prevalence of 73%. The prevalence of adolescents before bariatric surgery.26 Higher
elevated C-reactive protein, alanine aminotransferase, measures of loss-of-control eating are associated
and blood pressure decreased in the surgical group with less successful weight loss.27 However,
and was persistent or increased in the control group. a decrease in loss-of-control eating has been

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  25

associated with weight-loss interventions both surgery, additional data are needed for outcomes at
in a systematic review involving 20 of 21 studies longer time points and with consistent reporting
using behavioral, pharmacotherapy, and surgical across comorbidities.
interventions over variable periods,27 as well
as in the Teen-LABS study. In the Teen-LABS
study, prevalence of loss-of-control eating over
Clinical Case Vignettes
6 years after bariatric surgery declined from 32.4% Case 1
presurgically to 7.9% 1 year after surgery, with a A 10-year-old boy with a history of weight problems
rise to 14.5% 4 years after surgery, then a decline since age 5 or 6 years presents for weight-loss
to 11.5% 6 years after surgery.28 management. His height is 59.0 in (149.8 cm), and
In an 8-year follow-up of 58 of 74 patients weight is 163.8 lb (74.3 kg) (BMI = 33.1 kg/m2
undergoing RYGB, Inge et al reported outcomes of [149% of the 95th percentile). Screening for
patients who had surgery at a mean age of 17 years obesity comorbidities documents that he has low
with a mean presurgery BMI of 58.5 kg/m2.29 At HDL cholesterol. Abdominal ultrasonography
follow-up, mean BMI was 41.7 kg/m2. The shows an enlarged, echogenic liver.
prevalence of hypertension decreased from 47%
to 16%, dyslipidemia from 86% to 38%, and type 2 Which of the following interventions
diabetes from 16% to 2%. Mild anemia was present is most likely to successfully help
in 46%, hyperparathyroidism in 45%, and low this patient lose weight?
vitamin B12 in 16%. A. Lifestyle interventions
B. Bariatric surgery
Conclusion
Answer: B) Bariatric surgery
Currently, data regarding long-term follow-up
of bariatric surgery in adolescents beyond 5 years With respect to lifestyle interventions (Answer A),
are limited to patients who underwent RYBG. Barlow et al recently demonstrated minimal weight
The 3-year outcome data available for SG, the loss at 3 months in patients with severe obesity
most common procedure currently performed, (>120% of the 95th percentile) compared with those
are not as robust as the outcome data for bypass with modest obesity (110% of the 95th percentile),
surgery. From the weight-loss point of view, despite followed by significant weight gain at 12 months
a greater than 10 kg/m2 BMI decline, most patients in patients with severe obesity compared with
still have obesity after bariatric surgery, although weight returning to just below baseline in those
metabolic abnormalities and HRQoL substantially with modest obesity.3 This is in stark contrast to
improve. Nutritional deficiencies noted at baseline bariatric surgery interventions (Answer B) that
for vitamin D, albumin, and folate were noted result in significant weight loss at 12 months.
to be unchanged at 3 years by Inge et al, with
vitamin B12 deficiency increasing after both SG
Case 1 (continued)
and RYGB. Deficiencies of iron, vitamin B12, and
vitamin D have been described 5 years after RYGB. The patient participates in lifestyle interventions
In another study, anemia, low vitamin B12, and over the next 3 years, during which time he is
hyperparathyroidism have been reported 8 years noted to gain weight. His BMI is 47.8 kg/m2 at age
after RYGB. Mental health problems remain in 14 years. He is referred to an adolescent bariatric
patients after bariatric surgery and require ongoing surgery program. Dyslipidemia and an enlarged,
intervention. Although outcomes reported echogenic liver persist, but liver enzyme levels
to date are favorable for both weight loss and are normal. The patient now has mild systolic
comorbidity resolution 3 to 5 years after bariatric hypertension (blood pressure = 132/73 mm Hg

26  ENDO 2022 • Endocrine Case Management

[94th percentile; 78th percentile for age and Case 2
height]). He undergoes vertical SG.
An 8.9-year-old old girl with a history of
progressive obesity since age 3 to 4 years
How much change in BMI is expected
by 1 year after surgery? presents for weight management. Her height is
58.6 in (149 cm), and weight is 128.5 lb (58.3 kg)
A. –6 kg/m2 (BMI = 26.9 kg/m2 [123% of the 95th percentile]).
B. –13 kg/m2 She has a history of Chiari 1 malformation status
C. –18 kg/m2 post suboccipital decompression at age 6 years,
D. –23 kg/m2 migraine headaches, pseudotumor cerebri,
obstructive sleep apnea, chronic abdominal
Answer: B) –13 kg/m2 pain of unknown origin, anxiety, and obsessive-
compulsive behavior. Despite ongoing dietary
Average BMI change after SG is approximately
intervention, family therapy, and psychologic
–13 kg/m2 (95% CI, –11 to –17 kg/m2) (Answer
counseling, her weight continues to rise, and
B),11,12 whereas AGB results in a smaller degree of
she undergoes bariatric surgery at age 10 years.
weight loss and RYGB results in a greater degree
Weight loss after surgery is excellent, with her
of weight loss.11,12,14
BMI declining to 16.23 kg/m2 (34th percentile)
1 year after surgery.
Case 1 (continued)
One year after bariatric surgery, his BMI is Which of the following comorbidities
30.5 kg/m2. would be expected to have resolved at
1 year with successful weight loss?
Three to 5 years after bariatric surgery, A. Anxiety and obsessive-compulsive behavior
his BMI would be expected to fall into B. Obstructive sleep apnea
which of the following ranges? C. Pseudotumor cerebri
A. 35-40 kg/m2 D. A and C
B. >40 kg/m2 E. B and C
C. 30-35 kg/m2 F. All of the above
D. <30 kg/m2
Answer: E) B and C
Answer: C) 30-35 kg/m2
Both pseudotumor cerebri (Answer C) and
Patients usually reach their nadir weight 1 to obstructive sleep apnea (Answer B) have been
2 years after bariatric procedures, with some demonstrated to resolve16 or improve in the first
rebound thereafter.12,14 In this patient, baseline year after surgery.15-18 Mental health issues persist
BMI was 47.8 kg/m2 with a BMI decline of in a significant number of patients and may
–17 kg/m2 at 1 year. Given the rebound that require ongoing psychiatric intervention.
usually occurs and the data suggesting BMI at
3 years is near the BMI at 1 year, one might expect
his BMI to be approximately 30 to 35 kg/m2 Case 2 (continued)
(Answer C) at 3 years. Given her BMI of 16.93 kg/m2 (34th
percentile), should one be concerned that
she has developed an eating disorder?
A. Yes
B. No

ENDO 2022 • Adipose Tissue, Appetite, and Obesity  27

Answer: B) No surgery.26 However, their prevalence typically
decreases postsurgically and, when they remain,
Eating disorders are associated with obesity and they are associated with poor weight loss.27
are common in patients presenting for bariatric

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1. QuickStats: prevalence of obesity* and severe obesity† among persons aged 15. Sugerman HJ, Sugerman EL, DeMaria EJ, et al. Bariatric surgery for severely
2-19 years - National Health and Nutrition Examination Survey, 1999-2000 obese adolescents. J Gastrointest Surg. 2003;7(1):102-108. PMID: 12559191
through 2017-2018. MMWR Morb Mortal Wkly Rep. 2020;69(13):390. PMID: 16. Chandra V, Dutta S, Albanese CT, et al. Clinical resolution of severely
32240130 symptomatic pseudotumor cerebri after gastric bypass in an adolescent. Surg
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Obes. 2020;15(5):e12609. PMID: 31944617 loss among adolescents undergoing bariatric surgery. Surg Obes Relat Dis.
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bariatric surgery guidelines, 2018. Surg Obes Relat Dis. 2018;14(7):882-901. 19. Kalra M, Inge T, Garcia V, et al. Obstructive sleep apnea in extremely
PMID: 30077361 overweight adolescents undergoing bariatric surgery. Obesity Res.
5. Armstrong SC, Bolling CF, Michalsky MP, Reichard KW, Section on 2005;13(7):1175-1179. PMID: 16076986
Obesity, Section on Surgery. Pediatric metabolic and bariatric surgery: 20. Inge TH, Courcoulas AP, Jenkins TM, et al; Teen-LABS Consortium. Weight
evidence, barriers, and best practices. Pediatrics. 2019;144(6):e20193223. loss and health status 3 years after bariatric surgery in adolescents. N Engl J
PMID: 31656225 Med. 2015;374(2):113-123. PMID: 26544725
6. Bolling CF, Armstrong SC, Reichard KW, Michalsky MP. Metabolic 21. Olbers T, Beamish AJ, Gronowitz E, et al. Laparoscopic Roux-en-Y gastric
and bariatric surgery for pediatric patients with severe obesity. Pediatrics. bypass in adolescents with severe obesity (AMOS): a prospective, 5-year,
2019;144(6):e20193224. PMID: 31656226 Swedish nationwide study. Lancet Diabetes Endocrinol. 2017;5(3):174-183.
7. Kelly AS, Barlow SE, Rao G, et al. Severe obesity in children and adolescents: PMID: 28065734
identification, associated health risks, and treatment approaches: a 22. Jarvholm K, Bruze G, Peltonen M, et al. 5-year mental health and eating
scientific statement from the American Heart Association. Circulation. pattern outcomes following bariatric surgery in adolescents: a prospective
2013;128(15):1689-1712. PMID: 24016455 cohort study. Lancet Child Adolesc Health. 2020;4(3):210-219. PMID: 31978372
8. Kelleher DC, Merrill CT, Cottrell LT, Nadler EP, Burd RS. Recent national 23. Zeller MH, Pendery EC, Reiter-Purtill J, et al. From adolescence to young
trends in the use of adolescent inpatient bariatric surgery: 2000 through 2009. adulthood: trajectories of psychosocial health following Roux-en-Y gastric
JAMA Pediatr. 2013;167(2):126-132. PMID: 23247297 bypass. Surg Obes Relat Dis. 2017;13(7):1196-1203. PMID: 28465159
9. Bouchard ME, Tian Y, Linton S, et al. Utilization trends and disparities in 24. White B, Doyle J, Colville S, Nicholls D, Viner RM, Christie D. Systematic
adolescent bariatric surgery in the United States 2009-2017. Child Obes. 2021 review of psychological and social outcomes of adolescents undergoing
[Online ahead of print] PMID: 34647817 bariatric surgery, and predictors of success. Clin Obes. 2015;5(6):312-324.
10. English WJ, DeMaria EJ, Hutter MM, et al. American Society for Metabolic PMID: 26541244
and Bariatric Surgery 2018 estimate of metabolic and bariatric procedures 25. He J, Cai Z, Fan X. Prevalence of binge and loss of control eating among
performed in the United States. Surg Obes Relat Dis. 2020;16(4):457-463. children and adolescents with overweight and obesity: an exploratory meta-
PMID: 32029370 analysis. Int J Eat Disord. 2017;50(2):91-103. PMID: 28039879
11. Humayon S, Altieri MS, Yang J, Nie L, Spaniolas K, Pryor AD. Recent trends 26. Kim RJ, Langer JM, Baker AW, Filter DE, Williams NN, Sarwer DB.
of bariatric surgery in adolescent population in the state of New York. Surg Psychosocial status in adolescents undergoing bariatric surgery. Obes Surg.
Obes Relat Dis. 2019;15(8):1388-1393. PMID: 31262649 2008;18(1):27-33. PMID: 18085345
12. Black JA, White B, Viner RM, Simmons RK. Bariatric surgery for obese 27. Moustafa AF, Quigley KM, Wadden TA, Berkowitz RI, Chao AM. A
children and adolescents: a systematic review and meta-analysis. Obes Rev. systematic review of binge eating, loss of control eating, and weight loss in
2013;14(8):634-644. PMID: 23577666 children and adolescents. Obesity Res. 2021;29(8):1259-1271. PMID: 34227229
13. Pedroso FE, Angriman F, Endo A et al. Weight loss after bariatric surgery in 28. Goldschmidt AB, Khoury J, Jenkins TM, et al. Adolescent loss-of-control
obese adolescents: a systematic review and meta-analysis. Surg Obes Relat Dis. eating and weight loss maintenance after bariatric surgery. Pediatrics.
2018;14(3):413-422. PMID: 29248351 2018;141(1):e20171659. PMID: 29237801
14. Manco M, Mosca A, De Peppo F, et al. The benefit of sleeve gastrectomy 29. Inge TH, Jenkins TM, Xanthakos SA, et al. Long-term outcomes of bariatric
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Pediatr. 2017;180:31-37.e2. PMID: 27697327 up analysis. Lancet Diabetes Endocrinol. 2017;5(3):165-173. PMID: 28065736

28  ENDO 2022 • Endocrine Case Management

ADRENAL
Glucocorticoid-Induced
Adrenal Insufficiency
Alessandro Prete, MD. Institute of Metabolism and Systems Research, University of
Birmingham, Birmingham, United Kingdom; E-mail: [email protected]

Wiebke Arlt, MD, DSc. Institute of Metabolism and Systems Research, University of
Birmingham, Birmingham, United Kingdom; E-mail: [email protected]

Learning Objectives Significance of the

As a result of participating in this session, learners Clinical Problem
should be able to: Glucocorticoid-induced AI is among the most
• Identify patients at higher risk of common causes of cortisol deficiency.1,2 In the
glucocorticoid-induced adrenal insufficiency adult population, 0.5% to 1.8% are long-term
(AI). users of oral glucocorticoids, and the absolute
risk of glucocorticoid-induced AI in this group
• Diagnose and treat glucocorticoid-induced AI. is around 50%.3 Inhaled glucocorticoids are also
an established cause of HPA-axis suppression,
with approximately 8% of patients developing
glucocorticoid-induced AI.3 HPA-axis suppression
Main Conclusions is also common following intraarticular
Synthetic glucocorticoids are widely used for their glucocorticoid administration. Small-scale
antiinflammatory and immunosuppressive actions. studies have shown that up to half of patients
A possible unwanted effect of glucocorticoid can develop some degree of biochemical HPA-
treatment is the suppression of the hypothalamic- axis suppression in the first 2 months following
pituitary-adrenal (HPA) axis, which can lead to injection, but robust data regarding the duration
AI. Factors affecting the risk of glucocorticoid- and clinical consequences of HPA-axis suppression
induced AI include the duration of glucocorticoid in these patients are lacking.3 Glucocorticoid-
therapy, mode of administration, glucocorticoid induced AI is also possible following use of topical
dosage and potency, and concomitant drugs that glucocorticoids, but evidence is mostly anecdotal.
interfere with glucocorticoid metabolism. Signs A mismatch exists between the high
and symptoms of AI can be vague and nonspecific prevalence of “biochemical” glucocorticoid-
and can overlap with those of iatrogenic Cushing induced AI and the reporting of its “clinical”
syndrome and the underlying disorder for which consequences, suggesting potential underdiagnosis
glucocorticoids are prescribed. Glucocorticoid and lack of awareness among clinicians.
therapy should not be completely stopped until Considering the widespread use of glucocorticoids
recovery of adrenal function is verified. When across multiple medical specialties, the number of
glucocorticoid-induced AI is diagnosed or patients potentially exposed to harm is staggering,
suspected, patient education is essential to improve and the lack of a consensus regarding management
clinical outcomes. of glucocorticoid-induced AI contributes to
suboptimal clinical outcomes.

30  ENDO 2022 • Endocrine Case Management

Barriers to Optimal Practice overlap.1 Nonetheless, considering the various
contributing factors can help clinicians establish
• Low specificity of signs and symptoms of the individualized risk for each patient (Figure 1).
glucocorticoid-induced AI. It is important to note, however, that high-quality
evidence is limited.1
• Lack of tools to accurately stratify patients
Systemic glucocorticoids, especially those with
according to their risk of developing
longer half-life and higher potency, are more likely
glucocorticoid-induced AI.
to cause glucocorticoid-induced AI as compared
• Lack of consensus on how to assess with other administration routes because of
adrenal function in patients with suspected the direct negative feedback on the HPA axis.
glucocorticoid-induced AI. Short courses of high-dosage glucocorticoids
(<2 weeks) and pulse therapy (intermittent
intravenous administration over a few days or
Strategies for Diagnosis, weeks) are usually associated with swift recovery
Therapy, and/or Management of adrenal function. The possible exception to
this is the administration of frequently repeated
The risk of developing glucocorticoid-induced AI
short glucocorticoid courses, as regularly used in
is difficult to predict on an individual basis. The
the treatment of asthma and chronic obstructive
glucocorticoid formulation used, dosage, treatment
pulmonary disease and during emetogenic
duration, and time of administration during the
chemotherapy.1
day can affect this risk; there is a great degree of

Figure 1. Likelihood of Clinically Relevant Adrenal Suppression By Systemic and Inhaled Glucocorticoids

Systemic glucocorticoids include oral, intravenous, and intramuscular administration. The risk of developing
glucocorticoid-induced adrenal insufficiency is a continuum, and this chart is a guide only. Clinical judgment is required to
establish the risk on an individual basis.

ENDO 2022 • Adrenal  31

 Inhaled glucocorticoids can enter the systemic • Glucocorticoid-induced AI is possible in patients
circulation via the gastrointestinal tract or direct with cortisol values less than 10.0 μg/dL
absorption from the lungs and can exert negative (<275 nmol/L). Glucocorticoids should be
feedback on the HPA axis. Patients using higher continued (possibly switching treatment
dosages for longer periods, as well as those to a replacement dosage of short-acting
exposed to other glucocorticoids (eg, multiple hydrocortisone [eg, 15 mg hydrocortisone])
courses of rescue treatment for chronic obstructive and adrenal function should be reassessed
pulmonary disease exacerbations) carry the highest over time. Repeated tests include early-
risk of glucocorticoid-induced AI.1,4 morning cortisol and dynamic testing when
The data regarding glucocorticoid-induced results are indeterminate. Dynamic tests
AI associated with intraarticular glucocorticoid include the 250-mcg cosyntropin-stimulation
therapy are limited and heterogeneous. Small-scale test, overnight metyrapone-stimulation
studies identified asymptomatic glucocorticoid- test, or insulin tolerance test. Patients
induced AI in up to 60% of patients in the weeks must be educated on stress-dose coverage
following intraarticular glucocorticoid administration; (sick-day rules).
inflammatory arthropathies and repeated
injections with higher dosages increase this risk.1 HPA-axis recovery in patients with glucocorticoid-
Cases of glucocorticoid-induced AI have been induced AI can take months to years, and 2%
reported after exposure to nasal, intradermal, and to 7% of patients may never recover adrenal
transcutaneous glucocorticoid administration, but function.1 All patients at risk of or with established
short-term administration at the recommended glucocorticoid-induced AI should receive adequate
dosages is generally considered safe. Skin education. Special attention should be paid to:
inflammation, impaired barrier function, the • Increasing patient awareness (including over-
use of occlusive dressings, and the application the-counter drugs containing glucocorticoids
to sites with higher absorption (such as mucous and intraarticular glucocorticoid injections).
membranes, eyelids, and scrotum) affect the rate of
• Measures targeted towards adrenal crisis
systemic absorption with topical use.1
prevention.
In patients at high risk of glucocorticoid-induced
AI, glucocorticoids should not be discontinued until • Sick-day rules (ie, the need to increase the
recovery of the HPA axis is documented. When glucocorticoid replacement dose during
treatment is no longer needed for the underlying illness and other causes of major stress such as
disease in patients taking systemic glucocorticoids, trauma, surgery, childbirth).
the dosage should be gradually tapered to a dose
Strategies to improve clinical outcomes include
of 5 mg prednisolone-equivalent. Early-morning
providing clear information on glucocorticoid
serum cortisol should then be measured to guide
therapy, special situations that may require
management1,4:
adjustment of the glucocorticoid replacement
• Glucocorticoid-induced AI is unlikely in dosage, training on the use of injectable
patients with cortisol values greater than glucocorticoid therapy in emergency situations,
12.7 μg/dL (>350 nmol/L) and glucocorticoids and signs and symptoms of overreplacement and
can usually be discontinued. underreplacement, including those of adrenal
crisis. Patients with glucocorticoid-induced AI
• Glucocorticoid-induced AI is unlikely to be
should receive adequate education regardless of
relevant in basal conditions for patients with
the estimated duration of AI/time to recovery.
cortisol values 10.0 to 12.7 μg/dL (275 to
Patients with glucocorticoid-induced AI should
350 nmol/L). Daily glucocorticoids can be
wear medical alert IDs.
stopped, but the patient should be educated on
stress-dose coverage (sick-day rules).

32  ENDO 2022 • Endocrine Case Management

Clinical Case Vignettes receptor (18 times that of dexamethasone), which
explains the high risk of HPA-axis suppression
Important note: Cortisol cutoffs vary according to the
following repeated systemic absorption. Nonetheless,
cortisol assay used and local practices. The cortisol
cases of glucocorticoid-induced AI have been
values reported in the following cases were measured by
associated with all the medications listed above,
immunoassay (Abbott Alinity). For this immunoassay,
highlighting the importance of closely monitoring
the current cutoff used at our institution for a short
all patients treated with inhaled glucocorticoids.
250-mcg cosyntropin-stimulation test is a 30-minute
Treatment with high dosages of inhaled
cortisol value ≥16.3 μg/dL (≥450 nmol/L).
glucocorticoids put patients at a particularly high risk of
glucocorticoid-induced AI, up to 18.5% (Table 1).1 It
Case 1 is recommended that these patients receive appropriate
A 63-year-old woman is referred by her primary education, including being issued a steroid emergency
care physician because of an early-morning card, and undergo periodic clinical assessment for signs
cortisol value of 1.7 μg/dL (47 nmol/L). She has and symptoms of glucocorticoid-induced AI.5
a 4-month history of unintentional weight loss,
muscle mass loss, and tiredness. Asthma was Table 1. Factors Affecting Risk of Developing
Glucocorticoid-Induced Adrenal Insufficiency in
diagnosed at age 50 years, and she has been on Patients Receiving Inhaled Glucocorticoids
regular inhaled glucocorticoids for many years.
Treatment Treatment with high daily doses of inhaled
dosage glucocorticoids (regardless of treatment
Laboratory test results: duration) increases the risk of glucocorticoid-
induced adrenal insufficiency. High doses are:
ACTH = 6.7 pg/mL (10-60 pg/mL) (SI: 1.47 pmol/L
[2.2-13.2 pmol/L]) • Fluticasone propionate: >500 mcg daily
(adults), >200 mcg daily (children)
Serum cortisol 30 minutes after administration of
250 mcg cosyntropin = 4.0 μg/dL (SI: 110 nmol/L) • Beclometasone dipropionate (standard
particle inhalers): >1000 mcg daily
(adults); >400 mcg daily (children)
Recent pituitary MRI shows normal appearance of
• Beclometasone dipropionate (extra-fine
the hypothalamic-pituitary region. particle inhalers): >400 mcg daily (adults);
>200 mcg daily (children)
Which of the following inhaled • Budesonide: >800 mcg daily (adults);
400 mcg daily (children)
glucocorticoids is most commonly
• Ciclesonide: >320 mcg daily (adults);
associated with adrenal suppression? >160 mcg daily (children)
A. Ciclesonide • Fluticasone furoate: >100 mcg daily (adults)
B. Extra-fine particle beclometasone dipropionate • Mometasone furoate: >400 mcg daily (adults)

C. Fluticasone furoate Treatment Treatment for longer than 6 to 12 months

duration (regardless of the dosage used) increases
D. Fluticasone propionate the risk of glucocorticoid-induced adrenal
insufficiency
Answer: D) Fluticasone propionate Glucocorticoid Fluticasone propionate carries the highest
type risk of causing glucocorticoid-induced
This patient had been treated with inhaled adrenal insufficiency
fluticasone propionate (Answer D) for more than Concomitant • Concomitant use of other exogenous
5 years (initially 250 mcg daily for 2 years, then treatments glucocorticoids (including intermittent
use [eg, rescue glucocorticoids in chronic
500 mcg daily for 2 years, then 1000 mcg daily obstructive pulmonary disease])
for 18 months before being tested). Most cases of • CYP3A4 inhibitors (see Table 3)
glucocorticoid-induced AI in patients using inhaled Other factors • Lower BMI
glucocorticoids have been linked to fluticasone (children)
• Higher adherence to treatment
propionate. This drug has a long half-life (14.4 hours)
Partially based on information from manufactures’ summaries of product
and a strong binding affinity for the glucocorticoid characteristics, Global Initiative for Asthma (2018), British National
Formulary, and British National Formulary for Children.

ENDO 2022 • Adrenal  33

Case 2 Which of the following symptoms
can be found in patients with
An 84-year-old woman is admitted to hospital for
glucocorticoid-induced AI?
COVID-19–related pneumonia. She collapsed at
home and described symptoms of feeling light- A. Easy bruising
headed and fainting with no loss of consciousness; B. Hypoglycemia
she has been having shortness of breath and a C. Fatigue
productive cough for a few days. Secondary AI is D. All of the above
diagnosed during evaluation of hyponatremia:
Answer: D) All of the above
Random cortisol = 1.2 μg/dL (SI: 33 nmol/L)
ACTH = 9 pg/mL (10-60 pg/mL) (SI: 1.98 pmol/L All the signs and symptoms listed can be observed in
[2.2-13.2 pmol/L])
patients with glucocorticoid-induced AI (Answer D).
Cortisol 30 minutes after administration of 250 mcg
cosyntropin = 7.9 μg/dL (SI: 218 nmol/L) A high degree of clinical suspicion is paramount
when there is a history of glucocorticoid exposure.
She has a history of chronic obstructive pulmonary In fact, patients with glucocorticoid-induced
disease treated with beclomethasone dipropionate AI may be asymptomatic, present with varying
inhalers (800 mcg/daily) and steroid injections degrees of symptoms of cortisol deficiency and
into the knee joint every 6 months for the last iatrogenic Cushing syndrome, or present with life-
2 years to treat osteoarthritis. threatening adrenal crisis (Table 2). Importantly,
signs and symptoms of cortisol deficiency and
Cushing syndrome can coexist, depending on
when glucocorticoids are discontinued.
Another element of interest in this case is the
possible cumulative effect of intraarticular and

Table 2. Signs and Symptoms Associated With Glucocorticoid-Induced Adrenal Insufficiency and Adrenal Crisis

Iatrogenic adrenal insufficiency Iatrogenic Cushing syndrome Adrenal crisis

• General malaise • Proximal muscle weakness At least 2 of the following:
• Fatigue • Weight gain and central obesity • Hypotension or hypovolemic
shock
• Weakness • Disproportionate supraclavicular and
dorsocervical fat pads • Nausea or vomiting
• Dizziness (including postural dizziness)
• Facial and upper neck plethora • Severe fatigue
• Gastrointestinal symptoms (nausea, vomiting,
diarrhea, cramps, loss of appetite) • Facial rounding • Fever
• Weight loss • Skin atrophy, easy bruising, red stretch • Impaired consciousness
marks (including lethargy, confusion,
• Hypotension (including postural hypotension)
somnolence, collapse, delirium,
• Acne
• Headaches (usually in the morning) coma, seizures)
• Poor wound healing
• Arthralgias (especially in hand joints)
• Insomnia
• Myalgias
• Increased appetite
• Recurrent respiratory infections with slow recovery
• Irritability, impaired memory, depression
• Alabaster-like, pale skin
• Hypertension
• Poor linear growth (children)
• Abnormal glucose metabolism
• Poor weight gain (children)
• Menstrual irregularities (women)
• Hypoglycemia (more frequent in children)
• Poor linear growth (children)
• Hyponatremia
• Lymphocytosis
• Eosinophilia

34  ENDO 2022 • Endocrine Case Management

inhaled glucocorticoids in causing glucocorticoid- Answer: A) Bolus of intravenous hydrocortisone,
induced AI, emphasizing the potential risks associated 50 to 100 mg, followed by 200 mg hydrocortisone
with their systemic absorption. Patients with infusion/24 h + intravenous fluids
glucocorticoid-induced AI were found to carry a
higher risk of adrenal crisis than patients with other Many cases of adrenal crisis and hospitalization
etiologies of adrenal insufficiency and the most for glucocorticoid-induced AI have been described,
common trigger was infections, as in this case.6,7 A including several deaths.1 In this case, the patient’s
lack of awareness of glucocorticoid-induced AI and random cortisol measurement was less than
the presence of nonspecific signs and symptoms 1 μg/dL (<28 nmol/L) and her ACTH concentration
(which can be mistakenly attributed to other was 6 pg/mL (1.32 pmol/L), suggesting secondary
causes or to the disease for which glucocorticoids AI. This was later confirmed with a short 250-mcg
were prescribed) are likely contributors to the cosyntropin test (30-minute cortisol = 11.9 μg/dL
increased risk of life-threatening adrenal crisis in [329 nmol/L]). It is imperative to remember,
this patient population. however, that diagnostic measures should never
delay treatment (thus, Answer C is incorrect):
a patient with a suspected adrenal crisis must
Case 3 be promptly treated with lifesaving injectable
A 74-year-old woman is admitted to the hydrocortisone and fluid resuscitation.5
emergency department with collapse, vomiting, Continuous intravenous hydrocortisone
diarrhea, and hypotension. infusion should be favored over intermittent bolus
administration in the prevention and treatment of
Laboratory test results: adrenal crisis during major stress (Answer A).8,9
Sodium = 129 mEq/L (136-142 mEq/L) In fact, continuous intravenous hydrocortisone
(SI: 129 mmol/L [136-142 mmol/L]) has been shown to be the only delivery mode that
Plasma osmolality = 272 mOsm/kg (275-295 mOsm/kg) steadily maintains circulating cortisol in the range
(SI: 272 mmol/kg [275-295 mmol/kg]) observed during major stress, while intermittent
Urinary sodium = 107 mEq/L (SI: 107 mmol/L)
bolus administration of hydrocortisone results
She has been receiving steroid injections into the in frequent troughs with lower concentrations,
knee joint every 6 months for the past 2 years thereby potentially exposing patients with adrenal
(methylprednisolone acetate, 40 mg), and she uses insufficiency to periods of underreplacement
a topical steroid (betamethasone valerate, 0.1% (Figure 2) (thus, Answer B is incorrect).9
as required) for psoriasis with psoriatic arthritis.
Adrenal crisis is suspected, and measurement of Case 4
random ACTH and cortisol is requested.
A 63-year-old woman taking oral prednisolone
Which of the following is the for temporal giant-cell arteritis has been tapering
best treatment now? the dosage over a 3-year period, with the aim of
discontinuing treatment. While taking
A. Bolus of intravenous hydrocortisone, 50 to
prednisolone, 4 mg daily, early-morning cortisol is
100 mg, followed by 200 mg hydrocortisone
measured 24 hours after the last dose and is
infusion/24 h + intravenous fluids
documented to be 8.1 μg/dL (223 nmol/L). The
B. Bolus of intravenous hydrocortisone, 100 mg, patient’s regimen is switched from prednisolone to
followed by oral hydrocortisone, 20 mg 3 times twice-daily hydrocortisone (10 mg upon
daily, if the vomiting improves awakening + 5 mg at lunchtime), and a short
C. Intravenous fluids to control the hypovolemia 250-mcg cosyntropin-stimulation test is arranged.
while awaiting ACTH and cortisol results Cortisol 30 minutes after cosyntropin
D. None of the above administration is 14.9 μg/dL (411 nmol/L).

ENDO 2022 • Adrenal  35

Figure 2. Serum Cortisol Following Stress- The borderline result of the cosyntropin-
Dose Hydrocortisone Administration stimulation test suggests that the patient has
and Pharmacokinetic Modeling
sufficient adrenal cortisol reserve in baseline
conditions and is unlikely to require regular daily
glucocorticoid replacement (thus, Answers A and
B are incorrect).10 The patient should be educated
about hydrocortisone administration during major
stress (thus, Answer D is correct and Answer C
is incorrect).

Case 5
A 27-year-old woman has suspected
glucocorticoid-induced AI following multiple
cycles of high-dosage oral dexamethasone
for relapse of Philadelphia-negative acute
lymphoblastic leukemia (fatigue, hypotension,
random cortisol = 4.7 μg/dL [129 nmol/L];
ACTH = <5 pg/mL [<1.10 pmol/L]). She was
discharged from the hospital on twice-daily
hydrocortisone (10 mg + 5 mg) 3 months ago.
The patient also has a history of premature ovarian
insufficiency, and her primary care physician has
recently commenced oral hormone replacement
therapy (estradiol, 2 mg + dydrogesterone,
10 mg). The hematology consultant requested an
Serum cortisol (nmol/L) after hydrocortisone administered orally (Panel
A), intramuscularly (Panel B), as intravenous boluses (Panel C), or as
early-morning cortisol measurement 24 hours
continuous intravenous infusion (Panel D). Linear pharmacokinetic after the last dose of hydrocortisone (13.8 μg/dL
modeling was used to predict the serum cortisol response to initial 50
mg (Panel E) and 100 mg (Panel F) intravenous bolus injections followed [381 nmol/L]) and has referred the patient to the
by continuous intravenous infusion of 200 mg hydrocortisone over 24
hours. Adapted from Prete A et al. J Clin Endocrinol Metab, 2020; 105(7)
endocrinology department for further evaluation.
© Endocrine Society.

Which of the following is the

most appropriate next step?
Which of the following is the best next
step in this patient’s management? A. Reassess adrenal function
A. Continue hydrocortisone and measure early- B. Stop hydrocortisone and discharge
morning cortisol in 3 months C. Stop twice-daily hydrocortisone and advise
B. Restart prednisolone, 4 mg daily, and measure stress dosing only
early-morning cortisol in 3 months D. None of the above
C. Stop twice-daily hydrocortisone and discharge Answer: A) Reassess adrenal function
D. Stop twice-daily hydrocortisone and advise
stress dosing only The patient needs to stop oral hormone
replacement therapy and have her adrenal function
Answer: D) Stop twice-daily hydrocortisone reassessed (Answer A). The estrogen component
and advise stress dosing only increases corticosteroid-binding globulin levels
and consequently total serum cortisol. After
a washout of 6 weeks from oral estradiol, the

36  ENDO 2022 • Endocrine Case Management

result of the short 250-mcg cosyntropin test was, strong CYP3A4 inducers and inhibitors (Table
in fact, abnormal: 3). CYP3A4 is, in fact, the main pathway for the
inactivation of most prescribed glucocorticoids.
Baseline cortisol = 4.1 μg/dL (SI: 113 nmol/L)
30-Minute cortisol = 13.0 μg/dL (SI: 358 nmol/L) Strong CYP3A4 inhibitors (such as antifungal
drugs, clarithromycin, and antiretrovirals) can
The cortisol cutoffs discussed thus far do not increase the systemic exposure to glucocorticoids,
apply to patients treated with high-dosage oral leading to high risk of glucocorticoid-induced
estrogens as part of hormonal contraception AI. Conversely, strong CYP3A4 inducers (such
(oral, intramuscular, or implant), which must be as carbamazepine, phenytoin, rifampicin,
discontinued for at least 6 weeks to allow for an enzalutamide, and mitotane) increase the
unambiguous assessment. Interactions between metabolism of glucocorticoids and can trigger
exogenous glucocorticoids and other drugs are symptoms of cortisol deficiency, including adrenal
potentially relevant for patients at risk of or with crisis, in patients with glucocorticoid-induced AI.
established glucocorticoid-induced AI, chiefly

Table 3. Drug Interactions That Can Affect Patients at Risk of Glucocorticoid-Induced Adrenal Insufficiency

Interaction mechanism with exogenous Possible consequences for patients treated with
Drugs glucocorticoids exogenous glucocorticoids
Oral estrogens Increased corticosteroid-binding globulin levels Increased total serum cortisol levels, which affect the
interpretation of early-morning cortisol and dynamic
testing
CYP3A4 inducers Reduced systemic exposure to synthetic Increased risk of developing signs and symptoms
glucocorticoids of cortisol deficiency (including adrenal crisis) in
patients with underlying glucocorticoid-induced
adrenal insufficiency
CYP3A4 inhibitors Increased systemic exposure to synthetic Increased risk of developing glucocorticoid-induced
glucocorticoids adrenal insufficiency
Megestrol acetate Glucocorticoid activity (binds to the Increased risk of developing glucocorticoid-induced
glucocorticoid receptor) adrenal insufficiency
Medroxyprogesterone acetate Glucocorticoid activity (binds to the Increased risk of developing glucocorticoid-induced
(high dosages) glucocorticoid receptor) adrenal insufficiency

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outcomes in adrenal insufficiency: a multisite survey study. J Clin Endocrinol
Metab. 2021;106(3):e1408-e1419. PMID: 32995875

ENDO 2022 • Adrenal  37

Advances in the
Treatment of Congenital
Adrenal Hyperplasia
Adina F. Turcu, MD, MS. Division of Metabolism, Endocrinology, and Diabetes, University of
Michigan, Ann Arbor, MI; E-mail: [email protected]

Learning Objectives and continuous subcutaneous hydrocortisone

pumps; targeting ACTH excess via CRH receptor
As a result of participating in this session, learners
antagonists, ACTH antibodies, or ACTH receptor
should be able to:
antagonists; and inhibiting enzymes required for
• Describe established and upcoming therapies androgen synthesis.
for patients with classic and nonclassic In parallel with novel therapeutic developments,
congenital adrenal hyperplasia (CAH). growing evidence supports the use of
11-oxyandrogens as indicators of an adrenal vs
• Implement use of traditional and novel
gonadal source, with advantages over traditional
biomarkers for monitoring disease control and
androgens in guiding the management of patients
guiding therapy for patients with classic and
with CAH.
nonclassic CAH.

Significance of the
Main Conclusions Clinical Problem
Treatment of CAH focuses on 2 main aspects: (1) CAH is due to autosomal recessive pathogenic
hormonal replacement for adrenal insufficiency variants in genes encoding enzymes required for
in classic CAH and (2) suppression of adrenal cortisol synthesis. Defects in the gene encoding
androgen excess whenever clinically relevant. steroid 21-hydroxylase (CYP21A2) account for
Since they became available in the 1950s, most CAH cases.1 Severe forms of 21-hydroxylase
glucocorticoids have been the primary tool to deficiency (21-OHD) result in clinically overt
address both CAH treatment goals, with only a adrenal insufficiency and are termed “classic.”
few available preparations. While sufficient for the Milder enzymatic defects, in which both cortisol
treatment of adrenal insufficiency, glucocorticoid and aldosterone synthesis are compensated, are
dosages and timing of administration required termed “nonclassic.” While classic 21-OHD affects
for adrenal androgen suppression are linked to approximately 1 in 15,000 newborns,2 nonclassic
numerous off-target effects. Recent developments 21-OHD is relatively common, occurring in
to advance treatment of patients with CAH have approximately 1 in 1000 White individuals and in
focused on 2 fronts: (1) glucocorticoid delivery up to 1 in 30 individuals of certain ethnicities (eg,
that closely mimics the physiologic circadian Ashkenazi Jewish, Hispanic, and Mediterranean).3
rhythm and (2) nonglucocorticoid strategies to In all cases of 21-OHD, obstructed cortisol
overcome adrenal androgen excess. Examples synthesis prompts ACTH elevations, which,
include modified-release oral glucocorticoids in turn, stimulate adrenal cortical growth and

38  ENDO 2022 • Endocrine Case Management

steroidogenic flux. The combination of ACTH adrenal androgen excess leads to adverse
elevation and 21-OHD favors the overproduction effects typical of iatrogenic Cushing syndrome.
of adrenal androgens. Clinical manifestations of • Lack of reliable biomarkers to guide therapy.
adrenal androgen excess include virilization of
external genitalia in girls with classic 21-OHD,
premature pubarche, rapid somatic growth,
Strategies for Diagnosis,
advanced bone age, hirsutism, acne, irregular
menses, and subfertility.4-7 Sustained ACTH Therapy, and/or Management
elevations also promote the expansion of adrenal Steroid Therapy
rest tissue, such as testicular or ovarian adrenal
In patients with classic 21-OHD, oral
rest tumors.
glucocorticoid regimens aim to distribute
The 2 main treatment goals in 21-OHD are: (1)
diurnal replacement doses, as in any form of
to replace insufficient hormones (glucocorticoids
adrenal insufficiency. For this purpose, short-
and mineralocorticoids, when needed) and (2)
acting hydrocortisone, administered 2 or 3 times
to suppress excessive production of adrenal
daily, offers the lowest risk of glucocorticoid-
androgens. Since their first use in the 1950s, oral
induced adverse effects, and it is preferred
glucocorticoids have been the mainstay of 21-
in children (Table 1). A morning dose of an
OHD therapy. In addition to the typical daytime
intermediate-acting glucocorticoid (prednisone
replacement dosing common to all forms of
or prednisolone), or even a long-acting
adrenal insufficiency, bedtime glucocorticoids are
glucocorticoid (dexamethasone), can be considered
used in patients with 21-OHD to reduce the early-
in patients who prefer to minimize medication
morning rise in ACTH and the consequent adrenal
frequency, or when adherence is challenging. To
androgen excess. Supraphysiologic administration
counteract adrenal androgen excess, a low dose of
of glucocorticoids leads to obesity, dyslipidemia,
intermediate- or long-acting glucocorticoid can be
hyperglycemia, and bone loss.8-13
administered at bedtime.
Another important challenge in managing
21-OHD is the lack of reliable biomarkers to
Table 1. Available Oral Glucocorticoids
guide glucocorticoid dosing. Normalization
of 17α-hydroxyprogesterone can only be Average adrenal Androgen
insufficiency suppression
achieved with excessive glucocorticoid doses Relative replacement bedtime
and consequential iatrogenic Cushing syndrome, Glucocorticoid potency doses doses

which is not a reasonable tradeoff. Moreover, Hydrocortisone 1 15 to 20 mg daily *Not used

(divided in 2 to for this
17α-hydroxyprogesterone, androstenedione, and 3 doses) purpose
testosterone correlate poorly with clinical evidence due to short
half-life
of androgen excess,14,15 in part due to their dual
Prednisolone 4 5 mg in AM 1 to 3 mg
adrenal and gonadal origin. DHEA-S, the major
adrenal androgen precursor, is often paradoxically Prednisone 4 5 mg in AM 1 to 3 mg

low in patients with poorly controlled 21-OHD. Dexamethasone 30 1 mg in AM ≤1 mg

To closely mimic physiologic glucocorticoid

Barriers to Optimal Practice synthesis, and to minimize the adverse effects
of supraphysiologic doses, modified-release
• Limited treatment options beyond glucocorticoid formulations have been developed.
glucocorticoids. Plenadren (Shire Services BVBA, Belgium) is
• Nonphysiologic administration of a dual-release hydrocortisone tablet with an
glucocorticoids to suppress ACTH-driven outer immediate-release coating and an inner
sustained-release core approved in Europe for

ENDO 2022 • Adrenal  39

once-daily administration in patients with adrenal not be used without reliable contraceptive methods
insufficiency, but its use in patients with 21- due to feminization effects on male fetuses.
OHD does not achieve good control of androgen
excess.16 Chronocort (Diurnal Europe B.V., Emerging Nonglucocorticoid
The Netherlands) is a multiparticulate delayed-
release hydrocortisone formulation that provides Therapies
sustained drug delivery and is particularly useful Several therapeutic strategies that target adrenal
for suppressing the early-morning ACTH rise in androgen excess are being developed (Table 2).
patients with 21-OHD.17 Two oral small-molecule inhibitors of the pituitary
Further fine-tuning the delivery of corticotropin-releasing factor type 1 (CRF1)
glucocorticoids could theoretically be achieved receptors are currently in clinical trials:
with continuous intravenous or subcutaneous crinecerfont (Neurocrine Biosciences, Inc, USA)
delivery systems, but data are limited to small and tildacerfont (Spruce Biosciences, USA). By
studies. Like insulin pumps, such systems involve interrupting the signaling communication
relatively complex operational logistics and add between the hypothalamus and pituitary, these
risks, including malfunction and site infections.18,19 agents offer an alternative to bedtime
Patients with nonclassic 21-OHD have glucocorticoids to dampen the morning ACTH
compensated cortisol production and do not need rise. Other strategies to reduce ACTH elevation
replacement therapy. In women with nonclassic include antiACTH monoclonal antibodies21 and
21-OHD who are not interested in conceiving, ACTH receptor antagonists,22 but both are
oral contraceptives help reduce ovarian androgen experimental therapies and have not yet been
production and increase SHBG, which lowers tested in humans.
the fraction of bioavailable and free testosterone. Abiraterone acetate is a potent inhibitor
Spironolactone, primarily a mineralocorticoid of CYP17A1, an enzyme needed for both
receptor antagonist, is also an androgen receptor glucocorticoid and sex-hormone synthesis, and
antagonist at higher dosages, and it can be it is expressed in the adrenal glands and gonads.
added to further treat hirsutism and/or acne. Abiraterone acetate effectively reduces androgen
Spironolactone crosses the placenta, and it should synthesis and has been shown to decrease
mortality in men with castration-resistant prostate

Table 2. Novel Treatment Strategies in CAH

Treatment Administration Advantages Disadvantages

Glucocorticoids Modified-release Twice daily • Oral administration • Potential for iatrogenic
hydrocortisone Cushing syndrome
• Early-morning ACTH
(Plenadren,
suppression
Chronocort)
Subcutaneous Continuous • Close replication of circadian • Continuous device wear
hydrocortisone secretory patterns for ACTH
• Local irritation
infusion and cortisol
• Potential for malfunctioning
• Potential for ultradian pulsatility
replication if a real-time ACTH/ • High fixed costs and
cortisol monitoring is added complexity
Androgen biosynthetic CYP17A1 inhibitors Once daily • Highly effective • Does not lower ACTH
enzyme blockage (abiraterone
• Well-tolerated • Gonadal sex-steroid
acetate)
inhibition
CRH receptor type 1 Crinecerfont, Once daily • Reduce ACTH secretion • Long-term safety data are
antagonists tildacerfont lacking

Reprinted from Turcu AF & Auchus RJ. Curr Opin in Endocrinol Diabetes Obes, 2016; 23(3) © Wolters Kluwer Health, Inc. All rights reserved.

40  ENDO 2022 • Endocrine Case Management

cancer.23-25 In a study of 6 women with poorly More than testosterone, patients with 21-OHD
controlled classic 21-OHD, abiraterone acetate overproduce a set of androgens unique to the
normalized androstenedione when added to adrenal gland, called 11-oxygenated C19 steroids, or
physiologic hydrocortisone and fludrocortisone.26 11-oxyandrogens. Of these, 11β-androstenedione
Because it inhibits the production of gonadal sex is the most abundant, and its downstream
steroids, abiraterone acetate is not a good option metabolite 11-ketotestosterone is a potent
for reproductive-aged patients. Also, by posing androgen, bioequivalent to testosterone.30,31
a second block in the biosynthetic pathway of Higher serum concentrations of 11-oxyandrogens
cortisol, this agent is not sensible in patients with are associated with several clinical indicators of
nonclassic 21-OHD. suboptimal 21-OHD control, including larger
All therapies discussed above are adjunctive to adrenal glands, presence of testicular adrenal rest
glucocorticoid replacement. Future development tumors, and menstrual irregularities.32
of gene-based therapy27,28 has the potential to Serum 11-ketotestosterone assays are now
cure 21-OHD and fully eliminate the need for offered by some commercial laboratories, and its
glucocorticoids. measurement can be useful in cases with discrepant
traditional biomarkers. For example, in men
with 21-OHD, 11-ketotestosterone correlates
Monitoring Therapy
inversely with testosterone, and the former can
In women with 21-OHD, normal concentrations be high when testosterone is normal. In female
of testosterone and androstenedione typically patients with 21-OHD, 11-ketotestosterone and
indicate good disease control, although these testosterone are positively correlated, as they are
steroids correlate poorly with clinical stigmata of both produced primarily in the adrenal gland. In
hyperandrogenism. Disproportionately elevated patients with either classic and nonclassic 21-OHD,
androstenedione suggests suboptimally controlled 11-oxyandrogens are disproportionately higher
21-OHD. Elevated testosterone, however, can be than conventional androgens.33,34 In contrast,
seen in women with 21-OHD and concomitant androstenedione and testosterone concentrations
polycystic ovary syndrome. Excessive adrenal- are similar in patients with nonclassic 21-OHD and
derived progesterone contributes to irregular in those with hyperandrogenism of other etiologies
menses and infertility. In preparation for with similar clinical presentations, including
conceiving, the goal of glucocorticoid therapy is polycystic ovary syndrome.34
to suppress serum progesterone to concentrations
less than 0.6 ng/mL (<2.0 nmol/L), which is
associated with higher fertility rates in women Clinical Case Vignettes
with classic 21-OHD.29 Case 1
In men with 21-OHD, serum testosterone
A 29-year-old woman with nonclassic 21-OHD
concentrations have little value when used in
presents for routine follow-up. Menarche was at age
isolation. In healthy men, testosterone is produced
10 years. She struggles with irregular menses, acne,
primarily by the testes; conversely, uncontrolled
and facial hirsutism. All of her symptoms improved
21-OHD results in larger proportions of adrenal
while taking oral contraceptives. However, she
testosterone. An androstenedione-to-testosterone
stopped oral contraceptives approximately 1 year
ratio greater than 0.5 is suggestive of adrenal
ago when she got married and started trying to
androgen excess. Excessive amounts of adrenal
conceive. The couple met with a genetic counselor,
androgens lead to gonadotropin suppression.
and the husband’s genetic testing shows no
Normal serum testosterone concentrations along
pathogenic CYP21A2 variants. The patient’s only
with suppressed gonadotropins in men with
medication is a prenatal multivitamin.
21-OHD suggest abundant adrenal androgen
production and low gonadal testosterone.

ENDO 2022 • Adrenal  41

Laboratory test results (obtained 7 days after her a low dosage of prednisolone at bedtime (Answer
last menses): D). Prednisolone is preferred over its precursor,
prednisone, because the in vivo activation of
Testosterone = 81 ng/dL (8-60 ng/dL)
(SI: 2.8 nmol/L [0.3-2.1 nmol/L]) prednisone at such low dosages is inconsistent.
Androstenedione = 250 ng/dL (30-200 ng/dL) Studies suggest that hydrocortisone once or
(SI: 8.7 nmol/L [1.05-6.98 nmol/L]) twice daily is also associated with a decreased
DHEA-S = 90 µg/dL (44-333 µg/dL) (SI: 2.44 µmol/L risk of miscarriages in women with nonclassic
[1.19-9.00 µmol/L])
21-OHD.35 However, the mechanism of day-time
Progesterone = 2.0 ng/mL (≤1.0 ng/mL [follicular];
2.0-20.0 ng/mL [luteal]) (SI: 6.36 nmol/L hydrocortisone use in these patients is poorly
[≤3.2 nmol/L (follicular); 6.4-63.6 nmol/L understood. Because hydrocortisone is short acting
(luteal)]) (half-life of approximately 1.5 hours), the potential
17-Hydroxyprogesterone = 1230 ng/dL (<80 ng/dL of bedtime dosing (Answer C) to suppress early-
[follicular]) (SI: 37.3 nmol/L [<2.42 nmol/L])
morning ACTH is negligible.
Serum cortisol = 11.6 µg/dL (5-25 µg/dL)
(SI: 320.0 nmol/L [137.9-689.7 nmol/L]) Bedtime dexamethasone (Answer A) is
ACTH = 61 pg/mL (10-60 pg/mL) (SI: 13.4 pmol/L effective in suppressing the early-morning
[2.2-13.2 pmol/L]) ACTH rise, although it has a higher risk of
off-target adverse effects from nonphysiologic
glucocorticoid exposure. In addition, unlike
Which of the following treatment options
prednisone, prednisolone, and hydrocortisone,
should be recommended for this patient?
dexamethasone is not inactivated by the placental
A. Dexamethasone, 0.25 mg at bedtime 11β-hydroxysteroid dehydrogenase type 2, and
B. Flutamide, 250 mg daily it can suppress the fetal hypothalamic-pituitary-
C. Hydrocortisone, 5 mg at bedtime adrenal axis. Dexamethasone has been used in
D. Prednisolone, 2 mg at bedtime the first trimester of pregnancy in women at
risk for having a baby girl with classic 21-OHD
E. Spironolactone, 50 mg daily
to prevent virilization. Prenatal treatment with
Answer: D) Prednisolone, 2 mg at bedtime dexamethasone is controversial, as the maternal
and fetal risks are considered by many to outweigh
Patients with nonclassic 21-OHD have the benefits.36 In this vignette, the patient’s partner
normal production of glucocorticoids and had no identified CYP21A2 pathogenic variants, so
mineralocorticoids and do not need replacement prenatal treatment with dexamethasone does not
therapy for these hormones. However, to deserve consideration.
maintain normal cortisol synthesis, elevated Spironolactone (Answer E) is a mineral­
ACTH levels are needed to overcome the defective ocorticoid receptor antagonist, and, at high
21-hydroxylase. The combination of elevated dosages, is also an androgen receptor antagonist.
ACTH and 21-hydroxylase insufficiency result Spironolactone can be used in women with
in overproduction of adrenal progesterone and hyperandrogenism of various causes. However,
17α-hydroxyprogesterone, and their diversion spironolactone crosses the placenta and can cause
to formation of adrenal androgens. Limited data feminization of a male fetus. Hence, in reproductive-
suggest that the rates of subfertility are modest aged women, spironolactone must be used in
in women with nonclassic 21-OHD, but the risk conjunction with a reliable contraceptive method.
of early miscarriages is lower in women taking Flutamide (Answer B) is a nonsteroidal
glucocorticoids than in those who do not.35 The androgen receptor antagonist that has been
goal of therapy is to suppress the early rise of used in castration-resistant prostate cancer. Its
ACTH to overcome adrenal progesterone and adverse effects include hepatotoxicity, and it is not
androgen excess. This goal can be achieved with considered safe during pregnancy.

42  ENDO 2022 • Endocrine Case Management

Case 2 women with classic 21-OHD, abiraterone acetate
administered once daily along with hydrocortisone
A 61-year-old woman with classic congenital
replacement decreased circulating androgen
adrenal hyperplasia due to 21-OHD presents to
levels.26 As patients with classic 21-OHD already
establish care after recently relocating. Her medical
require full replacement doses of glucocorticoids,
history also includes type 2 diabetes mellitus,
the concern about interference with cortisol
osteoporosis, dyslipidemia, obesity, obstructive
synthesis by abiraterone is irrelevant. Abiraterone
sleep apnea, anxiety, and insomnia. She currently
also blocks the synthesis of gonadal sex steroids,
takes hydrocortisone, 10 mg in the morning
but this concern is limited to reproductive-aged
and 5 mg at 2 PM, and dexamethasone, 0.25 mg
women and not to postmenopausal women.
at bedtime. She is particularly concerned about
Preliminary data from clinical trials show that
diffuse alopecia and facial hirsutism.
CRF-1 receptor antagonists (Answer B) effectively
Laboratory test results: reduce ACTH and 17-hydroxyprogesterone in
patients with uncontrolled classic 21-OHD.37
ACTH = 190 pg/mL (10-60 pg/mL) (SI: 41.8 pmol/L
[2.2-13.2 pmol/L])
By directly blocking ACTH production, such
17-Hydroxyprogesterone = 4210 ng/dL nonsteroidal oral CRF-1 receptor antagonists
(<51 ng/dL [postmenopausal]) (SI: 127.6 nmol/L offer promising therapeutic advantages over
[<1.55 nmol/L]) supraphysiologic doses and times of administration
Testosterone = 92 ng/dL (8-60 ng/dL) of glucocorticoids.
(SI: 3.2 nmol/L [0.3-2.1 nmol/L])
DHEA-S = <15 μg/dL (15-157 μg/dL)
In this patient, increasing the bedtime dose of
(SI: <0.41 μmol/L [0.41-4.25 μmol/L]) dexamethasone (Answer C) further enhances the
risk of adverse effects, many of which the patient
already experiences (worsening hyperglycemia,
Which of the following treatment osteoporosis, sleep disturbances).
options should be considered next? Spironolactone (Answer A) is a mineral­
A. Add spironolactone, 25 mg daily ocorticoid and androgen receptor inhibitor. Adding
B. Enroll in a clinical trial of a corticotropin- spironolactone to the regimen of a patient with
releasing factor type 1 (CRF-1) receptor androgen excess is a reasonable option, but the
antagonist antiandrogenic effects are relatively modest and
C. Increase bedtime dexamethasone dosage to begin to occur at dosages of at least 100 mg daily.38
0.5 mg nightly
D. Stop dexamethasone and add abiraterone Case 3
acetate A 34-year-old man with classic CAH due to
E. B or D 21-OHD is seen for infertility. He and his wife
have been trying to conceive for about a year. He
Answer: E) Enroll in a clinical trial of a corticotropin- has small bilateral testicular adrenal rest tumors,
releasing factor type 1 (CRF-1) receptor antagonist (B) which have been stable according to recent
or stop dexamethasone and add abiraterone acetate (D) ultrasonography.
Abiraterone (Answer D) is a potent inhibitor His medications include hydrocortisone,
of CYP17A1 (17α-hydroxylase/17,20-lyase), an 10 mg in the morning and 10 mg at 2 PM, and
enzyme required for both cortisol and androgen prednisolone, 2 mg at bedtime.
synthesis. Abiraterone acetate improves survival in On physical examination, the patient is
patients with castration-resistant prostate cancer,23 well virilized. His blood pressure is 102/75 mm Hg,
and it was approved by the US FDA for this and pulse rate is 90 beats/min. His height is
indication in 2018. In a small, open-label study of 68 in (173 cm), and weight is 192 lb (87.1)

ENDO 2022 • Adrenal  43

(BMI = 29.2 kg/m2). Testicular volume is and by the adrenal glands. In men with 21-OHD,
approximately 26 mL bilaterally, and testes are a testosterone-to-androstenedione ratio less than
heterogeneous and firm. 2 is suggestive of suboptimal disease control.
11α-Hydroxyandrostenedione and its bioactive
Laboratory test results: peripheral metabolite, 11-ketotestosterone,
Serum total testosterone = 393 ng/dL are produced in large amounts in patients with
(300-900 ng/dL) (SI: 13.6 nmol/L uncontrolled 21-OHD. 11-Ketotestosterone
[10.4-31.2 nmol/L]) correlates inversely with testosterone in men with
LH = <0.20 mIU/mL (1.0-9.0 mIU/mL)
classic 21-OHD—the excess adrenal androgens
(SI: <0.20 IU/L [1.0-9.0 IU/L])
FSH = <0.20 mIU/mL (1.0-13.0 mIU/mL) suppress gonadotropins and, consequently,
(SI: <0.20 IU/L [1.0-13.0 IU/L]) gonadal testosterone. Thus, the best next step is to
ACTH = 135 pg/mL (10-60 pg/mL) measure gonadotropins and 11-ketotestosterone
(SI: 29.7 pmol/L [2.2-13.2 pmol/L]) (Answer A). While in healthy reproductive-
17-Hydroxyprogesterone = 4100 ng/dL (<220 ng/dL)
aged men, the adrenal contribution to the pool
(SI: 124.2 nmol/L [<6.67 nmol/L])
Androstenedione = 2200 ng/dL (65-210 ng/dL) of circulating testosterone is negligible, the
(SI: 76.8 nmol/L [2.27-7.33 nmol/L]) adrenal component might be significant in men
DHEA-S = 66 µg/dL (65-334 µg/dL) (SI: 1.79 μmol/L with uncontrolled CAH, as in this case, making
[1.76-9.05 μmol/L]) testosterone an unreliable biomarker (thus,
Answer C is incorrect).
Which of the following is the best next Serum 17-hydroxyprogesterone (Answer
step in this patient’s management? B) is useful for the diagnosis of CAH, but its
role in monitoring therapy is limited. A serum
A. Measure gonadotropins and
17-hydroxyprogesterone value in the normal range
11-ketotestosterone
typically indicates glucocorticoid overtreatment
B. Measure serum 17-hydroxyprogesterone and risk for associated adverse effects.39
C. Recommend fertility evaluation for the Testicular adrenal rest tumors develop in up
patient’s wife, as his testosterone concentration to 50% of adolescent boys and men with poorly
is normal controlled classic 21-OHD.13 These tumors
D. Refer for surgery for testicular adrenal rest contribute to male infertility via mass effect, Sertoli-
tumor removal cell and cell damage, and blood flow interruptions.
Intensified glucocorticoid treatment can be helpful
Answer: A) Measure gonadotropins in reducing the size of testicular adrenal rest tumors
and 11-ketotestosterone and restoring fertility, particularly if initiated before
Although this man with classic 21-OHD has a permanent fibrosis develops. Surgical removal
normal testosterone concentration, he most likely can be offered to alleviate pain if intensified
has hypogonadotropic hypogonadism due to glucocorticoid therapy fails, but restoration of
suppression of the hypothalamic-pituitary-gonadal fertility is uncommon.40 This patient had small and
axis by adrenal androgen excess. Testosterone stable testicular adrenal rest tumors, so surgical
and androstenedione are secreted by the gonads removal (Answer D) is not indicated.

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14. Speiser PW, Dupont J, Zhu D, et al. Disease expression and molecular 2016;11(7):e0159867. PMID: 27442248
genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J 32. Turcu AF, Mallappa A, Elman MS, et al. 11-Oxygenated androgens
Clin Invest. 1992;90(2):584-595. PMID: 1644925 are biomarkers of adrenal volume and testicular adrenal rest tumors in
15. Krone N, Braun A, Roscher AA, Knorr D, Schwarz HP. Predicting phenotype 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2017;102(8):2701-2710.
in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 PMID: 28472487
unrelated, well defined patients from southern Germany. J Clin Endocrinol 33. Turcu AF, Nanba AT, Chomic R, et al. Adrenal-derived 11-oxygenated
Metab. 2000;85(3):1059-1065. PMID: 10720040 19-carbon steroids are the dominant androgens in classic 21-hydroxylase
16. Quinkler M, Miodini Nilsen R, Zopf K, Ventz M, Oksnes M. Modified- deficiency. Eur J Endocrinol. 2016;174(5):601-609. PMID: 26865584
release hydrocortisone decreases BMI and HbA1c in patients with primary 34. Turcu AF, El-Maouche D, Zhao L, et al. Androgen excess and diagnostic
and secondary adrenal insufficiency. Eur J Endocrinol. 2015;172(5):619-626. steroid biomarkers for nonclassic 21-hydroxylase deficiency without
PMID: 25656494 cosyntropin stimulation. Eur J Endocrinol. 2020;183(1):63-71. PMID:
17. Mallappa A, Sinaii N, Kumar P, et al. A phase 2 study of Chronocort, 32487778
a modified-release formulation of hydrocortisone, in the treatment of 35. Bidet M, Bellanne-Chantelot C, Galand-Portier MB, et al. Fertility in women
adults with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab. with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase
2015;100(3):1137-1145. PMID: 25494662 deficiency. J Clin Endocrinol Metab. 2010;95(3):1182-1190.
18. Merza Z, Rostami-Hodjegan A, Memmott A, et al. Circadian hydrocortisone 36. Miller WL, Witchel SF. Prenatal treatment of congenital adrenal hyperplasia:
infusions in patients with adrenal insufficiency and congenital adrenal risks outweigh benefits. Am J Obstet Gynecol. 2013;208(5):354-359. PMID:
hyperplasia. Clin Endocrinol (Oxf). 2006;65(1):45-50. PMID: 16817818 23123167
19. Nella AA, Mallappa A, Perritt AF, et al. A phase 2 study of continuous 37. Auchus RJ, Sarafoglou K, Fechner PY, et al. Crinecerfont lowers elevated
subcutaneous hydrocortisone infusion in adults with congenital adrenal hormone markers in adults with 21-hydroxylase deficiency congenital adrenal
hyperplasia. J Clin Endocrinol Metab. 2016;101(12):4690-4698. PMID: hyperplasia. J Clin Endocrinol Metab. 2022;107(3):801-812. PMID: 34653252
27680873 38. Cumming DC. Use of spironolactone in treatment of hirsutism. Cleve Clin J
20. Turcu AF, Auchus RJ. Novel treatment strategies in congenital adrenal Med. 1990;57(3):285-287. PMID: 2357784
hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2016;23(3):225-232. PMID: 39. Silva IN, Kater CE, Cunha CF, Viana MB. Randomised controlled trial of
27032061 growth effect of hydrocortisone in congenital adrenal hyperplasia. Arch Dis
21. Gehrand AL, Phillips J, Malott K, Raff H. A long-acting neutralizing Child. 1997;77(3):214-218. PMID: 9370898
monoclonal ACTH antibody blocks corticosterone and adrenal gene 40. Claahsen-van der Grinten HL, Otten BJ, Takahashi S, et al. Testicular adrenal
responses in neonatal rats. Endocrinology. 2019;160(7):1719-1730. PMID: rest tumors in adult males with congenital adrenal hyperplasia: evaluation
31166572 of pituitary-gonadal function before and after successful testis-sparing
22. Sanders K, Mol JA, Kooistra HS, Galac S. Melanocortin 2 receptor surgery in eight patients. J Clin Endocrinol Metab. 2007;92(2):612-615. PMID:
antagonists in canine pituitary-dependent hypercortisolism: in vitro studies. 17090637
Vet Res Commun. 2018;42(4):283-288. PMID: 30187173

ENDO 2022 • Adrenal  45

Hypercortisolism: A
Challenging Disease to
Diagnose and Manage
Ricardo R. Correa, MD, EdD. Division of Endocrinology, Diabetes, and Metabolism,
Department of Medicine, University of Arizona College of Medicine Phoenix and Phoenix
VAMC, Phoenix, AZ; E-mail: [email protected]

Katherine A. Araque, MD, MSCR. University of Arizona College of Medicine, Phoenix, AZ;
E-mail: [email protected]

Learning Objectives the ability of clinicians to confidently recommend

next steps in management. Part of the problem in
As a result of participating in this session, learners
the diagnosis of Cushing syndrome is that there
should be able to:
are numerous pitfalls in hormonal diagnostic
• Perform the appropriate hormonal workup in assays that often preclude an early and correct
the assessment of hypercortisolism. diagnosis. For example, it is well established that
cortisol measurements by immunoassays can be
• Demonstrate an accurate clinical approach to
thwarted by cross-reactivity with other adrenal
the diagnosis of Cushing syndrome.
steroids (eg, cortisone) and other interferences
inherent to binding-protein concentrations.3
Surgical resection continues to be first-line
therapy for patients with hypercortisolism unless
Main Conclusions precluded by comorbidities. Medical treatment
Hypercortisolism, or Cushing syndrome, can be is usually reserved for patients with persistent or
a challenging diagnosis for clinicians to make. recurrent disease not amenable to curative surgical
It requires some level of expertise from the resection or when the clinical condition precludes
physician and the possibility of repeating tests surgery. Medical treatment is classified in various
several times. For example, in the evaluation of categories: (1) medications that directly affect
endogenous Cushing syndrome, the guideline the ACTH-secreting corticotroph adenoma, (2)
algorithm recommends documenting a positive steroidogenesis inhibitors, and (3) glucocorticoid
result for 2 of 3 tests to diagnose hypercortisolism. receptor antagonists. Finally, a third-line option in
Currently available tests include 24-hour urinary some patients is the use of radiation.
free cortisol measurement, late-night or bedtime The presentation of hypercortisolism varies
salivary cortisol measurement, and the 1-mg from patient to patient and sometimes only 1
dexamethasone-suppression test (DST).1 sign or symptom is present or the characteristics
In contrast, when adrenal hypercortisolism develop very quickly. This complicates the
is suspected, the most accurate test to detect diagnosis and is considered an uncommon
adrenal secretion of cortisol is the 1-mg DST.2 presentation of the disease.
Improving understanding of the utility of current
hypercortisolism diagnostic tests could enhance

46  ENDO 2022 • Endocrine Case Management

 • Inconsistent patient access to multidisciplinary
Significance of the teams, recommended laboratory tests, or
imaging modalities.
Clinical Problem
ACTH-dependent Cushing syndrome is a rare
disorder caused by an ACTH-secreting pituitary Strategies for Diagnosis,
adenoma or other ectopic ACTH-secreting tumor
Therapy, and/or Management
leading to endogenous hypercortisolism. ACTH-
independent Cushing syndrome is usually caused Endogenous Cushing syndrome has a variable
by an adrenal adenoma or, in rare cases, by an clinical presentation.5 Biochemical screening and
adrenocortical carcinoma.1,2 Signs and symptoms diagnostic tests include: (1) late-night or bedtime
can overlap with many other comorbidities such as salivary cortisol measurement (≥2 tests), (2)
obesity, metabolic syndrome, alcohol dependence, overnight 1-mg DST or low-dose 2-day DST, and
or depression. Optimal clinical outcomes require (3) 24-hour urinary free cortisol measurement
a detail-oriented diagnosis, management of (≥2 tests). Current guidelines advocate a
comorbidities, and careful treatment selection. combination of the described tests accounting for
Clinical judgment, index of suspicion, and clinical judgment, index of suspicion, and local test
laboratory and imaging results allow for early availability.3
diagnosis and guide management.3 Despite the After endogenous Cushing syndrome is
advancement of disease awareness, education confirmed, increased plasma ACTH measurements
for early recognition, availability of laboratory (>20 pg/mL [>4.4 pmol/L]) suggest ACTH-
testing, and newer imaging modalities, the mean dependent Cushing syndrome, while values
time to diagnosis is 38 months for patients with between 10 and 20 pg/mL (2.2 and 4.4 pmol/L)
an ACTH-secreting pituitary adenoma, 14 months can also be seen in patients with ACTH-
for patients with an ectopic ACTH-secreting independent Cushing syndrome. Values less than
tumor, and 30 months for adrenal Cushing 5 pg/mL (<1.1 pmol/L) are exclusively seen in
syndrome. Moreover, the time to early diagnosis ACTH-independent Cushing syndrome.
has not improved for recently treated patients in A summary of the recommended testing
comparison with the timelines in studies published modalities to distinguish between Cushing disease
before 2000.4 Ultimately, we need better education and an ectopic ACTH-secreting tumor are as
for nonendocrine and endocrine practitioners follows (Figure):
in pattern recognition of this condition and the • Inferior petrosal vein sampling (IPSS): IPSS
development of a more sensitive and specific test is the gold standard procedure to rule out
to detect hypercortisolism. ectopic ACTH production, particularly
when there are discordant findings from
Barriers to Optimal Practice noninvasive localization tests (pituitary
MRI, corticotropin-releasing hormone
• Physicians’ lack of awareness and insufficient (CRH)–stimulation test, 8-mg DST). IPSS
early recognition of the disease. is an invasive procedure that measures
• Lack of simple and effective biochemical ACTH in pituitary vs peripheral venous
screening approaches and reliance on a drainage. A basal ACTH inferior petrosal
combination of the recommended diagnostic sinus-to-peripheral ratio of 2 or greater or of
tests because of varying sensitivity and 3 or greater after stimulation suggests Cushing
specificity. disease. Prolactin measurements may improve
diagnostic accuracy.6

ENDO 2022 • Adrenal  47

Figure. Algorithm of Recent Consensus on Diagnosis and Management of Cushing Syndrome3

Reprinted from Fleseriu M et al. The Lancet Diabetes & Endocrinology, 2021; 9(12) © Elsevier Ltd. All rights reserved.

48  ENDO 2022 • Endocrine Case Management

• Ovine CRH-stimulation test: Increased plasma Treatment Modalities
ACTH of 35% or more from mean baseline to
The first-line treatment option for Cushing
15 to 30 minutes and increased serum cortisol
syndrome is surgery. Treatment of cortisol-
concentrations of 20% or more from mean
induced comorbidities should also be high priority.
baseline to 30 to 45 minutes after CRH suggest
Medical treatment is usually reserved for patients
Cushing disease.7 Additional protocols with
with persistent or recurrent disease not amenable
CRH or desmopressin administration can aid
to curative surgical resection or when the clinical
the confirmation Cushing disease.8,9
condition precludes surgery. Radiotherapy is
• High-dose (8-mg) DST: Serum cortisol reserved for patients with persistent or recurrent
suppression greater than 69% is observed in Cushing disease after transsphenoidal surgery.
77% of patients with Cushing disease. This test Bilateral adrenalectomy is used in selected patients
has variable accuracy. with persistent or recurrent Cushing disease who
• Pituitary MRI: Dedicated protocols to optimize do not respond to medical therapy.
the detection of pituitary microadenomas that Pharmacologic treatments for Cushing
may not be captured by 1.5T MRI are used. syndrome are classified in various categories:
Examples of these protocols include spoiled (1) medications that directly affect the ACTH-
gradient recalled acquisition echo with 1-mm secreting corticotroph adenoma (only for Cushing
slice intervals, fluid attenuation inversion disease), (2) steroidogenesis inhibitors, and (3)
recovery, T1-weighted turbo spin echo glucocorticoid receptor antagonists (Table).
sequences, and use of 3T and 7T magnets.
Pituitary adenomas smaller than 6 mm require Clinical Case Vignettes
IPSS, while adenomas 10 mm or larger may
not need IPSS if there is agreement with Case 1
additional biochemical localization test results. A 38-year-old woman seeks evaluation for a 30-lb
For 6- to 9-mm lesions, additional research is (14-kg) weight gain during the past year. She
required; however, most experts in a recent walks for 30 minutes daily and follows a healthy
consensus guideline advocated IPSS to confirm diet. Medical history is relevant for type 2 diabetes
the diagnosis in this situation.3 mellitus treated with metformin. Over the past
6 months, her hemoglobin A1c level has increased
Biochemical localization studies must be
from 6.5% to 8.0% (48 to 64 mmol/mol). Glipizide
performed while the patient is hypercortisolemic.
has been added to her treatment plan.
When results of noninvasive tests suggest Cushing
On physical examination, her blood pressure
disease, IPSS does not need to be performed.10
is 150/90 mm Hg, pulse rate is 75 beats/min,
Clinical presentation in combination with the
temperature is 98.4°F (37°C), and respiratory rate is
described test results determines diagnosis and
18 breaths/min. Her height is 65 in (165 cm), and
management. In cases where testing is suggestive of
weight is 220 lb (100 kg) (BMI = 36.6 kg/m2). She
ectopic ACTH-secreting tumors, combination
has erythematous, rounded facies, and prominent
of anatomical (CT and/or MRI) and functional
fat deposition in the supraclavicular area.
(68Ga-DOTATATE) imaging aids tumor
localization. Laboratory test results (after fasting 8 hours):
After biochemical confirmation of ACTH-
Hemoglobin A1c = 9.0% (4.0%-5.6%) (75 mmol/mol
independent Cushing syndrome, CT with adrenal
[20-38 mmol/mol])
protocol is the best next diagnostic step (Figure). Sodium = 137 mEq/L (136-142 mEq/L)
(SI: 137 mmol/L [136-142 mmol/L])
Potassium = 3.3 mEq/L (3.5-5.0 mEq/L)
(SI: 3.3 mmol/L [3.5-5.0 mmol/L])

ENDO 2022 • Adrenal  49

Table. Summary of Pharmacologic Medical Treatment Options for Cushing Syndrome

Agent Mechanism of Action Dosage Common adverse events FDA approval

Adrenal steroidogenesis inhibitors
Ketoconazole CYP11B1, CYP17 400 to 1600 mg daily every Hepatic dyscrasia, gastrointestinal No
inhibitor; requires acid 8 to 12 hours distress, male hypogonadism, drug
for biological activity interactions
Levoketoconazole CYP11B1, CYP17, and 150 to 600 mg every 12 Nausea, headache, peripheral No
CYP21A2 inhibitor hours edema, hypertension
Metyrapone CYP11B1 inhibitor; 500 mg to 6 g daily every 6 Gastrointestinal distress, hirsutism, No
variable access to 8 hours hypertension, hypokalemia
Mitotane Adrenolytic 250 mg to 8 g daily divided Gastrointestinal distress, Adrenocortical
every 6 to 8 hours central nervous system toxicity, cancer
gynecomastia, low white blood cell
count, high free T4, transaminitis,
high corticosteroid-binding globulin,
drug interactions, teratogenic
Etomidate CYP11B1 inhibitor Intravenous; validated Myoclonus, thrombophlebitis, No
intensive care unit protocols hypnotic effects
Osilodrostat CYP11B1 inhibitor Starting dosage of 1 mg Nausea, headache, adrenal Yes
twice daily in patients of insufficiency, QT prolongation,
Asian descent hirsutism
Starting dosage of 2 mg
twice daily in patients of
nonAsian descent
Maximum dosage: unlimited
Most patients require 4 to
14 mg total daily dose
Medications that target the pituitary tumor
Pasireotide Somatostatin analogue 600 to 900 mcg Hyperglycemia, bradycardia, Yes
(SSTR5); affinity for subcutaneous every QTc prolongation, transaminitis,
SSTR1, 2, 3, and 5, but 12 hours or LAR 10 to cholelithiasis, hypopituitarism
particularly for SSTR5 30 mg intramuscularly
Drug interactions (cyclosporin,
every 28 days
bromocriptine)
Cabergoline Dopamine agonist 1.5 to 7.0 mg weekly Transaminitis, cardiac valvular Yes
(DR2) (divided into 2 doses twice fibrosis, hypertension,
a week) gastrointestinal distress,
headaches, behavioral
abnormalities
Retinoic acid/ POMC downregulation Retinoic acid, 10 to 80 mg Liver injury, conjunctival irritation, No
isotretinoin daily, and isotretinoin, 20 to mucositis, arthralgia, transient
80 mg daily diarrhea
NOT CONSENSUS
GUIDELINES
R-roscovitine Selective inhibitor of 400 mg twice daily, 4 days Teratogenic, gastrointestinal No
the cyclin-dependent per week distress, hypokalemia
NOT CONSENSUS
kinase 2 (CDK-2)/cyclin
GUIDELINES
E signaling pathway
Glucocorticoid receptor antagonists
Mifepristone Glucocorticoid and 300 to 1200 mg daily Adrenal insufficiency, hypokalemia, Yes, in patients
progesterone receptor (but do not exceed 20 mg/kg vaginal bleeding, QTc prolongation, with type 2
antagonist per day) drug interactions diabetes mellitus
or glucose
intolerance
Relacorilant Glucocorticoid receptor 100 to 400 mg daily Back pain, headaches, peripheral No
antagonist edema, gastrointestinal distress,
NOT CONSENSUS
dizziness
GUIDELINES

50  ENDO 2022 • Endocrine Case Management

 Calcium = 8.8 mg/dL (8.2-10.2 mg/dL) adrenal CT (Answer D) or pituitary MRI (Answer
(SI: 2.2 mmol/L [2.1-2.6 mmol/L]) E), but neither is a first step in diagnosis.
Glucose = 187 mg/dL (70-99 mg/dL)
(SI: 0.04 mmol/L [3.9-5.5 mmol/L])
Creatinine = 0.8 mg/dL (0.6-1.1 mg/dL) Case 2
(SI: 70.7 µmol/L [53.0-97.2 µmol/L])
Total cholesterol = 300 mg/dL (<200 mg/dL) A 34-year-old man with a history of superior
(SI: 7.77 mmol/L [<5.18 mmol/L] sagittal venous thrombosis, recurrent deep venous
TSH = 1.2 mIU/L (0.5-5.0 mIU/L) thrombosis (treated with apixaban), hypertension,
Estimated glomerular filtration rate = >60 mL/min type 2 diabetes mellitus, 70-lb (31.8-kg) weight
per 1.73 m2 (>60 mL/min per 1.73 m2)
gain over 5 months, and fatty liver is referred for
additional workup.
Which of the following is the most
Laboratory test results:
appropriate next diagnostic step?
A. Measure late-night salivary cortisol Urinary free cortisol = 220 µg/24 h (4-50 µg/24 h)
(SI: 607.2 nmol/d [11-138 nmol/d])
B. Measure morning ACTH Repeated measurement = 200 µg/24 h
C. Measure random serum cortisol (SI: 552 nmol/d)
Late-night salivary cortisol (by liquid
D. Perform adrenal CT chromatography/mass spectrometry) = 0.42 µg/dL
E. Perform pituitary MRI (<0.13 µg/dL) (SI: 11.59 nmol/L [<3.6 nmol/L])
Repeated measurement = 0.53 µg/dL
Answer: A) Measure late-night salivary cortisol (SI: 14.62 nmol/L)
ACTH = 60 pg/mL (10-60 pg/mL) (SI: 13.2 pmol/L
Late-night salivary cortisol concentrations [2.2-13.2 pmol/L])
(Answer A) are thought to correlate with level 8-mg DST = serum cortisol suppression by 87% with
of free circulating plasma cortisol. An increase in therapeutic dexamethasone levels
blood cortisol is reflected by a change in the salivary Pituitary 1.5T MRI reveals no pituitary adenoma.
cortisol concentration within a few minutes.
Several factors may lead to false-positive results: Which of the following is the best next step?
• Disruption of normal circadian rhythm in A. Dexamethasone/CRH-stimulation test
patients with depression or in shift workers B. DST (1 mg)
• Licorice, chewing tobacco, contamination C. IPSS
from bleeding gums/recent tooth brushing, or D. Repeated pituitary MRI
cigarette smoking may cause elevated late-night
cortisol Answer: C) IPSS
• Use of exogenous steroid-containing lotions or This patient has ACTH-dependent endogenous
oral gels hypercortisolemia with negative findings on MRI.
• Stress immediately before collection Localization with an 8-mg DST is suggestive of
Cushing disease. Due to incongruence between
Neither measuring ACTH (Answer B) nor random the 2 reported noninvasive localization tests, the
serum cortisol (Answer C) is a screening test next step is to perform IPSS (Answer C). IPSS is
for hypercortisolism. After hypercortisolism is the gold standard invasive test in the evaluation of
diagnosed, ACTH can be measured to determine ACTH-dependent Cushing syndrome.
whether it is ACTH-dependent or independent. This patient already underwent 2 screening
Depending on the result, the Endocrine Society tests and had positive results, thus confirming the
guideline algorithm indicates whether to perform diagnosis of hypercortisolism. There is therefore
no need to do a 1-mg DST (Answer B).

ENDO 2022 • Adrenal  51

 Repeating the MRI (Answer D) would not yield ACTH inferior petrosal sinus-to-peripheral
any more information because the patient already (IPS/P) ratio of 2 or greater or of 3 or greater after
had a recent MRI that did not identify an adenoma. stimulation suggests Cushing disease. The best next
step is transsphenoidal surgery (Answer D). This
patient underwent transsphenoidal surgery, and
Case 2 (Continued)
the pathology report described a 2-mm adenoma
IPSS is performed during hypercortisolemia (see Table): in the right lobe of the pituitary. Biochemical
remission was subsequently achieved. The findings
Which of the following is the best next step? during transsphenoidal surgery confirmed that the
A. Another IPSS patient had pituitary hypercortisolism.
B. Chest CT There is no need to repeat IPSS (Answer A) or
C. 68Ga-DOTATATE scan to evaluate the patient for ectopic hypercortisolism
with a chest CT (Answer B) or 68Ga-DOTATATE
D. Transsphenoidal surgery
scan (Answer C).
Answer: D) Transsphenoidal surgery
Prolactin measurement during IPSS can improve Case 3
diagnostic accuracy and decrease the chance A 37-year-old woman without comorbidities
of false-negative results. A baseline prolactin presents to the emergency department with
inferior petrosal sinus-to-peripheral (IPS/P) ratio acute psychosis that rapidly evolves to depression
(ipsilateral to the dominant post-CRH ACTH with suicidal ideation and anorexia. Upon
IPS/P ratio) of 1.8 or greater suggests successful further interview, the patient reports weakness
catheterization during the procedure. A basal when walking upstairs, alopecia, and secondary

Time (min) Right petrosal-to- Left petrosal-to-

ACTH Right petrosal Left petrosal Peripheral peripheral ratio peripheral ratio
–5 260.3 pg/mL 78.5 pg/mL 27.0 pg/mL 9.64 2.90
(SI: 57.3 pmol/L) (SI: 17.3 pmol/L) (SI: 5.9 pmol/L)
0 4766.3 pg/mL 211.7 pg/mL 28.6 pg/mL 166.65 7.40
(SI: 1048.6 pmol/L) (SI: pmol/L) (SI: 6.3 pmol/L)
3 6218.3 pg/mL 433.7 pg/mL 24.7 pg/mL 251.75 17.55
(SI: 1368.0 pmol/L) (SI: 46.6 pmol/L) (SI: 5.4 pmol/L)
5 10,650.2 pg/mL 687.3 pg/mL 41.4 pg/mL 257.25 16.60
(SI: 2343.0 pmol/L) (SI: 151.2 pmol/L) (SI: 9.1 pmol/L)
10 9391.8 pg/mL 682.6 pg/mL 63.0 pg/mL 149.07 10.83
(SI: 2066.2 pmol/L) (SI: 150.2 pmol/L) (SI: 13.9 pmol/L)

Time (min) Right petrosal-to- Left petrosal-to-

prolactin Right petrosal Left petrosal Peripheral peripheral ratio peripheral ratio
–5 631.4 ng/mL 145.0 ng/mL 66.5 ng/mL 9.49 2.18
(SI: 27.5 nmol/L) (SI: 6.3 nmol/L) (SI: 2.9 nmol/L)
0 719.1 ng/mL 165.1 ng/mL 67.4 ng/mL 10.66 2.44
(SI: 31.3 nmol/L) (SI: 7.2 nmol/L) (SI: 2.9 nmol/L)
3 735.2 ng/mL 107.5 ng/mL 62.8 ng/mL 11.70 1.71
(SI: 32.0 nmol/L) (SI: 4.7 nmol/L) (SI: 2.7 nmol/L)
5 662.8 ng/mL 75.4 ng/mL 63.0 ng/mL 10.52 1.19
(SI: 28.8 nmol/L) (SI: 3.3 nmol/L) (SI: 2.7 nmol/L)
10 787.6 ng/mL 68.0 ng/mL 62.2 ng/mL 12.66 1.09
(SI: 34.2 nmol/L) (SI: 3.0 nmol/L) (SI: 2.7 nmol/L)

52  ENDO 2022 • Endocrine Case Management

amenorrhea. She has been taking valproic acid, Which of the following is the best next step?
600 mg daily; risperidone, 3 mg daily; sertraline, A. ACTH measurement
100 mg daily; diazepam, 5 mg daily; vitamin B12, B. Adrenal CT
100 mcg daily; vitamin D, 1000 IU daily; and
calcium, 1000 mg daily. C. Pituitary MRI
On physical examination, her blood pressure is D. Repeated 1-mg DST with dexamethasone
130/80 mm Hg. She has a rounded face, abdominal measurement
adiposity, muscle atrophy of the limbs, and
Answer: A) ACTH measurement
spontaneous bruising of the lower limbs.
After the diagnosis of endogenous Cushing
Laboratory workup (after 8 hours of fasting):
syndrome is established, serum ACTH is measured
Plasma glucose = 82 mg/dL (70-99 mg/dL) as a first step (Answer A) to determine the cause.
(SI: 4.6 mmol/L [3.9-5.5 mmol/L]) Patients with evidence of hypercortisolism and
White blood cell count = 4896/µL (4500-11,000/µL) elevated ACTH levels should undergo additional
(SI: 4.89 × 109/L [4.5-11.0 × 109/L])
Hematocrit = 42.6% (35%-45%) (SI: 0.426 [0.35-0.45])
testing, usually with pituitary MRI (Answer C).
Sodium = 141 mEq/L (136-142 mEq/L) Further testing after pituitary MRI may include
(SI: 141 mmol/L [136-142 mmol/L]) IPSS, CRH and desmopressin testing, and whole-
Potassium = 2.5 mEq/L (3.5-5.0 mEq/L) body CT.
(SI: 2.5 mmol/L [3.5-5.0 mmol/L]) Patients with low serum ACTH concentrations
Creatinine = 0.54 mg/dL (0.6-1.1 mg/dL)
(SI: 47.7 µmol/L [53.0-97.2 µmol/L])
should undergo adrenal imaging with CT
Serum cortisol (8 AM) = 20.7 µg/dL (5-25 µg/dL) (Answer B) and/or MRI to identify unilateral
(SI: 571.1 nmol/L [137.9-689.7 nmol/L]) masses with adjacent and contralateral atrophy or
Cortisol after 1-mg DST = 20.2 µg/dL bilateral disease.
(SI: 557.3 nmol/L) This patient already has documented elevated
Late-night salivary cortisol = 0.55 µg/dL
(<0.13 µg/dL) (SI: 15.2 nmol/L [<3.6 nmol/L])
urinary free cortisol and late-night salivary
Repeated measurement = 0.52 µg/dL cortisol, satisfying 2 of 3 screening tests necessary
(SI: 14.3 nmol/L) to diagnose hypercortisolism. Cortisol after 1-mg
Urinary free cortisol = 600 µg/24 h (4-50 µg/24 h) DST was elevated too. She has hypercortisolism,
(SI: 1656 nmol/d [11-138 nmol/d]) so there is no need to repeat a 1-mg DST
Repeated measurement = 550 µg/24 h
(SI: 1518 nmol/d)
(Answer D).

References
1. Carroll TB, Findling JW. The diagnosis of Cushing’s syndrome. Rev Endocr 7. Nieman LK, Oldfield EH, Wesley R, Chrousos GP, Loriaux DL, Cutler GB
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2. Biller BM, Grossman AB, Stewart PM, et al. Treatment of test for the differential diagnosis of adrenocorticotropin-dependent Cushing’s
adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J syndrome. J Clin Endocrinol Metab. 1993;77(5):1308-1312. PMID: 8077325
Clin Endocrinol Metab. 2008;93(7):2454-2462. PMID: 18413427 8. Tsagarakis S, Tsigos C, Vasiliou V, et al. The desmopressin and combined
3. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and CRH-desmopressin tests in the differential diagnosis of ACTH-dependent
management of Cushing’s disease: a guideline update. Lancet Diabetes Cushing’s syndrome: constraints imposed by the expression of V2 vasopressin
Endocrinol. 2021;9(12):847-875. PMID: 34687601 receptors in tumors with ectopic ACTH secretion. J Clin Endocrinol Metab.
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syndrome: a meta-analysis based on 5367 patients. J Clin Endocrinol Metab. 9. Ritzel K, Beuschlein F, Berr C, et al. ACTH after 15 min distinguishes
2020;105(3):dgz136. PMID: 31665382 between Cushing’s disease and ectopic Cushing’s syndrome: a proposal for
5. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s a short and simple CRH test. Eur J Endocrinol. 2015;173(2):197-204. PMID:
syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol 25953828
Metab. 2008;93(5):1526-1540. PMID: 18334580 10. Frete C, Corcuff J-B, Kuhn E, et al. Non-invasive diagnostic strategy
6. Sharma ST, Raff H, Nieman LK. Prolactin as a marker of successful in ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab.
catheterization during IPSS in patients with ACTH-dependent Cushing’s 2020;105(10):dgaa409. PMID: 32594169
syndrome. J Clin Endocrinol Metab. 2011;96(12):3687-3694. PMID: 22031511

ENDO 2022 • Adrenal  53

Pheochromocytoma and
Paraganglioma: Diagnosis and
Perisurgical Management
Annika M. A. Berends, MD. Department of Endocrinology, University Medical Center
Groningen, University of Groningen, Groningen, The Netherlands; E-mail: m.a.berends@
umcg.nl

Michiel N. Kerstens, MD, PhD. Department of Endocrinology, University Medical Center

Groningen, University of Groningen, Groningen, The Netherlands; E-mail: m.n.kerstens@
umcg.nl

Learning Objectives • Genetic testing should be offered to all patients

with a new diagnosis of PPGL, regardless of age.
As a result of participating in this session, learners
should be able to: • Management of PPGL is complex and requires
a multidisciplinary team of dedicated specialists
• Describe the main steps in the diagnostic in centers with broad expertise.
workup of a pheochromocytoma or
• Surgical resection of a PPGL is a high-risk
sympathetic paraganglioma (PPGL).
procedure for which optimal pretreatment
• Illustrate the optimal approach to the with antihypertensive drugs, preferably
perioperative management of patients with a α-adrenergic blockade, is required in
PPGL with respect to preoperative evaluation, combination with state-of-the-art surgical
surgical approach, and perioperative medical procedures and anesthetic techniques.
treatment.
• Identify drugs that can be given safely and drugs
that should be avoided in patients with PPGL.
Significance of the
Clinical Problem
PPGLs are rare chromaffin-cell tumors originating
Main Conclusions in the adrenal medulla (pheochromocytomas)
and sympathetic paraganglia (paragangliomas),
• Liquid chromatography/tandem mass
which share the capacity to synthesize and release
spectrometry is the preferred assay method for
catecholamines. If not recognized or treated in
measurement of metanephrines.
a timely manner, patients with PPGL are at risk
• A pheochromocytoma is unlikely in a to develop fatal cardiovascular complications
patient with an adrenal tumor that has an from the excessive amounts of circulating
unenhanced attenuation value on CT less than catecholamines, which may result in myocardial
10 Hounsfield units (HU). infarction, cardiomyopathy, arrhythmias,
cerebrovascular disease, or hypertensive

54  ENDO 2022 • Endocrine Case Management

emergencies with multiorgan failure. Another of all solid tumors in humans. Targeted next-
cause of mortality is related to metastatic disease. generation sequencing should be offered to all
Most PPGLs are benign, but approximately 15% patients with a new diagnosis of PPGL, regardless
are metastatic, and metastases are present at the of age. It is worth considering repeated next-
initial diagnosis in 10% to 30% of cases.1 generation sequencing in patients who tested
Diagnosis of PPGL can be challenging for negative in the past, as the number of newly
several reasons. Symptoms and signs are highly identified susceptibility genes is still growing.1
variable, which may impede early recognition. Surgery is the only curative treatment option
Importantly, PPGLs belong to the group for benign PPGL, but it should only be performed
of orphan diseases and, as such, the pretest in centers with a multidisciplinary management
probability of this disease is low. Biochemical team with sufficient expertise. During surgery,
confirmation is based on the demonstration of a patient is exposed to several stimuli that may
increased levels of metanephrines in plasma or evoke an uncontrolled and massive release
urine. Reliable assessment of metanephrines of catecholamines from the PPGL into the
requires advanced laboratory techniques, which circulation. This surge may result in potentially
are not always available. Even when using a life-threatening cardiovascular complications
robust assay with high specificity, the positive (“pheo crisis”). Hazardous stimuli can be either
predictive value is limited because of the low mechanical (eg, endotracheal intubation, incision,
pretest probability of PPGL. Therefore, selecting peritoneal insufflation, tumor manipulation)
patients with an estimated higher risk of PPGL or pharmacological (eg, metoclopramide, some
is important to improve the positive predictive neuromuscular-blocking agents). Over the years,
value of biochemical testing.1 Measurement of the perioperative mortality rate has dropped
metanephrines is recommended in the following significantly from approximately 40% in the early
clinical scenarios or patients: days to 0% to 3% when performed in a center with
extensive expertise. Major developments in PPGL
• Patients with signs and symptoms of PPGL management that most likely have contributed to
• Patients with a history of cardiovascular events this notable improvement in surgical outcomes
(including Takotsubo cardiomyopathy) with are advancements in medical imaging allowing
suggestive signs or symptoms of PPGL precise tumor localization, introduction of
• When an adrenal incidentaloma is identified if minimally invasive surgery, optimization of
the unenhanced attenuation value is 10 HU or presurgical treatment care, and refinement of
greater anesthetic techniques.2
• Patients who are lean (BMI <25 kg/m2) with
type 2 diabetes Barriers to Optimal Practice
• Patients with history of PPGL or are a known
• Due to the low incidence of PPGL, the
carrier of a germline pathogenic variant in one
diagnosis is often delayed and expertise in
of the PPGL susceptibility genes
its management is not widely available. In
• Patients who have features suggesting addition, the rarity of this disease is a barrier to
genetically determined or syndromic PPGL conducting well-controlled clinical trials.
(eg, medullary thyroid carcinoma, multiple
• There is insufficient awareness that
café-au-lait spots)1
measurement of metanephrines should be
About 40% of PPGL cases are hereditary with an considered when an adrenal incidentaloma
autosomal dominant pattern of inheritance. In is found.
fact, PPGLs have the highest rate of heritability

ENDO 2022 • Adrenal  55

• There is no uniformly accepted definition Imaging of PPGL
of hemodynamic instability, which impedes
In the diagnostic workup of PPGL, biochemical
comparative research to establish optimal
confirmation is followed by imaging studies to
perisurgical management.
locate the tumor. Cross-sectional imaging by
• The perisurgical risk of a patient with PPGL contrast-enhanced CT or MRI is usually sufficient
is difficult to predict, as determinants of to visualize the tumor. The addition of functional
hemodynamic instability during surgical imaging studies, however, improves the sensitivity
resection are largely unknown. and specificity, in particular for demonstrating
multifocal disease or metastases. Moreover,
functional imaging studies can be used to evaluate
Strategies for Diagnosis, the possibility of peptide-receptor radionuclide
Therapy, and/or Management therapy. Several radiotracers are available, and
the optimal choice depends on tumor genotype,
Biochemical Diagnosis of PPGL biology, size, and biochemical phenotype. The
Measurement of the O-methylated metabolites of European Association of Nuclear Medicine and the
catecholamines (ie, free metanephrines) in either Society of Nuclear Medicine and Molecular Imaging
plasma or 24-hour urine is considered to be the have recently proposed a clinical algorithm for
cornerstone for the biochemical diagnosis of PPGL. nuclear imaging investigations of PPGL (Table 1).4
Caffeine, cigarette smoking, and alcohol intake
Table 1. Proposed Clinical Algorithm for
should be withheld for approximately 24 hours Nuclear Imaging Investigations in Patients With
before testing to avoid false-positive results. Sample Pheochromocytoma and Paraganglioma.4
collection for plasma metanephrines should be done Third choice
after at least 20 minutes of supine rest. Laboratory (if 18F-DOPA
methods for assessment of metanephrines differ in First Second or 68Ga-SSA is
Diagnosis choice choice not available)
diagnostic performance. Liquid chromatography–
Pheochromocytoma 18
F-DOPA 68
Ga-SSA 18
F-FDG
tandem mass spectrometry has the highest (sporadic) or
sensitivity (98%-100%) and specificity (94%-96%) 123
I-MIBG

and is virtually unaffected by analytical interference.3 Inherited 18

F-DOPA I-MIBG
123 18
F-FDG
pheochromocytoma or 68Ga-
Liquid chromatography with electrochemical (except SDHx): NF1/ SSA
detection has good sensitivity (95%-100%), but it RET/VHL/MAX
might be affected by analytical interference from Head and neck 68
Ga-SSA 18
F-DOPA In-
111

medications such as acetaminophen, α-methyldopa, paraganglioma SSA/99mTc-SSA

(sporadic)
sulfasalazine, and sotalol. Immunoassays for
Extraadrenal 68
Ga-SSA 18
F-FDG 18
F-FDG and
metanephrines demonstrate insufficient diagnostic sympathetic and/ and -123I-MIBG
performance and should preferably not be used. or multifocal and/or 18
F-DOPA or 18F-FDG
metastatic and/or and 111In-
Apart from analytical interference, which is assay SDHx mutation SSA/99mTc-SSA
dependent, pharmacodynamic interference by
medications causing falsely elevated plasma or The algorithm can be proposed as per the clinical situation. This algorithm
should be practically adapted in each institution and evolve with time.
urinary metanephrines should also be considered. Abbreviations: 123I-MIBG, iodine-123-labeled metaiodobenzylguanidine;
Such interference is independent from the assay 18
F-FDA, fluorine-18-labeled fluorodopamine; 18F-DOPA, fluorine-18-
labeled fluorodihydroxyphenylalanine; 18F-FDG, fluorine-18-labeled
applied and can be encountered with drugs fluorodeoxyglucose; 68Ga-SSA, gallium-68-labeled somatostatin
analogue; 111In-SSA, indium-111-labeled somatostatin analogue; 99mTc-
such as antidepressants, phenoxybenzamine, SSA, technetium-99-labeled somatostatin analogue. Adapted with
MAO-inhibitors, sympathomimetics, and permission from Taïeb D et al. Eur J Nucl Med Mol Imaging, 2019;46(10)
© Springer-Verlag GmbH Germany, part of Springer Nature.
levodopa. Withdrawal of these medications
might be considered when initial testing yields a
positive result.

56  ENDO 2022 • Endocrine Case Management

Genetics of PPGL Perisurgical Management
PPGL has the highest known heritability rate Treatment of PPGL requires a multidisciplinary
among all solid tumors in humans; almost 40% team of dedicated specialists in centers that
of PPGLs are hereditary. Genetic testing should have extensive experience in managing
therefore be offered to patients with a new these complex patients. Minimally invasive
diagnosis of PPGL. Lack of family history of PPGL adrenalectomy (including the laparoscopic
does not preclude the presence of a germline transperitoneal, posterior retroperitoneal, and
pathogenic variant. Next-generation sequencing lateral retroperitoneal technique) is currently
is the preferred technique to analyze all relevant the preferred surgical approach for most
genes in a single testing panel. It is important to pheochromocytomas. Laparoscopic surgery
engage patients in shared decision-making before was found to be safe and resulted in a shorter
genetic testing.1 Currently, more than 20 different duration of surgery, shorter hospital stay, and
causative germline variants have been identified. lower complication rate, including less blood
Based on their transcriptional profile, PPGLs loss, when compared with open adrenalectomy.1
have been divided into 2 clusters. Cluster 1, or Bleeding complications, however, should not
the pseudohypoxia subgroup, includes pathogenic be neglected with the laparoscopic approach
variants in genes encoding the succinate (reported frequency of approximately 4%). Lateral
dehydrogenase complex (SDHx [ie, SDHA, SDHAF2, transperitoneal adrenalectomy and posterior
SDHB, SDHC, SDHD), VHL, EPAS1, FH, MDH2, retroperitoneoscopic adrenalectomy have been
or EGLN1 (PHD2). These pathogenic variants evaluated in 2 relatively small randomized
stabilize hypoxia-inducible factor 1α and 2α, which controlled trials, demonstrating either no
in turn activate genes that induce angiogenesis, difference or superiority of the posterior approach
metabolism, and proliferation. Cluster 2, or the with respect to perioperative and recovery
kinase signaling subgroup, includes pathogenic outcomes. Open adrenalectomy is advised as the
variants in the RET protooncogene, NF1, MAX, primary approach in case of large (usually >6 cm)
and TMEM127. In addition, 30% to 40% of sporadic or invasive PPGL.1
PPGLs have somatic driver variants in cluster Another important aspect of presurgical
1 genes (eg, VHL, EPAS1) or cluster 2 genes (eg, management is medical treatment to provide
NF1, RET). Cluster 3 genes have been identified symptom relief and control of hypertension. For
as a separate group of somatic variants resulting this purpose, α-adrenergic receptor blockers are
in increased expression of genes in the Wnt often considered the treatment of choice. Table 2
signaling pathway. These include genes include displays the proposed presurgical oral treatment
CSDE1 and MAML3.5 Germline pathogenic variants options for patients with PPGL.2 Instead of
in PPGL susceptibility genes demonstrate an orally administered medications, there are also
autosomal dominant inheritance pattern. In the some intravenous alternatives that could be
case of SDHD, SDAF2, and MAX variants, there considered in specific cases (Table 3).2 Tachycardia
is maternal imprinting. Thus, the disease is only frequently occurs in patients with PPGL, either as
manifest when the pathogenic variant is paternally a direct consequence of catecholamines or as an
inherited. SDHx variants are the most prevalent adverse effect of α-adrenergic receptor blockers.
(20%-30% of cases of PPGL), with the highest Tachycardia is effectively treated with either
frequency in SDHB (9%-10%) and SDHD (2%-9%). selective or nonselective β-adrenergic receptor
The risk of metastatic PPGL is also highest in blockers. An important point to keep in mind
cluster 1 tumors. In particular, development of when starting β-adrenergic receptor blockers is
metastatic PPGL is most often seen in patients that these drugs should only be started after a
with SDHB (~25%) and SDHA variants (~12%).6 patient is already receiving α-adrenergic receptor
blockade for several days. Otherwise, a crisis could

ENDO 2022 • Adrenal  57

be provoked due to unopposed stimulation of the is routinely performed, and placement of a
α-adrenergic receptors. It is usually advised to central venous catheter is strongly recommended
give intravenous saline during the last 24 hours for central venous pressure measurement and
prior to surgery. The hypothesis underlying this administration of vasoactive agents and fluid
practice is that high sodium should reduce the management. Transesophageal echocardiography
risk of preoperative orthostatic hypotension and might be considered for more optimal real-
postoperative hypotension. Supportive evidence time monitoring of intravascular volume status
for this is limited and based on only a few and early detection of myocardial wall motion
retrospective studies. abnormalities.7 Blood pressure should be kept within
In general, the anesthetic management aims safe limits during surgery. There is, however, no
to provide optimal hemodynamic stability during consensus with respect to the exact blood pressure
PPGL surgery and the postoperative stage. threshold values that require intervention by
Intraarterial blood pressure measurement is essential, the anesthesiologist and no clear agreement on
as it allows for real-time monitoring of hemodynamic the definition of hemodynamic instability. In the
fluctuations and frequent blood sampling. Urine PRESCRIPT study, these thresholds were defined as
output monitoring via urinary bladder catheterization a mean arterial pressure less than 60 mm Hg and a

Table 2. Suggested Presurgical Oral Treatment of Patients With PPGL2

Incremental dose
Drug Starting dosage steps* Dose range Comments
Phenoxybenzamine 10 mg daily 20 mg 10-140 mg Preferably started at least 7 to 14 days prior
to surgery, also in case of normotension;
or doses higher than starting dose are
Doxazosin ER 4 mg daily 4 mg 4-56 mg administered twice daily

Nifedipine ER 30 mg daily 30 mg 30-90 mg Add-on to α-adrenergic receptor blockade

in case of persistent hypertension (blood
or pressure supine >130/80 mm Hg, systolic
amlodipine 5 mg daily 5 mg 5-10 mg blood pressure upright >110 mm Hg)

or
Metyrosine 250 mg 3 times daily 250-500 mg 750-2000 mg
Metoprolol ER 50 mg daily 50 mg 50-200 mg Add-on in case of tachycardia (heart rate
supine >80 beats/min, heart rate upright
or >100 beats/min); preferably started after
Propranolol 20 mg 3 times daily 20 mg 20-240 mg sufficient preparation with α-adrenergic
receptor blockade (≥3 to 4 days)
or
Atenolol 25 mg daily 25 mg 25-100 mg
High-sodium ≥15 g … … Restoration of intravascular volume
chloride diet depletion; prevention of preoperative
orthostatic hypotension and postoperative
and hypotension
Saline, 0.9% 2 L/24 h … … Diet should be started >7 to 14 days
intravenously before surgery
Intravenous saline should be started
24 hours before surgery

*Dosage adjustments preferably every 2 to 4 days at the discretion of the clinician and guided by the response of blood pressure and/or heart rate
If supine blood pressure is greater than 160/100 mm Hg 24 hours before planned surgery, consider postponing surgery. Surgery is usually performed in the
morning, and the last dose of each oral drug should preferably be administered the evening before surgery. In case surgery begins after 12 AM, the last dose
of each oral drug should be administered at 7 AM the day of surgery. Only the administration of 0.9% saline should be continued during surgery. Adapted
from Berends AMA et al. J Clin Endocrinol Metab, 2020; 105(9) © Endocrine Society.

58  ENDO 2022 • Endocrine Case Management

Table 3. Suggested Intravenous Treatment of Hypertension and
Tachyarrhythmia in Case of PPGL Crisis or During Surgery2

Duration of
Onset of action (after
Indication Drug Dosage action discontinuation)
Hypertension
Step 1a Magnesium sulfateb Loading dose: 40-60 mg/kg followed by infusion of Immediate 30 min
1-4 g/h
Step 2 Phentolaminec Bolus: 2.5-5 mg at 1 mg/min, repeated every 3-5 min 1-2 min 10-30
2.5-5 mg at 1 mg/min, repeated every 3 to 5 min min
Continuous: 100 mg in 500 mL of 5% dextrose 1-5 min 5-11 h
20-100 mg/h
or
Urapidil Bolus: initial dose, 25-50 mg orolus: initial dose: 1-5 min 15-30 min, may
25-50 mg exceed 12 h after
prolonged infusion
or
Continuous: 10-15 mg/h
Step 3 Nicardipine Starting dose: 5 mg/h, increased by 2.5 mg/h every 2-4 min 5-15 min
5 min (if needed), maximum dose 15 mg/h
or
Clevidipine Starting dose: 1-2 mg/h, increase by doubling the dose Immediate 2-3 min
every 90 seconds (if needed), maximum dose 32 mg/h
Step 4 Sodium Starting dose: 0.5-1.5 mcg/kg per min, dosage range: 2-5 min 5-10 min
nitroprusside 0.5-4 mcg/kg per min; stop administration if no results
are achieved after 10 min of infusion, maximal dose for
10 min only
or
Nitroglycerine Infusion adjusted according to response within the
range of 10-200 mcg/mind
Tachyarrhythmias
Step 1 Esmolole Bolus: 500 mcg/kg in 1 min, repeat bolus after 5 min (if 1-5 min 15-30 min
needed)
Continuous: 25-100 mcg/kg per min, increase infusion
rate to 300 mcg/kg per min (if needed)
Step 2 Amiodarone Loading dose (bolus): 5 mg/kg, followed by infusion of 1-30 min 1-3 h
15 mcg/kg per min
or
Lidocaine Loading dose (bolus): 1 mg/kg, repeat after 5-10 min <2 min 15-20 min
(if needed)
Continuous: 2-4 mg/min (1-2 mg/mL),
maximum 300 mg/h

Suggested steps need to be individualized based on comorbidity.

a
Check for adequate pain treatment and depth of anesthesia.
b
Also prevention and treatment of tachyarrhythmias.
c
In case of norepinephrine-producing tumor, 2 mg before tumor manipulation.
d
Tachyphylaxis can occur after a continuous infusion greater than 24 hours.
e
In case of epinephrine- or dopamine-producing tumor, 20 mg before tumor manipulation.
Adapted from Berends AMA et al. J Clin Endocrinol Metab, 2020; 105(9) © Endocrine Society.

ENDO 2022 • Adrenal  59

systolic blood pressure greater than 160 mm Hg.8 D. The plasma metanephrine concentration
The number of vasoactive agents and volume is affected by ingestion of certain food
therapy (infusion of fluids, predominantly products
intravenous saline, to correct hypotension) required
to maintain the blood pressure within these limits Answer: C) Renal insufficiency may increase
may vary substantially among patients. Blood pressure the plasma metanephrine concentration
levels alone are therefore insufficient to evaluate Clinical manifestations of PPGL are highly variable
hemodynamic stability during PPGL resection. To and are related to the amounts, proportions, and
overcome this problem, a hemodynamic instability secretion patterns of catecholamines (ie, episodic
score has been developed consisting of 3 components or continuous). In a prospective cohort of patients
(hemodynamic variables including blood pressure with (n = 245) and without (n =1820) PPGL
and heart rate, volume therapy, and vasoactive (participants in whom metanephrines had been
agents), which provides a tool to quantify the determined), it was demonstrated that only 19%
degree of intraoperative hemodynamic instability.9 of patients with PPGL presented with the classic
triad of headache, palpitations, and sweating.10 In
Clinical Case Vignettes the same study, a score system was developed to
estimate PPGL risk. The likelihood was increased
Case 1 with a symptom score of 3 or greater, where 1
A 51-year-old woman with chronic hypertension, point was assigned to each of 7 features (ie, BMI
palpitations, and intermittent headaches is <25 kg/m2, heart rate ≥85 beats/min, pallor,
evaluated for the presence of a pheochromocytoma. sweating, palpitations, tremor, nausea), with a
She follows a diet rich in fruits and vegetables. She negative point for obesity. The patient in this
has no family history of pheochromocytoma. case had a symptom score of at least 3, so further
On physical examination, her blood pressure evaluation for PPGL was justified.
is 176/105 mm Hg and pulse rate is 88 beats/min. The interpretation of plasma or urinary
BMI is 22 kg/m2. metanephrine measurement is optimized when
using sex- and age-specific reference intervals
Laboratory test results: (thus, Answer A is incorrect).11 Negative test
Serum creatinine = 1.4 mg/dL (0.6-1.1 mg/dL) results virtually exclude PPGL, the exception being
(SI: 125.0 µmol/L [53.0-97.2 µmol/L]) very small or nonsecreting tumors. Elevations of
Plasma normetanephrine = 220 pg/mL (<165 pg/mL) any plasma metabolite greater than 2 times the
(SI: 1.20 nmol/L [<0.90 nmol/L])
upper reference limit or increases in 2 or more
Plasma metanephrine = 108 pg/mL (<99 pg/mL)
(SI: 0.55 nmol/L [<0.50 nmol/L]) metabolites are very rare in the absence of PPGL
3-Methoxytyramine = <0.04 nmol/L (<0.04 nmol/L) but occur in more than 80% of patients with PPGL
(thus, Answer B is incorrect).1
Catecholamine-rich foods may increase
Which of the following is correct regarding the plasma or urine concentration of
biochemical analysis for PPGL? 3-methoxytyramine, but they do not affect the
A. Plasma metanephrines are not affected by age plasma or urine concentration of metanephrine
or sex (thus, Answer D is incorrect).
B. PPGL can be safely excluded when the plasma A common problem in clinical practice is the
metanephrine elevation is less than 2 times the presence of kidney impairment. Plasma levels
upper normal limit of free metanephrines are frequently elevated
C. Renal insufficiency may increase the plasma in patients with stage 3 chronic kidney disease
metanephrine concentration (or worse) and in those on long-term dialysis
treatment (thus, Answer C is correct). In addition,

60  ENDO 2022 • Endocrine Case Management

PPGL is frequently suspected in patients with unenhanced attenuation value of the adrenal
chronic kidney disease, as both conditions share tumor also predicts a very low pheochromocytoma
similar signs and symptoms such as hypertension, risk. In a meta-analysis, it was shown that a
blood pressure swings, palpitations, and precontrast HU value less than 10 had a sensitivity
pulmonary edema. Optimized reference intervals of 99% for excluding pheochromocytoma.13 To
for plasma metanephrines in patients with chronic find 1 pheochromocytoma with a density less than
kidney disease have been established.12 10 HU, it was estimated that 1232 patients would
have to be screened by measuring metanephrines.
A limitation of this meta-analysis, however, is
Case 2
that all of the included studies were retrospective
A 65-year-old man with obesity is admitted to in design.
the thoracic surgery department for coronary In general, it is probably prudent to measure
artery bypass grafting the following day. The metanephrines in any patient with an adrenal
thoracic surgeon asks for advice on the finding incidentaloma before undergoing surgery. This
of a tumor in the right adrenal gland, which was decision should be balanced, however, against the
demonstrated 6 months earlier on CT of the risk and inconvenience of postponing surgery,
thorax and has not been evaluated. The adrenal as results of metanephrine measurement are
tumor measures 2.1 × 2.6 cm, has sharp margins, often not available within a day after blood
and has an unenhanced attenuation value of 8 sampling. In this case, information on the very
HU. The patient does not report any symptoms small risk of a pheochromocytoma provided
suggestive of PPGL and has hypertension the anesthesiologist the opportunity to take
controlled with an ACE inhibitor and a precautionary measures and be prepared for
β-adrenergic blocker. the unlikely event of hemodynamic instability
occurring during coronary artery bypass grafting
Which of the following is the best (thus, Answer A is correct and Answers B and C
advice for the thoracic surgeon? are incorrect). Apart from the absence of a clear
A. Continue with coronary artery bypass grafting indication for starting doxazosin, a further drop in
after informing the anesthesiologist about the already well-controlled blood pressure carries the
presence of the adrenal incidentaloma risk of inducing cardiac ischemia in a patient with
B. Measure plasma metanephrines and postpone coronary artery disease.
coronary artery bypass grafting
C. Start doxazosin, 8 mg once daily, and continue Case 3
with coronary artery bypass grafting as planned
A 35-year-old man is referred by the clinical
Answer: A) Continue with coronary artery bypass geneticist because of the recent finding of a
grafting after informing the anesthesiologist pathogenic variant in the SDHB gene identified on
about the presence of the adrenal incidentaloma family screening. He feels well, has no concerns,
and is normotensive. His father was the index
The median reported frequency of patient in whom the SDHB variant was first
pheochromocytoma in adrenal incidentalomas detected after resection of a PPGL at age 62 years.
is 7% (range, 1.4%-14%), although this
figure is probably an overestimation, as
pheochromocytoma is a rare disease. A recent
nationwide study in the Netherlands demonstrated
an incidence rate for pheochromocytoma of
0.46 per 100,000 person years. This patient
had a symptom score less than 3, and the low

ENDO 2022 • Adrenal  61

Which of the following tests is carriers of SDHA, SDHC, and SDHD variants (only
NOT indicated as part of the initial in case of parental inheritance for SDHD carriers).
workup of an asymptomatic carrier
of an SDHB pathogenic variant?
Case 4
A. 24-Hour ambulatory blood pressure monitoring
A 45-year-old man presents to the outpatient clinic
B. Examination by a urologist for evaluation of an incidentally found adrenal
C. Measurement of plasma metanephrines mass on ultrasonography performed for abdominal
D. MRI of the head and neck and thoracic, pain for which no cause was eventually established.
abdominal, and pelvic regions Other than abdominal pain, the patient has no
E. PET with 68Ga-DOTATATE concerns. Biochemical analysis confirms the diagnosis
of a pheochromocytoma. CT reveals a right
Answer: B) Examination by a urologist adrenal mass measuring 2.1 × 2.5 × 3.0 cm, with no
evidence for locally invasive or metastatic disease.
Apart from PPGL, including head and neck
The patient is referred to the endocrine surgeon
paragangliomas, patients with SDHx germline
for adrenalectomy.
pathogenic variants are also at increased risk for renal
cell carcinoma and gastrointestinal stromal tumors.
Which of the following additional
A recently issued consensus statement on initial
examinations should be
screening and follow-up of asymptomatic SDHx performed preoperatively?
variant carriers recommends initial screening with
24-hour ambulatory blood pressure monitoring A. Ambulatory blood pressure monitoring
(Answer A), symptom questionnaire, measurement B. Electrocardiography
of plasma metanephrines (Answer C), and MRI C. Echocardiography
of the head and neck and thoracic, abdominal, D. A and B
and pelvic regions (Answer D).14 In addition, E. B and C
asymptomatic adults who carry an SDHx variant
should have a baseline PET (Answer E). The expert F. A and C
panel did not reach consensus on the optimal PET G. All of the above
tracer to be used for this purpose, but it did refer
Answer: G) All of the above
to the recent EANM-SNMMI guideline, which
recommends the use of 68Ga-DOTA-somatostatin Preoperative evaluation of a patient with PPGL
analogue PET as the first-choice functional imaging should include detailed history taking, physical
modality (Table 1). For screening purposes, examination, electrocardiography (Answer B),
examination by a urologist does not have echocardiography (Answer C), and 24-hour
additional value, as renal cell carcinoma is best ambulatory blood pressure monitoring (Answer A).
diagnosed by imaging (thus, Answer B is correct). Thus, the best answer is “all of the above” (Answer G).
Follow-up consists of annual measurement Examination of cardiac function should be performed
of blood pressure, measurement of plasma in every patient regardless of physical performance,
metanephrines, and symptom questionnaire. MRI clinical picture, tumor size, cardiovascular risk factors,
of the aforementioned regions should be repeated or age. A smaller tumor size (<3 cm) does not
every 2 to 3 years. Recommended follow-up in protect against the occurrence of cardiovascular
children is similar, except for measurement of complications, and it has been shown that there is
metanephrines every 2 years. The first tumor no relationship between tumor size and the rate of
screening should be performed between age 6 and perisurgical complications. The clinical picture of
10 years for asymptomatic carriers of SDHB variants catecholamine-induced cardiomyopathy is often
and between 10 and 15 years in asymptomatic atypical, and this disorder might also develop in a

62  ENDO 2022 • Endocrine Case Management

patient at a young age in the absence of cardiovascular given orally. Doxazosin has been studied more
risk factors. Notably, preoperative abnormalities extensively than either prazosin or terazosin.
on electrocardiography or echocardiography Compared with doxazosin, phenoxybenzamine
are associated with an increased risk for cardiac has a longer duration of action and causes more
complications.15 reflex tachycardia due to the irreversible receptor
binding and blockade of the presynaptic α2
receptor, respectively. A practical disadvantage
Case 4 (continued)
of phenoxybenzamine is the relatively high cost
Nifedipine, 30 mg once daily, is started. Supine and its limited availability in several countries.
blood pressure is 152/85 mm Hg, and it drops In a recently published meta-analysis, there
to 140/75 mm Hg after 3 minutes in the upright were no differences found between groups with
position. Pulse rate is 88 beats/min. Laboratory respect to overall morbidity and mortality. There
measurements demonstrate normal electrolytes is only one randomized controlled trial on this
and normal kidney function. Electrocardiography topic (the PRESCRIPT study).8 In this study,
shows a sinus rhythm of 70 beats/min with no no differences were found in the total duration
abnormalities. Transthoracic echocardiography of blood pressure outside a predefined target
reveals a left ventricular ejection fraction of 58%, range. There was, however, less hemodynamic
stroke volume of 90 mL, and normal diastolic and instability during surgery after pretreatment
valvular function with no additional strain pattern with phenoxybenzamine. Furthermore, there
visible. were no differences between groups with
respect to postoperative hypotension, duration
Which of the following is the preferred of hospital stay, perioperative complications, or
next step in this patient’s management? adverse events.
A. Administer no pretreatment β-adrenergic receptor blockers (Answer D)
B. Increase the nifedipine dose to 60 mg once daily should only be started after a patient is already
C. Start doxazosin 4 mg once daily receiving α-adrenergic receptor blockade
D. Start metoprolol, 50 mg once daily for several days. Otherwise, a crisis could be
provoked due to unopposed stimulation of the
E. Start metyrosine, 250 mg 3 times daily α-adrenergic receptors.
Answer: C) Start doxazosin 4 mg once daily There are a few alternative drugs for
α-receptor blockers, such as calcium channel
Table 2 displays an overview of the suggested blockers (Answer B) and metyrosine (Answer E).
presurgical oral treatment of patients with Calcium channel blockers are most often used as
PPGL.2 In general, α-adrenergic receptor an add-on drug to α-receptor blockers if blood
blockers are advised as the treatment of first pressure control is not achieved sufficiently. These
choice. There is longstanding experience with drugs inhibit the catecholamine-mediated calcium
these agents, and their use is a good example influx in vascular smooth muscle cells, thereby
of targeted therapy, as these drugs specifically reducing vasoconstriction. Calcium channel
block the overstimulation of the α receptors by blockers do not cause tachycardia and have only
catecholamines. These drugs are started at least a moderate effect on preload reduction, which
7 to 14 days before surgery in a stepwise manner could be an advantage in case of coexisting heart
until blood pressure targets are achieved. Either failure. Presurgical monotherapy with oral calcium
a competitive, selective α1 receptor blocker (eg, channel blockers has been described, but they
doxazosin [Answer C], prazosin, or terazosin), should probably be used in only selected patients.
or a noncompetitive, nonselective α1 and α2 Another suggested preparation drug is metyrosine
receptor blocker (ie, phenoxybenzamine) may be (α-methyl-para-tyrosine), which significantly

ENDO 2022 • Adrenal  63

reduces circulating catecholamine levels through How should this patient be advised
inhibition of tyrosine hydroxylase, the key enzyme regarding antiemetic treatment?
catalyzing the rate-limiting step in catecholamine A. Data regarding safety of antiemetic therapy are
biosynthesis. In general, metyrosine should be conflicting
prescribed as an add-on drug to α-adrenergic B. Metoclopramide is superior to ondansetron
blockade, since monotherapy has been shown to be
C. Most antiemetic agents should only be given
less effective. Compared with α-receptor blockers
after sufficient α-adrenergic receptor blockade
and calcium channel blockers, metyrosine has
has been achieved
some disadvantages: it is expensive, has limited
availability, and has several adverse effects such D. No antiemetic medication is safe to use
as depression, anxiety, and somnolence. Of notice, preoperatively
the absence of hypertension does not preclude the Answer: C) Most antiemetics should only
occurrence of cardiovascular complications, and be given after sufficient α-adrenergic
normotensive patients therefore also require adequate receptor blockade has been achieved
medical pretreatment. The level of evidence
supporting pretreatment in patients with PPGL Several antiemetic medications have been
is moderate and mainly based on observational suggested to elicit a pheochromocytoma crisis,
studies and expert opinion. There are no either by direct or indirect stimulation of
randomized placebo-controlled trials on this topic. catecholamine release. Importantly, frequently
Several investigators have recently questioned prescribed antiemetics such as metoclopramide
the need for presurgical treatment, especially with and other dopamine receptor antagonists are
α-adrenergic receptor blockade.16 The few available contraindicated in this setting. Table 4 displays an
comparative studies suggesting that these drugs overview of the drugs that should be avoided and
could be omitted safely are without exception small- those drugs that can be given safely in patients
sized, retrospective in design, and flawed by several with PPGL. Most of these observations are based
methodological shortcomings. The debate about the on case reports. It is, however, best to avoid these
clinical value of presurgical α-receptor blockade can drugs or to only introduce them after sufficient
only be resolved by a well-designed randomized α-adrenergic receptor blockade has been achieved
controlled trial. Until then, it is advised to follow (Answer C).
the Endocrine Society’s guideline that all patients
with a functional PPGL, regardless of tumor size,
Case 6
degree of catecholamine production, or blood
pressure should undergo pretreatment (thus, A 56-year-old man is admitted to the hospital
Answer A is incorrect).1,3 because of cardiogenic shock. Physical
examination shows a strongly fluctuating blood
pressure, ranging from addition 112/70 mm Hg to
Case 5 193/95 mm Hg, pulse rate of 60 beats/min, sinus
A 70-year-old woman with pheochromocytoma rhythm, and peripheral oxygen saturation (SpO2)
is admitted to the hospital. Surgery is scheduled of 90% on room air. He is noted to have mild
in 2 weeks. She has been experiencing nausea and nonpitting bilateral ankle edema. He has a history
vomiting, which has compromised her adherence of coronary artery disease and has been taking
to doxazosin, 4 mg twice daily. On physical enalapril, metoprolol, acetylsalicylic acid, and a
examination, her blood pressure is 140/80 mm Hg, statin. Electrocardiography shows ST elevations,
and pulse rate is 75 beats/min with a normal and serum levels of cardiac-specific troponins
sinus rhythm. She would like a prescription for are increased. Transthoracic echocardiography
antiemetic treatment. is notable for a diffusely dyskinetic left ventricle,

64  ENDO 2022 • Endocrine Case Management

Table 4. Overview of Medications That Can Be Safely Used and Potential Precipitants of Adverse Outcomes
During Perioperative Anesthesia in Patients With PPGL2

Sedative-hypnotic agents used for anesthetic induction/ Sedative-hypnotic agents used for anesthetic induction/
maintenance maintenance
Inhalation agents Anxiolytic agents
Safe Comments Safe Comments
Sevoflurane Midazolam No anxiolytic agent is superior
Isoflurane Lorazepam
Enflurane Diazepam
Nitrous oxide Analgesic agents
Not safe Comments Safe Comments
Halothane Arrhythmogenic, sensitizing Fentanyl
the myocardium to circulating
catecholamines Sufentanil
Alfentanil
Desflurane Used without incident in some cases;
however, not recommended, can induce Remifentanil
sympathomimetic effects
Not safe Comments
Intravenous agents
Morphine These opioids cause histamine release,
Safe Comments thereby provoking catecholamine
Hydromorphone
release
Propofol
Pethidine*
Etomidate
Antiemetic agents
Dexmedetomidine
Safe Comments
Not safe Comments
Ondansetron
Ketamine Sympathomimetic effects
Not safe Comments
Thiopental Used without incident in some cases;
(thiopentone) however, not recommended, can Metoclopramide D2 receptor antagonists: cause indirect
precipitate hypertensive crises, linked to Chlorpromazine but potent release of catecholamines by
histamine-releasing properties Prochlorperazine stimulation of presynaptic D2 receptors

Neuromuscular-blocking agents Domperidone Can induce hypertensive crisis

Safe Comments Droperidol Severe hypertension due to increased

Haloperidol catecholamine efflux
Rocuronium
Cisapride Can stimulate catecholamine release
Vecuronium from PPGL cells through activation of
Not safe Comments serotonin type 4 receptors

Succinylcholine Can precipitate a hypertensive crisis and Miscellaneous

(suxamethonium) severe cardiac arrhythmias Not safe Comments
Pancuronium Histamine release, thereby causing Ephedrine Sympathomimetic effects, stimulates
severe pressor response catecholamine release from PPGL

Atracurium Cause histamine release, thereby Atropine Inhibits cardiac vagus and potentiates
Tobucurarine provoking catecholamine release, chronotropic effects of catecholamines
Mivacurium associated with severe arterial
hypertension and ventricular
*Pethidine is also known as meperidine, isonipecaine, lidol, operidine,
arrhythmias pethanol, and piridosal.
Cisatracurium Adverse reactions linked to histamine- Adapted from Berends AMA et al. J Clin Endocrinol Metab, 2020; 105(9)
releasing properties, thereby provoking © Endocrine Society.
catecholamine release

ENDO 2022 • Adrenal  65

consistent with the diagnosis of Takotsubo and emergency resection of a pheochromocytoma
cardiomyopathy with a reduced ejection fraction of (Answer F) should be avoided given the associated
15%. Coronary angiography reveals no significant high perioperative morbidity and mortality.
coronary stenosis. Cardiac ischemia is mainly Control of hypertension should be the initial
attributed to coronary spasms. An underlying treatment goal here, preferably achieved through
diagnosis of pheochromocytoma is suspected and medication that has rapid onset with a relatively
confirmed by additional biochemical testing and short duration of action, thereby enabling effective
CT that demonstrates a 3.5-cm right adrenal mass. dosage titration. There are no evidence-based
The patient is transferred to the intensive care unit recommendations with respect to the preferred
for hemodynamic stabilization. medical management of a pheochromocytoma
crisis. Several drugs have been described in
Which of the following is the best the literature (Table 3). In view of the patient’s
treatment recommendation? medical history of coronary artery disease,
A. Bolus of phentolamine intravenously urapidil (Answer D) should be the preferred
B. Bolus of sodium nitroprusside intravenously option. Urapidil is a competitive α1-adrenergic
receptor antagonist with central agonistic action at
C. Continuous administration of esmolol
serotonin 5-HT1A receptors and it does not cause
intravenously
reflex tachycardia.
D. Continuous administration of urapidil Phentolamine (Answer A) is contraindicated
intravenously in patients with coronary artery disease because it
E. Doxazosin orally twice daily can induce reflex tachycardia.
F. Emergency resection of the Sodium nitroprusside (Answer B) may reduce
pheochromocytoma coronary perfusion and induce intracoronary steal
G. No additional treatment is feasible given the due to a strong decline in mainly diastolic arterial
strong blood pressure swings pressure, which is undesirable in case of heart
failure and concomitant coronary artery spasm.
Answer: D) Continuous administration A β1 selective adrenergic receptor blocker,
of urapidil intravenously such as esmolol (Answer C), should be given in
case of tachyarrhythmia after achievement of
Pharmacotherapy is the mainstay of medical
sufficient α-adrenergic receptor blockade.
stabilization in case of a pheochromocytoma crisis,

References
1. Lenders JWM, Kerstens MN, Amar L, et al. Genetics, diagnosis, management 5. Berends AMA, Eisenhofer G, Fishbein L, et al. Intricacies of the molecular
and future directions of research of phaeochromocytoma and paraganglioma: machinery of catecholamine biosynthesis and secretion by chromaffin cells of
a position statement and consensus of the Working Group on Endocrine the normal adrenal medulla and in pheochromocytoma and paraganglioma.
Hypertension of the European Society of Hypertension. J Hypertens. Cancers (Basel). 2019;11(8):1121. PMID: 31390824
2020;38(8):1443-1456. PMID: 32412940 6. Amar L, Pacak K, Steichen O, et al. International consensus on initial
2. Berends AMA, Kerstens MN, Lenders JWM, Timmers HJLM. screening and follow-up of asymptomatic SDHx mutation carriers. Nat Rev
Approach to the patient: perioperative management of the patient with Endocrinol. 2021;17(7):435-444. PMID: 34021277
pheochromocytoma or sympathetic paraganglioma. J Clin Endocrinol Metab. 7. Naranjo J, Dodd S, Martin YN. Perioperative management of
2020;105(9):dgaa441. PMID: 32726444 pheochromocytoma. J Cardiothorac Vasc Anesth. 2017;31(4):1427-1439. PMID:
3. Lenders JWM, Duh Q-Y, Eisenhofer G, et al; Endocrine Society. 28392094
Pheochromocytoma and paraganglioma: an Endocrine Society clinical 8. Buitenwerf E, Osinga TE, Timmers HJLM, et al. Efficacy of α-blockers on
practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942. PMID: hemodynamic control during pheochromocytoma resection: a randomized
24893135 controlled trial. J Clin Endocrinol Metab. 2020;105(7):2381-2391. PMID:
4. Taïeb D, Hicks RJ, Hindié E, et al. European Association of Nuclear Medicine 31714582
Practice Guideline/Society of Nuclear Medicine and Molecular Imaging 9. Buitenwerf E, Boekel MF, van der Velde MI, et al. The haemodynamic
Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma instability score: development and internal validation of a new rating
and paraganglioma. Eur J Nucl Med Mol Imaging. 2019;46(10):2112-2137. method of intra-operative haemodynamic instability. Eur J Anaesthesiol.
PMID: 31254038 2019;36(4):290-296. PMID: 30624247

66  ENDO 2022 • Endocrine Case Management

10. Geroula A, Deutschbein T, Langton K, et al. Pheochromocytoma and 13. Buitenwerf E, Berends AMA, van Asselt ADI, et al. Diagnostic accuracy of
paraganglioma: clincial feature-based disease probability in relation to computed tomography to exclude pheochromocytoma: a systematic review,
catecholamine biochemistry and reason for disease suspicion. Eur J Endocrinol. meta-analysis, and cost analysis. Mayo Clin Proc. 2019;94(10):2040-2052.
2019;181(4):409-420. PMID: 31370000 PMID: 31515105
11. Eisenhofer G, Peitzsch M, Kaden D, et al. Reference intervals for LC-MS/ 14. Amar L, Pacak K, Steichen O, et al. International consensus on initial
MS measurements of plasma free, urinary free and urinary acid-hydrolyzed screening and follow-up of asymptomatic SDHx mutation carriers. Nat Rev
deconjugated normetanephrine, metanephrine and methoxytyramine. Clin Endocrinol. 2021;17(7):435-444. PMID: 34021277
Chim Acta. 2019;490:46-54. PMID: 30571948 15. Shen J, Yu R. Perioperative management of pheochromocytoma: the heart of
12. Pamporaki C, Prejbisz A, Małecki R, et al. Optimized reference intervals the issue. Minerva Endocrinol. 2013;38(1):77-93. PMID: 23435444
for plasma free metanephrines in patients with CKD. Am J Kidney Dis. 16. Groeben H, Walz MK, Nottebaum BJ, et al. International multicentre review
2018;72(6):907-909. PMID: 30146420 of perioperative management and outcome for catecholamine-producing
tumours. Br J Surg. 2020;107(2):e170-e178. PMID: 31903598

ENDO 2022 • Adrenal  67

Below the Tip of the
Iceberg: Just How Much
Aldosterone Is Out There?
Martin Reincke, MD. Medizinische Klinik und Poliklinik IV, Munich University Hospital,
Munich, Germany; E-mail: [email protected]

Learning Objectives patients with arterial hypertension and

hypokalemia, patients with arterial hypertension
As a result of participating in this session, learners
and obstructive sleep apnea, and patients with
should be able to:
arterial hypertension and adrenal incidentaloma.
• Describe the prevalence of and populations at Screening is performed using the sensitive, but
risk for endocrine hypertension. not specific, aldosterone-to-renin ratio (ARR).
The diagnosis requires confirmatory testing
• Describe the target population that should be
in most patients, using tests such as the saline-
screened for primary aldosteronism (PA).
loading test or the captopril challenge test. Subtype
• Order appropriate tests to diagnose and differentiation is carried out by means of CT
subtype PA. imaging of the adrenal glands in combination
• Initiate individualized treatment depending on with, as a gold standard, adrenal venous sampling
PA subtype. to distinguish between unilateral and bilateral
aldosterone production. Patients with PA have
an increased risk of stroke, myocardial infarction,
atrial fibrillation, and renal insufficiency compared
Main Conclusions with patients who have essential hypertension.
Early diagnosis and appropriate targeted therapy
PA, also called Conn syndrome, is a common
are critically important. Adrenalectomy is
cause of secondary hypertension associated with
indicated for patients with unilateral PA. In
high cardiovascular morbidity and mortality. PA
patients with BAH, therapy with spironolactone
remains underdiagnosed because it does not have
(starting dosage 25 mg daily, up-titrated according
a specific, easily identifiable feature and clinicians
to blood pressure, hypokalemia, and renin
are often unaware of the disease. The causes of PA
concentration) should be initiated.
can be a unilateral aldosterone-producing adrenal
adenoma (APA) or bilateral idiopathic adrenal
cortex hyperplasia (BAH). However, advances in
molecular histopathology challenge this traditional Significance of the
concept of PA as a binary disease. The classic Clinical Problem
hypokalemic form occurs more frequently in the
Once considered rare, PA is now thought to be
case of APA, whereas the normokalemic form
the most common secondary endocrine form
is mostly observed in patients with BAH. PA
of hypertension. The introduction of ARR as a
screening is required in patients with refractory
screening tool and its application to a widening
hypertension, younger patients with hypertension,
population of patients with hypertension have

68  ENDO 2022 • Endocrine Case Management

led to a marked increase in the detection of PA. Asymmetric bilateral primary aldosteronism
Most studies report PA prevalence rates between with some lateralization is common, and this
5% and 15%, with most affected patients being poses challenges in diagnosis and treatment.
normokalemic. Recent studies have suggested that
autonomous aldosterone secretion could be even
more frequent than currently accepted in patients Strategies for Diagnosis,
with hypertension. Variability in prevalence rates Therapy, and/or Management
reported in different studies is explained by the use
of different diagnostic methods and cutoffs. Introduction
Aldosterone excess in persons with PA PA is defined as hypertension caused by
is associated with deleterious effects on the disproportionately high aldosterone secretion
heart, vessels, brain, and kidney, which are with consequent low plasma renin and increased
partly independent of elevated blood pressure ARR. PA is the most common cause of endocrine
determined by hyperaldosteronism. These effects arterial hypertension: recent data indicate a
result in disproportionate degrees of organ prevalence of 5.8% in unselected hypertensive
damage for a given blood pressure and lead to left patients in primary care, 6% to 12% in patients in
ventricular hypertrophy, diastolic dysfunction, hypertensive outpatient clinics, and up to 30% in
heart failure, increased intima media thickening, patients with resistant hypertension.1
arterial stiffness, arterial wall inflammation, Compared with essential hypertension, PA is
stroke, renal hyperfiltration, albuminuria, and associated with increased morbidity and mortality,
glomerulosclerosis. In terms of metabolic effects, even when patients have the same blood pressure.
aldosterone excess causes decreased insulin This underscores the importance of a timely
secretion and insulin resistance leading to diabetes diagnosis of the affected patients, as there is an
mellitus, lower serum calcium and higher urinary excellent long-term prognosis after adequate
calcium excretion leading to hyperparathyroidism, therapy. A recently published meta-analysis
increased prevalence of osteoporosis and risk showed a decrease in mortality, which started to
of bone fractures, and sleep apnea through fluid become noticeable 5 to 7 years after initiation of
retention. therapy, especially in the group of patients who
underwent unilateral adrenalectomy. Mortality
Barriers to Optimal Practice decreased below that of patients with essential
hypertension.2
• The patient groups for whom screening is Diagnosing PA is a 3-part process: screening,
recommended account for approximately 50% confirmatory testing, and subtyping. The 2 most
of the hypertensive population. However, common causes of PA are APAs (accounting
currently fewer than 1% of patients with PA for approximately one-third of cases), which
are screened and treated during their lifetime. can be treated surgically by means of unilateral
adrenalectomy, and BAH (accounting for
• Subtyping using imaging and adrenal approximately two-thirds of cases), which can
venous sampling is driven by the intention be treated with mineralocorticoid receptor
to identify suitable candidates for unilateral antagonists. Rare causes are unilateral aldosterone-
adrenalectomy. Adrenal venous sampling is producing carcinomas and familial forms of the
complex, costly, and not widely available. disease caused by germline pathogenic variants
• The 2 subtypes of PA, unilateral and bilateral (familial hyperaldosteronism [FH] I-IV).
forms, represent extremes of a spectrum In recent years, important new articles on
of histomorphological and biochemical the diagnosis and treatment of PA have been
phenotypes and are not totally distinct. published.

ENDO 2022 • Adrenal  69

Diagnosis 100%. These results suggest that ARR has a limited
ability to identify patients with PA.4
Who should be screened? According to the
Endocrine Society guidelines, groups at risk for PA
should be screened, which applies to up to 50% of Confirmatory Testing
hypertensive patients.3 Screening is recommended Since ARR as a screening test has limited
for patients with the following: sensitivity and specificity, most patients with a
• Blood pressure >150/100 mm Hg on positive screening test should be further evaluated
3 different days with confirmatory testing. The principle of a
dynamic confirmation test is used here, which is
• Therapy-resistant hypertension intended to demonstrate the lack of aldosterone
(3 antihypertensive agents, including a suppressibility.
diuretic) Note: The intravenous saline-load test, captopril
• Controlled hypertension on challenge test, oral saline-load test, and fludrocortisone-
≥4 antihypertensive drugs suppression test are available as confirmation tests.
• Hypertension and hypokalemia These tests have similar diagnostic accuracies, but they
differ in adverse effects and feasibility.
• Hypertension and adrenal incidentaloma The diagnostic algorithm allows the
• Hypertension and sleep apnea confirmatory test to be bypassed in certain
• Hypertension and positive family history of situations: patients with high plasma aldosterone
early-onset hypertension or cerebrovascular (>20 ng/dL [>555 pmol/L]), low renin, and
event occurring at younger than 40 years spontaneous hypokalemia can proceed directly
to subtype differentiation.3,5 Very recently, a
• First-degree relatives with PA
study involving 240 patients undergoing the
saline-infusion test assessed discordance between
automated immunoassay and mass spectrometry–
Screening based measurements of plasma aldosterone. Plasma
Patients are screened using the ARR. In some aldosterone measured by immunoassays were
settings, renin activity has been replaced by respectively 86% and 58% higher than by mass
renin concentration because of its rapidity and spectrometry. Discordance was noted in 16% to
reproducibility. Plasma aldosterone measurement 32% of patients, who by adrenal venous sampling
using radioimmunoassay is also being gradually were classified as having BAH. Discordance was
replaced by much more precise mass spectrometry. eliminated by plasma purification to remove
Note: To achieve a high level of reliability when interferents. These findings raise concerns about
screening using ARR, care should be taken to ensure a the validity of automated immunoassay-based
liberal salt intake, to compensate for any hypokalemia diagnosis of PA.6
that may be present, and to take into consideration To simplify the diagnosis, the use of a so-
antihypertensive drugs that potentially interfere with called prediction score has been investigated
the renin-angiotensin-aldosterone system. several times. Recently, an Italian working group
In particular, β-adrenergic blockers and was able to create a flow chart and score with
mineralocorticoid receptor antagonists lead to various parameters (sex, antihypertensive drugs,
false-positive or false-negative screening results potassium, end-organ damage, renin, aldosterone)
due to their influence on renin secretion. A with which 22.8% of all confirmatory tests could
recently published meta-analysis, which included be bypassed.7
10 studies on a total of 4110 patients, showed
that the sensitivity of ARR varies between 10%
and 100% and the specificity ranges from 70% to

70  ENDO 2022 • Endocrine Case Management

Subtyping unilateral disease with a high specificity of 89%
to 100%.13-15 To simplify the diagnostic flow,
The rate of incidentaloma increases with age,
“prediction scores” based on steroid profiling or
so that bilateral adrenal venous sampling is
clinical parameters were also examined. Several
recommended for subtype differentiation.3 The
studies have demonstrated a difference in the
details of the adrenal vein catheter protocol
secretion of the hybrid steroids 18-hydroxycortisol
(sequential vs simultaneous withdrawal or
and 18-oxocortisol between patients with PA
cosyntropin-stimulated vs unstimulated
vs primary hypertension, but also between the
withdrawal) differ among centers. Adrenal venous
PA subtypes.16 A Japanese working group was
sampling is a costly and invasive procedure and is
able to show that the 18-oxocortisol values in ​​
very rarely associated with severe adverse effects
patients with unilateral APAs were significantly
(hemorrhage). It requires a high level of expertise
higher than in patients with BAH (diagnostic
and is therefore not widely available. Imaging
sensitivity 83%, specificity 99%).17 The authors
of the adrenal glands is always performed to not
proposed that by measuring 18-oxocortisol in
only visualize adrenal morphology, but also as a
their diagnostic model, mineralocorticoid receptor
planning tool to visualize adrenal vein anatomy.
antagonist therapy could be started directly in
Imaging also rules out the very rare adrenal
43% of patients with bilateral disease without the
carcinoma. Some older studies were able to show
need for adrenal venous sampling. Subsequently,
that adrenal venous sampling leads to more
another European study demonstrated a reduced
accurate lateralization than imaging (sensitivity
ability of 18-hydroxycortisol and 18-oxocortisol
95% vs 78%; specificity 100% vs 75%).8,9 A more
to discriminate between the 2 subtypes. Mass
recent European randomized controlled study
spectrometry measurement of 12 different steroids
of 200 patients with PA (SPARTACUS trial)
led to correct subtype classification in 80% of
showed no significant difference in the clinical
patients with PA.18 Although some of the steroids
and biochemical outcome when the therapeutic
used were different, these study findings suggest
decision for adrenalectomy was based on adrenal
that peripheral blood steroid profiling may make
venous sampling or CT10; however, this result has
adrenal venous sampling unnecessary in the future
not been confirmed in most other studies. In a
in patients with bilateral disease.
retrospective data analysis of a large multicenter
Modified criteria from confirmatory testing
cohort that included 18 centers, there were
are also useful in subtype differentiation. Various
again indications of inferiority of CT-based
studies have shown that subtype differentiation
decision-making vs adrenal venous sampling–
is possible based on results of the saline-infusion
based diagnostics.11,12 In additional studies, the
test using a score.19,20 The addition of clinical
discrepancy of CT vs catheter-based diagnostics
parameters (age, potassium, adrenal mass) may
could be demonstrated several times, so taken
increase the discriminatory ability of the saline-
together, adrenal venous sampling remains firmly
infusion test.21 Recently, Burello et al validated
anchored as the preferred test in the differential
prediction models for PA subtype diagnostics in a
diagnosis of PA.
large study using machine learning.22
Note: Adrenal venous sampling continues to be
A high expression of CXCR4 (CXC chemokine
the gold standard in the differential diagnosis of
receptor type 4) in APA could be demonstrated,
PA and paves the way for subtype-specific therapy:
correlating with the expression of CYP11B2
adrenalectomy for APA and mineralocorticoid receptor
(aldosterone synthase). In one study, the specific
antagonist treatment for BAH.
CXCR4 tracer 68Ga-pentixafor PET-CT showed
The guidelines recommend proceeding
a stronger uptake in patients with known APA.23
directly to adrenalectomy in certain situations
Functional imaging using ¹¹C-metomidate
(young age with pronounced clinical signs, adrenal
PET-CT also represents a promising method
mass in imaging).3 Various scores can predict

ENDO 2022 • Adrenal  71

for noninvasive subtype differentiation, as patients with nonclassic histopathology. Patients
recently published case reports suggest.24,25 The with nonclassic histopathology showed a higher
11
C-metomidate labels CYP11B2 activity in the absolute aldosterone concentration in the vein of
adrenal cortex. However, other studies show the (unresected) contralateral adrenal gland during
limited suitability, so further analyses appear adrenal venous sampling.
necessary.26 Prior to adrenalectomy, therapy with MR
antagonists should be initiated to compensate
for hypokalemia and control blood pressure.
Therapy
After adrenalectomy, follow-up is necessary
Current data suggest that adrenalectomy is to verify biochemical and clinical remission of
superior to mineralocorticoid receptor antagonist PA. Medical therapy with mineralocorticoid
therapy in terms of mortality, cardiovascular and receptor antagonists is recommended to treat
metabolic risk, kidney function, and quality of BAH. Drug therapy can also be prescribed for
life.27-29 Patients with PA who are treated with patients who cannot undergo operation for
mineralocorticoid receptor antagonists have a medical reasons or who decline to do so. A study
higher risk of atrial fibrillation than patients with by Hundemer et al compared cardiovascular
essential hypertension, while adrenalectomized outcomes among 3 groups: 205 patients with
patients no longer have an increased risk.30 unilateral disease who underwent adrenalectomy,
A large population-based study was able to 602 patients with BAH who received medical
demonstrate a reduced risk of diabetes mellitus in treatment, and more than 40,000 patients
adrenalectomized patients vs the risk in patients with primary hypertension.33 Despite similar
with essential hypertension, while patients blood pressure control, patients treated with
treated with medication showed an increased mineralocorticoid receptor antagonists had a
risk.29 The PASO study recently defined the significantly higher risk of cardiovascular events
criteria for surgical cure.10 The complete clinical than patients who underwent adrenalectomy,
cure represents the postoperative normalization while patients who underwent adrenalectomy
of blood pressure; complete biochemical cure had a significantly lower risk than patients with
represents normalization of serum potassium and primary hypertension. However, patients who
ARR. In the PASO study, 37% of 700 patients experienced renin normalization induced by
studied met criteria for complete clinical cure, mineralocorticoid receptor antagonist therapy
while 94% had complete biochemical remission. had a similar cardiovascular risk to that of
A recent nomenclature consensus workshop patients who underwent adrenalectomy. A similar
(HISTALDO, histopathology of primary conclusion was reached by another study showing
aldosteronism) supported use of CYP11B2 that the increased risk of atrial fibrillation in drug-
(aldosterone synthase)-based immunohistochemistry treated patients with PA was associated with renin
for classification of adrenal histopathology lesions suppression.34 This illustrates the importance of
in PA.31 It distinguished classic histopathologic adequate dosing of mineralocorticoid receptor
findings (APA, dominant aldosterone-producing antagonists.
nodules) from nonclassic ones (multiple Note: Mineralocorticoid receptor antagonists
aldosterone-producing micronodules, diffuse should be gradually titrated: the starting dosage of
adrenal hyperplasia). A prospective study spironolactone is 25 to 50 mg daily. The aim is to
over 3 years in 60 adrenalectomized patients32 normalize blood pressure, serum potassium levels, and
showed that APA or dominant aldosterone- renin levels. In addition, care should be taken to restrict
producing nodes were associated with higher salt intake.
initial aldosterone and ARR values and a higher
probability of postoperative remission (97.6% vs
66.7% [P = .002]) compared with observations in

72  ENDO 2022 • Endocrine Case Management

Summary Which of the following is the most likely
pretest probability for PA in this patient?
PA is the most common cause of endocrine arterial
hypertension, affecting 6% of the hypertensive A. <5%
population, most of whom are undiagnosed. The B. 5%-10%
diagnostic workup continues to consist of a 3-step C. 10%-15%
process: screening using ARR, confirmatory D. >15%
testing, and subtyping (with CT and adrenal venous
sampling). To simplify the diagnosis, so-called Answer: D) >15%
prediction scores are increasingly used. Steroid
This patient has resistant hypertension, as defined
profiling from peripheral blood (using liquid
by the American Heart Association and European
chromatography–mass spectrometry) could reduce
Society of Cardiology classification, and she should
the need for adrenal venous sampling in patients
be screened for PA according to all guidelines.
with bilateral disease. Functional imaging is also
The pretest probability for such a patient in most
a promising method for noninvasive subtype
studies between 15% and 30% (Answer D).
differentiation. Adrenalectomy offers the potential
for a cure by eliminating aldosterone excess, leading
to improved patient outcomes. In the case of drug Case 2
therapy, mineralocorticoid receptor antagonists A 33-year-old man with recent-onset grade 2 WHO
should be dosed adequately: the aim is to normalize hypertension has been evaluated for primary
blood pressure, potassium levels, and renin levels. aldosteronism. His height is 69 in (175 cm), and
weight is 165 lb (75 kg) (BMI = 24.4 kg/m2). He
Clinical Case Vignettes has spontaneously hypokalemia (lowest potassium
concentration, 2.6 mEq/L [2.6 mmol/L]), and he
Case 1 does not currently take any antihypertensive drugs.
A 44-year-old woman presents with an
8-year history of arterial hypertension. Her His biochemical workup shows the following
height is 67 in (170 cm), and weight is 181 lb hormone levels:
(82 kg) (BMI = 28.3 kg/m2). She has tried many Plasma aldosterone = 455 ng/dL (50-200 ng/dL)
antihypertensive medications, but her blood (SI: 12,622 pmol/L [1387-5548 pmol/L])
pressure has become increasingly unresponsive Plasma renin = <2 pg/mL (3-40 pg/mL)
(SI: <0.05 pmol/L [0.07-0.95 pmol/L])
in recent years. Currently, she takes candesartan, ARR = 152 (<20)
8 mg twice daily; chlortalidone, 25 mg daily;
and amlodipine, 5 mg twice daily. Her office These values are similar to those documented 1 week
blood pressure is 170/99 mm Hg and automated earlier. Abdominal CT without contrast shows a
ambulatory blood pressure monitoring reading is 1.5-cm adrenal mass with a density of 5 Hounsfield
161/95 mm Hg without night dipping. units. The contralateral adrenal gland is normal in
appearance.
Laboratory test results:
Serum creatinine, normal Which of the following diagnostic
Serum potassium = 3.8 mEq/L (SI: 3.8 mmol/L) procedures is most appropriate?
(on a low-salt diet)
A. Adrenal MRI
Serum sodium = 144 mEq/L (SI: 144 mmol/L)
B. Adrenal venous sampling
C. Confirmatory testing using saline-infusion test
D. No diagnostic testing; the patient can be
directly referred for right adrenalectomy

ENDO 2022 • Adrenal  73

Answer: D) No diagnostic testing; the patient can D. The results suggest probable cortisol secretion
be directly referred for right adrenalectomy in the left adrenal vein
E. All of the above
This young patient has a pronounced form of PA.
According to guideline recommendations, he does Answer: E) All of the above
not need confirmatory testing (Answer C) because
of the severe biochemical phenotype. He also does Answers A through D are all correct. The
not need adrenal venous sampling (Answer B) selectivity index (ratio of cortisol right and left
because he is younger than 35 years and the right adrenal / cortisol peripheral vein) is greater than
adrenal nodule is suggestive of a fat-rich adenoma 2.0, which suggests selective catheterization.
(Hounsfield units <10). Adrenal MRI (Answer A) There is strong lateralization to the right side
is not superior to adrenal CT in localizing adrenal (ratio aldosterone/cortisol right adrenal vein /
adenomas in patients with PA. Thus, the patient ratio aldosterone/cortisol left adrenal vein of 296
can be referred directly for right adrenalectomy [>4.0 indicate lateralization]). The contralateral
(Answer D). aldosterone/cortisol ratio is below the peripheral
aldosterone/cortisol ratio, and the absolute
aldosterone concentration in the right adrenal vein
Case 3 (400 ng/dL [11,096 pmol/L]) is minimally higher
A 55-year-old man with recent-onset grade 2 than in the periphery (320 ng/dL [8877 pmol/L]).
WHO hypertension has been diagnosed with PA The large adrenal mass on the right side, however,
based on an elevated ARR and nonsuppressed and the high cortisol concentration in the left
aldosterone in response to intravenous saline adrenal vein could suggest cortisol cosecretion. A
loading. Abdominal CT demonstrates a 3.5-cm 1-mg dexamethasone-suppression test should be
adrenal mass in the left adrenal gland and a 1.5-cm performed to rule this out.
right adrenal lesion. The patient undergoes
bilateral simultaneous unstimulated adrenal
venous sampling (see Table).

Which of the following interpretations

is most appropriate?
A. The adrenal venous sampling procedure is
technically successful for both adrenal glands,
in terms of selectivity index
B. The results suggest lateralization to the right
adrenal vein
C. The results suggest contralateral suppression
in the left adrenal vein

Selectivity
index adrenal
Source Cortisol Aldosterone veins Lateralization index
Right adrenal vein 35 µg/dL 14,500 ng/dL 7 414
(SI: 965.6 nmol/L) (SI: 402,230 pmol/L)
Peripheral vein 15 µg/dL 320 ng/dL 21
(SI: 413.8 nmol/L) (SI: 8877 pmol/L)
Left adrenal vein 277 µg/dL 400 ng/dL 18 1.4
(SI: 7641.9 nmol/L) (SI: 11,096 pmol/L)

74  ENDO 2022 • Endocrine Case Management

References
1. Yang Y, Reincke M, Williams TA. Prevalence, diagnosis and outcomes of in patients with primary aldosteronism. Hypertension. 2015;65(5):1096-1102.
treatment for primary aldosteronism. Best Pract Res Clin Endocrinol Metab. PMID: 25776074
2020;34(2):101365. PMID: 31837980 18. Eisenhofer G, Dekkers T, Peitzsch M, et al. Mass spectrometry-based adrenal
2. Meng Z, Dai Z, Huang K, et al. Long-term mortality for patients of primary and peripheral venous steroid profiling for subtyping primary aldosteronism.
aldosteronism compared with essential hypertension: a systematic review and Clin Chem. 2016;62(3):514-524. PMID: 26787761
meta-analysis. Front Endocrinol (Lausanne). 2020;11:121. PMID: 32210920 19. Nagano H, Kono T, Saiga A, et al. Aldosterone reduction rate after
3. Funder JW, Carey RM, Mantero F, et al. The management of primary saline infusion test may be a novel prediction in patients with primary
aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society aldosteronism. J Clin Endocrinol Metab. 2020;105(3):dgz092.
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Endocrinol Metab. 2020;105(7):dgaa282. PMID: 32449927 of prediction models for subtype diagnosis of patients with primary
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primary aldosteronism: implications of immunoassay inaccuracy. J Clin 32561919
Endocrinol Metab. 2021 [Online ahead of print] PMID: 34963138 23. Heinze B, Fuss CT, Mulatero P, et al. Targeting CXCR4 (CXC chemokine
7. Burrello J, Amongero M, Buffolo F, et al. Development of a prediction receptor type 4) for molecular imaging of aldosterone-producing adenoma.
score to avoid confirmatory testing in patients with suspected primary Hypertension. 2018;71(2):317-325. PMID: 29279316
aldosteronism. J Clin Endocrinol Metab. 2020;106(4):e1708-e1716. PMID: 24. Burton TJ, Mackenzie IS, Balan K, et al. Evaluation of the sensitivity and
33377974 specificity of (11)C-metomidate positron emission tomography (PET)-CT for
8. Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, van Heerden lateralizing aldosterone secretion by Conn’s adenomas. J Clin Endocrinol Metab.
JA, Role for adrenal venous sampling in primary aldosteronism. Surgery. 2012;97(1):100-109. PMID: 22112805
2004;136(6):1227-1235. PMID: 15657580 25. O’Shea PM, O’Donoghue D, Bashari W, et al.,= (11) C-Metomidate PET/
9. Nwariaku FE, Miller BS, Auchus R, et al. Primary hyperaldosteronism: effect CT is a useful adjunct for lateralization of primary aldosteronism in routine
of adrenal vein sampling on surgical outcome. Arch Surg. 2006;141(5):497- clinical practice. Clin Endocrinol (Oxf). 2019;90(5):670-679. PMID: 30721535
502. PMID: 16702522 26. Soinio, M., et al., Functional imaging with 11C-metomidate PET for subtype
10. Dekkers T, Prejbisz A, Schultze Kool LJ, et al; SPARTACUS Investigators. diagnosis in primary aldosteronism. Eur J Endocrinol. 2020;183(6):539-550.
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aldosteronism: an outcome-based randomised diagnostic trial. Lancet Diabetes 27. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Renal outcomes
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Hypertension. 2018;72(3):641-649. PMID: 29987100 30. Rossi GP, Maiolino G, Flego A, et al; PAPY Study Investigators.
13. Riester A, Fischer E, Degenhart C, et al. Age below 40 or a recently proposed Adrenalectomy lowers incident atrial fibrillation in primary aldosteronism
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aldosteronism. J Clin Endocrinol Metab. 2014;99(6):E1035-E1039. PMID: 31. Williams TA, Gomez-Sanchez CE, Rainey WE, et al. International
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prediction score to diagnose unilateral primary aldosteronism. J Clin 32. Meyer LS, Handgriff L, Lim JS, et al. Single-center prospective cohort study
Endocrinol Metab. 2012;97(10):3530-3537. PMID: 22918872 on the histopathology, genotype, and postsurgical outcomes of patients with
15. Sze WCC, Soh LM, Lau JH, et al. Diagnosing unilateral primary primary aldosteronism. Hypertension. 2021;78(3):738-746. PMID: 34024122
aldosteronism - comparison of a clinical prediction score, computed 33. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Cardiometabolic
tomography and adrenal venous sampling. Clin Endocrinol (Oxf). outcomes and mortality in medically treated primary aldosteronism: a
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18-hydroxycortisol, and 18-oxocortisol in the diagnosis of primary 34. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Incidence of
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18-oxocortisol can discriminate unilateral adenoma from bilateral diseases

ENDO 2022 • Adrenal  75

BONE AND MINERAL
METABOLISM
Denosumab Discontinuation
Bente L. Langdahl, MD, PhD, DMSc. Endocrinology and Internal Medicine, Aarhus
University Hospital, Aarhus, Denmark; E-mail: [email protected]

Learning Objectives collagen (CTX) and, in some cases, multiple

administrations of zoledronate during the first
As a result of participating in this session, learners
year after denosumab discontinuation to prevent
should be able to:
bone loss.
• Explain and discuss the pathophysiology
underlying the rebound increase in
bone turnover and bone loss following Significance of the
discontinuation of denosumab.
Clinical Problem
• Apply the current guidelines regarding
Denosumab is a fully human IgG2 monoclonal
follow-on treatment in patients discontinuing
antibody that neutralizes RANKL and thereby
denosumab.
potently decreases osteoclast recruitment and
activity, which leads to reduced bone turnover
and increased bone mineral density.1 Denosumab
reduces the risk of new vertebral fractures by 70%
Main Conclusions and the risk of hip and nonvertebral fractures by
Denosumab is an effective treatment of 40% and 20%, respectively, in postmenopausal
osteoporosis that leads to substantial increases women and is approved for the treatment of
in bone mass and clinically important reductions osteoporosis in postmenopausal women and
in fracture risk with few adverse effects. Most men and treatment of glucocorticoid-induced
patients should continue treatment; however, osteoporosis. Furthermore, the risk of adverse
some patients may need to discontinue treatment effects is low and a positive benefit-to-risk
due to comorbidities or adverse effects. ratio over 10 years has been demonstrated in
Furthermore, some patients want to discontinue postmenopausal women with osteoporosis.2
treatment because of normal or near-normal bone Denosumab is therefore a potent antiresorptive
mineral density (BMD) and absence of fractures treatment of osteoporosis; however, unlike
after years on treatment. Unlike bisphosphonates, bisphosphonates, denosumab’s effect is not
but like most other pharmacological treatments, maintained after discontinuation, as bone
denosumab has no continuing effect after it resorption increases rapidly leading to bone loss
is discontinued. Due to the accumulation of (the rebound phenomenon).3 This increase in
receptor activator of nuclear factor kappaB bone resorption increases fracture risk, especially
ligand (RANKL) and possibly osteoclasts during vertebral fractures. Post hoc analyses of data from
treatment with denosumab, a rebound activation the FREEDOM trial (phase 3 pivotal fracture trial)
of bone resorption is observed in patients who demonstrated that discontinuation of denosumab
discontinue denosumab after more than 1 to 2 treatment was associated with an increased risk
years of treatment. This can partly be prevented by of vertebral and multiple vertebral fractures
the administration of bisphosphonates, primarily compared with risk in women discontinuing
zoledronate. Patients need frequent monitoring placebo and that the risk was higher among
with measurement of C-telopeptide of type I women with prior vertebral fractures, longer

78  ENDO 2022 • Endocrine Case Management

duration of therapy, and more prominent BMD observational data are available. Pretreatment with
loss at the hip after discontinuation.4 Other bisphosphonates appears to be associated with a
studies have suggested that younger age and diminished increase in bone turnover markers
chronic kidney disease may also be risk factors in patients with osteoporosis who discontinue
for vertebral fractures after discontinuation of denosumab when compared with bone turnover
denosumab.5 markers in patients without bisphosphonate
Physicians should consider the issues exposure. However, no studies have found an
associated with discontinuation of denosumab effect of prior bisphosphonate treatment on BMD
when making the decision to initiate denosumab. loss following denosumab discontinuation.
Denosumab treatment has many benefits, Longer duration of denosumab treatment is
including prominent and continuing increases in associated with a more pronounced rebound in
BMD and easy administration, which supports bone resorption and subsequent bone loss after
adherence. However, the patient and the physician denosumab withdrawal. Therefore, duration of
should also be aware of the challenges associated denosumab treatment should be considered when
with denosumab’s discontinuation.5 interpreting the studies investigating the rebound
phenomenon and measures should be taken to
prevent or diminish this. A number of studies have
Barriers to Optimal Practice investigated the effects of other antiresorptive
drugs after denosumab discontinuation. The
• Lack of knowledge among physicians and
effects of alendronate after denosumab were
patients about the rebound phenomenon when
assessed in the DAPS study (Denosumab
denosumab is discontinued.
Adherence Preference Satisfaction). Alendronate
• Limited availability or reimbursement of for 1 year after 1 year of denosumab therapy
measuring CTX or bone turnover markers maintained the BMD gained with denosumab.6
in general or as frequently as is needed to
optimally manage patients in the first year
following denosumab discontinuation. Prevention of the Rebound
• Logistical challenges in the administration of
Phenomenon After Short-Term
zoledronate in general practitioner practices Denosumab Treatment
and/or lack of resources in the hospital setting Several studies have investigated the effects of
to see all patients discontinuing denosumab. zoledronate use after short-term denosumab
treatment. In general, zoledronate is more
effective in maintaining BMD when denosumab
Strategies for Diagnosis, has only been given for a few years. An
Therapy, and/or Management observational study of 11 women who received
zoledronate after discontinuation of denosumab
Denosumab Discontinuation for 2 years reported minimal loss of BMD gained
Bone turnover markers increase rapidly 6 months during denosumab treatment at all skeletal sites.
after the last denosumab injection and remain Similarly, a retrospective observational study
elevated until slowly decreasing to baseline of 18 postmenopausal women who received
levels after 1 to 2 years.3 BMD is lost and returns zoledronate after denosumab for 1.5 years on
to or even below pretreatment levels.3 There average showed preservation of BMD gained
is speculation whether the increase in bone during the denosumab treatment period.
turnover following denosumab discontinuation Furthermore, the initial results of the DATA-
is modified by treatment with bisphosphonates HD Extension trial indicated that a single
prior to denosumab therapy; however, only dose of zoledronate maintains the BMD gains

ENDO 2022 • Bone and Mineral Metabolism  79

achieved with a combination of teriparatide last denosumab injection found that 66% of the
and denosumab for 9 months followed by BMD gained with denosumab was retained at the
denosumab alone for 9 months at all skeletal spine and 49% was retrained at the hip 2 years
sites. A randomized controlled trial investigated after denosumab discontinuation. The bone
the efficacy of a single intravenous infusion of loss occurred within the first 18 months after
zoledronate in 57 postmenopausal women who zoledronate infusion.9
had been treated with denosumab for a mean The effect of bisphosphonates on the rebound
duration of 2.4 years and had achieved BMD phenomenon was speculated to be better if
in the osteopenic range. At 24 and 36 months, given when the increase in resorption was
BMD at the lumbar spine and femoral neck was already evident. To investigate this further, we
maintained. Patients treated with zoledronate conducted the ZOLARMAB study, a randomized
had small but significant increases in procollagen controlled trial evaluating zoledronate treatment
type 1 aminoterminal propeptide and CTX after discontinuation of long-term denosumab.10
during the first year but stabilization thereafter.7 The study included 61 postmenopausal women
Based on these results, it seems that the rebound and elderly men who had received denosumab
phenomenon after treatment with denosumab for for a mean duration of 4.6 years. The patients
up to 2.5 years can be controlled by administration were randomly assigned to receive a single 5-mg
of bisphosphonates, with most of the evidence zoledronate infusion either 6 months after the
focused on the use of zoledronate. last denosumab injection (6-month group, n =
20), 9 months after (9-month group, n = 20), or
when bone turnover markers were increased
Prevention of the Rebound
(observation group, n = 21). Patients in the 2 latter
Phenomenon After Long- groups were monitored monthly and promptly
Term Denosumab received an infusion of zoledronate if CTX
Several studies have investigated the effects of increased substantially (50% above the range for
antiresorptive drugs after discontinuation of postmenopausal women and elderly men) or if
denosumab following more than 2.5 years of they sustained a fragility fracture. Twelve months
treatment. Small observational studies and case after the initial zoledronate infusion, BMD had
reports seem to indicate that selective estrogen decreased significantly at the lumbar spine, total
receptor modulators and oral bisphosphonates do hip, and femoral neck in all 3 groups without
not prevent bone loss following discontinuation differences between groups. The decline in BMD
of long-term denosumab treatment.5 Most was more rapid in the 9-month group and in the
studies show that zoledronate is less effective observation group, which may at least in theory
in preventing BMD loss when the denosumab result in a higher fracture risk. Two women, both
treatment period exceeds 2.5 years compared with in the 9-month group, experienced a vertebral
a shorter duration of denosumab therapy. In a fracture. In addition, 10 patients in the 6-month
case series of 6 women receiving a single infusion group needed retreatment with zoledronate 6 or
of 5 mg zoledronate after 7 years of denosumab, 12 months after the initial treatment compared
a partial preservation of the BMD gained during with 5 patients in each of the 2 other groups.
denosumab treatment was observed at the spine, Based on these findings, we concluded that
while a complete loss of the bone gain was noted treatment with zoledronate, regardless of timing,
at the hip 2 years after zoledronate infusion.8 did not fully prevent BMD loss in patients with
An observational study of 120 postmenopausal osteopenia who had been treated with denosumab
women with osteoporosis treated for 2 to for 4.6 years.10
5 years with denosumab who received a single Similar to the findings in the ZOLARMAB
infusion of 5 mg zoledronate 6 months after the study, an observational study of 20 postmenopausal

80  ENDO 2022 • Endocrine Case Management

women who received a single 5-mg infusion of suggested as a possible treatment target. Hip
zoledronate after discontinuing denosumab when BMD between –2.5 and –1.5 has been proposed
bone turnover markers exceeded the upper limit by different working groups and societies.
of the premenopausal reference ranges also found However, a BMD-only–based concept is not
a secondary increase in bone turnover markers universally embraced and more data are needed.
after an initial decrease following zoledronate In addition, it is important to remember that the
administration. This suggests that a single infusion concept of a limited duration of treatment for
of zoledronate may not be sufficient to completely osteoporosis was developed based on the retention
control bone turnover in all patients discontinuing of bisphosphonates in bone and therefore cannot
long-term denosumab treatment. automatically be applied to denosumab or other
The rapid reversal of the beneficial skeletal treatments. The decision about treatment duration
effects of denosumab attributed to a transient should be individualized and should, in addition
increase in bone turnover overriding pretreatment to fracture-free period and BMD, also include
status has commonly been described as the an evaluation of additional risk factors of a
“rebound phenomenon.” It has been postulated high fracture-risk profile. These risk factors are
that osteoclast precursors remaining dormant mainly linked to prevalent osteoporotic fractures
during the treatment period retain their activity and concomitant comorbidities (eg, continuous
and/or that a high RANKL-to-osteoprotegerin use of glucocorticoids or aromatase inhibitors,
ratio ensues after denosumab is cleared from diabetes, inflammatory diseases, frailty, etc). In
the patient’s circulation. Although the exact patients considered to be at high risk for fracture,
pathophysiology of the rebound phenomenon is the efficacy and safety profile of denosumab
yet to be fully elucidated, the clinical data reviewed allows for long-term treatment, with existing
above suggest that denosumab discontinuation data supporting a duration of up to 10 years.
results in increased bone turnover and bone loss Regarding serious adverse effects, the FREEDOM
and in an augmented fracture risk compared with study investigating denosumab for up to 10 years
continuation of the drug. This observation gives reported 2 atypical femur fractures and 13 cases of
rise to the following questions related to clinical osteonecrosis of the jaw.
practice: Pending data on longer treatment duration
from registries, decisions regarding treatment
• What is the optimal treatment duration beyond 10 years should be individualized, as is the
with denosumab for patients at high risk for case with most medical treatments beyond the first
fracture? few years. These considerations also underscore
• What should be done after denosumab the importance of a careful assessment of the
discontinuation? indications to start denosumab treatment in the
• How should vertebral fractures be managed first place, especially in younger patients, who may
that occur after denosumab discontinuation? be at higher risk of fractures or bone loss following
discontinuation.
Regarding elective dental procedures where
Optimal Duration of Denosumab treatment discontinuation is demanded by the
dentist, it is suggested to perform the procedure
Treatment in Patients at
approximately 5 months after the last denosumab
High Risk for Fracture injection and resume treatment as soon as the
The goal of osteoporosis treatment is to achieve lesion is healed. This suggestion is based on expert
an acceptable level of fracture risk. As increase opinion only.
in BMD is a very strong mediator of fracture
risk reduction on treatment, BMD has been

ENDO 2022 • Bone and Mineral Metabolism  81

Optimal Treatment Strategy After keeping in mind that 1 to 2 years of treatment with
Denosumab Discontinuation bisphosphonates most likely has not led to sufficient
accumulation of bisphosphonates in the bone to
Current evidence regarding use of raloxifene and prevent future bone loss and therefore age- and/or
risedronate to prevent the rebound phenomenon menopause-related bone loss is likely to resume.
is not convincing and therefore the following In patients with gastrointestinal intolerability
will focus on the use of potent bisphosphonates. of oral bisphosphonates, inadequate response to oral
Current data suggest that the duration of bisphosphonates, or a long duration of denosumab
denosumab treatment is an important determinant treatment, the European Calcified Tissue Society
of the extent of the rebound phenomenon, position statement recommends administering
which may have potential implications for the zoledronate intravenously. The timing of this
type and duration of subsequent treatment with infusion is of great importance. In the ZOLARMAB
bisphosphonates. Very little data are available study, we found very rapid increases in CTX and
to help define the optimal timing of initiation of rapid bone loss in patients with delayed infusions
oral bisphosphonates in relation to denosumab of zoledronate (9 to 12 months after the last
discontinuation. Most of the few studies available denosumab injection). In addition, case series have
describe initiation of oral bisphosphonates reported multiple vertebral fractures at very early
6 months after the last denosumab injection. time points after 1 missed denosumab injection.
The European Calcified Tissue Society position The current recommendation is therefore to
statement on denosumab discontinuation5 initiate treatment with zoledronate 6 months
suggests performing DXA 6 months after the last after the last denosumab injection and to monitor
denosumab injection and starting treatment with the effect with measurement of bone turnover
an oral bisphosphonate, preferably alendronate, markers, for example, at 3 and 6 months after the
at that time. Measuring bone turnover markers zoledronate infusion. If bone turnover markers are
3 months after initiating the oral bisphosphonate increased (ie, above the mean found in age- and
is recommended to monitor adherence and efficacy. gender-matched cohorts) repeated infusion of
Regarding bisphosphonate treatment, an zoledronate should be considered. If bone turnover
adequate response is defined as a CTX level below markers are not available for monitoring a patient,
the mean in healthy premenopausal women, a pragmatic approach could be giving a second
the exact values depending on the assays. This infusion of zoledronate 6 months after the first
recommendation is supported by data from the infusion. Similar to oral bisphosphonates, and in
ReoLaus cohort in which patients with stable cases of otherwise low fracture risk, the duration
BMD at the spine after 1 year had mean CTX values of zoledronate treatment should be tailored to the
close to the premenopausal mean, significantly lower duration of increased bone turnover, although
than the mean CTX level in patients who lost BMD. as mentioned above, the optimal duration of
In patients with adequate response and low fracture zoledronate treatment may be adjusted when more
risk, treatment with an oral bisphosphonate can be data become available.
continued for 1 to 2 years (ie, the estimated time of
the rebound upregulation of bone turnover). It is,
however, recommended to continue the assessment Management of Vertebral
of bone turnover markers, initially after another Fractures Occurring After
3 months and if stable, every 6 months to ensure Denosumab Discontinuation
that they remain within the lower half of the
No data currently support the optimal
premenopausal reference range. At 1 to 2 years, a
management of vertebral fractures occurring
reevaluation including DXA should be performed
after denosumab discontinuation. The fractures
and the decision to discontinue oral bisphosphonate
seem to be caused by the high bone turnover
treatment should align with current guidelines,

82  ENDO 2022 • Endocrine Case Management

and/or the rapid bone loss that most likely of treatment with denosumab. In patients with
also comprises an element of deterioration of low fracture risk and a shorter duration of
bone microarchitecture. Quickly counteracting denosumab treatment (ie, up to 2.5 years), the
the increased bone turnover is therefore rebound phenomenon can probably be controlled
important, and since denosumab is a very potent by treatment with alendronate for 1 to 2 years.
antiresorptive agent with the ability to suppress If treatment with alendronate is not possible,
bone turnover markers in a matter of days, prompt zoledronate can be given once and repeated if
reinitiation of denosumab treatment may be bone turnover is inappropriately high after 3 to
the best solution. Alternatively, a combination 6 months. Patients who have been treated with
of denosumab with an osteoanabolic agent (eg, denosumab for a longer period (ie, more than
teriparatide) can be prescribed to stimulate 2.5 years) or who are still at high risk for fracture
bone formation and at the same time avoid the should receive zoledronate. Bone turnover
transient but rapid decrease in BMD, especially markers can provide clinical guidance on the
at cortical sites, reported with teriparatide timing and duration of zoledronate treatment.
subsequent to denosumab therapy. This is why Patients who experience vertebral fractures after
monotherapy with teriparatide after denosumab stopping denosumab need prompt treatment to
should be discouraged at the present time. reduce the high bone turnover.
Indeed, the combination of denosumab with
teriparatide, although currently off-label in most Figure. Osteoporosis Management With Denosumab
countries, has been shown to be highly effective
in improving BMD. However, the combination
treatment period should be followed by a potent
antiresorptive therapy (ie, zoledronate) to
consolidate BMD gains. Moreover, novel data
report that romosozumab following denosumab
for 1 year also results in BMD gains, although
more modest than with romosozumab treatment
in treatment-naïve patients. Vertebroplasty has
been identified as a potential precipitating risk
factor for subsequent vertebral fractures and
should therefore be avoided in this situation.

Summary and Conclusion

Discontinuation of denosumab following Abbreviations: BPs, bisphosphonates; BTMs, bone turnover markers.

at least 2 denosumab injections carries a Reprinted from Tsourdi E, Zillikens MC, Meier C et al. J Clin Endocrinol
Metab, 2021; 106(1) © Endocrine Society.
significant risk of a rebound effect, manifesting
as rapidly increasing bone resorptive activity,
considerable loss of the bone mass gained during Clinical Case Vignettes
denosumab treatment, and an augmented risk Case
for (multiple) vertebral fractures. To limit the
consequences of this phenomenon, it is currently A 70-year-old woman is diagnosed with
recommended to continue denosumab therapy osteoporosis. Alendronate is initiated, but she
or to prescribe a potent bisphosphonate when develops upper gastrointestinal adverse effects
denosumab is discontinued (see Figure). The and her regimen is switched to denosumab
rebound phenomenon depends on the duration after a few months. She responds well and has
increases in BMD at the spine and hip of 12.9%

ENDO 2022 • Bone and Mineral Metabolism  83

and 7.6%, respectively, after 6 years of treatment. I recommended continuing denosumab; however,
She is doing well, with no fractures and no the patient was determined to discontinue, and
adverse effects, but her BMD T-scores are still she did not want another parentally administrated
low: –3.4 at the spine and –3.8 at the hip. The treatment. She was therefore started on
patient has heard about patients discontinuing alendronate 6 months after the last denosumab
bisphosphonate treatment and would like to injection. Bone turnover markers, CTX, and
discontinue denosumab. procollagen type 1 aminoterminal propeptide
increased from unmeasurable levels at the time of
Which of the following is the alendronate initiation to 150% to 200% above the
best recommendation? premenopausal reference range after 6 months.
A. Continue denosumab BMD at the spine and hip decreased by 2.6% and
B. Discontinue denosumab and monitor CTX 20.4%, respectively. The patient then accepted
zoledronate treatment.
C. Give alendronate for 1 to 2 years and monitor
Continuing denosumab (Answer A) or giving
CTX; give zoledronate if CTX is uncontrolled
zoledronate for 1 to 2 years and monitoring CTX
D. Give zoledronate for 1 to 2 years and (repeating administration of zoledronate if CTX is
monitor CTX; repeat zoledronate if CTX is uncontrolled) (Answer D) are the recommended
uncontrolled options. However, giving alendronate for 1
E. Give zoledronate 6 and 12 months after the to 2 years and monitoring CTX (and giving
last denosumab injection zoledronate if CTX is uncontrolled) (Answer C)
and giving zoledronate 6 and 12 months after the
Answers: A) Continue denosumab or D) Give
last denosumab injection (Answer E) would also
zoledronate for 1 to 2 years and monitor CTX:,
reduce the rebound phenomenon but probably less
repeat zoledronate if CTX is uncontrolled
effectively than Answer D.

References
1. Cummings SR, San Martin J, McClung MR, et al; FREEDOM Trial. 6. Freemantle N, Satram-Hoang S, Tang ET, et al; DAPS Investigators. Final
Denosumab for the prevention of fractures in postmenopausal women with results of the DAPS (Denosumab Adherence Preference Satisfaction)
osteoporosis. N Engl J Med. 2009;361(8):756-765. PMID: 19671655 study: a 24-month, randomized, crossover comparison with alendronate in
2. Ferrari S, Lewiecki EM, Butler PW, et al. Favorable skeletal benefit/risk of postmenopausal women. Osteoporos Int. 2012;23(1):317-326. PMID: 21927922
long-term denosumab therapy: a virtual-twin analysis of fractures prevented 7. Anastasilakis AD, Papapoulos SE, Polyzos SA, Appelman-Dijkstra
relative to skeletal safety events observed. Bone. 2020;134:115287. PMID: NM, Makras P. Zoledronate for the prevention of bone loss in women
32092479 discontinuing denosumab treatment. A prospective 2-year clinical trial. J Bone
3. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment Miner Res. 2019;34(12):2220-2228. PMID: 31433518
and discontinuation on bone mineral density and bone turnover markers 8. Reid IR, Horne AM, Mihov B, Gamble GD. Bone loss after denosumab: only
in postmenopausal women with low bone mass. J Clin Endocrinol Metab. partial protection with zoledronate. Calcif Tissue Int. 2017;101(4):371-374.
2011;96(4):972-980. PMID: 21289258 PMID: 28500448
4. Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after 9. Everts-Graber J, Reichenbach S, Ziswiler HR, Studer U, Lehmann T. A single
discontinuation of denosumab: a post hoc analysis of the randomized infusion of zoledronate in postmenopausal women following denosumab
placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. discontinuation results in partial conservation of bone mass gains. J Bone
2018;33(2):190-198. PMID: 29105841 Miner Res. 2020;35(7):1207-1215. PMID: 31991007
5. Tsourdi E, Zillikens MC, Meier C, et al. Fracture risk and management of 10. Sølling AS, Harsløf T, Langdahl B. Treatment with zoledronate subsequent
discontinuation of denosumab therapy: a systematic review and position to denosumab in osteoporosis: a randomized trial. J Bone Miner Res.
statement by ECTS. J Clin Endocrinol Metab. 2021 [online ahead of print]. 2020;35(10):1858-1870. PMID: 32459005
PMID: 33103722

84  ENDO 2022 • Endocrine Case Management

Using the Best Available
Evidence to Personalize
Osteoporosis Treatment
E. Michael Lewiecki, MD. University of New Mexico Health Sciences Center, Albuquerque,
NM; E-mail: [email protected]

Micol S. Rothman, MD. University of Colorado School of Medicine, Aurora, CO; E-mail:
[email protected]

Learning Objectives medications used to treat them,5 casting into doubt

the applicability of the studies for some patients.
As a result of participating in this session, learners
Guidelines developed by experts interpreting the
should be able to:
best available medical evidence may be simpler,
• Assess fracture risk and tailor medication more intuitive, and easier to apply in clinical
choice accordingly. practice, but are open to criticism that they are
overly subjective and based on a lower level
• Identify strategies for treatment sequence with
of evidence. The application of any guideline
osteoporosis medications.
for making decisions for individual patients
• Recognize the onset and offset of treatment must consider all available clinical information.
effects of different osteoporosis medications. Individual fracture risk should be examined when
making treatment decisions. Additionally, prior
medication exposure and duration of treatment,
as well as patient preference, must be taken into
Main Conclusions account when thinking about future therapies.
Many clinical practice guidelines address the
management of patients with osteoporosis.1-4
These guidelines are often developed by societies Significance of the
or organizations that focus on specific patient
populations using divergent approaches to
Clinical Problem
analyzing and interpreting the medical evidence, Osteoporosis is a common disorder characterized
with or without consideration of cost-effectiveness, by low bone density and poor bone quality
and with differing views on inclusion of expert resulting in increased risk of fractures. Despite the
opinion. Guidelines that rely exclusively on availability of excellent tools to assess fracture risk
data derived from large, randomized, placebo- and approved medications that reduce fracture
controlled clinical trials are scientifically rigorous risk, most patients at risk for fractures are not
but tend to be restrictive, complex, and lacking being treated.6 The large treatment gap is now
the flexibility needed to address the needs of some recognized as a global crisis in the care of patients
patients. Many or most patients seen in clinical with osteoporosis.7
practice would not qualify for participation in
the clinical trials supporting the approval of the

ENDO 2022 • Bone and Mineral Metabolism  85

Barriers to Optimal Practice daily. He reports no fractures, but old chest x-rays
suggest prior compression fractures. Workup
Many factors contribute to the treatment gap,
for secondary causes, including vitamin D
including fear of medication adverse effects, poor
measurement, reveals no additional abnormalities
understanding of the balance of benefits and
other than a low morning testosterone
risks with treatment, inadequate communication
concentration of 250 ng/dL (8.7 nmol/L).
skills to quantify risk, lack of appreciation of the
potentially serious consequences of fractures, Which of the following treatments
failure to recognize that a prior fracture is due would best reduce this patient’s
to osteoporosis, reductions in reimbursement future risk of vertebral fracture?
for bone density testing (in the United States)
A. Calcium and vitamin D, weight-bearing
resulting in the closure of many office-based DXA
exercise as tolerated, and steroid taper (discuss
facilities, conflicting clinical practice guidelines,
with transplant team)
limited available time for physician-patient
encounters, and competing health care priorities. B. Subcutaneous teriparatide
C. Weekly oral alendronate
Strategies for Diagnosis, D. Weekly testosterone injections
Therapy, and/or Management Answer: B) Subcutaneous teriparatide
Many strategies to reduce the treatment gap This patient has severe osteoporosis with
have been proposed,8 including technology- very high fracture risk. Prevention of further
enabled collaborative learning, the prototype of compression fractures could be crucial to protect
which is Bone Health TeleECHO.9 Tools and his lung function. Pharmacologic therapy is
algorithms have been developed to help patients indicated (thus, Answer A is incorrect).
and providers alike better quantify the risks Given his low testosterone level, he should
and benefits of osteoporosis therapy. However, be worked up for true hypogonadism. However,
providers must recognize that there is not a “one even if further workup indicates he would benefit
size fits all” answer for many patients. At times, from testosterone replacement, there are no data
more than 1 visit and a variety of materials may be regarding the effect of testosterone on fracture risk
needed for patients to understand their diagnosis (thus, Answer D is incorrect). Endocrine Society
of osteoporosis and feel comfortable with guidelines suggest that hypogonadal men who are
initiation of medication. Clinical judgment, patient at high risk of fracture be treated with an agent with
preference, and other factors are key aspects of fracture-proven efficacy and that testosterone should
managing complex cases of osteoporosis. only be given “in lieu of a bone drug” if serum levels
are below 200 ng/dL (<6.9 nmol/L) on more than
Clinical Case Vignettes 1 occasion with symptoms of androgen deficiency
and if the fracture risk is borderline-high.10
Case 1 An 18-month, randomized, head-to-head trial
A 54-year-old man with a history of lung in 414 patients comparing teriparatide (Answer
transplant for chronic obstructive pulmonary B) to alendronate (Answer C) in patients with
disorder 1 year ago presents after DXA shows a glucocorticoid-induced osteoporosis showed larger
lowest T-score of –3.1 in the lumbar spine. He gains in spine bone mineral density (7.2% vs 3.4%)
had been treated with prednisone bursts prior and lower rates of vertebral compression fracture
to his lung transplant, has had several episodes (0.6 vs 6.1%) in the teriparatide-treated group.11
of rejection that required pulse doses of steroids, Although oral alendronate is a reasonable
and remains on a prednisone dosage of 10 mg choice if teriparatide is not financially feasible,

86  ENDO 2022 • Endocrine Case Management

is contraindicated, or is otherwise not desired not exist for any other osteoporosis therapy. We
by the patient, the strongest data for secondary know that stopping denosumab can lead to rapid
fracture prevention in this scenario would be rise in bone turnover markers, rapid decrease
with teriparatide. The American College of in bone mineral density, return of fracture risk
Rheumatology guidelines suggest alendronate to baseline, and possible increase in the risk of
for first-line therapy based on cost, while other multiple vertebral fractures.14 Ideally, there would
guidelines from Europe advocate for teriparatide have been discussion with the oral surgeon before
as first-line therapy in a patient at high risk.12 the tooth extraction to discuss the possibilities of a
Note that other anabolic agents (abaloparatide short delay of therapy, changing to an alternative
and romosozumab) are not US FDA-approved for medication, or performing extraction without
osteoporosis in men at this time. delaying or stopping denosumab.
When patients present with vertebral fracture
in the setting of stopping denosumab, kyphoplasty
Case 2
has not been shown to be beneficial and may,
A 67-year-old woman with a history of a in fact, lead to further compression fractures
Colles fracture at age 63 years was treated with (therefore, Answer B is correct, as this step should
denosumab for 4 years. On the advice of her NOT be advised now).15
oral surgeon, she stopped denosumab before It is crucial for this patient to resume some
having a tooth extraction 10 month ago and has type of osteoporosis therapy; however, there are
not resumed treatment since then. She returns multiple options as outlined in the remaining
for follow-up after a recent hospitalization for answer choices. If the patient has done well
multiple painful vertebral compression fractures. on denosumab, resumption of this medication
She has normal kidney function and no history of (Answer C) is reasonable. If she cannot commit
cardiovascular disease or malignancy. to resuming therapy every 6 months, giving
intravenous zoledronic acid (Answer A) could
Which of the following also be an option considering its antifracture
should NOT be advised? benefits and ease of administration. Although
A. Administer intravenous zoledronic acid there are concerns about bone loss when switching
B. Consult with interventional radiology for from denosumab to an anabolic agent,16 given
kyphoplasty this patient’s compression fractures and possible
C. Resume denosumab now need for ongoing dental work, anabolic therapy
D. Start anabolic therapy with teriparatide, (Answer D) could be an option as well. This
abaloparatide, or romosozumab would perhaps be best done in combination with
antiresorptive therapy.15
Answer: B) Consult with interventional
radiology for kyphoplasty Case 3
There has been much recent discussion of how A 56-year-old woman presents after recently
and when to stop/bridge denosumab if needed or stopping menopausal hormone therapy with patch
desired. First, it must be emphasized that there estradiol and daily progestin. She has been on this
is no role for a drug holiday with denosumab. therapy since the onset of menopausal symptoms
After stopping denosumab, treatment effect will in her early 50s. To her knowledge, she has never
be rapidly lost if another agent is not started. The had a fracture. She is not having hot flashes or
properties of bisphosphonates are unique in that other bothersome menopausal symptoms, but she
they are slowly released from the bone, providing worries about bone loss because her mother had
continuing protection for variable amounts of a hip fracture at age 78 years. Recent DXA shows
time after administration is stopped.13 This does

ENDO 2022 • Bone and Mineral Metabolism  87

T-scores of –2.1 in the spine and –1.8 in the femoral option would not be advised at this time.
neck. She wants to know how best to mitigate bone However, studies looking at bone mineral density
loss in the setting of stopping estrogen. and bone turnover markers confirm a rapid return
to high bone turnover marker levels, a different
Which of the following profile than that observed after stopping long-
statements is most correct? term bisphosphonate therapy, where a slow rise
A. A bisphosphonate could provide skeletal benefit of bone turnover markers can be expected.17,18
B. If spine imaging shows a previously Therefore, stopping estrogen would likely lead to
unrecognized vertebral fracture, she should an increase in serum C-telopeptide (thus, Answer
resume estrogen D is incorrect).
In a healthy patient with osteopenia and
C. She should avoid weight training due to her
no known fractures, weight training is not
low spine bone mineral density
contraindicated (thus, Answer C is incorrect).
D. Stopping estrogen will most likely decrease The latest Endocrine Society guidelines for
serum C-telopeptide, a marker of bone turnover postmenopausal osteoporosis suggest starting
Answer: A) A bisphosphonate could alternative treatments when estrogen is stopped
provide skeletal benefit in women with osteoporosis,13 but this does
not cover women at lower risk, such as this
This patient’s current fracture risk is likely low. patient. However, bisphosphonates can benefit
However, if imaging were to show compression postmenopausal women with osteopenia.19,20
fractures, a more aggressive option should be Given this patient’s concerns based on family
considered (thus, Answer B is incorrect). history, bisphosphonate therapy (Answer A) could
Since she has stopped menopausal hormone be an attractive option.21
therapy without symptoms, returning to this

References
1. Eastell R, Rosen CJ, Black DM, Cheung AM, Murad MH, Shoback D. 9. Lewiecki EM, Boyle JF, Arora S, Bouchonville MF 2nd, Chafey DH.
Pharmacological management of osteoporosis in postmenopausal women: Telementoring: a novel approach to reducing the osteoporosis treatment gap.
an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. Osteoporos Int. 2017;28(1):407-411. PMID: 27439373
2019;104(5):1595-1622. PMID: 30907953 10. Watts NB, Adler RA, Bilezikian JP, et al; Endocrine Society. Osteoporosis in
2. Cosman F, de Beur SJ, LeBoff MS, et al; National Osteoporosis Foundation. men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab.
Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2012;97(6):1802-1822. PMID: 22675062
2014;25(10):2359-2381. PMID: 25182228 11. Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in
3. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical glucocorticoid-induced osteoporosis. N Engl J Med. 2007;357(20):2028-2039.
Endocrinologists and American College of Endocrinology clinical practice PMID: 18003959
guidelines for the diagnosis and treatment of postmenopausal osteoporosis 12. Rothman MS, Olenginski TP, Stanciu I, Krohn K, Lewiecki EM. Lessons
- 2016--executive summary. Endocr Pract. 2016;22(9):1111-1118. PMID: learned with Bone Health TeleECHO: making treatment decisions when
27643923 guidelines conflict. Osteoporos Int. 2019;30(12):2401-2406. PMID: 31471665
4. Qaseem A, Forciea MA, McLean RM, Denberg TD, et al; Clinical Guidelines 13. Eastell R, Rosen CJ, Black DM, Cheung AM, Murad MH, Shoback D.
Committee of the American College of Physicians. Treatment of low bone Pharmacological management of osteoporosis in postmenopausal women:
density or osteoporosis to prevent fractures in men and women: a clinical an Endocrine Society* clinical practice guideline. J Clin Endocrinol Metab.
practice guideline update from the American College of Physicians. Ann Intern 2019;104(5):1595-1622. PMID: 30907953
Med. 2017;166(11):818-839. PMID: 28492856 14. Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O.
5. Dowd R, Recker RR, Heaney RP. Study subjects and ordinary patients. Clinical features of 24 patients with rebound-associated vertebral fractures
Osteoporos Int. 2000;11(6):533-536. PMID: 10982170 after denosumab discontinuation: systematic review and additional cases. J
6. Miller PD. Underdiagnosis and undertreatment of osteoporosis: the battle to Bone Miner Res. 2017;32(6):1291-1296. PMID: 28240371
be won. J Clin Endocrinol Metab. 2016;101(3):852-859. PMID: 26909798 15. Tsourdi E, Zillikens MC, Meier C, et al. Fracture risk and management of
7. Khosla S, Shane E. A crisis in the treatment of osteoporosis. J Bone Miner Res. discontinuation of denosumab therapy: a systematic review and position
2016;31(8):1485-1487. PMID: 27335158 statement by ECTS. J Clin Endocrinol Metab. 2020;dgaa756. PMID: 33103722
8. Khosla S, Cauley JA, Compston J, et al. Addressing the crisis in the treatment 16. Leder BZ, Tsai JN, Uihlein AV, et al. Denosumab and teriparatide transitions
of osteoporosis: a path forward. J Bone Miner Res. 2017;32(3):424-430. PMID: in postmenopausal osteoporosis (the DATA-Switch study): extension of
28099754 a randomised controlled trial. Lancet. 2015;386(9999):1147-1155. PMID:
26144908

88  ENDO 2022 • Endocrine Case Management

17. Greenspan SL, Emkey RD, Bone HG, Wet al. Significant differential effects of 20. Quandt SA, Thompson DE, Schneider DL, Nevitt MC, Black DM, Fracture
alendronate, estrogen, or combination therapy on the rate of bone loss after Intervention Trial Research G. Effect of alendronate on vertebral fracture
discontinuation of treatment of postmenopausal osteoporosis. A randomized, risk in women with bone mineral density T scores of -1.6 to -2.5 at the
double-blind, placebo-controlled trial. Ann Intern Med. 2002;137(11):875-883. femoral neck: the Fracture Intervention Trial. Mayo Clin Proc. 2005;80(3):343-
PMID: 12458987 349. PMID: 15757015
18. Wasnich RD, Bagger YZ, Hosking DJ, et al;Early Postmenopausal 21. Rothman MS, Olenginski TP, Stanciu I, Krohn K, Lewiecki EM. Lessons
Intervention Cohort Study Group. Changes in bone density and turnover learned with Bone Health TeleECHO: making treatment decisions when
after alendronate or estrogen withdrawal. Menopause. 2004;11(6 Pt 1):622- guidelines conflict. Osteoporos Int. 2019;30(12):2401-2406. PMID: 31471665
630. PMID: 15545790
19. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in
postmenopausal women with low bone mineral density. N Engl J Med.
2002;346(9):653-661. PMID: 11870242

ENDO 2022 • Bone and Mineral Metabolism  89

CARDIOVASCULAR
ENDOCRINOLOGY
Choosing Cholesterol-
Lowering Medications in
Patients With Liver Disease
Savitha Subramanian, MD. Department of Medicine, Division of Metabolism,
Endocrinology, and Nutrition, University of Seattle, Seattle, WA; E-mail: [email protected]

Learning Objectives liver disease. Lipoprotein X is an abnormal

lipoprotein particle containing free cholesterol
As a result of participating in this session, learners
often observed in acquired cholestatic liver
should be able to:
dysfunction. Skin xanthomas may arise and
• Appropriately stratify risk and manage patients marked hypercholesterolemia occurs in persons
with dyslipidemia in the setting of liver disease. with lipoprotein X. Treatment of the underlying
liver dysfunction, often requiring liver transplant,
• Initiate appropriate lipid-lowering therapy in
resolves abnormal lipoprotein X. Dyslipidemia that
patients with liver function test abnormalities.
occurs after liver transplant should be promptly
addressed with appropriate lipid-lowering therapy.

Main Conclusions
Mild transaminase elevations are a common
Significance of the
occurrence in persons with nonalcoholic/ Clinical Problem
metabolic fatty liver disease (NAFLD or recently Dyslipidemia is a common occurrence in
referred to as MAFLD), where hepatic steatosis individuals with NAFLD, and it drives
is associated with metabolic dysfunction such cardiovascular risk. NAFLD is increasing in
as insulin resistance, metabolic syndrome, prevalence and is currently estimated to affect
and type 2 diabetes mellitus. Statin therapy is nearly 25% of adults worldwide and is the leading
indicated for treatment of cardiovascular risk cause of liver disease. It is closely associated with
reduction in patients with NAFLD. Statin therapy other metabolic disorders such as obesity and type
decreases LDL-cholesterol levels and can improve 2 diabetes, and its prevalence is much higher in
transaminitis.1 Ezetimibe may also be used to persons with these conditions. An atherogenic
lower LDL cholesterol, but cardiovascular benefits dyslipidemia is often observed; NAFLD is now
in this population are still unknown. Fibrates can considered a cardiovascular risk factor, and risk
be used to treat moderate hypertriglyceridemia mitigation strategies are essential. However,
and are safe and usually well tolerated in patients individuals with NAFLD often have elevated liver
with NAFLD. However, evidence that treatment enzymes, and there is still clinician hesitancy in
of dyslipidemia with any lipid-lowering agent starting and/or continuing lipid-lowering therapy,
improves histology or liver-related outcomes in especially statins. Additionally, guidelines on lipid
patients with steatohepatitis is currently lacking. management in NAFLD are lacking.
Dyslipidemia is also described in patients The liver has a central role in cholesterol
with other liver disorders such as cholestatic metabolism, including cholesterol biosynthesis,

92  ENDO 2022 • Endocrine Case Management

storage, and excretion. Therefore, liver disease can moderate-to-advanced liver fibrosis compared
affect cholesterol levels, depending on the type of with what is observed in those without diabetes.
liver injury (eg, parenchymal, cholestatic, or mixed). Therefore, dyslipidemia of NAFLD should be
Hypercholesterolemia, with a relative increase of addressed in a timely manner by initiating statin
free cholesterol, is an early and peculiar metabolic therapy.3
alteration in cholestatic liver disease. Lipoprotein The liver has a central role in lipoprotein
composition and metabolism are altered, and an metabolism, as it is involved in the synthesis and/
anomalous lipoprotein called lipoprotein X is or clearance of all lipoproteins.4 Hepatocytes, a
present. Very high cholesterol levels (>1000 mg/dL major site of cholesterol metabolism, are a main
[>25.90 mmol/L]) levels can occur. This condition target of statins. Alanine aminotransferase elevations
is often underrecognized in clinical practice. occur independently of statins in patients with
NAFLD. Several studies have established the safety
of statins in patients with a baseline elevation in
Barriers to Optimal Practice liver enzymes. Statins decrease hepatic transaminases
in NAFLD. Risk of statin-induced hepatotoxicity
• Hesitancy using appropriate lipid-lowering
is not increased in individuals with NAFLD or
medication in the setting of transaminitis
NASH, and serious liver injury from statin therapy
associated with NAFLD and NASH.
is very rare in clinical practice. Statins should be
• Recognition of the underlying etiology leading avoided in patients with decompensated cirrhosis,
to dyslipidemia in liver disease. as there are very few safety data. Periodic monitoring
of serum alanine aminotransferase levels does not
detect or prevent serious liver injury due to statin
Strategies for Diagnosis, use and is therefore not recommended.5 Ezetimibe is
Therapy, and/or Management also associated with LDL-cholesterol reductions in
NAFLD; improvements in liver function have also
Lipid Disorders in NAFLD been observed. Effects on steatosis and NAFLD
Diagnosis activity score appear to be mixed. A post hoc analysis
Atherogenic dyslipidemia characterized by mild of the IMPROVE-IT study showed that patients
to moderate hypertriglyceridemia with low classified as being at high risk for liver fibrosis using
HDL cholesterol and increased small dense LDL the NAFLD fibrosis score showed greater reductions
particles is commonly observed. in recurrent cardiovascular disease with simvastatin
and ezetimibe compared with those classified as
Treatment being at low risk. PCSK9 inhibitors show promise
Cardiovascular morbidity and mortality are in decreasing intrahepatic fat in patients with
increased in patients with NAFLD. Metabolic NAFLD but further evidence is needed.
derangements are the primary contributor to
increased cardiovascular risk in these individuals.
NAFLD is associated with increased risk of fatal Lipid Disorders in Other
and nonfatal cardiovascular events, as well as other Liver Diseases
cardiac complications, such as cardiomyopathy, Cholestatic Liver Disease
cardiac valvular calcification, and cardiac The liver converts cholesterol to bile acids and
arrhythmias. This increased risk is independent removes free cholesterol via biliary excretion.
of traditional cardiovascular risk factors and is Cholestatic liver disease (primary biliary
proportional to the severity of liver disease.2 In cirrhosis or primary sclerosing cholangitis) due
individuals with type 2 diabetes and NALFD, to impaired bile flow results in accumulation of
atherogenic dyslipidemia is associated with bile acids and other metabolites in the liver and

ENDO 2022 • Cardiovascular Endocrinology  93

systemic circulation. In the setting of cholestatic be atherogenic. It is estimated, however, that about
liver disease, a unique, abnormal lipoprotein 10% of patients with primary biliary cirrhosis have a
with similar density to LDL but without its significant risk of cardiovascular disease and should
surface protein apolipoprotein B appears in the be treated with medications to reduce that risk.
circulation.6 These lipoproteins contain only
phospholipid and unesterified cholesterol and Dyslipidemia After Liver Transplant
are referred to as lipoprotein X. In cholestasis, Dyslipidemia is common following liver transplant,
there is impaired bile flow; it is believed that these occurring in more than 60% of transplant recipients.
lipoprotein-like lipoprotein X particles are due Posttransplant dyslipidemia is commonly observed in
to reflux of biliary lipoproteins into the systemic patients with higher BMI or type 2 diabetes before
circulation due to cholestasis. transplant; it can also develop in the absence of these
Extreme cholesterol elevations can occur comorbid conditions. Use of immunosuppressant
and result in artifactual abnormalities in medications, including calcineurin inhibitors and
electrolytes (hyponatremia) and hyperviscosity. mTOR inhibitor sirolimus, increase the risk of
Xanthomas can develop in the palms on occasion. dyslipidemia. Lipids should be regularly assessed in
Neuropathic symptoms can occur because of large liver transplant recipients.
xanthomas. Such striking cholesterol elevations Liver transplant recipients have increased
are reflective of significant liver dysfunction, and cardiovascular risk, especially those with features
hypercholesterolemia resolves only after liver of the metabolic syndrome or diabetes. Liver graft
dysfunction resolves. steatosis can occur. Statins are mostly safe to use in
Statins, ezetimibe, and fibrates have all been the posttransplant setting. Calcineurin inhibitors
shown to be safe in patients with cholestatic liver and several statins are metabolized by cytochrome
disease but are of limited benefit when serum P450 3A4, and concurrent use of higher dosages
cholesterol levels are markedly elevated. Blood may increase the risk of statin-associated myopathy.7
filtering using plasma exchange can be used as a
temporizing measure to decrease cholesterol levels;
only correction of underlying liver pathology (often
with liver transplant) results in complete reversal of
lipid abnormalities. Lipoprotein X is not believed to

Total HDL LDL Fasting plasma Hemoglobin

Time point cholesterol Triglycerides cholesterol cholesterol glucose A1c AST ALT
5 years ago 253 mg/dL 293 mg/dL 41 mg/dL 153 mg/dL 106 mg/dL 5.6% 22 U/L 61 U/L
(SI: 6.55 (SI: 3.31 (SI: 1.06 (SI: 3.96 (SI: 5.88 (38 mmol/mol) (SI: 0.37 (SI: 1.02
mmol/L) mmol/L) mmol/L) mmol/L) mmol/L) µkat/L) µkat/L)
5 years ago 274 mg/dL 275 mg/dL 40 mg/dL 179 mg/dL 130 mg/dL 6.2% 26 U/L 47 U/L
(atorvastatin, (SI: 7.10 (SI: 3.11 (SI: 1.04 (SI: 4.64 (SI: 7.22 (44 mmol/mol) (SI: 0.43 (SI: 0.78
10 mg daily, mmol/L) mmol/L) mmol/L) mmol/L) mmol/L) µkat/L) µkat/L)
started)
3 years ago 196 mg/dL 377 mg/dL 36 mg/dL 85 mg/dL 143 mg/dL 6.8% 23 U/L 64 U/L
(SI: 5.08 (SI: 4.26 (SI: 0.93 (SI: 2.20 (SI: 7.94 (51 mmol/mol) (SI: 0.38 (SI: 1.07
mmol/L) mmol/L) mmol/L) mmol/L) mmol/L) µkat/L) µkat/L)
Most recent 181 mg/dL 422 mg/dL 39 mg/dL … 150 mg/dL 7.1% 47 U/L 86 U/L
(SI: 4.69 (SI: 4.77 (SI: 1.01 (SI: 8.33 (54 mmol/mol) (SI: 0.78 (SI: 1.44
mmol/L) mmol/L) mmol/L) mmol/L) µkat/L) µkat/L)

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Reference ranges: fasting glucose, 70-99 mg/dL (SI: 3.9-5.5 mmol/L); hemoglobin A1c, 4.0%-5.6% (20-38 mmol/mol); ALT, 10-40 U/L (SI: 0.17-0.67 µkat/L);
AST, 20-48 U/L (SI: 0.33-0.80 µkat/L).

94  ENDO 2022 • Endocrine Case Management

Clinical Case Vignettes levels are likely a reflection of recent-onset
diabetes corresponding to weight gain. There
Case 1 is no indication to discontinue atorvastatin
A 44-year-old woman is referred for management (Answer A) at this time. Although increasing the
of dyslipidemia and gradually increasing elevated atorvastatin dosage to 40 mg daily (Answer B) is
liver enzymes first noted about 5 years ago. At that not necessarily wrong, it is not the best option,
time, atorvastatin (10 mg daily) was initiated, and as she had good LDL-cholesterol lowering on
she has continued this regimen. the dosage of 10 mg daily. Statins are not good
Laboratory test results are shown in the Table triglyceride-lowering agents.
(previous page). Instead, maximizing metformin therapy
She followed up with her primary care (Answer C) is a better option due to rising
provider for a few years. Recently, her hemoglobin hemoglobin A1c values.
A1c level has increased, type 2 diabetes has been Additionally, intermittent scanned continuous
diagnosed, and metformin has been initiated at a glucose monitoring (Answer D), if covered by
dosage of 500 mg twice daily. She reports a weight insurance, is acceptable. This patient specifically
gain of 15 lb (6.8 kg) in the past 18 months. Her came to clinic requesting use of intermittent
weight continues to increase, and physical activity scanned continuous glucose monitoring. She
levels have dropped. Abdominal ultrasonography incorporated lifestyle efforts and was able to
obtained as part of the evaluation for elevated liver decrease her hemoglobin A1c level to 6.1%
enzymes reveals hepatic steatosis. Her most recent (43 mmol/mol). Liver transaminase levels
hemoglobin A1c level is 7.5% (58 mmol/mol). decreased to what was observed 7 years prior.
There is a family history of premature Therefore, both Answers C and D are correct.
atherosclerotic cardiovascular disease in her mother,
and many family members have type 2 diabetes. She
Case 2
does not drink more than 1 alcoholic beverage a week.
She is commercially insured through her employer. A 24-year-old man with a diagnosis of primary
She is concerned about her liver test results sclerosing cholangitis is referred from hepatology
and seeks your recommendation. for management of very high cholesterol levels
and bumps on his elbows and palms.
Which of the following is the best next step?
Laboratory test results:
A. Discontinue atorvastatin and start fenofibrate
Total cholesterol = 1382 mg/dL (<200 mg/dL
B. Increase the atorvastatin dosage to 40 mg daily [optimal]) (SI: 35.79 mmol/L [<5.18 mmol/L])
C. Increase the metformin dosage to 1000 mg Triglycerides = 141 mg/dL (<150 mg/dL
twice daily [optimal]) (SI: 1.59 mmol/L [<1.70 mmol/L])
LDL cholesterol = 1347 mg/dL (<100 mg/dL
D. Start intermittent scanned glucose monitoring [optimal]) (SI: 34.89 mmol/L [mmol/L])
HDL cholesterol = 7 mg/dL (>60 mg/dL
Answer: C and D): Increase the metformin [optimal]) (SI: 0.18 mmol/L [>1.55 mmol/L])
dosage to 1000 mg twice daily (C) and start Serum sodium = measurements range from 129 to
intermittent scanned glucose monitoring (D) 133 mEq/L (129 to 133 mmol/L)
Alanine aminotransferase = 255 U/L (10-40 U/L)
This patient has a history of mild liver (SI: 4.26 µkat/L [0.17-0.67 µkat/L])
transaminase elevations, which have recently Aspartate aminotransferase = 298 U/L (20-48 U/L)
worsened. Low-intensity atorvastatin is safe and (SI: 4.98 µkat/L [0.33-0.80 µkat/L])
Total bilirubin = 6.0 mg/dL (0.3-1.2 mg/dL)
has been effective in lowering this woman’s LDL (SI: 102.6 µmol/L [5.1-20.5 µmol/L])
cholesterol. However, recent elevation in aspartate
aminotransferase and alanine aminotransferase

ENDO 2022 • Cardiovascular Endocrinology  95

Which of the following is the best Total cholesterol = 219 mg/dL (SI: 5.67 mmol/L)
next step in this patient’s care? Triglycerides = 178 mg/dL (SI: 2.01 mmol/L)
LDL cholesterol = 155 mg/dL (SI: 4.01 mmol/L)
A. Refer for LDL apheresis
B. Refer for therapeutic plasma exchange Therefore, the best answer is none of the above
C. Start colesevelam (Answer E).
D. Start pravastatin
E. None of the above Case 3
A 62-year-old woman is referred from hepatology.
Answer: E) None of the above She underwent liver transplant for NASH-related
In cholestatic liver disease, lipoprotein X (LDL- cirrhosis. At the 1-year postliver transplant biopsy,
like particles lacking apolipoprotein B on the macrovesicular steatosis was noted, and she was
surface) can be present in the circulation, occurring subsequently referred for treatment options. Her
in up to 45% of patients. Extreme cholesterol history is notable for hypertension and type 2
elevations can occur with resultant artifactual diabetes (managed with lifestyle efforts) prior to
abnormalities in electrolytes (hyponatremia) and transplant, as well as longstanding hyperlipidemia
hyperviscosity. Xanthomas can occur in the palms. with intolerance to statins. Multiple statins were
While statins (Answer D) seem to be safe tried over the years with significant muscle
in individuals with cholestatic liver disease, it is adverse effects. There is also a history of possible
highly unlikely statins will result in significant transient ischemic attack 3 years before transplant.
LDL-cholesterol reduction in a patient with such Currently, her immunosuppression regimen
marked hypercholesteremia. includes tacrolimus. She also takes ezetimibe
Colesevelam (Answer C) is a bile acid resin without issues. Metformin was recently added due
with only modest cholesterol-lowering ability. to rising hemoglobin A1c values.
LDL apheresis (Answer A), which physically Laboratory test results are shown in the Table.
removes LDL particles (by virtue of the presence
of apolipoprotein B on LDL) from the blood, will Which of the following therapies
not clear lipoprotein X, which lacks apolipoprotein should be added at this time?
B on its surface.
A. Bempedoic acid
Plasma exchange (Answer B) can be
useful in decreasing cholesterol levels, but B. Evolocumab
it is a temporizing measure. C. Icosapent ethyl
This patient underwent orthotopic liver D. Fenofibrate
transplant, which normalized lipid levels:

Time point Total cholesterol Triglycerides HDL cholesterol LDL cholesterol Hemoglobin A1c
Pretransplant (started 190 mg/dL 82 mg/dL 59 mg/dL 115 mg/dL 6.2%
ezetimibe, 10 mg daily) (SI: 4.92 mmol/L) (SI: 0.93 mmol/L) (SI: 1.53 mmol/L) (SI: 2.98 mmol/L) (44 mmol/mol)
1 year after transplant 195 mg/dL 430 mg/dL 54 mg/dL 141 mg/dL 6.6%
(continued ezetimibe, (SI: 5.05 mmol/L) (SI: 4.86 mmol/L) (SI: 1.40 mmol/L) (SI: 3.65 mmol/L) (49 mmol/mol)
10 mg daily, added
metformin)
After transplant; most 252 mg/dL 357 mg/dL 63 mg/dL 118 mg/dL 6.7%
recent measurements (SI: 6.53 mmol/L) (SI: 4.03 mmol/L) (SI: 1.63 mmol/L) (SI: 3.06 mmol/L) (50 mmol/mol)
(continued, ezetimibe,
10 mg daily)

Reference range: hemoglobin A1c, 4.0%-5.6% (20-38 mmol/mol).

96  ENDO 2022 • Endocrine Case Management

Answer: B) Evolocumab into an active drug by a specific isozyme that is
not present in skeletal muscle and can be used
Evolocumab (Answer B) is a PCSK9 inhibitor in patients with statin intolerance due to muscle
that can be used in individuals at high risk for adverse effects. LDL-cholesterol reduction of
atherosclerotic cardiovascular disease (such as approximately 18% to 28% is observed (36% to
this woman) who have not reached their LDL- 46% when used in combination with ezetimibe).
cholesterol targets. In this patient with type 2 However, safety in liver transplant recipients
diabetes, hypertension, and history of transient is unknown.
ischemic attack, the LDL-cholesterol goal is less Fenofibrate (Answer D) is an effective
than 70 mg/dL (<1.81 mmol/L). Addition of triglyceride-lowering agent; however, there
a PCSK9 inhibitor is an appropriate next step. are very limited data on use in liver transplant
Icosapent ethyl (Answer C) is also beneficial in recipients and there is lack of proven
patients at high cardiovascular risk when it is cardiovascular benefit to justify addition at
added to statin therapy; monotherapy benefit this time.
is unclear.
Bempedoic acid (Answer A) is a new agent This patient started PCSK9 inhibitor therapy with
that acts in the same cholesterol biosynthesis excellent response:
pathway as statins. It targets ATP-citrate lyase (an
Total cholesterol = 139 mg/dL (SI: 3.60 mmol/L)
enzyme that is upstream of HMG-CoA reductase), Triglycerides = 311 mg/dL (SI: 3.51 mmol/L)
upregulates LDL receptors, and therefore lowers LDL cholesterol = 16 mg/dL (SI: 0.41 mmol/L)
LDL cholesterol. Bempedoic acid is converted HDL cholesterol = 61 mg/dL (SI: 1.58 mmol/L)

References
1. Speliotes EK, Balakrishnan M, Friedman LS, and Corey KE. Treatment 5. Bays H, Cohen DE, Chalasani N, Harrison SA, The National Lipid
of dyslipidemia in common liver diseases. Clin Gastroenterol Hepatol. Association’s Statin Safety Task Force. An assessment by the Statin Liver
2018;16(8):1189-1196. PMID: 29684459 Safety Task Force: 2014 update. J Clin Lipidol. 2014;8(Suppl 3):S47-S57.
2. Targher G, Corey KE, Byrne CD. NAFLD, and cardiovascular and cardiac PMID: 24793441
diseases: factors influencing risk, prediction and treatment. Diabetes Metab. 6. Brandt EJ, Regnier SM, Leung EK, et al. Management of lipoprotein X and
2021;47(2):101215. PMID: 33296704 its complications in a patient with primary sclerosing cholangitis. Clin Lipidol.
3. Amor AJ, and Perea V. Dyslipidemia in nonalcoholic fatty liver disease. Curr 2015;10(4):305-312. PMID: 26413163
Opin Endocrinol Diabetes Obes. 2019;26(2):103-108. PMID: 30694825 7. Kellick KA, Bottorff M, Toth PP; The National Lipid Association’s Safety
4. Nemes K, Aberg F, Gylling H, Isoniemi H. Cholesterol metabolism Task Force. A clinician’s guide to statin drug-drug interactions. J Clin Lipidol.
in cholestatic liver disease and liver transplantation: from molecular 2014;8(Suppl 3):S30-S46. PMID: 24793440
mechanisms to clinical implications. World J Hepatol. 2016;8(22):924-932.
PMID: 27574546

ENDO 2022 • Cardiovascular Endocrinology  97

Update on Genetic Causes
of Hypercholesterolemia:
What’s New in the Evaluation
and Treatment of These
Hard-to-Treat Patients
Marc-Andre Cornier, MD. Division of Endocrinology, Diabetes, and Metabolic Diseases,
Medical University of South Carolina, Charleston, SC; E-mail: [email protected]

Learning Objectives therapies offer novel mechanisms to substantially

lower LDL cholesterol in these otherwise difficult-
As a result of participating in this session, learners
to-treat patients. Finally, in some patients, LDL
should be able to:
apheresis is necessary and should be considered.
• Recognize and initiate an appropriate
evaluation of patients with
hypercholesterolemia. Significance of the
• Provide individualized goals for treatment of Clinical Problem
hypercholesterolemia.
It was not until the turn of the 20th century that
• Explain different medical treatment options cholesterol was identified as a key component of
for cholesterol lowering. atherosclerosis and that feeding cholesterol to
• Be aware of other treatment options such rodents was shown to produce atherosclerosis. It
as new pharmacologic therapies and LDL was not until the 1930s, though, that the genetic
apheresis and recognize when to refer patients link between high cholesterol and coronary heart
to a lipid disorders specialist. disease (CHD) was identified and described as FH.
This disorder was later known to be consistent with
heterozygous FH and was associated with significantly
elevated cholesterol levels and increased risk for
Main Conclusions premature ASCVD. In the 1950s, the biosynthetic
pathways of cholesterol were further understood.1
Severe hypercholesterolemia usually has a genetic
LDL cholesterol was identified, and high levels
cause such as familial hypercholesterolemia (FH)
were determined to be associated with higher
and is associated with premature atherosclerotic
risk for CHD.2 It was not until the seminal work
cardiovascular disease (ASCVD). Aggressive,
of Brown and Goldstein in the 1970s that the
early treatment is warranted and necessary to
LDL receptor was identified and that a defect in
prevent ASCVD. Combination medical therapy is
the LDL-receptor gene was discovered to be the
typically necessary to adequately reduce the total
primary defect responsible for FH.3 We now know
cholesterol burden. The new PCSK9 modulating
that there are many different pathogenic variants

98  ENDO 2022 • Endocrine Case Management

in the LDL-receptor gene, and depending on the PCSK9 is an important regulator of LDL-
site of the variant, patients with homozygous FH receptor degradation because binding of PCSK9
are unable to produce any functional receptors or to the LDL receptor results in degradation of
are able to produce low levels of normally active the receptor, thereby preventing recycling of
LDL receptors. We also know that patients with the receptor. Individuals with elevated PCSK9
heterozygous FH have about half the normal levels due to gain-of-function pathogenic variants
amount of normally functional LDL receptors. in gene encoding PCSK9 may also have severe
ASCVD remains a major cause of death in the hypercholesterolemia clinically similar to that
United States and around the world. Cholesterol observed in patients with FH. Individuals with
is at the core of atherosclerosis development loss-of-function pathogenic variants in the gene
and is one of the major modifiable risk factors. encoding PCSK9 are associated with increased
Individuals with severe hypercholesterolemia due LDL-receptor function, very low levels of LDL
to a genetic cause are at greatly increased risk for cholesterol, and very low incidence of ASCVD.
premature ASCVD because of a high cumulative This knowledge has led to new treatment options
burden of cholesterol. Current guidelines for lowering LDL cholesterol, including inhibitors
recommend that any individual with an LDL- of PCSK9 by monoclonal antibodies and inhibition
cholesterol concentration greater than 190 mg/dL of the production of PCSK9.
(>4.92 mmol/L) should be treated aggressively.4 Severe hypercholesterolemia can occur in
Severe hypercholesterolemia can occur in the setting of mixed hyperlipidemias, which is
isolation, as seen in the different forms of FH, or it also associated with premature ASCVD. Familial
can be associated with other lipid abnormalities such combined hyperlipidemia is the most common
as concomitantly elevated triglycerides and/or genetic disorder of mixed hyperlipidemia
low HDL cholesterol such as in familial combined occurring in up to 1 in 250 persons. While a
hyperlipidemia and dysbetalipoproteinemia. specific gene variant has not been identified,
These disorders are also associated with a greatly affected individuals have increased production
increased risk for ASCVD. of apolipoprotein B–containing lipoproteins.
Isolated severe hypercholesterolemia is Familial dysbetalipoproteinemia is due to a
generally consistent with FH. Approximately genetic variation in apolipoprotein E (the E2
1 in 1 million persons is homozygous and has isoform). This is associated with reduced clearance
extremely high cholesterol levels with LDL- of remnant particles (chylomicron and VLDL
cholesterol concentrations often reaching greater remnants) and leads to planar and tuberous
than 600 mg/dL (>15.54 mmol/L). If untreated, xanthomas and premature ASCVD if untreated.
these individuals develop significant tendinous “Metabolic dyslipidemia” is the most common
xanthomas and are at risk for ASCVD and death cause of mixed hyperlipidemia associated with
at a very young age (before 20 years). More than other features of the metabolic syndrome, but it is
1600 pathogenic variants in the gene encoding generally associated with more modest elevations
the LDL receptor have been documented. The in cholesterol.
prevalence of heterozygous FH is as high as 1 in
200 to 300 persons depending on the population,
rendering FH as one of the most common serious
Barriers to Optimal Practice
genetic disorders. Untreated patients with
• Lack of effectiveness of available treatment
heterozygous FH typically have LDL-cholesterol
options.
levels in the range of 200 to 300 mg/dL (5.18 to
7.77 mmol/L) and can also develop xanthomas. • Adverse effects of currently available treatment
They are at increased risk for premature ASCVD options.
events before the fourth and fifth decades of life. • Cost of therapies.

ENDO 2022 • Cardiovascular Endocrinology  99

Strategies for Diagnosis, concentration greater than the 95th
percentile for age and sex (2 points)
Therapy, and/or Management
Diagnosis b. Clinical history:
Persons with homozygous FH typically have • Patient has premature (men <55 years,
LDL-cholesterol levels greater than 600 mg/dL women <60 years) CAD (2 points) or
(>15.54 mmol/L) and have a family history that other cardiovascular disease (1 point)
suggests both parents have heterozygous FH.
Such patients must be identified at a young age c. Physical examination:
and treated aggressively. Genetic testing can be • Tendon xanthomata (6 points)
done, but not all of the more than 1600 pathogenic
• Arcus cornealis at an age younger than
variants are identified by clinically available genetic
45 years (4 points)
testing. As such, negative results on genetic testing
does not exclude the diagnosis. Patients with d. Laboratory analysis:
heterozygous FH should be suspected in the setting
of an LDL-cholesterol concentration greater than • LDL cholesterol >330 mg/dL
160 mg/dL (>4.14 mmol/L) in children or greater (>8.55 mmol/L) (8 points)
than 190 mg/dL (>4.92 mmol/L) in adults. Most • LDL cholesterol 250-329 mg/dL
affected adults have an LDL-cholesterol level (>6.48-8.52 mmol/L) (5 points)
greater than 220 mg/dL (>5.70 mmol/L). FH should
• LDL cholesterol 190-249 mg/dL
also be suspected in the setting of the following
(>4.92-6.45 mmol/L) (3 points)
physical examination findings: (1) tendon xanthomas
at any age (most commonly in the Achilles tendon • LDL cholesterol 155-189 mg/dL
and finger extensor tendons; (2) corneal arcus in (>4.01-4.89 mmol/L) (1 points)
patients younger than 45 years; and (3) xanthelasmas • HDL cholesterol and triglycerides are
in patients younger than 20 to 25 years. normal
Different criteria have been established to help • DNA analysis: functional pathogenic
make the clinical diagnosis of FH: variant present in the LDL-receptor
1. Dutch or World Health Organization gene (8 points)
diagnostic criteria. Diagnosis of heterozygous
FH is certain when the point total is greater 2. Simon Broome Register Diagnostic Criteria
than 8, probable when 6 to 8, and possible for heterozygous FH:
when 3 to 5:
a. Definite FH is defined as:
a. Family history:
• Total cholesterol >260 mg/dL
• First-degree relative with known (6.73 mmol/L) or LDL cholesterol
premature (men <55 years, women >155 mg/dL (>4.01 mmol/L) in a
<60 years) cardiovascular disease child younger than 16 years or total
(1 point) cholesterol >290 mg/dL (>7.51 mmol/L)
• First-degree relative with known LDL- or LDL cholesterol >190 mg/dL
cholesterol concentration greater than (>4.92 mmol/L) in an adult PLUS
the 95th percentile for age and sex, tendon xanthomas in the patient or in
and/or with tendon xanthomata and/ a first- or second-degree relative
or arcus cornealis, or children younger OR
than 18 years with an LDL-cholesterol

100  ENDO 2022 • Endocrine Case Management

 • DNA-based evidence of an LDLR ASCVD risk factors should also be aggressively
pathogenic variant or familial defective managed, including hypertension, cigarette
apolipoprotein B100 smoking, and unhealthy lifestyle.
In patients with mixed hyperlipidemia, the
b. Possible FH is defined as: primary goal is to treat the hypercholesterolemia
• Total cholesterol >260 mg/dL to reduce the ASCVD risk as discussed above.
(>6.73 mmol/L) or LDL cholesterol Triglycerides should be targeted in patients with
>155 mg/dL (>4.01 mmol/L) in a severe elevations, (>400 or 500 mg/dL [>4.52 or
child younger than 16 years or total 5.65 mmol/L]) with a primary goal of reducing the
cholesterol >290 mg/dL (>7.51 mmol/L) risk of pancreatitis. Consideration should be given
or LDL cholesterol >190 mg/dL to prescribing icosapent ethyl to further reduce
(>4.92 mmol/L) in an adult ASCVD risk in patients with hypertriglyceridemia
and known ASCVD or in patients with diabetes
• And at least 1 of the following:
and multiple ASCVD risk factors.
ԗ Family history of myocardial
infarction at age younger than Treatment Options
50 years in second-degree relative
Medical Therapy
or younger than 60 years in first-
Medical therapy with high-intensity statins is the
degree relative
standard of care and cornerstone of treatment
ԗ Family history of elevated with a goal of reducing LDL cholesterol by 50%
cholesterol values >290 mg/dL or more.4 Patients who are homozygous and
(>7.51 mmol/L) in an adult first- most patients who are heterozygous, however,
or second-degree relative or need more LDL-cholesterol lowering than can
>260 mg/dL (>6.73 mmol/L) in be achieved by statin therapy alone. Multiple
a child or sibling younger than drugs are usually necessary and often may not be
16 years sufficient. Other medical treatment options to
consider include PCSK9 inhibitors, ezetimibe,
It is also important to also consider secondary
bempedoic acid, inclisiran, bile acid sequestrants,
causes of hypercholesterolemia in these patients,
and niacin. In patients who are homozygous,
including hypothyroidism, nephrotic syndrome,
lomitapide and evinacumab are possible options.
cholestatic liver disease, medications, and diet.
Statins are the gold standard therapy due to
the number of clinical trials that have shown
Treatment Goals benefit in patients with and without FH. Recent
The primary treatment goal is to reduce the evidence suggests that combination therapy with
risk of ASCVD-related events. Current joint ezetimibe or PCSK9 inhibitors confers further
guidelines published by the American College of risk reduction.5-7 There is less evidence in support
Cardiology and the American Heart Association of other treatment options such as combination
in 2018 have established that all individuals with therapy with bile acid sequestrants. More recently,
an LDL-cholesterol value greater than 190 mg/dL there have been 2 trials with negative outcomes
(>4.92 mmol/L) should be treated with a high- regarding the addition of niacin to statin therapy.
intensity statin (atorvastatin, 40/80 mg or Two PCSK9 inhibitors, alirocumab and
rosuvastatin, 20/40 mg) to lower LDL cholesterol evolocumab, have now been approved in the
by at least 50%.4 Secondary goals for primary United States for the treatment of heterozygous
prevention are to lower LDL-cholesterol levels FH8,9 and should be considered as an important
to less than 100 mg/dL (<2.59 mmol/L). Other treatment option for those patients who do not

ENDO 2022 • Cardiovascular Endocrinology  101

respond adequately to statins +/- ezetimibe. must be repeated on a regular basis, generally
These agents lower LDL cholesterol 60%, on every 1 to 2 weeks. Some patients are able to
average, beyond maximally tolerated statin extend the frequency of apheresis with newer
therapy. These agents have also been approved medical therapies. Because of the frequent need for
for the treatment of homozygous FH with vascular access, many, if not most, patients require
LDL-cholesterol lowering 20% to 40% beyond fistulas. Successful treatment of patients with LDL
maximally tolerated statin therapy.10 Inclisiran is apheresis requires a well-coordinated team of
small interfering RNA that inhibits translation experienced personnel.12
of PCSK9 and thus the production of PCSK9.
It was recently approved for use in Europe and Nonlipid Treatments
the United States to treat heterozygous FH. It Lifestyle modification, including cigarette smoking
is dosed at baseline, 3 months, and then every cessation, increased physical activity, and reduced
6 months thereafter as a subcutaneous injection. saturated fat intake should be recommended to
Inclisiran reduces LDL-cholesterol levels by 50% all patients with hypercholesterolemia. Secondary
to 55%, on average, beyond maximally tolerated causes of hyperlipidemia should also be treated
statin therapy.11 Bempedoic acid, an inhibitor of if present. Hypertension and diabetes should be
adenosine triphosphate citrate lyase upstream aggressively treated. Antiplatelet therapy with
from HMG-CoA reductase in the cholesterol low-dosage aspirin should be considered.
synthesis pathway, is also approved for the
treatment of heterozygous FH. It is taken orally at Clinical Case Vignettes
a dosage of 180 mg daily and results in 15% to 27%
LDL-cholesterol lowering depending on other Case 1
background therapy. A 45-year-old woman is referred for evaluation
Lomitapide and evinacumab are also approved and management of hyperlipidemia. She was
for the treatment of homozygous FH. Lomitapide otherwise healthy until she had a transient
is a microsomal triglyceride transfer protein ischemic attack and myocardial infarction with
inhibitor that is taken orally at a dosage of 5 to stent placement 2 years ago. Atorvastatin,
60 mg daily. Lomitapide has been shown to reduce 80 mg daily, was started after her myocardial
LDL cholesterol by up to 40% in those who can infarction for “high” cholesterol, but she developed
tolerate it. Fat in the diet must be restricted significant muscle aches on this treatment. Her
to prevent diarrhea. Because it inhibits VLDL cardiologist then tried rosuvastatin, 20 mg daily,
secretion, triglycerides can accumulate in the but she again developed muscle aches. She has
liver, leading to hepatotoxicity. Evinacumab is a been able to tolerate pravastatin, 20 mg daily.
monoclonal antibody against ANGPTL3, which She has not had any further ASCVD events to
is dosed as a monthly intravenous infusion. this point. She also takes clopidogrel, carvedilol,
Evinacumab has been shown to reduce LDL lisinopril, and sertraline. Her other medical
cholesterol by 45% to 50%. problems include hypertension and depression.
Her family history is notable for her father having
Apheresis a myocardial infarction in his 40s and her brother
LDL apheresis, the direct removal of cholesterol, undergoing coronary artery bypass graft surgery in
has been shown to prolong survival. Apheresis his early 50s. She does not smoke cigarettes, tries
should be considered in patients at high risk such to eat a diet low in saturated fat, and walks 2 miles
as those with known ASCVD whose condition every day.
has been refractory to medical therapy and/or Physical examination findings are unremarkable
those intolerant to medical therapy. LDL apheresis except for the presence of arcus cornealis.
only temporarily removes LDL particles and thus

102  ENDO 2022 • Endocrine Case Management

Laboratory test results (sample drawn while fasting): first be tried. This could be done by increasing
the dosage of the current treatment (pravastatin),
Total cholesterol = 247 mg/dL (SI: 6.40 mmol/L)
Triglycerides = 100 mg/dL (SI: 1.13 mmol/L) trying a different higher-potency statin such
LDL cholesterol = 175 mg/dL (SI: 4.53 mmol/L) as simvastatin or pitavastatin (Answer D), or
HDL cholesterol = 52 mg/dL (SI: 1.35 mmol/L) retrying atorvastatin or rosuvastatin at a lower
Complete metabolic panel, normal dosage (Answer C). It would also be reasonable
to try combination therapy with an agent such as
Question 1. What should this patient’s ezetimibe (Answer B), bempedoic acid, or a bile
primary LDL-cholesterol goal be? acid sequestrant in addition to maximized statin
therapy. Finally, PCSK9 inhibitors (Answer A) are
A. LDL cholesterol <100 mg/dL (<2.59 mmol/L)
also approved for the treatment of heterozygous
B. LDL cholesterol <70 mg/dL (<1.81 mmol/L) FH in patients who have not achieved control on
C. LDL-cholesterol reduction >50% maximally tolerated statin therapy. These agents
D. Lowest LDL-cholesterol level she can tolerate are the most likely to achieve good control of severe
hypercholesterolemia. Aggressive medical therapy
Answer: C) LDL-cholesterol reduction >50% may also help prevent the need for LDL apheresis.
Based on current guidelines, the primary goal would Apheresis might be a good option if this patient’s
be to treat this patient with high-intensity statin LDL cholesterol cannot be controlled with
therapy with a goal of reducing her LDL cholesterol aggressive medical therapy and/or she continues
by 50% or more (Answer C). Unfortunately, to have recurrent ASCVD events. Before the
she has been unable to tolerate high-intensity approval of PCSK9 inhibitors, apheresis was more
statin therapy. In addition, a more aggressive commonly used as a way to control the overall
LDL-cholesterol goal aiming for concentrations cholesterol burden to which these patients
lower than 70 mg/dL (<1.81 mmol/L) (Answer are exposed.
B) is a reasonable secondary goal in light of her
known clinical ASCVD. An LDL-cholesterol goal Case 2
less than 100 mg/dL (<2.59 mmol/L) (Answer A 56-year-old man with a complex medical history
A) is not aggressive enough. While potentially recently moved to the area and seeks your help. He
practical, aiming for the lowest LDL-cholesterol was diagnosed with “homozygous FH” and significant
level she can tolerate (Answer D) is not specific coronary artery disease and has been treated with
or aggressive enough and is not supported by LDL apheresis. He was first diagnosed 15 years
any guidelines. ago, although he knew that his cholesterol was
very high since age 30 years. He has had multiple
Question 2. What are the treatment options?
stents and myocardial infarctions and is status post
A. Add a PCSK9 inhibitor coronary artery bypass graft surgery before apheresis
B. Add ezetimibe was started. He has had LDL-cholesterol levels in the
C. Retry atorvastatin or rosuvastatin at a lower range of 500 to 600 mg/dL (12.95 to 15.54 mmol/L)
dosage and has xanthomas of the knuckles, as well as
D. Try a different more effective statin such as the Achilles tendons. He has a very strong family
simvastatin or pitavastatin history of heart disease in both parents and knows
of family members who have cholesterol levels
E. All of the above
greater than 300 mg/dL (>7.77 mmol/L). He has
Answer: E) All of the above been intolerant to statins because of myopathy.
Colesevelam led to significant gastrointestinal
All of these options are reasonable to consider and adverse effects, niacin led to intolerable flushing,
try (Answer E). Maximizing statin therapy should

ENDO 2022 • Cardiovascular Endocrinology  103

and ezetimibe caused muscle aches. He finally C. Add a PCSK9 inhibitor
started LDL apheresis 4 years ago, which has D. Continue LDL apheresis
helped reduce the occurrence of new ASCVD E. All of the above
events. He has had more trouble with angina,
however, since moving to a higher altitude. Answer: E) All of the above

Question 1. What should this patient’s All of these options are reasonable to consider
LDL-cholesterol goal be? and try (Answer E). At this time, LDL apheresis
(Answer D) should be continued, as he has had
A. LDL cholesterol <150 mg/dL (<3.9 mmol/L)
persistent disease and apheresis has helped reduce
B. LDL cholesterol <100 mg/dL (cholesterol event rates. It would also be reasonable, though,
2.6 mmol/L) to add medical therapy to see if the frequency of
C. LDL-cholesterol reduction >50% apheresis could be reduced. All 3 listed medical
D. Lowest LDL-cholesterol level he can tolerate treatment options are approved for patients with
E. Treatment with statin therapy is primary goal homozygous FH. While all of these agents are
associated with a high cost, they are much less
Answer: D) Lowest LDL-cholesterol level he can tolerate expensive than frequent apheresis.
PCSK9 inhibitors (Answer C) are approved
Based on current guidelines, the primary goal
for the treatment of homozygous FH with LDL-
would be to treat this patient with high-intensity
cholesterol lowering of 20% to 30%.
statin therapy to reduce his LDL cholesterol by
Lomitapide (Answer B) has been shown
50% or more. However, he has persistent ASCVD.
to lower LDL cholesterol up to 40% at higher
As such, his LDL cholesterol should be treated as
dosages, but it can be difficult to tolerate.
aggressively as he can tolerate (thus, Answer D is
Evinacumab (Answer A) lowers LDL cholesterol
correct and Answers A, B, C, and E are incorrect).
45% to 50% as a monthly intravenous infusion.
Question 2. What are the treatment options? Combinations of these newer agents have not
been studied.
A. Add evinacumab
B. Add lomitapide

References
1. Bloch K. The biological synthesis of cholesterol. Science. 1965;150(3692):19- 7. Schwartz GG, Step PG, Szarek M, et al; ODYSSEY OUTCOMES Committees
28. PMID: 5319508 and Investigators. Alirocumab and cardiovasular outcomes after acute
2. Gofman JW, Glazier F, Tamplin A, Strisower B, De Lalla O. Lipoproteins, coronary syndrome. N Engl J Med. 2018;379(22):2097-2107. PMID: 30403574
coronary heart disease, and atherosclerosis. Physiol Rev. 1954;34(3):589-607. 8. Raal FJ, Stein EA, Dufour R, et al; RUTHERFORD-2 Investigators.
PMID: 13185756 PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial
3. Goldstein JL, Brown MS. Familial hypercholesterolemia: identification of a hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind,
defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase placebo-controlled trial. Lancet. 2015;385(9965):331-340. PMID: 25282519
activity associated with overproduction of cholesterol. Proc Natl Acad Sci U S 9. Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II:
A. 1973;70(10):2804-2808. PMID: 4355366 78 week results with alirocumab treatment in 735 patients with heterozygous
4. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/ familial hypercholesterolaemia. Eur Heart J. 2015;36(43):2996-3003. PMID:
AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on 26330422
the management of blood cholesterol: a report of the American College of 10. Raal FJ, Honarpour N, Blom DJ, et al; TESLA Investigators. Inhibition of
Cardiology/American Heart Association Task Force on Clinical Practice PCSK9 with evolocumab in homozygous familial hypercholesterolaemia
Guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350. PMID: 30423393 (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet.
5. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin 2015;385(9965):341-350. PMID: 25282520
therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387- 11. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at
2397. PMID: 26039521 high cardiovasular risk with elevated LDL cholesterol. N Engl J Med.
6. Sabatine MS, Giugliano RP, Keech AC, et al; FOURIER Steering Committee 2017;376(15):1430-1440. PMID: 28306389
and Investigators. Evolocumab and clinical outcomes in patients with 12. Heigl F, Hettich R, Eder B, Arendt R. Lipoprotein apheresis standard for
cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. PMID: apheresis competence centers--an updated synthesis and amendment to pre-
28304224 existing standards. Atheroscler Suppl.2013;14(1):57-65. PMID: 23357142

104  ENDO 2022 • Endocrine Case Management

PCSK9 Inhibitors: Basic
Biology to Clinical Outcomes
Connie B. Newman, MD, MACP. Department of Medicine, Division of Endocrinology,
Diabetes and Metabolism, New York University Grossman School of Medicine, New York,
NY; Email: [email protected]

Learning Objectives and evolocumab are administered subcutaneously

once or twice monthly. Inclisiran is administered
As a result of participating in this session, learners
subcutaneously 3 times the first year and twice
should be able to:
annually thereafter. Alirocumab and evolocumab
• Describe the mechanism of action of are indicated as adjunct to diet alone or with other
medications that reduces LDL cholesterol lipid-lowering therapies to lower LDL-C in adults
(LDL-C) by targeting proprotein convertase with ASCVD or primary hyperlipidemia, including
subtilisin/kexin type 9 (PCSK9). heterozygous familial hypercholesterolemia and
homozygous familial hypercholesterolemia, and
• Explain the indications, dosing, efficacy, and
to reduce risk of myocardial infarction and stroke
safety of medications that reduce the synthesis
in adults with ASCVD. Evolocumab is approved
or inhibit the action of PCSK9.
for pediatric patients with homozygous familial
• Appropriately prescribe PCSK9 inhibitors hypercholesterolemia who are 10 years or younger.
and small interfering RNA (siRNA) to reduce Inclisiran has an indication for LDL-C reduction
LDL-C and manage excess cardiovascular risk. in adults taking statins who have heterozygous
familial hypercholesterolemia or clinical ASCVD.
Effects of inclisiran on cardiovascular disease are
being studied. Available data show that the main
Main Conclusions adverse effects for the monoclonal antibodies and
PCSK9 binds to and escorts LDL receptors to the inclisiran are injection site reactions. A monoclonal
hepatic lysosome, where the receptor is degraded. antibody or the siRNA, alone or in addition to statin
Pathogenic gain-of-function variants in the therapy, reduces LDL-C by 50% or more. Very low
PCSK9 gene are associated with higher LDL-C; LDL-C levels have been observed in persons taking
loss-of-function variants are associated with alirocumab or evolocumab. The cardiovascular
low LDL-C and decreased risk of atherosclerotic benefit of lowering LDL-C below 25 mg/dL
cardiovascular disease (ASCVD). Medications (<0.65 mmol/L) has not been established, although
targeting PCSK9 to lower LDL-C include randomized controlled trials show that levels below
monoclonal antibodies to PCSK9 (alirocumab, 15 mg/dL (<0.39 mmol/L) are not harmful.
evolocumab) and a novel siRNA (inclisiran). Medications targeting PCSK9 are useful,
Alirocumab and evolocumab inhibit binding of with or without other lipid-lowering therapies,
PCSK9 to the LDL receptor, thus increasing LDL- for reducing LDL-C in patients with familial
receptor recycling, which clears LDL-C. Inclisiran, hypercholesterolemia or ASCVD. Inclisiran is
which is approved in the United Kingdom, a novel advanced therapy with the potential
Europe, and United States, degrades PCSK9 (if affordable) to change the treatment paradigm
mRNA, reducing PCSK9 synthesis. Alirocumab for hypercholesterolemia.

ENDO 2022 • Cardiovascular Endocrinology  105

 Barriers to Optimal Practice
Significance of the
• Insufficient knowledge of the benefits of
Clinical Problem PCSK9 inhibitors.
Elevated LDL-C is the root cause of atherosclerosis,
• Cost of medication; lack of coverage by some
and it increases the risk of ischemic heart disease,
insurance plans.
which is the number 1 cause of mortality in
the United States (Centers for Disease Control • Poor adherence.
report 2019 https://www.cdc.gov/nchs/data/ • Fear of adverse effects.
nvsr/nvsr70/nvsr70-08-508.pdf).1 Globally,
• Fear of injections.
ischemic heart disease was the leading cause of
death, followed by stroke, in 2019 (World Health
Organization https://www.who.int/news-room/
fact-sheets/detail/the-top-10-causes-of-death).2
Strategies for Diagnosis,
However, in low-income countries, neonatal Therapy, and/or Management
conditions were the number 1 cause of death in Management of LDL-C With
2019, followed by lower respiratory infections,
Medications Targeting PCSK9
ischemic heart disease, and stroke (World Health
Organization https://www.who.int/news-room/ This chapter will describe the biology of PCSK9,
fact-sheets/detail/the-top-10-causes-of-death).2 effects of new medications targeting PCSK9 on
In numerous randomized controlled trials with lipids, lipoproteins, and ASCVD; safety concerns;
a median duration of 4 years, statins have been shown and approved indications and dosages in the United
to reduce LDL-C and cardiovascular morbidity States. Medication cost will be covered briefly.
and mortality in adults with ASCVD, diabetes
mellitus, hypertension, previous stroke, or transient Biology of PCSK9
ischemic attack, and kidney disease (except end- PCSK9 is a protein that binds to hepatic LDL
stage kidney disease), as well as in persons without receptors and inhibits LDL-receptor recycling by
ASCVD or any of these disorders.3,4 Statins do escorting the LDL receptor to the hepatic lysosome,
not reduce ASCVD in adults with congestive where the LDL receptor is degraded.6,7 Inhibition
heart failure or in those on dialysis. When added of the binding of PCSK9 to the LDL receptor, or
to statin therapy, nonstatin medications such as reduction in PCSK9 synthesis through interference
ezetimibe (which has data showing ASCVD risk with PCSK9 mRNA, increases the recycling
reduction), bile acid sequestrants, and bempedoic of hepatic LDL receptors, which increases the
acid further lower LDL-C (Table). However, number of LDL receptors to clear LDL-C, thus
patients taking statins or statins plus any of the reducing LDL-C levels in the circulation.
above nonstatin medications who have an LDL-C Genetic variants in the PCSK9 gene that
concentration above 70 mg/dL (>1.81 mmol/L), increase PCSK9 function are associated with
or in certain cases above 55 mg/dL (>1.42 mmol/L), heterozygous familial hypercholesterolemia.8
may still have excess ASCVD risk.5 The However, PCSK9 variants are associated
development of medications targeting PCSK9 with fewer than 1% of cases of familial
has advanced our ability to reduce LDL-C to low hypercholesterolemia. About 80% to 90% of
levels (25 to 50 mg/dL [0.65 to 1.30 mmol/L]) persons with familial hypercholesterolemia have
and potentially further reduce ASCVD (as shown loss-of-function variants in the LDL-receptor gene
by randomized controlled trials of monoclonal and 5% to 10% have genetic variants in the gene
antibodies to PCSK9). encoding the apolipoprotein B receptor.
Persons with PCSK9 loss-of-function variants
have lifelong low levels of LDL-C and reduced

106  ENDO 2022 • Endocrine Case Management

risk of ASCVD.9 In one study, African American Effect on Lipids and Lipoproteins
participants with loss-of-function heterozygous In randomized controlled trials, evolocumab and
PCSK9 variants had lower LDL-C levels (by alirocumab alone and in statin-treated adults
35 mg/dL [0.91 mmol/L]) and the risk of coronary reduce LDL-C by about 50% to 60%.12,13
heart disease was reduced by 49%.10 White Several randomized controlled trials comparing
participants with loss-of-function heterozygous inclisiran with placebo have demonstrated that
PCSK9 variants were found to have reduced inclisiran given on days 1, 30, 270, and 540
LDL-C levels (by 13 mg/dL [0.34 mmol/L]) and reduced LDL-C by about 50% in patients taking
an 18% lower risk of coronary heart disease. statins. ORION-10 evaluated LDL-C changes
Medications targeting PCSK9 approved for use in response to inclisiran in 1561 statin-treated
in the United States, Europe, and other countries are patients (31% women) with ASCVD (mean age,
monoclonal antibodies to PCSK9 and a novel siRNA: 66 years [range, 35-90 years]).14 Subcutaneous
injection of inclisiran 284 mg on days 1, 90, 270,
• Human monoclonal antibodies directed against and 540 in 781 participants reduced mean LDL-C
PCSK9 (evolocumab and alirocumab) inhibit by 51%, mean non–HDL-C by 47%, and mean
the binding of PCSK9 to the LDL receptor. apolipoprotein B by 45%. The Figure shows
This increases the recycling of LDL receptors inclisiran’s effects on LDL-C compared with placebo
and results in lower plasma LDL-C. The LDL in the randomized controlled trial ORION-11.
receptor on the surface of the hepatocyte binds
to LDL, forming a complex that enters the Effects on ASCVD
liver through endocytosis. The LDL receptor Large randomized, placebo-controlled ASCVD
is separated from LDL in the lysosome where outcomes trials of alirocumab (ODYSSEY
LDL is broken down into amino acids (from OUTCOMES)12 in statin-treated patients
apolipoprotein B), cholesterol, and free fatty acids. with acute coronary syndrome and trials of
Cholesterol may be excreted (in an unesterified evolocumab (FOURIER)13 in statin-treated
form or after conversion into bile acids) via the patients with ASCVD demonstrated a relative
bile or incorporated into VLDL in the liver. risk reduction in ASCVD events of 15% and
• A double-stranded siRNA (inclisiran) directs absolute reduction of 1.6% and 2.0%, respectively,
the catalytic breakdown of PCSK9 mRNA, in the PCSK9 inhibitor treatment groups. The
thus reducing the synthesis of PCSK9. Lower median duration of follow-up was 2.8 years
levels of PCSK9 in the liver increase the in ODYSSEY OUTCOMES and 2.2 years in
recycling of LDL receptors, which increase FOURIER. The mean LDL-C concentrations
LDL uptake into the liver and excretion of in ODYSSEY OUTCOMES in an on-treatment
cholesterol via the bile, as described previously. analysis were 38 mg/dL (0.98 mmol/L), 42 mg/dL
Inclisiran is approved for use in the United (1.09 mmol/L), and 53 mg/dL (1.37 mmol/L) at
States, Europe, and other countries. Inclisiran 4, 12, and 48 months, respectively. In FOURIER,
is conjugated on the sense strand with the mean LDL-C concentration was 30 mg/dL
triantennary N-acetylgalactosamine to increase (0.78 mmol/L) at 4 months.
uptake by hepatocytes. After inclisiran doses A prespecified analysis of FOURIER found
of 284 mg on day 1 and day 90, mean serum that evolocumab significantly reduced ASCVD
PCSK9 levels have been shown to be reduced risk in participants with and without diabetes,
by 75% at day 120 and 69% at day 180.11 did not increase the risk of new-onset diabetes,
and did not worsen glycemia.15 In addition, a
prespecified analysis of ODYSSEY OUTCOMES
showed that the absolute reduction in ASCVD
events in participants assigned to alirocumab was

ENDO 2022 • Cardiovascular Endocrinology  107

2-fold greater in those with diabetes than in those Indications
without diabetes, and the risk of new diabetes was Indications for evolocumab and alirocumab in the
not increased.16 United States:
The effect of inclisiran on cardiovascular events in
patients with ASCVD is being studied in ORION-4. • As adjunct to diet alone or in combination
with other LDL-C–lowering therapies in
Safety adults with primary hyperlipidemia, including
The main adverse events in patients taking heterozygous familial hypercholesterolemia,
alirocumab and evolocumab are injection site to reduce LDL-C. Evolocumab is indicated
reactions characterized by itching, swelling, for patients with heterozygous familial
and/or erythema. Hypersensitivity reactions hypercholesterolemia who are 10 years and
such as angioedema are rare. Impaired cognitive older.
function had been suggested in early trials, but • As adjunct to other LDL-C–lowering
was not shown in the EBBINHAUS study,17 which therapies in adults with homozygous familial
involved a subgroup analysis of the FOURIER hypercholesterolemia to reduce LDL-C.
cardiovascular disease outcomes trial. Evolocumab is indicated for patients with
Statins increase the risk of newly diagnosed homozygous familial hypercholesterolemia
diabetes, especially in patients with risk factors for who are 10 years and older.
diabetes, by an estimated 0.2% per year depending • To reduce the risk of myocardial infarction
upon the population.18 The mechanism is not and stroke in adults with established
known. Genetic studies have shown 10% to cardiovascular disease. Evolocumab also has
29% higher risk of new diabetes in persons with an indication for reduction in risk of coronary
loss-of-function variants in the PCSK9 gene.19- revascularization in adults with cardiovascular
21
Nevertheless, new-onset diabetes has not disease; alirocumab also has an indication for
been detected in FOURIER (evolocumab)15 or reduction in risk of unstable angina requiring
ODYSSEY OUTCOMES (alirocumab).16 However, hospitalization.
diabetes was not detected as an adverse event of
statins until about 20 years after approval when Indication for inclisiran in the United States:
multiple large trials of a median duration of 4 years
were completed.22 Whether there is an increased • As adjunct to diet and maximally tolerated
risk of diabetes associated with long-term statin therapy for the treatment of adults with
treatment with PCSK-9 inhibitors that begins in heterozygous familial hypercholesterolemia
adulthood is unknown.23 or clinical ASCVD who require additional
Inclisiran may cause injection site reactions, lowering of LDL-C. The effect on
as shown in the analysis of ORION-9, -10, and cardiovascular morbidity and mortality has not
-11, which were placebo-controlled trials with a been determined.
duration of 18 months.24 While there was a small Indication for inclisiran in Europe:
increase in bronchitis (4.3% inclisiran vs 2.7%
placebo), there was no evidence of differences in • For adults with primary hypercholesterolemia
liver function tests, creatine kinase, or platelet (familial hypercholesterolemia and nonfamilial
count. More long-term data are needed, and an hypercholesterolemia) or mixed dyslipidemia
ongoing cardiovascular disease outcomes trial will as adjunct to diet, in combination with a statin
provide more information about safety. alone or a statin with other lipid-lowering
therapies. Inclisiran is also indicated alone
or in combination with other lipid-lowering

108  ENDO 2022 • Endocrine Case Management

 therapies for patients who do not tolerate The annual cost of alirocumab and
statins or for whom a statin is contraindicated. evolocumab without insurance is about $5800
(reduced from an initial cost of $14,000) in the
United States. Insurance companies may require
Dosages
preclearance, which may require the prescriber to
Alirocumab and evolocumab may be administered
document that other lipid-lowering medications
subcutaneously every 2 weeks or every month;
have failed. About 75% of Medicare prescriptions
dosages are shown in the Table. For patients with
for evolocumab cost patients less than $50 a
an inadequate LDL-C response, the dosage of
month, and the cost is even lower in patients who
alirocumab may be increased from 75 mg to 150 mg
are eligible for the low-income subsidy plan. Most
every 2 weeks. Similarly, for patients who do not
patients with Medicaid coverage pay $10 a month,
have an adequate LDL-C response at 12 weeks, the
and others pay less than $50 a month. Insurance
dosage of evolocumab may be increased from 140 mg
plans vary in their coverage of evolocumab.
every 2 weeks to 420 mg every month. For patients
Amgen has a no-cost plan (Amgen Safety Net
with homozygous familial hypercholesterolemia on
Foundation) for patients who do not have
apheresis, the dosage of evolocumab may be initiated
insurance or cannot afford the medicine.
at 420 mg every 2 weeks.
Alirocumab is covered by most Medicare Part D
Evolocumab can be administered via a prefilled
plans with a copay. Regeneron has a $25 copay plan
autoinjector, or prefilled syringe, every 2 weeks, or
for alirocumab for eligible patients with insurance
a single-use body infusor with a prefilled cartridge.
not funded by a government plan. Regeneron
Alirocumab is available in prefilled injection pens.
also has a patient assistance program for patients
Inclisiran is given as 284 mg subcutaneously in a
without health or prescription insurance who meet
single prefilled syringe at 3 months and 6 months after
income restrictions. Patients prescribed alirocumab
the initial dose and subsequently every 6 months.
who are covered by Medicare may qualify for the
low-income subsidy plan.
Estimates of Cost
In England, the list price for 1 pack of inclisiran,
This information was accessed January 29, 2022,
284 mg, costs close to £2000. A population health
from websites of Regneron, Amgen, Novartis,
agreement between the manufacturer of inclisiran
England’s National Health Service, and others.
(Novartis) and England’s National Health Service
and NHS Improvement has been reached. Under this

Table. Nonstatin LDL-C–Lowering Medications

Estimated LDL-C
Medication Mechanism of action Dosage for LDL-C reduction reduction
Ezetimibe Binds to Nieman Pick N1L1 receptor; prevents 10 mg orally daily 15% to 20%
gastrointestinal absorption of cholesterol
Alirocumab Monoclonal antibody to PCSK9; prevents LDL 75 mg to 150 mg subcutaneously every 56% to 61% on top of
receptor degradation by inhibition of PCSK9 2 weeks or 300 mg every 4 weeks statin
Evolocumab Monoclonal antibody to PCSK9; prevents LDL 140 mg subcutaneously every 2 weeks 63% to 71% on top of
receptor degradation by inhibition of PCSK9 or 420 mg subcutaneously every month statin
(or every 2 weeks as needed)
Inclisiran Small interfering RNA that directs breakdown 284 mg subcutaneously initial dose, at 52% on top of statin
of mRNA for PCSK9 3 months, and then every 6 months
Cholestyramine Bile acid sequestrant; reduces cholesterol pool 8 to 16 g orally daily, divided doses 12% to 25%
Colesevelam Bile acid sequestrant; reduces cholesterol pool 1250 to 1875 mg orally twice daily 15% to 18%
Bempedoic acid ATP citrate lyase inhibitor; inhibits cholesterol 180 mg orally daily 17% on top of statin
synthesis

ENDO 2022 • Cardiovascular Endocrinology  109

Figure. Mean Percentage Change from Baseline in LDL-C in Patients With ASCVD on Maximally Tolerated
Statin Therapy, Assigned to Inclisiran or Placebo (ORION-11)

From US Prescribing Information. 2021. Novartis Pharmaceuticals, downloaded from FDA website January 9, 2022.

agreement, inclisiran, 284 mg, may be ordered by Question 1. Which of these options would
primary care in England at the price of £45 per pack. be appropriate for lipid management in this
The price of inclisran in the United States is patient? (may choose more than 1 answer)
not known at this time. Inclisiran is expected to A. Add bempedoic acid, 180 mg daily
cost $3250 per injection or $6500 annually for B. Add evolocumab, 140 mg subcutaneously
2 doses. The first year requires 3 doses and will every 2 weeks
therefore be more expensive.
C. Add inclisiran, 284 mg subcutaneously first dose
D. Discontinue atorvastatin and start
Clinical Case Vignettes rosuvastatin, 20 mg daily
Case 1 E. Recommend no change in medications
A 68-year-old man with type 2 diabetes mellitus, Answer: B or C) Add evolocumab, 140 mg
hypertension controlled on valsartan, and a history of subcutaneously every 2 weeks (B), or add
myocardial infarction describes intermittent pain in inclisiran, 284 mg subcutaneously first dose (C)
his chest accompanied by nausea that is intensified
by physical activity. Current medications are This patient has type 2 diabetes and ASCVD.
atorvastatin, 80 mg daily; ezetimibe, 10 mg daily; Despite an LDL-C concentration of 75 mg/dL
valsartan, 80 mg daily; metformin, 2000 mg daily; (1.94 mmol/L), he is now having chest pain,
semaglutide, 7 mg daily; and vitamin D, 2000 IU daily. most likely due to coronary ischemia. He is taking
high-intensity statin therapy and ezetimibe. His
Laboratory test results: symptoms indicate that he would benefit from
Total cholesterol = 160 mg/dL (SI: 4.14 mmol/L) additional reduction of LDL-C.
LDL-C = 75 mg/dL (SI: 1.94 mmol/L) The most effective medications to add to statin
Triglycerides = 175 mg/dL (SI: 1.98 mmol/L) therapy to further reduce LDL-C (by about 50%)
HDL-C = 50 mg/dL (SI: 1.30 mmol/L) to decrease ASCVD events are PCSK-9 inhibitors
Hemoglobin A1c = 7.2% (55 mmol/mol)
(evolocumab or alirocumab) or the siRNA

110  ENDO 2022 • Endocrine Case Management

inclisiran. Inclisiran has not been proven to reduce and is taking rosuvastatin, 10 mg daily; ezetimibe,
ASCVD; the clinical trial is ongoing. 10 mg daily; and colesevelam, 3 tablets (625 mg
each) twice daily.
Question 2. What should this On physical examination, her blood pressure
patient’s LDL-C target be? Why? is 115/80 mm Hg and pulse rate is 68 beats/min.
A. <100 mg/dL (SI: <2.59 mmol/L) BMI is 23 kg/m2, and waist circumference is 29 in
B. <70 mg/dL (SI: <1.81 mmol/L) (73.7 cm). There are xanthelasmas in both eyes. She
has dry skin and no rash or tendinous xanthomas.
C. <55 mg/dL (SI: <1.42 mmol/L)
Examination findings are otherwise normal.
D. <40 mg/dL (SI: <1.04 mmol/L)
Current lipid panel results:
Answer: C) <55 mg/dL (<1.42 mmol/L)
Total cholesterol = 160 mg/dL (SI: 4.14 mmol/L)
This patient has a history of myocardial infarction, LDL-C = 90 mg/dL (SI: 2.33 mmol/L)
as well as multiple risk factors for ASCVD, and HDL-C = 50 mg/dL (SI: 1.30 mmol/L)
is now having chest pain, suggesting that LDL-C Triglycerides = 100 mg/dL (SI: 1.13 mmol/L)
should be reduced further. The American Heart
Association/American College of Cardiology Other laboratory test results:
guidelines from 2018 suggest that treatment Hemoglobin A1c = 4.9% (4.0%-5.6%) (30 mmol/mol
of patients with ASCVD should aim to reduce [20-38 mmol/mol])
LDL-C by 50%. Although goals are not specified, Creatinine = 1.0 mg/dL (0.6-1.1 mg/dL)
it is stated that patients with ASCVD and an (SI: 88.4 µmol/L [53.0-97.2 µmol/L])
LDL-C concentration greater than 70 mg/dL Liver function, normal
(>1.81 mmol/L) would benefit from LDL-C
reduction with a statin and, if needed, by the addition Question 1. What is the most likely diagnosis?
of nonstatin medications. The European Society
A. Familial combined hyperlipidemia
of Cardiology/European Atherosclerosis Society
2019 cholesterol management guidelines specify an B. Heterozygous familial hypercholesterolemia
LDL-C goal of less than 55 mg/dL (<1.42 mmol/L) C. Homozygous familial hypercholesterolemia
(Answer C) for patients with ASCVD. D. Polygenic hypercholesterolemia
E. Type III hyperlipidemia
Case 2 Answer: B) Heterozygous familial
A 30-year-old woman presents for evaluation hypercholesterolemia
and management of high cholesterol. Hyper­
cholesterolemia was diagnosed 10 years ago. At This patient has heterozygous familial
that time, she had tendon xanthomas and the hypercholesterolemia (Answer B), as demonstrated
following laboratory test results: by an elevated LDL-C concentration in a young
adult, normal HDL-C and triglyceride levels, the
Total cholesterol = 290 mg/dL (SI: 7.51 mmol/L) presence of tendon xanthomas at diagnosis, and
LDL-C = 220 mg/dL (SI: 5.70 mmol/L)
HDL-C = 50 mg/dL (SI: 1.30 mmol/L)
family history of premature ASCVD in a second-
Triglycerides = 100 mg/dL (SI: 1.13 mmol/L) degree relative. In addition, the patient’s mother
has a history of very high cholesterol and is being
Current medications are atorvastatin, 80 mg daily; treated with multiple medications.
ezetimibe, 10 mg daily; and vitamin D, 2000 IU daily. The patient has not undergone genetic testing.
Her maternal grandfather, now deceased, had a Homozygous familial hypercholesterolemia
myocardial infarction at age 45 years. Her 65-year- (Answer C) is rare, and if untreated, affected
old mother has a history of very high cholesterol

ENDO 2022 • Cardiovascular Endocrinology  111

persons develop ASCVD early and may have a and mortality is not known. This patient needs
myocardial infarction in their teen years. high-intensity statin therapy (eg, atorvastatin,
Familial combined hyperlipidemia (Answer 40 or 80 mg daily, or rosuvastatin, 20 mg
A) is characterized by elevations in LDL-C and daily), which lowers LDL-C by 50% or more.
triglycerides. Rosuvastatin, 10 mg daily (Answer D), is a
Polygenic hypercholesterolemia (Answer D) moderate-intensity statin.
is the most common type of hypercholesterolemia
and shares some features of heterozygous familial Question 3. One year later, the patient’s LDL-C
hypercholesterolemia. Cholesterol levels may concentration is 20 mg/dL (0.52 mmol/L) (on
be as high as those seen in this patient but are 2 measurements). What is the next step?
usually lower. Triglycerides are normal. Tendon A. Continue all medications at the current dosages
xanthomas and xanthelasmas may be present. B. Discontinue ezetimibe
However, the history of premature coronary heart
C. Lower the dosage of atorvastatin
disease and young age at presentation suggest that
this patient’s diagnosis is heterozygous familial D. Lower the dosage of the PCSK9 inhibitor
hypercholesterolemia. E. Stop the PCSK9 inhibitor
Type III hyperlipidemia (Answer E), also
Answer: A) Continue all medications
known as dysbetalipoproteinemia, is characterized
at the current dosages
by elevations in total cholesterol, triglycerides, and
LDL-C and low HDL-C concentrations. Clinical trials show that very low LDL-C levels
(≤15 mg/dL [≤0.39 mmol/L]) are not harmful,
Question 2. What is the next step although evidence for a benefit regarding ASCVD
for cholesterol management? has not been established.25 Prespecified analysis of
A. Add alirocumab or evolocumab ODYSSEY OUTCOMES found that in patients
B. Add bempedoic acid with ASCVD, risk did not differ in participants
C. Discontinue ezetimibe and add a with LDL-C concentrations below 25 mg/dL
PCSK9 inhibitor (<0.65 mmol/L) or participants with concentrations
of 25 to 50 mg/dL (0.65 to 1.30 mmol/L).26 In
D. Switch atorvastatin, 80 mg daily, to
ODYSSEY Outcomes, LDL-C fell below 15 mg/dL
rosuvastatin, 10 mg daily
(<0.39 mmol/L) on 2 occasions in 730 patients
Answer: A) Add alirocumab or evolocumab who had been treated for a median of 6.8 months,
and these patients were blindly switched from
This patient has a lifelong history of elevated alirocumab to placebo as per the protocol.12
LDL-C because of heterozygous familial However, there was no evidence that these low
hypercholesterolemia, and therefore LDL-C levels caused harm. There was no increased
should be further reduced to below 70 mg/dL incidence of diabetes or neurocognitive disorders
(<1.81 mmol/L). Alirocumab and evolocumab in patients treated with alirocumab. None of
(Answer A) are monoclonal antibodies to PCSK9 these participants developed hemorrhagic stroke.
and would be anticipated to reduce the LDL-C In the FOURIER study, 1335 patients assigned
concentration from 90 mg/dL (2.33 mmol/L) to to evolocumab had LDL-C concentrations on
45 to 50 mg/dL (1.17 to 1.30 mmol/L). treatment less than 15 mg/dL (<0.39 mmol/L), and
Ezetimibe may be continued; it reduces LDL-C 504 patients had concentrations below 10 mg/dL
by 18% to 20% and reduces the risk of ASCVD (<0.26 mmol/L).27 There was no evidence that
(thus, Answer C is incorrect). such low levels of LDL-C were unsafe. Thus, this
Bempedoic acid (Answer B) reduces LDL-C patient should continue all medications at the
by 17%, but its effect on cardiovascular morbidity current dosages (Answer A).

112  ENDO 2022 • Endocrine Case Management

References
1. Xu J, Murphy SL, Kochanek KD, Arias E. Deaths: final Data for 2019. and the effect of evolocumab on glycaemia and risk of new-onset diabetes:
National Vital Statistics Reports. Vol 70(8). National Center for Health a prespecified analysis of the FOURIER randomised controlled trial. Lancet
Statistics. 2021. DOI: https://dx.doi.org/10.15620/cdc:106058 Diabetes Endocrinol. 2017;5(12):941-950. PMID: 28927706
2. World Health Organization. The top 10 causes of death. Available at: https:// 16. Ray KK, Colhoun HM, Szarek M, et al; ODYSSEY OUTCOMES Committees
www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death. and Investigators. Effects of alirocumab on cardiovascular and metabolic
3. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baignet C, Blackwell outcomes after acute coronary syndrome in patients with or without diabetes:
L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled
a meta-analysis of data from 170,000 participants in 26 randomised trials. trial. Lancet Diabetes Endocrinol. 2019;7(8):618-628. PMID: 31272931
Lancet. 2010;376(9753):1670-1681. PMID: 21067804 17. Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized
4. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the trial of evolocumab. N Engl J Med. 2017;377(7):633-643. PMID: 28813214
efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532-2561. *18. Newman CB, Preiss D, Tobert JA, et al; American Heart Association Clinical
PMID: 27616593 Lipidology, Lipoprotein, Metabolism and Thrombosis Committee, a Joint
5. Authors/Task Force M, ESC Committee for Practice Guidelines (CPG); ESC Committee of the Council on Atherosclerosis, Thrombosis and Vascular
National Cardiac Societies. 2019 ESC/EAS guidelines for the management of Biology and Council on Lifestyle and Cardiometabolic Health; Council
dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis. on Cardiovascular Disease in the Young; Council on Clinical Cardiology;
2019;290:140-205. PMID: 31591002 and Stroke Council. Statin safety and associated adverse events: a scientific
*6. Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL statement from the American Heart Association. Arterioscler Thromb Vasc
catabolism. J Lipid Res. 2009;50(Suppl):S172-S177. PMID: 19020338 Biol. 2018;39(2):e38-e81. PMID: 30580575
*7. Rosenson RS, Hegele RA, Fazio S, Cannon CP. The evolving future of 19. Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and
PCSK9 inhibitors. J Am Coll Cardiol. 2018;72(3):314-329. PMID: 30012326 HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med.
*8. Gidding SS, Champagne MA, de Ferranti SD, et al; American Heart 2016;375(22):2144-2153. PMID: 27959767
Association Atherosclerosis, Hypertension, and Obesity in Young Committee 20. Lotta LA, Sharp SJ, Burgess S, et al. Association between low-density
of Council on Cardiovascular Disease in Young, Council on Cardiovascular lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a
and Stroke Nursing, Council on Functional Genomics and Translational meta-analysis. JAMA. 2016;316(13):1383-1391. PMID: 27701660
Biology, and Council of Lifestyle and Cardiometabolic Health. The agenda 21. Schmidt AF, Swerdlow DI, Holmes MV, et al. PCSK9 genetic variants and
for familial hypercholesterolemia: a scientific statement from the American risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes
Heart Association. Circulation. 2015;132(22):2167-2192. PMID: 26510694 Endocrinol. 2017;5(2):97-105. PMID: 27908689
9. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in 22. Newman CB. Safety of statins and non-statins for treatment of dyslipidemia
PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. in update in the diagnosis and management of dyslipidemia. Endocrinol Metab
2006;354(12):1264-1272. PMID: 16554528 Clin North Am. In press.
10. Kent ST, Rosenson RS, Avery CL, et al. PCSK9 loss-of-function variants, 23. Lee J, Hegele RA. PCSK9 inhibition and diabetes: turning to Mendel for
low-density lipoprotein cholesterol, and risk of coronary heart disease and clues. Lancet Diabetes Endocrinol. 2017;5(2):78-79. PMID: 27939390
stroke: data from 9 studies of Blacks and Whites. Circ Cardiovasc Genet. 24. Wright RS, Ray KK, Raal FJ, et al; ORION Phase III Investigators.
2017;10(4):e001632. PMID: 28768753 Pooled patient-level analysis of inclisiran trials in patients with familial
*11. Leqvio (inclisiran) injection. Prescribing information. Novartis hypercholesterolemia or atherosclerosis. J Am Coll Cardiol. 2021;77(9):1182-
Pharmaceuticals, 2021. Accessed January 9, 2022. https://www.novartis.us/ 1193. PMID: 33663735
sites/www.novartis.us/files/leqvio.pdf *25. Tobert J. LDL cholesterol: how low can we go? in update in the diagnosis
12. Schwartz GG, Steg PG, Szarek M, et al; ODYSSEY OUTCOMES Committees and management of dyslipidemia. Endocrinol Metab Clin North Am. In press.
and Investigators. Alirocumab and cardiovascular outcomes after acute *26. Schwartz GG, Steg PG, Bhatt DL, et al; ODYSSEY OUTCOMES Committees
coronary syndrome. N Engl J Med. 2018;379(22):2097-2107. PMID: 30403574 and Investigators. Clinical efficacy and safety of alirocumab after acute
13. Sabatine MS, Giugliano RP, Keech AC, et al; FOURIER Steering Committee coronary syndrome according to achieved level of low-density lipoprotein
and Investigators. Evolocumab and clinical outcomes in patients with cholesterol: a propensity score-matched analysis of the ODYSSEY
cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. PMID: OUTCOMES Trial. Circulation. 2021;143(11):1109-1122. PMID: 33438437
28304224 27. Giugliano RP, Pedersen TR, Park J-G, et al; FOURIER Investigators. Clinical
14. Ray KK, Wright RS, Kallend D, et al; ORION-10 and ORION-11 efficacy and safety of achieving very low LDL-cholesterol concentrations with
Investigators. Two phase 3 trials of inclisiran in patients with elevated LDL the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the
cholesterol. N Engl J Med. 2020;382(16):1507-1519. PMID: 32187462 FOURIER trial. Lancet. 2017;390(10106):1962-1971. PMID: 28859947
15. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy * Suggested reading
of the PCSK9 inhibitor evolocumab in patients with and without diabetes

ENDO 2022 • Cardiovascular Endocrinology  113

DIABETES MELLITUS
AND GLUCOSE
METABOLISM
Disparities in Diabetes
Care and Evidence-Based
Programs to Address Them
Rocio I. Pereira, MD. Division of Endocrinology, Denver Health, Denver, CO, and University
of Colorado School of Medicine, Aurora, CO; E-mail: [email protected]

Learning Objectives are beyond our control as clinicians, by identifying

SDoH factors in our clinical practices and referring
As a result of participating in this session, learners
patients to evidence-based programs to address
should be able to:
these factors, we can improve the care of racial/
• Summarize the nature and extent of disparities ethnic minority patients, thereby decreasing
in diabetes and diabetes care. disparities. A solid understanding of the health
effects of social factors and a working knowledge
• Apply knowledge of social determinants of
of health equity best practices will enable us
health (SDoH) and health equity best practices
to address and/or compensate for factors that
to identify patient barriers to diabetes care and
perpetuate disparities.
refer patients to appropriate evidence-based
In this session, we will become familiar with
programs.
SDoH, identify the health equity best practice
elements in successful interventions, and examine
their potential effects in closing the health equity
gap in diabetes care.
Main Conclusions
Diabetes mellitus and its complications
disproportionately affect racial and ethnic minority
communities in the United States. Persons of
Significance of the
color, including those from Black, Latino, Asian, Clinical Problem
and Native American populations, have a higher In 2019, there were more than 460 million persons
prevalence of diabetes, diabetes complications, with diabetes worldwide and more than 34 million
and diabetes mortality, than those from nonLatino in the United States.1 In 2017, diabetes care costs
White populations. These disparities are not in the United States totaled $327 billion and
explained by biological or behavioral differences accounted for $1 of every $4 spent on health care.
across populations, but rather are a result of SDoH Racial and ethnic minority communities in the
and unequal treatment in the health care system United States have disproportionately higher rates
due to longstanding systemic racism in our society. of diabetes than nonLatino White communities.1
Persons of color with diabetes, regardless of Minority communities also experience higher rates
diabetes type, are more likely to face social barriers of diabetes complications and higher mortality.
to obtaining health care such as food and housing Compared with rates of end-stage kidney disease
insecurity, low or no access to health services, high for nonLatino white adults, rates are 1.5 times
costs of medications and diabetes technology, and as high for Latino adults and 3 times as high for
provider inertia. Although many of these factors Black adults.1 Diabetes mortality in major cities in

116  ENDO 2022 • Endocrine Case Management

the United States are on average twice as high for Strategies for Diagnosis,
Black adults as they are for White adults.2 Between
Therapy, and/or Management
2013 and 2017, there were more than 7000 excess
deaths among Black individuals per year due to The case management strategies reviewed here
racial inequalities in diabetes death in major US include assessment of SDoH factors that present
cities.2 barriers to diabetes self-management, referral of
Racial/ethnic disparities in diabetes, as patients to appropriate evidence-based programs
with other health conditions, are primarily and services, and adoption of provider-specific
a result of social factors and SDoH, which tools and system-level interventions to improve
disproportionately affect persons of color due to care for individuals from racial/ethnic minority
historic and persistent systemic racism. Persons groups.
who experience lower education access and Recognition of SDoH factors that present
quality, economic instability, unhealthy social and barriers to diabetes self-management is the first
community interactions, poor neighborhoods step. Once these factors are recognized, the
and unhealthy built environments, and lower clinician can more appropriately work to address
access to and quality of health care, also are more or compensate for them.
likely to have diabetes, higher hemoglobin A1c, Barriers to optimal diabetes care occur at
more frequent diabetic ketoacidosis, higher rates 3 different levels: patient, provider, and health
of diabetes complications, and higher diabetes system.4 When identifying interventions to reduce
mortality.3 Furthermore, unequal care experienced diabetes care disparities within a specific medical
by minority communities further increases practice, clinic, or health care organization, it is
disparities. Endocrinologists and primary care important to consider interventions at each of
providers can start to close care disparity gaps by these levels. Health care interventions focused
identifying patient-specific SDoH that adversely at any of these levels have been shown to reduce
affect diabetes care and by referring patients to racial/ethnic disparities in diabetes outcomes.5
evidence-based diabetes programs. However, most
clinical providers, including endocrinologists, do Screening for and Addressing SDoH
not have the knowledge and skills to appropriately
SDoH have typically been considered at a
identify and address SDoH, or sufficient familiarity
population and community level, but recent
with health equity best practices to incorporate
efforts in Canada and the United States are aimed
these into their routine workflows.
at identifying and addressing SDoH factors in
clinical settings. The Protocol for Responding
Barriers to Optimal Practice to and Addressing Patient’s Assets, Risks, and
Clinicians caring for patients with diabetes from Experiences (PRAPARE) toolkit6 authored by
ethnic/racial minority groups face the following the National Association of Community Health
potential barriers to diabetes management: Centers provides guidance on incorporating SDoH
screening into clinical care in community health
• Patient-level barriers: patient social factors center settings. The PRAPARE patient survey
that affect diet, physical activity, and self- collects race, ethnicity, and language (REAL)
management behaviors. data, and assesses for food and housing insecurity,
• Provider-level barriers: clinical inertia, lack poverty, and immigrant status, among other
of cultural competence, and communication factors. A recent review by Frier et al7 describes
barriers (including language). emerging strategies to identify social determinant–
related barriers to diabetes self-management in
• System-level barriers: reactive instead of
clinical settings. The authors note the importance
proactive system.
of using an individualized approach and bringing

ENDO 2022 • Diabetes Mellitus and Glucose Metabolism  117

relevance to the screening by considering an Patient Interventions
individual’s personal circumstances and whether
Patient-level interventions to decrease disparities
they perceive the SDoH issue to be a barrier to
in diabetes care focus on supporting healthy
diabetes self-management. Addressing SDoH
diet and exercise habits, increasing diabetes self-
factors that present barriers to diabetes self-
management knowledge, and addressing social
management can lead to improved diabetes
health barriers. Patient-level interventions can
care. This is especially relevant for minority
be general quality improvement initiatives or
communities that are disproportionately affected
can be culturally tailored to specific racial/ethnic
by SDoH factors.
populations. These interventions can take place
The most important consideration when
within or outside the health care system and can
discussing SDoH with a patient is to do so in a
be implemented with in-person and/or virtual
supportive and nonjudgmental manner. Ideally,
strategies.
this discussion should take place after the
clinician and patient have established a trusting Diabetes Self-Management
relationship. In a clinical practice where SDoH Education and Support
data are available at the time of the clinical visit, Patient education and support services should
clinicians should review these data and ask follow national standards such as the 2022
the patient whether the SDoH factors they are National Standards for Diabetes Self-Management
experiencing present barriers to their diabetes Education and Support (DSMES)8 published by the
care. An example of this in a patient who reports American Diabetes Association and Association of
having food insecurity is to ask: “Does not Diabetes Care & Education Specialists.
having enough food at home affect your diabetes The 2022 National Standards outline 6
management?” If yes, “In what way?” and “Do you evidence-based requirements for successful
ever skip meals?” or “What types of foods do you DSMES efforts:
eat when you are running out of food at home?”
Follow-up questions could tie in medication- 1. Support for DSMES services: leadership
taking behavior: “When you skip a meal, do support.
you still inject meal-time insulin? What about 2. Population and service assessment: alignment of
long-acting insulin?” In a clinical practice where the intervention with the target population’s
SDoH information is not available at the time of needs and preferences.
the visit, the clinician can focus SDoH questions
based on the clinical situation. For instance, for a 3. DSMES team: a designated team including at
patient who is not taking prescribed medications least 1 DSMES quality coordinator to oversee
regularly, the clinician could ask “Does the cost of effective implementation, evaluation, tracking,
your medication make it difficult for you to get and reporting of DSMES service outcomes.
it from the pharmacy regularly?” Or, in the case 4. Delivery and design of DSMES services: use of
of a patient who reports taking their medications a curriculum to guide evidence-based content
differently from what is prescribed, the clinician and delivery, ensure consistency, and serve as
might ask: “Are you able to read the medication a resource for the team; DSMES curriculum
instructions on your medication bottles?” For must include the following core content:
a patient who has not come to clinic in the
ԗ Pathophysiology of diabetes and treatment
recommended amount of time, the clinician might
options
ask “Is it difficult for you to get transportation for
your clinic visits?” or “Does the cost of your visit ԗ Healthy coping
make it difficult for you to come see me more ԗ Healthy eating
frequently?”
ԗ Being active

118  ENDO 2022 • Endocrine Case Management

 ԗ Taking medication Although telehealth interventions have
ԗ Monitoring proven benefit for minority and nonminority
populations, uptake of this intervention is lower
ԗ Reducing risk (treating acute and chronic among racial/ethnic minorities. Telemedicine use
complications) has been reported to be lower for patients older
ԗ Problem-solving and behavior change than 65 years, for those who speak a language
strategies other than English, and for patients on public
health insurance. The most common barriers to
5. Person-centered DSMES: services should be telemedicine service use reported were perceived
provided over the patient’s lifespan, and each lower quality of care and technological barriers.
patient’s DSMES plan should be unique and
based on the patient’s concerns, needs, and Elements of Successful Patient-
priorities. Level Interventions
Patient-level interventions that are effective in
6. Measuring and demonstrating outcomes of decreasing diabetes disparities use interpersonal
DSMES services: ongoing continuous quality skill and social networks such as family members,
improvement strategies will measure the effect peer-support groups, interactive or one-on-one
of DSMES services, and systematic evaluation education, and community health workers.5
of process and outcome data will be used to Interventions that make use of community
identify areas for improvement and to guide health workers are particularly effective since
service optimization. they are able to address multiple SDoH factors,
DSMES teams working in collaboration with including cultural and language barriers, lack
primary care have been shown to be the most of transportation, and trust issues. Culturally
effective approach to overcoming therapeutic tailored interventions appear to be more effective
inertia. DSMES lowers hemoglobin A1c by at least among racial/ethnic minorities than generalized
0.6%, which is equivalent to the effect of many diabetes self-management training interventions.5
diabetes medications, but with no adverse effects. However, these data are mostly limited to Black
and Latino communities, since few interventions
Telehealth Interventions have been tested in Alaskan Native/American
The increased use of telehealth interventions Indian populations. Expansion is also needed
during the COVID-19 pandemic has led to for older racial/ethnic minorities who remain
concerns for worsening health disparities understudied despite representing the fastest
for communities of color with low access to growing population of persons with diabetes.
technology. A recent pooled analysis of telehealth
interventions focused on improved diabetes Provider Interventions
control among Black and Latino adults with
Provider-level interventions are focused on
diabetes found that patient-level telehealth
decreasing clinical inertia, defined as a lack of
interventions are generally effective for these
medication intensification when intensification
minority groups, with a mean reduction in
is clinically indicated. These interventions can
hemoglobin A1c of 0.476%.9 Interventions in
include use of provider reminder systems and
this analysis were delivered via telephone, text
tools to increase use of provider guidelines such
messaging, web-based portals, and/or virtual
as the Standards of Medical Care in Diabetes-2022 10,11
visits; were conducted over an average period of
authored by the American Diabetes Association,
9 months; and varied in intensity of contact from
continuing medical education, computerized
daily, weekly, to monthly.
decision-support reminders, in-person feedback,
or problem-based learning.

ENDO 2022 • Diabetes Mellitus and Glucose Metabolism  119

 In-person feedback to providers has been primary care team, and working as a nurse in
reported to be superior to computerized decision- case management. Nonphysician providers can be
support in creating sustained provider behavioral instrumental in extending the care that specialists
change and health outcomes. Relevant to racial/ are able to provide.
ethnic minorities, who are more likely to be Medical assistance programs improve
managed by a primary care provider rather than prescription adherence and clinical outcomes,
an endocrinologist, and more likely to have worse decrease hospitalizations, and reduce hospital costs.
diabetes control than that of White individuals, Health care services for persons with limited
primary care provider interventions resulted in English proficiency can be improved by providing
hemoglobin A1c control similar to that seen in language translation and interpretation services,
a diabetes specialty clinic. Patients with higher increasing the number of language-concordant
hemoglobin A1c values at baseline had the greatest providers on staff, and/or making medical
reduction in hemoglobin A1c.5 language courses available to existing staff.
There are insufficient data on the effectiveness Language-concordant services often, although
of provider interventions focused on provider not always, result in better clinical outcomes for
communication, cultural competence, or shared patients with limited English proficiency.12
decision-making, despite positive correlations
between enhanced communication and shared
decision-making and diabetes control. Similarly,
Clinical Case Vignettes
there is a growing awareness of the associations Case 1
between provider bias and health disparities, A 21-year-old Black man with type 1 diabetes is
but there are insufficient data to conclude that seen in an endocrinology clinic for follow-up.
programs to decrease provider bias improve care Diabetes was diagnosed 2 years ago, and he first
for minority populations. met you in clinic 1 year ago. He has rescheduled
multiple prior visits and tells you today that he is
Health System Interventions almost out of his insulin and supplies. He requests
refills for all his medications. He is on basal and
Health system interventions include innovative
bolus insulin pens but would like a more affordable
use of health care staff (case managers, community
alternative. He states he has no hypoglycemia, but
health workers, or nonphysician clinicians)
he admits that he has not been checking his blood
to provide improved patient services. Other
glucose more than once or twice weekly.
interventions include use of medical assistance
programs to increase patient access to newer
Which of the following is the best course of
medications and disease management systems
action for this patient’s diabetes management?
(which identify the populations of interest; have
guidelines for performance standards for care; A. Change insulin pens to vials and syringes and
conduct nurse care management of identified schedule a follow-up visit next month
individuals, and use a health information system B. Change insulin pens to NPH and regular insulin
for tracking and monitoring). and schedule a follow-up visit next month
Case management, particularly when C. Discuss his concerns regarding his current
community health workers are used for this insulin pens and order a continuous
purpose, is particularly effective in improving glucose monitor
care for minority individuals. Community health D. Discuss his concerns regarding his current
workers can be effective in helping patients make/ insulin pens and identify the barriers to
keep appointments with primary care providers attending clinic visits; develop a plan of care
and subspecialists, acting as an adjunct to the based on those discussions

120  ENDO 2022 • Endocrine Case Management

Answer: D) Discuss his concerns regarding his current Case 2
insulin pens and identify the barriers to attending clinic
A 50-year-old Hispanic, Spanish-speaking
visits; develop a plan of care based on those discussions
woman is referred for management of type 2
The best approach is to discuss this patient’s diabetes. You do not speak Spanish but are able
concerns regarding his current insulin pens and to conduct the visit with the assistance of a phone
identify the barriers to attending clinic visits interpreter. The patient has had diabetes for more
(Answer D). A plan of care can be developed based than 20 years. Her blood glucose used to be well
on this discussion. controlled, but for the past 6 months, her values
Changing from insulin pens to vials and have been high (in the range of 200 to 400 mg/dL
syringes (Answer A) could potentially decrease his [11.1-22.2 mmol/L]). She has had no changes
medication costs. However, we currently do not in her diet or exercise habits. She reports taking
have enough information to know if he is able to her medications as prescribed, and these include
afford analogue insulins in a vial. This answer also metformin, a weekly GLP-1 receptor agonist, and
does not address the patient’s barriers to keeping an SGLT-2 inhibitor. Her hemoglobin A1c value
clinic appointments. last month was 11.0% (97 mmol/mol). Review
Changing insulin pens to NPH and regular of her medications reveals that she is not taking
insulin (Answer B) potentially addresses the her medications as prescribed. When you review
cost issue. However, NPH insulin does have an possible SDoH barriers with her, you learn that
increased risk of hypoglycemia compared with she only completed grade school and does not read
insulin analogues, so it would be best to verify very well. You also learn that she does not drive
that this is the best possible choice for the patient and relies on public transportation to get to the
at this time. This answer also does not address clinic. The ride today took her 1 hour.
barriers to making it to clinic. Use of continuous
glucose monitoring (Answer C) could make Which of the following is the best
glucose monitoring easier for the patient and allow course of action in this patient’s care?
for the collection of more glucose data to inform A. Encourage her to increase her current
insulin dose changes. However, it is unclear medications to the prescribed amounts and to
whether the patient would be able to afford a start insulin
continuous glucose monitor, and this should be B. Encourage her to start insulin and transfer her
discussed. This answer also does not address the care to a Spanish-speaking colleague
problem with attending clinic visits. C. Refer her to a community health worker–
Upon further discussion with the patient and directed DSMES program
some research of his medication formulary, it
D. Review the prescribed dosages of her
became clear that alternative insulin analogues
medications and encourage her to start taking
were covered. His prescriptions were changed to
them appropriately
alternative analogue pens. Further conversation
also reveals that the patient must ask for a day off Answer: C) Refer her to a community health
from work every time he comes to clinic. After worker–directed DSMES program
some discussion, it was decided that the patient
would see a physician every 6 months, but he The best strategy is to refer this patient to a
would see the endocrinology nurse practitioner community health worker–directed DSMES
in between these visits, as the nurse practitioner’s program (Answer C). She has multiple social
schedule was more flexible and aligned with his barriers making it difficult to access care,
days off. including low health literacy, language barriers,
and transportation barriers. These barriers can
be addressed by a community health worker who

ENDO 2022 • Diabetes Mellitus and Glucose Metabolism  121

can help the patient compare her list of prescribed Reviewing her prescribed medications and
medications with the medications she is taking, encouraging her to take them as prescribed
instruct her on dosages, and answer nonclinical (Answer D) is unlikely going to improve her care
questions. if her health literacy and transportation barriers
Transferring her care to a Spanish-speaking are not addressed.
colleague (Answer B) could help, but it may not Encouraging the patient to increase her
be necessary, and will not address the barriers of current medications to the prescribed amounts and
low literacy and transportation needs. Language to start insulin (Answer A) is also unlikely to work
concordance between physicians and patients if SDoH are not addressed first.
can improve care when it results in better
communication and a more trusting relationship.

References
1. Centers for Disease Control and Prevention. National Diabetes Statistics with type 2 diabetes-a review of the literature. Health Soc Care Community.
Report. Available at: https://www.cdc.gov/diabetes/data/statistics-report/ 2020;28(4):1119-1133. PMID: 31852028
index.html. Accessed May 2022. 8. Davis J, Fischl AH, Beck J, et al. 2022 National Standards for Diabetes
2. Rosenstock S, Whitman S, West JF, Balkin M. Racial disparities in diabetes Self-Management Education and Support. Sci Diabetes Self Manag Care.
mortality in the 50 most populous US cities. J Urban Health. 2014;91(5):873- 2022;48(1):44-59. PMID: 35049403
885. PMID: 24532483 9. Anderson A, O’Connell SS, Thomas C, Chimmanamada R. Telehealth
3. Hill-Briggs F, Adler NE, Berkowitz SA, et al. Social determinants of health interventions to improve diabetes management among black and hispanic
and diabetes: a scientific review. Diabetes Care. 2020;44(1):258-279. PMID: patients: a systematic review and meta-analysis. J Racial Ethn Health Disparities.
33139407 2022:1-12. PMID: 35000144
4. Chin MH, Walters AE, Cook SC, Huang ES. Interventions to reduce racial 10. American Diabetes Association. Introduction: standards of medical care in
and ethnic disparities in health care. Med Care Res Rev. 2007;64(5 Suppl):7S- diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S1-S2. PMID: 34964812
28S. PMID: 17881624 11. American Diabetes Association Professional Practice Committee, Draznin
5. Peek ME, Cargill A, Huang ES. Diabetes health disparities: a systematic B, Aroda VR, et al. 9. Pharmacologic approaches to glycemic treatment:
review of health care interventions. Med Care Res Rev. 2007;64(5 Suppl):101S- standards of medical care in diabetes-2022. Diabetes Care. 2022;45(Suppl
156S. PMID: 17881626 1):S125-S143. PMID: 34964831
6. National Association of Community Health Centers and Association of Asian 12. Diamond L, Izquierdo K, Canfield D, Matsoukas K, Gany F. A systematic
Pacific Community Health Organizations. PRAPARE Toolkit. Available at: review of the impact of patient-physician non-English language concordance
https://prapare.org/. Accessed May 2022. on quality of care and outcomes. J Gen Intern Med. 2019;34(8):1591-1606.
7. Frier A, Devine S, Barnett F, Dunning T. Utilising clinical settings to PMID: 31147980
identify and respond to the social determinants of health of individuals

122  ENDO 2022 • Endocrine Case Management

Time in Range: The New
Hemoglobin A1c?
Jane E. B. Reusch, MD. University of Colorado School of Medicine, Division of
Endocrinology, Metabolism, Diabetes, Aurora, CO; E-mail: [email protected]

Learning Objectives in a telemedicine setting, and detailed profiles on

hyperglycemia and hypoglycemia not available
As a result of participating in this session, learners
with blood glucose monitoring or hemoglobin
should be able to:
A1c testing. This technology has been deployed in
• Describe current guidelines on glycemic populations and was demonstrated to improve
targets across the spectrum of diabetes, overall glycemic control. Given these benefits,
including those for type 1 diabetes, type 2 what are the unanswered questions? Based on
diabetes, gestational diabetes, and drug- the recent American Diabetes Association and
induced diabetes. European Association for the Study of Diabetes
guidance for the management of type 1 diabetes,
• Master the information generated using
all individuals capable of using this technology
continuous glucose monitoring (CGM) and
should have access to it and TIR can be considered
have a clear understanding of the following
the equivalent of hemoglobin A1c. In contrast, in
metrics: time in range (TIR), time below range
the majority of the more than 537 million people
(TBR), and time above range (TAR).
globally living with diabetes, assessment of overall
glycemic control and its relationship to outcomes
is still most accessibly addressed using hemoglobin
A1c or fingerstick blood glucose monitoring. It
Main Conclusions is critical to continuously evaluate the balance
Metrics for assessing overall glycemic control among patient burden, access to education, cost-
and glucose profiles in persons with and at risk effectiveness, access to the Internet and/or smart
for diabetes mellitus have evolved rapidly over phones, patient interface with new technology,
the last decade. We now have technology that diabetes literacy and numeracy, and the effect on
can provide real-time CGM in easily accessible quality of life and clinical outcomes. So, is TIR the
systems. These devices can be used across the new hemoglobin A1c? Hemoglobin A1c still has a
lifespan and many have capabilities for remote central role in diabetes management, and TIR and
data access. The relationship between data be used to assess goal-directed therapy and has
generated using CGM and values obtained using added value.
hemoglobin A1c or fingerstick blood glucose
monitoring are now well established, and the
correlations are very strong. Data demonstrating a
clear relationship between CGM metrics, such as
Significance of the
TIR, and diabetes complications are accumulating Clinical Problem
in the literature. As such, CGM offers real-time Diabetes is a common clinical condition currently
biofeedback to the individual with diabetes, affecting more than 37 million people in the
accessible data for the clinician, which can be used United States alone, and it is defined by glucose

ENDO 2022 • Diabetes Mellitus and Glucose Metabolism  123

values and/or hemoglobin A1c.1 Working with option to use CGM at the time of diagnosis, time
individuals living with diabetes to optimize their of change in medical management, or as a tool to
blood glucose values requires an investment on guide choice of therapy. In each of these settings, it
the part of the provider and the individual with is not the TIR alone but the comprehensive CGM
diabetes. The evolution from urine dipstick blood profile that is most informative.
glucose to the use of CGM in the last 50 years has Implied in the title of this session is a bias to
changed the landscape and enhanced our capacity consider that CGM is appropriate for all. To keep
to nearly normalize blood glucose in certain this conversation balanced, we must consider
individuals living with diabetes. Improvements the implications of this question in the clinical
in blood glucose control decrease microvascular setting. TIR is predictive of hemoglobin A1c.
complications of diabetes, including retinopathy, More to the point, 14-day CGM can generate a
neuropathy, and nephropathy. Epidemiological glucose management indicator that aligns with
evidence supports a significant correlation hemoglobin A1c very well. CGM offers more
between glycemic burden over time and the most information than hemoglobin A1c or fingerstick
common macrovascular complications of diabetes, blood glucose monitoring. Hemoglobin A1c
atherosclerotic cardiovascular disease and heart measures average glycemic burden and not low
failure. As such, tools to optimize glycemic control or high blood glucose, whereas fingerstick blood
are increasingly useful in diabetes management. glucose detects certain patterns but may or may
The question remains, which tool and in which not capture hyperglycemia and hypoglycemia.
setting? CGM captures the full picture and provides
Guidance from primary care and subspecialty metrics, including TIR, TBR, TAR, and glucose
societies endorse individualized glucose targets management indicator. Figure 1 illustrates the
for patients living with diabetes. These targets consensus ambulatory glucose profile report
are based on the likelihood to benefit vs risk from generated from a CGM download.1,4,5 Does this
more or less intensive glucose control. The most increase in data available using CGM mean
recent summary of glycemic targets is outlined in that clinical practice guidance should replace
the 2022 American Diabetes Association Standards hemoglobin A1c with TIR, or perhaps replace
for Medical Care of Diabetes.1 Depending on hemoglobin A1c with CGM? The answer to this
the glycemic target for a given individual, the question is “no” in 2022. Either can be used to
management strategy (diet, exercise, medications), assess achievement of glycemic targets.6 The
the risk of hypoglycemia, and access to care and objective for the practicing clinician is to use tools
technology, differing strategies for monitoring that will optimize outcomes and safety for an
treatment response are warranted. For individual with diabetes in their clinic.
individuals with type 1 diabetes, recent-onset One useful strategy for determining when and
diabetes, younger age, long life expectancy, and in whom to use CGM is to consider who would
fewer comorbidities, the use of newer diabetes benefit and how. Glucose is not static and glucose
management tools should be actively considered, variability is not well characterized using either
as they have demonstrated improvement in hemoglobin A1c or blood glucose monitoring by
glycemic control.2,3 For individuals using agents fingerstick. Let’s imagine different fingerstick
that could increase risk of hypoglycemia, use blood glucose monitoring and CGM scenarios
of CGM can be exceptionally useful for risk where an individual has a hemoglobin A1c value of
mitigation. In contrast, for individuals at low 7.0% (53 mmol/mol). In a scenario of an individual
risk for hypoglycemia whose diabetes is managed with all blood glucose monitoring values before
with diet and physical activity, agents without meals and at bedtime in the target range, lows and
hypoglycemia risk and simple tools for achieving highs can still be missed. Using CGM in Figure
hemoglobin A1c targets may suffice. It is also an 2, an individual could have a TIR ranging from

124  ENDO 2022 • Endocrine Case Management

Figure 1. Consensus Ambulatory Glucose Profile Report Generated from CGM Download

© 2022 International Diabetes Center at Park Nicollet, Minneapolis, MN. Used with permission. Visit AGPreport.org for more information.

40% to 90%. For example, if a patient had a TIR of of 90% and a hemoglobin A1c level of 7.0%
50% and a hemoglobin A1c level between 6.0% and (53 mmol/mol), one would expect that most of
7.0% (42 and 53 mmol/mol), one would need to the blood glucose values not in range were above
be exceptionally concerned about hypoglycemia range. It is also quite possible for a patient with
lowering the overall glucose burden represented substantial hyperglycemia and hypoglycemia (high
in the hemoglobin A1c. If a patient had a TIR glycemic variability) to have excellent hemoglobin

ENDO 2022 • Diabetes Mellitus and Glucose Metabolism  125

A1c with dangerous glycemic profiles. This figure However, incorporation into a clinical practice
demonstrates with undeniable clarity that CGM requires setting up an infrastructure for approval,
offers additional insight. These data can inform download, and interpretation of the data. A
medical decision-making both for the provider and responsive health care system requires the
the patient with diabetes. Worth noting, patients capacity to educate the patient on the use of CGM,
treated with insulin and noninsulin therapies can processes in place to efficiently download the
have significant glucose variability for which CGM data for review and use for medical management
data could inform choice of behavior modification7 of diabetes, infrastructure to facilitate effective
and or antihyperglycemic agent. interactions with third-party payers for coverage
of this technology, systems to incorporate data
Figure 2. CGM Data Illustrating Different TIR into the electronic health record, and standard
Possible With Same Hemoglobin A1c Level operating procedures for communication with
the patient. For the correctly selected patient,
the benefit can be exceptional, both in terms of
glycemic control and prevention or avoidance of
hypoglycemia. Few systems outside of diabetes
centers have streamlined this process to optimize
care. This is a current gap in many health care
systems with the proven assets for patient care
driving change in process of care. A system
must be in place to enable safe and effective use
of CGM. In my experience, it is crucial for the
diabetes care provider to work with their practice,
Reprinted with permission from the diaTribe Foundation resource page:
https://diatribe.org/time-range.
third-party payers, and clinic staff to establish
a system of care to support the use of CGM for
the right patient population. If these stipulations
Barriers to Optimal Practice cannot be embedded into a provider’s clinical
setting, partnerships with certified diabetes care
• Choosing the optimal patient who will benefit and education specialists or endocrinology/
from CGM technology. diabetes centers should be established to enable
• Justifying CGM to third-party payers and the access to this technology, which is now the
system within the clinic to determine coverage. standard of care for patients with diabetes.
• Building adequate infrastructure for education 1. Identification of patients most likely to
about and use of CGM devices in the clinic, benefit from CGM technology. (This is not
access and review of CGM data, and electronic exhaustive; please see American Diabetes
health record documentation of CGM data. Association Standards of Medical Care for
• Implementing billing structures to support Diabetes for a complete list.)3,4
implementation of this technology.
a. Patients on insulin therapy: The use of CGM
and assessment of TIR, TBR, and TAR
are essential for the safe management of
Strategies for Diagnosis, patients living with type 1 diabetes or
Therapy, and/or Management of patients with any type of diabetes on
The routine use of CGM (all aspects, not just multiple daily insulin injections (MDI).
TIR) offers benefits for assessment of goal- Patients treated with MDI, insulin pump
directed therapy and clinical decision-making. therapy (including CGM-augmented

126  ENDO 2022 • Endocrine Case Management

 insulin pump therapy and hybrid closed- ii. Most companies offer the educational
loop systems) are able to communicate opportunity for providers to wear
with their provider using this technology devices.
for fine-tuning diabetes management
and decreasing hypoglycemia. For b. Education on technical aspects of CGM
patients treated with basal insulin insertion and care (as above).
alone, use of CGM and TIR, TBR, and c. Data downloading, reports, and decision
TAR can optimize the use of additional tools.
antihyperglycemic agents to achieve
i. HIPAA-compliant platforms are
glycemic targets. In these settings, TIR
available for provider download.
can be used in lieu of hemoglobin A1c for
assessing glycemic targets with the added ii. Education is available for use of the
value of providing information about ambulatory glucose profile and other
hyperglycemia and hypoglycemia. insights embedded in the reports.
b. Patients with inadequate glycemic control: For d. Process of care infrastructure for CGM
patients who have suboptimal glycemic review and communication with the patient.
control on their current regimen and/
or have glycemic variability, the use i. Certified diabetes care and education
of CGM and TIR, TBR, and TAR can specialists or others developing this
be informative for guiding medical expertise within the clinic can set up
management and choice of glucose- the infrastructure for initiating patients
lowering medication. on the devices and educating patients
on the processes for downloading and
c. Patients in high-risk work settings: CGM is
sharing data with the practice.
particularly important for those operating
machinery or engaging in extensive ii. Support staff from each of the device
physical activity. manufacturers can be partnered with
to facilitate optimal use by the patient.
d. Patients in remote settings: Telemedicine
access to the CGM-derived metrics TIR, iii. Troubleshooting for alarms or sensor
TBR, and TAR can inform point-of- malfunctions can be done either
care decision-making for remote clinical by the practice or in some cases
decision-making. through support from the device
manufacturers.
In many health care systems, there is a stipulation
that the individual using CGM technology be e. Cost of technology and coverage by third-
embedded in a clinical practice with expertise in party payers (need process).
the use of this technology.
i. Third-party payers have specific
2. Provider and patient comfort with the use of rules, as do integrated health care
and interpretation of CGM technology. systems such as the Veterans
Health Administration and Kaiser
a. Education on different CGM models, Permanente, for eligible individuals
readers, report downloading, apps. (see above). These rules are in
continuous evolution; as the evidence
i. Education can be obtained through
for benefit continues to increase, the
certified diabetes care and education
patient populations covered continues
specialists, device companies, and
to increase.
continuing medical education sessions.

ENDO 2022 • Diabetes Mellitus and Glucose Metabolism  127

 ii. As providers, we need to advocate for Clinical Case Vignettes
access to this technology for correctly
selected patients. Case 1
A 31-year-old man was diagnosed with new-
3. Educational support for optimal use of onset type 1 diabetes after an episode of diabetic
technology. ketoacidosis 6 months ago. He is preparing
to transition from MDI to automated insulin
a. Formal provider education is needed, delivery. His current regimen consists of insulin
analogous to electrocardiography glargine, 24 units at bedtime; meal coverage
interpretation. insulin-to-carbohydrate ratio of 1:10; and
correction factor of 1:30 over 120 mg/dL. He does
i. The ambulatory glucose profile
not correct at bedtime due to fear of hypoglycemia.
outlines the metrics that should be
CGM download is shown (see image).
considered upon review of CGM
beyond TIR.
ii. Algorithms have been established for
the review of CGM download to guide
clinical decision-making.
b. CGM download, interpretation, and
communication back to the patient.
i. Within the clinical practice setting,
a process of care must be established
for the review of CGM, and timelines
should be set up for communication
with the patient.
ii. Embedding these processes into the After reviewing the data, which of the
post-visit care plan can facilitate following should be the first area of concern?
optimal communication. A. Daytime glucose profiles
iii. When possible, remote access for B. High and very high total 33%
CGM data can optimize review and C. Low and very low total 3.9%
follow-up communication with the
D. Nocturnal glucose profiles
patient.
Answer: D) Nocturnal glucose profiles
c. Patient education on pattern recognition
and thresholds for contacting provider. In review of the patient’s download, there is a
At each patient visit, an assessment of trend for blood glucose to drop through the night
diabetes literacy and numeracy around by more than 100 mg/dL (5.6 mmol/L). As such,
CGM use and pattern recognition should any changes in his regimen that lower overall
be addressed. Interval visits with educators glucose concentrations may place the patient at
should be arranged if the patient is unable risk for nocturnal hypoglycemia (Answer D). The
to use the device to optimally guide their priority in CGM review is to look for patterns that
decision-making. could place the patient at risk for hypoglycemia.
The Table and Figure show targets of therapy
using CGM.

128  ENDO 2022 • Endocrine Case Management

Table. Standardized CGM Metrics for clinical care a booster and would like input on his diabetes
1. Number of days CGM device is management. Recent laboratory testing reveals
worn (recommend 14 days) a hemoglobin A1c level of 7.8% (62 mmol/mol).
2. Percentage of time CGM device is He is concerned about elevated glucose values.
active (recommend 70% of data
from 14 days)
His regimen consists of insulin glargine, 2 units
3. Mean glucose
in the evening, and insulin aspart, 5 units with
breakfast and 2 units at lunch and dinner. He
4. Glucose management indicator
had recurrent nocturnal hypoglycemia requiring
5. Glycemic variability (%CV)
target ≤36%*
third-party assistance when on insulin glargine,
3 to 4 units daily; severe nocturnal hypoglycemia
6. TAR: % of readings and time Level 2
>250 mg/dL (>13.9 mmol/L) hyperglycemia when on insulin degludec, 2 units daily; and severe
7. TAR: % of readings and time Level 1 nocturnal hypoglycemia when administering lunch
181-250 mg/dL (10.1-13.9 mmol/L) hyperglycemia or dinner aspart doses greater than 2 units. CGM
8. TIR: % of readings and time In range data are shown (see image).
70-180 mg/dL (3.9-10.0 mmol/L)
9. TBR: % of readings and time Level 1
54-69 mg/dL (3.0-3.8 mmol/L) hyperglycemia
10. TBR: % of readings and time Level 2
<54 mg/dL (<3.0 mmol/L) hyperglycemia
CGM, continuous glucose monitoring; CV, coefficient of variation; TAR,
time above range; TBR, time below range, TIR, time in range. *Some
studies suggest that %CV targets (<33%) provide additional protection
against hypoglycemia for those receiving insulin or sulfonylureas.

Reprinted from American Diabetes Association Professional Practice

Committee; Draznin B et al. Diabetes Care, 2022; 45(Suppl 1); and Holt
RIG et al. Diabetes Care, 2021; 44(11).

After reviewing the data, what should be

the priority to discuss with this patient?
A. Achieving a TIR of at least 70%
B. Blood glucose trends before lunch and dinner
C. Postdinner and nighttime glucose elevations
D. No changes recommended at this time
Answer: D) No changes recommended at this time
The patient is not having hypoglycemia, and
this is an outstanding overall result. He has a
70-plus-year history of diabetes without clinically
significant complications. There is no evidence
that very tight glycemic control would improve
any clinically significant aspect of this patient’s
Case 2 life. It is noted in the vignette’s stem that most
minor changes in insulin have previously resulted
A 92-year-old man has a 70-year history of type in hypoglycemia. Therefore, no changes are
1 diabetes without complications. He has been recommended at this time (Answer D).
shuttered in his assisted living home during the
COVID pandemic. He is now vaccinated with

ENDO 2022 • Diabetes Mellitus and Glucose Metabolism  129

Case 3 patient see that the SGLT-2 inhibitor may be
beneficial in addressing postprandial glucose in
A 68-year-old woman with a 10-year history of
addition to the kidney benefit it provides.
type 2 diabetes is managed with metformin. An
SGLT-2 inhibitor is added for kidney indications.
CGM data are shown (see images). Case 3 (Continued)

What information from this patient’s Should CGM use be continued in this setting?
CGM is useful in decision-making?
A. Yes
A. Glycemic variability
B. No
B. Nocturnal blood glucose values
C. Only as needed
C. Postprandial blood glucose values
D. Helping the patient see that a change needs to Answer: B) No
be made CGM is not needed in this setting (Answer B),
Answer: A) Glycemic variability as there appears to be no indication of risk for
hypoglycemia.
The glycemic variability observed in this patient’s
CGM data (Answer A) can be used to help the

References
1. American Diabetes Association Professional Practice Committee; Draznin 5. Carlson AL, Criego AB, Martens TW, Bergenstal RM. HbA(1c): the glucose
B, Aroda VR, et al. 6. Glycemic targets: standards of medical care in management indicator, time in range, and standardization of continuous
diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S83-S96. PMID: 34964868 glucose monitoring reports in clinical practice. Endocrinol Metab Clin North
2. Dicembrini I, Cosentino C, Monami M, Mannucci E, Pala L. Effects of real-time Am. 2020;49(1):95-107. PMID: 31980124
continuous glucose monitoring in type 1 diabetes: a meta-analysis of randomized 6. Desouza CV, Holcomb RG, Rosenstock J, et al. Results of a study comparing
controlled trials. Acta Diabetol. 2021;58(4):401-410. PMID: 32789691 glycated albumin to other glycemic indices. J Clin Endocrinol Metab.
3. Holt RIG, DeVries JH, Hess-Fischl A, et al. The management of type 1 2020;105(3):677-687. PMID: 31650161
diabetes in adults. A consensus report by the American Diabetes Association 7. Merino J, Linenberg I, Bermingham KM, et al. Validity of continuous glucose
(ADA) and the European Association for the Study of Diabetes (EASD). monitoring for categorizing glycemic responses to diet: implications for use
Diabetes Care. 2021;44(11):2589-2625. PMID: 34593612 in personalized nutrition. Am J Clin Nutr. 2022 [Online ahead of print] PMID:
4. American Diabetes Association Professional Practice Committee; Draznin 35134821
B, Aroda VR, et al. 7. diabetes technology: standards of medical care in
diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S97-S112. PMID: 34964871

130  ENDO 2022 • Endocrine Case Management

Closed-Loop Insulin Delivery
Sue A. Brown, MD. Division of Endocrinology, University of Virginia, Charlottesville, VA;
E-mail: [email protected]

Learning Objectives Significance of the

As a result of participating in this session, learners Clinical Problem
should be able to: Reports suggest that people with T1DM are not
• Explain the functionality of different meeting established glycemic targets.5,6 A variety
automated insulin delivery (AID) systems. of tools and devices have been developed in an
effort to address these deficiencies. For people
• Evaluate the effect of changes to glycemic with T1DM, one key advancement in the past
parameters on algorithmic performance in 5 years has been the availability of AID devices.
AID systems. These systems consistently improve time in target
range (70-180 mg/dL [3.9-10.0 mmol/L]), reduce
hypoglycemia (<70 mg/dL [<3.9 mmol/L]), and
often improve hemoglobin A1c when compared
Main Conclusions with not using an AID device.1-4
AID devices have demonstrated consistent These devices consist of an insulin pump, a
improvement in glycemic outcomes for people continuous glucose monitoring (CGM) system,
with type 1 diabetes mellitus (T1DM).1-4 As such, and an algorithm that is either embedded in the
AID devices are increasingly used for glycemic pump/device or on a phone app. These algorithms
control, as there remains a gap in achieving use data from both the CGM and insulin pump to
glycemic goals for many people with T1DM.5,6 “close the loop” and make insulin dosing decisions
Each AID device has unique algorithms with automatically based on algorithmic targets. As of
different functionalities that are important for February 2022, there are 4 AID systems that are
clinicians to understand. Current AID systems currently FDA-approved in the United States,
are hybrid closed-loop controllers in which as well as other systems available outside the
the devices are intended to be used alongside United States. Health care practitioners need to
carbohydrate counting to deliver meal boluses. understand how the algorithms are configured and
Therefore, adjustment of carbohydrate ratios how individual algorithms are affected by insulin
remains one of the most important parameters parameter adjustments. This discussion will focus
that affects glycemic outcomes in currently on the use of the FDA-approved AID devices
available AID systems. Adjustments to basal rates for clinicians to consider for optimal glycemic
and correction factors affect some AID systems but management in a person with T1DM.
not others. An understanding of which parameters
are truly adjustable and their potential impact on
Barriers to Optimal Practice
algorithmic performance is relevant for optimal
use of these AID systems. • It can be challenging for clinicians to efficiently
analyze the significant quantity of data
available with contemporary AID devices to
develop optimal treatment-related decisions.

ENDO 2022 • Diabetes Mellitus and Glucose Metabolism  131

• This challenge is further compounded by the algorithm is critical to determining which options
variety of algorithmic approaches to glycemic can be adjusted to individualize it for a person
control that require an understanding of the with T1DM.7-9 This discussion is focused on the
specifics of each device. more common use of AID devices in T1DM with
commercially available options in the United
States as of February 2022. The 4 AID devices
Strategies for Diagnosis, discussed are the 670G, 770G, Control-IQ (C-IQ),
Therapy, and/or Management and Omnipod 5 (OP5).

It is important to untangle the terminology related

to the variety of systems available and described Insulin Delivery
in the literature (Table). An AID system consists Insulin delivery can come from several sources
of 3 main components: a CGM, an insulin pump, in an AID system: (a) user-initiated meal and
and an algorithm connecting the devices (closed- correction boluses; (b) AID algorithm-initiated
loop system or AID). Each system can be operated insulin delivery given as a microbolus every 5
in a manual mode where the AID algorithm is minutes and constantly adjusted to meet the
not activated. When CGM is not being used for prevailing targets; and (c) in some systems,
insulin delivery, some studies refer to this mode discrete automated boluses given periodically
as sensor-augmented pump (SAP). Systems or that are generally of a higher magnitude than the
modes that only use CGM to decrease or suspend microboluses every 5 minutes.
insulin delivery with no ability to automatically
increase insulin delivery are often termed low-
Changing Algorithmic Targets
glucose suspend (LGS) or predictive-low glucose
suspend (PLGS) systems depending on whether In general, the changing of a target will directly
the CGM threshold for insulin attenuation is based affect insulin delivery. The general concept of a
on a fixed or a predictive value. This discussion target or target range is similar across devices:
focuses on AID systems that are capable of insulin will be increased if CGM is predicted to
increasing and decreasing insulin automatically be above the prevailing target and insulin will be
based on device-specific algorithmic solutions. decreased or paused if CGM is predicted to be
These systems can also be referred to as AID or below the prevailing target. The algorithm targets
closed-loop control or artificial pancreas systems. are used to guide automated insulin delivery by
Each system has a variety of inputs into the the device, and some systems allow adjustment
algorithm. Understanding the inputs into the by time of day. The algorithm targets can be

Table. Types of Insulin Delivery System Configurations

CGM+ pump connection Insulin delivery System abbreviation Definition Description Examples
Not driven by CGM No effect on SAP Sensor- CGM and pump not Any CGM + Any
insulin Augmented connected, operate insulin pump
Pump independently operated separately
Driven by CGM Only decreases LGS Low Glucose Suspends at a user-set 630G
insulin Suspend threshold Manual 670G
(suspend on low)
PLGS Predictive- Decreases or suspends Basal-IQ
Low Glucose based on predicted Manual 670G
Suspend glucose (suspend before low)
Driven by CGM Increases and HCL (a type of AID) Hybrid AID device where 670G/770G
decreases insulin Closed-Loop people are expected to Control-IQ
bolus after meals Omnipod 5

132  ENDO 2022 • Endocrine Case Management

different from the targets used for a user-requested when calculating the meal or correction bolus,
meal or correction bolus done through the bolus thus compensating for the additional insulin
calculator. Current targets are: delivered by the AID device.
• 670G/770G: Fixed algorithmic target of
120 mg/dL (6.7 mmol/L). This can be changed Hypoglycemic Treatments
by activating the temp target feature that Because these systems can suspend insulin for
raises the target to 150 mg/dL (8.3 mmol/L). prolonged periods, it is typical that a person enters
Note: When a user requests a correction a hypoglycemic episode with a lower amount
bolus, the target used in the bolus calculator is of insulin-on-board. This means that fewer
150 mg/dL (8.3 mmol/L). carbohydrates may be needed to treat an individual
• C-IQ: “Normal mode” algorithmic target range hypoglycemic event. This varies by individual but
of 112.5 to 160 mg/dL (6.2-8.9 mmol/L); could be as much as 10% to 40% less carbohydrate
“sleep mode”: gradual tightening of target administration (eg, 8-16 g rather than 16-24 g).
down to 112.5 to 120 mg/dL (6.2-6.7 mmol/L) AID systems generally respond well to the rebound
over the scheduled sleep time; “exercise hyperglycemia that occurs following hypoglycemic
activity”: raises target to 140 to 160 mg/dL treatments, but occasionally this additional insulin
(7.8-8.9 mmol/L). Note: when a user requests can set up a recurrent hypoglycemic event later.
a correction bolus, the target used in the bolus
calculator is 110 mg/dL (6.1 mmol/L). Exercise
• OP5: Five available algorithmic targets Exercise remains a glycemic challenge with current
of 110 mg/dL (6.1 mmol/L), 120 mg/dL AID systems. Most systems have a mechanism for
(6.7 mmol/L), 130 mg/dL (7.2 mmol/L), setting a temporary target that can be selected by
140 mg/dL (7.8 mmol/L), or 150 mg/dL the user. Traditional methods to avoid exercise-
(8.3 mmol/L) that can be preprogrammed at induced hypoglycemia by ingesting carbohydrate
different times of day (eg, if there is a need prior to activity may result in a greater amount of
for a different target overnight vs daytime). insulin-on-board than desired as the AID system
The “activity” function temporarily changes reacts to the rise in CGM. This can be mitigated
the target to 150 mg/dL (8.3 mmol/L). Note: by adjusting targets and may even require the
the selected algorithmic target is the same one disconnection of the pump for some types of
used for user-requested correction boluses. activity. The following adjustable targets are:
• 670G/770G: Has a temp target of 150 mg/dL
Meal Boluses (8.3 mmol/L), which can be used during exercise.
Adjustment of carbohydrate ratios remains a key • C-IQ: Has an exercise activity that
intervention because current AID systems rely increases the target to 140 to 160 mg/dL
on carbohydrate counting. For this reason, they (7.8 to 8.9 mmol/L). Of note, the additional
are considered hybrid closed-loop controllers (a automated corrections that can occur hourly
type of AID system). Although AID systems can are still active during the exercise activity.
adjust insulin during the postprandial period to • OP5: Has an activity function the increases the
compensate for inaccurate or missed meal boluses, target to 150 mg/dL (8.3 mmol/L).
the systems consistently perform better when
carbohydrate intake is entered as part of a meal
bolus. In general, it is strongly recommended that
the bolus calculator function of each system be
used to ensure that insulin-on-board is considered

ENDO 2022 • Diabetes Mellitus and Glucose Metabolism  133

Total Daily Insulin corrections not automated insulin delivery by
the device)
Many current systems are oriented toward
incorporating total daily insulin (TDI) as an
important driver of algorithmic solutions. Therefore,
each of the current systems tracks TDI and uses it to Clinical Case Vignettes
some degree to adjust insulin delivery. Depending on Case 1
the system, TDI may be updated at different times.
A 55-year-old man with T1DM has no
• 670G/770G: Uses a running TDI over complications and a recent hemoglobin A1c
approximately 6 days with a fading memory measurement of 6.7% (50 mmol/mol). He currently
to determine the AID parameters in effect (eg, uses an AID device (670G) with the summary
auto basal rate and insulin sensitivity factor). information shown (see Figure). Although he is
meeting glycemic targets, he requests advice on
• C-IQ: An initial input for TDI is required with
how to handle postprandial hyperglycemia after
a new system start but then uses a rolling 6-day
dinner. He estimates carbohydrates carefully and
average for determining TDI, which has a role in
administers his meal bolus on time.
modulating the automated insulin microboluses.
• OP5: Updates TDI with each pod change If a parameter change is needed, which of
(eg, every 3 days) and is used to determine an the following changes is the most direct way
adaptive basal rate. to address his postprandial hyperglycemia?
A. Decrease insulin action time to increase insulin
delivery for the meal
Preset Insulin Parameters B. Decrease the carbohydrate ratio at dinner to
Preset basal rates and correction factors are always increase insulin delivery for the meal
relevant when the AID system is being operated in C. Decrease the correction factor (insulin
manual mode for all current systems. Preset basal sensitivity factor) to increase automated
rates, however, are not used during automated mode insulin delivery by the algorithm
for the 670/770G and are only used for the very first
D. Increase the basal rate because that is the most
system pod of OP5 to gauge the TDI. Thereafter,
direct way to affect automated insulin delivery
these systems use the TDI to determine the effective
by the algorithm
basal rate. The C-IQ system does use the preset basal
rate, and its adjustment will have some influence E. Lower the target of the algorithm for the
on insulin delivery. The correction factor has no postprandial dinner or overnight period
relevance for automated mode in 670G/770G, is only Answer: B) Decrease the carbohydrate ratio at
used for user-request boluses for OP5, and is used dinner to increase insulin delivery for the meal
for both user-requested boluses and some insulin
delivery calculations during AID use for C-IQ. The The carbohydrate ratio (Answer B) is the only
most relevant parameters that can be adjusted by an applicable intervention in the 670G/770G systems
AID system to alter insulin delivery are: that would directly adjust insulin effectively for
a meal.
• 670G/770G: carbohydrate ratio, duration of Decreasing insulin action time to increase
insulin action insulin delivery for the meal (Answer A) is a
• C-IQ: carbohydrate ratio, correction factor, consideration, as it is an adjustable parameter
basal rates, setting of sleep schedule and programming a shorter insulin action
• OP5: carbohydrate ratio, setting of AID target, time may help with increasing insulin delivery.
correction factor (only used for user-requested

134  ENDO 2022 • Endocrine Case Management

However, it is not the preferred parameter in this while moving items between apartments. He
situation and cannot be adjusted to specific time required several hypoglycemic treatments and was
segments. eating throughout the day. He misses occasional
Increasing the basal rate (Answer D) and meal boluses, including on the day shown in
decreasing the correction factor (insulin sensitivity the Figure, and is not using exercise mode. He
factor) (Answer C) are not viable options because asked for your advice on strategies to avoid
basal rates or correction factors cannot be adjusted hypoglycemia during this type of activity.
when the automated mode is activated. Both are
system-determined settings based on TDI. Which of the following would be
Lowering the target of the algorithm for a reasonable initial adjustment
the postprandial dinner or overnight period for this type of activity?
(Answer E) is not feasible because the target of A. Decrease the basal rate
the algorithm itself cannot be lowered below B. Increase insulin action time to decrease
fixed targets (120 mg/dL [6.7 mmol/L] during insulin delivery
auto mode or 150 mg/dL [8.3 mmol/L] during
C. Increase the carbohydrate ratio to decrease
temp target).
insulin delivery for meals
D. Increase the correction factor to decrease
Case 2 automated insulin delivery by the device
A 21-year-old college student has T1DM E. Increase the target of the algorithm
without complications and a recent hemoglobin during activity
A1c measurement of 6.9% (52 mmol/mol). He
currently uses an AID device (C-IQ). The Figure Answer: E) Increase the target of the
shows a day when he experienced hypoglycemia algorithm during activity

ENDO 2022 • Diabetes Mellitus and Glucose Metabolism  135

Decreasing the basal rate (Answer A), increasing Increasing the carbohydrate ratio (Answer C)
the carbohydrate ratio (Answer C), increasing the would not be as effective because there are not
correction factor (Answer D), and increasing the many user-requested boluses, and he has mostly
target of the algorithm during activity (Answer E) automated correction boluses throughout the day.
are all options that could be adjusted in this system Increasing insulin action time (Answer B),
and will affect insulin delivery. the duration of insulin action for the algorithm
Increasing the target of the algorithm (Answer component, cannot be adjusted in this system.
E) is the preferred initial strategy, as he can
activate the exercise activity option to temporarily Case 3
increase the algorithm target to 140 to 160 mg/dL
(7.8 to 8.9 mmol/L). He was not doing strenuous A 45-year-old woman has T1DM without
activity but rather sustained light activity that is complications and a recent hemogloblin A1c
likely to respond to this approach. measurement of 7.6% (60 mmol/mol). She is
Increasing the correction factor (Answer D) currently using an insulin pump and CGM that are
would be the next best option, as this may directly not connected and will be transitioning to an AID
lower the amount of the periodic automated device (OP5). She does consistent meal bolusing
correction boluses. during the day, and because of her concerns about
Decreasing the basal rate (Answer A) can hypoglycemia at night, she has a lower basal
affect insulin delivery, but it would have less of an rate overnight. She notes she often wakes in the
intended effect, as the system can increase basal morning with higher glucose values.
rates significantly if needed.

136  ENDO 2022 • Endocrine Case Management

What is the most effective parameter E) is the most effective method to adjust overall
that could be adjusted to improve automated insulin delivery for this device.
her glycemic outcomes once the Therefore, it is reasonable to choose a lower target
OP5 AID device is initiated? (eg, 110 or 120 mg/dL [6.1 or 6.7 mmol/L]).
A. Decrease the carbohydrate ratio at dinner to Increasing the basal rate (Answer D) will not
increase insulin delivery for the meal affect automated insulin delivery by the device
B. Decrease the correction factor to increase after the very first pod has been changed and this
automated insulin delivery by the device is therefore not a long-term solution.
Decreasing the correction factor to increase
C. Decrease the duration of insulin action time
automated insulin delivery by the device (Answer
D. Increase the basal rate because that is the most B) is not preferred solution as written because
direct way to affect automated insulin delivery adjusting the correction factor with this system
by the device will only affect the user-directed boluses, not the
E. Lower the target of the algorithm for automated insulin delivery for this device.
postprandial dinner or overnight period Decreasing the carbohydrate ratio at dinner
(Answer A) and decreasing the duration of insulin
Answer: E) Lower the target of the algorithm
action time (Answer C) are adjustable factors that
for postprandial dinner or overnight period
will affect user-direct boluses and are reasonable to
Lowering the target of the algorithm for consider if more nuanced adjustments are needed
postprandial dinner or overnight period (Answer once the algorithmic targets are set.

References
1. Bergenstal RM, Garg S, Weinzimer SA, et al. Safety of a hybrid closed- 6. Miller KM, Foster NC, Beck RW, et al; T1D Exchange Clinic Network.
loop insulin delivery system in patients with type 1 diabetes. JAMA. Current state of type 1 diabetes treatment in the U.S.: updated data from
2016;316(13):1407-1408. PMID: 27629148 the T1D exchange clinic registry. Diabetes Care. 2015;38:971-978. PMID:
2. Garg SK, Weinzimer SA, Tamborlane WV, et al. Glucose outcomes with the 25998289
in-home use of a hybrid closed-loop insulin delivery system in adolescents 7. Messer LH, Forlenza GP, Sherr JL, et al. Optimizing hybrid closed-loop
and adults with type 1 diabetes. Diabetes Technol Ther. 2017;19(3):155-163. therapy in adolescents and emerging adults using the MiniMed 670G system.
PMID: 28134564 Diabetes Care. 2018;41(4):789-796. PMID: 29444895
3. Brown SA, Kovatchev BP, Raghinaru D, et al; IDCL Trial Research Group. 8. O’Malley G, Messer LH, Levy CJ, et al; iDCL Trial Research Group. Clinical
Six-month randomized, multicenter trial of closed-loop control in type 1 management and pump parameter adjustment of the control-IQ closed-loop
diabetes. N Engl J Med. 2019;381(18):1707-1717. PMID: 31618560 control system: results from a 6-month, multicenter, randomized clinical trial.
4. Brown SA, Forlenza GP, Bode BW, et al; Omnipod 5 Research Group. Diabetes Technol Ther. 2021;23(4):245-252. PMID: 33155824
Multicenter trial of a tubeless, on-body automated insulin delivery system 9. Berget C, Sherr JL, DeSalvo DJ, et al. Clinical implementation of the
with customizable glycemic targets in pediatric and adult participants with Omnipod 5 automated insulin delivery system: key considerations for training
type 1 diabetes. Diabetes Care. 2021;44(7):1630-1640. PMID: 34099518 and onboarding people with diabetes. Clinical Diabetes. 2022;40(2):168-184.
5. Foster NC, Beck RW, Miller KM, et al. State of type 1 diabetes management
and outcomes from the T1D exchange in 2016-2018. Diabetes Technol Ther.
2019;21(2):66-72. PMID: 30657336

ENDO 2022 • Diabetes Mellitus and Glucose Metabolism  137

NEUROENDOCRINOLOGY
AND PITUITARY
Perioperative Management
of Pituitary Adenomas
Ismat Shafiq, MD. Division of Endocrinology and Metabolism, University of Rochester, NY;
E-mail: [email protected]

Learning Objectives include cortisol-producing adenomas (Cushing

disease), GH-producing adenomas (acromegaly),
As a result of participating in this session, learners
prolactinomas, TSH-producing adenomas, and
should be able to:
rare FSH/LH-producing adenomas. Pituitary
• Perform preoperative assessment and manage microadenomas are smaller than 10 mm,
pituitary hormonal dysfunction. and macroadenomas are larger than 10 mm.
Macroadenomas larger than 40 mm are giant
• Explain the need for intraoperative stress-dose
tumors. Population-based studies have indicated
glucocorticoid treatment.
an increase in the incidence of pituitary adenomas
• Assess pituitary function postoperatively in ranging from about 3.9 to 7.4 cases per 100,000
functional and nonfunctional adenomas. per year.1 Transsphenoidal surgery is the primary
treatment for large nonfunctioning adenomas
and functioning adenomas except prolactinomas.2
Crowder et al reported an increase in pituitary
Main Conclusions surgeries from 26.7 to 36.2 per million per year
The perioperative management of pituitary over the last decade.3 Thorough preoperative
adenomas requires an experienced multidisciplinary hormonal evaluations of the hypothalamic-
team that includes an endocrinologist, pituitary axis are imperative to guide
neuroophthalmologist, and neurosurgeon for management decisions during the perioperative
optimal patient care. Appropriate preoperative and postoperative periods. The postoperative
assessment is crucial to guide perioperative and period requires close monitoring for AI, DI, and
postoperative management decisions. All patients hyponatremia/SIADH to prevent mortality.
should have a thorough evaluation for hormonal
overproduction and deficiencies. Close monitoring Barriers to Optimal Practice
for adrenal insufficiency (AI), diabetes insipidus
(DI), and syndrome of inappropriate antidiuretic • Limited and variable information to identify
hormone secretion (SIADH)/hyponatremia is appropriate treatment strategies for pituitary
necessary in the early postoperative period. adenomas in the perioperative period.
• Limited experience of endocrinologists and
neurosurgeons managing pituitary adenomas
Significance of the in hospitals with a low volume of patients with
Clinical Problem these tumors.
Pituitary adenomas are benign intracranial
neoplasms that are categorized based on
functional status or size. Functional adenomas

140  ENDO 2022 • Endocrine Case Management

Strategies for Diagnosis, Measurement of basal serum cortisol at
8:00 AM is an easy and reliable way to assess
Therapy, and/or Management
the hypothalamic-pituitary-adrenal axis (HPA),
Preoperative Evaluation and it should be done in all patients with
and Management pituitary adenomas. A morning serum cortisol
According to society guidelines and consensus concentration between 8 and 15 µg/dL (220
statements, all patients with pituitary and 413 nmol/L) suggests an intact HPA axis.
incidentalomas should undergo laboratory A morning serum cortisol concentration less
evaluation for hormone excess and deficiency.2,4,5 than 3 µg/dL (<83 nmol/L) confirms AI. A
The initial preoperative workup of pituitary serum cortisol concentration less than 8 µg/dL
adenomas should include evaluation for hormone (<220 nmol/L) warrants further investigation
excess and hormone deficiency. with a cosyntropin-stimulation test (CST). A
normal CST result is defined by an increase in
Evaluation for Hormone Excess cortisol greater than 18 µg/dL (>500 nmol/L) after
Measuring serum prolactin is crucial to exclude injection of 250 mcg of an ACTH analogue. All
a prolactinoma, as medical therapy with patients with adrenal insufficiency should be started
dopamine agonists is the first-line treatment on glucocorticoid replacement preoperatively.
for this type of tumor. Serum prolactin levels The standard dosages for glucocorticoid
generally correspond to the tumor size. A serum replacement are prednisone, 5 to 7.5 mg daily,
prolactin concentration greater than 250 ng/mL or hydrocortisone, 15 to 30 mg daily.7-10 At
(>10.9 nmol/L) suggests a macroprolactinoma. our pituitary center, we use prednisone, 5 mg,
There may be a discrepancy between tumor size or hydrocortisone, 15 mg, in divided doses
and prolactin level in the setting of cystic adenoma preoperatively in patients diagnosed with AI.
and assay artifact. If the prolactin concentration is Free T4 should be measured in patients with
between 20 and 200 ng/dL (0.9 and 8.7 nmol/L) pituitary adenomas. TSH measurement is not
in a patient with a macroadenoma, consider a reliable test in patients with pituitary disease,
obtaining serum prolactin in serial dilution to and the result can be low, normal, or minimally
assess for evaluation of a falsely low level due elevated. The Endocrine Society recommends
to the hook effect in the assay, especially in treating all patients with central hypothyroidism
patients with giant tumors. Current prolactin preoperatively. Emerging data suggest treating
immunoassays are sensitive, and falsely low patients based on the degree of hypothyroidism.
prolactin levels are infrequently observed.6 The degree of hypothyroidism defines
IGF-1 should be measured for GH assessment. perioperative risk and mortality. Perioperative
If the IGF-1 is equivocal, further confirmation treatment with levothyroxine is recommended for
tests can be performed in selected patients. patients with severe hypothyroidism (myxedema
Glucocorticoid excess should be evaluated by coma, severe symptoms of hypothyroidism, free
measuring salivary cortisol on 2 consecutive nights T4 <0.5 ng/dL [<6.4 pmol/L]) to avoid cardiac and
or by 24-hour urine collection for free cortisol respiratory compromise, postoperative ileus, and
excretion or a 1-mg overnight dexamethasone- hyponatremia. Preoperative treatment may not be
suppression test. necessary for mild to moderate hypothyroidism
since studies have not shown any difference
Evaluation for Hormone Deficiency in mortality or cardiovascular outcomes.11-13
Current guidelines recommend evaluation However, given the paucity of data, the decision to
for hypopituitarism in all patients with treat patients with central hypothyroidism should
pituitary adenomas. be individualized based on history, symptoms, and
other comorbidities.

ENDO 2022 • Neuroendocrinology and Pituitary  141

 IGF-1 should be measured to assess for GH Glucocorticoid stress dosing varies among
deficiency. GH deficiency does not warrant further practices. Inder et al recommend using
preoperative testing or treatment. hydrocortisone, 50 mg every 8 hours, with rapid
Evaluation of gonadal function depends on the tapering to a physiologic dose within 48 hours. The
patient’s sex and age. There is no need to measure use of dexamethasone, 4 mg, on the day of surgery
gonadotropins in premenopausal women with followed by a quick taper has also been suggested.16
regular periods. In premenopausal women with Others have used hydrocortisone, 30 mg
irregular menses, LH, FSH, and estradiol can be used intravenously every 8 hours, on the day of surgery
to screen for hypogonadotropic hypogonadism. with a taper in the next 48 hours. At our center, all
FSH measurement in postmenopausal women can patients receive dexamethasone, 4 mg, as stress-
be helpful, as low levels suggest hypopituitarism. dose glucocorticoids during anesthesia induction.
Morning testosterone and gonadotropin levels
should be measured in all men. Treatment of Postoperative Evaluation
hypogonadism can be deferred until 3 months
after surgery if it persists. and Management
DI is rare in patients with pituitary Postoperative follow-up includes assessment of the
adenomas. DI is common in craniopharyngiomas, HPA axis, monitoring DI and/or hyponatremia,
hypophysitis, and metastatic disease. In patients assessing the thyroid/gonadal axis, and evaluating
with polyuria and polydipsia, a diagnosis can functional adenoma.13
be established by measuring serum sodium and
urine osmolality. DI should be suspected if the HPA Axis
serum sodium concentration is at or greater than The Pituitary Society Delphi panel recommends
145 mEq/L (≥145 mmol/L) with urine osmolality checking basal morning cortisol levels 1 to
less than 100 mOsm/kg. Preoperative medical 5 days postoperatively to evaluate the HPA axis.
treatment with desmopressin can be considered to Published studies have measured basal morning
relieve symptoms in selected patients. cortisol on the first postoperative day. The
threshold for a normal morning serum cortisol
value in this context varies among studies. A
Intraoperative Management morning serum cortisol concentration of 8 to
Glucocorticoid management at the time of surgery 15 µg/dL (220 to 413 nmol/L) generally suggests
varies among local practices. The main questions an intact HPA axis.
when considering glucocorticoid management
are: (1) who should receive stress-dose steroids • In patients with an intact HPA axis
preoperatively and (2) what is the optimal preoperatively, we check morning cortisol
glucocorticoid stress dose? on postoperative day 1. We currently use
Historically, intraoperative empiric “stress- a cortisol cutoff of 10 µg/dL (275 nmol/L)
dose” glucocorticoids have been given to all to define intact HPA axis, in contrast to
patients undergoing pituitary surgery to prevent a cutoff of 14 µg/dL (386 nmol/L) in our
adrenal crisis. Several clinical studies have previously published study.17 We have
demonstrated that intraoperative stress-dose not noticed any change in postoperative
steroids are not necessary in patients with an outcomes using the lower cortisol cutoff. If
intact HPA axis.14-16 At our institution, we do not the morning cortisol concentration is greater
give stress-dose steroids preoperatively to patients than 10 µg/dL (>275 nmol/L), patients are
with a preserved HPA axis. Intraoperative stress- not discharged on any glucocorticoids. If the
dose glucocorticoids are advisable in patients with morning cortisol concentration is less than
known or suspected adrenal insufficiency. 10 µg/dL (<275 nmol/L), patients are started
on prednisone, 5 mg daily. Morning cortisol

142  ENDO 2022 • Endocrine Case Management

 is checked on postoperative day 5 to reassess have intact thirst mechanisms. In selected
the HPA axis and to assess the need for patients with a serum sodium concentration
glucocorticoid replacement. greater than 145 mEq/L (>145 mmol/L),
• In patients with a preoperative cortisol desmopressin, 0.10 mg (oral dose), is given
concentration less than 10 µg/dL to relieve symptoms at night. Alternatively,
(<275 nmol/L)/AI, hydrocortisone, 20 mg desmopressin, 1 to 2 mcg subcutaneously,
twice daily, is given on postoperative day 1; can be used. Intranasal desmopressin is often
the dosage is then decreased to 10 mg twice avoided immediately after surgery due to nasal
daily on postoperative day 2, followed by congestion. A continuous desmopressin dose
hydrocortisone 10 mg/5 mg. We measure is not favored, as DI is transient and may be
morning cortisol 1 to 2 weeks later, after followed by the second phase of SIADH.13,18,19
holding hydrocortisone for 24 hours. An • SIADH may occur independently from DI.
attempt is made to decrease the hydrocortisone The hyponatremia associated with SIADH is
dosage or reassess soon if the morning due to the aberrant release of ADH, surgical
cortisol concentration is greater than manipulation of the gland, untreated adrenal
10 µg/dL (>275 nmol/L). If the morning insufficiency, and central hypothyroidism.
cortisol concentration remains less than SIADH generally occurs 5 to 7 days after surgery
10 µg/dL (<275 nmol/L), glucocorticoid and lasts 14 days. The incidence varies from
replacement is continued. Three months 1.8% to 25%. At our institution, we measure
postoperatively, dynamic testing is performed serum sodium on postoperative day 6. Most
to evaluate the HPA axis. cases of SIADH-induced hyponatremia
are mild and treated with fluid restriction.
Severe hyponatremia is defined as a sodium
Diabetes Insipidus
level less than 125 mEq/L (<125 mmol/L).
The postsurgical triphasic response includes
The management of severe hyponatremia
transient DI, followed by SIADH/hyponatremia,
requires hospital admission and treatment
and then permanent DI.
with fluid restriction, sodium tablets, and/or
• The initial DI phase is from surgical traction hypertonic saline.13,18,19
and disruption of the nerve terminal at the • The third phase is DI again, which can be
posterior pituitary leading to polyuria and permanent. Chronic DI is present in 2% of
polydipsia. The DI phase is most common patients after pituitary surgery. The treatment
and occurs in about 25% to 30% of patients. aim is to reduce symptoms of polyuria and
Most DI resolves spontaneously within 7 days. polydipsia. Desmopressin should be used
Close monitoring of patient symptoms, fluid at the lowest possible dosage with a goal
intake, urine output, and serial plasma sodium serum sodium value greater than 140 mEq/L
with urine osmolarity is paramount for early (>140 mmol/L). Oral tablets (dose ranges from
diagnosis in the postoperative period. At 0.1 to 0.2 mg tablets) or nasal spray (10 mcg)
our center, we monitor patient symptoms can be used for long-term replacement in
and perform laboratory assessment if urine divided doses. We generally recommend
output is greater than 200 cc/h for 3 hours. patients hold off desmopressin 1 day a week
We routinely measure serum sodium and to assess for spontaneous late recovery
urine osmolality on postoperative day 1 in from DI.18,19
all patients after surgery. We instruct the
patient to drink to thirst in the immediate
postoperative period. Most patients do not
need any medical treatment because they

ENDO 2022 • Neuroendocrinology and Pituitary  143

Postoperative Evaluation and Management (<138 nmol/L). If the value is greater than
of Thyroid and Gonadal Axis 5 µg/dL (>138 nmol/L), close monitoring
with serial serum cortisol measurements is
• Thyroid axis: The consensus is to check recommended. Some pituitary centers start
thyroid function 6 to 8 weeks after pituitary glucocorticoids regardless of the cortisol value
surgery. At our institution, we assess thyroid to avoid the risk of AI. At our institution,
function 2 weeks after surgery. we measure morning cortisol and ACTH on
• Gonadal axis: The guidelines recommend postoperative day 1. We generally treat with
checking the gonadal axis 6 to 12 weeks glucocorticoids if the morning value is less
after surgery. At our institution, we evaluate than 10 µg/dL (<275 nmol/L). Hydrocortisone,
patients 12 weeks postoperatively. 30 mg in divided doses, is initially prescribed,
followed by a drop of 5 mg every 2 weeks.
Postoperative Evaluation and Management
in Patients With Functioning Adenomas
Clinical Case Vignettes
• Prolactinomas: Surgery is recommended
for patients with prolactinomas for whom
Case 1
medical treatment fails. Dopamine agonists A 66-year-old woman has peripheral vision loss
are usually held the day before surgery in on routine eye examination. Neuropathology
patients with macroprolactinomas. The examination confirms bitemporal visual field
serum prolactin level may be checked on defects. MRI reveals a 3.2-cm pituitary adenoma
postoperative day 1 or 2 to evaluate for with suprasellar extension and compression of the
remission. A prolactin concentration less optic apparatus.
than 10 ng/mL (<0.43 nmol/L) is suggestive
Laboratory test results:
of cure, especially in the setting of a
microadenoma.6,20 Prolactin = 57.8 ng/mL (4-30 ng/mL)
(SI: 2.51 nmol/L [0.17-1.30 nmol/L])
• Acromegaly: GH may be measured Cortisol (8 AM) = 12.6 µg/dL (5.0-25 µg/dL)
postoperatively for evaluation, although the (SI: 347.6 nmol/L [137.9-689.7 nmol/L])
cutoff to define remission is unclear. IGF-1 Free T4 = 0.8 ng/dL (0.8-1.8 ng/dL)
takes longer to normalize, so it should be (SI: 10.3 pmol/L [10.30-23.17 pmol/L])
measured 6 to 12 weeks postoperatively. IGF-1 = 71 ng/mL (67-195 ng/mL)
(SI: 9.3 nmol/L [8.8-25.5 nmol/L])
• Cushing disease: Serum morning cortisol is
measured postoperatively to see if a patient is Her gonadotropin levels are inappropriately low
in remission. Disease remission is defined as a for menopause.
serum cortisol concentration less than 5 µg/dL Medications include sertraline, 50 mg daily,
(<138 nmol/L), preferably less than 2 µg/dL and a multivitamin.
(<55 nmol/L) in the immediate postoperative On physical examination, her blood pressure
period. Persistent disease should be suspected is 159/83 mm Hg, pulse rate is 63 beats/min, and
if the morning cortisol concentration is greater BMI is 35.19 kg/m².
than 5 µg/dL (>138 nmol/L).21 A small subset A nonfunctioning pituitary adenoma
of patients may develop hypocortisolemia is diagnosed.
in the late postoperative period. The
decision to start glucocorticoids varies from
center to center. Most experts recommend
starting glucocorticoid treatment if the
cortisol concentration is less than 5 µg/dL

144  ENDO 2022 • Endocrine Case Management

In preparation for surgery, the patient should Postoperative laboratory test results:
be treated with which of the following?
Cortisol (8 AM) = 28 µg/dL (5.0-25 µg/dL)
A. Hydrocortisone (SI: 772.5 nmol/L [137.9-689.7 nmol/L])
B. Hydrocortisone and levothyroxine Sodium = 140 mEq/L (136-142 mEq/L)
(SI: 140 mmol/L [136-142 mmol/L])
C. Levothyroxine Urine osmolality = 187 mOsm/kg
D. No changes (150-1150 mOsm/kg) (SI: 187 mmol/kg
[150-1150 mmol/kg]) (with symptoms of
Answer: C) Levothyroxine polyuria)

This patient has a nonfunctioning pituitary She is not treated with desmopressin.
adenoma with evidence of multiple axis
insufficiency in the form of inappropriately Which of the following is the best
low sex hormones for menopause and mild next step in this patient’s care?
central hypothyroidism. The morning cortisol A. Advise fluid restriction
concentration is greater than 10 µg/dL B. Follow-up in 2 weeks in the clinic
(>275 nmol/L) and there is no clinical evidence of C. Measure serum sodium on postoperative
AI. Thus, preoperative glucocorticoid treatment day 5 to 7
(Answers A and B) is not necessary. The
D. Prescribe desmopressin at bedtime and advise
Endocrine Society guidelines and the Pituitary
to use if symptomatic
Society Delphi panel recommend treating
patients with central hypothyroidism (thus, Answer: C) Measure serum sodium
Answer C is correct and Answer D is incorrect). on postoperative day 5 to 7
However, some experts may decide to monitor
patients with mild hypothyroidism because SIADH-related hyponatremia is one of the
the risk of developing cardiac or respiratory reasons for hospital admission following pituitary
problems is low in a patient with mild to surgery. Symptoms vary depending on the degree
moderate hypothyroidism. of hyponatremia. The common symptoms with
mild to moderate hyponatremia are headaches,
confusion, weakness, nausea, and decreased
Case 2 appetite. SIADH usually occurs 5 to 7 days after
A 38-year-old woman has an incidental 1.5-cm transsphenoidal surgery; thus, following up in 2
pituitary macroadenoma found on imaging for weeks (Answer B) is incorrect. According to society
evaluation of headaches. guidelines, serum sodium levels should be measured
on postoperative day 5 to 7 (Answer C). DI is
Preoperative laboratory test results:
transient and is expected to resolve spontaneously;
Prolactin = 52.2 ng/mL (4-30 ng/mL) thus, medical therapy with desmopressin (Answer
(SI: 2.27 nmol/L [0.17-1.30 nmol/L]) D) should be avoided to prevent hyponatremia.
Free T4, normal Fluid restriction alone (Answer A) would not be
Cortisol (8 AM), normal
helpful in managing hyponatremia.
She has an intrauterine device for contraception.
She underwent transsphenoidal surgery, with Case 3
final pathology showing gonadotroph cell
type adenoma. A 36-year-old woman with a left 1.4-cm adrenal
incidentaloma is found to have an elevated cortisol
concentration of 9.1 µg/dL (251.0 nmol/L) after
1 mg of dexamethasone is administered at 11:00 PM.

ENDO 2022 • Neuroendocrinology and Pituitary  145

Laboratory test results: Answer: D) Serial serum morning cortisol measurement
with instructions to call if symptoms of AI develop
Salivary cortisol measurements (11:00 PM-
12:00 AM) = 0.17, 0.16, 0.13 µg/dL) Delayed remission is described in patients
(<0.13 µg/dL) (SI: 4.7 nmol/L, 4.4 nmol/L,
3.6 nmol/L [<3.6 nmol/L]) with Cushing disease after surgery. Frequent
Urinary cortisol = 85 µg/24 h (4-50 µg/24 h) monitoring of morning cortisol with detailed
(SI: 234.6 nmol/d [11-138 nmol/d]) information on signs and symptoms of AI is
ACTH = 123 pg/mL (10-60 pg/mL) recommended (Answer D). It is advised to
(SI: 12.1 pmol/L [2.2-13.2 pmol/L]) discharge the patient with hydrocortisone
She undergoes transsphenoidal surgery, and the or prednisone with instructions to start
final pathology describes a pituitary adenoma, with glucocorticoids if symptoms develop during
densely granulated corticotroph (ACTH) cells. a weekend or if she does not have access to
the laboratory.
Postoperative laboratory test results: Glucocorticoid treatment is initated when
ACTH = 28 pg/mL (10-60 pg/mL)
the serum cortisol concentration is less than
(SI: 6.2 pmol/L [2.2-13.2 pmol/L]) 5 µg/dL (<138 nmol/L) after pituitary surgery in
Cortisol = 11.3 µg/dL (5.0-25 µg/dL) patients with Cushing disease (thus, Answer A
(SI: 311.7 nmol/L [137.9-689.7 nmol/L]) is incorrect).
Repeated surgery (Answer C) and radiation
Which of the following is the best next step? treatment (Answer B) are indicated in patients
with persistent hypercortisolemia after initial
A. Initiation of glucocorticoid replacement surgery, which is too soon to assess immediately
B. Radiation treatment after surgery.
C. Repeated surgery
D. Serial serum morning cortisol measurement with
instructions to call if symptoms of AI develop

References
1. Daly AF, Beckers A. The epidemiology of pituitary adenomas. Endocrinol 8. Montes-Villarreal J, Perez-Arredondo LA, Rodriguez-Gutierrez R, et al.
Metab Clin North Am. 2020;49(3):347-355. PMID: 32741475 Serum morning cortisol as a screening test for adrenal insufficiency. Endocr
2. Freda PU, Beckers AM, Katznelson L, et al; Endocrine Society. Pituitary Pract. 2020;26(1):30-35. PMID: 31461355
incidentaloma: an Endocrine Society clinical practice guideline. J Clin 9. Gasco V, Bima C, Geranzani A, et al. Morning serum cortisol level
Endocrinol Metab. 2011;96(4):894-904. PMID: 21474686 predicts central adrenal insufficiency diagnosed by insulin tolerance test.
3. Crowther S, Rushworth RL, Rankin W, Falhammar H, Phillips LK, Torpy Neuroendocrinology. 2021;111(12):1238-1248. PMID: 33406519
DJ. Trends in surgery, hospital admissions and imaging for pituitary 10. Kumar R, Carr P, Wassif W. Diagnostic performance of morning serum
adenomas in Australia. Endocrine. 2018;59(2):373-382. PMID: 29103185 cortisol as an alternative to short synacthen test for the assessment of adrenal
4. Fleseriu M, Bodach ME, Tumialan LM, et al. Congress of Neurological reserve; a retrospective study. Postgrad Med J. 2020;98(1156):113-118. PMID:
Surgeons systematic review and evidence-based guideline for pretreatment 33122342
endocrine evaluation of patients with nonfunctioning pituitary adenomas. 11. Himes CP, Ganesh R, Wight EC, Simha V, Liebow M. Perioperative
Neurosurgery. 2016;79(4):E527-E529. PMID: 27635959 evaluation and management of endocrine disorders. Mayo Clin Proc.
5. Tritos NA, Fazeli PK, McCormack A, et al; Pituitary Society Delphi 2020;95(12):2760-2774. PMID: 33168157
Collavorative Group. Pituitary Society Delphi Survey: an international 12. Kohl BA, Schwartz S. Surgery in the patient with endocrine dysfunction. Med
perspective on endocrine management of patients undergoing Clin North Am. 2009;93(5):1031-1047. PMID: 19665618
transsphenoidal surgery for pituitary adenomas. Pituitary. 2022;25(1):64-73. 13. Woodmansee WW, Carmichael J, Kelly D, Katznelson L; AACE
PMID: 34283370 Neuroendocrine and Pituitary Scientific Committee. American Association
6. Melmed S, Casanueva FF, Hoffman AR, et al; Endocrine Society. Diagnosis of Clinical Endocrinologists and American College of Endocrinology Disease
and treatment of hyperprolactinemia: an Endocrine Society clinical practice State Clinical Review: postoperative management following pituitary surgery.
guideline. J Clin Endocrinol Metab. 2011;96(2):273-288. PMID: 21296991 Endocr Pract. 2015;21(7):832-838. PMID: 26172128
7. Karaca Z, Tanriverdi F, Atmaca H, et al. Can basal cortisol measurement 14. Tohti M, Junyang L, Zhou Y, Yuebing H, Zhuang Y, Chiyuan M. Is peri-
be an alternative to the insulin tolerance test in the assessment of the operative steroid replacement therapy necessary for the pituitary adenomas
hypothalamic-pituitary-adrenal axis before and after pituitary surgery? Eur J treated with surgery? A systematic review and meta-analysis. PLoS One.
Endocrinol. 2010;163(3):377-382. PMID: 20530552 2015;10(3):e0119621. PMID: 25775019

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15. Garcia-Luna PP, Leal-Cerro A, Rocha JL, Trujillo F, Garcia-Pesquera F, 18. Whitaker SJ, Meanock CI, Turner GF, et al. Fluid balance and secretion
Astorga R. Evaluation of the pituitary-adrenal axis before, during, and after of antidiuretic hormone following transsphenoidal pituitary surgery. A
pituitary adenomectomy. Is perioperative glucocorticoid therapy necessary? preliminary series. J Neurosurg. 1985;63(3):404-412. PMID: 4020468
Acta Endocrinol (Copenh). 1990;122(1):83-88. PMID: 2154904 19. Burke WT, Cote DJ, Penn DL, et al. Diabetes insipidus after endoscopic
16. Inder WJ, Hunt PJ. Glucocorticoid replacement in pituitary surgery: transsphenoidal surgery. Neurosurgery. 2020;87(5):949-955. PMID: 32503055
guidelines for perioperative assessment and management. J Clin Endocrinol 20. Amar AP, Couldwell WT, Chen JCT, Weiss MH. Predictive value of serum
Metab. 2002;87(6): 2745-2750. PMID: 12050244 prolactin levels measured immediately after transsphenoidal surgery. J
17. Manuylova E, Calvi LM, Vates GE, Hastings C, Shafiq. Morning serum Neurosurg. 2002;97(2):307-314. PMID: 12186458
cortisol level after transsphenoidal surgery for pituitary adenoma 21. Rutkowski MJ, Breshears JD, Kunwar S, Aghi MK, Blevins LS. Approach to
predicts hypothalamic-pituitary-adrenal function despite intraoperative the postoperative patient with Cushing’s disease. Pituitary. 2015;18(2):232-
dexamethasone use. Endocr Pract. 2015;21(8):897-902. PMID: 26121454 237. PMID: 25702104

ENDO 2022 • Neuroendocrinology and Pituitary  147

Shifting Fluids: Syndrome of
Inappropriate Antidiuretic
Hormone Secretion and
Diabetes Insipidus
Julia Kharlip, MD. Penn Pituitary Center, University of Pennsylvania, Philadelphia, PA;
E-mail: [email protected]

Learning Objectives Significance of the

Clinical Problem
• Describe approaches to monitor for and
prevent delayed hyponatremia following Delayed hyponatremia due to syndrome of
pituitary surgery. inappropriate antidiuretic hormone secretion
(SIADH) is the most common cause of readmission
• Evaluate and manage hyponatremia in patients for patients undergoing pituitary surgery. While
with permanent central diabetes insipidus (DI). mild in most, SIADH is symptomatic and severe in
• Recognize the importance of education for some patients. It can be flanked by 2 transitions of
patients with permanent DI. fluid volume status when preceded and followed
by DI, presenting a significant treatment challenge
due to the rapidity of transitions.
Gastrointestinal illness in a patient
Main Conclusions chronically treated for central DI can lead to
severe hyponatremia as a result of continued
• Fluid restriction as a part of structured follow- desmopressin administration. Once hyponatremia
up program is a promising approach to delayed sets in, its treatment presents its own challenge of
hyponatremia after pituitary surgery. avoiding overly rapid correction and ODS.
• Severe hyponatremia can lead to neurologic Hyponatremia is common in patients chronically
sequalae requiring expedient therapy; however, treated for DI, but it should always prompt an
this must be balanced against a risk of osmotic investigation for causes and treatment adjustment
demyelination syndrome (ODS) with rapid to eliminate it. For example, central DI can resolve
overcorrection. Patients with chronic DI treated in some patients with pituitary lesions or history
with desmopressin are at high risk for this of surgery and clinicians should stay attuned to this
dual-risk scenario at a time of gastrointestinal possibility to be prepared to discontinue therapy
illness, trauma, procedures, or surgeries. that puts the patient at risk for hyponatremia.
• Accurate diagnosis of DI is essential to
avoid iatrogenic hyponatremia related to
inappropriate desmopressin therapy.

148  ENDO 2022 • Endocrine Case Management

Barriers to Optimal Practice by depressed mental status, mild to moderate
hyponatremia is treated with volume restriction or
• Clinical states of salt-water abnormalities vaptans.1,4,5 In most patients, treatment is weaned
often present at transition or when multiple within days when SIADH resolves, but one must
derangements are present at once, creating stay vigilant for the possibility of the third phase
diagnostic dilemmas. of DI to ensure that alert patients have free access
to water and that DDAVP is available to prevent a
• The rapid nature of autodiuresis that
rapid sodium rise.
follows hyponatremia presents a significant
management challenge to avoid ODS even
in the critical care setting. Accurate input/ Gastrointestinal Illness in
output monitoring is required, as well as Patients With Chronic DI
exceedingly rapid access to laboratory data and
A shift to and from hypovolemic hyponatremia
significant investment of time and expertise.
accompanies several clinical situations that are likely
This challenge is magnified in patients with DI
to arise in the lifetime of a patient chronically treated
due to a potential for an even greater degree of
for DI: gastrointestinal illness, blood loss, and need for
sodium rise if DI is left untreated.
hospitalization/anesthesia are among most common.
Patient education is critical, and “sick-day rules”
can be used for patients with DI, similar to those
Strategies for Diagnosis, used for patients with adrenal insufficiency (Box 1).
Therapy, and/or Management
Box 1. Patient Instructions for Self-Care in Case
Delayed Hyponatremia of Diabetes Insipidus During a Diarrheal Illness
Delayed hyponatremia due to SIADH is the most 1. Early contact: If you develop a diarrheal illness, please
common cause of hospital readmission for patients notify us early in the illness by calling the on-call line and
stay in touch for the duration of the illness if managing
undergoing pituitary surgery.1-3 A recent meta- at home.
analysis of 27 studies found an incidence of overall 2. Hydration by mouth: Please try to hydrate as much as
and symptomatic delayed hyponatremia to be possible with an electrolyte-rich fluid (Pedialyte, broth,
or WHO oral rehydration solution, which can be made at
10.5% (95% CI, 7.4%-14.7%) and 5.0% (95% CI, home: http://www.rehydrate.org/ors/ort.htm).
3.6%-6.9%), respectively.3 3. Stay vigilant for signs of severe dehydration: Please
Delayed hyponatremia is preceded by DI in keep an eye on your hydration status: you should be able
to see bubbles of saliva under the tongue. Dry lips, coated
3% to 4% of patients (“biphasic response”) and tongue, small amounts of dark urine, or feeling dizzy are
is preceded by and followed by permanent DI signs of dehydration. If starting to feel week, lethargic, or
lightheaded, please head to the emergency department
(“triphasic response”) in 1.1% patients.2 The and call us when on the way, so we can communicate with
shift from DI (the first phase) to SIADH (the your emergency care team.
second phase) commonly occurs rapidly over 4. Desmopressin: During dehydrated state from diarrhea, the
requirement for desmopressin/DDAVP temporarily goes
several hours on postoperative days 6 to 8,1,4,5 so away/decreases.
hyponatremia in this situation is always acute ԗ Please take your next scheduled DDAVP only at the time
(<48 hours of duration). The treatment approach of “breakthrough”/when symptoms of diabetes insipidus
symptoms return: high output of light-colored urine and
mirrors that of other causes of SIADH and depends significant thirst.
on the presence of alterations in mental status as ԗ Once you have breakthrough symptoms, please resume
seen in patients with severe hyponatremia (serum taking desmopressin/DDAVP without delay.
sodium <125 mEq/L [<125 mmol/L]) or mild to ԗ If going to the emergency department, please bring
moderate hyponatremia (mild: 130-134 mEq/L desmopressin/DDAVP with you.

[130-134 mmol/L]; moderate: 125-129 mEq/L 5. Vomiting or febrile diarrheal illness: A reminder that a
vomiting or a febrile diarrheal illness always requires care
[125-129 mmol/L]). While hypertonic saline must at a medical facility.
be used for severe hyponatremia accompanied

ENDO 2022 • Neuroendocrinology and Pituitary  149

Patients with a vomiting illness must be cared Box 3. Considerations for Hospitalized
Patients With Diabetes Insipidus
for at a medical facility because vomiting makes
oral rehydration impossible. Patients who are • Encourage patients to bring desmopressin to the emergency
department or hospital and allow physician-directed
otherwise well with self-limited diarrhea can be administration to avoid delays related to procuring the
treated at home, but with a low threshold for medication
transition to hospital care. • In case of severe hyponatremia (serum sodium <125 mEq/L
[<125 mmol/L]):
Patients with DI requiring hospitalization
‐ Transfer patient to higher level of care for close sodium
need close endocrine care for the duration of monitoring every 4 to 6 hours and strict input/output
their hospital stay. Providing the emergency care monitoring
staff with a letter or procedure/hospitalization ‐ Identify treatment strategy based on severity of
hyponatremia and the presence of mental status change
recommendations for patients can facilitate safe
‐ Determine sodium goal of correction based on risk of
care (Box 2). Patients with DI and hyponatremia osmotic demyelination syndrome
are at risk for ODS during autodiuresis unless ‐ Correct any potassium deficits accounting for the
desmopressin is resumed in a timely fashion and expected sodium increase as part of the overall sodium
goal of correction
free water is actively replaced. Considerations for
‐ Provide free access to water in awake patients and
hospitalized patients are shown in Box 3. identify water replacement plan in patients experiencing
autodiuresis
Box 2. Sample Procedure Letter for Patients With ‐ Hold desmopressin for shortest period needed to confirm
Diabetes Insipidus Requiring Anesthesia* autodiuresis:
‐ We use urine output ≥500 mL over any 2 hours
As you know, Ms/Mr. @NAME@ (@DOB@) has diabetes
and bedside specific gravity <1.010 to resume
insipidus. This should not preclude her/him from having
desmopressin as long as the sodium measured
surgical procedures. I understand she/he is scheduled to
within the previous 6 hours was at the low limit or
undergo an outpatient procedure with you under general
normal
anesthesia.
‐ We order STAT sodium and urine osmolality prior
Diabetes insipidus makes the patient sensitive to fluid shifts.
to desmopressin to use for the next round of clinical
1. The patient should continue to take the oral desmopressin decision-making*
as prescribed the day before and the day of the procedure.
2. As the patient will be NPO from midnight prior to the *Others have described an approach concurrent with measures for
procedure, I recommend that she/he be scheduled first hyponatremia and preventive desmopressin administration.6
thing in the morning to avoid being deprived of free water
for too long.
3. A STAT sodium measurement should be checked prior Accurate Diagnosis of Central DI
to induction of anesthesia. Depending on duration of the
procedure, sodium should be checked every 3 to 4 hours. Accurate diagnosis of central DI can be
4. If the patient is excessively thirsty before the procedure or if challenging, but it is critical to avoiding iatrogenic
the procedure will take longer than an hour, please consider
giving her/him D5W1/2NS intravenously at a maintenance hyponatremia. In a patient with polyuria (urine
rate during the procedure. output >3 L daily) and urine osmolality less than
5. Please avoid administration of hypotonic fluids when the 800 mOsm/kg, DI can be diagnosed by either
patient is in an antidiuresis state (desmopressin had been
given and the urine output is <200 mL/h) using a traditional water-deprivation or copeptin-
6. If the patient’s mental status does change at any time, I based algorithm (Figure).
recommend checking a stat serum sodium level. After the
procedure, she/he should have access to free water to drink
to thirst. Clinical Case Vignettes
These recommendations have been discussed with @name@.
Please do not hesitate to call me with any further questions.
Case 1
Sincerely, A 54-year-old woman with a pituitary adenoma
traveled out of state for transsphenoidal resection.
* Developed with Dr. Lauren Fishbein. Postoperatively, her urine output was 6 L per day,
and she was given desmopressin on postoperative
days 1 and 2. After discharge, she was staying at

150  ENDO 2022 • Endocrine Case Management

Figure. Algorithm for Diagnosing Diabetes Insipidus

Reprinted with permission from Christ-Crain M et al. Nat Rev Dis Primers, 2019; 5(1) © Springer Nature Limited.

a local hotel in anticipation of her postoperative In view of her recent history of postoperative DI,
visit. She was drinking large amounts of the report of marked thirst in recent days, and
water because her mouth was dry from mouth low specific gravity, the emergency department
breathing due to nasal packing and the heat (the physician prescribes desmopressin.
air conditioner at the hotel was broken). On
postoperative day 7, she experiences headache, Which of the following is the best next
became rapidly obtunded, and is brought to the treatment step in addition to close
emergency department where her blood pressure monitoring of sodium and mental status
is documented to be 148/76 mm Hg with a pulse in the intensive care unit setting?
rate of 72 beats/min. She appears euvolemic. A. Continue desmopressin
Laboratory test results: B. Stop desmopressin; initiate 3% saline until
mental status improves
Serum sodium = 113 mEq/L (136-144 mEq/L) C. Stop desmopressin; initiate 800 mL fluid
(SI: 113 mmol/L [136-144 mmol/L])
Serum potassium = 4.1 mEq/L (3.6-5.1 mEq/L) restriction
(SI: 4.1 mmol/L [3.6-5.1 mmol/L]) D. Stop desmopressin; initiate tolvaptan
Rapid urine specific gravity by dipstick = 1.004
E. B or D
(1.010-1.030)
Cortisol, normal
Answer: B) Stop desmopressin; initiate
TSH, normal
Free T4, normal 3% saline until mental status improves

ENDO 2022 • Neuroendocrinology and Pituitary  151

This patient’s hyponatremia on postoperative third phase”), so it is important to ensure adequate
day 7 was not due to prior doses of desmopressin access to water and desmopressin therapy (in the
administered on postoperative days 1 and 2 case of DI) if yet another shift of fluid status occurs.
given this medication’s short half-life (12 to Treating with fluid restriction only (Answer
24 hours). Her reportedly high water intake C) is not expeditious enough, as it is likely to
after hospital discharge was most likely due to produce a change of only several mEq/L (mmol/L)
dry mouth rather than polydipsia and had most over days.
likely exacerbated the degree of hyponatremia. The role of vaptans (Answer D) in patients
Importantly, the observed specific gravity of with SIADH after pituitary surgery is being
1.004 (which corresponds to a urine osmolality actively explored, particularly in the context
of approximately 190 mOsm/kg), while low, does of using them instead of water deprivation
not point to DI. A normal physiologic response to for patients with severe hyponatremia once
severe hyponatremia is production of maximally consciousness is restored and for those with mild
dilute urine (specific gravity, undetectable; urine to moderate hyponatremia.5
osmolality <100 mOsm/kg). Thus, her low but Hypertonic saline (Answer B) remains
detectible specific gravity in the face of severe the standard of care in patients with severe
hyponatremia is consistent with SIADH. hyponatremia with alteration of consciousness.
Given the timeline of postoperative day 7,
this is most likely acute hyponatremia as part of Case 1 (continued)
a biphasic or triphasic response seen in patients
undergoing pituitary surgery.1-3 Appropriate steps to reduce the risk of
Given her diagnosis of acute hyponatremia readmission due to delayed hyponatremia
due to SIADH, continued treatment with include any of the following EXCEPT?
desmopressin is contraindicated (thus, A. Daily phone contact with her treatment team
Answer A is incorrect). In patients with acute, during first postoperative week
severe hyponatremia (sodium <120 mEq/L B. Fluid restriction to 1 L during postoperative
[<120 mmol/L]) and depressed mental status, the days 4 through 8
primary goal of therapy is the expedient correction C. Laboratory measurement of serum sodium
of sodium to restore consciousness.8 The standard at a laboratory offering STAT processing on
of care is administration of 3% saline as a bolus or postoperative day 7
continuous infusion with close sodium monitoring
D. Patient education to (1) drink only to
due to hypertonic saline’s rapid efficacy and
thirst once discharged and (2) to notify her
reliability. The initial goal of correction is a
treatment team immediately if symptoms of
sodium level that restores consciousness (rather
hyponatremia occur
than to a specific increment or to a completely
normal level). Otherwise well outpatients who E. Self-directed desmopressin administration by
recently underwent pituitary surgery are generally the patient at home
at low risk for ODS. While the exact degree of Answer: E) Self-directed desmopressin
sodium correction needed to restore consciousness administration by the patient at home
varies among patients, the range corresponds
to 4 to 8 mEq/L (4 to 8 mmol/L) in the first 24 Self-directed desmopressin administration by
hours—the same conservative increment that is patients at home (Answer E) has not been studied
known to be safe for other patients who are not as an approach to the management of postoperative
at very high risk for ODS. Once the SIADH phase diabetes insipidus and can potentially increase the
resolves, these patients experience autodiuresis risk of readmission due to delayed hyponatremia
and even subsequent aquaresis if DI follows (“the given a rapid transition from DI to the SIADH

152  ENDO 2022 • Endocrine Case Management

phase. The risk of delayed hyponatremia can in a setting of a diarrheal illness. She reports
be increased by inappropriate self-dosing by a her blood pressure was in the 120s/80s mm Hg
patient as they enter the SIADH stage.1,5,9 Timely with a fast heart rate. She was given intravenous
discontinuation of desmopressin used during the hydrocortisone for presumed adrenal insufficiency
first DI phase is important before the patient enters causing hyponatremia (sodium = 126 mEq/L
the SIADH stage, and it often requires daily contact [126 mmol/L]). Her potassium concentration was
with the patient recovering at home (as happens in normal. She was subsequently discharged. Her
patients treated on a fast-track discharge pathway, COVID test result was negative, and no other
an approach used by some pituitary centers.10 cause of her diarrheal illness was identified. She is
Patient education regarding the risk of SIADH now at home, still feeling unwell, weak, and with
and its symptoms (Answer D), daily phone contact continued diarrhea. She notes that her mouth
(Answer A), and routine sodium monitoring on feels very dry. She is pushing fluids (water) per
postoperative days 7 or 8 (Answer C) have been emergency department recommendations.
described by several centers dedicated to pituitary
surgery.4,9-11 However, few factors have been In addition to increasing her oral
consistently identified as risk factors for SIADH hydrocortisone dosage (to account for
beyond patient age,3 and given its precipitous rapid gastrointestinal transit) for the
onset, none of the described interventions have duration of her diarrheal illness, which
been able to reduce hospital readmission or of the following is the most appropriate
prevent severe symptomatic hyponatremia.9,11 A step to address her condition?
recently described approach of 1 L fluid restriction A. Consider use of an antidiarrheal agent because
on postoperative days 4 to 8 (Answer B) for a bacterial cause of diarrhea is not suspected
patients without preceding DI appears to reduce B. Hold desmopressin spray until there is a
readmission rates12 and will most likely become the clear breakthrough with increased thirst and
prevailing strategy in managing these patients once frequency and volume of light-colored urine
there is a better understanding of the approach C. Hydrate with a solute-containing liquids
to the 5% to 6% of patients with preceding DI.13 (Pedialyte, WHO homemade rehydration
The fluid restriction approach does require close solution) until mouth/lips are no longer dry and
contact with patients during the first postoperative there are bubbles of saliva under the tongue
week, especially for those patients who are
D. Maintain close contact, monitor orthostatic
managed on a fast-track to discharge pathway.
blood pressure and heart rate at home, reassess
sodium and urine osmolality/specific gravity
Case 2 in 24 to 48 hours provided there is a trend
A 27-year-old woman with a history of childhood for clinical improvement, but have a low
craniopharyngioma resection, hypopituitarism, and threshold to return to emergency department,
DI has just moved and seeks to establish endocrine particularly if she has difficulty tolerating oral
care locally. She is on an appropriate regimen for intake, worsening lethargy, lightheadedness, or
hypopituitarism and takes desmopressin spray, a long duration of hyponatremia is suspected
10 mcg each nostril twice daily. Review of her recent E. All of the above
laboratory data shows appropriate free T4 and IGF-1
levels and sodium concentrations ranging from 139 to Answer: E) All of the above
141 mEq/L (139 to 141 mmol/L). Hypovolemic hyponatremia is a well-recognized
She sends a portal message reporting a brief visit clinical scenario in the general population and is
to a local emergency department (at the height of caused by the loss of gastrointestinal secretions,
COVID-19 pandemic) for “adrenal insufficiency” which are hypotonic. However, the increased

ENDO 2022 • Neuroendocrinology and Pituitary  153

risk of hyponatremia due to continued use of to take her desmopressin spray over the weekend
desmopressin despite hypovolemia is a common “to avoid excessive urination in addition to diarrhea.”
but underrecognized clinical scenario for patients In the hospital, she was managed by holding
with chronic DI. desmopressin and repleting intravascular volume.
Excessive loss of hypotonic solute via the Her urine output was followed closely. Her sodium
gastrointestinal tract with concurrent water normalized. Once urine output was greater than
and desmopressin administration leads to 500 mL over 2 hours with a low bedside specific
disproportionate water retention and likely gravity, desmopressin was appropriately resumed
hyponatremia. At the time of intravascular depletion (48 hours after hospital admission).
(such as due to gastrointestinal illness, excessive At a subsequent clinic telehealth visit, she
sweating, or blood loss), there is an increase in was reminded to call the office on-call line at the
proximal sodium and water reabsorption, which time of an illness. “Sick-day rules” were reviewed
leads to reduced delivery of water to collecting for both adrenal insufficiency and DI, and she
tubules that are under AVP control. Consequently, took a picture of the strategies to keep on her
DI temporarily remits, and continued administration phone. Both she and her husband programmed
of desmopressin further leads to hyponatremia. the on-call phone number into their cell phones.
Hence, desmopressin should be held (Answer B). A conversation with the emergency department
Once intravascular volume is restored, (which at colleague caring for her during her first admission
home can be achieved with oral hydration with would have most likely prevented the chain of the
solute-containing fluids [Answer C] in patients who events that led to her severe hyponatremia.
are able to drink and are otherwise hemodynamically
stable) the aquaresis resumes, indicated by the usual Case 3
DI breakthrough symptoms of increased thirst and
urination, and it is safe to resume desmopressin. A 44-year-old woman with Cushing disease
Importantly, this outpatient management undergoes pituitary surgery. She is not cured
approach is not appropriate for most patients but has now developed DI that persists past the
because of risk of ODS following autocorrection immediate postoperative period. Subsequently,
and resumption of aquaresis, especially if she undergoes bilateral adrenalectomy. Her
resumption of desmopressin therapy is delayed.8,14 regimen now includes hydrocortisone, 10 mg on
Risk of ODS is especially high in patients with a awakening and 10 mg at 3 PM; fludrocortisone,
serum sodium concentration less than 125 mEq/L 0.1 mg daily; and desmopressin tablets, 0.1 mg at
(<125 mmol/L), hypokalemia, alcohol abuse, bedtime and 0.05 mg at 10 AM.
malnutrition, liver disease, poor health literacy, On physical examination, her blood pressure
and lack of social support. Patients who are is 127/75 mm Hg, pulse rate is 72 beats/min, and
otherwise well, hemodynamically stable, able to body surface area is 1.52 m2.
hydrate orally, have access to solute-containing Laboratory test results:
oral rehydration solutions, and have a short
duration of diarrheal illness might be cautiously ACTH = 130 pg/mL (10-60 pg/mL)
managed at home with close supervision and (SI: 28.6 pmol/L [2.2-13.2 pmol/L])
Sodium = 137 mEq/L (136-144 mEq/L)
instructions to resume desmopressin right at (SI: 137 mmol/L [136-144 mmol/L])
breakthrough (Answer D). Potassium = 4.2 mEq/L (3.6-5.1 mEq/L)
By the time this patient’s portal message (SI: 4.2 mmol/L [3.6-5.1 mmol/L])
was received, she was back in the emergency Plasma renin activity = 0.3 ng/mL per h
department (brought in by her husband due to (0.6-4.3 ng/mL per h)
lethargy), and she had a sodium concentration of Three years after the initial pituitary surgery,
117 mEq/L (117 mmol/L). She, in fact, continued she reports she has been feeling well and her

154  ENDO 2022 • Endocrine Case Management

cushingoid physical findings have mostly resolved. daily hydrocortisone dosage (Answer A) that is
She describes daily breakthrough symptoms of appropriate for her body surface area and allows
increased thirst with frequent urination of straw- her to feel well on most days is not the right
colored urine between 7 PM and bedtime. While approach and would likely lead to overtreatment.
she finds these symptoms tolerable, over the past It is also unlikely that her fludrocortisone
6 months she has had 3 episodes of headache and dosage is insufficient given her appropriate
nausea that led to emergency department visits. vital signs, appropriate sodium and potassium
Review of these records reveals stable vital signs concentrations outside of these episodes, and
on arrival and a pattern of hyponatremia with a plasma renin activity suggesting a plentiful
serum sodium concentration that ranges from fludrocortisone dosage. Thus, increasing her
128 to 131 mEq/L (128 to 131 mmol/L). One fludrocortisone dosage (Answer C) is incorrect.
episode occurred while presenting at a high-stakes Both a change in the approach to managing her
professional dinner meeting that was causing much headaches to prevent acute adrenal insufficiency
psychological stress. She recalls taking an extra (Answer B), as well as eliminating excessive water
dose of 0.05 mg of desmopressin that evening to retention causing hyponatremia (Answer D) are
eliminate breakthrough during the meeting. plausible approaches that should be further explored.

Which of the following are the most likely

cause(s) of her emergency department visits
Case 3 (continued)
and the best approaches to address them? The patient is seen by a headache specialist who
A. Her headaches and nausea with associated prescribes an effective abortive regimen, and
hyponatremia represent acute adrenal she is given instructions to take an additional
insufficiency and should be addressed with an hydrocortisone dose with the onset of headache. She
increased daily hydrocortisone dosage is instructed to eliminate as-needed desmopressin
self-dosing and is reminded “to drink only to thirst.”
B. Her severe headaches cause symptoms of acute
She follows the instructions meticulously, but she
adrenal insufficiency, including nausea and
has another 2 episodes over the next 4 months.
hyponatremia; these should be addressed with
early pain control and appropriate stress doses Which of the following is the best
of hydrocortisone next step to address this patient’s
C. Her headaches and nausea are caused periodic hyponatremia?
by hyponatremia due to an inadequate A. Monitor sodium at regular intervals to determine
fludrocortisone dosage, which should whether hyponatremia occurs outside of these
be increased episodes and occurs while she is asymptomatic
D. Her headaches and nausea are caused B. Reduce the desmopressin dosage
by hyponatremia; the hyponatremia is
C. Monitor intake and output via patient-
caused by periodic excessive water and/or
provided timed logs
desmopressin intake
D. Give guidance regarding safe intake parameters
E. B and D
E. All of the above
Answer: E) B and D
Answer: E) All of the above
While this patient’s presentation during
emergency department visits may represent acute Because concerns related to acute adrenal
adrenal insufficiency due to a mismatch between insufficiency have now been excluded, all of
physiologic stress related to painful headache and the listed strategies (Answer E) can be used to
her daily hydrocortisone dosage, increasing her try to address periodic hyponatremia related to

ENDO 2022 • Neuroendocrinology and Pituitary  155

suspected mismatch between water intake and Based on the results of the water-
desmopressin dosing. Periodic hyponatremia is deprivation test, which of the
not uncommon in patients chronically treated for following is the best next step?
DI and has been reported in up to one-third of A. Administer a saline-stimulated copeptin test
patients,15 but it should always be investigated and B. Continue desmopressin at a lower dosage and
addressed. Although daily breakthrough to allow impose a strict daily fluid intake limit
for release of any retained water is not routinely
C. Continue desmopressin but at a lower dosage
required for chronic care of patients with DI,7 it is
particularly surprising that this patient continues D. Stop desmopressin; she no longer has DI
to experience hyponatremia despite reporting daily Answer: D) Stop desmopressin; she no longer has DI
breakthrough symptoms.
After approximately 8 hours of fluid deprivation,
the patient’s urine osmolality had reached more
Case 3 (continued)
than 700 mOsm/kg and had plateaued over 3
Over the next 2 months, the patient’s successive measurements, at which point the
desmopressin dosage is reduced, and routine calculated serum osmolality was 302 mOsm/kg.
weekly monitoring of sodium is arranged. The At that time, 2 mcg of subcutaneous DDAVP was
patient is asked to provide intake and output administered, but the urine osmolality failed to
logs, which show that input and output are increase more than 9% (~5% increase). These data
well matched. She reports more uncomfortable are consistent with a normal concentrating ability.
breakthrough symptoms, as would be expected Of note, plasma antidiuretic hormone,
given the desmopressin dosage reduction, although appropriately processed and sent to a
and yet hyponatremia is still noted during reference laboratory, returned undetectable at
routine monitoring. The patient undergoes water- the beginning and at the end of test—a common
deprivation testing (see Table). false-positive result best explained by the high
preanalytical instability of AVP (arginine
vasopressin) in samples.7,16
In summary, results of this patient’s water-
deprivation test support intact concentrating
ability and resolution of DI. In fact, amelioration
or resolution of DI within years of pituitary

Time Sodium Serum osmolality Urine osmolality Urine output Antidiuretic hormone Other
8:46 139 mEq/L (SI: 139 mmol/L) 292 mOsm/kg 238 mOsm/kg 500 mL <0.5 pg/mL Weight: 80.7 kg
10:36 141 mEq/L (SI: 141 mmol/L) 295 mOsm/kg 291 mOsm/kg 400 mL …
13:39 143 mEq/L (SI: 143 mmol/L) 295 mOsm/kg 586 mOsm/kg 300 mL …
14:55 142 mEq/L (SI: 142 mmol/L) 295 mOsm/kg 743 mOsm/kg 325 mL …
17:00 143 mEq/L (SI: 143 mmol/L) 293 mOsm/kg 719 mOsm/kg 175 mL <0.5 pg/mL Weight: 80 kg
(<1% decrease)
19:00 141 mEq/L (SI: 141 mmol/L) 302 mOsm/kg 772 mOsm/kg 100 mL 19:41 2 mcg
subcutaneous
DDAVP
20:20 143 mEq/L (SI: 143 mmol/L) 292 mOsm/kg 818 mOsm/kg 50 mL Protocol
stopped

Antidiuretic hormone reference range: 0-6.9 pg/mL.

156  ENDO 2022 • Endocrine Case Management

surgery or neurohypophysitis has been previously A saline-stimulated copeptin test (Answer A)
described.17,18 This patient has been feeling well off could have been used in this clinical circumstance
desmopressin therapy (Answer D). instead of a water-deprivation test, but this was not
Continuing a lower dosage of desmopressin available at the time of this patient’s evaluation.
with or without fluid restriction (Answers B and C) Given the clear evidence of resolved DI, a saline-
would lead to hyponatremia. stimulated copeptin test would not add value.

References
1. Loh JA, Verbalis JG. Disorders of water and salt metabolism associated with 11. Deaver KE, Catel CP, Lillehei KO, Wierman ME, Kerr JM. Strategies to
pituitary disease. Endocrinol Metab Clin North Am. 2008;37(1):213-234, x. reduce readmissions for hyponatremia after transsphenoidal surgery for
PMID: 18226738 pituitary adenomas. Endocrine. 2018;62(2):333-339. PMID: 29961198
2. Hensen J, Henig A, Fahlbusch R, Meyer M, Boehnert M, Buchfelder 12. Winograd D, Staggers KA, Sebastian S, Takashima M, Yoshor D, Samson
M. Prevalence, predictors and patterns of postoperative polyuria and SL. An effective and practical fluid restriction protocol to decrease the risk of
hyponatraemia in the immediate course after transsphenoidal surgery hyponatremia and readmissions after transsphenoidal surgery. Neurosurgery.
for pituitary adenomas. Clin Endocrinol (Oxf). 1999;50(4):431-439. PMID: 2020;87(4):761-769. PMID: 31993647
10468901 13. Perez-Vega C, Tripathi S, Domingo RA, et al. Fluid restriction after
3. Lee C-C, Wang Y-C, Liu YT, Huang Y-C, et al. Incidence and factors transsphenoidal surgery for the prevention of delayed hyponatremia: a
associated with postoperative delayed hyponatremia after transsphenoidal systematic review and meta-analysis. Endocr Pract. 2021;27(9):966-972. PMID:
pituitary surgery: a meta-analysis and systematic review. Int J Endocrinol. 34265453
2021;2021:6659152. PMID: 33936198 14. Achinger SG, Arieff AI, Kalantar-Zadeh K, Ayus JC. Desmopressin acetate
4. Bohl MA, Ahmad S, Jahnke H, Shepherd D, Knecht L, White WL, Little (DDAVP)-associated hyponatremia and brain damage: a case series. Nephrol
AS. Delayed hyponatremia is the most common cause of 30-day unplanned Dial Transplant. 2014;29(12):2310-2315. PMID: 25107337
readmission after transsphenoidal surgery for pituitary tumors. Neurosurgery. 15. Behan LA, Sherlock M, Moyles P, et al. Abnormal plasma sodium
2016;78(1):84-90. PMID: 26348011 concentrations in patients treated with desmopressin for cranial diabetes
5. Kleindienst A, Georgiev S, Schlaffer SM, Buchfelder M. Tolvaptan versus insipidus: results of a long-term retrospective study. Eur J Endocrinol.
fluid restriction in the treatment of hyponatremia resulting from SIADH 2015;172(3):243-250. PMID: 25430399
following pituitary surgery. J Endocr Soc. 2020;4(7):bvaa068. PMID: 32666012 16. Morgenthaler NG. Struck J, Alonso C, Bergmann A. Assay for the
6. MacMillan TE, Tang T, Cavalcanti RB. Desmopressin to prevent rapid measurement of copeptin, a stable peptide derived from the precursor of
sodium correction in severe hyponatremia: a systematic review. Am J Med. vasopressin. Clin Chem. 2006;52(1):112-119. PMID: 16269513
2015;128(12):1362.e15-24. PMID: 26031887 17. Nishizawa S, Ohta S, Oki Y. Spontaneous resolution of diabetes insipidus
7. Christ-Crain M, Bichet DG, Fenske WK, et al. Diabetes insipidus. Nat Rev Dis after pituitary stalk sectioning during surgery for large craniopharyngioma.
Primers. 2019;5(1):54. PMID: 31395885 Endocrinological evaluation and clinical implications for surgical strategy.
8. Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and Neurol Med Chir (Tokyo). 2006;46(3):126-134; discussion 134-135. PMID:
treatment of hyponatremia: expert panel recommendations. Am J Med. 16565582
2013;126(10 Suppl 1):S1-S42. PMID: 24074529 18. Glynn N, O’Brien D, Agha A. Late recovery of cranial diabetes insipidus
9. Bohl MA, Ahmad S, White WL, Little AS. Implementation of a postoperative following pituitary surgery. Horm Res Paediatr. 2013;80(3):217-220. PMID:
outpatient care pathway for eelayed hyponatremia following transsphenoidal 24051558
surgery. Neurosurgery. 2018;82(1):110-117. PMID: 28449052
10. Lobatto DJ, Vliet Vlieland TPM, van den Hout WB, et al. Feasibility, safety,
and outcomes of a stratified fast-track care trajectory in pituitary surgery.
Endocrine. 2020;69(1):175-187. PMID: 32361869

ENDO 2022 • Neuroendocrinology and Pituitary  157

Multiple Endocrine Neoplasia
Type 1 Across the Lifespan
Maria Luisa Brandi, MD, PhD. FIRMO Foundation, Florence, Italy; E-mail: marialuisa@
marialuisabrandi.it

Learning Objectives We have identified key steps to assist clinicians

in providing comprehensive care when treating
As a result of participating in this session, learners
this disorder. Acquiring the knowledge and skills
should be able to:
to make an early diagnosis can mitigate the burden
• Diagnose multiple endocrine neoplasia type of MEN 1 for patients and their families.
1 (MEN 1) and perform periodic clinical Genetic testing of patients with a clinical
monitoring in young patients. diagnosis of MEN 1 can confirm the diagnosis.
Genetic testing can identify asymptomatic family
• Recognize classic and nonclassic tumors of
members carrying the MEN1 pathogenic variant,
MEN 1, as the latter are increasingly relevant
as well as determine which family members can
in the course of the disease.
be excluded from clinical monitoring if they do
not carry the MEN1 pathogenic variant. Genetic
testing can also help to recognize potential
phenocopies that occur in 5% to 10% of families
Main Conclusions with MEN 1. The risk of developing malignant
MEN 1 is a rare autosomal dominant disorder tumors justifies early recognition of the disease
caused by alterations in the MEN1 gene located and early pharmacological or surgical treatments.
on chromosome 11q13.1 Patients with MEN 1 Early diagnosis allows for early screening, thus
classically develop tumors of the endocrine glands decreasing morbidity and increasing quality of life
and also nonendocrine neoplasia, with potential and life expectancy. Moreover, young adults with
involvement of more than 20 organs.1 The most MEN 1 face difficult family-planning decisions, as
harmful MEN 1–related tumors are pancreatic and MEN 1 is an inherited disorder with the potential
gastroduodenal neuroendocrine tumors, thymic to be passed on to children. Genetic counseling
carcinoids, and adrenocortical carcinomas. Patients and the option of in vitro fertilization with
with MEN 1 have a decreased life expectancy. The preimplantation genetic diagnosis are substantial
disease has a long course; however, the late course undertakings for these patients.
of the disease, including causes of death, are not The MEN 1 phenotype encompasses varying
fully understood. combinations of more than 20 different endocrine
MEN 1 is often viewed exclusively as a disorder and nonendocrine tumor types. These are
that is only symptomatic during adulthood. As a characterized by loss of heterozygosity at 11q13
result, children and adolescents with MEN 1 may in the tumor tissue (Figure). Endocrine tumors
receive inadequate care because their signs and are diagnosed either by hormone measurements
symptoms are misdiagnosed as unrelated to MEN or imaging techniques. The clinical diagnosis
1. Because adverse consequences of lack of care are of MEN 1 requires the presence of 2 or more
potentially permanent and progressive, this delay is of the following neoplasms in the proband:
harmful to patients. parathyroid gland tumors, anterior pituitary

158  ENDO 2022 • Endocrine Case Management

tumors, and duodeno-pancreatic neuroendocrine
tumors. Other tumors associated with MEN Significance of the
1 include thymus and lung neuroendocrine
tumors, type 2 gastric neuroendocrine tumors, Clinical Problem
adrenocortical tumors, pheochromocytomas, MEN 1 is often viewed exclusively as a disorder
facial angiofibromas, hibernomas, meningiomas, expressed in adulthood and, as a result, children
ependymomas, leiomyomas, lipomas, and breast with MEN 1 may receive inadequate care because
cancer (increased risk in female patients). While their symptoms are overlooked. Recent studies
lung neuroendocrine tumors, breast cancer, support the need for comprehensive screening for
parathyroid carcinoma, and adrenocortical endocrine neoplasms during childhood to enable
carcinoma are rare in patients with MEN 1, they early tumor recognition and intervention before
are potentially deadly neoplasias.1 the development of adverse sequelae. However, in
general, screening for MEN 1 begins relatively late
in childhood.
MEN 1 is a complex disorder. The array of
tumors linked to MEN 1 is constantly increasing.

Figure. Neoplasms associated with MEN 1.

Adapted from Brandi M et al. Endocr Rev, 2021; 42(2) © Endocrine Society.

ENDO 2022 • Neuroendocrinology and Pituitary  159

Physicians of different specialties must be educated be educated on the importance of early disease
to avoid missing the diagnosis. A practical MEN recognition and on monitoring for various
1 chart should be developed and distributed to neoplasms during a patient’s lifetime, as the
clinicians who may encounter patients with disease is chronic and progressive. Patients
undiagnosed MEN 1. A basic understanding of require treatment regimens that prevent tumoral
MEN 1 as a condition affecting patients’ whole progression as early as possible. Early recognition
bodies, lives, and families is the first step toward of associated tumors can be achieved with
accomplishing improved patient care. well-designed follow-up that includes regular
biochemical monitoring to assess endocrine status
and radiological examinations to detect tumor
Barriers to Optimal Practice development or growth. Understandably, not all
The incidence of MEN 1 manifestations in endocrinologists are experts in every rare disease.
childhood is not well characterized and may Nonetheless, endocrinologists are likely to be
be underestimated. Moreover, there is lack of the first health care provider to see patients with
consensus regarding the optimal management of MEN 1, so their understanding of the nuances
MEN 1–associated tumors in children. Finally, of this particular disorder can aid in its diagnosis
genetic testing should be performed at birth in and treatment. This includes awareness that
children who have a parent with MEN 1, but this MEN 1 also affects children and can have a highly
is not routinely done. heterogeneous presentation. Failure to unite a
Constrained office visit time restricts clinicians constellation of MEN 1 manifestations may result
from providing all-inclusive management in delayed or incorrect diagnosis and inappropriate
of patients with MEN 1. Clinicians may feel surgery or other treatments.
pressured to focus on the most obvious MEN 1
manifestations, but they should be aware that
patients are likely to experience additional ongoing Disorders Linked to MEN1
MEN 1–related manifestations. Furthermore, Pathogenic Variants
given the complex nature of this disorder, not MEN 1 is characterized by a large array of
all manifestations of MEN 1 can be handled endocrine and nonendocrine tumors. Tumors
by the same specialist, risking disorganized attributed to the disorder are usually characterized
communication among different departments. by loss of heterozygosity at 11q13, the location
A checklist for testing for manifestations should of the MEN1 gene, resulting in biallelic loss of
be developed. MEN1. Tumors can be diagnosed by detection of
hormonal oversecretion or by imaging.
Classic MEN 1–associated endocrinopathies
Strategies for Diagnosis,
include parathyroid tumors, pituitary tumors,
Therapy, and/or Management and duodeno-pancreatic neuroendocrine tumors.
The burden of MEN 1 influences the lives Other endocrine tumors include thymus and
of patients’ families, friends, and colleagues. lung neuroendocrine tumors, type 2 gastric
Recognizing the disease at an early stage and neuroendocrine tumors, adrenocortical tumors,
evaluating the overall signs, symptoms, and and pheochromocytomas. Nonendocrine
complications with sustained attention to detail tumors include collagenomas, hibernomas,
has the potential to reduce this disease burden. facial angiofibromas, lipomas, meningiomas
This requires continuous engagement from the ependymomas, leiomyomas, and breast cancer.
informed patient. Screening should be conducted for all of these
In this Meet the Professor session dedicated conditions as part of follow-up. Guidelines do
to MEN 1 across the lifespan, clinicians will not indicate the need for radiological or clinical

160  ENDO 2022 • Endocrine Case Management

examination by specialists (eg, dermatologists) with MEN 1, underscoring the need to perform
with regard to nonendocrine tumors. Future genetic testing and to start surveillance screening
guidance about management of MEN 1 will in early childhood.3 The current guidelines,
hopefully include this information. published in 2012, recommend phenotype
Recently, the prevalence of hypercoagulability screening in children by age 5 years, along with
with increased risk of venous thromboembolism early genetic testing.4 However, in a recent
was shown to be higher in germline pathogenic publication, a child was reported to be affected
variant–positive patients with MEN 1 relative to by primary hyperparathyroidism at age 4 years.
the general population.2 Risk was similar to that Presymptomatic screening recommendations
found in patients with different types of cancer for patients with MEN 1 have been based on the
and Cushing syndrome. MEN 1–associated lifetime youngest age at which disease manifestations
incidence rates are about 2-fold higher than the have been described and this may not be the
estimated incidence rate in the general population optimal timing, as disease signs in children can
and are comparable to the known risk in the be overlooked.
setting of various cancer types. Neuroendocrine Genetic testing in clinical practice has
tumors were present in 80% of the affected patient become widespread and is considered routine in
population, and 42% of patients experienced tertiary medical centers. In a recent report, young
perioperative venous thromboembolism.2 patients with MEN 1 and an exon 2 pathogenic
variant appear to have a 2-fold greater risk for
developing both neuroendocrine tumor and
Management of Children With
distant metastasis.5 However, genetic testing in the
MEN1 Pathogenic Variants pediatric population is not without complexities
Parental MEN 1 was shown to be associated and ethical challenges that must be considered.
with high vulnerability of neonates, and this did Early recognition of MEN 1 can prompt close
not seem to correlate with antenatal maternal monitoring for MEN 1–related neoplasms,
hypercalcemia.1 Newborns whose parents have hopefully resulting in decreased morbidity and
MEN 1 exhibit a number of complications, such as mortality.
lower body weight, hypoglycemia, hypocalcemia, Primary hyperparathyroidism is often the first
and increased postnatal mortality, mostly linked to and most commonly observed endocrinopathy
infections. The excess risk was not fully explained in young patients with MEN 1 (75%). Primary
by maternal MEN 1 or antenatal hypercalcemia. hyperparathyroidism in children with MEN 1 is
The penetrance of MEN 1 manifestations usually asymptomatic, even if a higher incidence
is age-dependent, but this does not mean that of rickets and osteomalacia is demonstrated in the
children are never affected. Until recently, pediatric population than in adults. Published data
epidemiological and clinical information on MEN on parathyroidectomy in these patients are limited
1 in childhood was derived mainly from clinical to adolescents. In any case, the parathyroidectomy
case reports. Only in the last few years have there should be subtotal to avoid secondary
been publications that include screening data. hypoparathyroidism. No data are available on the
While approximately 20% of affected patients are use of cinacalcet in children with MEN 1.
diagnosed with the disease in the first 2 decades of Pituitary tumors are the second most common
life, clinically relevant symptoms and signs are rare tumor in young patients with MEN 1 (>30%),
in children. In a recent retrospective analysis of with the earliest documented manifestation
80 patients with MEN 1 who commenced tumor at age 10 years. Prolactinomas are the most
surveillance at 18 years or younger, 70% developed frequently diagnosed pituitary tumors in children
an endocrine tumor by age 18 years. These with MEN 1. The possibility of progression to
findings will affect counseling for young patients malignancy and resistance to dopamine therapy in

ENDO 2022 • Neuroendocrinology and Pituitary  161

some but not others represent important reasons enhancing mass expanding the sella turcica
to screen young patients with MEN 1. (Figure). In the last year, he has had reduced
Clinically relevant neuroendocrine tumors growth velocity, and his height declined to the
are rarely described in children with MEN 1, 11th percentile.
with the youngest patient diagnosed at age 8
years. However, the systematic use of endoscopic
ultrasonography in patients with MEN 1 brought
the occurrence of occult neuroendocrine tumors
to 42% of pediatric cases. The aggressiveness of
gastrinomas in children with MEN 1 and brain
damage caused by hypoglycemia in the setting
of insulinomas support the need for active
surveillance for neuroendocrine tumors in children.
Children with MEN 1 who present with
a single endocrine tumor should be evaluated
through multiple imaging modalities for other
potential endocrine tumors. Moreover, children
who present with a tumor type described in
MEN 1 (usually rare at young ages) should be
tested for germline MEN1 pathogenic variants.
In the last decade, several reports have
indicated that morbidity is not uncommon in
children and young adults affected by MEN 1. His prolactin concentration is 2776 ng/mL
Early diagnosis in these patients could (121 nmol/L) in the emergency department, and
potentially contribute to lowering morbidity GH levels are undetectable.
and even mortality in adulthood. Problems to In a recent systematic review,
be considered in the decision to activate active macroprolactinomas were more common in girls
tumor surveillance are psychological and financial than in boys in the younger-than-20 years age
burden. Expert physicians who communicate group, but the proportion of macroprolactinomas
well with parents and children are crucial in vs microprolactinoms was greater in males,
the construction of appropriate diagnostic and particularly for large invasive tumors.6
therapeutic paths for young patients with MEN 1. Recognition of pituitary disease and effective
Following recommendations in the most recent treatments for MEN 1 have made this a rare cause
guidance articles is certainly important, but we of morbidity and death in affected patients.
must bear in mind that their application in real life This patient had no maternal history of
can be challenging. MEN 1. However, the father and paternal
grandmother were affected by MEN 1, but
this information had never been relayed to the
Clinical Case Vignettes divorced wife. Genetic testing confirmed that the
Case 1 patient had the same MEN1 pathogenic variant as
his father (in exon 2).
A 7-year-old boy is admitted to the emergency Medical therapy was initiated with
department due to loss of consciousness while cabergoline, 0.25 mg twice weekly. Long-term
biking. A history of headaches and visual medical treatment in children and adolescents is
disturbances is noted. He is neurologically intact safe and is effective in three-quarters of patients,
upon arrival, except for recall deficit. Brain with surgery or radiotherapy needed in some
and pituitary MRI shows a 2.5 × 1.8 × 1.9-cm patients with resistant disease. In this patient,

162  ENDO 2022 • Endocrine Case Management

tumor shrinkage (>50% after 6 months) was had hyperparathyroidism by age 11 years, and 2
achieved with a cabergoline dosage of 2.0 mg cutaneous lipomas were evident at age 12 years.
weekly. His prolactin concentration normalized He had no signs or symptoms of excessive
and signs and symptoms resolved. The patient’s neuroendocrine function.
growth rate improved while treated with Genetic testing at birth would have been
cabergoline, and his serum GH concentration useful for this patient, so appropriate biochemical
normalized as well. At 11 months of follow-up, his screening could have been undertaken and
height was at the 19th percentile. hyperprolactinemia could have been diagnosed
After 15 years follow-up, the patient was before complications developed. Given the rarity
still being treated with cabergoline at a dosage of pediatric pituitary tumors, children presenting
of 0.25 mg twice weekly. His height was 72.8 in with a pituitary tumor should undergo genetic
(185 cm), and sexual development was normal. testing for pathogenic variants in genes known
The patient was monitored every 6 months for to cause pituitary tumors in children (MEN1, AIP,
pituitary function, and MRI was performed PRKAR1A, CDKN2A, DICER1, among others). A
annually. Once a year, the patient was evaluated panel approach could be applied, or individual
for all potential MEN 1–associated tumors. He genes could be selected based on the phenotype.

References
1. Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD. Multiple endocrine 5. Christakis I, Qiu W, Hyde SM, et al. Genotype-phenotype pancreatic
neoplasia type 1: latest insights. Endocr Rev. 2021;42(2):133-170. PMID: neuroendocrine tumor relationship in multiple endocrine neoplasia type 1
33249439 patients: a 23-year experience at a single institution. Surgery. 2017;163(1):212-
2. Lee ME, Ortega-Sustache YM, Agartala SK, et al. Patients with MEN1 are 217. PMID: 29122330
at increased risk for venous thromboembolism. J Clin Endocrinol Metab. 6. Yang A, Cho SY, Park H, et al. Clinical, hormonal, and neuroradiological
2021;106(2):e460-e468. PMID: 32756962 characteristics and therapeutic outcomes of prolactinomas in children and
3. Shariq OA, Lines KE, English KA, et al. Multiple endocrine neoplasia type 1 adolescents at a single center. Front Endocrinol (Lausanne). 2020;11:527. PMID:
in children and adolescents: clinical features and treatment outcomes. Surgery. 32849307
2021;171(1)77-87. PMID: 34183184
4. Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice
guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol
Metab. 2012;97(9):2990-3011. PMID: 22723327

ENDO 2022 • Neuroendocrinology and Pituitary  163

Aggressive Pituitary Tumors
Nienke Biermasz, MD. Department of Internal Medicine, Division of Endocrinology, Leiden
University Medical Center, Leiden, The Netherlands; E-mail: [email protected]

Learning Objectives if the tumor is functioning. For patients with

refractory disease, temozolomide is the formally
As a result of participating in this session, learners
recommended drug, although it is effective
should be able to:
in only 30% to 40% of cases. Last-resort or
• Distinguish aggressive tumors from benign- emerging treatments are radionuclide treatment,
behaving pituitary adenomas and recognize immunotherapy, angiogenesis-directed therapies,
tumors at risk for aggressive behavior. and possibly rescue surgery and radiotherapy.
These treatments do not yet have an established
• Use currently identified predictive factors
role in management and should be considered on a
for pituitary tumor aggressiveness in
patient-by-patient basis.3-5 Trials of new drugs are
individualized follow-up planning in clinic.
urgently needed.
• Discuss current state-of-the-art
multidisciplinary management of aggressive
pituitary tumors.
Significance of the
Clinical Problem
Aggressive pituitary tumors cause significant
Main Conclusions morbidity due to local invasion and uncontrolled
Aggressive pituitary tumors comprise a very hormone excess and increased mortality, especially
small subset of pituitary lesions. Although ideally in patients who do not respond to temozolomide.
these rare tumors are treated in expert centers, Early identification of an aggressive pituitary
awareness that regular pituitary tumors may tumor is challenging because such tumors may
develop into aggressive tumors after many years is initially seem unremarkable or because risk factors
important for all physicians providing surveillance such as the Ki-67 labeling index and invasiveness
for pituitary tumors.1 are not perfectly discriminative. Emerging
An aggressive tumor is best defined by a treatment options are needed for a small subset
combination of aggressive behavior; invasiveness of patients, but investigational drug trials are not
in surrounding tissues; multiple recurrences; widely available, and optimal management should
rapid growth; and/or resistance to conventional be determined with a multidisciplinary care team.
treatments with endocrine drugs, surgery, and
radiotherapy. Pituitary carcinoma may also Barriers to Optimal Practice
metastasize. These features, when isolated,
can also be observed in nonaggressive tumors, Given the lack of reliable outcome data on specific
which makes identifying aggressive tumors treatment options, management of these tumors
very challenging.2 Clinical predictive factors are depends on real-world experience. Ideally, groups
invasion and growth, and pathological predictive of experts could provide guidance regarding
factors are Ki-67 labeling index and mitotic count. management. Recording cases in registries would
First-line multidisciplinary management is be helpful to start collecting better outcomes data.
repeated surgery and radiotherapy, as well as drugs Prevalence data are also lacking.

164  ENDO 2022 • Endocrine Case Management

 Collaboration among care team members There are several issues with the clinical
could assist in flagging patients at risk for components of the definition:
developing aggressive disease, and a more
intensive surveillance protocol could be designed • An invasive tumor is not always an aggressive
to detect aggressive behavior early, leaving tumor, as this feature can also be seen in
more time for surgical and radiotherapeutic nonaggressive adenomas (eg, drug-sensitive
strategies. Centralized evaluation of pathology tumors or tumors without a tendency
specimens would be an important step in better to grow fast). However, once a tumor is
understanding the biological behavior of these determined to have radiological invasiveness,
tumors. Better descriptions of clinical behavior are it is probably irresectable. Radiological
also key in understanding the clinical course. invasiveness is described by the Knosp
Guidance on how care of patients with classification (cavernous sinus) or by the less-
aggressive pituitary tumors deviates from care of used HARDY classification. Invasiveness as
patients with nonaggressive pituitary adenomas observed during surgery may be different from
has been difficult to provide because outcomes expected based on preoperative imaging, and
are heterogenous. Ongoing endocrine care for therefore surgical outcomes may differ among
hormone excess and deficiency, in addition to the stages. There is also biological invasiveness;
oncological trajectory, remains important. for example, invasiveness in the medical
cavernous sinus wall or in the skull base.
Giant adenomas may invade the skull base or
Strategies for Diagnosis, grow intraventricularly. They are usually not
Therapy, and/or Management aggressive, although they might be considered
as such. The definition of invasiveness is not
A small subset (<5%) of generally benign-behaving
straightforward.
pituitary adenomas evolve into aggressive
pituitary tumors. In contrast to patients with • Rapid tumor growth rate is not a
nonaggressive pituitary adenomas who are treated straightforward clinical component. There is
according to well-known algorithms with a no consensus for defining a rapid growth rate
combination of neurosurgery, endocrine drugs, because evidence-based data are not available
and/or radiotherapy with no concern of tumor and there is no consensus about the way
progression, aggressive pituitary tumors present such growth should be evaluated in clinical
with unpredictable, unusual growth patterns. practice. Tumor volume measurements are the
These tumors can metastasize and are refractory to most precise assessment; however, a maximal
standard treatments. There is a clinical impression diameter would probably suffice, even though
that the prevalence of aggressive pituitary tumors tumors are noncircular and sometimes difficult
is rising, but epidemiological data are scarce.6-9 to demarcate precisely. Maximal diameter
The European Society of Endocrinology can be measured in the outpatient setting.
recommends considering the presence of an The RECIST guidelines align with oncology
aggressive pituitary tumor in patients with evaluation protocols. According to RECIST
radiologically invasive tumors, unusually rapid criteria, progressive disease is defined as a
tumor growth rate, or clinically relevant tumor new lesion or a 20% or greater increase in
growth despite optimal standard therapies. longest diameter (or at least 5 mm). With
These features share considerable overlap with pituitary disease, there is usually a single lesion
other adenomas; invasiveness alone is not a and evaluation is done with MRI instead of
discriminating feature. In addition, the definition CT. There is a practical definition proposed
of growth is not straightforward. for clinically relevant tumor growth: new,
worsening, or imminent signs and symptoms

ENDO 2022 • Neuroendocrinology and Pituitary  165

 related to the complications caused by the affect vision. For patients with aggressive tumors,
tumor growth, independent of the relative there is ideally continuity of ophthalmological
or absolute increase in tumor size. Unusually care (by one ophthalmologist). This parameter
rapid tumor growth by 20% or greater in may guide treatment decisions, and there
the longest diameter or in the sum of the should be a low threshold to reevaluate if the
longest diameters (when multiloculated patient has new-onset symptoms. Screening for
residual disease) in less than 6 to 12 months, metastasis should be considered if a patient has
independent of whether this constitutes site-specific symptoms and discrepant hormone
clinically relevant tumor growth, constitutes excess for the pituitary lesions. Most cases of
rapid tumor growth. Even in patients who metastasis are in the cranium or the spinal
have tumors with unusual growth velocity, cord. Also, if a nonfunctioning tumor shifts to
reviewing sequential MRI is important. become a functioning tumor, this can be a sign
• Optimal standard therapy is currently left of aggressiveness.
to an individual clinician’s judgment. Many Histopathologic characteristics may
patients with tumors considered to be indicate potential aggressiveness. As a first
aggressive have a history of repeated surgery, step, determining the Ki-67 labeling index is
radiotherapy, and drug treatment. Despite recommended. In patients with a Ki-67 labeling
these treatment efforts, the tumors tend to index greater than 3%, determining the mitotic
recur. Some prolactinomas require higher index and p53 is advised. Tumors often develop
than recommended dosages of cabergoline. aggressive behavior many years after initial
Growth despite these strategies is suspicious diagnosis and pathologic evaluation. Ki-67 is
for aggressiveness. related to aggressiveness; however, it may also
be low in patients with aggressive disease. A
Several additional diagnostic tools can help higher Ki-67 index is a red flag for potential
distinguish aggressive from nonaggressive aggressiveness, and surveillance protocols for
pituitary tumors. These tools are not evidence- such patients should be more rigorous. The
based, but used in experienced hands, they European Pituitary Pathology Club has proposed
can be used to help optimize treatment. The a practical 5-tiered classification: 1a noninvasive,
cornerstone of diagnostic imaging for pituitary nonproliferative; 1b proliferative, noninvasive;
tumors is dedicated pituitary MRI with 2- to 2a invasive but nonproliferative; 2b proliferative
3-mm slices. In addition to standard series, axial and invasive; and 3 pituitary carcinoma. In
coupes are helpful. The skull base is best evaluated this classification, proliferation is defined by
with CT. Suitability of peptide radioreceptor the presence of 2 of 3 proliferation markers
therapy could be evaluated with somatostatin (p53, Ki-67, mitotic index).
receptor PET-CT. Determining the best schedule Debulking surgery carefully planned
for surveillance MRI is critical. Generally, we with a multidisciplinary team may be a good
recommend every 3 to 6 months for tumors option, although the anatomical relationships
with suspected aggressiveness unless very stable. can be challenging. Many patients receive
Clinicians must also be aware of the possibility of radiotherapy. When standard medical options
distant metastases. Endocrine workup is needed fail, temozolomide, and possibly immunotherapy
to evaluate for hormone excess and deficiency. should be considered.
There might be a discrepancy in radiological Several factors are involved in tumorigenesis,
progression and endocrine progression, so but their relationship to aggressiveness is
laboratory evaluation and imaging are both not well studied (changes in tumor cells
needed. Ophthalmological function is critical to and microenvironment).
monitor in patients with pituitary tumors that may

166  ENDO 2022 • Endocrine Case Management

 Temozolomide is the cornerstone for treating Case 1 (Continued)
aggressive pituitary tumors, but this drug is
Over the next 5 years, there is gradual tumor
not effective in a relevant subset. There are
growth with increasing optic chiasmatic
innovations with peptide receptor radionuclide
compression. Reoperation is required, and
therapy and immunotherapy. These approaches
pathologic examination again shows a low Ki-67
are highly individualized. Outcome data of drugs
labeling index. The patient’s ACTH concentration
other than temozolomide have been mainly
is 300 pg/mL (66 pmol/L).
limited to case reports.
Is there any reason to change the
Clinical Case Vignettes above-mentioned diagnosis?
A. Yes
Case 1
B. No
A 52-year-old woman presents with a giant
pituitary adenoma that has destroyed the skull base Answer: B) No
and the left orbit. There is suprasellar extension
intracranially, encasement of the carotid artery, There are no additional arguments to revise the
and compression of the temporal lobe. She has no diagnosis (Answer B). Watchful waiting should
pituitary hormone deficiencies, but she does have be continued. Additional radiotherapy could be
partial epilepsy related to the pituitary adenoma. an option.
There are increased ACTH values (262 pg/mL
[57.6 pmol/L]) without clear signs of biochemical Case 2
or clinical Cushing disease. She has severe
A 49-year-old woman presents with Cushing
visual field defects, and surgery is scheduled for
syndrome. She has a Hardy grade IIA
debulking of tumor mass. The Ki-67 labeling index
macroadenoma and undergoes endoscopic surgery.
is less than 2%, and there is weak ACTH staining.
She is subsequently in remission and is temporarily
hydrocortisone-dependent. Pathologic staining is
Which of the following is the
positive for ACTH, there are no mitoses, and the
most likely diagnosis?
Ki-67 labeling index is not available. Postoperative
A. Aggressive pituitary tumor MRI shows no residual disease.
B. Giant adenoma Three years later, she has a biochemical
C. Silent corticotroph tumor recurrence and now there is an 18-mm
D. Both A and B macroadenoma with invasion in the cavernous
sinus, grade 3BE. Pathology documents a Ki-67
E. Either B or C
labeling index of 7%, p53 is negative, and there is
Answer: E) Either B or C minor cellular polymorphy.

At this stage, it is difficult to judge whether this Which of the following is the
giant adenoma is also “aggressive.” Findings most likely diagnosis?
on pathological evaluation are unremarkable. A. Aggressive tumor
The tumor’s growth pattern fits with being
aggressive. There is ACTH secretion and B. Recurrence of Cushing disease
ACTH-positive staining. However, there is not C. Either an aggressive tumor or recurrence of
clear hypercortisolism. This is either a silent Cushing disease—difficult to discriminate
corticotroph tumor (Answer C) or simply a giant Answer: C) Either an aggressive tumor or recurrence
adenoma (Answer B). Thus, Answer E is correct. of Cushing disease—difficult to discriminate
This patient requires close follow-up.

ENDO 2022 • Neuroendocrinology and Pituitary  167

The pathology and clinical course in this vignette with good response 1.5 years later. The patient’s
are consistent with the diagnosis of an aggressive condition and the tumor are stable; she is
tumor, as well as recurrence of Cushing disease. wondering about stopping temozolomide.
However, the patient had not yet received
radiotherapy, so in theory, this tumor could have What is your suggestion? What
been stabilized with radiotherapy. is this patient’s prognosis?
This is a highly individualized plan, with
advantages and disadvantages. The standard advice
Case 2 (Continued) is to evaluate after 3 months. If there is a positive
Two years later, the patient experiences a new response, temozolomide will be continued, as
recurrence. Radical resection is not possible. The long as the patient tolerates it and continues
Ki-67 labeling index is again 7%. Postoperative responding. There are no evidence-based trials on
radiotherapy is administered. Two years later, best practices.
there is growth despite radiotherapy. She has
some ophthalmoplegia. Temozolomide is started

References
1. Raverot G, Ilie MD, Lasolle H, et al. Aggressive pituitary tumours and 6. Ilie MD, Jouanneau E, Raverot G. Aggressive pituitary adenomas and
pituitary carcinomas. Nat Rev Endocrinol. 2021;17(11):671-684. PMID: carcinomas. Endocrinol Metab Clin North Am. 2020;49(3):505-515. PMID:
34493834 32741485
2. Raverot G, Burman P, McCormack A, et al; European Society of 7. Trouillas J, Jaffrain-Rea M-L, Vasiljevic A, et al. Are aggressive pituitary
Endocrinology. European Society of Endocrinology Clinical Practice tumors and carcinomas two sides of the same coin? Pathologists reply to
Guidelines for the management of aggressive pituitary tumours and clinician’s questions. Rev Endocr Metab Disord. 2020;21(2):243-251. PMID:
carcinomas. Eur J Endocrinol. 2018;178(1):G1-G24. PMID: 29046323 32504268
3. McCormack A, Dekkers OM, Petersenn S, Popovic V, Trouillas J, Raverot 8. Honegger J, Reincke M, Petersenn S, eds. Pituitary Tumors: A Comprehensive
G, Burman P; ESE survey collaborators. Treatment of aggressive pituitary and Interdisciplinary Approach. Elsevier Press; 2021.
tumours and carcinomas: results of a European Society of Endocrinology 9. Trouillas J, Jaffrain-Rea M-L, Vasiljevic A, Raverot G, Roncaroli F, Villa
(ESE) survey 2016. Eur J Endocrinol. 2018;178(3):265-276. PMID: 29330228 C. How to classify the pituitary neuroendocrine tumors (PitNET)s in 2020.
4. Trouillas J, Burman P, McCormack A, Petersenn S, Popovic V, Dekkers O, Cancers (Basel). 2020;12(2):514. PMID: 32098443
Raverot G. Aggressive pituitary tumours and carcinomas: two sides of the
same coin? Eur J Endocrinol. 2018;178(6):C7-C9. PMID: 29588294
5. Duhamel C, Ilie MD, Salle H, et al. Immunotherapy in corticotroph and
lactotroph aggressive tumors and carcinomas: two case reports and a review
of the literature. J Pers Med. 2020;10(3):88. PMID: 32823651

168  ENDO 2022 • Endocrine Case Management

Controversies in the
Field of Acromegaly
Elena V. Varlamov, MD. Departments of Medicine (Endocrinology, Diabetes, and Clinical
Nutrition) and Neurological Surgery, and Pituitary Center, Oregon Health & Science
University, Portland, OR; E-mail: [email protected]

Maria Fleseriu, MD. Departments of Medicine (Endocrinology, Diabetes, and Clinical

Nutrition) and Neurological Surgery, and Pituitary Center, Oregon Health & Science
University, Portland, OR; E-mail: [email protected]

Learning Objectives patients for whom suspicion of acromegaly is

reasonably high.
As a result of participating in this session, learners
should be able to: • Pituitary surgery is first-line treatment for
most patients in the United States, unless
• List possible limitations of IGF-1 and GH contraindicated, not feasible, or declined by
assays in the diagnosis of acromegaly. the patient. Use of primary medical therapy
• Describe indications for adjuvant medical has increased over time.
therapy for patients with acromegaly after • First-generation somatostatin receptor ligands
pituitary surgery. (SRLs), lanreotide Autogel and octreotide
• Explain the role of a personalized approach (injectable and oral), are most commonly
to medical management of patients used for persistent biochemical/radiologic
with acromegaly. disease postoperatively, although pegvisomant
could also be used as initial therapy in some
• Select medical therapy for acromegaly based
patients. The SRL dosage should be escalated
on tumor characteristics, IGF-1 and GH levels,
for biochemical control (normal IGF-1 and
comorbidities, and patient goals.
GH <1.0 ng/mL [<1.0 µg/L]) to the maximal
dosage approved/tolerated. If a tumor has
characteristics associated with resistance to
SRLs (negative somatostatin receptor type
Main Conclusions 2 receptor, sparsely granulated type, T2-
weighted MRI hyperintensity, pathogenic
• The oral glucose tolerance test (OGTT)
variant in the aryl hydrocarbon receptor-
GH cutoff for diagnosis of acromegaly is
interacting protein gene [AIP], high Ki67
0.4 ng/mL (0.4 µg/L) using modern GH assays.
index), pasireotide LAR or a combination of
Patients with mild acromegaly may have a GH
an SRL and pegvisomant could be considered.
concentration less than 0.4 ng/mL (<0.4 µg/L)
Cabergoline can be useful in selected patients
assessed by OGTT.
with mild acromegaly.
• IGF-1 and GH levels are affected by various
• Radiation therapy is third-line treatment for
physiologic and pathologic states, as well as
most patients, except those who have large,
medications. Careful clinical evaluation, repeat
invasive, or enlarging residual tumors after
testing, and pituitary MRI are necessary in

ENDO 2022 • Neuroendocrinology and Pituitary  169

 surgery. Radiation therapy is associated with implemented in patients not cured by surgery.
hypopituitarism and requires medical therapy Radiotherapy is generally reserved for patients
for GH excess while awaiting effects. in whom medical therapy fails and those with
• Quality of life and symptom improvement invasive and aggressive tumors.10
are important determinants of successful Development of new medical therapies,
treatment outcomes; clinicians should discovery of predictive factors for success or
evaluate symptoms in all patients even after failure of different treatments, increased awareness
biochemical control is achieved. of possible treatment-related complications,
as well as understanding the patient’s personal
goals have led to the new concept of personalized
management of acromegaly. This approach takes
Significance of the into consideration tumor type, size, IGF-1 and GH
levels, patient symptoms, comorbid conditions,
Clinical Problem and patient preferences.11
Acromegaly is a rare condition resulting from Although biochemical control typically
chronic GH and IGF-1 excess.1 Most cases are results in significant improvement of a
due to a GH-secreting pituitary adenoma; less patient’s symptoms, the “goal” target (normal
than 1% are caused by an ectopic GHRH- or GH- age- and sex-adjusted IGF-1 concentration
producing neuroendocrine tumor.2 Prevalence of and GH concentration <1 ng/mL [<1.0 µg/L])
acromegaly is 85 in 10 million,3 which is higher is sometimes still associated with persistent
than previously thought, probably due to increased symptomatology (arthralgias, sweating, fatigue,
awareness and improved diagnostic means. soft-tissue swelling).12 Clinicians should
Untreated or uncontrolled acromegaly is consider therapy adjustment in patients with
associated with multisystem complications ongoing symptoms.
resulting in a roughly 2-fold increased mortality Lastly, long-term follow-up and regular
rate, primarily driven by cardiovascular disease. reassessment of biochemical and tumor control
Cerebrovascular disease (often attributed to pituitary are important. Patients in clinical and biochemical
radiation therapy), sleep apnea, and cancer likely also remission should be periodically screened
add to the increased mortality, although this has not for recurrence.
been demonstrated consistently.3,4 Normalization
of GH and IGF-1, as well as identification and
treatment of comorbidities, reduces mortality rates
Barriers to Optimal Practice
to that of the general population.1,5-8 In addition to
• GH and IGF-1 assays are heterogeneous.
attaining biochemical control, treatment goals also
Discrepancies exist among laboratories,
include tumor removal/shrinkage, symptom control,
complicating diagnosis and monitoring if
and improved quality of life.
testing is performed in different laboratories.
Transsphenoidal removal of a GH-producing
adenoma is usually first-line treatment in the • OGTT and IGF-1 measurement have
United States and should be performed by an limitations in the diagnosis of mild acromegaly.
experienced neurosurgeon. Despite technological • Histopathology reports do not always include
advances, the long-term surgical cure rate is less information that can guide treatment choice
than 65%,9 most likely because many patients or determine prognosis (eg, sparsely vs
present with larger and invasive tumors, making granulated GH-secreting tumors, presence of
complete tumor excision difficult.5 Adjunctive somatostatin receptor type 2).
medical therapy to normalize GH and/or
• SRL monotherapy is effective in less than 50%
IGF-1 levels, as well as to shrink the tumor, is
of patients in unselected populations; thus,

170  ENDO 2022 • Endocrine Case Management

 patients often require a switch to a different Difficulties in the Diagnosis of Acromegaly
agent or combination therapy. Diagnosis of acromegaly is not always
straightforward. Patients may lack “classic”
clinical symptoms and signs, particularly in mild
Strategies for Diagnosis, cases. Some present only with complications,
Therapy, and/or Management such as sleep apnea, glucose intolerance or
diabetes, osteoarthritis, carpal tunnel syndrome,
Clinical Scenario or hypertension, which leads to suspicion
A 63-year-old woman with a history of of acromegaly. IGF-1 is the recommended
hypertension, prediabetes, sleep apnea, benign screening test in all patients who present with
thyroid nodules, breast cancer in remission, and classic symptoms and with a combination of
meningioma resection 10 years ago presents comorbidities associated with acromegaly, as well
with a 1.5 × 0.9-cm pituitary adenoma found on as in patients with a pituitary mass.5 OGTT with
surveillance MRI. The adenoma does not touch the assessment of GH nadir is performed when IGF-1
optic chiasm. She also has meningioma recurrence. levels are mildly elevated or equivocal. Both tests
have limitations related to established cutoffs,
Laboratory test results: assay performance, physiologic factors affecting
IGF-1 = 312 ng/mL (53-287 ng/mL) (SI: 40.9 nmol/L the results as well as the clinical scenario—whether
[6.9-37.6 nmol/L]) they are performed to establish a diagnosis or to
Random GH = 0.9 ng/mL (≤4.9 ng/mL) (SI: 0.9 µg/L assess for remission after surgery.
[≤4.9 µg/L]) IGF-1 is a protein secreted in the liver
The rest of her pituitary function is normal. under GH stimulation. Its half-life is 15 hours,
OGTT shows GH suppression to 0.31 ng/mL and it is a surrogate marker for GH disorders,
(0.31 µg/L) with a concurrent glucose value of especially GH excess.5 IGF-1 levels should be
242 mg/dL (13.4 nmol/L). This is regarded as interpreted in the context of established age-
normal at an outside institution and the patient and sex-adjusted reference ranges. Since these
is followed up conservatively for pituitary differ between various IGF-1 assays, borderline
adenoma but undergoes another resection of results can create difficulties in both diagnosis
meningioma. On follow-up, IGF-1 remains and decision making, particularly for monitoring
persistently mildly elevated. The patient has patients during treatment. Various physiologic
headaches but no changes in hand or foot size, factors can influence IGF-1 levels (Table 1).13,14
sweating, or joint pain. On 3-year follow-up “Falsely” elevated IGF-1 may be related to
imaging, the pituitary adenoma has enlarged to inadequately established reference ranges in a
1.7 × 1.4 × 1.3 cm with optic chiasm compression. reference population.15
She is referred to your institution and undergoes GH has a pulsatile secretion pattern and is also
transsphenoidal surgery. Pathologic examination subject to different physiologic influences (Table 1).
reveals a sparsely granulated somatotroph In healthy individuals, glucose loading suppresses
adenoma. Her postoperative IGF-1 concentration GH by inhibiting GHRH and/or potentiating
is 98 ng/mL (49-279 ng/mL) (SI: 12.8 nmol/L somatostatin release. The cutoff of nadir GH
[6.4-36.5 nmol/L]). less than 1.0 ng/mL (<1.0 µg/L) on 75-g OGTT
How should one interpret discrepant was recommended,5 but using new ultrasensitive
biochemical results when evaluating for acromegaly? assays, a GH value less than 0.4 ng/mL (<0.4 µg/L)
has been proposed as a revised cutoff.10 However,
some patients with acromegaly suppress to
less than 0.4 ng/mL (<0.4 µg/L).16 One study
found that 7 of 40 of patients had a GH value

ENDO 2022 • Neuroendocrinology and Pituitary  171

Table 1. Factors That Affect IGF-1 and GH Levels

Factors that ↑ IGF-1 Factors that ↓ IGF-1 Factors that ↑ GH Factors that ↓ GH

• Parenteral testosterone • Oral estrogen, selective • Oral estrogen, midcycle • Age (post­menopausal)
estrogen receptor modulators
• Pregnancy • Significantly uncontrolled • High BMI
• Severe obesity diabetes
• Late-stage adolescence
• Prolonged fasting and • Kidney failure
• Inadequate limits of
malnutrition
normality • Prolonged fasting and
• Liver disease malnutrition
• Assay interference
• Kidney disease • Liver disease
• Uncontrolled diabetes • Acute critical illness
• Acute illness

less than 0.4 ng/mL (<0.4 µg/L) on 100-g Pituitary surgery is performed, and pathologic
OGTT; these patients had baseline GH values examination shows a mammosomatotroph
less than 4.3 ng/mL (<4.3 µg/L) and most had adenoma, somatostatin receptor type 2 receptor
microadenomas. However, nonsuppression negative. Her 3-month postoperative IGF-1
of GH (GH >0.4 ng/mL [>0.4 µg/L]) has been concentration is 469 ng/mL (61.4 nmol/L) and
demonstrated in healthy slim individuals and her GH concentration is 10.2 ng/mL (10.2 µg/L),
in women taking oral estrogen.17 Additionally, indicating persistent acromegaly. MRI shows
patients with uncontrolled diabetes can have interval resection of a pituitary mass and
nonsuppressed GH levels. Therefore, these factors postsurgical changes.
must be considered when interpreting OGTT results. How should one decide what adjuvant
When the initial evaluation is equivocal treatment option to choose in the era of
and results are discrepant and/or do not fit with personalized medicine?
the clinical picture, retesting is recommended.
MRI should be obtained if clinical suspicion for Surgical Remission Criteria
acromegaly is high, even if OGTT is normal. Disease control after surgery or on medical
Repeated MRI is warranted if biochemical and therapy is defined as normal IGF-1 and a
clinical progression is evident when the patient is random GH concentration less than 1.0 ng/mL
followed by observation. (<1.0 µg/L), the biochemical profile associated
with normalization of mortality.5 Patients with
a GH value greater than 1.0 ng/mL (>1.0 µg/L)
Clinical Scenario
may benefit from OGTT for additional evaluation.
A 35-year-old woman presents with a 1.9-cm Discrepant results, most commonly GH less than
pituitary adenoma identified radiographically 1 ng/mL (<1.0 µg/L) and elevated IGF-1 levels,
during amenorrhea workup. She also has may occur postoperatively, and the current
headaches, hirsutism, increased sweating, consensus statement recommends relying on
increased shoe and ring size, puffiness under her IGF-1 with close follow-up. IGF-1 seems to
eyes, and occasional snoring. correlate better with comorbidities than GH nadir
levels; furthermore, IGF-1 is more predictive
Laboratory test results:
than nadir GH in assessing insulin sensitivity and
IGF-1 = 963 ng/mL (113-297 ng/mL) clinical symptoms after surgery.18
(SI: 126.1 nmol/L [14.8-38.9 nmol/L])
Prolactin = 148 ng/mL (4-23 ng/mL)
(SI: 6.44 nmol/L [0.17-1.00 nmol/L])

172  ENDO 2022 • Endocrine Case Management

Persistent Disease After Surgery often leads to better biochemical control. More
Persistent disease after surgery is treated with medical than 70% of patients achieve greater than 20%
therapy for which there are a variety of options. tumor volume reduction on SRL therapy.20
Oral octreotide capsules are approved for patients
Somatostatin Receptor Ligands whose disease is controlled on injectable SRLs.
SRLs remain the first-line medical treatment In a double-blind randomized controlled trial
for many patients.1,5,19 These agents bind to of 56 patients who previously responded to
somatostatin receptors on somatotroph adenoma long-acting injectable SRLs, approximately
cells, suppressing both GH secretion and tumor 60% vs 20% in the placebo group maintained
cell proliferation. Octreotide long-acting biochemical control.21 Another phase 3 trial,
release (LAR), and deep subcutaneous lanreotide assessing maintenance of response to oral
depot/Autogel are equally effective injectable octreotide capsules vs switching to injectable
formulations of first-generation SRLs (Table 2). SRLs showed noninferiority of oral octreotide
Approximately 30% to 60% of patients19 achieve capsules (91% [CI: 80%-97%]) to injectable SRLs
biochemical control; such variable response is (100% [CI: 91%-100%]) at 36 weeks for patients
thought to be related to preselection of patients who responded to both therapies.22 Therefore,
for GH responsiveness in the studies, different oral octreotide capsules may be considered as an
definitions of remission, prior treatments, duration alternative for patients whose disease is controlled
of follow-up, and other factors. Dosage escalation on injectable SRLs and for whom injections present

Table 2. Summary of Medical Therapies for Acromegaly

Class Agent Notes Possible adverse effects

First-generation SRL Octreotide LAR, 10 to • Administered by a health care Gastrointestinal distress
40 mg every 4 weeks, professional, as it requires cholelithiasis, liver
Affinity to somatostatin
intramuscularly reconstitution function enzyme elevation,
receptor type, arranged by
hyperglycemia or hypoglycemia,
order from the strongest to Lanreotide Autogel, 60 to • May be self-administered bradycardia
the weakest: 2 > 5, 3 > 1 > 4 120 mg every 4 to 8 weeks, (prefilled syringes)
deep subcutaneously Intolerance of 1 drug does not
indicate cross-intolerance to
Octreotide, 50 to 100 mcg • Rarely used alone other
3 times daily, subcutaneously
• Sometimes used for treatment of
acromegaly related headaches
Octreotide capsules, 20 mg • Indicated for patients controlled
twice daily, up to 80 mg daily, on injectable SRL
orally
• Could improve several symptoms
in selected patients
• Must be taken on empty stomach
or 2 hours after meal
Newer-generation SRL Pasireotide LAR, 40 to • Biochemical control in 20% Hyperglycemia/diabetes mellitus
60 mg every 4 weeks, of cases resistant to first- (~60%), QT prolongation, liver
Higher affinity to
intramuscularly generation SRL function enzyme elevation
somatostatin receptor type 5
D2 receptor agonist Cabergoline, 1 to 5 mg • For mild IGF-1 elevation or in Nausea, dizziness, worsening
weekly, orally combination therapy mood disorders and impulse
control disorders
GH receptor antagonist Pegvisomant, 10 to 40 mg • Effective in >60% in real-life Liver function enzyme elevation
daily, subcutaneously scenario
QT prolongation
2 to 3 times per week • Could improve glycemic control
regimens can be used
• No antitumor effect
• GH levels remain elevated and
should not be monitored

ENDO 2022 • Neuroendocrinology and Pituitary  173

a burden, as well as for those who experience Dopamine agonists effectively achieve
breakthrough symptoms at the end of the injection biochemical control in some patients, with variable
cycle due to wear-off. Food reduces absorption of degree of tumor volume reduction. Because of
oral octreotide capsules; thus, lack of adherence limited efficacy, cabergoline is considered mainly
to correct food-medication instructions can in patients with very mild disease or in those
decrease efficacy. treated with combination therapy.32
Resistance to first-generation SRLs has been Combination medical therapy is used when
observed in patients with sparsely granulated monotherapy fails to achieve control or when
somatotroph adenomas, somatostatin receptor lower dosages are desired to minimize adverse
type 2-negative adenomas, T2-MRI hyperintense effects of individual medications.24 A combination
adenomas, large and invasive tumors, AIP gene of a first-generation SRL and pegvisomant
pathogenic variants, high Ki67 proliferation index, provides 80% to 97% IGF-1 normalization,
and younger age.5,23,24 Pasireotide LAR is a newer- allowing lower or less frequent pegvisomant
generation SRL with greater somatostatin receptor dosages (once or twice weekly), with lower cost
type 5 affinity and higher efficacy than octreotide and improved tolerability.33,34 The combination
LAR (31.3% vs 19.2%, P = .007)25 or LAN25-27; of pasireotide LAR and pegvisomant allows for
tumor volume reduction is approximately 40%.25 reduction in the pegvisomant dosage by as much
However, biochemical response may also be as 66% compared with the combination of a first-
driven by action on somatostatin receptor type 2.28 generation SRL and PEG. However, the frequency
Efficacy in patients resistant to first-generation of diabetes doubles.35 As both types of drugs are
SRLs is approximately 20%. The adverse effect associated with liver function enzyme elevation,
profile is similar, except for higher rates of close monitoring is needed. The combination of an
hyperglycemia/diabetes (~60%). Therefore, close SRL and cabergoline is also relatively well-tolerated
monitoring and the addition of metformin, a and may be considered for patients with mild IGF-1
GLP-1 receptor agonist, and a DPP-4 inhibitor has elevations. The combination of pegvisomant and
been recommended.29 Hyperglycemia is less likely cabergoline is reasonable if a patient with mild
to occur in younger patients, those with normal disease is intolerant to SRLs or when combination
glucose tolerance, and those without hypertension of an SRL and pegvisomant is cost prohibitive.
or dyslipidemia history. Hyperglycemia is Long-term efficacy and safety of various
reversible with pasireotide LAR discontinuation.30 combination therapies need further study.5,24
Pegvisomant, a GH receptor antagonist, blocks Emerging medical therapies for acromegaly
IGF-1 production in the liver. It reduces IGF-1 in a include a nonpeptide selective somatostatin
dose-dependent manner, achieving IGF-1 control receptor type 2 agonist paltusotine, antisense
in greater than 90% of patients at dosages of up oligonucleotides (cimdelirsen), long-acting
to 40 mg daily. Real-life observation data show a subcutaneous octreotide, and another SRL,
lower control rate, 53% at year 1 and 75% at year 10, somatoprim. Temozolomide is used off-label in
attributed to lower dosages (mean = 14.0 mg daily combination with other medical therapies for
at year 1 and 18.2 mg daily at year 10) and slower patients with aggressive GH-secreting tumors.6,24
titration rates outside of clinical trials.31 Tumor Primary medical therapy in lieu of surgery may
volume increase is 3% to 7%.31 Pegvisomant be considered for patients with smaller adenomas
improves fasting and postprandial glycemia and without optic chiasm compromise, those who
could be beneficial for patients with diabetes. are not surgical candidates or decline surgery,
Additionally, a long half-life (60 to 138 hours) and those with empty sella due to “burnt-out”
allows reduced frequency of injections (2 to 3 times adenoma. SRLs are most commonly used for this
weekly), thus lessening the injection burden. purpose as they reduce tumor volume and control
GH hypersecretion; pegvisomant is also an option

174  ENDO 2022 • Endocrine Case Management

in these patients, as risk of tumor progression is required until the radiation “kicks in,” which
low. Data on preoperative use of medial therapy in occurs in 40% to 60% of patients at 5 years.37
order to improve postsurgery biochemical outcomes Hypopituitarism occurs in 25% to 50% at 5 years.10
are conflicting; therefore, this strategy is not used Radiation-induced cerebrovascular disease,
routinely. In rare clinical scenarios, such as a patient secondary tumors, and cranial nerve palsy may
with severe pharyngeal thickness and severe sleep be less frequent with modern focused stereotactic
apnea syndrome, preoperative therapy may be techniques.10
considered to possibly reduce perioperative morbidity. Reoperation is considered for patients
Further study is needed to assess utility of presurgical with identifiable resectable tumor for whom
medical treatment in patients with acromegaly.5,36 postoperative medical therapy failed after initial
Radiation (conventional and stereotactic) surgery or with tumor regrowth. New developing
is mostly third-line treatment in those for nuclear medicine techniques (eg, 11C-Met PET-CT)
whom surgery and medical therapy fail, but it may help localize residual somatotroph adenomas
is recommended postoperatively in patients if no visible tumor is seen on MRI.38
with aggressive somatotroph adenomas. Due The Figure summarizes the algorithm for
to slow effect onset, bridge medical therapy is medical management of acromegaly.

Figure. Suggested Algorithm for Medical Management of Acromegaly1,5-8,9,10,32

Adapted from Ting Lim DS & Fleseriu M. Endocr Pract, 2022; 28(3) © AACE. Published by Elsevier Inc. All rights reserved.

ENDO 2022 • Neuroendocrinology and Pituitary  175

Clinical Case Vignettes liver or kidney disease (Table 1) (thus, Answers
A and C are incorrect). This patient lacked any
Case 1 confounders.
A 59-year-old woman presents with a 6 × 6 × 9-mm In the setting of equivocal results, OGTT
pituitary adenoma discovered incidentally could help make the diagnosis; here it clearly
during workup for dizziness and ataxia. She has demonstrated GH nonsuppression after
diabetes mellitus controlled on metformin and documented hyperglycemia, confirming the
neuropathy. She has no obvious acromegalic diagnosis of mild acromegaly (Answer B).
features, no hand enlargement, excessive sweating, The patient underwent pituitary surgery, and
joint pain, or headache. IGF-1 measurement is pathologic examination confirmed a GH-positive
mildly elevated at 276 ng/mL (40-217 ng/mL) pituitary adenoma with biochemical remission.
(SI: 36.2 nmol/L [5.3-28.4 nmol/L]). A repeated Her postoperative IGF-1 concentration was
IGF-1 measurement in a different laboratory is 152 ng/mL (37-208 ng/mL) (SI: 19.9 nmol/L
266 ng/mL (53-287 ng/mL) (SI: 34.8 nmol/L [4.8-27.2 nmol/L]) and GH concentration was
[6.9-37.6 nmol/L]). GH levels on OGTT are 0.16 ng/mL (0.16 µg/L).
1.3 ng/mL (1.3 µg/L), 1.4 ng/mL (1.4 µg/L),
2.0 ng/mL (2.0 µg/L), and 1.6 ng/mL (1.6 µg/L)
Case 2
with glucose values of 195 mg/dL (10.8 mmol/L),
119 mg/dL (6.6 mmol/L), 83 mg/dL A 66-year-old woman has acromegaly due
(4.6 mmol/L), and 70 mg/dL (3.9 mmol/L). Other to a 1.5-cm pituitary macroadenoma. She
pituitary function is normal. has a history of osteopenia, colonic polyps,
sleep apnea, controlled type 2 diabetes
How should one interpret the above results? mellitus, and hypertension. Her IGF-1 value is
A. Patient’s results are discrepant; therefore, a 652 ng/mL (75-263 ng/mL) (SI: 85.4 nmol/L
diagnosis cannot be established [9.8-34.4 nmol/L]), and her GH value is
20.3 ng/mL (SI: 20.3 µg/L). She undergoes
B. Patient’s OGTT results are abnormal,
pituitary surgery, and pathologic examination
confirming acromegaly
shows mammosomatotroph adenoma.
C. Patient’s first IGF-1 value is falsely high, second Postoperatively at 3 months, her IGF-1 value is
IGF-1 value is normal; acromegaly is excluded 262 ng/mL (32-238 ng/mL) (SI: 34.3 nmol/L
Answer: B) Patient’s OGTT results are [4.2-31.2 nmol/L]), and her GH value is
abnormal, confirming acromegaly 0.4 ng/mL (SI: 0.4 µg/L). IGF-1 continues to
be high 6 months after surgery. MRI shows
This patient presented with an incidental postoperative changes and a possible small residual
microadenoma, and management depends adenoma. Many of her acromegaly symptoms have
on the presence or absence of mass effect and improved or resolved.
hormonal hypersecretion. There is no mass effect
and seemingly no symptoms, but she has some Which of the following is the best
comorbidities potentially related to acromegaly, therapeutic choice for this patient?
namely type 2 diabetes and neuropathy. Her initial A. Lanreotide, 60 mg every 6 weeks
IGF-1 measurement was elevated and the second B. Oral octreotide capsules, 20 mg twice daily
one was normal, which is a common scenario
C. Pasireotide, 40 mg daily
in mild disease given assay variability, as well
as intra-patient IGF-1 variability. One should D. Pegvisomant, 10 mg daily
consider factors that can reduce IGF-1 levels E. No therapy
such as oral estrogen, uncontrolled diabetes, and
Answer: A) Lanreotide, 60 mg every 6 weeks

176  ENDO 2022 • Endocrine Case Management

This patient presents with mildly elevated IGF-1 and pituitary macroadenoma (somatostatin
nonsuppressed GH 3 to 6 months postoperatively, receptor type 2 staining not available),
which indicates persistent disease. If results of a with an initial IGF-1 concentration of
laboratory workup at 3 months are borderline, a 513 ng/mL (106-368 ng/mL) (SI: 67.2 nmol/L
repeated biochemical evaluation is warranted, and [13.9-48.2 nmol/L]) and prolactin concentration
medical therapy should be started for persistently of 73 ng/mL (3-20 ng/mL) (SI: 3.17 nmol/L
elevated IGF-1, as in this scenario. Thus, [0.13-0.87 nmol/L]). Postoperatively, her
recommending no therapy (Answer E) is incorrect. IGF-1 value is 375 ng/mL (106-368 ng/mL)
Long-acting first-generation SRLs such as (SI: 49.1 nmol/L [13.9-48.2 nmol/L]) and GH
lanreotide or octreotide are the first choice for value is 2.62 ng/mL (2.62 µg/L). Notably, she is
persistent, biochemically active acromegaly, on a combined oral contraceptive. MRI shows
particularly in patients with a low likelihood a 1.6. × 1.1-cm residual pituitary adenoma with
for resistance. Lanreotide, 60 mg every 6 weeks bilateral extension into the cavernous sinuses,
(Answer A), is correct. Although the typical but she declines reoperation and is started on
lanreotide regimen is every 4 weeks, it is FDA octreotide LAR, 30 mg every 4 weeks. IGF-1
approved with extended interval between doses, normalizes within 4 months, but GH remains
which also maintains control in mild disease and greater than 1.0 ng/mL (>1.0 µg/L). The residual
reduces the injection burden. tumor shrinks to 1.1 × 0.7 cm on follow-up MRI
Pegvisomant (Answer D), although effective, at 1 year. Additionally, cabergoline, 0.25 mg twice
is rarely first-line therapy in patients with mild weekly, is prescribed for hyperprolactinemia and
disease, except in selected patients. persistent galactorrhea.
Among SRLs, pasireotide LAR (Answer
C) is also second-line therapy and is mostly Laboratory test results after 3 years of treatment:
considered for resistant cases. It also carries a risk IGF-1 = 320 ng/mL (79-276 ng/mL) (SI: 41.9 nmol/L
of worsening diabetes in this patient. [10.3-36.2 nmol/L])
Oral octreotide capsules (Answer B) could GH = 3.4 ng/mL (SI: 3.4 µg/L)
be effective if her acromegaly is controlled on a Tumor size is stable. She is no longer on an oral
long-acting SRL; this maybe a good option if she contraceptive pill and notes mild headaches and
demonstrates control on lanreotide but has end-cycle increased sweating.
breakthrough symptoms or dislike of injections.
Cabergoline (not given as a choice here) is How should this patient’s therapy be
not FDA approved but can potentially control adjusted to control her disease?
GH and IGF-1 in patients with mild acromegaly
A. Add pegvisomant
and as part of combination therapy. Dosages
required are higher than what is prescribed to B. Administer radiation therapy
treat prolactinoma; if the dosage exceeds 2 to 3 mg C. Increase the octreotide LAR dosage to 40 mg
weekly, echocardiography should be performed every 4 weeks
at baseline and after treatment is initiated as D. Perform reoperation
needed, depending on the clinical picture and E. Switch to different first-generation SRL, such
national guidelines. as lanreotide
Answer: C) Increase the octreotide LAR
Case 3 dosage to 40 mg every 4 weeks
A 40-year-old woman with acromegaly presents
to discuss treatment. She has a history of a This patient showed both biochemical and clinical
2.7-cm mixed GH- and prolactin-secreting response to octreotide LAR plus cabergoline.
However, it was an incomplete response, evident

ENDO 2022 • Neuroendocrinology and Pituitary  177

after stopping the oral contraceptive pill. Estrogen airway for intubation noted by otolaryngology.
in the oral contraceptive pill was most likely She would like to avoid surgery, and her treatment
decreasing IGF-1 liver production, while GH team also prefers a nonoperative approach at
production remained abnormal. Since she has this time, but surgery will be considered if her
not yet tried a maximum dosage of octreotide, laryngeal edema improves with treatment.
one should attempt to maximize the dosage
(Answer C). Which of the following therapies
Switching to lanreotide (Answer E) is not should this patient start?
expected to improve biochemical control, as it A. Combination therapy with lanreotide and
is not more effective than octreotide; switching pegvisomant
could play a role if there are issues with octreotide B. Octreotide LAR, 20 mg every 4 weeks
LAR injections administration per se.
C. Pasireotide, 60 mg every 4 weeks
Adding pegvisomant (Answer A) would be a
reasonable next step if the patient does not achieve D. Pegvisomant, 40 mg daily
biochemical control with the maximum octreotide Answer: C) Pasireotide, 60 mg every 4 weeks
dosage or she does not tolerate it. Of note, when
adding pegvisomant, it would be reasonable to This patient needs therapy that will effectively
simultaneously reduce the octreotide dosage. lower her IGF-1 and reduce tumor size. Tumor
Radiation is usually third-line treatment if medical size reduction is an important therapeutic goal.
therapy fails. Since her tumor is T2-isointense with areas of
Reoperation (Answer D) may be offered to hyperintensity, it may potentially be resistant
some patients; however, this patient previously to first-generation SRLs. This patient does not
declined another surgery. have diabetes mellitus. Therefore, pasireotide
(Answer C) is a good choice for this patient, but
close monitoring for hyperglycemia will still
Case 4
be required.
A 56-year-old woman is diagnosed with Octreotide LAR may also be used; however,
acromegaly due to a 2-cm pituitary adenoma, the dosage of 20 mg every 4 weeks (Answer B) is
which is T2-isointense with areas of unlikely to achieve biochemical control, especially
hyperintensity. The adenoma does not touch the given risk factors for resistance.
optic chiasm. Pegvisomant (Answer D) will likely effectively
lower her IGF-1, although it will not reduce tumor
Laboratory test results:
size (and she has a large tumor).
IGF-1 = 781 ng/mL (53-287 ng/mL) Combination therapy with lanreotide and
(SI: 102.3 nmol/L [6.9-37.6 nmol/L]) pegvisomant (Answer A) may also be effective, but
GH = 20.6 ng/mL (0.01-3.61 ng/mL)
(SI: 20.6 µg/L [0.01-3.61 µg/L])
rarely are 2 medications started simultaneously.
Prolactin = 7 ng/mL (4-30 ng/mL) The goal in this case is to shrink the tumor and
(SI: 0.30 nmol/L [0.17-1.30 nmol/L]) achieve faster biochemical control.
Hemoglobin A1c = 5.6% (4.0%-5.6%) (38 mmol/mol
[20-38 mmol/mol])

She has vocal cord paralysis related to previous

surgery for compressive goiter and has a difficult

178  ENDO 2022 • Endocrine Case Management

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hormone nadir during oral glucose tolerance test in adults. Eur J Endocrinol. switching to pasireotide in acromegaly patients controlled with pegvisomant
2019;181(1):55-67. PMID: 31096183 and somatostatin analogues: PAPE extension study. Eur J Endocrinol.
18. Bidlingmaier M, Friedrich N, Emeny RT, et al. Reference intervals for 2018;179(5):269-277. PMID: 30076159
insulin-like growth factor-1 (igf-i) from birth to senescence: results from 36. Fleseriu M, Hoffman AR, Katznelson L; AACE Neuroendocrine and Pituitary
a multicenter study using a new automated chemiluminescence IGF-I Scientific Committee. American Association of Clinical Endocrinologists
immunoassay conforming to recent international recommendations. J Clin and American College of Endocrinology Disease State Clinical Review:
Endocrinol Metab. 2014;99(5):1712-1721. PMID: 24606072 management of acromegaly patients: what is the role of pre-operative medical
19. Carmichael JD, Bonert VS, Nuno M, Ly D, Melmed S. Acromegaly therapy? Endocr Pract. 2015;21(6):668-673. PMID: 26135961
clinical trial methodology impact on reported biochemical efficacy rates of 37. Gheorghiu ML. Updates in outcomes of stereotactic radiation therapy in
somatostatin receptor ligand treatments: a meta-analysis. J Clin Endocrinol acromegaly. Pituitary. 2017;20(1):154-168. PMID: 28210908
Metab. 2014;99(5):1825-1833. PMID: 24606084 38. Koulouri O, Kandasamy N, Hoole AC, et al. Successful treatment of
20. Caron PJ, Bevan JS, Petersenn S, et al; PRIMARYS Investigators. Tumor residual pituitary adenoma in persistent acromegaly following localisation
shrinkage with lanreotide Autogel 120 mg as primary therapy in acromegaly: by 11C-methionine PET co-registered with MRI. Eur J Endocrinol.
results of a prospective multicenter clinical trial. J Clin Endocrinol Metab. 2016;175(5):485-498. PMID: 27562400
2014;99(4):1282-1290. PMID: 24423301

ENDO 2022 • Neuroendocrinology and Pituitary  179

Management of Nonsecretory
Pituitary Tumors When
Surgery Fails
Mark Gurnell, MD, PhD. Wellcome–MRC Institute of Metabolic Science, University of
Cambridge and Addenbrooke’s Hospital, Cambridge, United Kingdom; E-mail: mg299@
medschl.cam.ac.uk

Learning Objectives pituitary tumor center of excellence) is required

to guide further management and should be
As a result of participating in this session, learners
informed by:
should be able to:
• High-quality postsurgical imaging of the sella
• Adopt a systematic approach to the assessment
and parasellar regions.
of patients with nonfunctioning pituitary
adenomas (NFPAs) who have undergone • Detailed pathological characterization of the
primary surgery. resected tumor, including cell lineage markers.
• Explain the limitations of standard MRI • Assessment of the patient’s endocrine status
techniques in discriminating residual disease (extent of hypopituitarism).
from posttreatment remodeling and in • Assessment of the patient’s nonendocrine
predicting future aggressive vs indolent status (eg, visual function, presence or absence
behavior. of comorbidities, pregnancy, childhood).
• Determine which patients with NFPAs • Local expertise, including neurosurgery/
require additional therapy following otolaryngology, neurooncology, clinical trials.
surgery and which patients can be managed
through surveillance. Management options include:
• Advise when radiotherapy should be • Surveillance (clinical, ophthalmic, radiological).
considered or when alternative medical • Repeated surgery and/or radiotherapy.
therapies may be indicated.
• Trial of existing pituitary-directed medical
therapy (eg, dopamine agonist).
• Systemic chemotherapy (eg, temozolomide) in
Main Conclusions aggressive tumors/pituitary carcinoma.
Surgery remains the primary treatment for most • Trial of novel therapies (ideally in the context
patients with NFPAs in whom there are clinical of a clinical trial).
grounds for intervention (eg, compression of
the visual pathways). However, in a significant
proportion of patients, persistent or recurrent
disease is suspected or confirmed. In this context,
multidisciplinary expertise (provided through a

180  ENDO 2022 • Endocrine Case Management

Significance of the
Clinical Problem
Pituitary adenomas affect 1 in 1200 persons. A
significant proportion (25%-50%) are nonsecretory
(NFPA) and come to attention when they have
enlarged sufficiently to compress adjacent Figure 2. Suspected residual pituitary tumor following primary
surgery, but with stable appearance over time.
neurological structures (eg, optic chiasm)
and/or cause pituitary hormone insufficiency
(hypopituitarism). Another subgroup is diagnosed Barriers to Optimal Practice
incidentally during imaging of the brain
performed for an unrelated indication. When • Current disease biomarkers (clinical,
required, transsphenoidal surgery is the preferred laboratory, pathological) have limited ability
primary treatment and permits rapid and effective to distinguish tumors that are likely to regrow
decompression of the visual pathways. However, and/or behave aggressively from those with
complete surgical resection is not possible in all more indolent behavior.
patients, with the attendant risk of tumor regrowth.1
• Standard clinical MRI sequences do not always
Current clinical, laboratory, pathological, and
reliably discriminate postoperative remodeling
radiological parameters do not reliably distinguish
from residual tumor or identify remnants that
tumors that are likely to recur and/or behave more
are likely to enlarge.
aggressively from those that will follow a more
indolent course (Figures 1 and 2). Accordingly, most • High rates of additional pituitary hormone
centers initially recommend a standard “one-size-fits- deficits have been reported in patients
all” approach to postoperative surveillance, combining undergoing repeat surgery and/or
periodic MRI, ophthalmic assessment, and evaluation radiotherapy (30%-60%).
of endocrine status.1,2 Traditionally, radiotherapy • Prospective multicenter studies examining the
has been favored when there is a significant remnant efficacy and tolerability of existing pituitary-
in the anticipation of mitigating tumor regrowth, directed medical treatments (eg, dopamine
although it carries a risk of additional impairment agonists, somatostatin receptor ligands) and
of pituitary function.1,2 There is also increasing novel therapies in mitigating NFPA tumor
recognition that apparent residual disease is not (re)growth are lacking.
universally associated with regrowth/expansion
(Figure 2). However, if a conservative approach is
pursued, this is often resource intensive and may Strategies for Diagnosis,
be associated with increased patient anxiety.
Therapy, and/or Management
NFPA is a diagnosis of exclusion. It is
appropriate, therefore, to consider all available
information (clinical features, previous endocrine
investigations, histopathology) before deciding
on the next step in the management of NFPA
after primary surgery. Low-grade hormonal
hypersecretion (eg, GH or ACTH) is sometimes
Figure 1. Progressive pituitary tumor regrowth
following primary surgery. overlooked and may require dynamic testing
for exclusion. This is particularly relevant if

ENDO 2022 • Neuroendocrinology and Pituitary  181

immunohistochemistry reveals PIT-1 or T-PIT
transcription factor expression. Similarly,
comprehensive screening for hypopituitarism
should be undertaken to help inform the
discussion regarding the potential risks of further
treatment. Genetic screening (eg, for familial
Figure 3. Standard clinical imaging (T1 spin echo MRI with
isolated pituitary adenoma) should also be gadolinium [T1 SE MRI (+Gad)]) demonstrating suspected
considered in young patients and in those with a residual tumor (yellow arrow) following primary surgery, with
normal pituitary tissue displaced to the right of the sella (white
suggestive personal or family history. arrow). However, molecular imaging (11C-methionine PET/
CT coregistered with volumetric MRI (Met-PET/MRCR) shows
tracer uptake only within the normal gland, consistent with
What constitutes surgical failure? postoperative remodeling in the left hemi-sella rather than
residual adenoma.
To fail
verb: to be unsuccessful in achieving Treatment Options Following
one’s goal Primary Pituitary Surgery1-3
In the absence of pathological hormone secretion, Further Surgery
the main goals of pituitary surgery for NFPAs are: The decision to proceed with adjuvant therapy
• Protection, stabilization, and rescue of vision. following primary surgery for NFPA should ideally
be guided by a multidisciplinary specialist team in
• Preservation and recovery of pituitary function. a pituitary tumor center of excellence. This allows
These goals may be achieved without complete a full and careful evaluation of whether a repeated
resection of the tumor, and indeed more surgery by a highly skilled pituitary surgeon
“aggressive surgery” can result in less favorable could provide added benefit without significantly
outcomes, including injury to key neurovascular increasing risk (eg, more extensive debulking to
structures within the cavernous sinus or damage facilitate radiotherapy without causing additional
to the remaining normal gland with more pituitary deficits).
widespread pituitary dysfunction (including
cranial diabetes insipidus). The demonstration of Pituitary Radiotherapy
possible, or even likely, residual tumor on early As already highlighted, the routine use of
postoperative imaging should not therefore be radiotherapy postoperatively to mitigate regrowth
considered an immediate indication for adjuvant of NFPA is no longer supported. However, in
therapy, especially if the visual pathways have patients with significant tumor remnants that are
been adequately decompressed. Surveillance enlarging and not amenable to further surgery,
is a reasonable option, especially in the early radiotherapy may arrest growth or induce tumor
phase following surgery when histology has not shrinkage. Conventional fractionated radiotherapy
identified any concerning features. (eg, 45-55 Gy, delivered in 25-30 fractions, using
In addition, it is important to recognize the image-guided, intensity-modulated techniques)
potential limitations of standard clinical MRI achieves high control rates at 10 and 20 years
in the discrimination of residual tumor from (75%-90%), but carries a risk of hypopituitarism
postoperative remodeling—not all apparent (~50% at 10 years) and second tumors (~1%-2%),
remnants will turn out to be tumor (Figure 3). and may predispose to premature cerebrovascular
disease, although the latter is debated. Stereotactic
radiosurgery has been reported to achieve
control rates of up to 95% at 5 years; however,
larger tumors, suprasellar extension, and
lower radiation doses have all been linked with

182  ENDO 2022 • Endocrine Case Management

suboptimal control, while hypopituitarism, Novel Therapeutic Approaches
visual disturbance, and cranial neuropathies may Several novel treatment targets have been
complicate treatment. Case selection bias may identified in NFPAs, which may permit targeting
also at least partially explain why outcomes from with small-molecule modulators, although clinical
conventional fractionated radiotherapy can appear trials are awaited. These include the folate receptor
less impressive. and the PI3K/AKT/mTOR pathway. Peptide
receptor radionuclide therapy, which is dependent
Medical Therapy on tumoral somatostatin receptor expression, has
also been tried, but with limited success.
Dopamine Agonists
Several retrospective studies have reported
tumor stabilization or even shrinkage in patients Clinical Case Vignettes
with residual or recurrent NFPAs treated with
Case 1
dopamine agonists (most commonly cabergoline)
following primary surgery. Timing of treatment A 59-year-old man is seen in the endocrinology
initiation (early [preventative—ie, when residual clinic. He underwent transsphenoidal
tumor suspected on postoperative MRI] vs delayed pituitary surgery 3 years ago for an NFPA
[remedial—ie, upon detection of regrowth during (immunohistochemistry of the resected tumor
follow-up]) may influence effectiveness. However, demonstrated SF-1 positivity, with Ki-67 labeling
routine adoption of such an approach must be index of 1.6%). Twelve months ago, he received
balanced against the potential risks of long-term adjunctive conventional fractionated radiotherapy
dopamine agonist therapy, and further prospective (45 Gy in 25 fractions) for an enlarging right
multicenter studies will be required to establish the cavernous sinus remnant.
effectiveness and safety of this approach. On physical examination, there are no stigmata
of endocrine dysfunction. Visual fields are normal.
Somatostatin Receptor Ligands There is no cranial neuropathy.
Evidence for the routine use of first-generation
somatostatin receptor ligands (octreotide, Laboratory test results:
lanreotide) in the management of residual or Prolactin = 39 ng/mL (4-23 ng/mL) (SI: 1.70 nmol/L
recurrent NFPAs is currently lacking. Although [0.17-1.00 nmol/L])
tumor stabilization has been reported in some TSH = 1.22 mIU/L (0.5-5.0 mIU/L)
small-scale studies, there is little evidence of tumor Free T4 = 1.10 ng/dL (0.8-1.8 ng/dL) (SI: 14.2 pmol/L
[10.30-23.17 pmol/L])
shrinkage. Similarly, there is a paucity of data Cortisol (8 AM) = 15.5 μg/dL (5-25 μg/dL)
to support combined treatment with dopamine (SI: 427.6 nmol/L [137.9-689.7 nmol/L])
agonists and somatostatin receptor ligands or with IGF-1 = 179 ng/mL (78-220 ng/mL) (SI: 23.4 nmol/L
second-generation somatostatin receptor ligand [10.2-28.8 nmol/L])
therapy (eg, pasireotide). FSH = 3.5 mIU/mL (1.0-13.0 mIU/mL) (SI: 3.5 IU/L
[1.0-13.0 IU/L])
Temozolomide LH = 2.7 mIU/mL (1.0-9.0 mIU/mL) (SI: 2.7 IU/L
[1.0-9.0 IU/L])
Temozolomide, an oral alkylating agent, is
Total testosterone = 237 ng/dL (300-900 ng/dL)
normally reserved for the treatment of aggressive (SI: 8.2 nmol/L [10.4-31.2 nmol/L])
pituitary adenomas and pituitary carcinomas.3
Findings in patients with NFPAs indicate 20% Pituitary MRI is shown (see Images).
to 25% response with a further 50% of patients
achieving stable disease.

ENDO 2022 • Neuroendocrinology and Pituitary  183

 Laboratory test results:
Prolactin = 17 ng/mL (4-23 ng/mL) (SI: 0.74 nmol/L
[0.17-1.00 nmol/L])
TSH = 2.68 mIU/L (0.5-5.0 mIU/L)
Free T4 = 1.13 ng/dL (0.8-1.8 ng/dL) (SI: 14.5 pmol/L
[10.30-23.17 pmol/L])
Cortisol (8 AM) = 17.0 μg/dL (5-25 μg/dL)
(SI: 469.0 nmol/L [137.9-689.7 nmol/L])
ACTH = 52 pg/mL (10-60 pg/mL) (SI: 11.4 pmol/L
Which of the following is the [2.2-13.2 pmol/L])
most appropriate next step in IGF-1 = 179 ng/mL (84-223 ng/mL) (SI: 23.4 nmol/L
this patient’s management? [11.0-30.5 nmol/L])
FSH = 5.5 mIU/mL (1.0-13.0 mIU/mL)
A. Arrange another transsphenoidal surgery (SI: 5.5 IU/L [1.0-13.0 IU/L])
B. Arrange for surveillance MRI in 6 to LH = 2.2 mIU/mL (1.0-9.0 mIU/mL)
12 months (SI: 2.2 IU/L [1.0-9.0 IU/L])
Total testosterone = 265 ng/dL (300-900 ng/dL)
C. Commence dopamine agonist therapy (SI: 9.2 nmol/L [10.4-31.2 nmol/L])
D. Commence somatostatin receptor
ligand therapy Pituitary MRI is shown (see Images).
E. Commence temozolomide chemotherapy
Answer: B) Arrange for surveillance
MRI in 6 to 12 months
The patient is clinically well, with no
neuroophthalmic complications and well-
preserved pituitary function. The radiological
appearances on the latest scan are consistent with
Which of the following is the most
postradiotherapy changes. No further intervention
appropriate next treatment?
is required at this stage. Surveillance (Answer B) is
therefore the most appropriate approach. A. Dopamine agonist therapy
B. Somatostatin receptor ligand therapy
Case 2 C. Stereotactic radiosurgery
D. Temozolomide chemotherapy
A 53-year-old man is seen in the pituitary
multidisciplinary clinic. He has undergone E. Transcranial pituitary surgery
transsphenoidal pituitary surgery on 2 previous Answer: D) Temozolomide chemotherapy
occasions for an NFPA. Following the second
operation, immunohistochemistry demonstrated This patient has an aggressive pituitary tumor,
T-PIT positivity, weak positive staining for exhibiting radiological invasiveness with
ACTH, and a Ki-67 labeling index of 8%. He then significant tumor growth despite optimal standard
underwent conventional fractionated radiotherapy treatments. Conventional pituitary-directed
(50 Gy in 30 fractions), which was completed medical therapies typically have limited efficacy in
18 months ago. this context, whereas temozolomide (Answer D)
On physical examination, there are no yields a clear survival benefit.
stigmata of Cushing syndrome. He is otherwise
eupituitary. Visual fields are normal. There is no
cranial neuropathy.

184  ENDO 2022 • Endocrine Case Management

References
1. Yavropoulou MP, Tsoli M, Barkas K, Kaltsas G, Grossman A. The natural 3. Raverot G, Burman P, McCormack A, et al; European Society of
history and treatment of non-functioning pituitary adenomas (non- Endocrinology. European Society of Endocrinology Clinical Practice
functioning PitNETs). Endocr Relat Cancer. 2020;27(10):R375-R390. PMID: Guidelines for the management of aggressive pituitary tumours and
32674070 carcinomas. Eur J Endocrinol. 2018;178(1):G1-G24. PMID: 29046323
2. Esposito D, Olsson DS, Ragnarsson O, Buchfelder M, Skoglund T,
Johannsson G. Non-functioning pituitary adenomas: indications for pituitary
surgery and post-surgical management. Pituitary. 2019;22(4):422-434. PMID:
31011999

ENDO 2022 • Neuroendocrinology and Pituitary  185

PEDIATRIC
ENDOCRINOLOGY
Precocious Puberty: Evidence-
Based Management
Maria G. Vogiatzi, MD. Department of Pediatrics, Division of Endocrinology and Diabetes,
Children’s Hospital of Philadelphia, Philadelphia, PA; E-mail: [email protected]

Learning Objectives Long-term therapeutic outcomes are reassuring.

Advancements in genetics have started to identify
As a result of participating in this session, learners
monogenic causes of idiopathic CPP.
should be able to:
• Describe secular trends for onset of thelarche
and menarche and associations with body Significance of the
weight, and explain their clinical relevance when
evaluating a child with signs of sexual precocity.
Clinical Problem
A decrease in the age of thelarche brings a growing
• Develop an approach to the evaluation and
number of girls aged 6 to 8 years to medical
management of a child with central precocious
attention. However, the age of menarche has
puberty (CPP).
decreased minimally, and longitudinal studies
• List various forms of GnRH analogues, explain suggest that the tempo of puberty is slower
monitoring of therapeutic effectiveness, among those with earlier breast development.1
and describe short- and long-term CNS pathology is rare at this age. Pediatric
treatment outcomes. endocrinologists must consider these secular
trends in the evaluation and management of such
girls.
Clinical care using GnRH analogue therapy
Main Conclusions has changed over the last several years. New
A decrease in the age of onset of thelarche that is longer-acting GnRH analogue formulations
linked to obesity has been reported over the past have entered the market.1 Widespread use of
several years. However, the tempo of pubertal ultrasensitive LH assays has decreased the need
progression is slower in many girls older than for stimulation testing for diagnostic purposes
7 years, and adult height may not be adversely and treatment monitoring. Regardless, there
affected. For this group of patients, clinicians is paucity of well-designed, controlled studies
must distinguish between rapidly advancing to guide evidence-based care for children with
puberty and slowly progressing puberty. A period CPP, and more research is needed to compare
of careful monitoring has been suggested as an the efficacy and long-term outcomes of the most
approach in the decision-making process for recent depot preparations. Long-term outcomes of
starting GnRH analogue therapy. In addition, the GnRH analogue administration regarding obesity,
number of longer-acting GnRH analogue options cardiovascular risk factors, fertility, and bone mass
has increased. Monitoring the effectiveness of are reassuring.1 The effect of GnRH analogue
GnRH analogue treatment is primarily clinical therapy on the psychosocial adjustment in children
rather than hormonal based. Height outcomes in with CPP is uncertain.
treated girls older than 7 years remain unclear.

188  ENDO 2022 • Endocrine Case Management

Barriers to Optimal Practice onset of puberty in association with increased
BMI. Based on the above secular trends,
• Clinical studies in CPP are hampered by clinical observation for 4 to 6 months has been
the lack of well-designed controlled studies, proposed for girls who experience onset of breast
small sample size, and heterogeneous design. development between age 7 and 8 years to assess
Management decisions are frequently not the tempo of pubertal progression and before
supported by clear practice guidelines. considering suppression of puberty.1 Evidence
of rapid pubertal progression increases the risk
• Data regarding boys with CPP, associations of
for short adult height and supports starting a
gonadarche with obesity, response to GnRH
GnRH analogue.
analogue therapy, and long-term outcomes
are limited.
Laboratory Assessment
With the introduction of ultrasensitive LH assays,
random LH measurements have become the
Strategies for Diagnosis, most valuable laboratory tool in the diagnosis
Therapy, and/or Management of CPP. The use of GnRH or GnRH analogue–
Diagnosis stimulation tests is typically reserved for patients
in whom there is a strong clinical suspicion for
Secular Trends on Gonadarche and How CPP and a prepubertal random LH value.1 Pelvic
They May Influence Decisions About ultrasonography is not always useful for the
Initiation of GnRH Analogue Therapy diagnosis of CPP. Brain MRI is recommended
In recent years, many studies have reported a in all boys with CPP given their greater risk for
decrease in the age of onset of thelarche. The pathology. The risk of CNS pathology in girls
Breast Cancer and Environment Research between age 6 and 8 years is small. In this age
Program, a large prospective longitudinal study range, the incidence of tumors that would require
in the United States, observed the median ages intervention is 1.6% according to a recent meta-
for onset of Tanner stage 2 breast development analysis that included approximately 1800 girls.1
at 8.8, 9.3, 9.7, and 9.7 years for Black, Hispanic, Based on these results, it has been suggested that
White, and Asian girls, respectively. Girls girls with CPP should have brain MRI performed
with high BMI tend to achieve stage 2 breast routinely if they are younger than 6 years or have
development at younger ages. Similar trends have symptoms suggestive of CNS pathology.
been observed in Europe and Asia.2 This has led
some investigators to propose a younger age than
8 years as a cutoff for definition of sexual precocity Genetics of CPP
in girls. Despite this pronounced decrease in the Approximately 90% of girls and 25% to 60% of
age of thelarche, however, the age of menarche has boys have idiopathic CPP, with no identifiable
decreased minimally. Longitudinal studies suggest causes explaining the sexual precocity. The onset
that the tempo of pubertal progression is slower of puberty is regulated by a functionally connected
among those with earlier breast development.1,2 and well-organized neuronal network that can
In addition, population-based gonadotropin send signals that either stimulate or inhibit the
levels among girls who experience earlier breast generation of GnRH pulses.3 Environmental
development does not support activation of the factors, such as nutritional status or adoption, can
hypothalamic-pituitary-gonadal axis, suggesting influence the age of gonadarche via interactions
that many cases of breast development around with this GnRH neuronal network. Genes, such
age 6 to 8 years represent benign thelarche. kisspeptin (KISS1), kisspeptin receptor (KISS1R),
Data are less consistent in boys, although the makorin ring finger 41 protein 3 (MKRN3), and
preponderance of studies also support an earlier delta-like homolog 1 (DLK1), have a key role in

ENDO 2022 • Pediatric Endocrinology  189

GnRH pulse regulation. Pathogenic variants in clear for girls with onset of puberty at age 7 years
these genes are associated with idiopathic CPP. Of or older. A systematic review of 6 controlled
these genes, loss-of-function pathogenic variants studies (2 randomized) of GnRH analogues vs
in MKRN3 have been identified so far as the most no treatment in 332 girls with onset of puberty
frequent monogenic cause of idiopathic CPP.3 older than 7 years found no evidence that GnRH
analogue therapy improves adult height, while
untreated girls reached an adult height similar to
Management
midparental height.1,4
GnRH Analogue Formulations GnRH analogue therapy may lead to a decrease
and Monitoring of Therapy in height velocity. To improve growth rate in
The number of available long-acting GnRH children with CPP and persistently low adult
analogue formulations has increased over the years height prediction, the use of a GnRH analogue
in the United States with the use of the histrelin combined either with low-dosage estrogen or
implant in 2007 and the most recent introduction oxandrolone was examined in a limited number
of leuprolide acetate intramuscular 3-month depot of studies. Although the results were promising,
at doses of 11.25 mg and 30 mg; intramuscular there have not been further studies to support this
triptorelin 6-month depot; and subcutaneous practice.4 Adding GH to GnRH analogue therapy
leuprolide acetate 6-month depot. Clinical to the regimen of patients with CPP was examined
suppression and growth rate appear similar with in several studies. The results show modest
all formulations. Data on adult height and long- improvement in adult height of approximately
term outcomes with the 6-month triprorelin 3 cm in those who received GH, according to a
and 6-month subcutaneous leuprolide are still recent meta-analysis.4
unavailable. Decisions about what formulations
to use are based on family and patient preference Psychosocial Adjustment in CPP and
and cost rather than specific guidelines.1 While the Effect of GnRH Analogue Therapy
prescription of a GnRH analogue is not weight- Previous studies of patients with CPP have
based in the United States, the GnRH analogue described high rates of depression, suicidal
dosages used in different countries, such as thoughts, and behavior problems. These findings
Europe, China, or Japan, are much smaller and in have been inconsistent. More recently, the
the range of 10 to 350 mcg/kg. National Longitudinal Study of Adolescent and
Monitoring during therapy has been shifted Adult Health has linked early age of menarche
to clinical evidence of suppression rather than with higher rates of depression and antisocial
strict hormonal monitoring. During therapy with behavior in adult life.5 These associations may be
longer-acting formulations, values of random LH partially explained by postpubertal stressful life
with ultrasensitive assays are frequently above events, such as increased likelihood of teenage
the established prepubertal range despite clinical pregnancy and childbearing, as well as sexual
evidence of pubertal suppression.1 and physical assault, that perpetuate long-term
vulnerabilities. Whether GnRH analogue therapy
Effect of GnRH Analogue Therapy on Height has any effect on these parameters is unknown.
In older published reports, untreated CPP leads Smaller studies of children treated with GnRH
to a height loss in adults of about 20 cm in men analogues provide inconsistent results about
and 12 cm in women compared with height in rates of psychologic concerns and how they are
the average population.4 Height loss in CPP is influenced by GnRH analogue therapy.
inversely correlated with the age at puberty onset.
GnRH analogue therapy leads to improved adult
height compared with predicted adult height at
the start of therapy. Height outcomes are less

190  ENDO 2022 • Endocrine Case Management

GnRH Analogue Adverse Effects than the 99th percentile since her toddler years
and Long-Term Outcomes and body odor and pubic hair development since
Adverse effects of GnRH analogue therapy are age 5 years. Examination findings are significant
rare and include local reactions, sterile abscess for Tanner 2 breast development with additional
formation after depot injections, hot flushes, adipomastia. Pubic hair is Tanner stage 3. She has
withdrawal bleeding in girls with advanced generalized obesity with acanthosis on the neck
puberty, and sporadic case reports of convulsions. and in the axillae. Her family history is negative
Hypertension with use of triptorelin has rarely for precocity, and review of her growth shows
been reported. Pituitary apoplexy and prolonged stable linear growth at the 75th percentile with no
QT interval in association with GnRH analogue recent acceleration.
therapy have been reported in men with prostate
cancer but not in pediatric patients. Screening Laboratory test results:
electrocardiography is recommended in children Baseline ultrasensitive LH =
with cardiac disease or those who are treated with 0.1 mIU/mL (0.02-0.30 mIU/mL)
medications that increase the QT interval. (SI: 0.1 IU/L [0.02-0.30 IU/L])
FSH = 2.3 mIU/mL (0.26-3.0 mIU/mL)
Long-term outcome data focus primarily on
(SI: 2.3 IU/L [0.26-3.0 IU/L])
girls, while data in boys are limited. Although 17-Hydroxyprogesterone (8 AM) = 75 ng/dL
children with CPP have increased body weight (0-90 ng/dL) (SI: 2.27 nmol/L [0-2.72 nmol/L])
compared with their peers at diagnosis, GnRH DHEA-S = 85 µg/dL (16-96 µg/dL) (SI: 2.3 µmol/L
analogue therapy does not appear to lead to obesity [0.43-2.60 µmol/L])
in adulthood. In a study by Lazar et al, women Her bone age is 8 years and 10 months. Adult height
with a history of CPP (treated or untreated) had prediction is 61 in (155 cm) according to Bailey-
the same BMI and cardiovascular risk as matched Pinneau (average maturation table) compared with
healthy control participants. In this cohort, midparental height of 63 in (160 cm).
education, marital status, and pregnancy rates
were the same as those of control participants and Which of the following is the best next
not affected by GnRH analogue therapy. Data are step in this patient’s management?
conflicting about the development polycystic ovary
A. Observation
syndrome in women with a history of CPP, while
a small number of studies indicate that GnRH B. Order pelvic ultrasonography
analogue therapy does not increase the risk for C. Perform a GnRH-stimulation test
polycystic ovary syndrome. Changes in bone mass D. Both B and C
with GnRH analogue therapy are addressed in a
few studies that do not provide long-term follow Answer: A) Observation
up. Results indicate a decrease in bone mineral The girl in this vignette has Tanner stage 2 breast
density during GnRH analogue therapy and a development and a random LH measurement by
resumption of bone accrual after GnRH analogue ultrasensitive assay in the prepubertal range. Her
discontinuation. Bone mineral density has been bone age is advanced, but the advancement may
reported in the normal range in late adolescence. be related to obesity. A LH random measurement
may miss the diagnosis of CPP in approximately
Clinical Case Vignettes 25% of children, and a GnRH-stimulation test
(Answer C) should be performed if CPP is
Case 1 clinically suspected and the provider wants to
A 7-and-3/12-year-old girl presents with a consider GnRH analogue therapy.1 However,
6-month history of breast development. She has the onset of thelarche in girls with obesity is
a history of rapid weight gain with a BMI greater increasingly common above age of 7 years in many

ENDO 2022 • Pediatric Endocrinology  191

instances, and pubertal progression in such girls Case 1 (continued)
tends to be slow and adult height is not affected.1,2
The child is treated with a histrelin implant.
It has been suggested, therefore, to observe these
She returns a year after implant at age 9 years.
girls (Answer A) for 4 to 6 months to assess the
There is no progression in breast development
tempo of puberty before starting GnRH analogue
(Tanner stage 2) and minimal advancement in
therapy.1,2 Findings from pelvic ultrasonography
pubic hair growth. Her growth rate is stable, as it
(Answer B) are not a diagnostic criterion for CPP.
was pretreatment. BMI percentiles remain in the
same range and greater than the 99th. Repeated
Case 1 (continued) bone age is interpreted as having advanced
The child returns 6 months later at age 7 and from 10 years to between 10 and 11 years
9/12 years. Her mother reports some increase in over the course of the past year. A random
both breast and pubic hair development. Review LH measurement (by ultrasensitive assay) is
of systems is otherwise unremarkable. Her growth 0.6 mIU/mL 10 months after implantation.
chart indicates an increase in growth rate, while
her BMI percentile is unchanged at greater Which of the following is the best next
than the 99th. Her repeated LH measurement is step in this patient’s management?
0.4 mIU/mL and repeated bone age is interpreted A. Order pelvic ultrasonography
to be 10 years. The family is interested in GnRH B. Perform a GnRH-stimulation test
analogue treatment. C. Provide reassurance about the
treatment course
How would you counsel the family about
D. Replace the histrelin implant
GnRH analogue therapy for this girl?
A. GnRH analogue therapy is unlikely to improve Answer: C) Provide reassurance
adult height about the treatment course
B. GnRH analogue therapy is likely to worsen Random ultrasensitive LH values above the
adult BMI established prepubertal range have been described
C. MRI of the brain should be performed before with histrelin despite clinical suppression of
therapy initiation puberty. No additional workup such as pelvic
D. Both A and C ultrasonography (Answer A) or a GnRH-
stimulation test (Answer B) is suggested
Answer: A) GnRH analogue therapy is unless there is clinical evidence that puberty is
unlikely to improve adult height not suppressed.1 Thus, the patient should be
There is no clear evidence that GnRH analogue reassured about the treatment course (Answer
therapy improves final height in girls with CPP C). Current evidence indicates that histrelin
who are older than 7 years (Answer A).1,4 Long- can effectively suppress puberty for longer than
term outcomes in women with a history of 12 months; thus, replacement (Answer D) is not
CPP show similar BMI and cardiovascular risk necessary now.
factors regardless of GnRH analogue therapy
(thus, Answer B is incorrect).1 The risk of CNS Case 1 (continued)
pathology in girls aged 6 to 8 years appears small,
The family has questions about length of GnRH
and MRI of the brain has been suggested in this
analogue therapy and resumption of puberty.
age group if they have relevant symptoms. The
girl in this vignette has no headaches or other
symptoms suggestive of a CNS process, thus MRI
of the brain (Answer C) is incorrect.1

192  ENDO 2022 • Endocrine Case Management

What should this family be told What should this family be told
about GnRH analogue therapy? about depression and psychosocial
A. Age of menarche after stopping GnRH distress in this patient group?
analogue therapy is variable A. Girls with early menarche are at greater risk
B. The decision to discontinue GnRH analogues for depression as adolescents and adults
should consider the psychological readiness of B. GnRH analogue therapy significantly
the child ameliorates psychosocial distress
C. Treatment beyond the bone age of 12.5 years is C. Neither A nor B
unlikely to significantly improve adult height D. Both A and B
D. All the above
Answer: A) Girls with early menarche are at greater
Answer: D) All the above risk for depression as adolescents and adults
There are no clear guidelines for therapy According to a large recent epidemiological study,
discontinuation.1 The decision is individualized earlier age at menarche is associated with higher
based on the child’s readiness to progress in rates of depressive symptoms in adolescence and
puberty and growth assessment (Answer B). In adulthood (Answer A).6 Whether GnRH analogue
terms of growth, it appears that height gains therapy ameliorates these symptoms (Answer B)
decrease beyond the bone age of 12.5 years in is unclear.1
girls and 14 in boys (Answer C),1,4 although more
recent data support further therapy in select Case 2 (continued)
patients. Resumption of menses after stopping
GnRH analogue therapy varies from several The patient’s mother requests evaluation of the
months to more than 2 years (Answer A).1 younger sister. She is 6 and 6/12 years old and has
had recent onset of breast development.
On physical examination, breast development
Case 2 is Tanner stage 2. A random ultrasensitive LH
An 8-and-10/12-year-old girl experienced measurement is 1.2 mIU/mL and bone age is
menarche 4 months ago. Breast development was interpreted to be 8 years.
first appreciated at age 7-and-6/12 years. She is Genetic analysis is considered.
otherwise healthy and is doing well in school.
Menses have been regular. Which of the following is true about
On physical examination, her height is 57 in genetic analysis in this patient’s case?
(145 cm), and BMI is at the 75th percentile, Breast A. Genetic analysis is likely to yield
and pubic hair are Tanner stage 4. Her bone age negative results
is interpreted to be 13.5 years. Her midparental B. Genetic analysis is likely to reveal an activating
height is 64 in (163 cm). Her mother reports pathogenic variant in MKRN3
initial difficulties handling menses, but “things are
C. Genetic analysis is likely to reveal an activating
getting better.”
pathogenic variant in KISS1
D. Kisspeptin and MKRN3 levels can serve as
biomarkers for genetic causes of CPP
Answer: A) Genetic analysis is likely
to yield negative results
The overall estimated prevalence of MKRN3
variants in persons with CPP is 9.0%. The

ENDO 2022 • Pediatric Endocrinology  193

prevalence of pathogenic variants in familial cases Activating pathogenic variants in the KISS1
of CPP is variable among different studies, but gene have been identified in persons with CPP,
according to a recent meta-analysis, the estimated but they are rare (thus, Answer C is incorrect).6
pooled prevalence is 19.0% (95% CI, 0.05-0.36).5 Serum concentrations of kisspeptin increase
Thus, genetic analysis is unlikely to reveal an with puberty, while MKRN3 concentrations
etiology (Answer A). decrease. Serum concentrations of kisspeptin and
MKRN3 has an inhibitory role in pubertal MKRN3 are being considered as biomarkers of
onset, and loss-of-function pathogenic variants puberty. However, neither serves as a biomarker
(not activating variants [Answer B]) in the for genetic causes of CPP (thus, Answer D
MKRN3 gene are the most frequent monogenic is incorrect).
cause of CPP.6

References
1. Bangalore Krishna K, Fuqua JS, Rogol AD, et al. Use of gonadotropin- 4. Wit JM. Should skeletal maturation be manipulated for extra height gain?
releasing hormone analogs in children: update by an international Front Endocrinol (Lausanne). 2021;12:812196. PMID: 34975773
consortium. Horm Res Paediatr. 2019;91(6):357-372. PMID: 31319416 5. Valadares LP, Meireles CG, De Toledo IP, et al. MKRN3 mutations in central
2. Tenedero CB, Oei K, Palmert MR. An approach to the evaluation precocious puberty: a systematic review and meta-analysis. J Endocr Soc.
and management of the obese child with early puberty. J Endocr Soc. 2019;3(5):979-995. PMID: 31041429
2021;6(1):bvab173. PMID: 34909516 6. Mendle J, Ryan RM, McKone KMP. Early menarche and internalizing and
3. Schneider Aguirre R, Eugster EA. Central precocious puberty: from genetics externalizing in adulthood: explaining the persistence of effects. J Adolesc
to treatment. Best Pract Res Clin Endocrinol Metab. 2018;32(4):343-354. PMID: Health. 2019;65(5):599-606. PMID: 31500947
30086862

194  ENDO 2022 • Endocrine Case Management

Dilemmas in Diabetes
Mellitus in Youth
Philip S. Zeitler, MD, PhD. Department of Pediatrics, Section of Endocrinology, University of
Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO; E-mail: Philip.Zeitler@
childrenscolorado.org

Learning Objectives on their ethnic heritage and/or family history.

Furthermore, the prevalence of obesity in the
As a result of participating in this session, learners
entire western population is rising, but this does
should be able to:
not protect against T1DM. In the United States,
• Describe the challenges related to evaluation approximately 30% of youth with T1DM diabetes
and management of prediabetes in youth. have obesity. Because of this overlap, clinical
features are insufficient for determination of
• Guide the evaluation and management of
diabetes type, and the clinician is often faced with
adolescents with obesity who have new-onset
a patient with T1DM who also has features of
diabetes mellitus.
insulin resistance (eg, dyslipidemia, hypertension,
fatty liver, polycystic ovary syndrome, etc). This
requires changes to the historical management
of T1DM. Taken together, the changing nature
Main Conclusions of pediatric diabetes necessitates informed
The pediatric diabetologist is faced with physiology-based approaches to evaluation and
limitations in the evaluation and management of management, including familiarity with changing
diabetes in adolescents, including unique features guidelines for management of glycemic and
of pathophysiology, the effect of childhood obesity nonglycemic outcomes.
and puberty, the substantial clinical overlap
between type 1 and type 2 diabetes mellitus
(T1DM and T2DM), and limited information
on the earliest periods of disease. Emerging
Significance of the
information suggests that mild glycemic elevations Clinical Problem
are normal during puberty and that there is very The incidence and prevalence of diabetes in
substantial reversion to normoglycemia in youth. youth, both T1DM and T2DM, are increasing in
Thus, the current criteria used for identification the United States and in many other regions of
of youth with “prediabetes” are suspect. These the globe.1 At the same time, the prevalence of
realities have made it difficult to design studies obesity is increasing in the general population,
of optimal treatment of “prediabetes” in youth and this is mirrored in the rate of obesity among
and for pediatric clinicians to be confident youth with diabetes. This makes the distinction
in managing mild dysglycemia. Although the between T1DM and T2DM more complex than
incidence of T2DM diabetes has increased in the past. Furthermore, the distinction of
dramatically in youth over the last 3 decades, diabetes type in children is even more challenging
T1DM diabetes remains as, or more, common than in adults with new-onset diabetes. While
than T2DM, even among high-risk youth based the pathophysiology of T1DM has been well

ENDO 2022 • Pediatric Endocrinology  195

described and includes a steady loss of β-cell Barriers to Optimal Practice
function until the typical metabolic decompensation
that characterizes onset of clinical disease, the • There is no well-established, physiologically
course of youth-onset T2DM is only beginning to valid definition of prediabetes in youth, and
be understood. Studies indicate that youth-onset most youth found to have prediabetes by
T2DM has several unique aspects. For example, current definitions (based on adult American
there is an important association of T2DM with Diabetes Association criteria) will revert to
pubertal development, most likely related to the normoglycemia without intervention. This
transient reduction in insulin sensitivity that occurs creates challenges for both study design in
in children as they enter puberty2 and the need this population, as well as selection of optimal
for compensation in insulin secretion, which may treatment approaches.
lead to hyperglycemia in youth with limited β-cell
• Lifestyle change, the backbone of obesity
capacity. Furthermore, dysglycemia occurring
treatment and mitigating risk for diabetes,
during puberty, including both “prediabetes”
is difficult to achieve in youth with obesity,
and clinically overt diabetes, may be reversible
who often come from challenged backgrounds
in some youth due to the dynamic nature of the
and family environments. There is currently
underlying insulin resistance. Yet, it is critical to
limited evidence to support pharmacologic
understand that while decline in β-cell function
approaches for youth at risk for diabetes.
also occurs in adults with T2DM, when there is
progressive β-cell failure leading to overt diabetes in • Despite rising incidence of T2DM, T1DM
youth, it is more rapid, resulting in more frequent remains prevalent, even among high-risk
presentation with metabolic decompensation and youth. Furthermore, rising rates of obesity
greater challenges in achieving and maintaining and minority representation in the general
glycemic targets after initiation of therapy.3-8 population are mirrored in the pediatric
Finally, there is evidence of microvascular T1DM population, such that presenting
complications and risk markers for macrovascular clinical features are not reliable for
complications at the time of diagnosis, along with determination of diabetes type.
rapid progression of complications in youth with • The rising rates of obesity in individuals with
T2DM.9-11 Importantly, many of the microvascular T1DM, as well as the increased percentage of
and macrovascular complications seen in youth- individuals with T1DM who come from ethnic
onset T2DM are associated with visceral adiposity and cultural backgrounds at increased risk for
and insulin resistance, suggesting similar risk in obesity-related cardiovascular disease, mean
individuals with T1DM complicated by obesity that the pediatric diabetologist is increasingly
and obesity-related comorbidities.12 called on to manage cardiovascular risk factors,
Taken together, the changing epidemiology of which have not historically been a focus of
diabetes in youth, the unique features of T2DM in T1DM care.
youth, and the increasing prevalence of obesity in
the population create challenges for the clinician
evaluating and managing adolescents with Strategies for Diagnosis,
obesity and evidence of dysglycemia, metabolic
Therapy, and/or Management
dysfunction, and/or new-onset diabetes. This
evolution requires reconsideration of historical With the rise of childhood obesity and youth-
approaches to managing and monitoring of onset T2DM, greater attention has been paid to
youth with diabetes and a deeper familiarity with the trajectory of disease development, whereas
approaches to mitigate cardiorenal risk. historically the focus has been dominated by
T1DM. Pediatric clinician knowledge of the

196  ENDO 2022 • Endocrine Case Management

concept and treatment of prediabetes in adults evolving diabetes based on previously published
has resulted in interest in identifying prediabetes epidemiologic data showing a much lower
in youth and potentially initiating treatment to prevalence of diabetes in this group of normal-
prevent disease progression. Yet, the meaning weight youth.19,20 In adults, hemoglobin A1c values
of glycemic measures in youth are not fully in the prediabetes range have been shown to
understood, as all youth experience metabolic correlate with impaired glucose tolerance (IGT)
changes during puberty, including transient insulin and impaired fasting glucose (IFG) by OGTT.21 No
resistance, and little is known about the effect of similar study has been performed to date in youth.
these metabolic changes on the distribution of OGTT is often considered the gold standard
glycemia. However, despite this lack of knowledge, test for diagnosing diabetes. While there is
the American Diabetes Association adult criteria evidence that adults with a 2-hour glucose
for the diagnosis of diabetes and prediabetes value in the prediabetes range are at high risk
have been extrapolated to youth. In 2010, the for progression to diabetes,15 the evidence for
American Diabetes Association added criteria for this association in youth is lacking. In fact, in a
use of hemoglobin A1c for screening and diagnosis study of 117 adolescents with obesity, 45.5% of
of diabetes (ie, >6.5% [>48 mmol/mol]) and 33 youth with IGT reverted to normal glucose
prediabetes (ie, >5.7%-6.4% [39-46 mmol/mol]).13 tolerance after a mean of 20.4 months of follow-
Indeed, hemoglobin A1c measurement has some up.22 The substantial variability in OGTT seen
advantages over the traditional diagnostic tests over time may be, in part, related to variability
(fasting or 2-hour glucose), including no need for in the physiologic changes in glucose metabolism
fasting and less influence of acute circumstances of occurring during the well-described transient
the testing day. The decision to add hemoglobin insulin resistance of puberty.23,24 This transient
A1c to the criteria was based on improvements insulin resistance of puberty may also alter glucose
in assay standardization, correlation with metabolism in normal-weight youth and lead to
2-hour glucose values, and population studies transient increases in glycemia, similar to changes
demonstrating increased prevalence of retinopathy seen with lipids during puberty.25-27 Therefore,
in adults at high risk for T2DM.14,15 In adults, a there is not a full understanding of whether
prediabetes hemoglobin A1c value has been shown elevations into the adult prediabetes range with
to predict progression to diabetes, as well as risk any measure of glycemia are meaningful in youth.
for retinopathy. However, studies validating While the mean hemoglobin A1c value was
the use of a prediabetes hemoglobin A1c value slightly higher in youth who were overweight
to predict risk for progression to diabetes or or obese, the distribution of hemoglobin A1c in
diabetes complications in youth are lacking. We the overweight/obese cohort was very similar
and others have shown correlation of hemoglobin to the distribution in the normal-weight cohort.
A1c with other measures of glycemia (eg, oral Thus, a proportion of youth with obesity have a
glucose tolerance testing [OGTT] and continuous hemoglobin A1c value in the adult “prediabetes”
glucose monitoring) in the context of screening range, but these same hemoglobin A1c values are
for T2DM in youth with obesity.16,17 In the absence within the distribution for normal-weight youth,
of a full understanding of physiologic changes in raising questions about how meaningful the adult-
glycemia during puberty, the meaning of any of based cutoffs are for defining prediabetes in youth.
these measures of glycemia remains unclear. In In fact, analysis of the HEALTHY cohort reported
a large cohort of racially and ethnically diverse that of those with a prediabetes hemoglobin
midpubertal youth, 1 of 50 healthy-weight A1c level at baseline (6th grade, n = 128), only 1
youth had a hemoglobin A1c measurement in the progressed to diabetes, while 53% had a normal
“prediabetes” range.18 These elevated hemoglobin hemoglobin A1c value, and the rest continued to
A1c values are highly unlikely to represent have a hemoglobin A1c value in the prediabetes

ENDO 2022 • Pediatric Endocrinology  197

range at follow-up (8th grade).28 While large, determining diabetes type. There are features of
prospective, longitudinal cohort studies exploring presentation and phenotype that may be useful in
whether hemoglobin A1c, or any other measure of developing a presumption of T1DM or T2DM,
glycemia, can predict progression to diabetes in although there is substantial overlap between
youth have not been done, a large retrospective characteristics of T2DM and T1DM in adolescents
study of more than 11,000 youth with obesity with obesity, making these features of limited
has reported that progression to diabetes among value. The degree of pubertal development
youth with a hemoglobin A1c value less than 6.0% may be the most useful, although in a negative
(<42 mmol/mol) occurs in less than 6% and even fashion: youth with T2DM are almost always
for those with a hemoglobin A1c value between in puberty, with a mean age of diagnosis of 13
6.0% and 6.5% (42 and 48 mmol/mol), progression to 14 years and Tanner stage 4 to 5. They are
is only around 18%.29 Therefore, clinicians caring rarely prepubertal.32,33 Most importantly, diabetes
for youth with obesity and dysglycemia should be autoantibody testing should be done in all youth
cautious when undertaking interventions beyond with the clinical diagnosis of T2DM because of
lifestyle change until efficacy has been directly the high frequency of islet-cell autoimmunity in
demonstrated in the pediatric population. patients with otherwise ‘‘typical’’ T2DM34; the
When a child or adolescent with obesity presence of antibodies predicts rapid development
presents with apparent diabetes-range of insulin requirement, as well as risk for
hyperglycemia, definitive diagnosis and typing of development of other autoimmune disorders.
diabetes requires 2 steps: (1) confirmation of the Diabetes autoantibody testing also should also be
presence of diabetes followed by (2) determination considered in overweight/obese pubertal children
of diabetes type. This is rarely a problem in with a clinical picture of T1DM (weight loss,
T1DM because of the characteristic symptomatic ketosis/ketoacidosis), some of whom may have
presentation with metabolic decompensation, T2DM and be able to be weaned off insulin for
but on occasion, youth are identified with mild to extended periods.35,36 Finally, monogenic forms
moderate dysglycemia without the other hallmark of diabetes, such as maturity-onset diabetes of
features of T1DM, and the confirmation of the young should be considered in individuals
diabetes may need to be considered more carefully. who have a presentation and course that are not
The criteria and classification of diabetes are characteristic of either T1DM or T2DM.
provided in the American Diabetes Association Initial treatment of the adolescent with
annual guidelines and the International Society obesity and diabetes must consider that diabetes
for Pediatric and Adolescent Diabetes clinical type is often not certain in the first few weeks of
practice consensus guidelines.30,31 While the treatment, that 10% to 15% of adolescents with
American Diabetes Association has added new-onset diabetes and obesity have T1DM,
hemoglobin A1c as a diagnostic criterion based and that a substantial percentage of adolescents
on prediction of retinopathy risk, this assumes with T2DM present with clinically significant
use of a laboratory-measured, DCCT-aligned ketoacidosis.37,38 Therefore, initial treatment
assay—not point-of-care testing. In the absence should be based on the clinical presentation, while
of symptoms, hyperglycemia detected incidentally maintaining an open mind regarding both the
or under conditions of acute physiologic stress diabetes type and eventual therapy.
may be transitory and should not be regarded as Adolescents presenting with acidosis require
diagnostic of diabetes. Therefore, in the absence of initiation of intravenous insulin, no matter
unambiguous chronic symptoms of hyperglycemia, the diabetes type. However, once acidosis is
a second test on a different day is required. resolved, subsequent therapy depends on the
After the diagnosis of diabetes is established, provisional clinical diagnosis. In those patients
careful consideration should be given to for whom the provisional diagnosis is T1DM, the

198  ENDO 2022 • Endocrine Case Management

diabetes care team should proceed with the usual adolescents with diabetes and obesity remains
education and insulin therapy. In those patients unclear and poorly studied. Although the GLP-1
for whom the clinical impression is T2DM or receptor agonist liraglutide has been approved
antibodies have been shown to be negative, for use in adolescents with T2DM, weight loss
basal insulin at a dose of 0.2 to 0.4 units/kg once in the pivotal study was not as impressive as
daily is started and titrated based on fingerstick seen in adults. While potentially more effective
glucose measurements. Insulin is administered GLP-1 receptor agonists such as dulaglutide and
at whatever time of day is the most likely to semaglutide are being actively studied in youth,
promote good engagement with therapy. At no data are yet available. Similarly, although
the same time, metformin is initiated at 500 mg SGLT-2 inhibitors have been shown to improve
once daily and is titrated weekly to a maximally hyperglycemia, as well as lead to substantial weight
tolerated dosage, with a target of 2000 mg daily. loss (and reduction in cardiorenal risk) in adults,
Insulin can generally be discontinued within a data are not yet available in youth. Similarly,
few weeks once antibody negativity has been the role for antihyperglycemia agents, such as
confirmed. Asymptomatic patients with an metformin, GLP-1 receptor agonists, and SGLT-2
initial hemoglobin A1c value greater than 9.0% inhibitors, as adjunct agents in youth with obesity
or 10.0% (75 or 86 mmol/mol) may also require and T1DM is intriguing, as they offer potential
initiation of once-daily basal insulin therapy to reduction in weight, insulin resistance, and
allow sufficient recovery of β-cell function for cardiorenal risk, but studies are only now being
successful monotherapy with oral medication. undertaken, and use of these agents is optimally
However, results from the TODAY study suggest done in the setting of a research study.
that initiation of metformin and basic dietary There are currently distinctions between
intervention results in a hemoglobin A1c value in recommendations for monitoring comorbidities
the nondiabetic range, with or without insulin.35,36 and complications in youth with T1DM and
Asymptomatic adolescents with obesity who T2DM, with earlier and more aggressive
present with less decompensation can be started monitoring in T2DM because of the evidence
on metformin alone, with a high likelihood of for earlier and more rapid onset of microvascular
initial success. and macrovascular abnormalities.39 However,
Lifestyle change is critical to treatment the presence of insulin resistance in youth with
of obesity, whether the patient has T1DM or T1DM and obesity and the association of kidney,
T2DM, and clinicians should initiate a lifestyle retinal, nerve, vascular, and heart disease with
modification program, including nutrition and insulin resistance, as well as glycemia, suggest that
physical activity, for children and adolescents it may be appropriate to undertake an approach
at the time of T2DM diagnosis.38 Interventions to monitoring in these individuals that is more
include promoting a healthy lifestyle through like the recommendations for T2DM. Studies
behavior change, including nutrition, exercise addressing this question are needed but may
training, weight management, and cigarette be difficult to undertake because of the need to
smoking cessation. However, the challenges in prevent acute and chronic negative outcomes in
implementing lifestyle modifications in adolescents individual patients.
are greater than in adults because adolescents
with obesity typically come from families where
overeating and sedentary lifestyle are the norm.
Clinical Case Vignettes
Thus, many adolescents with T2DM do not Case 1
maintain the recommended lifestyle changes and A 10-year-old African American girl sees a new
remain overweight with suboptimal diabetes primary care provider who notes that she has had
control. The role of weight-loss medications for longstanding elevation in BMI (>98th percentile)

ENDO 2022 • Pediatric Endocrinology  199

and has moderate acanthosis nigricans on warranted given her longstanding obesity and
examination. She has Tanner stage 3 breast family history of diabetes risk.
and pubic hair development and has not had
menarche. Family history is notable for T2DM in Case 2
her mother, who had diabetes during pregnancy,
as well as in her maternal grandmother. A point- A 16-year-old Latina girl was diagnosed with
of-care hemoglobin A1c measurement is 5.9% diabetes 3 years ago by her primary care physician.
(41 mmol/mol). The primary care provider tells At that time, diabetes type was determined based
the family that the patient has prediabetes and on presentation and family history of T2DM. She
refers her to the diabetes center. was started on metformin, 2000 mg daily, but she
reports that she took this for only a few months.
Which of the following is the most important Since that time, she has been off all medications
next step in this patient’s management? and reports no symptoms of diabetes, including no
A. Measure liver transaminases polyuria, polydipsia, or weight loss. One month
ago, she was admitted to the hospital following
B. Order lipid panel
a suicide attempt. During that admission, she
C. Refer for multidisciplinary lifestyle was noted to have a glucose value of 550 ng/dL
intervention (30.5 mmol/L) and glucosuria, with small ketones
D. Repeat the hemoglobin A1c measurement to and normal pH. Her hemoglobin A1c value was
confirm prediabetes 12.5% (113 mmol/mol). She was treated by the
E. Start metformin, 500 mg daily inpatient team with subcutaneous basal-bolus
insulin and restarted on metformin. She is referred
Answer: C) Refer for multidisciplinary to the diabetes center for further evaluation. At
lifestyle intervention that visit, her BMI is 28 kg/m2 and blood pressure
Although the patient has a mildly elevated is 125/72 mm Hg.
hemoglobin A1c value in the adult prediabetes
Given the length of time since her
range on point-of-care hemoglobin A1c testing,
initial diagnosis, obtaining which of the
the implication of a hemoglobin A1c value in this
following is the most important next
range in youth is unclear. Evidence suggests that
step in this patient’s evaluation?
such elevations are likely to be nonprogressive and
often transient. Therefore, there is no compelling A. Fasting and stimulated C-peptide
argument supporting initiation of pharmacologic measurements
therapy (Answer E) in adolescents with mild B. Fasting lipid panel
degrees of glycemia. Since there is little value in C. Home glucose measurements
diagnosing “prediabetes” in youth, there is no D. Liver transaminase measurements
value in repeating the test (Answer D).
E. Pancreatic autoantibody assessment
Although abnormal lipids (Answer B)
and elevated liver transaminases (Answer A) Answer: E) Pancreatic autoantibody assessment
suggesting fatty liver are often seen in youth with
obesity, the patient is African American, making Even though this patient has had diabetes for
fatty liver and elevated triglycerides (the only lipid 3 years without severe metabolic decompensation
abnormality that may be of clinical relevance at off treatment, there is no clinical characteristic
this age) less likely. with 100% sensitivity in excluding T1DM.
Referral of this patient to a structured Since T1DM remains more common than
multidisciplinary program (Answer C) is T2DM at all ages and in most ethnicities, the
a priori risk for T1DM is higher than T2DM,

200  ENDO 2022 • Endocrine Case Management

despite “typical” characteristics. Furthermore, features suggesting T2DM, and she was referred
even among those racial/ethnic groups where to the diabetes center. She was previously healthy
T2DM is more common in adolescents (African and took no medications. Findings on review of
American, American Indian), T1DM still systems are normal.
occurs. Furthermore, a substantial percentage On physical examination, her BMI is
of adolescents with T1DM in the United States 35 kg/m2 and blood pressure is 145/82 mm Hg.
have obesity and obesity does not protect from Her hemoglobin A1c measurement is 7.8%
autoimmunity. Therefore, even in this setting, (62 mmol/mol).
the most important step in the evaluation of an
adolescent with diabetes is rigorous determination Laboratory test results:
of diabetes type (Answer E). The presence of Glutamic acid decarboxylase antibodies, positive
positive antibodies, no matter the phenotype, is Islet antigen 2 antibodies, positive
associated with more rapid progression to insulin Zinc transporter 8 antibodies, positive
ALT = 87 U/L (10-40 U/L) (SI: 1.45 µkat/L
requirement, and patients with positive antibodies [0.17-0.67 µkat/L])
should be treated with insulin irrespective of how LDL cholesterol = 160 mg/dL (SI: 4.14 mmol/L)
they are doing on oral therapy. HDL cholesterol = 24 mg/dL (SI: 0.62 mmol/L)
Measurement of fasting C-peptide (Answer A) Triglycerides = 545 mg/dL (SI: 6.16 mmol/L)
may be helpful in determining degree of insulin Urine albumin-to-creatinine ratio = 45 mg/g creat
(<30 mg/g creat)
resistance, and stimulated C-peptide may be a
reasonable measure of insulin secretory capacity,
potentially contributing to the distinction of Multiple daily insulin injections are started. At a
T2DM from T1DM. However, this is only true follow-up visit 6 months later, her blood pressure
in the setting of stable metabolic status. During is 148/84 mm Hg, and the following laboratory
acute decompensation, insulin and C-peptide test results are documented:
secretion are transiently decreased. Measurement Hemoglobin A1c = 7.1% (54 mmol/mol)
of C-peptide may be more useful in asymptomatic ALT = 55 U/L (SI: 0.92 µkat/L)
patients, in patients who have recovered from LDL cholesterol = 145 mg/dL (SI: 3.76 mmol/L)
decompensation, or in patients with presumed HDL cholesterol = 28 mg/dL (SI: 0.73 mmol/L)
Triglycerides = 254 mg/dL (SI: 2.87 mmol/L)
T2DM who have a persistent insulin requirement.
Urine albumin-to-creatinine = 22 mg/g creat
The remaining options would be important
to obtain at diagnosis in individuals with obesity
and diabetes, regardless of diabetes type but would Which of the following is the best next
be unlikely to make an immediate difference step in this patient’s management?
in therapeutic decisions. However, the specific A. Start atorvastatin, 10 mg daily
screening done would depend on whether the B. Start canagliflozin, 100 mg daily
individual has positive antibodies (TSH, celiac
C. Start fenofibrate, 67 mg daily
antibodies, lipids [Answer B]) or negative
antibodies (lipids, AST/ALT [Answer D], urine D. Start lisinopril, 10 mg daily
albumin, creatinine clearance). E. Start vitamin E, 600 IU daily
Answer: D) Start lisinopril, 10 mg daily
Case 3
Although guidelines suggest that treatment of
A 15-year-old Latina girl has been recently
both hypertension and elevated LDL cholesterol
diagnosed with diabetes after presenting with mild
is indicated, evidence for clinical benefit of
diabetic ketoacidosis. Metformin was initiated
treating elevated blood pressure in adolescence is
by her primary care provider based on clinical
stronger. While an argument could be made for

ENDO 2022 • Pediatric Endocrinology  201

starting atorvastatin (Answer A), the increased orthostatic proteinuria is common in adolescents.
risk in a reproductive-aged female patient relative ACE inhibitors are the agents of choice due to
to the risk of lisinopril would favor addressing proven kidney protection, even if blood pressure
hypertension first (thus, Answer D is correct). is normal. Albumin excretion should be repeated
Obesity in individuals of Latino heritage at 3- to 6-month intervals, and therapy should be
is often associated with insulin resistance titrated to achieve a normal albumin-to-creatinine
abnormalities, including lipid abnormalities, ratio. Non–diabetes-related causes of kidney
endothelial and cardiac dysfunction, increased disease should be excluded, and consultation
procoagulant and inflammatory markers, should be considered if an albumin-to-creatinine
increased hepatic and muscle lipid deposition, ratio greater than 300 mg/g is present. In adults,
mitochondrial dysfunction, increased plasma the use of SGLT-2 inhibitors (Answer B) has been
uric acid, ovarian hyperandrogenism, and sleep shown to reduce progression of kidney disease and
disorders, all of which increase cardiovascular risk. may become standard in prevention of diabetic
Given the increased prevalence of comorbidities kidney disease for all ages over time, but it is not
in individuals with obesity and T1DM at the time yet approved for this use in youth with T1DM.
of diagnosis, evaluation should occur either at the Testing for dyslipidemia should be performed
time of initial diagnosis or upon reestablishment soon after diagnosis when blood glucose control
of metabolic stability. has been achieved and annually thereafter. Lipid
Blood pressure should be measured at every goals are as follows:
clinic visit and normalized for sex, height, and
LDL cholesterol = <100 mg/dL (SI: <2.59 mmol/L)
age. Initial treatment of blood pressure above the Triglycerides = <150 mg/dL (SI: <1.70 mmol/L)
95th percentile consists of weight loss, limitation HDL cholesterol = >40 mg/dL (SI: >1.04 mmol/L)
of dietary salt, and increased physical activity.
After 6 months, if blood pressure is still above If LDL cholesterol is above goal, blood
the 95th percentile, an ACE inhibitor is started to glucose control should be maximized and
achieve blood pressure values that are less than dietary counseling should be provided (dietary
the 90th percentile. If the ACE inhibitor is not cholesterol <200 mg daily, saturated fat <7% of
tolerated due to adverse effects (mainly cough), total calories, and fat <30% of total calories). If
an angiotensin receptor blocker may be use. LDL cholesterol remains higher than 130 mg/dL
Combination therapy may be required if blood (>3.37 mmol/L) after 6 months, statin therapy
pressure does not normalize on single-agent should be started with a target of less than
therapy. Workup of hypertension not responsive 100 mg/dL (<2.59 mmol/L). The use of statins
to initial medication should also include kidney in sexually active adolescent girls must be
ultrasonography and echocardiography. carefully considered and the risks explicitly
Urinary albumin excretion should be assessed discussed. Elevated triglycerides are not treated
at diagnosis and annually. Moderately increased for cardiovascular disease prevention. However,
albumin excretion is defined as an albumin-to- if fasting triglycerides are greater than 500 mg/dL
creatinine ratio of 30 to 299 mg/g creat in a spot (>5.65 mmol/L), a fibric acid (Answer C) should
urine sample and severely increased albumin be considered due to significantly increased risk
excretion defined as greater than 300 mg/g. for acute pancreatitis, with a treatment goal of less
Because an elevated value can be secondary to than 150 mg/dL (<1.70 mmol/L).
exercise, cigarette smoking, menstruation, and Hepatic steatosis is present in 25% to 50%
orthostasis, the diagnosis of persistent abnormal of adolescents with obesity, particularly in
albumin excretion requires documentation of 2 individuals of Latino or Asian heritage, and
of 3 consecutive abnormal values obtained on more advanced forms of fatty liver disease
different days, preferably on rising, as benign are increasingly common and associated with

202  ENDO 2022 • Endocrine Case Management

progression to cirrhosis, portal hypertension, and However, due to the potential for progression to
liver failure. Fatty liver is now the most frequent steatohepatitis, fibrosis, and cirrhosis, ongoing
cause of chronic liver disorders among youth with monitoring of liver enzymes is recommended,
obesity and is the most common reason for liver with referral for biopsy if enzymes remain
transplant in adults in the United States. Although markedly elevated.
pharmacologic treatment with metformin and In addition, the clinician should explore
vitamin E (Answer E) has been studied, this the possibility of polycystic ovary syndrome,
has not been proven beneficial in adolescents depression, eating disorders, and sleep disturbance
with fatty liver. Therapies that improve and address these as appropriate.
insulin resistance appear to improve fatty liver.

References
1. Dabelea D, Mayer-Davis EJ, Saydah S, et al. Prevalence of type 1 and type 15. International Expert Committee. International Expert Committee report
2 diabetes among children and adolescents from 2001 to 2009. JAMA. on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care.
2014;311(17):1778-1786. PMID: 24794371 2009;32(7):1327-1334. PMID: 19502545
2. Hannon TS, Janosky J, Arslanian SA. Longitudinal study of physiologic 16. Nowicka P, Santoro N, Liu H, et al. Utility of hemoglobin A(1c) for
insulin resistance and metabolic changes of puberty. Pediatr Res. diagnosing prediabetes and diabetes in obese children and adolescents.
2006;60(6):759-763. PMID: 17065576 Diabetes Care. 2011;34(6):1306-1311. PMID: 21515842
3. Rascati K, Richards K, Lopez D, Cheng L-I, Wilson J. Progression to insulin 17. Chan CL, Pyle L, Newnes L, Nadeau KJ, Zeitler PS, Kelsey MM. Continuous
for patients with diabetes mellitus on dual oral antidiabetic therapy using the glucose monitoring and its relationship to hemoglobin A1c and oral glucose
US Department of Defense Database. Diabetes Obes Metab. 2013;15(10):901- tolerance testing in obese and prediabetic youth. J Clin Endocrinol Metab.
905. PMID: 23531154 2015;100(3):902-910. PMID: 25532041
4. Kahn SE. Clinical review 135: the importance of β-cell failure in the 18. Kelsey MM, Severn C, Hilkin AM, Pyle L, Nadeau KJ, Zeitler PS. Puberty is
development and progression of type 2 diabetes. J Clin Endocrinol Metab. associated with a rising hemoglobin A1c, even in youth with normal weight. J
2001;86(9):4047-4058. PMID: 11549624 Pediatr. 2021;230:244-247. PMID: 33300876
5. Kahn SE, Lachin JM, Zinman B, et al; ADOPT Study Group. Effects of 19. Demmer RT, Zuk AM, Rosenbaum M, Desvarieux M. Prevalence of
rosiglitazone, glyburide, and metformin on β-cell function and insulin diagnosed and undiagnosed type 2 diabetes mellitus among US adolescents:
sensitivity in ADOPT. Diabetes. 2011;60(5):1552-1560. PMID: 21415383 results from the continuous NHANES, 1999-2010. Am J Epidemiol.
6. TODAY Study Group. Effects of metformin, metformin plus rosiglitazone, 2013;178(7):1106-1113. PMID: 23887044
and metformin plus lifestyle on insulin sensitivity and β-cell function in 20. SEARCH for Diabetes in Youth Study Group, Liese AD, D’Agostino RB Jr,
TODAY. Diabetes Care. 2013;36(6):1749-1757. PMID: 23704674 et al. The burden of diabetes mellitus among US youth: prevalence estimates
7. Zeitler P, Hirst K, Copeland KC, et al; TODAY Study Group. HbA1c from the SEARCH for Diabetes in Youth Study. Pediatrics. 2006;118(4):1510-
after a short period of monotherapy with metformin identifies durable 1518. PMID: 17015542
glycemic control among adolescents with type 2 diabetes. Diabetes Care. 21. American Diabetes Association. Diagnosis and classification of diabetes
2015;38(12):2285-2292. PMID: 26537182 mellitus. Diabetes Care. 2010;33(Suppl 1):S62-S69. PMID: 20042775
8. Copeland KC, Zeitler P, Geffner M, et al; TODAY Study Group. 22. Weiss R, Taksali SE, Tamborlane WV, Burgert TS, Savoye M, Caprio S.
Characteristics of adolescents and youth with recent-onset type 2 diabetes: Predictors of changes in glucose tolerance status in obese youth. Diabetes Care.
the TODAY cohort at baseline. J Clin Endocrinol Metab. 2011;96(1):159-167. 2005;28:902-909. PMID: 15793193
PMID: 20962021 23. Amiel SA, Sherwin RS, Simonson DC, Lauritano AA, Tamborlane WV.
9. Sellers EAC, Yung G, Dean HJ. Dyslipidemia and other cardiovascular risk Impaired insulin action in puberty. A contributing factor to poor glycemic
factors in a Canadian First Nation pediatric population with type 2 diabetes control in adolescents with diabetes. N Engl J Med. 1986;315(4):215-219.
mellitus. Pediatr Diabetes. 2007;8(6):384-390. PMID: 18036065 PMID: 3523245
10. Hannon TS, Arslanian SA. The changing face of diabetes in youth: lessons 24. Moran A, Jacobs DR Jr, Steinberger J, et al. Association between the insulin
learned from studies of type 2 diabetes. Ann N Y Acad Sci. 2015;1353:113-137. resistance of puberty and the insulin-like growth factor-I/growth hormone
PMID: 26448515 axis. J Clin Endocrinol Metab. 2002;87(10):4817-4820. PMID: 1234479
11. Dart AB, Martens PJ, Rigatto C, Brownell MD, Dean HJ, Sellers EA. 25. Morrison JA, Laskarzewski PM, Rauh JL, et al. Lipids, lipoproteins, and
Earlier onset of complications in youth with type 2 diabetes. Diabetes Care. sexual maturation during adolescence: the Princeton maturation study.
2014;37(2):436-443. PMID: 24130346 Metabolism. 1979;28(6):641-649. PMID: 449703
12. Today Study Group, Bjornstad P, Drews KL, Caprio S, et al. Long-term 26. Tell GS, Mittelmark MB, Vellar OD. Cholesterol, high density lipoprotein
complications in youth-onset type 2 diabetes. N Engl J Med. 2021;385(5):416- cholesterol and triglycerides during puberty: the Oslo Youth Study. Am J
426. PMID: 34320286 Epidemiol. 1985;122(5):750-761. PMID: 4050768
13. American Diabetes Association. 2. Classification and diagnosis of diabetes: 27. Porkka KV, Viikari JS, Ronnemaa T, Marniemi J, Akerblom HK. Age and
standards of medical care in diabetes-2019. Diabetes Care. 2019;42(Suppl gender specific serum lipid and apolipoprotein fractiles of Finnish children
1):S13-S28. PMID: 30559228 and young adults. The Cardiovascular Risk in Young Finns Study. Acta
14. Report of the Expert Committee on the Diagnosis and Classification of Paediatr. 1994;83(8):838-848. PMID: 7981561
Diabetes Mellitus. Diabetes Care. 1997;20(7):1183-1197. PMID: 9203460 28. Buse JB, Kaufman FR, Linder B, et al; HEALTHY Study Group. Diabetes
screening with hemoglobin A(1c) versus fasting plasma glucose in a

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 multiethnic middle-school cohort. Diabetes Care. 2013;36(2):429-435. PMID: 34. Klingensmith GJ, Laffel L, Pyle L, et al; TODAY Study Group. The presence
23193207 of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype.
29. Love-Osborne KA, Sheeder JL, Nadeau KJ, Zeitler P. Longitudinal follow up Diabetes Care. 2010;33(9):1970-1975. PMID: 20519658
of dysglycemia in overweight and obese pediatric patients. Pediatr Diabetes. 35. Laffel L, Chang N, Grey M, et al; TODAY Study Group. Metformin
2018;19(2):199-204. PMID: 28856775 monotherapy in youth with recent onset type 2 diabetes: experience from
30. Zeitler P, Fu J, Tandon N, et al; International Society for Pediatric and the prerandomization run-in phase of the TODAY study. Pediatric Diabetes.
Adolescent Diabetes. ISPAD clinical practice consensus guidelines 2014. Type 2012;13(5):369-375. PMID: 22369102
2 diabetes in the child and adolescent. Pediatr Diabetes. 2014;15(Suppl 20):26- 36. Kelsey MM, Geffner ME, Guandalini C, et al; Treatment Options for
46. PMID: 25182306 Type 2 Diabetes in Adolescents and Youth Study Group. Presentation and
31. American Diabetes Association. 2. Classification and diagnosis of diabetes: effectiveness of early treatment of type 2 diabetes in youth: lessons from the
standards of medical care in diabetes. Diabetes Care. 2021;44(Suppl 1):S15-S33. TODAY study. Pediatr Diabetes. 2016;17(3):212-221. PMID: 25690268
PMID: 33298413 37. Pinhas-Hamiel O, Dolan LM, Zeitler PS. Diabetic ketoacidosis among obese
32. Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type 2 diabetes among African-American adolescents with NIDDM. Diabetes Care. 1997;20(4):484-
North American children and adolescents: an epidemiological review and 486. PMID: 9096965
public health perspective. J Pediatr. 2000;136(5):664-672. PMID: 10802501 38. Copeland KC, Silverstein J, Moore KR, et al; American Academy of
33. Copeland KC, Zeitler P, Geffner M, et al; TODAY Study Group. Pediatrics. Management of newly diagnosed type 2 diabetes mellitus (T2DM)
Characteristics of adolescents and youth with recent-onset type 2 diabetes: in children and adolescents. Pediatrics. 2013;131:e648-e664. PMID: 23359574
the TODAY cohort at baseline. J Clin Endocrinol Metab. 2011;96(1):159-167. 39. Arslanian S, Bacha F, Grey M, Marcus MD, White NH, Zeitler P. Evaluation
PMID: 20962021 and management of youth-onset type 2 diabetes: a position statementy by the
American Diabetes Association. Diabetes Care. 2018;41(12):2648-2668. PMID:
30425094

204  ENDO 2022 • Endocrine Case Management

Novel Therapies in the
Treatment of Congenital
Hyperinsulinism
Diva D. De Leon-Crutchlow, MD, MSCE. Department of Pediatrics, Children’s Hospital
of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania,
Philadelphia, PA; E-mail: [email protected]

Learning Objectives First-line therapy for hyperinsulinism

is diazoxide, a KATP channel opener. Lack of
As a result of participating in this session, learners
responsiveness to diazoxide suggests that
should be able to:
the hyperinsulinism is due to a KATP channel
• Describe the clinical manifestations, pathogenic variant and, therefore, the possibility
genetics, and natural history of congenital of focal hyperinsulinism should be considered
hyperinsulinism (HI). and genetic testing should be promptly ordered.
The finding of a recessive paternally inherited
• Discuss the therapeutic approach to children
variant in either 1 of the 2 genes encoding the
with HI.
KATP channel has a sensitivity of 97% for focal
hyperinsulinism. When focal hyperinsulinism is
suspected, specialized imaging with 18F-DOPA
PET for lesion localization and surgical resection
Main Conclusions is indicated. For patients with diazoxide-
Hyperinsulinism is the most common cause of unresponsive, diffuse HI, somatostatin analogues
persistent hypoglycemia in neonates, infants, are second-line therapy; when this fails,
and children. Hyperinsulinism can be acquired pancreatectomy may be required. Children with HI
secondary to perinatal factors, such as birth require ongoing monitoring of glycemic control,
asphyxia, or it can be genetic. There are multiple treatment-associated adverse effects, and growth
genetic forms of hyperinsulinism, but the most and development. Several novel therapies are in
common and severe form is due to inactivating development and are in clinical trials.
pathogenic variants in the genes encoding the
β-cell KATP channels. This form of hyperinsulinism
can be diffuse or focal. Focal hyperinsulinism
can be cured by surgical removal of the lesion.
Significance of the
The diagnosis of hyperinsulinism is established Clinical Problem
by the demonstration that insulin secretion/ HI is the most common cause of persistent
actions are not appropriately turned off during hypoglycemia in neonates, infants, and children.
hypoglycemia. However, one must be aware HI is a rare condition with an estimated incidence
that during evaluation and diagnosis, plasma in the United States and Europe of 1 in 20,000
insulin concentrations are not always elevated live births. Despite advances in the understanding
in hyperinsulinism. of the molecular genetics and pathophysiology of
HI, affected children continue to have high rates

ENDO 2022 • Pediatric Endocrinology  205

of neurodevelopmental and neurobehavioral that persists beyond this period should be further
problems, which affect up to 50% of patients. investigated.1
Prompt diagnosis and establishment of effective Hyperinsulinism due to dysregulation of
therapy are critical for optimizing neurological insulin secretion is the most common cause of
outcomes. However, new therapies are needed persistent hypoglycemia in neonates, infants,
for children who are unresponsive to currently and children. Hyperinsulinism can be secondary
available treatment. to perinatal factors, such as perinatal asphyxia
and maternal preeclampsia, or it can be caused
by genetic defects in the pathway that regulates
Barriers to Optimal Practice insulin secretion. HI may also be associated
with syndromes in which HI is only one of
• Failure to identify neonates with persistent
the manifestations of the condition. The most
hypoglycemia due to HI before discharge from
common syndromes associated with HI are
the newborn nursery.
Beckwith-Wiedemann syndrome and Kabuki
• Lack of access to specific, accurate, and fast syndrome. The mechanisms by which perinatal
genetic testing with appropriate interpretation, stress causes hyperinsulinism is not yet elucidated,
which is critical to identifying children with but this form of transient hyperinsulinism
the focal form of HI. can be as severe as the genetic forms, and it is
• Lack of access to specialized imaging and also associated with poor neurodevelopmental
expertise for identifying, localizing, and outcomes,2 thus, at-risk neonates should be
surgically removing focal lesions. screened after birth for hypoglycemia and undergo
• Lack of recognition and prevention of adverse an appropriate diagnostic evaluation.1
effects associated with HI therapies.
• Limited therapeutic treatment options Genetic Forms of Hyperinsulinism
for children with diazoxide-unresponsive HI due to genetic defects in the insulin regulatory
diffuse HI. pathway is a genetically and phenotypically
heterogenous condition.3 More than 10 loci have
been associated with HI, but the most common
Strategies for Diagnosis, and severe form of HI is caused by inactivating
Therapy, and/or Management pathogenic variants in ABCC8 and KCNJ11, the
genes encoding the β-cell ATP-sensitive potassium
Introduction (KATP) channels, known as KATP-HI.4 Histologically,
In the normal newborn, the plasma glucose KATP-HI can be diffuse or focal. Diffuse KATP-HI is
concentration decreases after birth, reaching a caused by recessive biallelic variants or dominant
nadir of about 55 to 60 mg/dL (3.0 to 3.3 mmol/L) monoallelic variants in ABCC8 or KCNJ11. In
at approximately 2 hours of life and staying focal KATP-HI, affected β cells are limited to a very
lower than the normal range for older children small part of the pancreas, and it is caused by the
and adults for 3 to 5 days. This phenomenon of combination of a paternally inherited recessive
physiological adaptation is known as transitional ABCC8 variant or KCNJ11 variant together with
hypoglycemia. During this period of physiological paternal isodisomy of the 11p15 chromosomal
transitional hypoglycemia, the plasma glucose region confined to the pancreatic lesion.
concentration remains relatively stable and then Focal HI can be cured if the lesion is surgically
increases steadily, reaching the normal range 3 removed. The second most common HI subtype
to 5 days after birth. More severe hypoglycemia, is hyperinsulinism hyperammonemia syndrome,
symptomatic hypoglycemia, or hypoglycemia which is caused by activating monoallelic

206  ENDO 2022 • Endocrine Case Management

variants in GLUD1, the gene encoding glutamate specificity 100%).6 A common misconception is
dehydrogenase. The phenotype of GLUD1- that the plasma insulin concentration is always
associated HI is characterized by fasting and high in HI; however, it is not uncommon for
protein-induced hypoglycemia, hyperammonemia, plasma insulin to be “low” and even undetectable.
and neurological manifestations such as absence Additional laboratory evaluation may help
seizures and learning problems. A less common establish the diagnosis of the specific HI subtype.
form of HI is caused by monoallelic activating For example, plasma ammonia is elevated in HI
variants in the GCK gene (encoding glucokinase) due to activating pathogenic variants in GLUD1,
that sets the threshold for glucose-stimulated and plasma C4-OH acylcarnitine and urine
insulin secretion in the β cell. Activating variants 3-hydroxyglutaric acid levels are elevated in HI
in the GCK gene result in a lower threshold due to inactivating pathogenic variants in HADH.
for glucose-stimulated insulin secretion and Genetic testing is important for determining
hyperinsulinism. Dominant inactivating variants the specific genetic form of HI and for family
in HNF1A and HNF4A cause a biphasic phenotype counseling, but it is particularly essential for
with transient hyperinsulinism early in infancy identifying children with focal HI. The finding of
and childhood followed by diabetes later in life. a paternally inherited recessive variant in ABCC8
Other less frequent genetic causes of HI include and KCNJ11 predicts focal HI with a sensitivity
biallelic inactivating variants in the HADH gene, of 97%.4
which encodes short-chain 3-hydroxyacyl-CoA
(SCHAD), and monoallelic inactivating variants Treatment
in the UCP2 gene, which encodes uncoupling
protein-2. Pathogenic variants in the promoter Once the diagnosis of HI is established, specific
region of the SCL16A1 gene, which encodes treatment should be initiated. Diazoxide, a KATP
monocarboxylate transporter 1 (MCT1), result in channel opener, is the only drug with regulatory
the aberrant expression of this β-cell disallowed approval for the treatment of HI and is first-line
gene and cause a form of hyperinsulinism therapy for this condition.7 The dosage range of
characterized by exercise-induced hypoglycemia. diazoxide is 5 to 15 mg/kg per day divided into
More recently, pathogenic variants in noncoding 2 daily doses. To prevent complications from
regions of the HK1 gene (encoding hexokinase diazoxide-induced fluid retention, diuretic therapy
1), another β-cell disallowed gene, have been should be initiated concomitantly with diazoxide.
recognize as a cause of HI.5 Dosage selection and dosage escalation should
be carefully considered, weighing the response
and potential for adverse effects. Because of its
Diagnosis long half-life, it may take up to 5 days to achieve
The diagnosis of HI is established by a full therapeutic effect. An important next step
demonstrating that insulin secretion/actions is to assess the responsiveness to diazoxide,
are not appropriately turned off in the presence which has important diagnostic and therapeutic
of hypoglycemia (plasma glucose <50 mg/dL implications. Responsiveness to diazoxide is
[<2.8 mmol/L]).6 The typical laboratory findings defined by the demonstration that the cardinal
include detectable insulin (sensitivity 82%; feature of HI, hypoketotic hypoglycemia, is
specificity 100%), low plasma free fatty acids corrected by treatment. This is best assessed by a
(<1.7 mmol/L; sensitivity 87%; specificity 100%), fasting test demonstrating that the child can fast
low plasma β-hydroxybutyrate (<1.8 mmol/L; for 12 to 18 hours with plasma glucose values
sensitivity 100%; specificity 100%), and a glycemic of 70 mg/dL or higher (≥3.9 mmol/L) or that
response to a pharmacologic dose of glucagon plasma β-hydroxybutyrate increases to greater
(>30 mg/dL (>1.7 mmol/L); sensitivity 89%; than 1.8 mmol/L before plasma glucose decreases

ENDO 2022 • Pediatric Endocrinology  207

below 50 to 60 mg/dL (2.8 to 3.3 mmol/L) tachyphylaxis. In our HI program, we start with
during fasting. Lack of responsiveness to a continuous intragastric infusion of dextrose
diazoxide suggests the possibility that HI is due to 20% given around the clock until the child is
inactivating variant(s) in the KATP channel genes, old enough to introduce octreotide. Typically,
which account for up to 90% of cases of diazoxide- we introduce octreotide at 4 to 6 months of age
unresponsive HI. For these patients, rapid genetic and dose it twice daily, with a small dose of 2 to
testing for variants in ABCC8 and KCNJ11 is critical 3 mcg/kg given in the morning and a slightly
to determine the likelihood of focal HI.4 higher dose of 4 to 5 mcg/kg given 6 hours later
Surgery is the treatment of choice for with continuous intragastric dextrose 20% for
focal HI, but before surgery, it is important to 12 hours overnight. At about 1 year of age, we
localize the lesion. These lesions are not visible transition from octreotide to lanreotide, 60 mg
using conventional imaging techniques such monthly. In some patients, the introduction of
as ultrasonography, CT, and MRI; however, lanreotide allows for discontinuation of overnight
specialized imaging using 18F-DOPA PET is dextrose.
almost 100% accurate in localizing focal lesions.8 Near-total pancreatectomy is indicated when
Expert assessment of the pancreatic histology medical therapy fails. Because hypoglycemia
during surgery using frozen biopsies and surgical persists in up to 50% of children with diffuse HI
expertise are key for surgical success. Therefore, after pancreatectomy, a gastrostomy tube is placed
these children should be referred to an HI center of at the time of surgery to facilitate management
excellence for management by a multidisciplinary of residual hypoglycemia using continuous
team of experts. The reported cure rate for focal intragastric dextrose.
HI is 97%.9 The successful management of children with
For diazoxide-unresponsive patients with hyperinsulinism requires a stepwise approach
nonfocal HI, treatment options are limited. with continuous assessment and adjustment of
Off-label use of the somatostatin analogue the treatment according to the response. Ongoing
octreotide has been the longstanding second- monitoring to assess for glycemic control,
line treatment for HI,10 but its effectiveness is therapy-associated adverse effects, and growth
limited by the development of tachyphylaxis. and development is recommended. In addition
Because of its association with potentially fatal to at-home monitoring of glycemic control,
necrotizing enterocolitis, octreotide is not a yearly assessment of fasting tolerance in the
recommended for infants younger than 8 weeks. hospital setting is important to guide treatment
The recommended octreotide dosage range is 5 adjustments. Children who have undergone 50%
to 20 mcg/kg per day. Long-acting somatostatin or greater pancreatectomy should be monitored
analogues, octreotide LAR and lanreotide, are for diabetes and pancreatic insufficiency. Ninety-
convenient options for children older than 1 one percent of children who undergo near-
year. An alternative treatment approach for total pancreatectomy require insulin by age
diazoxide-unresponsive patients who are either 14 years. The frequency of neurodevelopmental
not eligible or are unresponsive to octreotide and neurobehavioral problems in children
is the use of a continuous infusion of dextrose with hyperinsulinism is 40% to 50%; therefore,
through a gastrostomy tube.11 Typically, dextrose neurodevelopmental assessments should be
20% is used and because of tolerance, the maximal performed throughout childhood.
glucose infusion rate administrated through Multiple new therapies for HI are in
this route is 10 mg/kg per min. Continuous development and promise to make possible a
intragastric dextrose is also used in combination personalized approach to treatment of children
with octreotide, an approach that allows for less with HI in an effort to improve their long-
frequent dosing of octreotide and avoidance of term outcomes. Therapies currently in clinical

208  ENDO 2022 • Endocrine Case Management

trials include a peptide antagonist of the GLP-1 C. Initiate hydrocortisone replacement therapy
receptor, a short-acting soluble glucagon analogue, for adrenal insufficiency
a long-acting glucagon analogue, a selective D. Order rapid genetic testing for ABCC8 and
nonpeptide somatostatin receptor 5 agonist, and KCNJ11 to assess the likelihood of diazoxide
an allosteric inhibitor of the insulin receptor. For responsiveness
up-to-date information about clinical trials in HI,
visit www.clinicaltrials.gov. Answer: B) Initiate diazoxide and
chlorothiazide at the same time

Clinical Case Vignettes The clear history of perinatal stress suggests

a diagnosis of perinatal stress-induced
Case 1 hyperinsulinism. Therefore, genetic testing
A 10-day-old male newborn has persistent (Answer D) is unlikely to be useful. Perinatal
hypoglycemia requiring a glucose infusion rate stress-induced hyperinsulinism may affect up
of 18 mg/kg per min. At 37 weeks’ gestation, to 50% of neonates at risk. The clinical course is
the infant was born by emergency cesarean heterogenous; some cases are mild and resolve
delivery performed for fetal distress associated within days, while others may be severe and
with maternal preeclampsia. Birth weight was persist for several weeks to months. This form
5 lb 4 oz (2373 g) (small for gestational age). His of hyperinsulinism is responsive to therapy
initial plasma glucose concentration was 16 mg/dL with diazoxide, but these infants may be more
(0.89 mmol/L). susceptible to developing diazoxide adverse effects,
particularly edema.12 Therefore, it is recommended
A critical sample was obtained during a
that diuretic therapy be initiated concomitantly
spontaneous episode of hypoglycemia (plasma
with diazoxide (Answer B). Although the
glucose = 50 mg/dL [2.8 mmol/L]):
likelihood of developing adverse events may be
Plasma insulin = 3 µIU/mL (should be undetectable higher in this population of infants, this does
during hypoglycemia) (SI: 20.8 pmol/L) not represent a contraindication of diazoxide
Plasma β-hydroxybutyrate = <0.3 mmol/L
treatment (Answer A), particularly because of
(≥1.8 mmol/L during hypoglycemia)
Plasma free fatty acids = 13.8 mg/dL the high risk of neurodevelopmental sequelae if
(≥47.9 mg/dL during hypoglycemia) hypoglycemia is not prevented.
(SI: 0.49 mmol/L [≥1.7 mmol/L]) A singe low GH or cortisol value at the time
Cortisol = 3 µg/dL (≥10 ug/dL during hypoglycemia) of fasting hypoglycemia has poor specificity for
(SI: 82.8 nmol/L [≥275.9 nmol/L])
the respective diagnoses of GH deficiency and
GH = 10.0 ng/mL (≥10.0 ng/mL during
hypoglycemia) (SI: 10.0 µg/L [≥10.0 µg/L]) adrenal insufficiency.13 Thus, hydrocortisone
(Answer C) is not indicated now. If GH or cortisol
In response to glucagon (1 mg), plasma glucose deficiency is suspected, stimulation testing should
increases to 94 mg/dL (5.2 mmol/L). be performed.

Which of the following is the best next

step in this patient’s management? Case 2
A. Avoid diazoxide as it is contraindicated A 5-month-old female infant presents to the
because of the high likelihood of adverse emergency department after a witnessed seizure
effects episode at home. Her parents report previous
episodes of irritability and “eye deviation” that
B. Initiate diazoxide and chlorothiazide at the
resolved after feedings. Birth history is remarkable
same time
for large-for-gestational birth weight (9 lb 9 oz
[4335 g] at 38 weeks’ gestation) and “transient”

ENDO 2022 • Pediatric Endocrinology  209

hypoglycemia that required intravenous dextrose later in infancy. The phenotype of this form of
for 5 days after birth. hyperinsulinism is characterized by hypoglycemia,
hyperammonemia, and neurological
At the time of presentation with seizures, a critical manifestations with seizures in up to 60% of
sample was obtained during a spontaneous episode patients. Hyperinsulinism hyperammonemia
of hypoglycemia: syndrome is responsive to diazoxide and is
Plasma glucose = 47 mg/dL (70-100 mg/dL) associated with elevated ammonia. Genetic testing
(SI: 2.6 mmol/L [3.9-5.6 mmol/L]) help establish the diagnosis. However, measuring
Plasma insulin = 12 µIU/mL (should be undetectable ammonia and treating for hyperammonemia to
during hypoglycemia) (SI: 83.3 pmol/L)
prevent further seizure episodes (Answer C) is
Plasma β-hydroxybutyrate = <0.4 mmol/L
(≥1.8 mmol/L during hypoglycemia) incorrect because treatment of hyperammonemia
Plasma free fatty acids = 8.5 mg/dL is not indicated.
(≥47.9 mg/dL during hypoglycemia) Persistence of plasma glucose values lower
(SI: 0.3 mmol/L [≥1.7 mmol/L]) than 70 mg/dL (<3.9 mmol/L), even with frequent
In response to glucagon (1 mg), plasma glucose feedings, suggests that the hyperinsulinism is
increases to 118 mg/dL (6.5 mmol/L). After 5 days not responsive to diazoxide. Ninety percent
of therapy with diazoxide, 15 mg/kg per day, and of diazoxide-unresponsive cases are due to
with feeds every 3 hours, prefeed plasma glucose inactivating pathogenic variants in the KATP
values are in the range of 60 to 80 mg/dL (3.3 to channel genes, and up to 50% of these are focal.
4.4 mmol/L). Thus, the appropriate next step is to assess diazoxide
responsiveness by performing a fasting test in
Which of the following is the best next addition to obtaining genetic testing (Answer D).
step in this patient’s management? The use of continuous feedings to treat
hyperinsulinism (Answer A) should be avoided
A. Continue diazoxide; place a gastrostomy tube
because it can result in feeding aversion.
for initiation of overnight continuous feedings
Rather than committing to therapy with
B. Discontinue diazoxide; initiate octreotide in octreotide (Answer B), every effort should be made
combination with continuous feedings overnight to evaluate for the possibility of focal disease, which
C. Measure ammonia and treat for is curable. If focal HI is ruled out, octreotide can then
hyperammonemia to prevent further seizure be considered for diazoxide-unresponsive patients.
episodes
D. Perform a fasting test to guide the next steps in Case 3
addition to ordering genetic testing
A 4-month-old female infant has persistent
Answer: D) Perform a fasting test to guide the hypoglycemia and congenital hypothyroidism.
next steps in addition to ordering genetic testing The infant was born by vaginal delivery at
38 weeks’ gestation with a birth weight of 7 lb 6 oz
Children with focal disease are more likely
(3345 g). The neonatal period was complicated by
to present at an older age and have seizures
respiratory distress, transient hypoglycemia, and
at presentation compared with children with
feeding issues. Newborn screening was remarkable
diffuse HI.14 However, the history of “transient”
for an elevated TSH value of 80 mIU/L. Thyroid
hypoglycemia in the newborn period suggests late
hormone replacement was initiated. She was
recognition of the HI diagnosis, rather than late
also found to have a ventricular septal defect
presentation. Hyperinsulinism hyperammonemia
on echocardiography. The infant presented at
syndrome is caused by an activating pathogenic
2 months of age with lethargy and was found to
variant in the GLUD1 gene. It is the second most
have hypoglycemia.
common genetic form of HI and may present

210  ENDO 2022 • Endocrine Case Management

Results from a critical sample at the end of a This infant’s critical sample is consistent with the
diagnostic fast: diagnosis of hyperinsulinism. Although plasma
insulin was undetectable, it is not detectable in
Plasma glucose = 48 mg/dL (70-100 mg/dL)
(SI: 2.7 mmol/L [3.9-5.6 mmol/L]) about 18% of patients with HI. There are a few
Plasma insulin = <2 µIU/mL (should be undetectable explanations for this. Most commonly, the falsely
during hypoglycemia) (SI: 13.9 pmol/L) low insulin concentration is due to hemolysis of
Plasma β-hydroxybutyrate = 1.3 mmol/L the sample, which can happen when the critical
(≥1.8 mmol/L during hypoglycemia)
sample is obtained from an indwelling catheter
Plasma free fatty acids = 21.4 mg/dL
(≥47.9mg/dLduringhypoglycemia)(SI:0.76mmol/L and results in degradation of insulin. The low
[≥1.7 mmol/L during hypoglycemia]) plasma β-hydroxybutyrate and free fatty acids, as
well as the robust glycemic response to glucagon,
In response to glucagon (1 mg), plasma glucose confirm the diagnosis of HI. The physical
increases to 131 mg/dL (7.3 mmol/L). Physical characteristics of the infant suggest the diagnosis
examination findings are remarkable for of Kabuki syndrome; thus, genetic testing (Answer
microcephaly (head circumference <5th percentile), A) should include, in addition to HI-specific genes,
elongated eyelids, and persistent fetal finger pads. testing for Kabuki syndrome, which is part of most
HI genetic panels.
Which of the following statements Before considering imaging with 18F-DOPA
is true regarding this patient’s PET (Answer D), diazoxide responsiveness
evaluation and management? should be assessed and genetic testing should be
A. A syndromic cause of hyperinsulinism should ordered. If the child is diazoxide-responsive and/
be considered and appropriate genetic testing or genetic testing confirms the diagnosis of Kabuki
should be ordered syndrome, 18F-DOPA PET would not be indicated.
B. Diazoxide is contraindicated because of the A ventricular septal defect is not necessarily a
history of ventricular septal defect contraindication for the use of diazoxide (Answer B);
C. Octreotide is contraindicated because of the a comprehensive assessment of the risk vs benefits
history of hypothyroidism should be performed for each case.
D. The patient should be referred to a center of Hypothyroidism is not a contraindication for
excellence for 18F-DOPA PET using octreotide (Answer C), but thyroid function
should be followed in children receiving therapy
Answer: A) A syndromic cause of with somatostatin analogues. If the child is
hyperinsulinism should be considered and unresponsive to diazoxide, octreotide should be
appropriate genetic testing should be ordered considered as second-line therapy if focal HI is not
suspected.

References
1. Thornton PS, Stanley CA, De Leon DD, et al; Pediatric Endocrine Society. 5. Wakeling MN, Owens NDL, Hopkinson JR, et al. A novel disease mechanism
Recommendations from the Pediatric Endocrine Society for evaluation and leading to the expression of a disallowed gene in the pancreatic beta-cell
management of persistent hypoglycemia in neonates, infants, and children. J identified by non-coding, regulatory mutations controlling HK1. medRxiv.
Pediatr. 2015;167(2):238-245. PMID: 25957977 2022;doi: https://doi.org/10.1101/2021.12.03.21267240.
2. Avatapalle HB, Banerjee I, Shah S, et al. Abnormal neurodevelopmental 6. Ferrara C, Patel P, Becker S, Stanley CA, Kelly A. Biomarkers of insulin for
outcomes are common in children with transient congenital hyperinsulinism. the diagnosis of hyperinsulinemic hypoglycemia in infants and children. J
Front Endocrinol (Lausanne). 2013;4:60. PMID: 23730298 Pediatr. 2016;168:212-219. PMID: 26490124
3. Rosenfeld E, Ganguly A, De Leon DD. Congenital hyperinsulinism disorders: 7. Brar PC, Heksch R, Cossen K, et al. Management and appropriate use of
genetic and clinical characteristics. Am J Med Genet C Semin Med Genet. diazoxide in infants and children with hyperinsulinism. J Clin Endocrinol
2019;181(4):682-692. PMID: 31414570 Metab. 2020;105(12):dgaa543.
4. Snider KE, Becker S, Boyajian L, et al. Genotype and phenotype correlations 8. States LJ, Saade-Lemus S, De Leon DD. 18-F-L 3,4-Dihydroxyphenylalanine
in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab. PET/computed tomography in the management of congenital
2013;98(2):E355-E363. PMID: 23275527 hyperinsulinism. PET Clin. 2020;15(3):349-359. PMID: 32498990

ENDO 2022 • Pediatric Endocrinology  211

9. Adzick NS, De Leon DD, States LJ, et al. Surgical treatment of congenital 12. Thornton P, Truong L, Reynolds C, Hamby T, Nedrelow J. Rate of serious
hyperinsulinism: Results from 500 pancreatectomies in neonates and adverse events associated with diazoxide treatment of patients with
children. J Pediatr Surg. 2019;54(1):27-32. PMID: 30343978 Hyperinsulinism. Horm Res Paediatr. 2019;91(1):25-32.
10. Welters A, Lerch C, Kummer S, et al. Long-term medical treatment in 13. Kelly A, Tang R, Becker S, Stanley CA. Poor specificity of low growth
congenital hyperinsulinism: a descriptive analysis in a large cohort of patients hormone and cortisol levels during fasting hypoglycemia for the diagnoses
from different clinical centers. Orphanet J Rare Dis. 2015;10:150. PMID: of growth hormone deficiency and adrenal insufficiency. Pediatrics.
26608306 2008;122(3):e522-e528. PMID: 18694902
11. Vajravelu ME, Congdon M, Mitteer L, et al. Continuous intragastric 14. Lord K, Dzata E, Snider KE, Gallagher PR, De Leon DD. Clinical presentation
dextrose: a therapeutic option for refractory hypoglycemia in congenital and management of children with diffuse and focal hyperinsulinism: a review
hyperinsulinism. Horm Res Paediatr. 2019;91(1):62-68. PMID: 30086540 of 223 cases. J Clin Endocrinol Metab. 2013;98(11):E1786-E1789. PMID:
24057290

212  ENDO 2022 • Endocrine Case Management

Approach to Pediatric
Lipid Disorders
Ambika P. Ashraf, MD. Division of Pediatric Endocrinology & Diabetes, University of
Alabama at Birmingham, Birmingham, AL; E-mail: [email protected]

Learning Objectives Nonpharmacologic approaches involve

therapeutic lifestyle changes, including appropriate
As a result of participating in this session, learners
dietary interventions, daily moderate-to-vigorous
should be able to:
physical activity, maintenance of healthy weight,
• Describe the initial evaluation and and avoidance of cigarette smoking.
management of pediatric patients with Statins remains the initial lipid-lowering
lipid disorders. medication for children 10 years and older who
have a persistently elevated LDL-C concentration
• Provide an overview of dyslipidemia
of 190 mg/dL or higher (≥4.92 mmol/L) or for
phenotypes: isolated elevation of LDL
those who have LDL-C concentrations between
cholesterol (LDL-C), hypertriglyceridemia,
130 and 189 mg/dL (3.37 and 4.90 mmol/L), based
and combined dyslipidemia with elevated
on the presence of additional risk factor(s)/risk
triglycerides, low HDL cholesterol (HDL-C),
condition(s).
and varying levels of LDL-C.
In patients with combined dyslipidemia,
• Develop a practical management statin therapy is indicated for non–HDL-C
approach, including dietary and lifestyle concentrations greater than 145 mg/dL
recommendations and pharmacologic agents (>3.76 mmol/L) to reduce the ASCVD risk.
by dyslipidemia phenotype. Fibrates or omega-3 fatty acids can be used
judiciously in patients with triglyceride
concentrations greater than 400 mg/dL
(>4.52 mmol/L) to prevent acute pancreatitis.
Main Conclusions Currently, intense dietary fat restriction
Dyslipidemias are highly prevalent in youth is the recommended treatment of severe
and can be due to genetic (monogenic or hypertriglyceridemia, even though several novel
polygenic) causes or most commonly acquired therapeutic agents are in development.
due to secondary causes such as insulin resistance,
obesity, and metabolic syndrome. Elevations of
LDL-C, mild-to-moderate hypertriglyceridemia, Significance of the
and combined dyslipidemia are associated with
risk for premature atherosclerotic cardiovascular
Clinical Problem
disease (ASCVD) later in life, whereas severe The field of pediatric lipidology is an emerging
hypertriglyceridemia is associated with acute discipline in the United States and internationally.
pancreatitis risk. It is essential to rule out Premature cardiovascular diseases account for
secondary factors and manage underlying 30% of mortality in the United States. Children
risk factors. with dyslipidemia have an increased risk of
becoming adults with dyslipidemia who are

ENDO 2022 • Pediatric Endocrinology  213

at risk for premature ASCVD and strokes. training and resources to administer high-quality
Early identification of the risk factors and early care to this unique pediatric patient population.
treatment may prevent future morbidity and
mortality from ASCVD.
Both genetic and nongenetic dyslipidemias are
Strategies for Diagnosis,
widely prevalent1 and are manifested at younger Therapy, and/or Management
ages as a consequence of obesity and the diabetes Screening
epidemic. Factors implicated in the development of
In 1992, the National Cholesterol Education
dyslipidemias include insulin resistance, metabolic
Program presented the first guidelines for pediatric
syndrome, obesity, prediabetes, and diabetes.
lipidology, focusing primarily on management
Children with familial hypercholesterolemia (FH)
of LDL-C. Today, the most comprehensive
(prevalence = 1 in 300)2 and familial combined
recommendations for screening and management
hyperlipidemia (FCHL) (prevalence = 1 in 100)3
come from the 2011 National Heart Lung and
experience lifelong cumulative exposure to
Blood Institute pediatric guidelines4 and the 2019
elevated LDL-C concentrations and a projected
American Heart Association updated guidelines.5
20% increase in risk for premature cardiovascular
The National Heart Lung and Blood Institute
disease. Pediatric lipidologists increasingly
guidelines recommend “universal screening” with
confront an issue of epidemic proportions
a nonfasting lipid profile for children between
of dyslipidemia as the initial presentation of
ages 9 and 11 years and repeated measurements
metabolic dysregulation associated with obesity.
obtained between 17 and 21 years. This accounts
for the fact that the total cholesterol concentration
Barriers to Optimal Practice peaks at 9 to 11 years of age and decreases by 10%
The absence of physical characteristics of FH (eg, to 20% during puberty. In the case of an abnormal
xanthoma) in childhood makes it difficult to identify lipid profile, repeating a fasting lipid profile within
this at-risk population without universal screening. 2 to 12 weeks of the initial lipid screening is
Use of family history can be inaccurate since family recommended.
history may only be positive in a small proportion The National Heart Lung and Blood Institute
of patients due to a variety of factors such as pediatric guidelines were the first to emphasize
incomplete or unknown family history, young screening for dyslipidemia in the presence of
age of parents, or unrecognized hyperlipidemia in risk factors and conditions. Selective screening is
family members. With the increasing incidence of recommended in all children 2 years or older who
obesity, insulin resistance, metabolic syndrome, have potential risk factors for early cardiovascular
prediabetes and type 2 diabetes, nongenetic causes disease (Table). Initial screening can be done with
of dyslipidemia are manifested at younger ages a nonfasting lipid profile to measure non–HDL-C;
and dyslipidemia severity is exacerbated. Hence, all if abnormal, a fasting lipid profile can be obtained
children and adolescents aged 2 years or older who within 2 to 12 weeks. For borderline abnormal
have potential risk factors/conditions for premature values (ie, between the 75th and 95th percentiles),
cardiovascular disease should undergo selective repeated screening is suggested every 1 to 2 years.
screening. Moreover, FH may coexist with obesity Decisions regarding medication therapy should be
or insulin resistance, and the dyslipidemia phenotype made on an individual basis.
may be complex. The care of children with lipid
disorders is currently spread among several Diagnosis
subspecialists, including both pediatric and adult
The dyslipidemia phenotype is often helpful in
providers. These providers may lack the necessary
determining the mostly likely cause. It is also
important to recognize that one etiology does not

214  ENDO 2022 • Endocrine Case Management

Table. Cardiovascular Risk Factors and Risk Conditions

Risk-enhancing factors Risk-enhancing conditions

• Obesity (BMI ≥95th to <99th percentile) • Chronic inflammatory disease (eg, systemic lupus
erythematosus, systemic juvenile idiopathic arthritis)
• Insulin resistance–related comorbidities (eg, nonalcoholic fatty
liver disease, polycystic ovary syndrome) • HIV infection
• Current cigarette smoker or significant exposure to secondhand • Childhood cancer survivor with cardiotoxic chemotherapy only
smoke
• Adolescent depressive and bipolar disorders
• White-coat hypertension
• Congenital heart disease involving (1) obstructive lesions of the
• HDL-C <40 mg/dL (<1.04 mmol/L) left ventricle and aorta; (2) cyanotic congenital heart defects
leading to Eisenmenger syndrome; and (3) congenital coronary
• Elevated lipoprotein (a)
artery anomalies in isolation or in association with other
• Elevated apolipoprotein B congenital defects

Moderate-risk factors Moderate-risk medical conditions

• Confirmed hypertension (blood pressure >95th percentile or • Kawasaki disease with regressed coronary aneurysms
≥130/80 mm Hg on 3 separate occasions)
• Heterozygous familial hypercholesterolemia
• Severe obesity (BMI ≥99th percentile or ≥35 kg/m2)
• Chronic inflammatory disease
• Multiple risk factors (≥3 risk enhancers)
• Nephrotic syndrome
• Childhood cancer survivor with exposure to chest irradiation
• Chronic kidney disease

High-risk factors High-risk medical conditions

• Current cigarette smoker • Diabetes mellitus, type 1 and type 2
• Multiple comorbidities—any moderate-risk condition plus • End-stage kidney disease/postkidney transplant
≥2 additional risk enhancers
• Postorthotopic heart transplant
• Kawasaki disease with current aneurysms
• Homozygous familial hypercholesterolemia
Positive family history: First-degree relatives (biological parents and siblings) or second-degree relatives (biological grandparents,
aunts, and uncles) with any of the following before age 55 years in a male or 65 years in a female: myocardial infarction, stroke,
angina, coronary artery bypass, stent, angioplasty, sudden cardiac death, or parent with total cholesterol >240 mg/dL (>6.22 mmol/L).

From Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics,
128(Suppl 5), S213; De Ferranti et al. Circulation, 2019; 139(13); Ashraf AP et al. J Clin Endocrinol Metab, 2021; 106(12).

preclude another; namely, an underlying genetic of combined dyslipidemia, it is important to

etiology can be exacerbated by a secondary cause calculate non–HDL-C. Non–HDL-C is calculated
of dyslipidemia, such as diabetes. A substantial as the difference between total cholesterol and
number of children with endocrinologic disorders HDL-C. The management of elevated triglycerides
have “mixed type” dyslipidemia with variable is dependent on the etiology, concomitant
elevations of LDL-C and triglycerides.6 symptoms, and degree of elevation.

Therapy Clinical Case Vignettes

Both LDL-C and non–HDL-C are used as Case 1
targets to evaluate the cardiovascular disease–
A 10-year-old girl with normal BMI and blood
related risks associated with dyslipidemia.
pressure has hypercholesterolemia. Her father has
Recommendations for medical therapy,
hypercholesterolemia and type 2 diabetes and had
particularly for LDL-C elevation, are based on the
a myocardial infarction at age 42 years. He takes
number and severity of risk factors in addition
rosuvastatin, 40 mg daily.
to the actual LDL-C concentration. In the case

ENDO 2022 • Pediatric Endocrinology  215

The patient’s lipid profile: secretion and catabolism of apolipoprotein
B–containing lipoproteins. However, given
Total cholesterol = 322 mg/dL (SI: 8.34 mmol/L)
Triglycerides = 188 mg/dL (SI: 2.12 mmol/L) her positive family history, normal BMI, and
HDL-C = 47 mg/dL (SI: 1.22 mmol/L) absence of other contributing factors, polygenic
LDL-C = 237 mg/dL (SI: 6.14 mmol/L) hypercholesterolemia is not the correct choice.
Thyroid function, normal FCHL (Answer A) and metabolic syndrome
Hemoglobin A1c, normal
(Answer C) present with combined dyslipidemia
Albumin, normal
in youth with obesity or insulin resistance-related
She takes no medications. A repeated lipid profile conditions, in contrast to this patient who has
obtained 6 months after implementing dietary and isolated LDL-C elevation and normal BMI.
lifestyle changes has similar values.
When should one consider a diagnosis of FH?
Which of the following is the FH presents with isolated LDL-C elevations,
most likely diagnosis? usually greater than 160 mg/dL (>4.14 mmol/L),
A. FCHL often with a family history of premature ASCVD-
related events, such as angina, myocardial
B. FH
infarction, and stroke. FH can occur in the
C. Metabolic syndrome form of heterozygous hypercholesterolemia
D. Polygenic hypercholesterolemia (HeFH) or the more severe homozygous disease
(HoFH) where the LDL-C levels are greater
Answer: B) FH
than 400 mg/dL (>10.36 mmol/L). FH is due to
The dyslipidemia phenotype in this otherwise impaired cholesterol metabolism from monogenic
healthy, normal-weight child who has family pathogenic variants that cause dysfunction
history of premature cardiovascular disease of the LDL receptor (ie, variants in the gene
is consistent with isolated LDL-C elevation. encoding the LDL receptor, LDL receptor ligand,
Notably, she does not have any secondary causes apolipoprotein B, LDL receptor regulating enzyme
of hypercholesterolemia. Elevated LDL-C could PCSK9, or LDL receptor adaptor protein-1
be due to acquired causes, genetic predisposition, [LDLRAP1]).
or both. It is important to rule out conditions
such as hypothyroidism; nephrotic syndrome; What is the nonpharmacologic
diabetes; and drugs such as isotretinoin, atypical management of hypercholesterolemia?
antipsychotic agents, or oral contraceptives. Management of elevated LDL-C includes
The clinical picture in this patient is consistent therapeutic lifestyle changes plus lipid-lowering
with a diagnosis of FH (Answer B) based on the medications, especially statins. Lifestyle
persistently elevated LDL-C concentration greater modifications with the “cardiovascular health
than 190 mg/dL (>4.92 mmol/L), a family history integrated lifestyle diet” (CHILD diet) and daily
of premature cardiovascular disease in her father, moderate to vigorous physical activity remain
and absence of secondary causes for elevated the cornerstone for management of pediatric
cholesterol. Children with an LDL-C level of hypercholesterolemia.4 Sources of saturated fat
190 mg/dL or greater (≥4.92 mmol/L) without any include high-fat animal foods such as ground
secondary causes have a high likelihood of FH and beef and processed meats, cheese, high-fat milk
almost certainly require pharmacotherapy. and ice cream, and tropical oils such as coconut
Another differential diagnosis to consider and palm oils. Dietary cholesterol is only derived
is polygenic hypercholesterolemia (Answer D), from animal foods, which also tend to be higher
which can be due to environmental factors, diet, in saturated fat. Thus, decreasing saturated fat
or monogenic or polygenic factors affecting consumption is associated with reduction in

216  ENDO 2022 • Endocrine Case Management

dietary cholesterol. Diet and exercise modifications importance of concomitant contraceptive use. The
can only reduce the LDL-C by 10% to 20%. After goal of LDL-C lowering is to achieve an LDL-C
3 to 6 months of lifestyle modification, statins can level of 130 mg/dL or less (≤3.37 mmol/L). A
be used for the treatment of persistently elevated lower LDL-C treatment goal may be considered if
LDL-C concentrations of 160 mg/dL or higher the child has diabetes or if there is a strong family
(≥4.14 mmol/L). history of premature cardiovascular disease.
Evolocumab is a PCSK9 inhibitor. A dose
What is the pharmacologic management of 420 mg once monthly administered as a
of hypercholesterolemia? subcutaneous injection is approved for children
Treatment of children with elevated LDL-C is 10 years and older with HeFH and HoFH if
based on assessment of lipid levels and associated they have not achieved therapeutic goals on
risk factors or risk conditions. Statin therapy statin therapy.
should be considered after a 6-month trial of In patients with HoFH, the management
lifestyle management with the CHILD-2 LDL approach may include a maximally tolerated
diet in children 10 years or older: (1) if LDL-C high-intensity statin along with ezetimibe and
is 190 mg/dL or greater (≥4.92 mmol/L), (2) if bile acid resins. Regular plasmapheresis is also
LDL-C is 160 mg/dL or greater (≥4.14 mmol/L) recommended in the management of HoFH. Drugs
plus a positive family history or there is acting through the LDL receptor such as PCSK9
1 high-risk factor/condition or 2 moderate risk inhibitors (eg, evolocumab for those older than
factors/conditions, (3) if LDL-C is 130 mg/dL 10 years and alirocumab for patients older than
or greater (≥3.37 mmol/L) plus 2 high-risk 18 years) are approved for use in HoFH. Drugs
factors/conditions or there is 1 high-risk factor/ that act independently of LDL receptor such as
condition and 2 moderate-risk factors/conditions ANGPTL3 inhibition (eg, evinacumab from age
or clinical cardiovascular disease (Table).7 Drug 12 years and lomitapide from age 18 years) are also
therapy can be considered for children as young treatment options.8
as 8 years if LDL-C remains 190 mg/dL or
greater (≥4.92 mmol/L) after a trial of lifestyle Is there any role for cardiac imaging?
management and when there is a clinical suspicion Cardiovascular imaging is not required for
or genetic diagnosis of FH, the presence of at children with HeFH. Cardiovascular imaging at
least 1 high-risk factor or risk condition, or the diagnosis is indicated in children with HoFH (ie,
presence of at least 2 moderate-risk factors or electrocardiography, echocardiography, age-
risk conditions. appropriate stress testing, and coronary artery
All commercially available statins are FDA imaging, including angiography).
approved, with pravastatin, rosuvastatin, and
pitavastatin starting at age 8 years and all others at
Case 2
age 10 years, for treatment of persistently elevated
LDL-C of 160 mg/dL or greater (≥4.14 mmol/L) A 13-year-old boy with a BMI greater than the
after 3 to 6 months of lifestyle modification in 99th percentile has the following lipid profile:
patients with clinical findings consistent with FH. Total cholesterol = 234 mg/dL (SI: 6.06 mmol/L)
Statins are well tolerated in children and have Triglycerides = 494 mg/dL (SI: 5.58 mmol/L)
an excellent safety profile. The most commonly LDL-C = 126 mg/dL (SI: 2.59 mmol/L)
reported adverse effects are muscle-related Non–HDL-C = 201 mg/dL (SI: 5.21 mmol/L)
HDL-C = 33 mg/dL (SI: 0.85 mmol/L)
symptoms, while hepatic transaminase elevations
occur relatively infrequently. Pubertal girls should His family history is notable for obesity,
be advised about concerns of teratogenicity with hypertriglyceridemia, hypercholesterolemia, and
statin use in pregnancy and counseled on the premature ASCVD in multiple relatives. After the

ENDO 2022 • Pediatric Endocrinology  217

implementation of therapeutic lifestyle changes, he triglycerides and non–HDL-C concentrations)
loses 5 lb (2.3 kg). with dietary modification or reduction in body
weight. In contrast, patients with FCHL appear
A repeated fasting lipid profile obtained 12 weeks to have elevated non–HDL-C as does this patient
after the initial laboratory tests documents the (an indicator of excessive apolipoprotein B
following values: production).
Total cholesterol = 286 mg/dL (SI: 7.41 mmol/L) Familial hypertriglyceridemia (Answer A)
Triglycerides = 173 mg/dL (SI: 1.95 mmol/L) generally presents with hypertriglyceridemia. In
LDL-C = 121 mg/dL (SI: 3.13 mmol/L) the presence of secondary causes, such as type 2
Non–HDL-C = 248 mg/dL (SI: 6.42 mmol/L)
diabetes, hypothyroidism, and certain medications,
HDL-C = 38 mg/dL (SI: 0.98 mmol/L)
etc, combined dyslipidemia may be expressed in
patients with associated minor variants in the
Which of the following is this genes controlling triglyceride metabolism. These
patient’s most likely diagnosis? patients have a higher ASCVD risk related to
A. Familial hypertriglyceridemia the degree of LDL-C and triglyceride elevation.
B. FCHL Polygenic hypercholesterolemia (Answer
D) is unlikely in this patient with combined
C. Metabolic syndrome
dyslipidemia since polygenic hypercholesterolemia
D. Polygenic hypercholesterolemia is predominantly characterized by elevated LDL-C
Answer: B) FCHL concentrations, similar to FH.

This patient has combined dyslipidemia and What is the role of non–HDL-C?
obesity most likely due to FCHL (Answer B), given Calculation of non–HDL-C is important in the
the variable elevations in LDL-C, persistently management of these patients. Non–HDL-C
elevated non–HDL-C, positive family history of encompasses all atherogenic molecules with an
premature ASCVD, and marked variability in lipid apolipoprotein B–containing particle. Non–
profiles in patients and relatives. HDL-C is elevated in this patient and hence he
Combined dyslipidemia (mixed dyslipidemia) most likely has FCHL, which is associated with
manifests as elevated triglycerides and low HDL-C increased risk of premature ASCVD. Although
with variable LDL-C. Combined dyslipidemia triglyceride levels are typically between 200 and
is the most common lipid abnormality in 500 mg/dL (2.26 and 5.65 mmol/L) in this setting,
childhood and adolescence. Usually, triglyceride many gene-environment interactions (high-
levels are between 150 and 400 mg/dL (1.70 and carbohydrate diet, obesity, sedentary lifestyle,
4.52 mmol/L) and HDL-C levels are less than estrogen, glucocorticoids, etc) can raise fasting
40 mg/dL (<1.04 mmol/L). The main differential serum triglyceride concentrations to greater than
diagnosis of combined dyslipidemia includes 500 mg/dL (>5.65 mmol/L) and postprandial
obesity-induced dyslipidemia (ie, dyslipidemia triglycerides to greater than 1000 mg/dL
of metabolic syndrome due to visceral adiposity (>11.30 mmol/L). For all patients with combined
and insulin resistance) (Answer C) and FCHL dyslipidemia, secondary factors must be ruled out.
(Answer B). Even though obesity-associated
dyslipidemia overlaps phenotypically with FCHL, What is the nonpharmacologic
LDL-C concentrations are rarely greater than management of hypercholesterolemia?
160 mg/dL (>4.14 mmol/L) in patients with The crucial step in treatment is intensive dietary
dyslipidemia due to obesity/metabolic syndrome. and lifestyle changes and removal of offending
In the case of obesity-induced dyslipidemia, drugs. In almost all cases, dyslipidemia of obesity
lipid abnormalities generally improve (ie, responds well to lifestyle intervention, including

218  ENDO 2022 • Endocrine Case Management

weight loss, changes in dietary composition, and Case 3
increased physical activity. A decrease in weight/
A 2-month-old girl presents with failure to thrive.
BMI will lead to significant improvement in
Her serum is lipemic, and the following values
triglycerides and HDL-C. Changes in dietary
are documented:
quality and composition (even without weight
loss) are also effective in the management of high Total cholesterol = 1295 mg/dL (SI: 33.54 mmol/L)
triglycerides and combined dyslipidemia. Such Triglycerides = 26,000 mg/dL (SI: 293.8 mmol/L)
HDL-C = 8 mg/dL (SI: 0.21 mmol/L)
dietary modifications could include avoiding
added sugars, limiting simple carbohydrates and Amylase and lipase levels are normal for age.
replacing them with complex carbohydrates
and/or low-glycemic load diets, increasing fiber What is the most likely cause of severe
intake, and reducing calorie intake. Each of these hypertriglyceridemia in this patient?
changes is an effective management strategy for A. Dysbetalipoproteinemia
combined dyslipidemia. Children and adolescents
B. Familial chylomicronemia syndrome
aged 5 to 17 years are recommended to have at
least 60 minutes of moderate to vigorous intensity C. FCHL
physical activity every day. D. Multifactorial chylomicronemia syndrome

What is the pharmacologic management Answer: B) Familial chylomicronemia syndrome

of hypercholesterolemia? This patient has had hyperchylomicronemia
Judicious use of pharmaceutical agents such from early infancy, indicating she has familial
as statins, fibrates, or omega-3 fatty acids can chylomicronemia syndrome (FCS) (Answer B),
be considered. Pharmacologic management most likely secondary to autosomal recessive
is geared towards reduction of ASCVD risk lipoprotein lipase deficiency. FCS is an autosomal
later in life. The primary treatment target is recessive disorder due to homozygous or
LDL-C. If LDL-C is greater than 160 mg/dL compound heterozygous pathogenic variants
(>4.14 mmol/L), statin treatment is recommended. in the LPL gene, which encodes lipoprotein
The secondary treatment target is non–HDL-C. lipase (~80% of cases), or in genes regulating the
For triglyceride concentrations between 150 lipoprotein lipase complex: APOC2, APOA5, LMF1,
and 400 mg/dL (1.70 and 4.52 mmol/L) and or GPIHBP1.
non–HDL-C concentrations greater than Mild-to-moderate triglyceride elevations
145 mg/dL (>3.76 mmol/L) despite 6 months of typically reflect high VLDL and high numbers
therapeutic lifestyle changes in children 10 years of remnant lipoprotein particles, while severe
and older, statins are first-line therapy. In the hypertriglyceridemia is due to excess accumulation
case of a triglyceride concentration greater of chylomicrons. Chylomicrons are produced
than 400 mg/dL (>4.52 mmol/L), fibrates are in the intestine in response to dietary fat, and
used along with therapeutic lifestyle changes. VLDL is produced in the liver. Lipoprotein lipase
The role of omega-3 fatty acids in pediatric is the key enzyme involved in the hydrolysis
hypertriglyceridemia is debated. While over-the- of triglycerides in the circulating chylomicrons
counter omega-3 supplements are not beneficial, and VLDL. Lipoprotein lipase deficiency leads
icosapent ethyl, 4 g daily, may be used in older to impaired clearance of triglyceride-containing
children with hypertriglyceridemia. Treatment lipoproteins (ie, chylomicrons and VLDL)
goals are triglyceride levels less than 150 mg/dL from the circulation. These severe triglyceride
(<1.70 mmol/L) and non–HDL-C levels less than elevations could be due to monogenic causes
145 mg/dL (<3.76 mmol/L). such pathogenic variants in the lipoprotein lipase

ENDO 2022 • Pediatric Endocrinology  219

complex, known as FCS, or the multifactorial medium-chain triglyceride oil and coconut oil
chylomicronemia syndrome. are not recommended. In a child requiring a
Multifactorial chylomicronemia syndrome daily caloric intake of 1800 calories, medium-
(Answer D) is due to coexistence of minor genetic chain triglyceride oil should be limited to less
variants (ie, rare heterozygous variants in the than 1 to 2 tablespoons daily (eg, 2 tablespoons
5 FCS-related genes and/or accumulated common of medium-chain triglyceride oil have 28 g of
variants in many other loci associated with fat and 252 calories). The primary objective
small increases in triglyceride levels identified in is to prevent pancreatitis by maintaining
genome-wide association studies) and secondary triglyceride concentrations below 1000 mg/dL
factors. Such patients may present with baseline (<11.30 mmol/L). Medications are ineffective in
normal to moderate triglyceride levels, which the management of FCS.
may change to severe hypertriglyceridemia In patients with multifactorial
secondary to a metabolic insult. In this infant, chylomicronemia syndrome, who almost always
the early onset of severe hypertriglyceridemia have a combination of genetic and secondary
and lack of secondary factors make multifactorial causes for triglyceride elevation, adding a fibrate
chylomicronemia syndrome an unlikely diagnosis is helpful to reduce the risk of acute pancreatitis.
in this infant. Currently, there are no FDA-approved
Familial dysbetalipoproteinemia (Answer A) is medications to treat severe hypertriglyceridemia;
unlikely in this patient because it is characterized hence, it is crucial to follow a strict low-fat diet.
by equal elevations of total cholesterol and For patients older than 18 years, lomitapide and
triglycerides (usually >300 mg/dL) due to the volanesorsen are clinical options in Europe.
combination of homozygous apolipoprotein E2 Initial management of acute pancreatitis
genotype or a rare binding-defective dominant secondary to severe hypertriglyceridemia
variant in the APOE gene in the presence of a is administration of intravenous fluids and
secondary metabolic insult. withholding oral intake. Insulin infusion can be
FCHL (Answer C) can be excluded, as it is tried in patients with diabetes or insulin deficiency
suggested by combined dyslipidemia of later onset, to rapidly lower triglycerides. Withholding oral
not isolated severe triglyceride elevations of early intake rapidly decreases chylomicron synthesis
onset, as in this patient. and reduces saturation of lipoprotein lipase
sites with triglyceride-rich lipoproteins, leading
What is the management of severe to a rapid decrease in the serum triglyceride
hypertriglyceridemia? concentration. Once oral intake is resumed,
Triglyceride concentrations greater than a diet very low in fat (<15% of total calories)
1000 mg/dL (>11.30 mmol/L) are associated can be initiated. After the patient’s condition is
with a significant risk of acute pancreatitis. stable, dietary management for multifactorial
Proper dietary management of severe chylomicronemia syndrome includes avoiding
hypertriglyceridemia is crucial to prevent simple carbohydrates and following a low-fat diet,
pancreatitis.9 The treatment mainstay for FCS which can be slowly titrated to dietary fat content
is restricting fat intake to less than 10% to 15% limited to less than 30% of total daily caloric intake
of dietary calories. Medium-chain triglycerides to maintain triglycerides at a lower level. Strict
in the diet are absorbed directly into the portal glycemic control in patients with diabetes is also
circulation without the need for incorporation recommended. Weight loss is essential in patients
into chylomicron packaging and, hence, do not who are overweight or obese.
require lipoprotein lipase for absorption. Thus,
part of the dietary fat could be consumed as
medium-chain triglycerides. Over-the-counter

220  ENDO 2022 • Endocrine Case Management

Case 4 should be repeated in 6 months. Hence,
stringent fat restriction to less than 15% of
A 14-year-old boy with a BMI of 38 kg/m2
total dietary fat (Answer D) is incorrect. If the
presents for follow-up of type 2 diabetes.
fasting triglyceride concentration is greater
Laboratory test results (sample drawn while fasting): than 1000 mg/dL (>11.30 mmol/L), this would
be required.
Hemoglobin A1c = 8.0% (4.0%-5.6%) (64 mmol/mol
[20-38 mmol/mol]) • If repeated LDL-C is greater than
Total cholesterol = 245 mg/dL (SI: 6.35 mmol/L) 130 mg/dL (>3.37 mmol/L), statin treatment is
Triglycerides = 380 mg/dL (SI: 4.29 mmol/L) recommended to achieve a goal value less than
HDL-C = 36 mg/dL (SI: 0.93 mmol/L)
LDL-C = 133 mg/dL (SI: 3.44 mmol/L)
130 mg/dL (<3.37 mmol/L) and ideally less
Amylase, normal than 100 mg/dL (<2.59 mmol/L). Therefore,
Lipase, normal statin treatment (Answer C) is correct.
• If triglycerides are greater than
Which of the following is the 400 mg/dL (>4.52 mmol/L) fasting or
best management option? greater than 1000 mg/dL (>11.30 mmol/L)
nonfasting, fibrates are recommended to
A. Fenofibrate
reduce the risk for pancreatitis. Since this
B. Omega-3 fatty acids patient’s triglycerides are less than 400 mg/dL
C. Statin (<4.52 mmol/L), fenofibrate (Answer A) and
D. Stringent fat restriction to <15% of total omega-3 fatty acids (Answer B) are incorrect.
dietary fat • Strict glycemic control is recommended in
Answer: C) Statin patients with diabetes.
• Weight reduction, decreasing simple
carbohydrates, and increasing dietary omega-3
How should dyslipidemia be managed fatty acids are also recommended.
in patients with type 2 diabetes?
Patients with type 2 diabetes require careful • Lipid goals are: LDL-C <100 mg/dL
management. Dyslipidemia in these patients (<2.59 mmol/L); HDL-C >35 mg/dL
consists of elevated triglycerides, decreased (>0.91 mmol/L); and triglycerides <150 mg/dL
HDL-C, and occasionally, elevated LDL-C. (<1.70 mmol/L).
These patients also have elevated small, dense
LDL particles, elevated VLDL-C, non–HDL-C, How should dyslipidemia be managed
and apolipoprotein B increasing their high risk in patients with type 1 diabetes?
for future ASCVD. The American Diabetes According to the American Diabetes Association
Association and International Society for Pediatric guidelines,10 lipid testing should be performed in
and Adolescent Diabetes guidelines recommend patients with type 1 diabetes when initial glycemic
lipid screening in patients with new-onset type 2 control has been achieved and the patient is 2
diabetes once glycemic control has been achieved years or older. If LDL-C is 100 mg/dL or less
or 3 months after diagnosis, with annual screening (≤2.59 mmol/L), subsequent testing should be
conducted thereafter. performed at age 9 to 11 years; if this is normal,
• If LDL-C is above goal, glycemic control the lipid profile should be repeated every 3 years.
should be optimized, the American Heart • If LDL-C is abnormal, a lipid profile should be
Association Step 2 diet should be implemented repeated in 6 months.
(<30% of calories as total fat, <7% saturated
fat, and <200 mg cholesterol daily), and testing

ENDO 2022 • Pediatric Endocrinology  221

• After age 10 years, addition of a statin is as above. Similarly, the American Heart
suggested for patients who, despite medical Association classifies both type 1 diabetes
nutrition therapy and lifestyle changes, and type 2 diabetes as high-risk conditions
continue to have LDL-C concentrations for which statin treatment is indicated when
greater than 160 mg/dL (>4.14 mmol/L) or the LDL-C concentration is greater than
greater than 130 mg/dL (>3.37 mmol/L) plus 1 130 mg/dL (>3.37 mmol/L).5,12
or more cardiovascular disease risk factor. • There are no recommendations regarding
• In contrast, the International Society for measurement of apolipoprotein B or screening
Pediatric and Adolescent Diabetes guidelines11 lipoprotein (a).
specify to consider treating at an LDL-C • The goal LDL-C concentration is less than
concentration greater than 130 mg/dL 100 mg/dL (<2.59 mmol/L).
(>3.37 mmol/L) down to the same goal

References
1. Gidding SS, Leibel RL, Daniels S, Rosenbaum M, Van Horn L, Marx GR. 6. Wilson DP, McNeal C, Blackett P. Pediatric dyslipidemia: recommendations
Understanding obesity in youth. A statement for healthcare professionals for clinical management. South Med J. 2015;108(1):7-14. PMID: 25580750
from the Committee on Atherosclerosis and Hypertension in the Young 7. Ashraf AP, Sunil B, Bamba V, et al. Case studies in pediatric lipid disorders
of the Council on Cardiovascular Disease in the Young and the Nutrition and their management. J Clin Endocrinol Metab. 2021;106(12):3605-3620.
Committee, American Heart Association. Writing Group. Circulation. PMID: 34363474
1996;94(12):3383-3387. PMID: 8989156 8. Sunil B, Foster C, Wilson DP, Ashraf AP. Novel therapeutic targets
2. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant and agents for pediatric dyslipidemia. Ther Adv Endocrinol Metab.
hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype 2021;12:20420188211058323. PMID: 34868544
relationship, and clinical outcome. Eur Heart J. 2015;36(9):560-565. PMID: 9. Valaiyapathi B, Sunil B, Ashraf AP. Approach to hypertriglyceridemia in the
24585268 pediatric population. Pediatr Rev. 2017;38(9):424-434. PMID: 28864733
3. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. 10. American Diabetes Association Professional Practice Committee; American
Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels Diabetes Association Professional Practice Committee; Draznin B, et al. 14.
in 176 families and delineation of a new inherited disorder, combined Children and adolescents: standards of medical care in diabetes–2021. Diabetes
hyperlipidemia. J Clin Invest. 1973;52(7):1544-1568. PMID: 4718953 Care. 2021;44(Suppl 1):180-199. PMID: 34964865
4. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 11. Donaghue KC, Marcovecchio ML, Wadwa RP, et al. ISPAD clinical practice
Reduction in Children and Adolescents; National Heart, Lung, and Blood consensus guidelines 2018: microvascular and macrovascular complications in
Institute. Expert panel on integrated guidelines for cardiovascular health children and adolescents. Pediatr Diabetes. 2018;19(Suppl 27):262-274. PMID:
and risk reduction in children and adolescents: summary report. Pediatrics. 30079595
2011;128(Suppl 5):S213-S256. PMID: 22084329 12. Sunil B, Ashraf AP. Dyslipidemia in pediatric type 2 diabetes mellitus. Curr
5. De Ferranti SD, Steinberger J, Ameduri R, et al. Cardiovascular risk reduction Diab Rep. 2020;20(10):53. PMID: 32909078
in high-risk pediatric patients: a scientific statement from the American Heart
Association. Circulation. 2019;139(13):e603-e634. PMID: 30798614

222  ENDO 2022 • Endocrine Case Management

Approach to Fractures
in Children
Rachel I. Gafni, MD. Skeletal Disorders and Mineral Homeostasis Section, National Institute
of Dental and Craniofacial Research, NIH, Bethesda, MD; E-mail: [email protected]

Learning Objectives • Off-label use of bisphosphonates may

be considered in some patients, with
As a result of participating in this session, learners
appropriate monitoring.
should be able to:
• Recognize the most common causes of
recurrent fractures in children and develop a
plan of evaluation for these patients. Significance of the
• List current indications for obtaining a dual- Clinical Problem
energy x-ray absorptiometry (DXA) scan and Fractures are frequent in children and adolescents
understand its interpretation and limitations due to the geometry of the growing skeleton and
in children. high levels of physical activity. Affected children
• Develop a treatment and monitoring plan, may experience pain, skeletal deformity, and
keeping in mind the potential comorbidities missed school days; with severe fractures, surgical
that may be associated with the underlying intervention may be required. Thus, when fractures
disease and/or its therapy. are recurrent, it is important to determine whether
there are underlying pathologic factors contributing
to bone fragility. The differential diagnosis for
recurrent fractures is extensive, ranging from
Main Conclusions rare genetic disorders to common nutritional
deficiencies, and thus an in-depth evaluation is
• Fractures are common in children and required. While DXA is the standard screening tool,
adolescents, particularly during times of interpretation in the pediatric population differs
peak growth. from that in adults and is frequently misunderstood.
Therefore, proper evaluation for children with
• Low bone mineral density (BMD) and fragility
recurrent fractures is critical for making the
fractures in children and adolescents may be
diagnosis and initiating the correct therapy.
caused by a variety of genetic, medical, or
nutritional conditions.
• DXA is a useful screening tool for low BMD; Barriers to Optimal Practice
however, correlation with fracture risk in sick
populations has not been well established. • Fractures are common in children, leading to
delay in evaluation for underlying pathology.
• Identifying the cause of low BMD and
reversing the underlying disease may lead to • DXA is most commonly done in adults,
partial or complete skeletal recovery. particularly in postmenopausal women.
Therefore, it is often difficult for practitioners
to find a local densitometry center skilled in

ENDO 2022 • Pediatric Endocrinology  223

 the performance and interpretation of DXA Evaluating the Child With
in children. Recurrent Fractures
• There are no FDA-approved therapies for History and Physical Examination
definitive treatment of osteoporosis in children. Given the long list of possible causes of skeletal
fragility (Box), a systematic evaluation is crucial.4,5
A careful history and physical examination with
Strategies for Diagnosis, special attention to family history, comorbidities,
Therapy, and/or Management kidney stones, dental issues, birthmarks/bruising,
hyperextensibility, back/joint pain, rachitic
Fractures in Childhood deformities, and identification of dysmorphic
Fractures are common in children, occurring in features are important. Dietary habits should
approximately 50% of boys and 33% of girls. The be reviewed to identify relevant nutritional or
fracture rate peaks between ages 11 and 15 years, caloric insufficiencies. A detailed fracture history
with girls peaking earlier, consistent with the should include patient age, number of fractures,
earlier pubertal growth spurt. The most common site, severity, and mechanism, as well as the
site for fracture is the forearm (about 25%-30% adequacy of fracture healing. A history concerning
of fractures).1 Risk factors for fractures include for nonaccidental trauma should be addressed
intrinsic factors such as bone density, size, and promptly. Minor finger and toe fractures
geometry, as well as extrinsic factors such as activity occurring with an appropriate trauma are usually
and impact. High participation in youth sports excluded from the definition of significant fracture
may be contributing to an increase in childhood history, unless excessive.
fractures, including overuse insufficiency fractures.
When evaluating a child with fractures for Laboratory Investigation
underlying pathology, one should consider the site In a patient with a clinically significant fracture
and mechanism of fracture, as well as any known history, laboratory studies assessing bone and
medical conditions in the child. For example, a mineral metabolism should be completed.
finger fracture sustained while playing basketball These include measurement of albumin-
in an otherwise healthy child is generally not of corrected calcium, phosphate, magnesium,
concern, while a femur or a vertebral fracture creatinine, 25-hydroxyvitamin D, and intact
after falling from a standing height would be PTH. Measurement of 1,25-dihydroxyvitamin
unexpected. There is no set-in-stone rule for when D and FGF23 should be considered if the history
a child with fractures should undergo DXA. In suggests calcipenic or phosphopenic rickets.
general, DXA is considered for children with a Additional screening laboratory tests such as
“clinically significant fracture history,” defined as2: complete chemistry panels, complete blood cell
count, erythrocyte sedimentation rate, tissue
1. A vertebral compression fracture or transglutaminase antibodies, and thyroid function
2. 2 or more long bone fractures before age tests may be considered, driven by the history
10 years or and physical examination, to identify systemic
3. 3 or more long bone fractures before age 19 years undiagnosed conditions. Age-appropriate normal
ranges should be used for interpretation of
In addition, DXA should be considered for laboratory results, especially blood phosphate, which
children with medical conditions or for children is significantly higher in neonates and gradually
who are receiving treatments known to affect decreases during childhood and adolescence until
bone density, even in the absence of fractures.3 finally reaching the adult normal range. Urinary
creatinine and calcium excretion should be
measured; 24-hour collections are ideal. Again,

224  ENDO 2022 • Endocrine Case Management

age-specific urinary calcium and creatinine normal may be falsely elevated in patients with tall stature.
references should be applied and 24-hour collections Mathematical models have been developed to
should be corrected for body weight (normal calcium correct for variations in bone size; one method
excretion: <4 mg/kg per 24 h or <0.1 mmol/kg per is to use the height Z-score to adjust the BMD
day). Genetic testing is commercially available for Z-score. One online calculator specific to Hologic
many of the causes of skeletal fragility. densitometers can be found here: https://zscore.
research.chop.edu/calcpedbonedens.php.7 Other
Dual-Energy X-ray Absorptiometry factors that may confound DXA interpretation
When ordering screening DXA in children, include altered pubertal timing, surgical hardware,
consensus guidelines recommend assessing the and compression fractures (which decrease bone
postero-anterior lumbar spine and the total area and artifactually increase BMD).
body-less head.2-4 The head is excluded because A BMD Z-score between –2 and +2 SD
it is disproportionally large compared with the is considered to be within the normal range.
rest of the skeleton in children and may confound However, the correlation between BMD and
interpretation of low BMD. These 2 sites are the fracture risk in children is not well-established,
most reproducible with the greatest availability particularly in children with chronic diseases.
of normal reference databases. Reference Thus, the diagnosis of osteoporosis not based on
databases used should be specific to the brand DXA alone; rather, it is a clinical diagnosis.2 For
of densitometer. Using these databases, one example, a child with an atraumatic vertebral
can calculate the Z-score, which is the standard compression fracture is considered to have
deviation score compared with age-, sex-, and osteoporosis, even when DXA results are within
race-matched healthy controls. T-scores, which the normal range. Of note, BMD may be markedly
calculate the standard deviation scores compared elevated in sclerosing bone disorders such as
with young adults at peak bone mass, should osteopetrosis. Finally, DXA cannot distinguish
never be used in children. Alternative sites between osteoporosis and osteomalacia (impaired
such as the proximal femur and distal radius are mineralization).
more affected by changes in skeletal growth but
may be informative in older adolescents. DXA Additional Testing
acquisition requires careful positioning of the Guided by the history and physical examination,
patient to ensure that the data generated can be radiographs may be useful for identifying rickets,
interpreted compared with normal databases. In brachydactyly, fibrous dysplasia, or other skeletal
children with scoliosis, contractures, or skeletal abnormalities seen with several disorders
deformity, appropriate positioning may be difficult associated with bone fragility. In patients at high
or impossible. In such patients, lateral distal femur risk for osteoporosis due to known underlying
DXA may be performed and interpreted using conditions or treatments (eg, leukemia, muscular
published normative databases.6 dystrophy, chronic glucocorticoid use), lateral
Results from DXA include bone mineral spine films may uncover asymptomatic vertebral
content measured in grams, area in cm2, and BMD fractures, particularly in the thoracic region.8
reported in g/cm2. As DXA is a 2-dimensional In cases of hypercalciuria, kidney
image of a 3-dimensional structure, this ultrasonography is recommended to evaluate for
measurement output is better described as “areal nephrocalcinosis.
BMD” (aBMD), as it does not represent true Collaboration with other specialists, including
density, which is calculated as mass per volume. orthopedics, nephrology, hematology, neurology,
Therefore, aBMD is highly affected by bone size rheumatology, genetics, and gastroenterology, is
such that patients with short stature for age may often essential in arriving at the correct diagnosis.
have artifactually low aBMD. Conversely, aBMD

ENDO 2022 • Pediatric Endocrinology  225

Box. Selected Causes of Skeletal Fragility in Children4
• Nutritional/malabsorptive
Primary bone disorders ԗ Vitamin D deficiency
• Osteogenesis imperfecta ԗ Celiac disease
• Osteoporosis pseudoglioma syndrome ԗ Anorexia nervosa
• Ehlers-Danlos syndrome ԗ Relative energy deficiency in sport (RED-S)
• Marfan syndrome ԗ Biliary atresia
• Homocystinuria ԗ Cystic fibrosis
• Hajdu-Cheney syndrome • Iatrogenic
• Fibrous dysplasia ԗ Glucocorticoids
• Hypophosphatasia ԗ Anticonvulsants
• Pycnodysostosis ԗ Methotrexate
• Osteopetrosis ԗ Radiation therapy
• Idiopathic juvenile osteoporosis
Adapted from Boyce AM & Gafni RI. J Clin Endocrinol Metab, 2011; 96(7)
Secondary bone disorders
© Endocrine Society.
• Chronic inflammatory conditions
ԗ Rheumatologic disease
ԗ Inflammatory bowel disease
Management
• Nephrology Once acute fractures are managed by the
ԗ Nephrotic syndrome orthopedist, the primary goal is the prevention
ԗ Renal insufficiency of future fractures. Optimization of nutrition
ԗ Tubulopathies/acidosis and ensuring adequate calcium and vitamin D
ԗ Hypercalciuria intake is appropriate for all patients. Weight-
• Neurology/reduced mobility bearing exercise and/or physical therapy should
ԗ Cerebral palsy be encouraged and tailored to the capacity of the
ԗ Muscular dystrophies
individual, keeping in mind that patients with
ԗ Posttraumatic/spinal cord injury
recurrent fractures due to anorexia nervosa or
relative energy deficiency in sport (RED-S) will
• Hematology/oncology
need to reduce or alter their exercise routine.9 In
ԗ Leukemia/malignancy
otherwise healthy children with normal BMD and
ԗ Thalassemia
an explainable mechanism of injury, observation is
ԗ Sickle cell anemia
often the best course. In children for whom a clear
ԗ Mastocytosis
bone-impairing disease is identified, treating the
• Endocrinology
underlying disorder is the first step, as the growing
ԗ Hypogonadism
skeleton has tremendous capacity for remodeling
ԗ Growth hormone deficiency
and restoring bone density.8 For example, vitamin
ԗ Cushing syndrome
D deficiency rickets in a toddler responds entirely
ԗ Hyperthyroidism
over time with appropriate supplementation.
ԗ Diabetes mellitus
However, many conditions are incompletely
ԗ Rickets (calcipenic and phosphopenic)
reversible, ongoing, or progressive, warranting
pharmaceutical intervention.
Currently approved therapies for osteoporosis
in adults include antiresorptive drugs
(bisphosphonates, selective estrogen receptor
modulators, RANK-ligand analogues) and
anabolic drugs (teriparatide, PTHrP analogues,
sclerostin antibody). To date, none of these

226  ENDO 2022 • Endocrine Case Management

medications have been approved for use in Clinical Case Vignettes
children. The greatest experience in pediatrics
has been off-label use of bisphosphonates over Case 1
the last 25 years.10 Bisphosphates are analogues of A 12-and-11/12-year-old girl presents with a
pyrophosphates that are not degraded by skeletal history of 5 fractures: 3 supracondylar fractures
pyrophosphatases. They are incorporated into at ages 3, 5, and 9 years; an L3 compression
newly forming bone where they can remain fracture at age 10 years while skiing; and an
for decades. When released, bisphosphonates L1 compression fracture at age 12 years while
inhibit osteoclast function resulting in suppressed sledding. She seems otherwise healthy with
bone resorption. The most commonly used normal puberty, and height percentile was 85%
bisphosphonates in children are pamidronate and to 90% before the vertebral fractures. DXA of the
zoledronate, given intravenously every 3 months lumbar spine at age 10 years showed a Z-score
and every 6 to 12 months, respectively. The –0.94; DXA was repeated at age 12 years with a
treatment regimen varies among institutions, but, Z-score of –1.4.
in general, the initial dose is reduced to prevent
the acute-phase reaction that is frequently seen Which of the following is the most
with the first infusion. important thing to do next?
The most common adverse effects seen A. Counsel her on increasing dietary calcium and
with bisphosphonates are acute-phase reactions, vitamin D intake
hypocalcemia, hypophosphatemia, and bone pain. B. Perform genetic testing for type 1 osteogenesis
These transient adverse effects are usually easily imperfecta
managed with calcium, calcitriol, nonsteroidal
C. Reassure her that these fractures are consistent
antiinflammatory drugs and, occasionally, short
with high-impact sports (sledding and skiing)
bursts of glucocorticoids. Calcium and vitamin D
and counsel her to be more careful
intake should also be optimized prior to initiating
bisphosphonate therapy. Oral nitrogen-containing D. Recalculate her BMD Z-scores adjusted for
bisphosphonates have not been well-studied in height Z-score
children and can cause irritant esophagitis; therefore, Answer: D) Recalculate her BMD Z-scores
they are used less frequently in pediatric patients adjusted for height Z-score
and should be avoided in those with reflux and
cognitive impairment. Bisphosphonate-associated This patient has tall stature, which can artifactually
osteonecrosis of the jaw has been reported in adults increase aBMD measurement. In this case, the
but has not been seen in children. Regardless, patient’s height SD is approximately +1.5, while
a thorough dental evaluation with necessary her uncorrected aBMD Z-scores are negative
extractions performed is recommended prior to the and decreasing. When the aBMD Z-scores were
first bisphosphonate dose. Prolonged and excessive corrected for her tall stature (Answer D), the
use of bisphosphonate can lead to bisphosphonate- Z-score was –1.4 at age 10 years and –1.94 at age
induced osteopetrosis, characterized by defects in 12 years. Given that her fractures were in the
skeletal modeling. Thus, periodic DXA scans (every lumbar vertebrae, which can reduce the DXA area
6 to 12 months) and wrist or knee x-rays (every 1 to measurement, the true aBMD may have been even
3 years) are recommended to avoid overtreatment. lower than that.
The timing for bisphosphonate interruption (drug Vertebral fractures are uncommon in children,
holidays) or discontinuation is not well established. even with vigorous activity (thus, Answer C is
In general, these strategies can be considered when incorrect).
the BMD Z-score is greater than –2 and/or the child While patients with type 1 osteogenesis
is no longer having fractures. imperfecta often have normal stature, correct

ENDO 2022 • Pediatric Endocrinology  227

analysis of DXA and assessment of other D. Zoledronate infusion with reassessment of
laboratory tests should be done before genetic DXA in 6 months
testing (Answer B).
Increasing calcium and vitamin D intake Answer: B) Nutritional counseling and decreased
(Answer A) may be an important therapeutic running with cross-training and pool exercises
option for this patient; however, it is important to This patient has relative energy deficiency in sport
appropriately interpret the results of testing prior (RED-S), formerly known as the “female athlete
to developing a treatment plan. triad.” RED-S is characterized by disordered
This patient was ultimately diagnosed with eating, oligomenorrhea or amenorrhea, and
celiac disease, and her BMD improved on a gluten- decreased bone health. Affected patients can
free diet. be difficult to treat because they are often very
competitive and goal oriented. Treatment is
Case 2 centered on normalizing eating, increasing body
fat, and reducing the repetitiveness of impact
A 15-year-old girl has sustained several stress
loading (Answer B). Over time, these efforts lead
fractures in her tibias that have healed very slowly.
to return of menses and improved bone health.
On questioning, you learn that she is a competitive
While an oral contraceptive (Answer C) may be
runner and is hoping to get a scholarship to a
indicated in this patient to prevent pregnancy, this has
division 1 college. Between school and practices,
not been shown to improve bone density in patients
her eating is erratic, and she grabs quick meals and
with RED-S. Studies in patients with anorexia
snacks whenever she can. She is very thin, and her
nervosa indicate that when supplemental estrogen is
last menses was 9 months ago. On DXA, her total
needed, the transdermal route is more effective.
body-less head Z-score is –2.2.
A leg brace (Answer A) may be useful in the
Which of the following should acute management of a stress fracture but will
be recommended? not address the underlying pathology or prevent
future fracture.
A. Leg brace to stabilize her tibia
Bisphosphonate therapy (Answer D) would
B. Nutritional counseling and decreased running not be indicated before implementing these other
with cross-training and pool exercises measures and in the absence of a true fragility fracture.
C. Oral contraceptive to restore her menses

Acknowledgment
Work in the author’s laboratory is supported by the Intramural Research Program of the National Institutes
of Health, National Institute of Dental and Craniofacial Research.

228  ENDO 2022 • Endocrine Case Management

References
1. Hedström EM, Svensson O, Bergström U, Michno P. Epidemiology of fractures 7. Zemel BS, Kalkwarf HJ, Gilsanz V, et al. Revised reference curves for bone
in children and adolescents. Acta Orthop. 2010;81(1):148-153. PMID: 20175744 mineral content and areal bone mineral density according to age and sex
2. Gordon CM, Leonard MB, Zemel BS; International Society for Clinical for black and non-black children: results of the bone mineral density in
Densitometry. 2013 Pediatric Position Development Conference: executive childhood study [published correction appears in J Clin Endocrinol Metab.
summary and reflections [published correction appears in J Clin Densitom. 2013;98(1):420]. J Clin Endocrinol Metab. 2011;96(10):3160-3169. PMID:
2014;17(4):517]. J Clin Densitom. 2014;17(2):219-224. PMID: 24657108 21917867
3. Guss CE, McAllister A, Gordon CM. DXA in children and adolescents. J Clin 8. Ward LM, Ma J, Lang B, et al; Steroid-Associated Osteoporosis in the
Densitom. 2021;24(1):28-35. PMID: 32111573 Pediatric Population (STOPP) Consortium. Bone morbidity and recovery in
4. Boyce AM, Gafni RI. Approach to the child with fractures. J Clin Endocrinol children with acute lymphoblastic leukemia: results of a six-year prospective
Metab. 2011;96(7):1943-1952. PMID: 21734001 cohort study. J Bone Miner Res. 2018;33(8):1435-1443. PMID: 29786884
5. Weber DR. Bone health in childhood chronic disease. Endocrinol Metab Clin 9. Joy E, De Souza MJ, Nattiv A, et al. 2014 female athlete triad coalition
North Am. 2020;49(4):637-650. PMID: 33153671 consensus statement on treatment and return to play of the female athlete
6. Weber DR, Boyce A, Gordon C, et al. The utility of DXA assessment at the triad. Curr Sports Med Rep. 2014;13(4):219-232. PMID: 25014387
forearm, proximal femur, and lateral distal femur, and vertebral fracture 10. Ward LM. Part 2: when should bisphosphonates be used in children with chronic
assessment in the pediatric population: 2019 ISCD official position. J Clin illness osteoporosis? Curr Osteoporos Rep. 2021;19(3):289-297. PMID: 34146247
Densitom. 2019;22(4):567-589. PMID: 31421951

ENDO 2022 • Pediatric Endocrinology  229

REPRODUCTIVE
ENDOCRINOLOGY
Polycystic Ovary Syndrome
Across the Lifespan
Melanie Cree Green, MD, PhD. Department of Pediatrics, Endocrine Section, University
of Colorado Anschutz Campus and Children’s Hospital Colorado, Aurora, CO; E-mail
[email protected]

Kathleen M. Hoeger, MD, MPH. Department of Obstetrics and Gynecology, Division of

Reproductive Endocrinology, University of Rochester, Rochester, NY; E-mail kathy_hoeger@
urmc.rochester.edu

Learning Objectives Connection with peer-support networks should be

encouraged.
As a result of participating in this session, learners
should be able to:
• Accurately diagnose polycystic ovary syndrome Significance of the
(PCOS) in patients of any age.
Clinical Problem
• Determine how and when to screen for and
PCOS is a common menstrual disorder in women,
treat related metabolic disease.
estimated to affect 10% to 15% of all reproductive-
• Explain management options for obesity- aged women, and it can affect females across the
related PCOS concerns. lifespan.1 The prevalence of PCOS in women who
• Describe the best initial fertility options for also have obesity may be even higher, up to 1 in 5
patients with PCOS. women. The underlying pathology of PCOS is not
well understood, but it may be related to increased
• Identify additional PCOS-related conditions
LH secretion, increased ovary sensitivity to LH and
to screen for and treat and determine when to
insulin, and excess insulin concentrations.1 Some
refer to other specialists.
women have a genetic predisposition for PCOS.2,3
Hormone differences can be detected in childhood
in girls whose mothers have PCOS.4 A history
of early adrenarche (<8 years) and menarche
Main Conclusions (<10 years) is associated with a higher risk of
PCOS is a very common disorder in women developing PCOS.5 PCOS can first be diagnosed
and affects females from childhood through in adolescence, with the presentation of irregular
menopause. PCOS evaluation must be complete, menses, although many women do not present
but it should not include ovary ultrasonography until adulthood when they experience difficulty
in adolescents. PCOS can affect metabolic and with conception.6-9 Approximately 60% of women
psychologic health, and once it is diagnosed, with PCOS become overweight; persistent weight
affected patients should be screened for the full gain and difficulty with weight loss are common
spectrum of associated conditions. Treatment presenting concerns.1 PCOS symptoms can
plans should be developed with the patient to meet continue through menopause, when hormonal
their unique needs and identified treatment goals. alterations resolve, but metabolic complications

232  ENDO 2022 • Endocrine Case Management

can continue, although potentially at the same and ethnicity, similar to risks for metabolic disease
rates as those of women without PCOS.10,11 in women without PCOS.25
A key component of PCOS is menstrual In addition to hormonal and metabolic
dysfunction, with many reproductive system consequences, PCOS affects many other aspects
consequences. Due to ovulatory dysfunction, of health. Women with PCOS have higher rates
PCOS is a leading cause of female infertility.1 of mood disruption and disordered eating.26,27
Ovulation induction is a primary therapy for Increased rates of depressive symptoms have been
infertility in patients with PCOS. Women noted in adolescents with PCOS.28 Sleep duration
with PCOS undergoing ovulation induction and circadian rhythms may also be altered in some
have increased risk of multiple gestation and women with PCOS, which can further contribute
ovarian hyperstimulation, so careful assessment to metabolic disease.17,29 Beyond the typical clinical
is required and oral agents are preferred as the manifestations of hyperandrogenism, including
starting treatment. Additionally, long periods hirsutism, acne, and alopecia, PCOS is associated
of amenorrhea increase the risk for endometrial with hidradenitis suppurativa.30 Acanthosis is also
hyperplasia. The rates of endometrial cancer are common, particularly in adolescents.31
higher in women with PCOS and are thought
to be related to extended periods without
endometrial shedding.12 There does not appear to
Barriers to Optimal Practice
be an increased risk for breast or ovarian cancer
• Diagnosis of PCOS can be challenging,
when controlled for obesity.12
especially in adolescents.
PCOS is associated with many long-term
detrimental metabolic consequences, including • PCOS affects many systems, and patient care
hypertension, central adiposity, dyslipidemia, therefore requires longer appointment times
hyperglycemia, type 2 diabetes, nonalcoholic fatty and multidisciplinary care.
liver disease, and obstructive sleep apnea.1,13-17
These metabolic risks are in excess in women
with PCOS and are not just a consequence of Strategies for Diagnosis,
related obesity. The relative risk of developing Therapy, and/or Management
type 2 diabetes is almost 4 times higher in
women with PCOS compared with risk in Diagnosis
control patients after adjustment for age and On average, it takes up to 4 physician visits and
is 2.4 times higher after further adjustment for more than 2 years for patients to be diagnosed
BMI.18 The risk for diabetes in adolescent girls is with PCOS. Efforts should be made to expedite
even higher.16 Lipid abnormalities are common, an accurate diagnosis.32 PCOS should be
in up to 70% of affected women, with low HDL considered in any woman with irregular menses,
cholesterol being the most common abnormality.19 especially if the patient also manifests signs
Epidemiological studies have not yet defined a of clinical hyperandrogenism. The diagnostic
clear increase in long-term cardiovascular events, criteria were updated in the 2018 international
but the risk factors for cardiovascular disease, guidelines, in particular for adolescents, and
early atherosclerosis deposition, and endothelial have been further clarified (Table 1).1,31 History
dysfunction are present in women with PCOS.20 should be comprehensive, including age at
Rates of nonalcoholic fatty liver disease are 2- to menarche, timing of menses, signs or symptoms
3-fold higher in women with PCOS, as are rates of of hyperandrogenism, dermatologic history,
obstructive sleep apnea.21-24 The risks for metabolic sleep, obesity history if relevant, fertility plans,
disease seem to vary depending on a patient’s race prior treatments, family history of PCOS, type 2
diabetes, and early cardiovascular death. Mood

ENDO 2022 • Reproductive Endocrinology  233

Table 1. Diagnostic Characteristics of PCOS in Adolescents

1. Menstrual Primary amenorrhea >15 years of age

abnormalities
>3 years after thelarche
Oligomenorrhea Irregular menses are normal during the first gynecologic year
>1 year postmenarche, >90 days for any cycle
>1 to <3 years postmenarche cycle length <21 or >45 days
>3 years postmenarche to perimenopause: <21 or >35 days or <8 cycles per year
2. Clinical or Clinical Acne: severe or cystic acne unresponsive to topical treatment
biochemical evidence hyperandrogenism
of hyperandrogenism Hirsutism: use Ferriman-Gallwey score, score of >4 to 8 is abnormal depending on
race and ethnicity
Androgenic alopecia: Ludwig alopecia scale (score of 0-4)
Biochemical Ideally liquid chromatography–tandem mass spectrometry should be used for most
hyperandrogenism accurate measurement of total testosterone
Calculated free testosterone concentration, free androgen index, or calculated
bioavailable testosterone should be used, as those with obesity can have low SHBG
and “normal” total testosterone
A morning sample during menses will yield the highest concentrations
Because of estrogen’s effects on SHBG and altered gonadotropin-dependent
androgen production, androgen concentrations cannot be interpreted if an individual
is taking estrogen-containing medications
When determination of androgen concentrations is essential for women on hormonal
contraception, they must have ≥3 months of withdrawal with provision of alternative
forms of contraception
Other diagnostic Ovarian imaging <8 years postmenarche ovarian ultrasonography should not be used to diagnose
considerations polycystic ovary morphology due to the high prevalence of multifollicular ovary
morphology
>8 years postmenarche demonstrating ≥20 antral follicles per ovary or ≤10 cm
volume in a single ovary is diagnostic
PCOS is a diagnosis Exclude other causes of amenorrhea/oligomenorrhea:
of exclusion
• Pregnancy: β-hCG
• Thyroid abnormalities: TSH
• Prolactinoma: prolactin
• Primary gonadal failure: FSH
• Hypothalamic amenorrhea: FSH, history
• Absence of uterus, outflow obstruction: pelvic ultrasonography
Exclude other causes of hyperandrogenism:
• Congenital adrenal hyperplasia due to 21-hydroxylase deficiency:
17-hydroxyprogesterone
• Other disorders of steroidogenesis
• Tumor: consider imaging if testosterone or DHEA-S is greatly elevated
• Cushing syndrome can be considered, but testing is not routine
Other laboratory tests Antimullerian hormone should not be used routinely to diagnose PCOS due to lack of
assay standardization or validated cutoffs
Additional Insulin resistance and hyperinsulinemia are not diagnostic criteria for PCOS
considerations
Obesity is not a diagnostic criterion for PCOS

234  ENDO 2022 • Endocrine Case Management

should be screened in all women with PCOS at Hormonal therapies are primarily to address
the time of diagnosis. The physical examination endometrial health, and those with estrogen
should be comprehensive and assess for severity can reduce symptoms of hyperandrogenism.1
of acne, hirsutism as scored by the modified Metformin (goal dosage 2000 mg daily) is
Ferriman-Gallwey scale,33 androgenic alopecia,34 prescribed to moderately decrease testosterone and
acanthosis nigricans, skin tags, hidradenitis hyperandrogenic symptoms and prevent diabetes
suppurativa, thyroid size, airway and tonsil in adults. Metformin can contribute to weight loss
size, liver size, peripheral edema, and striae size in patients of all ages. Metformin is thought to be
and color. more effective if a patient already has evidence
of dysglycemia.1 In women with obesity, early
data suggest that GLP-1 receptor agonists are a
Management
promising option for PCOS, and bariatric surgery
Treatment Modalities is highly effective.37-41
PCOS care should be delivered in an empathetic
manner and be patient-centered. Goals should
be set collaboratively, as there are currently high Clinical Case Vignettes
rates of treatment dissatisfaction.1,32,36 Screening Case 1
and treatment of conditions related to PCOS are
described in Tables 2 and 3. All patients should A 14-year-old girl presents with irregular menses.
be counseled on developing or maintaining a She had menarche 15 months ago and has had 1
healthy lifestyle, including food, activity, and stress additional menses since then (5 months ago). She
management components. Women may benefit has acne on her face, chest, and back. She is not
from being connected with peer-support groups.36 bothered by excess hair growth. She has struggled
with weight since she started puberty. She stopped

Table 2. Screening for Conditions Related to PCOS

Condition Testing modality Frequency

Skin conditions Physical exam, referral to dermatology if needed Every visit
Infertility Assessment of other factors contributing to fertility, When desired by the patient; should be discussed at
ovulation induction; referral to fertility clinic if needed regular visits to inform and advise
Hyperlipidemia Fasting lipid panel At diagnosis; frequency of repeated measurement
depends on presence of hyperlipidemia and
cardiovascular disease risk
Hypertension Resting blood pressure Every visit
24-hour ambulatory blood pressure
Dysglycemia 2-hour 75-g oral glucose tolerance test or hemoglobin At diagnosis, then every 1 to 3 years (every 3 to
A1c measurement 6 months in adolescents with prediabetes)
Nonalcoholic fatty Alanine aminotransferase, if elevated referral to At diagnosis, then every 1 to 3 years
liver disease hepatology for transient elastography or biopsy
Obstructive sleep Screening question on snoring, daytime sleepiness, At diagnosis, then every 1 to 3 years
apnea morning headaches, restless sleep
Referral to sleep/pulmonary for polysomnography
if needed
Quality of life/sexual PCOS quality of life survey,35 referral to psychology/ At diagnosis and at every visit if needed
dysfunction psychiatry if needed
Mood disorder Mood screening survey, referral to psychology/ At diagnosis and at every visit if needed
psychiatry if needed
Disordered eating Eating history, referral to psychology/psychiatry At diagnosis and at every visit if needed
if needed

ENDO 2022 • Reproductive Endocrinology  235

Table 3. Approaches to Treating Conditions Associated With PCOS

Endometrial health/contraception Obesity or weight gain

• Combined hormonal contraceptive pills, patch, or ring • Nutritional modification
• Cyclic progesterone every 3 months*† • Activity/exercise plans
• Daily progesterone*† ԗ No type of exercise is superior
• Long-acting contraception; implantable 3-year progesterone or • Metformin
progesterone intrauterine device42*
• Weight-loss medication
• Metformin†
• Avoid weight gain–causing medications
• Bariatric surgery
Fertility Dermatologic
• Lifestyle modification with weight loss if patient has obesity • Hirsutism: combined hormonal contraceptive, spironolactone,
topical eflornithine, laser hair reduction, electrolysis
• Metformin
• Acne: combined hormonal contraceptives, spironolactone,
• Letrozole
benzoyl peroxide, salicylic acid, topical antibiotic, topical
• Clomiphene citrate retinoid, oral retinoid
• In vitro fertilization • Hidradenitis: chlorhexidine gluconate, oral minocycline/
doxycycline
Optimize metabolic control, especially glucose if patient has
diabetes • Acanthosis: lactic acid lotion, metformin

Other metabolic conditions such as diabetes, nonalcoholic fatty liver disease, obstructive sleep apnea, hypertension, hyperlipidemia,
depression, or anxiety should be treated in standard-of-care fashion for each condition

* Will not decrease testosterone or dermatologic manifestations of PCOS.

† Not effective contraception.

playing sports partly because she felt like it was D. No, we do not know her serum testosterone
exacerbating the boils on her groin and under her concentration
bra. She is now home schooled as she was having E. Yes, this is a classic presentation for PCOS
problems with friends and having trouble getting
up in the morning. Her family history is notable Answer: C) Yes, she has gone >90 days between
for type 2 diabetes in her mother and PCOS in a menses in the second menarcheal year
paternal aunt.
For adolescents, oligomenorrhea in the second
On physical examination, she is overweight
menarcheal year is considered abnormal if
(BMI = 92nd percentile) and is not hypertensive.
there are more than 90 days between menses
She has moderate acne. Her Ferriman-Gallwey
(Answer C). Primary amenorrhea 3 years after
score is 12, including scores of 3 on the upper lip
thelarche is also considered abnormal, but the
and chin. She also has active hidradenitis under the
age of thelarche was not noted in the vignette—a
breasts and on the groin and grade 4 acanthosis on
reminder to be comprehensive in obtaining
the neck.
pubertal history. The diagnosis of PCOS can be
made based on oligomenorrhea and clinical signs
Does this patient meet international
of hyperandrogenism after all other causes of each
guideline criteria for PCOS?
have been ruled out.
A. No, she is only 15 months postmenarche
B. Yes, she had menarche 4 years after breast
development, so technically had delayed menses
C. Yes, she has gone >90 days between menses in
the second menarcheal year

236  ENDO 2022 • Endocrine Case Management

Additional questions: What would be the Case 2
benefits of combined oral contraceptives
A 35-year-old G1P1001 woman with PCOS and
for her? What would you recommend
obesity (BMI = 55 kg/m2) presents with concerns
regarding her hirsutism? What can you
about weight gain and metabolic risks. Her
suggest for the hidradenitis and acanthosis?
What other conditions would you like weight has fluctuated over time, and she has been
to get more information about? unsuccessful sustaining weight loss (see Figure).
Elevated testosterone can contribute to acne,
hirsutism, and hidradenitis, and all may
be improved with treatment of combined
hormonal contraception. A combined hormonal
contraceptive could decrease her risk for
endometrial cancer and cause regular (or
suppressed) menses, if desired. Note that the
patient states that she is not bothered by hirsutism
despite a clinically significant Ferriman-Gallwey
score. This is a reminder that treatments should
be patient-led. She is describing symptoms She is interested in options for losing weight
of hidradenitis, which can be managed with and controlling her metabolic risks. She has a
topical chlorhexidine gluconate and referral to levonorgestrel intrauterine device in place and is
dermatology. Hidradenitis is noted as a barrier experiencing amenorrhea with this treatment. She
to implementing an exercise program and has not had significant hair growth changes since
treating this may be necessary before the patient delivery.
is willing to increase activity. Other barriers to Recommended testing includes an oral glucose
implementing lifestyle changes could be explored. tolerance test, lipid panel, and TSH measurement.
Her history of being home-schooled and having She currently takes metformin. While this has
trouble with friends is concerning for possible not been effective in achieving her weight-loss
struggles with mood. Her difficulty getting up in goals, she has lost 3% to 4% of her peak weight.
the morning could be related to obstructive sleep Her hemoglobin A1c measurement is 5.9%
apnea or a circadian rhythm shift and may require (41 mmol/mol).
referral to sleep medicine for a full evaluation.
Metabolic screening should be performed and, Which of the following treatment
because of her weight, family history of diabetes, options would you NOT discuss for
and presence of acanthosis, she may be at higher metabolic health and weight loss?
risk for dysglycemia. If she has evidence of A. Meeting with a dietician to see if she is
dysglycemia, she would be a good candidate for properly following a ketogenic diet
metformin. Because she is overweight but not B. Encouraging her to increase her active minutes
obese, neither appetite suppressants nor bariatric per day from 30 to 60
surgery would be recommended. However,
C. Starting a weight-loss medication
if she had obesity, those treatments would be
considerations, in conjunction with an intensive D. Doubling her dosage of metformin
lifestyle program. E. Inquiring about sleep habits and ordering a
sleep study if suspicious for obstructive sleep
apnea
Answer: D) Doubling her dosage of metformin

ENDO 2022 • Reproductive Endocrinology  237

The metformin dosage could be increased to which is associated with amelioration of insulin
2000 mg daily, but exceeding this dosage is not resistance, hyperandrogenism, menstrual
advised (Answer D). This patient is at very high irregularity, and ovulatory dysfunction. Compared
risk for metabolic disease, and this risk is increased with metformin, bariatric surgery is associated
by having PCOS. The risk for nonalcoholic fatty with improved menstrual control. While data
liver disease is 2-fold higher in women with suggest improved odds of conception with
PCOS, rates of type 2 diabetes are 8-fold higher bariatric surgery compared with metformin,
in women with obesity, and rates of obstructive current data are insufficient to use it as a primary
sleep apnea are 2-fold higher in patients with fertility intervention.
PCOS.18,22,23,43 She presents with concerns about
obesity. A personalized conversation around this Case 3
chief concern should include reinforcement of
dietary and exercise education with consideration A 32-year-old G0 woman would like to conceive.
of a dietician visit and discussion of options to She has used combined oral contraceptive pills
sustain weight loss. Poor sleep and depression for the past 10 years with no adverse effects. She
can contribute to weight gain or failure to lose has had routine gynecologic examinations with
weight and may need to be addressed first. Options no significant medical problems. She was married
include FDA-approved medications for weight 2 years ago and stopped using combined oral
loss (Table 4). contraceptive pills 6 months ago. As her menses
Overall, there are limited data on GLP-1 did not resume spontaneously, her gynecologist
receptor agonists in patients with PCOS from ordered bloodwork and ultrasonography. PCOS
randomized controlled trials but a meta-analysis was subsequently diagnosed. In her medical
of trials comparing GLP-1 receptor agonists with records, her blood pressure is 126/74 mm Hg, BMI
metformin suggests improved weight reduction is 42.4 kg/m2, TSH and prolactin concentrations
with GLP-1 receptor agonists.12 are normal, and total testosterone concentration
Bariatric surgery in patients with PCOS is 63 ng/dL (2.2 nmol/L). Both ovaries have a
promotes significant weight loss within 1 year, volume greater than 10 mL.

Table 4. FDA-Approved Medications for Weight Loss

FDA-approved Placebo-subtracted
antiobesity medications Mechanism of action weight loss Contraindications
Orlistat Lipase inhibitor, -2.6 kg Pregnancy, malabsorption
fat malabsorption syndromes, cholestasis
Lorcaserin Selective 5HT receptor antagonist, -3.2 kg Pregnancy
promotes satiety
Phentermine-toprimate Norepinephrine-releasing agent/ -8.8 kg Pregnancy, hyperthyroidism, glaucoma,
GABA receptor modulator, reduces MAOIs
appetite
Naltrexone-buproprion Opioid antagonist/dopamine and -5.0 kg Pregnancy, uncontrolled hypertension,
norepinephrine reuptake inhibitor, seizure disorder, anorexia, bulimia, drug
reduces food intake or alcohol withdrawal, long-term opioid
use, MAOIs
Liraglutide GLP-1 agonist, -5.3 kg Pregnancy, personal or family history
delays gastric emptying of medullary thyroid cancer or multiple
endocrine neoplasia type 2
Semaglutide (2021) GLP-1 analogue, reduces appetite -12.7 kg Pregnancy, personal or family history
of medullary thyroid cancer or multiple
endocrine neoplasia type 2

Courtesy W. Vitek.

238  ENDO 2022 • Endocrine Case Management

Which of the following is the best next evaluation and evaluation of the uterus and
step in this patient’s management? fallopian tubes. Ovulation induction (Answer
A. Review the use of letrozole as a first-line agent A) is the next line of intervention as she has
for ovulation induction anovulation. The international guidelines for
B. Screen for diabetes, dyslipidemia, and the management of infertility in PCOS note
depression and then initiate letrozole that letrozole should be considered first-line
pharmacological treatment to improve ovulation,
C. Recommend a nutrition consult and return
pregnancy, and live birth rates in women with
to the office after 3 months of lifestyle
PCOS with anovulatory infertility and no other
modification
infertility factors.1
Answer: B) Screen for diabetes, dyslipidemia, Data regarding weight reduction prior to
and depression and then initiate letrozole fertility attempts (Answer C) in the setting of
normal glycemia are mixed for PCOS. However, a
In this setting, the preconception counseling randomized controlled trial evaluating 6 months
should include metabolic assessment (Answer B) of weight reduction prior to fertility attempts
to determine whether there is glucose intolerance improved ovulation rates in response to medical
before attempting pregnancy. Additional ovulation induction.44
assessments should include male partner

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1996;81(3):1237-1243. PMID: 8772605 Endocrinol (Oxf). 2019;90(4):570-578. PMID: 30585648
6. Legro RS, Arslanian SA, Ehrmann DA, et al; Endocrine Society. Diagnosis 14. Lim SS, Kakoly NS, Tan JWJ, et al. Metabolic syndrome in polycystic ovary
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practice guideline. J Clin Endocrinol and Metab. 2013;98(12):4565-4592. PMID: 2019;20(2):339-352. PMID: 30339316
24151290 15. Sarkar M, Terrault N, Chan W, et al. Polycystic ovary syndrome (PCOS) is
7. Martin KA, Anderson RR, Chang RJ, et al. Evaluation and treatment of associated with NASH severity and advanced fibrosis. Liver Int. 2019;40:355-
hirsutism in premenopausal women: an Endocrine Society clinical practice 359. PMID: 31627243
guideline. J Clin Endocrinol Metab. 2018;103(4):1233-1257. PMID: 29522147 16. Hudnut-Beumler J, Kaar JL, Taylor A, Kelsey MM, Nadeau KJ, Zeitler P, et
8. Goodman NF, Cobin RH, Futterweit W, et al; American Association of al. Development of type 2 diabetes in adolescent girls with polycystic ovary
Clinical Endocrinologists (AACE); American College of Endocrinology syndrome and obesity. Pediatr Diabetes. 2021;22(5):699-706. PMID: 33870630
(ACE); Androgen Excess and PCOS Society. American Association of Clinical 17. Simon S, Rahat H, Carreau A-M, et al. Poor sleep is related to metabolic
Endocrinologists, American College of Endocrinology, and Androgen Excess syndrome severity in adolescents with PCOS and obesity. J Clin Endocrinol
and PCOS Society disease state clinical review: guide to the best practices in Metab. 2020;105(4):e1827-e1834. PMID: 31901092
the evaluation and treatment of polycystic ovary syndrome - Part 2. Endocr 18. Kakoly NS, Earnest A, Teede HJ, Moran LJ, Joham AE. The impact of obesity
Pract. 2015;21(12):1415-1426. PMID: 26642102 on the incidence of type 2 diabetes among women with polycystic ovary
syndrome. Diabetes Care. 2019;42(4):560-567. PMID: 30705063

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19. Wild RA, Rizzo M, Clifton S, Carmina E. Lipid levels in polycystic ovary 32. Gibson-Helm M, Teede H, Dunaif A, Dokras A. Delayed diagnosis and a lack
syndrome: systematic review and meta-analysis. Fertil Steril. 2011;95(3):1073- of information associated with dissatisfaction in women with polycystic ovary
1079 e1-e11. PMID: 21247558 syndrome. J Clin Endocrinol Metab. 2017;102(2):604-612. PMID: 27906550
20. Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessment of 33. Yildiz BO, Bolour S, Woods K, Moore A, Azziz R. Visually scoring hirsutism.
cardiovascular risk and prevention of cardiovascular disease in women with Hum Reprod Update. 2010;16(1):51-64. PMID: 19567450
the polycystic ovary syndrome: a consensus statement by the Androgen 34. Ludwig E. Classification of the types of androgenetic alopecia (common
Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol baldness) occurring in the female sex. Br J Dermatol. 1977;97(3):247-254.
Metab. 2010;95(5):2038-2049. PMID: 20375205 PMID: 921894
21. Cree-Green M, Bergman BC, Coe GV, et al. Hepatic steatosis is common in 35. Williams S, Sheffield D, Knibb RC. The polycystic ovary syndrome quality of
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not insulin resistance. Obesity (Silver Spring). 2016;24(11):2399-2406. PMID: Open. 2018;5(2):2055102918788195. PMID: 30038788
27804265 36. Cree-Green M. Worldwide dissatisfaction with the diagnostic process and
22. Kumarendran B, Sumilo D, O’Reilly MW, et al. Increased risk of obstructive initial treatment of PCOS. J Clin Endocrinol Metab. 2017;102(2):375-378.
sleep apnoea in women with polycystic ovary syndrome: a population-based PMID: 28359108
cohort study. Eur J Endocrinol. 2019;180(4):265-272. PMID: 30763274 37. Lee R, Joy Mathew C, Jose MT, Elshaikh AO, Shah L, Cancarevic I. A review
23. Fernandez RC, Moore VM, Van Ryswyk EM, et al. Sleep disturbances in of the impact of bariatric surgery in women with polycystic ovary syndrome.
women with polycystic ovary syndrome: prevalence, pathophysiology, impact Cureus. 2020;12(10):e10811. PMID: 33042653
and management strategies. Nat Sci Sleep. 2018;10:45-64. PMID: 29440941 38. Frossing S, Nylander M, Chabanova E, et al. Effect of liraglutide on ectopic fat
24. Gutierrez-Grobe Y, Ponciano-Rodriguez G, Ramos MH, Uribe M, Mendez- in polycystic ovary syndrome: a randomized clinical trial. Diabetes Obes Metab.
Sanchez N. Prevalence of non alcoholic fatty liver disease in premenopausal, 2018;20(1):215-218. PMID: 28681988
posmenopausal and polycystic ovary syndrome women. The role of estrogens. 39. Jensterle M, Goricar K, Janez A. Metformin as an initial adjunct to low-
Ann Hepatol. 2010;9(4):402-409. PMID: 21057159 dose liraglutide enhances the weight-decreasing potential of liraglutide in
25. Andrisse S, Garcia-Reyes Y, Pyle L, Kelsey MM, Nadeau KJ, Cree-Green M. obese polycystic ovary syndrome: randomized control study. Exp Ther Med.
Racial and ethnic differences in metabolic disease in adolescents with obesity 2016;11(4):1194-1200. PMID: 27073422
and polycystic ovary syndrome. J Endocr Soc. 2021;5(4):bvab008. PMID: 40. Jensterle M, Kravos NA, Goricar K, Janez A. Short-term effectiveness of low
33644620 dose liraglutide in combination with metformin versus high dose liraglutide
26. Cooney LG, Dokras A. Depression and anxiety in polycystic ovary syndrome: alone in treatment of obese PCOS: randomized trial. BMC Endocr Disord.
etiology and treatment. Curr Psychiatry Rep. 2017;19(11):83. PMID: 28929349 2017;17(1):5. PMID: 28143456
27. Cooney LG, Lee I, Sammel MD, Dokras A. High prevalence of moderate 41. Nylander M, Frossing S, Clausen HV, Kistorp C, Faber J, Skouby SO.
and severe depressive and anxiety symptoms in polycystic ovary syndrome: Effects of liraglutide on ovarian dysfunction in polycystic ovary syndrome: a
a systematic review and meta-analysis. Hum Reprod. 2017;32(5):1075-1091. randomized clinical trial. Reprod Biomed Online. 2017;35(1):121-127. PMID:
PMID: 28333286 28479118
28. Benson J, Severn C, Hudnut-Beumler J, et al. Depression in girls with 42. Buyers E, Sass AE, Severn CD, Pyle L, Cree-Green M. Twelve-month
obesity and polycystic ovary syndrome and/or type 2 diabetes. Can J Diabetes. continuation of the etonogestrel implant in adolescents with polycystic ovary
2020;44(6):507-513. PMID: 32792104 syndrome. J Pediatr Adolesc Gynecol. 2021;34(1):33-39. PMID: 32919086
29. Wang F, Xie N, Wu Y, et al. Association between circadian rhythm 43. Kumarendran B, O’Reilly MW, Manolopoulos KN, et al. Polycystic ovary
disruption and polycystic ovary syndrome. Fertil Steril. 2021;115(3):771-781. syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease
PMID: 33358334 in women: a longitudinal study based on a United Kingdom primary care
30. Garg A, Neuren E, Strunk A. Hidradenitis suppurativa is associated with database. PLoS Med. 2018;15(3):e1002542. PMID: 29590099
polycystic ovary syndrome: a population-based analysis in the United States. J 44. Legro RS, Dodson WC, Kris-Etherton PM, et al. Randomized controlled
Invest Dermatol. 2018;138(6):1288-1292. PMID: 29378201 trial of preconception interventions in infertile women with polycystic ovary
31. Pena AS, Witchel SF, Hoeger KM, et al. Adolescent polycystic ovary syndrome. J Clin Endocrinol Metab. 2015;100(11):4048-4058. PMID: 26401593
syndrome according to the international evidence-based guideline. BMC Med.
2020;18(1):72. PMID: 32204714

240  ENDO 2022 • Endocrine Case Management

Beginner’s Guide to Gender-
Affirming Hormone Therapy
for Transgender and
Gender-Diverse Adults
Caroline J. Davidge-Pitts, MB, BCh. Division of Endocrinology, Diabetes, Metabolism, and
Nutrition, Mayo Clinic, Rochester, MN; E-mail: [email protected]

Sean J. Iwamoto, MD. Division of Endocrinology, Metabolism, and Diabetes, Department

of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus;
Endocrinology Service, Medicine Service, Rocky Mountain Regional Veterans Affairs
Medical Center; and UCHealth Integrated Transgender Program, Aurora, CO; E-mail:
[email protected]

Learning Objectives investigate ways to mitigate and prevent potential

GAHT-related risks. Feminizing GAHT typically
As a result of participating in this session, learners
relies on exogenous estrogen and antiandrogen
should be able to:
therapies, while the mainstay of masculinizing
• Recognize that gender-affirming hormone GAHT is exogenous testosterone. Feminization
therapy (GAHT) can be provided to or masculinization with these regimens
transgender and gender-diverse (TGD) improves mental health and quality of life for
patients in safe and effective ways. TGD individuals. Endocrine Society guidelines
recommend evaluating patients every 3 months
• Describe GAHT regimens and monitoring
during the first year and then 1 to 2 times per
recommendations.
year to measure hormone levels and monitor for
• Interpret laboratory test results of patients appropriate signs of physical changes or adverse
taking GAHT. effects.1 More data are being published on how
• Review screening recommendations GAHT affects laboratory values in TGD patients,
and special considerations in older with most analyte concentrations moving into
TGD individuals. physiologic reference ranges that align with
patients’ gender identity (eg, feminizing GAHT is
associated with decreases in serum creatinine and
hematocrit). It is also recommended to screen for
Main Conclusions conditions in TGD patients if organs or tissues
are present for which screening guidelines exist
TGD patients continue to face challenges related
for cisgender adults. More research is needed
to health care access and health disparities.
to inform future guidelines on TGD-specific
There is growing interest among clinicians to
screening, especially related to cardiovascular
provide safe and effective gender-affirming care
disease risk.
(including GAHT) and among researchers to

ENDO 2022 • Reproductive Endocrinology  241

 improvements in insurance coverage overall, there
Significance of the continues to be inequity among insurance plans on
what services are covered.8
Clinical Problem Although the COVID-19 pandemic has led
TGD individuals have gender identities that differ to significant strains on the health care system,
from their sex recorded at birth. This gender access to telemedicine has allowed marginalized
incongruence can lead to clinically significant communities, particularly in rural areas, to
distress or impaired ability to function in social, obtain care. However, it is important to also
occupational, or other important areas.2 Insurance recognize that telehealth visits could exacerbate
coverage for TGD-related services has improved voice dysphoria and appearance anxiety for TGD
over recent years, with subsequent increased patients. Many patients might have concerns about
demand for providers with competence in TGD safety and privacy, and internet access might not
health care; however, barriers to obtaining always be reliable.9 Nonetheless, for TGD patients
gender-affirming care remain.3 The health with a preference for telemedicine, virtual health
care profession continues to face challenges in can be an important tool to close some of the gaps
providing optimal care for the TGD population, in gender-affirming care access.
and there is a significant paucity of TGD-related
education in medical school and postgraduate
training programs.4 Considering the central role
Strategies for Diagnosis,
of endocrinologists in medical management of Therapy, and/or Management
gender dysphoria/incongruence, particularly with The goal of GAHT is to induce physical changes
GAHT, it is essential that endocrinologists receive that align with an individual’s gender identity,
the necessary education to optimize gender- thereby alleviating the distress associated with
affirming care for TGD patients. gender dysphoria/gender incongruence. Several
organizations (eg, Endocrine Society,1 World
Barriers to Optimal Practice Professional Association for Transgender Health,10
and the University of California, San Francisco11)
TGD individuals can be marginalized by negative provide guidelines to aid clinicians who care for
social stigma, internalized transphobia, and TGD individuals. Studies have demonstrated
prejudices, and they face multiple obstacles in that gender-affirming medical and surgical
seeking and maintaining health care compared interventions help to alleviate gender dysphoria
with the general population.5,6 Epidemiologic and improve well-being.12,13 The Table includes
studies have repeatedly shown high rates of terminology often used in this space.
adverse health outcomes in the setting of
minority stress.
Although, in general, access to care has greatly Criteria for Initiating GAHT in Adults
improved in the last decade due to increased social Per the most recent Endocrine Society (2017) and
awareness and improved insurance coverage, World Professional Association for Transgender
several barriers to receiving optimal care remain Health (version 7) guidelines, the criteria for
for TGD individuals. Access to gender-affirming initiating GAHT in adults include: (1) persistent,
providers continues to be limited. This is in part well-documented gender dysphoria/gender
due to limited education in TGD health. Many incongruence, (2) the capacity to make a fully
specialties, including endocrinology, report lack informed decision and to consent to treatment,
of training in this area,7 thereby leading to a (3) the age of majority in a given country, and
downstream lack of confidence and competence (4) mental health concerns, if present, must be
in providing care to TGD patients. Despite reasonably well-controlled.

242  ENDO 2022 • Endocrine Case Management

Table. Selected Terminology in the Care of TGD Individuals

Term Definition
Terms representing independent aspects of one’s identity (ie, not the same things)
Gender identity The innate and internal sense of gender that is not visible to other people
Sex recorded at birth Also hear “sex assigned at birth,” “assigned female at birth,” “assigned male at birth”
Gender expression The external manifestations of a person’s gender; may or may not conform to the socially defined behaviors and
external characteristics that are historically referred to as masculine or feminine (eg, clothing, haircut, jewelry,
social interactions, speech patterns)
Sexual orientation Term that characterizes pattern of romantic or sexual attraction to other people, independent of gender identity
Terms used when discussing gender identity
Gender incongruence When a person’s gender identity or gender expression differs from that person’s sex recorded at birth or what
is typically associated with the designated sex recorded at birth; not everyone with gender incongruence has
gender dysphoria or seeks treatment
Gender dysphoria The distress and unease associated with gender incongruence; the phrase “gender identity disorder” is no
longer used, particularly after the 2013 American Psychiatric Association’s DSM-5 replaced it with “gender
dysphoria”
Transgender An adjective that encompasses people whose gender identity or gender expression differs from their sex
recorded at birth; independent of the decision whether to use GAHT or undergo gender-affirming surgery, and
inclusive of gender nonbinary people; the terms “transgendered” and “transgenders” should not be used
Examples:
A person who was assigned female at birth but whose gender identity or gender expression is (more) male/
masculine may identify as a transgender man, transgender male, transmasculine, or something else
A person who was assigned male at birth but whose gender identity or gender expression is (more) female/
feminine may identify as a transgender woman, a transgender female, transfeminine, or something else
Gender nonbinary May represent people who identify and present themselves as both or alternatively male and female, as neither
male nor female, or with a gender identity outside the male/female binary; may include genderqueer, gender-
fluid, pan-gender, polygender

Cisgender An adjective for people whose gender identity and gender expression align with their sex recorded at birth
(ie, not transgender)

Adapted from Iwamoto SJ et al. Ther Adv Endocrinol Metab, 2019;10 © SAGE Publications.

We acknowledge that most current GAHT these alternative dosages or regimens to guide
guidelines are binary in their recommendations evidence-based GAHT recommendations. For this
for hormone dosages, meaning that hormone GAHT chapter, we will focus on current binary
dosages and goal hormone levels are extrapolated GAHT recommendations.
from physiologic cisgender female and male
reference ranges. The University of California Feminizing Gender-Affirming
San Francisco provides useful “initial-low” dosing
recommendations for patients who may desire Hormone Therapy
lower dosages of GAHT or slower titration (eg, Endocrine Society guidelines, most recently
some gender nonbinary patients) or need less updated in 2017,1 recommend evaluation of
GAHT due to medical history. For our growing medical conditions that could be exacerbated
number of nonbinary and gender-diverse patients by feminizing GAHT (fGAHT). Baseline
who identify outside the transgender female-male laboratory workup, which can vary depending
binary, it is equally as important to guide GAHT on patient risk profile and age, could assess
initiation and management with their goals and metabolic status, complete blood cell count, liver
expectations in mind, but also acknowledge enzymes, electrolytes, and sex steroid hormones
the need for more outcomes research related to (if relevant). We also recommend assessment of

ENDO 2022 • Reproductive Endocrinology  243

immunization status, evaluation for substance use, testosterone levels and are not recommended as
and testing for HIV and other sexually transmitted first-line therapy because of potentially serious
infections. All patients initiating fGAHT should hepatotoxic effects.
be informed about fertility effects and counseled Gonadotropin-releasing hormone (GnRH)
regarding options for fertility preservation prior analogues reduce the secretion of gonadotropins,
to initiation. which in turn decreases stimulation of gonadal
The approach to fGAHT depends on several testosterone production. GnRH analogues can
factors including patient preference, differences be considered in TGD individuals who cannot
in the regional availability of medications, and tolerate other antiandrogens, in situations where
cost considerations. fGAHT aims to lower and/or adequate testosterone suppression cannot be
block testosterone along with estrogen to inhibit achieved with standard antiandrogen therapy, or
testosterone secretion and provide feminizing in patients who require a lower estrogen dosage
physical changes. (eg, older patients and those at risk of venous
Estrogen lowers testosterone secretion from thromboembolism or vascular disease).16 In
the gonads by inhibiting the hypothalamic- practice, the use of GnRH analogues is limited in
pituitary-gonadal (HPG) axis. 17β-Estradiol is many countries because of cost.
recommended over other estrogen preparations The role of progestins in fGAHT remains
such as ethinyl estradiol and conjugated equine unclear, although they are often requested to
estrogens due to a more favorable risk profile.1 enhance breast development and improve mood.17
In addition, 17β-estradiol can be measured and Currently, progestins are not recommended by
monitored with commercial estradiol assays. Endocrine Society guidelines as part of standard
Transdermal and parenteral preparations are fGAHT but can be considered as part of an
potentially less thrombogenic by avoiding the individualized approach.
first-pass effect, as opposed to oral estrogens.1,15 On initiation of fGAHT, sex steroid hormones
Antiandrogens block androgen action and can should be maintained in the physiologic range
have an inhibitory effect on testosterone secretion. for cisgender women: estradiol, 100-200 pg/mL
Spironolactone is a mineralocorticoid receptor (367-734 pmol/L) and testosterone, <50 ng/dL
antagonist that blocks the androgen receptor at (<1.7 nmol/L). Although precise onset and timing
higher dosages. Spironolactone also inhibits the of feminizing physical changes in response to
secretion of testosterone from the gonads, possibly medical interventions are not well-defined, most
due to progestin and estrogenlike effects. It is physical changes begin within a few months and
generally safe and well-tolerated, although it can continue to progress over 2 to 3 years.
induce hyperkalemia, hypotension, and increased fGAHT is generally considered safe when
urination. Cyproterone acetate is a progestin with prescribed and monitored by an experienced
androgen-blocking properties. Adverse effects medical provider. Nevertheless, it is important to
include hepatotoxicity, mood disturbances, and acknowledge risks, so that precipitating factors can
multifocal meningiomas. Although cyproterone be addressed. In a recent large electronic medical
acetate is widely used in Europe, it is not available record–based study of transgender women in the
in the United States. 5α-Reductase inhibitors (eg, United States who were mostly on oral estradiol,
finasteride) block conversion of testosterone to the incidence rate for venous thromboembolism
dihydrotestosterone, potentially increasing the was higher than both cisgender male and cisgender
testosterone level. 5α-Reductase inhibitors have female control groups, and the difference was
been associated with adverse mood alterations more pronounced with increased follow-up
and are therefore not recommended as first- over time.18 Evidence on the risks of fGAHT in
line agents. Nonsteroidal androgen receptor transgender women older than 50 years is lacking.
antagonists (eg, bicalutamide) do not reduce Outcomes data are limited by hormone regimens,

244  ENDO 2022 • Endocrine Case Management

type, and route, and cardiovascular risk profiles and cost should also be considered when selecting
and are difficult to match. The goal of fGAHT route of testosterone administration.
in aging transgender women is to promote Testosterone is available in parenteral and
feminizing hormone effects and limit venous transdermal formulations. Testosterone esters
thrombosis, cardiovascular, and breast cancer (cypionate or enanthate) drawn from a vial into a
risks. It is important to discuss potentially tapering syringe can be administered weekly or every other
the estradiol dosage and/or switching from oral to week, subcutaneously or intramuscularly, with
transdermal/injectable estradiol to minimize risks. both routes producing similar testosterone levels.
However, estradiol dosages that are decreased Subcutaneous injections are preferred by many
too much could risk increased masculinization patients.21 A new autoinjector with testosterone
in individuals without gonadectomy. There enanthate provides subcutaneous testosterone;
continues to be a paucity of data with respect to however, it is only available in 3 doses and
cardiovascular risk in older transgender women. insurance coverage can be limited. Testosterone
However, a recent Dutch mortality study revealed undecanoate is much longer-acting, requiring an
more observed deaths due to cardiovascular injection every 3 months (in the clinic setting,
disease compared with the number of deaths with rare risks of pulmonary oil microembolism
of the same cause in the general population and anaphylaxis). It is more common outside the
over 5 decades.19 Risk of ischemic stroke is also United States, but it is available through a Risk
higher with use of oral estrogens as opposed Evaluation and Mitigation Strategy program.
to transdermal preparations. In a systematic Transdermal testosterone comes in the form
review, 8 cases of stroke were reported in a of gels (of varying percentages depending on
pooled population of 859 individuals on estrogen preparation) and patches. Gels and patches are
therapy.20 The recent transfeminine cohort study applied to clean and dry skin daily. Currently,
showed that the incidence rate of ischemic stroke Endocrine Society guidelines and others
was 4.8 per 1000 person-years as opposed to 1.2 acknowledge the lack of data on the safety and
in reference men and 1.9 in reference women, efficacy of masculinization with other routes of
with a particular increase in incidence after 6 years testosterone administration, including buccal,
of treatment.18 While it is important to consider implants/pellets, compounded preparations, and
cardiovascular risk and risk factors in fGAHT the recently FDA-approved oral testosterone.
management due to increases in relative risk in Parenteral or transdermal testosterone can be
some studies, absolute risks remain low. These used to achieve total testosterone levels within
potential long-term risks due to fGAHT must the physiologic range for cisgender men. Target
be balanced (and better studied) with the well- concentrations of total testosterone are 400 to
documented short-term mental health risks related 700 ng/dL (13.9-24.3 nmol/L), with caveats
to withholding fGAHT. based on route and timing of administration.
Testosterone ester injections (cypionate or
enanthate) can result in peak (1 to 2 days after
Masculinizing Gender-
injecting) and trough (1 to 2 days prior to next
Affirming Hormone Therapy injection) levels, depending on the timing of the
Unlike fGAHT, masculinizing GAHT (mGAHT) laboratory test and the most recent injection. If
typically relies on administering a single drawn midway between injections, the above
hormone, testosterone, to initiate and maintain target range can be the goal. If patients are unable
masculinization. Testosterone alone is usually to have a mid-dose blood draw, measuring a
enough to suppress the HPG axis and, therefore, peak or trough level to ensure the serum total
endogenous estradiol production. Patient testosterone concentration remains within
preferences, regional availability of medications, the laboratory’s reference range for cisgender

ENDO 2022 • Reproductive Endocrinology  245

men may be more appropriate. Testosterone individuals, while there were 0 cases of stroke in
undecanoate can result in steady testosterone 340 participants. The recent transmasculine cohort
levels over several months, with levels drawn study showed no significant increase in incidence
just prior to the next injection. Transdermal of venous thromboembolism, ischemic stroke,
preparations also provide stable levels of serum or myocardial infarction compared with rates
testosterone over time. The testosterone in either cisgender men or women.18 However,
concentration can be measured after 1 week a Dutch cohort recently documented a higher
of daily application, at least 2 hours after that rate of myocardial infarction among transgender
day’s application. We do not currently have men than in reference cisgender women but not
recommendations for the goal concentration for in reference cisgender men.25 More research is
free testosterone while on mGAHT; however, needed regarding long-term cardiovascular disease
accurate assays to measure free testosterone risk in patients taking mGAHT, with particular
remain unavailable for most. focus on duration of mGAHT and age at initiation.
mGAHT is also considered safe when
prescribed and monitored by a gender-affirming
clinician. After starting testosterone, masculinizing
Clinical Case Vignettes
physical changes typically begin within a few Case 1
months and continue to progress for 1 to 2 years A 19-year-old transgender woman is referred for
but may take up to 5 years. During discussions initiation of fGAHT. The patient’s sex recorded at
about effects, we mention that some mGAHT- birth was male, but she experienced a persistent
related physical effects may be permanent desire to be female since age 7 years. She has
if testosterone is discontinued, including followed with her local therapist since age 16 years
facial hair, androgenic alopecia, deeper voice, who confirms persistent gender dysphoria/
and clitoromegaly. incongruence. She has a history of depression,
In most TGD patients, testosterone use results which is stable. There are no other medical
in menstrual suppression within the first year, concerns, and she does not smoke cigarettes.
more often with parenteral testosterone than with Physical examination findings are unremarkable.
transdermal testosterone.22 When bleeding persists You initiate fGAHT with estradiol and
and other medications are desired (ie, not surgery), spironolactone.
norethindrone acetate and other progestins
(eg, oral, parenteral, intrauterine device) or a Which of the following laboratory changes
GnRH analogue (if available and affordable) can is expected with this medical therapy?
be prescribed. A. Decrease in HDL cholesterol
An increase in hematocrit leading to
B. Decrease in hemoglobin and hematocrit
erythrocytosis (hematocrit >50%) is well-
documented in TGD persons taking mGAHT.23,24 C. Decrease in potassium
If testosterone levels are elevated above goal, D. Increase in serum creatinine
the testosterone dosage can be decreased in this
setting. Other causes of secondary erythrocytosis Answer: B) Decrease in hemoglobin and hematocrit
should also be evaluated, including tobacco It is important for clinicians to understand how
smoking and obstructive sleep apnea. The GAHT will affect laboratory testing, although this
concerns about secondary erythrocytosis is an evolving area in transgender health.
increasing the risk for cardiovascular disease With the decrease in endogenous testosterone
in this population have not borne out in recent levels, hemoglobin and hematocrit are expected
studies. In the previous systematic review, venous to decrease into the female range due to reduced
thromboembolism was reported in 1 of 771 erythropoiesis (thus, Answer B is correct).23

246  ENDO 2022 • Endocrine Case Management

 Regarding the renal system, androgen • Hypogonadism with no plan to take
deprivation is one factor that reduces creatinine hormone therapy
(thus, Answer D is incorrect). There is also likely a • Presence of risk factors for bone loss
direct effect of the estradiol on the kidney.26 and/or fracture (eg, glucocorticoid use,
With respect to lipid panel changes, estradiol hyperparathyroidism)
can have a neutral effect on HDL cholesterol, or
increase its value (thus, Answer A is incorrect).20 • Follow-up bone mineral density testing is
Considering this patient is taking indicated when the results are likely to influence
spironolactone, one would not expect a decrease in treatment decisions. Examples include:
potassium, as this is a potassium-sparing diuretic ԗ Baseline low bone density
(thus, Answer C is incorrect).
ԗ Use of GnRH analogues without hormone
therapy
Case 2 ԗ Nonadherence to or inadequate doses of
A 60-year-old transgender woman presents for her hormone therapy
annual visit. She has been on fGAHT for 6 years.
ԗ Plan to discontinue hormone therapy
She has not undergone gender-affirming surgeries.
She has no acute concerns. Her only medication ԗ Presence of risk factors for bone loss
is lisinopril for hypertension. Family history is and/or fracture (eg, glucocorticoid use,
pertinent for prostate cancer in her father. Blood hyperparathyroidism)
pressure is normal at the visit. Bone mineral density testing intervals are based
on the clinical scenario—typically every 1 to
Which of the following general
2 years until bone mineral density is stable or
screenings should be recommended?
improved, followed by longer intervals thereafter.
A. Mammography Calcium and vitamin D supplementation is
B. Bone density assessment also recommended (following age-appropriate
C. Prostate-specific antigen measurement recommendations for cisgender women). Bone
D. A and C mineral density screening (Answer B) is not
indicated in this patient because she has not
E. No screening advised
undergone gonadectomy, she has been on stable
Answer: D) A and C hormone therapy with estradiol, and she has no
other risk factors for bone loss.
Preventive care for patients on GAHT includes Clinicians should follow age-appropriate breast
standard recommendations for sex recorded at cancer screening recommendations after 5 years
birth and age, with few TGD-specific screening of estrogen therapy plus monthly self-examination
recommendations from the Endocrine Society and or follow individualized recommendations if
other organizations.27 Advising no screening for the patient has a family history of breast or
this patient (Answer E) is incorrect. ovarian cancer. Clinicians should also follow
Baseline bone mineral density testing is age-appropriate prostate cancer screening
indicated for TGD patients who have any of recommendations for cisgender men. Expect
the following28: prostate-specific antigen levels to decrease by
• History of gonadectomy or therapy that lowers approximately 50% (even in the presence of
endogenous gonadal steroid levels before prostate cancer). Normal laboratory reference
initiation of hormone therapy ranges may not apply. Thus, the best answer is
both mammography (Answer A) and prostate-
specific antigen measurement (Answer C).

ENDO 2022 • Reproductive Endocrinology  247

Case 3 regular intervals while a patient is on mGAHT.
Testosterone can lead to weight gain, thought to
A 49-year-old transgender man presents to
be associated with increases in muscle/lean mass
endocrine clinic for follow-up after starting
and abdominal fat.29 However, some patients may
testosterone 1 year ago. He is happy with
lose weight, which can be due to increased physical
masculinizing effects and is excited about his
activity, self-esteem, and energy associated with
upcoming gender-affirming chest surgery. He
taking mGAHT.
has noticed a 10-lb (4.5-kg) weight gain despite
Testosterone is also associated with consistent
exercising 5 days per week. He has a family
increases in systolic blood pressure (Answer A)
history of cardiovascular disease, and he is anxious
and less consistent increases in diastolic blood
about his risk. His BMI is 24.5 kg/m2, up from
pressure.30
22.8 kg/m2 1 year ago.
At 1 year, LDL cholesterol is increased from
Which of the following is also likely to be baseline (Answer B), and HDL cholesterol is
increased now compared with baseline? decreased (not increased [Answer C]). Changes
in total cholesterol and triglycerides are less
A. Systolic blood pressure
consistent (thus, Answer D is incorrect).20
B. LDL cholesterol Cardiovascular disease risk in TGD adults is
C. HDL cholesterol an important area in need of more research. We
D. Triglycerides lack data on how to best calculate cardiovascular
E. A and B disease risk in this population. Factors include
age at initiation of GAHT and length of GAHT
Answer: E) A and B exposure. As such, clinicians may choose to
calculate risk based on sex recorded at birth,
Per Endocrine Society guidelines, weight, blood affirmed gender, or average the two.27
pressure, and lipids should be measured at

References
1. Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of 8. Bakko M, Kattari SK. Transgender-related insurance denials as barriers to
gender-dysphoric/gender-incongruent persons: an Endocrine Society clinical transgender healthcare: differences in experience by insurance type. J Gen
practice guideline. J Clin Endocrinol Metab. 2017;102(11):3869-3903. PMID: Intern Med. 2020;35(6):1693-1700. PMID: 32128693
28945902 9. Pankey TL, Heredia D Jr, Vencill JA, Gonzalez CA. Gender-affirming
2. Valentine SE, Shipherd JC. A systematic review of social stress and mental telepsychology during and after the COVID-19 pandemic: recommendations
health among transgender and gender non-conforming people in the United for adult transgender and gender diverse populations. J Health Serv Psychol.
States. Clin Psychol Rev. 2018;66:24-38. PMID: 29627104 2021;47(4):181-189. PMID: 34693297.
3. Warner DM 2nd, Mehta AH. Identifying and addressing barriers to 10. Coleman E, Bockting W, Botzer M, Cohen-Kettenis PT, De Cuypere G,
transgender healthcare: where we are and what we need to do about it. J Gen Feldman J, Fraser L, Green J, Knudson G, Meyer W, Monstrey S. Standards
Intern Med. 2021;36(11):3559-3561. PMID: 34254221 of care for the health of transsexual, transgender, and gender-nonconforming
4. Fraser L, Knudson G. Education needs of providers of transgender people, version 7. Int J Transgenderism. 2012;13:165-232.
population. Endocrinol Metab Clin North Am. 2019;48(2):465-477. PMID: 11. UCSF Transgender Care, Department of Family and Community Medicine,
31027553 University of California San Francisco. Guidelines for the primary and
5. Feldman JL, Luhur WE, Herman JL, Poteat T, Meyer IH. Health and health gender-affirming care of transgender and gender nonbinary people. 2nd ed.
care access in the US transgender population health (TransPop) survey. Deutsch MB, ed. June 2016. Available at transcare.ucsf.edu/guidelines. Access
Andrology. 2021;9(6):1707-1718. PMID: 34080788 May 2022.
6. Pellicane MJ, Ciesla JA. Associations between minority stress, depression, 12. Nguyen HB, Chavez AM, Lipner E, et al. Gender-affirming hormone use
and suicidal ideation and attempts in transgender and gender diverse in transgender individuals: impact on behavioral health and cognition. Curr
(TGD) individuals: systematic review and meta-analysis. Clin Psychol Rev. Psychiatry Rep. 2018;20(12):110. PMID: 30306351
2022;91:102113. PMID: 34973649 13. Wernick JA, Busa S, Matouk K, Nicholson J, Janssen A. A systematic review
7. Davidge-Pitts C, Nippoldt TB, Danoff A, Radziejewski L, Natt N. of the psychological benefits of gender-affirming surgery. Urol Clin North Am.
Transgender health in endocrinology: current status of endocrinology 2019;46(4):475-486. PMID: 31582022
fellowship programs and practicing clinicians. J Clin Endocrinol Metab. 14. Iwamoto SJ, Defreyne J, Rothman MS, et al. Health considerations for
2017;102(4):1286-1290. PMID: 28324050 transgender women and remaining unknowns: a narrative review. Ther Adv
Endocrinol Metab. 2019;10:2042018819871166. PMID: 31516689

248  ENDO 2022 • Endocrine Case Management

15. Zucker R, Reisman T, Safer JD. Minimizing venous thromboembolism in 23. Madsen MC, van Dijk D, Wiepjes CM, Conemans EB, Thijs A, den Heijer M.
feminizing hormone therapy: applying lessons from cisgender women and Erythrocytosis in a large cohort of trans men using testosterone: a long-term
previous data. Endocr Pract. 2021;27(6):621-625. PMID: 33819637 follow-up study on prevalence, determinants, and exposure years. J Clin
16. Maheshwari A, Nippoldt T, Davidge-Pitts C. An approach to nonsuppressed Endocrinol Metab. 2021;106(6):1710-1717. PMID: 33599731
testosterone in transgender women receiving gender-affirming feminizing 24. Oakes M, Arastu A, Kato C, et al. Erythrocytosis and thromboembolic events
hormonal therapy. J Endocr Soc. 2021;5(9):bvab068. PMID: 34278180 in transgender individuals receiving gender-affirming testosterone. Thromb
17. Iwamoto SJ, T’Sjoen G, Safer JD, et al. Letter to the editor: “Progesterone Res. 2021;207:96-98. PMID: 34592628
is important for transgender women’s therapy-applying evidence for 25. Nota NM, Wiepjes CM, de Blok CJM, Gooren LJG, Kreukels BPC, den Heijer
the benefits of progesterone in ciswomen”. J Clin Endocrinol Metab. M. Occurrence of acute cardiovascular events in transgender individuals
2019;104(8):3127-3128. PMID: 30860591 receiving hormone therapy. Circulation. 2019;139(11):1461-1462. PMID:
18. Getahun D, Nash R, Flanders WD, et al. Cross-sex hormones and acute 30776252
cardiovascular events in transgender persons: a cohort study. Ann Intern Med. 26. Maheshwari A, Dines V, Saul D, Nippoldt T, Kattah A, Davidge-Pitts C.
2018;169(4):205-213. PMID: 29987313 The effect of gender-affirming hormone therapy on serum creatinine in
19. de Blok CJ, Wiepjes CM, van Velzen DM, et al. Mortality trends over five transgender individuals. Endocr Pract. 2022;28(1):52-57. PMID: 34474185
decades in adult transgender people receiving hormone treatment: a report 27. Iwamoto SJ, Grimstad F, Irwig MS, Rothman MS. Routine screening for
from the Amsterdam cohort of gender dysphoria. Lancet Diabetes Endocrinol. transgender and gender diverse adults taking gender-affirming hormone
2021;9(10):663-670. PMID: 34481559 therapy: a narrative review. J Gen Intern Med. 2021;36(5):1380-1389. PMID:
20. Maraka S, Singh Ospina N, Rodriguez-Gutierrez R, et al. Sex steroids and 33547576
cardiovascular outcomes in transgender individuals: a systematic review 28. Rosen HN, Hamnvik O-PR, Jaisamrarn U, et al. Bone densitometry in
and meta-analysis. J Clin Endocrinol Metab. 2017;102(11):3914-3923. PMID: transgender and gender non-conforming (TGNC) individuals: 2019 ISCD
28945852 official position. J Clin Densitom. 2019;22(4):544-553. PMID: 31327665
21. Figueiredo MG, Gagliano-Juca T, Basaria S. Testosterone therapy with 29. Irwig MS. Testosterone therapy for transgender men. Lancet Diabetes
subcutaneous injections: a safe, practical, and reasonable option. J Clin Endocrinol. 2017;5(4):301-311. PMID: 27084565
Endocrinol Metab. 2022;107(3)614-626. PMID: 34698352 30. Irwig MS. Cardiovascular health in transgender people. Rev Endocr Metab
22. Defreyne J, Vanwonterghem Y, Collet S, et al. Vaginal bleeding and spotting Disord. 2018;19(3):243-251. PMID: 30073551
in transgender men after initiation of testosterone therapy: a prospective
cohort study (ENIGI). Int J Transgend Health. 2020;21(2):163-175. PMID:
32935087

ENDO 2022 • Reproductive Endocrinology  249

Diagnosis and Treatment
of Male Hypogonadism
Channa N. Jayasena, PhD. Department of Endocrinology, Imperial College London,
Hammersmith Hospital, London, United Kingdom; E-mail: [email protected]

Learning Objectives cancer, but it might unmask an incidental prostate

tumor. The Endocrine Society recommends prostate
As a result of participating in this session, learners
surveillance using digital rectal examination and
should be able to:
serum PSA measurement in men older than 40 years.
• Confidently diagnose hypogonadism. Testosterone may increase thrombosis risk, but the
absolute risk is very small. There is uncertainty about
• Guide the approach to treatment of
the cardiovascular safety of testosterone, and this
hypogonadism, including judgment of risk-
should be discussed with hypogonadal men who have
benefit of testosterone therapy.
established cardiac disease.

Main Conclusions Significance of the

Primary hypogonadism is a straightforward diagnosis Clinical Problem
identified by elevated serum gonadotropin and low Hypogonadism is a common endocrine condition
serum testosterone concentrations. Furthermore, that is becoming more challenging to manage.
men with serum morning fasted total testosterone An increasing proportion of evaluated men have
concentrations less than 230 ng/dL (<8 nmol/L) are manifestations of “functional” hypogonadism
likely to be hypogonadal. When testosterone levels such as aging and comorbidities including obesity.
are borderline (230-350 ng/dL [8-12 nmol/L]), it is Furthermore, there is no binary biochemical
important to consider the strength of clinical features threshold of testosterone that can reliably
together with other biological markers, including distinguish hypogonadal from eugonadal men.
hematocrit. Calculated free testosterone may be Unless biochemical features are compelling, they
considered when SHBG levels are abnormal, but its need to be framed within the likely etiology and
utility is entirely dependent on total testosterone and clinical context to make a secure diagnosis.
SHBG assay performance. Testosterone treatment This session will provide a pragmatic,
is commonly administered using transdermal gels, evidence-based discussion to optimize the
long-acting testosterone injections, and short-acting diagnosis and management of hypogonadism.
testosterone injections, but other methods are Focus will be given to borderline cases that are
available. Patient needs and preferences should be most challenging in real-world clinical practice.
taken into account when selecting the appropriate
treatment regimen for hypogonadism. “Peak and
trough” symptoms and erythrocytosis may be Barriers to Optimal Practice
problematic when using testosterone injections,
• Diagnosis requires interpretation of
in which case changing to transdermal gels may be
biochemistry within the clinical context;
preferable. Testosterone does not cause prostate
inconsistency between assays and “cut-points”

250  ENDO 2022 • Endocrine Case Management

 creates variation among clinicians in defining Laboratory Investigations
which patients have male hypogonadism. Obvious biochemical features of hypogonadism
• Some nonhypogonadal men display include the following: serum LH >10.0 mIU/mL
testosterone-seeking behavior due to the (>10.0 IU/L) (ie, primary hypogonadism);
perception that testosterone treatment may serum LH far below the reference range (ie,
improve many nonspecific symptoms. hypogonadotropic hypogonadism); serum
morning fasted total testosterone <230 ng/dL
• Concerns remain over the cardiovascular (<8 nmol/L) (requires 2 measurements).3
safety of testosterone treatment, particularly
in older men with hypogonadism, which may Serum Morning Fasted Total Testosterone
modify prescribing habits. Concentration 230-350 ng/dL (8-12 nmol/L)
Patients with values in this range may be normal
or hypogonadal, so consideration of other evidence
Strategies for Diagnosis, is important. In the United States, 300 ng/dL
Therapy, and/or Management (10.4 nmol/L) is commonly quoted as a “threshold”
for diagnosing hypogonadism.1 However, assays
Diagnosis and hormonal levels may result in variation.
The diagnosis of male hypogonadism requires The 2.5th and 97.5th percentiles for serum
both convincing clinical features and indicative total testosterone were reported as 265 ng/dL
biochemistry.1 (9.2 nmol/L) and 916 ng/dL (31.8 nmol/L),
respectively, in more than 9000 healthy nonobese
History young men from Europe and North America
Look for specific clinical features of male using the Centers for Disease Control and
hypogonadism, which may be sexual (reduced Prevention reference method.4,5 Furthermore, the
libido/sexual activity, erectile dysfunction, and European Male Ageing Study observed that in
reduced spontaneous erections), developmental approximately 3400 men aged 40 to 79 years, the
(delayed puberty, cryptorchidism, known odds of experiencing sexual symptoms increased
Klinefelter syndrome), or hematological (anemia); with either a total testosterone concentration
drugs (androgenic steroids, strong opioids); bone less than 230 ng/dL (<8 nmol/L) (regardless of
fractures or osteoporosis; vasomotor flushes; calculated free testosterone) or total testosterone
prior cancer treatment; and anemia.1,2 However, concentration less than 317 ng/dL (<11 nmol/L)
the following clinical features are nonspecific, (with calculated free testosterone <6.3 ng/dL
not helpful diagnostically, and are less likely to [<220 pmol/L]).6 When serum testosterone results
improve with testosterone treatment: disturbances are borderline, the strength of clinical features
of mood or sleep and reduced concentration together with diagnostic features such as anemia
(sometimes termed “brain fog”). and low bone mineral density can help decide on
the diagnosis if results are equivocal.
Examination
Check if the voice pitch is postpubertal. Look Testosterone Concentration >350 ng/dL (>12 nmol/L)
for male-pattern hair growth, gynecomastia, There is very little published evidence from
testicular volume, and evidence of cryptorchidism interventional trials that testosterone treatment
or orchidopexy (groin scars, affected testis is often improves symptoms better than placebo in
reduced in size).1,2 men with hypogonadism and a testosterone
concentration greater than 345 ng/dL
(>12 nmol/L).2

ENDO 2022 • Reproductive Endocrinology  251

Role of Free Testosterone in Diagnosis Monitoring Testosterone Treatment
Free testosterone estimation may add value if
Treatment Efficacy and Satisfaction
total testosterone levels are borderline and SHBG
The most important aspect of monitoring is to
levels are abnormally high or low. Someone
ensure that the patient tolerates treatment and
with a serum testosterone concentration of
feels symptom relief from the testosterone therapy
300 ng/dL (10.4 nmol/L) and SHBG concentration
chosen. Inadequate symptom control may indicate
of 1.12 µg/mL (10 nmol/L) will have a higher free
subtherapeutic levels of testosterone therapy,
testosterone than if the SHBG concentration is
in which case the dosage could be increased (eg,
11.24 µg/mL (100 nmol/L). Free testosterone is
for a gel) or the dose interval could be shortened
difficult to measure reliably within laboratories
(eg, for a long-acting injectable preparation).
(using equilibrium dialysis), and results may be
If symptoms persist despite attainment of
inaccurate.1 Calculated free testosterone using
testosterone levels above 250 ng/dL (>12 nmol/L),
the Vermeulen formula is a broadly accepted
one should reassess whether other comorbidities
surrogate of free testosterone measurement,
may be contributing to symptoms. The patient
which has shown clinical validity in many
should be asked whether the mode of testosterone
studies.7 The original Vermeulen equation was
administration “works for them.” For instance,
validated using assays for testosterone and SHBG
men with young children are often concerned
that are no longer available but has recently
about cross-contamination risks associated with
been revalidated using current state-of-the-art
gels. Conversely, men with pronounced peak
methods.8 Controversy remains about the level
and trough symptoms may respond better to
of importance that should be placed on calculated
either long-acting injections, implants, or daily
free testosterone in the diagnosis of male
preparations.
hypogonadism.9 Furthermore, its performance
is entirely dependent on assay performance of Prostate Safety
serum total testosterone and SHBG. Clinicians Testosterone deprivation causes prostatic
should liaise closely with clinical biochemistry atrophy. However, no statistical relationship
colleagues in their own clinic to be informed exists between serum PSA levels and circulating
regarding the limitations of current assays. testosterone levels in the eugonadal range (ie, the
In summary, calculated free testosterone is a saturation hypothesis).12 Furthermore, multiple
second-line test when SHBG is abnormal or studies have failed to show that testosterone
when total testosterone is in the borderline range therapy increases risks of de novo prostate
for patients with clinical features suggestive of cancer.13,14 Therefore, patients can be reassured
androgen deficiency. that testosterone therapy does not cause prostate
cancer. However, an existing prostate cancer
Testosterone Therapy might be hidden by hypogonadism (causing gland
Currently available testosterone formulations, and tumor shrinkage), and testosterone therapy
dosages, administration, and their benefits and might accelerate its growth. Prostate cancer is
disadvantages are presented in the Table.2,10,11 The extremely rare in men younger than 40 years, and
clinician should support the patient to identify a no monitoring is recommended for this age group.
suitable testosterone formulation through a Endocrine Society guidelines recommend prostate
structured needs assessment and by providing the surveillance prior to and during testosterone
patient with a rationale of benefits and treatment for men older than 40 years.1 This
disadvantages of each testosterone formulation. includes serum PSA measurement and digital
rectal examination. Any abnormality on digital
rectal examination, a PSA increase of 1.4 ng/mL
(1.4 µg/L) within 12 months, or a serum PSA

252  ENDO 2022 • Endocrine Case Management

Table. Available Testosterone Formulations Used to Treat Male Hypogonadism

Formulation and dosage Administration and monitoring Advantages Disadvantages

Transdermal topical testosterone gels Clear alcohol gel available in Physiological levels Skin irritation for some
and axillary solution sachets, tubes, and pumps; of serum testosterone patients; takes time to apply;
applied to dry, clean skin on with no “peak and potential transfer to female
20 to 80 mg testosterone in
shoulders, abdomen, upper arms, troughs” between partner or child
transdermal gel once daily
or thighs (avoid genital area) applications; dosage
60 to 120 mg of testosterone solution easily adjustable to
Monitor total testosterone 2 to
applied in the axillae once daily (not individual needs; no
6 hours after gel application and
available in the United Kingdom) pain of injections
2 to 3 weeks after treatment
initiation or dosage adjustment,
aiming for midnormal value
Long-acting testosterone Injected slowly into the gluteal Less noticeable “peak Requires large muscle bulk for
undecanoate intramuscular injections muscle and trough” symptoms injection
750 to 1000 mg in ampoule of oily Second injection (loading dose) Convenient due Slow withdrawal of effect if
preparation every 8 to 14 weeks may be given at 6 weeks and to infrequent reversal is required
subsequent doses are typically administration
Rare pulmonary
every 8 to 14 weeks
microembolism presenting
Injection interval is adjusted with severe coughing during
based on trough total injection
testosterone level, aiming for
Cannot be self-administered
lower end of normal reference
range; monitor trough total
testosterone and hematocrit at
least annually
Short-acting testosterone injections Can be self-administered Dose flexibility Sometimes marked “peak
and convenient and trough” symptoms
1. Combined testosterone esters, eg, Injection interval is adjusted
administration, due to supraphysiological
250 mg/mL intramuscularly every 3 based on trough total
relatively inexpensive testosterone levels after
to 4 weeks containing propionate, testosterone level, aiming for
injection
30 mg; phenylpropionate, 60 mg; lower end of normal reference
isocaproate, 60 mg; decanoate, range; monitor trough total Erythrocytosis due to higher
100 mg testosterone and hematocrit at overall testosterone exposure
least annually vs other preparations
2. Testosterone enanthate or
cypionate, 150 to 200 mg
intramuscularly every 2 weeks or
50 to 100 mg intramuscularly or
subcutanenously once weekly
Bioadhesive buccal testosterone Testosterone is absorbed from Easy and fast to apply Risk of gum-related adverse
tablet the buccal mucosa over 12 hours; events
Serum testosterone
monitor testosterone levels 2 to
30-mg controlled-release tablets levels remain within May detach when eating
6 hours after tablet application,
applied to the upper gum twice daily physiological range shortly after application
aiming for midnormal reference
without significant
range
peaks and troughs
Subcutaneous testosterone implants 3 to 6 pellets every 4 to 6 months Convenient—twice or Painful procedure with risk of
thrice a year application infection
Testosterone pellets, 100 or Pellets implanted under local
200 mg (to a total of 600 to 1200 mg anaesthetic Risk of spontaneous extrusion
testosterone per dose) of pellets
Oral testosterone undecanoate Absorption improved when taken Easy and convenient Low bioavailability and very
capsules, 40 mg with fatty meal administration high interindividual and
intraindividual variability in
1 to 3 capsules (40 to 120 mg) twice or Swallow without chewing Suitable for patients
absorption
thrice daily with meals who cannot tolerate
other forms of Testosterone levels are often
treatment subtherapeutic

Not all preparations are available within individual countries. The suggested dosing may require an individualized regimen.2,10,11
Adapted from Jayasena CN et al. Clin Endocrinol (Oxf), 2022;96(2) © John Wiley & Sons Ltd.

ENDO 2022 • Reproductive Endocrinology  253

concentration above 4 ng/mL (>4 µg/L) should In summary, testosterone treatment has uncertain
trigger urological referral. It is therefore important effects on cardiovascular and cerebrovascular
to ask men about new or worsening lower urinary risk. In men with low cardiovascular risk,
tract symptoms within the first few months of concerns about cardiovascular safety should
initiating testosterone treatment, particularly if not be a factor discouraging the initiation of
they have other risk factors such as Black ethnicity, testosterone treatment. However, men with high
strong family history of prostate cancer, or are cardiovascular risk should be counseled that the
older than 65 years. cardiovascular safety of testosterone therapy is
uncertain. The US FDA–mandated TRAVERSE
Hematocrit study will provide robust evidence on this topic.22
A recent observational study suggested that
testosterone treatment was associated with
Bone Mineral Density
increased risk of venous thromboembolism.15
Men should be told that testosterone treatment Testosterone increases bone mineral density23
can increase the risk of thrombosis, but that and would be predicted to reduce fracture risk in
the absolute risk is low. Annual hematocrit hypogonadal men (although fracture reduction has
measurement is mandatory to ensure that not been proven). There is currently insufficient
erythrocytosis is avoided.1 If hematocrit is elevated evidence to justify routine bone densitometry.
above 50% (>0.50), the testosterone dosage could However, assessment should be considered in
be reduced, the dose interval could be lengthened, individuals at high risk, such as those with known
or the patient’s regimen could be switched to fractures, with hypogonadism onset during
transdermal testosterone treatment, which has early adulthood, or who are on glucocorticoid
a lower risk of erythrocytosis than injectable treatment.
testosterone.16 If hematocrit reaches 54% (0.54),
testosterone therapy should be stopped until levels Clinical Case Vignettes
drop again, and hematological referral should be
considered. One should evaluate for secondary Case 1
causes of elevated hematocrit. A 38-year-old man has been experiencing low
mood, reduced libido, inability to maintain
Cardiovascular Safety erections during intercourse, and loss of early-
morning erections over the last 6 months. His
There is controversy about the effects of symptoms have been progressively worsening.
testosterone treatment on cardiovascular He underwent orchidectomy following testicular
risk. Interventional and observational studies torsion 11 years ago. He has never been treated
have reported contradictory results regarding for cancer and has no comorbidities. He takes no
cardiovascular event risk, but no interventional medications and has a BMI of 24.7 kg/m2.
studies have been published that have been
powered to assess cardiovascular safety.17,18 The Laboratory test results:
National Institutes of Health testosterone trials
Serum LH = 12.5 mIU/mL (2.0-10.0 mIU/mL)
reported increases in noncalcified plaque volume (SI: 12.5 IU/L [2.0-10.0 IU/L])
and total plaque volume following testosterone Serum FSH = 14.2 mIU/mL (2.0-10.0 mIU/mL)
treatment vs placebo.19 The US FDA recommends (SI: 14.2 IU/L [2.0-10.0 IU/L])
that men on testosterone treatment be advised Total testosterone (9 AM, fasting) = 282 ng/dL and
303 ng/dL (SI: 9.8 nmol/L and 10.5 nmol/L)
of the potential cardiovascular risks,20 but other
SHBG = 41 µg/mL (20-60 µg/mL) (SI: 365 nmol/L
regulatory agencies have concluded that there [178-534 nmol/L])
is insufficient evidence to link testosterone Hematocrit = 38% (40%-54%) (SI: 0.38 [0.40-0.54])
treatment to increased cardiovascular risk.21

254  ENDO 2022 • Endocrine Case Management

Is testosterone treatment indicated? Low serum testosterone is common. However,
A. Yes only 2% of men aged 40 to 90 years fulfilled the
B. No criteria for late-onset hypogonadism defined by
European Male Ageing Study as: (1) low libido,
Answer: A) Yes loss of morning erections and loss of spontaneous
erections; (2) low testosterone defined as total
This case illustrates the importance of testosterone less than 230 ng/dL (<8 nmol/L) or a
corroborative evidence when serum testosterone combination of testosterone less than 317 ng/dL
levels are borderline. One of the testosterone (<11 nmol/L) and calculated free testosterone less
measurements is above a common “threshold” for than 6.3 ng/dL (220 pmol/L). This man has a low
diagnosis (300 ng/dL [10.4 nmol/L]), but assays SHBG level, so his calculated free testosterone
are subject to variation. He has specific (sexual) is normal. His comorbidity may be contributing
symptoms of hypogonadism. Orchidectomy to his symptoms, and weight loss should be
confers a higher risk of hypogonadism, and his offered as an alternative to testosterone therapy.
elevated gonadotropins show that he has testicular Thus, testosterone therapy should not be offered
failure. Furthermore, he has borderline anemia, (Answer B).
which supports the diagnosis of hypogonadism.
Testosterone treatment is indicated (Answer A).
Case 3
Case 2 A 71-year-old man has been experiencing low
libido, inability to maintain erections during
A 61-year-old man has been experiencing tiredness, intercourse, and loss of early-morning erections.
low mood, low libido, and inability to put on muscle His symptoms have been worsening over the last
bulk when exercising for the last 2 years. He does year. He had a myocardial infarction 3 years ago
not experience early-morning erections but can with left anterior descending coronary stenting.
maintain erections during intercourse. He has high He takes nitrates, aspirin, a statin, and an ACE
cholesterol treated with a stain, hypertension treated inhibitor. His BMI is 27.3 kg/m2.
with a calcium channel blocker, and type 2 diabetes
treated with metformin. His BMI is 33.7 kg/m2. Laboratory test results:
Laboratory test results: Serum LH = 15.5 mIU/mL (2.0-10.0 mIU/mL)
(SI: 15.5 IU/L [2.0-10.0 IU/L])
Serum LH = 2.5 mIU/mL (2.0-10.0 mIU/mL) Serum FSH = 27.1 mIU/mL (2.0-10.0 mIU/mL)
(SI: 2.5 IU/L [2.0-10.0 IU/L]) (SI: 27.1 IU/L [2.0-10.0 IU/L])
Serum FSH = 3.3 mIU/mL (2.0-10.0 mIU/mL) Total testosterone (9 AM, fasting) = 176 ng/dL
(SI: 3.3 IU/L [2.0-10.0 IU/L]) (SI: 6.1 nmol/L) and 170 ng/dL (SI: 5.9 nmol/L)
Total testosterone (9 AM, fasting) = 256 ng/dL SHBG = 2.9 µg/mL (2.2-6.7 µg/mL)
(SI: 8.9 nmol/L) and 265 ng/dL (SI: 9.2 nmol/L) (SI: 26 nmol/L [20-60 nmol/L])
SHBG = 1.35 µg/mL (2.25-6.74 µg/mL) Calculated free testosterone = 8.1 ng/dL
(SI: 12 nmol/L [20-60 nmol/L]) (SI: 0.28 nmol/L)
Calculated free testosterone = 8.07 ng/dL Hematocrit = 37% (40%-54%) (SI: 0.37 [0.40-0.54])
(SI: 0.28 nmol/L)
Hematocrit = 42% (40%-54%) (SI: 0.42 [0.40 to 0.54]) DXA documents a lumbar T-score of –2.7 and
femoral neck T-score of –1.6.
Is testosterone treatment indicated? Is testosterone treatment indicated?
A. Yes A. Yes
B. No B. No
Answer: B) No Answer: A) Yes

ENDO 2022 • Reproductive Endocrinology  255

This patient has anemia, osteoporosis, elevated should discuss the uncertain cardiac effects of
gonadotropins, and unequivocally low serum testosterone. However, the benefits of treatment
testosterone. Under normal circumstances, for sexual health, bone health, and anemia are
testosterone treatment would be a straightforward substantial. Therefore, testosterone treatment
decision. However, he has a strong history of should be considered if possible (Answer A).
cardiac disease. The patient and his cardiologist

References
1. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men 14. Santella C, Renoux C, Yin H, Yu OHY, Azoulay L. Testosterone replacement
with hypogonadism: an Endocrine Society clinical practice guideline. J Clin therapy and the risk of prostate cancer in men with late-onset hypogonadism.
Endocrinol Metab. 2018;103(5):1715-1744. PMID: 29562364 Am J Epidemiol. 2019;188(9):1666-1673. PMID: 31145457
2. Jayasena CN, Anderson RA, Llahana S, et al. Society for Endocrinology 15. Walker RF, Zakai NA, MacLehose RF, et al. Association of testosterone
guidelines for testosterone replacement therapy in male hypogonadism. Clin therapy with risk of venous thromboembolism among men with and without
Endocrinol (Oxf). 2022;96(2):200-219. PMID: 34811785 hypogonadism. JAMA Intern Med. 2020;180(2):190-197. PMID: 31710339
3. Ponce OJ, Spencer-Bonilla G, Alvarez-Villalobos N, et al. The efficacy and 16. Jick SS, Hagberg KW. The risk of adverse outcomes in association with use
adverse events of testosterone replacement therapy in hypogonadal men: a of testosterone products: a cohort study using the UK-based general practice
systematic review and meta-analysis of randomized, placebo-controlled trials. research database. Br J Clin Pharmacol. 2013;75(1):260-270. PMID: 22574772
J Clin Endocrinol Metab. 2018 [online ahead of print] PMID: 29562341 17. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and
4. Travison TG, Vesper HW, Orwoll E, et al. Harmonized reference ranges for cardiovascular events among men: a systematic review and meta-analysis
circulating testosterone levels in men of four cohort studies in the United of placebo-controlled randomized trials. BMC Med. 2013;11:108. PMID:
States and Europe. J Clin Endocrinol Metab. 2017;102(4):1161-1173. PMID: 23597181
28324103 18. Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular risk associated with
5. Brambilla DJ, Matsumoto AM, Araujo AB, McKinlay JB. The effect of diurnal testosterone-boosting medications: a systematic review and meta-analysis.
variation on clinical measurement of serum testosterone and other sex Expert Opin Drug Saf. 2014;13(10):1327-1351. PMID: 25139126
hormone levels in men. J Clin Endocrinol Metab. 2009;94(3):907-913. PMID: 19. Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone treatment and
19088162 coronary artery plaque volume in older men with low testosterone. JAMA.
6. Wu FCW, Tajar A, Beynon JM, et al; EMAS Group. Identification of 2017;317(7):708-716. PMID: 28241355
late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 20. US Food and Drug Administration. Drug safety communication: FDA
2010;363(2):123-135. PMID: 20554979 cautions about using testosterone products for low testosterone due to
7. Goldman AL, Bhasin S, Wu FCW, Krishna M, Matsumoto AM, Jasuja R. A aging; requires labeling change to inform of possible increased risk of heart
reappraisal of testosterone’s binding in circulation: physiological and clinical attack and stroke with use. January 2014. Available at: https://www.fda.gov/
implications. Endocr Rev. 2017;38(4):302-324. PMID: 28673039 media/91048/download
8. Fiers T, Wu F, Moghetti P, Vanderschueren D, Lapauw B, Kaufman JM. 21. European Medicines Agency EMA/706140/2014: No consistent evidence of
Reassessing free-testosterone calculation by liquid chromatography-tandem an increased risk of heart problems with testosterone medicines. November
mass spectrometry direct equilibrium dialysis. J Clin Endocrinol Metab. 21, 2014. Available at: https://www.ema.europa.eu/en/documents/referral/
2018;103(6):2167-2174. PMID: 29618085 testosterone-article-31-referral-no-consistent-evidence-increased-risk-heart-
9. Handelsman DJ. Free testosterone: pumping up the tires or ending the free problems-testosterone_en.pdf
ride? Endocr Rev. 2017;38(4):297-301. PMID: 28898980 22. A study to evaluate the effect of testosterone replacement therapy (TRT) on
10. Llahana S. Testosterone therapy in adult men with hypogonadism. In: the incidence of major adverse cardiovascular events (MACE) and efficacy
Llahana S, Follin C, Yedinak C, Grossman A, eds. Advanced Practice in measures in hypogonadal men (TRAVERSE). Available at: https://www.
Endocrinology Nursing. Springer International Publishing; 2019:885-902. clinicaltrials.gov/ct2/show/NCT03518034
11. Bhasin S, Jameson JL. Disorders of the testes and male reproductive system 23. Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of testosterone
In: Jameson JL, ed. Harrison’s Endocrinology. 4th ed. McGraw Hill Education; treatment on volumetric bone density and strength in older men with low
2017:159-185. testosterone: a controlled clinical trial. JAMA Intern Med. 2017;177(4):471-479.
12. Morgentaler A, Traish AM. Shifting the paradigm of testosterone and PMID: 28241231
prostate cancer: the saturation model and the limits of androgen-dependent
growth. Eur Urol. 2009;55(2):310-320. PMID: 18838208
13. Lenfant L, Leon P, Cancel-Tassin G, et al. Testosterone replacement therapy
(TRT) and prostate cancer: an updated systematic review with a focus on
previous or active localized prostate cancer. Urol Oncol. 2020;38(8):661-670.
PMID: 32409202

256  ENDO 2022 • Endocrine Case Management

Management Strategies for
Primary Ovarian Insufficiency
in Adolescence: Protecting
Long-Term Health
Lawrence C. Layman, MD. Reproductive Endocrinology, Infertility, and Genetics,
Department of Obstetrics and Gynecology, Medical College of Georgia at Augusta
University, Augusta, GA; E-mail: [email protected]

Learning Objectives • Autoimmune disorders, pathogenic variants

in genes associated with POI, and history of
As a result of participating in this session, learners
chemotherapy/radiation should be considered.
should be able to:
• Hormone treatment with estrogen may
• Discuss the clinical presentation of primary alleviate vasomotor and urogenital symptoms
ovarian insufficiency (POI) in adolescence. and lower the risk for future osteoporosis and
• Describe a rational diagnostic approach to the cardiovascular disease.
adolescent with POI. • Practically speaking, fertility is extremely unlikely
• Explain how POI affects long-term health. in women with POI without an egg donor.
• Guide the management of POI.

Significance of the
Main Conclusions Clinical Problem
POI, formerly known as premature ovarian failure,
• Diagnosis of POI in adolescent patients rests is usually defined as hypoestrogenic amenorrhea
upon amenorrhea and elevated gonadotropins for 3 to 6 months and elevated gonadotropins
with estrogen deficiency. on at least 2 occasions 4 weeks apart. POI has
• Chromosomal abnormalities, particularly been typically stated to occur in approximately
a 45,X cell line, must be excluded in all 1% of women younger than age 40 years in the
adolescents with primary amenorrhea United States (globally 2%-3%).1 Ovarian function
who have POI and should be considered in may cease prior to, during, or after puberty has
adolescents with secondary amenorrhea and been completed. Affected patients present with
POI depending upon stature. amenorrhea and hypoestrogenism with elevated
gonadotropins. Particular attention should be
• The absence of somatic anomalies should not
given to pubertal development and stature.
be a reason to dismiss Turner syndrome.
Potential etiologies include chromosomal, genetic,
autoimmune, and history of chemotherapy and/or
radiation.1,2

ENDO 2022 • Reproductive Endocrinology  257

 It is important to recognize and exclude a 45,X should be determined. A family history, preferably
cell line (Turner syndrome), as this has important a pedigree, should be obtained, documenting
consequences for long-term health, particularly relatives with other associated disorders,
cardiovascular complications consisting of anomalies, and/or POI.
cardiac valve abnormalities and aortic dilatation A complete physical examination should be
predisposing to dissection.3 If a patient has a 46,XX performed with particular attention to height,
karyotype, fragile X syndrome and associated weight, thyroid gland, and Tanner staging of
autoimmune disorders should be excluded.1,2,4 breast development and pubic hair. A full pelvic
Hormone treatment with estrogen and examination is challenging to perform in these
progesterone is important to treat vasomotor and hypogonadal girls and is best avoided (particularly,
urogenital symptoms and to prevent osteoporosis a speculum exam).5 If the patient allows, a Q-tip
and cardiovascular disease.1,2 Fertility, in most cases, can be placed into the vagina to document a patent
requires egg donation and in vitro fertilization. outflow tract, which is expected if the patient has
POI. If no vagina is identified, etiologies other
than POI must be considered.
Barriers to Optimal Practice Female adolescents without breast
development (Tanner stage 1) or impaired breast
• It is not normal to have absent breast
development (Tanner stage 2 to 3) by age 13
development by age 13 years, no period by age
to 14 years are nearly always hypoestrogenic.
15 years, or be amenorrheic for more than 4
Similarly, female adolescents with breast
to 6 months. In any of these circumstances, an
development without menarche are also likely
evaluation is necessary.
to be hypoestrogenic. If the adolescent has had
• POI can be diagnosed in adolescence prior to normal breast development with menarche and
the onset of puberty, during puberty, or once then ceases to menstruate, it must be determined
puberty is completed. whether she is hypoestrogenic. Typically,
• There is fear/misunderstanding that hormone amenorrhea of 3 to 6 months’ duration should
therapy conveys risks similar to those of be investigated.2,5 This may be accomplished in
treatment in natural menopause. several different ways, including serum estradiol
measurement, progestin withdrawal test, or
vaginal maturation index. It is important to
Strategies for Diagnosis, know whether the estradiol assay used is able
to discriminate low from low-normal values
Therapy, and/or Management
(normal follicular-phase levels 30-300 pg/mL
Diagnosis of POI [110.1-1101.3 pmol/L]; hypogonadism <30 pg/mL
Girls without breast development by age 13 to [<110.1 pmol/L]). Administering 7 to 10 days
14 years and/or without menarche by age 15 to of medroxyprogesterone acetate may be helpful
16 years, as well as adolescents with suspected if the estradiol value is inconclusive. A normal
hypogonadism, should be examined and evaluated. eugonadal response is a full period; spotting and
Pubertal milestones should be ascertained, absence of bleeding within a week of the last pill
including thelarche, pubarche, growth velocity, suggests hypoestrogenism. A vaginal maturation
peak height velocity, and menarche. A thorough index with a preponderance of parabasal cells
history of these timepoints is important, as well (small cells with large nucleus, which indicate
as the presence of any other associated disorders, hypoestrogenism) rather than estrogenic
including thyroid disease, adrenal disease, or other superficial cells (large cells with a small pyknotic
autoimmune phenomena. A history of malignancy nucleus) when collected with a Q-tip inserted into
with exposure to chemotherapy and/or radiation the vagina also suggests hypogonadism.5

258  ENDO 2022 • Endocrine Case Management

 Laboratory studies include the measurement of and malignancy. If the adolescent already has
serum estradiol, FSH, LH, TSH (with or without breast development, estradiol with cyclic progestin
free T4), and prolactin. In the United States, is indicated.1,2 For convenience, oral contraceptives
patients with POI typically have FSH levels greater are an acceptable convenient alternative in most
than 40.0 mIU/mL (>40.0 IU/L) (in Europe patients. This therapy can be administered until
>25.0 mIU/mL [>25.0 IU/L]) on 2 occasions the patient has reached the age of menopause
4 weeks apart, elevated LH levels, and normal (~early 50s) and should not be perceived to
thyroid function and prolactin levels.1,2 Once have the same risks as menopausal hormone
hypergonadotropic hypogonadism is diagnosed, replacement. Estradiol is important for protecting
karyotype analysis is indicated for all patients against bone loss that could lead to osteoporosis,
with primary amenorrhea and for those with preventing urogenital atrophy and dyspareunia,
short stature (<63 in [<160 cm]) with secondary and preventing cardiovascular disease.1,2
amenorrhea. This is true regardless of whether
the individual has Turner syndrome stigmata. A Management
45,X cell line requires lifetime medical surveillance
for cardiac and kidney dysfunction. If the patient Discussion regarding the management of the
has a 46,XX karyotype, fragile X syndrome testing adolescent with POI involves multiple facets.
should be offered to assess for the presence of an Estrogen treatment is important for prevention of
FMR1 premutation CGG expansion. If fragile X osteoporosis and cardiovascular disease. Fertility
testing is negative, a targeted POI gene panel can is very unlikely without an egg donor because
be considered, as 20% to 25% of affected patients expectant management, oral medications such as
possess pathogenic variants in 1 of approximately clomiphene citrate, injectable gonadotropins, or
30 genes. Because of the common (30%) in vitro fertilization all result in very low—but not
association of autoimmune disease, including zero—pregnancy rates (~5%). This is particularly
autoimmune thyroiditis, Addison disease, and type true for patients with Turner syndrome.1,2
1 diabetes, ordering fasting glucose measurement, If the patient has Turner syndrome, cardiac
as well as TPO antibodies and 21-hydroxylase echocardiography is indicated to exclude a dilated
antibodies should be considered. Alternatively, aorta, bicuspid aortic valve, or other cardiac
8-AM cortisol measurement is also reasonable.1,2 anomaly.3 Regular follow-up is suggested to
reduce the likelihood of aortic dissection, which
may complicate 2% of pregnancies. For this
Therapy reason, egg donation in a patient with Turner
A discussion with the patient and involved family syndrome is usually discouraged. Baseline kidney
members is important to address the psychologic ultrasonography is also indicated to exclude
stress that comes from knowing that there is congenital anomalies such as horseshoe kidney or
impaired ovarian function and that pregnancy unilateral kidney agenesis.
chances are extremely low. Patients with In patients with a normal karyotype,
primary amenorrhea, particularly those without pregnancy with egg donation appears to be safe. It
breast development, will benefit from estradiol is important to determine whether the patient has
administration by either oral or transdermal an FMR1 premutation, which increases the risk of
routes. Once breast development is adequate having affected male offspring (50% of males will be
(which may take 6 to 12 months depending on affected; 50% of females will be carriers). Even if the
development) or the patient has a menstrual bleed, patient’s chance of pregnancy is low, her diagnosis
adding progestin for 7 to 10 days per month helps could be beneficial to share with other family
protect the endometrium from long periods of members. Gene panels can help to determine the
unopposed estrogen and subsequent hyperplasia etiology of POI in patients with a 46,XX karyotype,

ENDO 2022 • Reproductive Endocrinology  259

but most cases are due to autosomal recessive Although it looks like she had some breast
inheritance, so do not present significant risks for development (ie, estrogen exposure), delayed
offspring should the patient conceive. puberty is usually defined as no breast
Yearly assessments for thyroid function, development by age 13 to 14 years and/or no
diabetes mellitus, and cortisol should be period by age 15 to 16 years. She is clearly beyond
considered, and studies should be performed, this and needs evaluation. Thus, expectant
especially if symptoms develop.1,2 If 2 or management (Answer A) is incorrect.
more autoimmune disorders are present, She did not bleed in response to progestin and
then autoimmune polyglandular syndrome has a low estradiol level, so she has hypogonadism.
is diagnosed.6 Autoimmune polyglandular Serum FSH measurement (Answer C) (usually
syndrome type I is a rare monogenic disorder along with LH) will help delineate whether the
due to pathogenic variants in the AIRE gene and defect is hypothalamic/pituitary or gonadal.
is characterized by mucocutaneous candidiasis, Outflow obstruction is unlikely since a vagina
hypoparathyroidism, Addison disease, type 1 is present. Thus, transabdominal ultrasonography
diabetes, and hypothyroidism. More than 50% (Answer D) will not add much at this point. The
of affected females develop POI. Types II though uterus and ovaries are small, which could be
IV are adult diseases: autoimmune polyglandular observed in a patient with hypogonadism from
syndrome type II (Addison disease + another any cause (or even be missed by ultrasonography).
endocrine disorder), type III (type 1 diabetes + Karyotype analysis (Answer B) is not
autoimmune thyroid disease), and type IV (2 or needed since it is not yet known whether she
more other endocrinopathies). These adult types are has hypergonadotropic hypogonadism or
more common than type I and are multifactorial vs hypogonadotropic hypogonadism.
autosomal dominant in some cases.6
Case 1 (Continued)
Clinical Case Vignettes Laboratory test results:
Case 1 FSH = 57.0 mIU/mL (3.0-10.0 mIU/mL)
An 18-year-old woman seeks evaluation because (SI: 57.0 IU/L [3.0-10.0 IU/L])
LH = 33.0 mIU/mL (3.0-10.0 mIU/mL)
she has never had a period. She has Tanner stage 3 (SI: 33.0 IU/L [3.0-10.0 IU/L])
breast development. Her referring physician gave
her 7 days of medroxyprogesterone, and she did Repeated measurement 4 weeks later shows
not bleed. an FSH concentration of 25.0 mIU/mL
On physical examination, a Q-tip was able to (25.0 IU/L) and LH concentration of 22.0 mIU/mL
be inserted into her vagina. (22.0 IU/L). Her vital signs are normal. Her height
Her estradiol concentration is 10 pg/mL is 61 in (155 cm) and BMI is 22 kg/m2.
(30-50 pg/mL [follicular phase]) (SI: 36.7 pmol/L
[110.1-183.6 pmol/L]). Which of the following is the best next step?
A. Brain MRI
Which of the following is the best next step?
B. DXA
A. Expectant management
C. Gene panel
B. Karyotype analysis
D. Karyotype analysis
C. Serum FSH measurement
D. Transabdominal ultrasonography Answer: D) Karyotype analysis

Answer: C) Serum FSH measurement Karyotype analysis (Answer D) is necessary to rule

out a chromosomal abnormality, namely Turner

260  ENDO 2022 • Endocrine Case Management

syndrome. In this case, it is prudent to ask the Fragile X syndrome is an X-linked dominant
laboratory to count chromosomes in 50 cells rather disorder due to full expansion of the triplet
than the standard 20 to exclude 45,X cell-line repeat in the FMR1 gene (Answer A). Affected
mosaicism. Most patients with Turner syndrome male patients typically have varying degrees
are shorter than 60 in (<152 cm), and this patient of intellectual disability or autism, facial
is 61 in (155 cm). Counting approximately 30 abnormalities, and macroorchidism. Female
cells excludes 10% mosaicism, and counting 50 to patients with the full expansion can have
60 cells excludes 5% mosaicism.3 She could have a intellectual disability, which is usually less severe,
45,X cell line with or without mosaicism (46,XX but they do not have POI. Females in a family
or 47,XXX; 46,XY is unlikely, as she has had some with known fragile X syndrome and who have the
breast development). Alternatively, she could have premutation have an increased risk of POI (15%
a karyotype demonstrating 46,XX with an Xp to 20%). If the proband is ascertained because of
deletion, an Xq deletion, an isochromosome X in POI, the risk for a premutation is about 3% to 4%
which she has an X chromosome with 2 long (q) if no other family members are affected, but the
arms (and missing the p arm), or a translocation risk is 10% to 15% if 2 or more family members are
involving an autosome or a Y chromosome with affected. In this patient’s family history, the first-
X. If she has Turner syndrome, there is a high risk degree cousin with autism and the family history of
of cardiovascular anomalies and an increased risk POI are suggestive of fragile X syndrome. Male and
of kidney anomalies, which would be important to female patients with a premutation have increased
know to guide her management.3 risk of tremors/ataxia when they get older.
Brain MRI (Answer A) is important if FSHR (Answer C) pathogenic variants are
gonadotropins are low or normal (hypogonadotropic associated with resistant ovary syndrome, in which
hypogonadism), but not in this case. patients have multiple follicles and POI.
Although DXA (Answer B) will be important SHOX (Answer D) pathogenic variants may
for long-term management, it is not important in cause short stature, Leri-Weill dyschondrosteosis,
the diagnosis. and Langer mesomelic dysplasia, both of which
A gene panel (Answer C) is not appropriate yet, as have skeletal anomalies among others.
it would not be necessary if she has Turner syndrome. FOXL2 (Answer B) pathogenic variants have
blepharophimosis-ptosis epicanthus syndrome,
in which eyelid abnormalities are accompanied
Case 1 (Continued)
by POI.
Her karyotype is reported as 46,XX with 50 None of these disorders is associated with the
cells counted. A more detailed family history intellectual disability or tremor/ataxia that can be
is obtained, and she states that her mother had associated with FMR1 pathogenic variants.
menopause at age 33 years and a maternal aunt
never had children but had some type of tremor.
She also has a first cousin with autism. Case 1 (Continued)
This 18-year-old patient with POI asks about
Which of the following genes should treatment, including questions about fertility.
be considered for testing?
A. FMR1 She should be counseled that her
B. FOXL2 chances of fertility are:
C. FSHR A. 5%
D. SHOX B. 25%
C. 50%
Answer: A) FMR1 D. 75%

ENDO 2022 • Reproductive Endocrinology  261

Answer: A) 5% not be counseled that they will never conceive—
however, the chances are low (Answer A).
Treatment consisting of expectant management, Only egg donation has the potential to result in
ovulation induction, or in vitro fertilization using pregnancy rates of approximately 50%, depending
the patient’s own eggs offers very low pregnancy on sperm and uterine factors.
rates. POI, particularly in patients with a normal
karyotype, may wax and wane, so they should

References
1. Stuenkel CA, Gompel A, Davis SR, Pinkerton JAV, Lumsden MA, Santen 4. Layman LC. Would combined glucocorticoid and gonadotropin therapy
RJ. Approach to the patient with new onset secondary amenorrhea: is this improve pregnancy rates in women with primary ovarian insufficiency? F S
primary ovarian insufficiency? J Clin Endocrinol Metab. 2022;107(3):825-835. Rep. 2020;1(3):171-172. PMID: 34223237
PMID: 34693971 5. Layman LC, Reindollar RH. The diagnosis and treatment of pubertal
2. McGlacken-Byrne SM, Conway GS. Premature ovarian insufficiency. Best disorders. Adolesc Med. 1994;5(1):37-56. PMID: 10358259
Pract Res Clin Obstet Gynaecol. 2021 [Online ahead of print] PMID: 34924261 6. Kahaly GJ, Frommer L. Polyglandular autoimmune syndromes. J Endocrinol
3. Zhong Q, Layman LC. Genetic considerations in the patient with Turner Invest. 2018;41(1):91-98. PMID: 28819917
syndrome--45,X with or without mosaicism. Fertil Steril. 2012;98(4):775-779.
PMID: 23020909

262  ENDO 2022 • Endocrine Case Management

THYROID
Molecular Diagnosis of
Indeterminate Thyroid Nodules
Bryan R. Haugen, MD. Division of Endocrinology, Metabolism and Diabetes, University of
Colorado School of Medicine, Aurora, CO 80045. E-mail: [email protected]

Sarah E. Mayson, MD. Division of Endocrinology, Metabolism and Diabetes, University of

Colorado School of Medicine, Aurora, CO 80045. E-mail: [email protected]

Learning Objectives Significance of the

Clinical Problem
• Appropriately assess the strengths and
limitations of molecular testing in patients FNA is recommended to evaluate for malignancy
with indeterminate thyroid nodule cytology. in thyroid nodules meeting criteria for biopsy
according to validated ultrasound risk stratification
• Summarize what is known about the long- systems, including the 2015 American Thyroid
term outcomes of nonoperatively managed Association (ATA) Guidelines for Patients with
thyroid nodules with indeterminate Thyroid Nodules and Differentiated Thyroid
cytopathology and negative molecular testing. Cancer and the American College of Radiology
(ACR) Thyroid Imaging Reporting and Data
System (TI-RADS). The Bethesda System for
Reporting Thyroid Cytopathology (TBSRTC) is
Main Conclusions widely accepted as a standard reporting system
for thyroid cytopathology. This system includes
• Currently available molecular tests have 3 indeterminate reporting categories (Bethesda
high sensitivity to rule out malignancy and III-V), each of which is associated with a different
reasonable specificity to rule in malignancy predicted risk for malignancy. The 2017 TBSRTC
for patients with indeterminate thyroid proposes that the risk for malignancy for atypia
nodule cytology. of undetermined significance/follicular lesion of
• Sonographic features of the thyroid nodule undetermined significance (AUS/FLUS) (Bethesda
must be considered when interpreting III) cytology is 6% to 18% when noninvasive
molecular test results for patients with follicular thyroid neoplasm with papillary-like
indeterminate cytology. nuclear features (NIFTP) is considered benign and
• Certain pathogenic variants can be associated 10% to 30% when NIFTP is considered malignant.1
with familial syndromes. Providers should be Furthermore, the predicted risk for malignancy
aware of these variants and consider referral to for follicular neoplasm/suspicious for follicular
genetic counseling when appropriate. neoplasm (FN/SFN) (Bethesda IV) is 10% to 40%
when NIFTP is considered benign and 25% to 40%
• The presence of higher-risk pathogenic when NIFTP is considered malignant. The risk
variants (TERT promoter, TP53, PIK3CA, for malignancy associated with both categories
etc) may help guide more or less aggressive remains low enough to not justify surgical
management/monitoring, but more studies resection for all patients, yet high enough to not
are needed. justify monitoring for all.

264  ENDO 2022 • Endocrine Case Management

 The historical management of patients with Strategies for Diagnosis,
indeterminate cytopathology, especially prior
Therapy, and/or Management
to TBSRTC, was diagnostic thyroid surgery (ie,
lobectomy) to definitively rule in or rule out Before being adopted into clinical practice,
cancer. This approach has many disadvantages, molecular tests should be evaluated to confirm
including financial costs and operative risks, their analytical validity, clinical validity, and
and leads to overtreatment or undertreatment clinical utility. Analytical validation refers to the
in up to 60% of patients. Postoperative accuracy of the test to measure what it is intended
hypothyroidism necessitating lifelong thyroid to measure in the context of limited input material
hormone replacement occurs in approximately or in the presence of contamination (eg, blood), as
20% of patients after lobectomy and is even more well as the reproducibility of the test to produce
prevalent in patients with underlying chronic the same results over repeated runs. Clinical
autoimmune thyroiditis who have normal thyroid validation evaluates the ability of a diagnostic
function before surgery. test to rule out disease (sensitivity, negative
Since 2011, a number of molecular platforms predictive value [NPV]) and rule in disease
have been developed to assist in the diagnostic (specificity, positive predictive value [PPV]). Both
evaluation of thyroid nodules with indeterminate sensitivity and specificity are inherent properties
cytopathology. Molecular testing can help of the diagnostic test and thus can be compared
identify nodules that are unlikely to be malignant among different studies in different populations.
(posttest probability of malignancy ≤5%), allowing However, PPV and NPV are influenced by disease
these nodules to be triaged to clinical rather prevalence. NPV increases and PPV decreases as
than operative management. In addition, some prevalence falls, while the opposite is observed
molecular tests can identify specific genetic when prevalence rises. Clinical utility refers to the
alterations in the nodule, which may help to psychological, social, and economic consequences
inform patient management. of testing and impact on health outcomes in the
context of the individual, family, and society.
Molecular platforms for the evaluation of
Barriers to Optimal Practice indeterminate thyroid nodules use different
testing approaches. These include assessment
• Regional or institutional variation in the for single nucleotide variants (point mutations),
prevalence of malignancy/NIFTP of Bethesda insertions/deletions, gene fusions, chromosomal
III-IV thyroid nodules influences the copy number alterations, and/or abnormal gene
performance of molecular tests used in clinical expression using DNA, mRNA, miRNA, or
practice. a combination thereof. The Afirma Genomic
• There are limited studies evaluating the Sequencing Classifier (GSC) and Xpression Atlas
longer-term outcomes of thyroid nodules (XA), ThyroSeq v3 Genomic Classifier (GC), and
with indeterminate cytopathology and ThyGeNEXT/ThyraMIR are currently the best
negative results for the molecular tests that are studied, most widely available molecular diagnostic
currently available. tests in the United States. All are based on earlier
• More research is needed to clearly define the versions of the same/similar tests.
prognostic and therapeutic implications of the Afirma GSC requires a fresh FNA specimen
many genetic alterations that can be identified that is immediately placed into a proprietary
through molecular testing. collection vial. The test primarily uses mRNA
expression and machine-learned algorithms to risk
stratify indeterminate thyroid nodules as benign
or suspicious. An upstream mutation/fusion panel

ENDO 2022 • Thyroid  265

allows for specific gene variants highly correlated a binary positive/negative result, all ThyroSeq GC
with thyroid cancer (BRAF V600E, RET/PTC1, test results include a detailed report of the genetic
or RET/PTC3 fusions) to be identified, thus alterations that were identified and the estimated
bypassing the core classifier. There are additional risk of malignancy associated with the identified
upstream components to identify parathyroid variants. The ThyroSeq GC clinical validation
tissue and medullary thyroid carcinoma. The study was a prospective blinded multicenter study
Afirma GSC clinical validation study was a blinded of 286 Bethesda III-V thyroid nodules, including
multicenter study of 191 Bethesda III/IV thyroid 154 Bethesda III and 93 Bethesda IV nodules. The
nodules, which used retained samples from the overall sensitivity was 94%, specificity was 82%,
prospective Afirma Gene Expression Classifier NPV was 97%, and PPV was 66%. The prevalence
(GEC) validation trial. The overall sensitivity was of cancer/NIFTP was 28%. The study included 11
91%, specificity was 68%, NPV was 96%, and PPV nodules (4%) that were NIFTP on histopathology,
was 47%. The prevalence of thyroid cancer was all of which were classified as positive.5
24% (NIFTP prevalence not known). One of the The performance of Afirma GSC and
key improvements of Afirma GSC over the earlier ThyroSeq GC was recently compared in a single-
version (GEC) is its improved specificity, mostly center randomized pragmatic clinical trial that
owed to its superior performance in Hurthle-cell included 372 indeterminate thyroid nodules.6
nodules (specificity of 58.8% for GSC vs 11.8% The majority of nodules with negative molecular
for GEC in Hurthle-cell nodules).2 Afirma XA is a results were managed nonoperatively. The
separate test that can be ordered reflexively when prevalence of cancer/NIFTP was 19.6%. Overall,
GSC is positive. XA uses whole-transcriptome 49% of patients were able to avoid diagnostic
RNA sequencing to identify gene variants and surgery. Importantly, there was no significant
fusions. The original version of XA included 511 difference in the observed sensitivity, specificity,
thyroid-related genes, while the current expanded NPV, or PPV of Afirma GSC and ThyroSeq GC.
panel includes 593 genes (905 variants and 235 This trial provides real-world data that the 2 tests
fusion pairs). A recent study of more than 16,000 perform similarly well in clinical practice.
GSC suspicious Bethesda III/IV nodules detected 1 ThyGeNEXT/ThyraMIR can be performed
or more mutation/fusion in 42% of nodules using using fresh FNA specimens, formalin-fixed
the original panel and 44% using the expanded histopathologic specimens, or ethanol-fixed FNA
panel.3 Because XA is an RNA-based test, it cannot smears. This multiplatform test combines next-
detect mutations/fusions that are present in generation sequencing of DNA and mRNA to
noncoding regions of DNA (eg, TERT promoter). evaluate for 42 gene variants and 38 gene fusions
ThyroSeq v3 GC has been analytically with qRT-PCR to measure expression levels of 10
validated for use with fresh FNA specimens and miRNAs. The test uses a proprietary algorithm to
FNA smears. Better preservation of nucleic acid ultimately yield a positive, negative, or “moderate”
material is observed with ethanol-fixed vs air- result. The ThyGeNEXT/ThyraMIR clinical
dried smears.4 ThyroSeq GC uses next-generation validation study was a multicenter retrospective
sequencing of DNA and mRNA to evaluate for 5 cross-sectional cohort study with pathologist
classes of genetic alterations in 112 thyroid cancer- blinding. The initial study set included 309
related genes. These include point mutations, archived samples, while the final study set
insertions/deletions, gene fusions, chromosomal included 197 Bethesda III/IV nodules after 59
copy number alterations, and gene expression were excluded due to insufficient material and
alterations. Each genetic alteration that is 53 samples were excluded because of lack of
identified is assigned a score between 0 and 2, and histopathology consensus. The prevalence of
the total score is calculated for the sample. A score cancer/NIFTP was 30%. The observed sensitivity
of 2 or more is considered positive. In addition to was 93%, specificity was 90%, NPV was 95%,

266  ENDO 2022 • Endocrine Case Management

and PPV was 74%. The risk of disease with a normal-appearing cervical lymph nodes. The
moderate result was 30%. When calculating test patient has no compressive symptoms.
sensitivity, the authors counted the 15 moderates
with malignant histopathology as true positives. What is the most appropriate management
When calculating test specificity, they counted to recommend for this patient? What
the 35 moderates with benign histology as true proportion of thyroid nodules deemed benign
negatives. Finally, the authors separately reported on molecular testing are eventually resected,
prevalence-adjusted statistical parameters. and what is the frequency of malignancy? Are
Following adjustment of disease prevalence to there are any clinical or radiographic risk
14%, the test sensitivity was 95%, specificity was factors that predict missed thyroid cancer?
90%, NPV was 97%, and PPV was 75%. The risk Published studies of thyroid nodules with
of disease with a moderate result was 39%.7 The indeterminate cytology and negative molecular
performance of ThyGeNEXT/ThyraMIR should testing that are followed nonoperatively are
ideally be confirmed in a prospective multicenter generally reassuring. A recent study from the
clinical validation study. University of California Los Angeles group
Molecular diagnostic testing has become a found that patients with nodules classified as
commonly used tool to help triage indeterminate benign on molecular testing who were followed
thyroid nodules into 2 groups: (1) those that longitudinally with ultrasound surveillance did not
are likely to be benign and can be managed experience a decline in health-related quality of life
nonoperatively, similar to benign (Bethesda II) or worsening anxiety or depression over time.8
nodules, and (2) those that are likely to represent Reported rates of surgical resection of thyroid
thyroid cancer or NIFTP and should be treated nodules classified as benign on molecular testing
surgically. In addition, some molecular tests range from 5% to 25%, but missed malignancies
can identify specific genetic alterations that are are uncommon.9-12 Studies assessing the longer-
associated with indolent, or conversely, aggressive term outcomes of molecularly benign thyroid
forms of thyroid cancer. In this context, molecular nodules evaluated with currently available tests are
test results also have the potential to inform presently limited, but would be expected to yield
clinical management decisions, as we will discuss similarly low false-negative rates. A prospective
in some of the cases that follow. cohort of 95 indeterminate thyroid nodules
with negative molecular testing (Afirma GEC or
Clinical Case Vignettes ThyroSeq v2) were followed for a median of 26.7
months to determine the frequency of delayed
Case 1 resection and the false-negative rate of molecular
A 70-year-old man with no risk factors for testing. Immediate surgery was performed for
thyroid cancer underwent initial evaluation of 12 nodules (11 benign, 1 NIFTP) and delayed
a left thyroid nodule 2.5 years ago. Ultrasound surgery for 10 (6 benign, 4 malignant). The overall
examination demonstrated a 3.2-cm isoechoic false-negative rate was 5.8%. Change in nodule
solid nodule with well-defined regular borders appearance on ultrasonography (increase in
and no suspicious lymph nodes. Ultrasound- size and/or development of suspicious features)
guided FNA demonstrated AUS (Bethesda III) was correlated with malignancy.12 A larger
cytopathology with architectural atypia. Molecular retrospective study of 289 molecular benign
testing with Afirma GSC was negative. The nodules (Afirma GEC or GSC) found that the
patient has pursued clinical and ultrasonography false-negative rate was significantly higher for
follow-up for his nodule. Today his neck thyroid nodules that were considered to have
examination and ultrasonography demonstrate high risk for malignancy based on ultrasound
stable size and appearance of the nodule and risk stratification.11

ENDO 2022 • Thyroid  267

 In conclusion, molecularly benign thyroid but the BRAF V600E variant confers nearly
nodules that have high-risk sonographic findings 100% risk of thyroid cancer.16 There is increasing
at baseline or develop suspicious features during evidence that many patients with small papillary
follow-up are most likely to represent missed thyroid carcinoma (PTC) (<1 cm) may safely
thyroid cancers. The interval development of undergo active surveillance or deferred therapy
suspicious sonographic findings should prompt instead of immediate surgery.17-19 Of note, younger
further evaluation of the nodule (eg, repeat FNA) patients (<40 years) tend to have a higher rate of
and possible resection. In contrast, the thyroid disease progression than older patients.17 Studies
nodule described in this case demonstrated low- are ongoing to determine whether properly
risk sonographic findings at baseline, which have selected patients with PTC up to 1.5 to 2 cm could
been stable on subsequent imaging follow-up. be candidates for active surveillance.
Continued clinical and ultrasonography follow-up There are multiple components to “properly
would be the most appropriate management to selected patients,” but one important component
recommend for this patient. is tumor location. Tumors with clear normal
tissue surrounding them on ultrasonography are
Case 2 at lowest risk for extrathyroidal extension and are
good candidates for surveillance. Surgical resection
A 33-year-old man undergoes neck is generally recommended when there is a question
ultrasonography for “fluctuating neck adenopathy” of extrathyroidal extension on ultrasonography
after COVID vaccination. Imaging demonstrates a and for those tumors located posteriorly, with
left 1.4-cm isoechoic nodule with coarse internal potential for posterior or tracheal extension. This
hyperechoic echoes. He has no neck symptoms. patient underwent a planned left lobectomy that
Serum TSH concentration is 1.8 mIU/L. was converted to thyroidectomy when the surgeon
Ultrasound-guided FNA cytology is categorized as noted tumor adherence to the trachea. Final
AUS (Bethesda III) with a microscopic description pathology noted extrathyroidal extension.
of “many nuclear grooves and rare nuclear
pseudoinclusions.” Results of Afirma GSC testing
are suspicious and identify the BRAF V600E Case 3
pathogenic variant. A 28-year-old woman with a history of a uterine
fibroid tumor and stage I breast cancer presents
What is the best way to sonographically for evaluation of a left thyroid nodule detected on
evaluate for extrathyroidal extension? What PET/CT imaging done in the context of her recent
are the best next steps for this patient? Does breast cancer diagnosis. The thyroid nodule was not
cancer location in the thyroid influence noted to be fluorodeoxyglucose-avid. The patient’s
the approach (monitoring vs surgery)? mother died of breast cancer. The patient’s father
and older sister are healthy. Her younger brother
Isoechoic nodules are generally classified as having
has a nonsevere form of autism spectrum disorder.
a low sonographic risk pattern.13 This nodule
Subsequent neck ultrasonography confirms
would be classified as TI-RADS TR4 (4 points,
the presence of a 1.6-cm isoechoic solid nodule
moderately suspicious).14 Still images may be useful
in the left mid pole of the thyroid gland with
to identify potential extrathyroidal extension,
well-defined regular borders and no contralateral
which is most easily identified in the anterior
nodules or abnormal lymph nodes. Her serum
thyroid. If there is question of extrathyroidal
TSH concentration is 2.0 mIU/L. The patient
extension on still images, video clips, when
undergoes ultrasound-guided FNA of the thyroid
available, can be helpful.
nodule, which reveals AUS cytology (Bethesda III),
In general, a suspicious Afirma GSC result
and molecular testing with ThyroSeq v3 is positive
confers approximately 50% risk of malignancy,15

268  ENDO 2022 • Endocrine Case Management

for a PTEN variant (c.388C>T [p.R130]). This is papillomatous papules, gastrointestinal polyposis,
identified in the sample at 50% allele frequency. No and macrocephaly. Cowden syndrome has been
additional genetic alterations are detected. estimated to affect 1 in 200,000 to 250,000
persons, but it is most likely underrecognized.
What is the significance of the identified Thyroid involvement in Cowden syndrome is
PTEN gene variant? Does the reported allelic usually multinodular and bilateral. Benign thyroid
frequency have potential significance? nodules and thyroid cancer occur in approximately
How should this patient be managed? 75% and 35% of affected individuals, respectively.24
Thyroid cancer is most often diagnosed in women
Pathogenic variants in the phosphatase and
and young adults, but it can be present at any age,
tensin homolog gene (PTEN) are observed in
even in early childhood. Although both PTC and
both benign and malignant thyroid tumors and
FTC are observed in Cowden syndrome, FTC in
can occur as either germline or sporadic events.
particular is overrepresented compared with its
PTEN is a phosphatase that negatively regulates
incidence in the general population. The National
AKT, leading to the induction of apoptosis. Loss
Comprehensive Cancer Network recommends
of this tumor suppressor leads to increased cell
age-based screening for breast, uterine, and
survival. A study of 95 sporadic thyroid neoplasms
thyroid cancers, as well as renal ultrasonography
documented PTEN alterations in 11 tumors:
and colonoscopy for patients with Cowden
in 26% of benign or atypical adenomas and in
syndrome. Initiation of annual screening thyroid
6% of thyroid carcinomas.20 PTEN alterations
ultrasonography begins at the time of diagnosis in
have been associated with thyroid cancer
adults and at age 7 years in children.25
tumor progression. A study of 779 advanced
The thyroid nodule in this case was
differentiated and anaplastic thyroid cancers
documented to have the PTEN c.388C> T (p.R130)
documented PTEN pathogenic variants in 11%
variant through molecular testing; this specific
of anaplastic cancers. In the group of advanced
pathogenic variant has been recurrently associated
differentiated cancers, PTEN alterations were
with PTEN hamartoma tumor syndrome.24 The
identified in 17% of Hurthle-cell carcinomas, in
variant was detected in the sample at an allele
14% of follicular thyroid carcinomas (FTCs), and
frequency of 50%, where the allele frequency is
in only 2% of PTCs.21 Another study screened 259
the proportion of sequencing reads containing
unselected patients with differentiated thyroid
the gene variant divided by the total number of
cancer for germline PTEN pathogenic variants.
reads through the locus. Documentation of an
The frequency of PTEN alterations was only 0.8%
allele frequency near 50% should raise concern
across all thyroid cancers, but it was 4.8% when
for a germline pathogenic variant. However,
only follicular cancers were considered.22
evaluation for the same variant in nonneoplastic
Germline pathogenic variants in PTEN may
tissue is required to prove that the alteration is not
lead to the PTEN hamartoma tumor syndrome,
somatic. Referral to a genetic counselor should
one of the most common known causes of
be offered to the patient in the context of the
syndromic nonmedullary thyroid cancer. PTEN
molecular test results and her personal and family
hamartoma tumor syndrome encompasses several
history of Cowden syndrome features. A genetic
distinct phenotypes, including Cowden syndrome,
counselor can discuss genetic testing with the
Bannayan-Riley-Ruvalcaba syndrome, and Proteus
patient and her family and provide information on
and Proteus-like syndromes.23 Cowden syndrome
the mode of inheritance and clinical implications
is an autosomal dominant disorder resulting
of a germline PTEN pathogenic variant.
from inherited or de novo PTEN pathogenic
The patient met with a genetic counselor, and
variants. It is associated with a high risk of
testing confirmed the presence of a germline PTEN
benign and malignant tumors (breast, thyroid,
pathogenic variant. Because the documented
kidney, and endometrium), trichilemmomas,

ENDO 2022 • Thyroid  269

PTEN variant is germline, it can be concluded patients with minimally invasive FTC are age
that the thyroid nodule in question has no genetic and tumor size.27 Multivariate analyses from 292
alterations that are somatic and is very likely benign. patients with minimally invasive FTC showed that
The nodule can thus be managed conservatively tumor size larger than 4 cm was an independent
without surgery at this time; however, the patient predictor of worse disease-free survival and
will require routine screening for thyroid cancer disease-specific survival.28 Therefore, patients with
on an ongoing basis with annual clinical neck minimally invasive FTC larger than 4 cm should
examination and thyroid ultrasonography.25 be approached differently than patients with
smaller tumors. Furthermore, this patient had an
rhTSH-stimulated thyroglobulin concentration of
Case 4
409 ng/mL (409 µg/L) after thyroidectomy, which
A 63-year-old woman is noted to have an isoechoic is also a very concerning feature. The 2 most
3.5-cm left thyroid nodule during evaluation for common sites for distant metastases in patients
amiodarone-induced thyrotoxicosis (AIT) type with FTC are the lungs and bone. Imaging of the
2. AIT resolves. Results from FNA of the thyroid lungs (generally with noncontrast chest CT) and/
nodule are benign. The nodule slowly grows over or bones (nuclear medicine scan, skeletal MRI)
6 years. Results from repeated FNA are follicular would be reasonable next steps for this patient.
neoplasm (Bethesda IV). Based on growth and When the thyroglobulin concentration of
cytology, the patient undergoes left lobectomy, 20.0 ng/mL (20.0 µg/L) on levothyroxine therapy
which demonstrates a 6.4-cm minimally invasive was noted, the patient underwent a diagnostic 123I
FTC (no angioinvasion seen). Based on the whole-body scan and was noted to have an iliac
size, the patient has completion thyroidectomy crest lesion on SPECT imaging. After treatment
(no additional cancer) and rhTSH-stimulated with 146 mCi 131I, the patient was noted to have
radioiodine remnant ablation with 30 mCi 131I multiple bone metastases (bilateral iliac crests, left
(uptake in thyroid bed region only, thyroglobulin femur, left fifth rib, inferior pubic ramus) and a
= 409 ng/mL [409 µg/L]). Three months after left lower lung nodule.
treatment, findings on neck ultrasonography are Tissue was sent for ThyroSeq GC testing,
normal, her TSH concentration is 0.17 mIU/L, which revealed an HRAS Q61R variant and a
and thyroglobulin concentration is 1.7 ng/mL TERT 124C>T promoter variant. RAS variants are
(1.7 µg/L) with negative thyroglobulin antibodies. common in FTC. TERT promoter variants are rare
At 12 months, her serum thyroglobulin and TSH in minimally invasive FTC but are associated with
concentrations are 20.0 ng/mL (20.0 µg/L) and poor prognosis in differentiated thyroid cancer.29,30
0.5 mIU/L, respectively. There are no studies exploring the utility of
genetic testing in minimally invasive FTC, but
How accurate are assessments of angioinvasion this could be considered in older patients and in
and capsular invasion in FTC >4 cm? Is the patients with larger tumors to determine whether
postoperative stimulated thyroglobulin higher-risk variants are present (TERT promoter,
concentration concerning? Is there a role
TP53, PIK3CA, etc) if monitoring with or without
for molecular testing in large, minimally
radioiodine is being considered.
invasive FTC? If she has persistent cancer,
what are the most likely sites of persistent
disease? What is the most appropriate
next management step for this patient?
Minimally invasive FTC generally has an indolent
course and can often be treated with lobectomy
alone.26 Risk factors for distant metastases in

270  ENDO 2022 • Endocrine Case Management

Acknowledgment
The authors would like to thank Dr. Yuri Nikiforov, MD, PhD, from the Division of Molecular and
Genomic Pathology at the University of Pittsburgh Medical Center, for providing the ThyroSeq report that
served as the basis for Case 3.

References
1. Cibas ES, Ali SZ. The 2017 Bethesda system for reporting thyroid 16. Rossi M, Buratto M, Bruni S, et al. Role of ultrasonographic/clinical profile,
cytopathology. Thyroid. 2017;27(11):1341-1346. PMID: 29091573 cytology, and BRAF V600E mutation evaluation in thyroid nodule screening
2. Patel KN, Angell TE, Babiarz J, et al. Performance of a genomic sequencing for malignancy: a prospective study. J Clin Endocrinol Metab. 2012;97(7):2354-
classifier for the preoperative diagnosis of cytologically indeterminate thyroid 2361. PMID: 22535974
nodules. JAMA Surg. 2018;153(9):817-824. PMID: 29799911 17. Miyauchi A, Kudo T, Ito Y, et al. Estimation of the lifetime probability of
3. Hu MI, Waguespack SG, Dosiou C, et al. Afirma genomic sequencing disease progression of papillary microcarcinoma of the thyroid during active
classifier and Xpression Atlas molecular findings in consecutive Bethesda surveillance. Surgery. 2018;163(1):48-52. PMID: 29103582
III-VI thyroid nodules. J Clin Endocrinol Metab. 2021;106(8):2198-2207. PMID: 18. Ho AS, Luu M, Zalt C, et al. Mortality risk of nonoperative papillary thyroid
34009369 carcinoma: a corollary for active surveillance. Thyroid. 2019;29(10):1409-
4. Nikiforova MN, Lepe M, Tolino LA, et al. Thyroid cytology smear slides: an 1417. PMID: 31407637
untapped resource for ThyroSeq testing. Cancer Cytopathol. 2021;129(1):33- 19. Molinaro E, Campopiano MC, Pieruzzi L, et al. Active surveillance in
42. PMID: 32697051 papillary thyroid microcarcinomas is feasible and safe: experience at a
5. Steward DL, Carty SE, Sippel RS, et al. Performance of multigene genomic single Italian center. J Clin Endocrinol Metab. 2020;105(3):e172-e180. PMID:
classifier in thyroid nodules with indeterminate cytology: a prospective 31652318
blinded multicenter study. JAMA Oncol. 2019;5(2):204-212. PMID: 30419129 20. Dahia PL, Marsh DJ, Zheng Z, et al. Somatic deletions and mutations in
6. Livhits MJ, Zhu CY, Kuo EJ, et al. Effectiveness of molecular testing the Cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res.
techniques for diagnosis of indeterminate thyroid nodules: a randomized 1997;57(21):4710-4713. PMID: 9354427
clinical trial. JAMA Oncol. 2021;7(1):70-77. PMID: 33300952 21. Pozdeyev N, Gay LM, Sokol ES, et al. Genetic analysis of 779
7. Lupo MA, Walts AE, Sistrunk JW, et al. Multiplatform molecular advanced differentiated and anaplastic thyroid cancers. Clin Cancer Res.
test performance in indeterminate thyroid nodules. Diagn Cytopathol. 2018;24(13):3059-3068. PMID: 29615459
2020;48(12):1254-1264. PMID: 32767735 22. Nagy R, Ganapathi S, Comeras I, et al. Frequency of germline PTEN
8. Schumm MA, Nguyen DT, Kim J, et al. Longitudinal assessment of quality of mutations in differentiated thyroid cancer. Thyroid. 2011;21(5):505-510.
life following molecular testing for indeterminate thyroid nodules. Ann Surg PMID: 21417916
Oncol. 2021;28(13):8872-8881. PMID: 34292427 23. Yehia L, Eng C. 65 years of the double helix: one gene, many endocrine and
9. Deaver KE, Haugen BR, Pozdeyev N, Marshall CB. Outcomes of Bethesda metabolic syndromes: PTEN-opathies and precision medicine. Endocr Relat
categories III and IV thyroid nodules over 5 years and performance of the Cancer. 2018;25(8):T121-T140. PMID: 29792313
Afirma gene expression classifier: a single-institution study. Clin Endocrinol 24. Yehia L, Eng C. PTEN Hamartoma Tumor Syndrome. In: Adam MP,
(Oxf). 2018;89(2):226-232. PMID: 29791966 Ardinger HH, Pagon RA, et al, eds. GeneReviews. PMID: 20301661
10. Angell TE, Frates MC, Medici M, et al. Afirma benign thyroid nodules 25. NCCN clinical practice guidelines in oncology.: National Comprehensive
show similar growth to cytologically benign nodules during follow-up. J Clin Cancer Network (NCCN). 2021.
Endocrinol Metab. 2015;100(11):E1477-E1483. PMID: 26353010 26. Goffredo P, Cheung K, Roman SA, Sosa JA. Can minimally invasive follicular
11. Endo M, Porter K, Long C, et al. Features of cytologically indeterminate thyroid cancer be approached as a benign lesion?: a population-level analysis
molecularly benign nodules treated with surgery. J Clin Endocrinol Metab. of survival among 1,200 patients. Ann Surg Oncol. 2013;20(3):767-772. PMID:
2020;105(11):e3971-e3980. PMID: 32772084 23111705
12. Zhu CY, Donangelo I, Gupta D, et al. Outcomes of indeterminate thyroid 27. Sugino K, Ito K, Nagahama M, et al. Prognosis and prognostic factors for
nodules managed nonoperatively after molecular testing. J Clin Endocrinol distant metastases and tumor mortality in follicular thyroid carcinoma.
Metab. 2021;106(3):e1240-e1247. PMID: 33394039 Thyroid. 2011;21(7):751-757. PMID: 21615311
13. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid 28. Ito Y, Hirokawa M, Masuoka H, et al. Prognostic factors of minimally
Association management guidelines for adult patients with thyroid nodules invasive follicular thyroid carcinoma: extensive vascular invasion significantly
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Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid 29. Moon S, Song YS, Kim YA, et al. Effects of coexistent BRAFV600E and
Cancer. Thyroid. 2016;26(1):1-133. PMID: 26462967 TERT promoter mutations on poor clinical outcomes in papillary thyroid
14. Tessler FN, Middleton WD, Grant EG, et al. ACR Thyroid Imaging, cancer: a meta-analysis. Thyroid. 2017;27(5):651-660. PMID: 28181854
Reporting and Data System (TI-RADS): white paper of the ACR TI-RADS 30. Liu R, Bishop J, Zhu G, Zhang T, Ladenson PW, Xing M. Mortality risk
Committee. J Am Coll Radiol. 2017;14(5):587-595. PMID: 28372962 stratification by combining BRAF V600E and TERT promoter mutations
15. Patel KN, Angell TE, Babiarz J, et al. Performance of a genomic sequencing in papillary thyroid cancer: genetic duet of BRAF and TERT promoter
classifier for the preoperative diagnosis of cytologically indeterminate thyroid mutations in thyroid cancer mortality. JAMA Oncol. 2017;3(2):202-208. PMID:
nodules. JAMA Surg. 2018;153(9):817-824. PMID: 29799911 27581851

ENDO 2022 • Thyroid  271

What’s Wrong With This
Picture? Challenging Cases
in Thyroid Ultrasonography
Jennifer A. Sipos, MD. Division of Endocrinology, The Ohio State University, Columbus, OH;
E-mail: [email protected]

Learning Objectives Significance of the

As a result of participating in this session, learners Clinical Problem
should be able to: Thyroid nodules are a common clinical entity,
• Define suspicious sonographic findings and the sheer volume in the general population
on ultrasonography of thyroid nodules precludes aspiration of all identified lesions.
and categorize thyroid nodules using the Furthermore, most thyroid nodules are benign.
American Thyroid Association (ATA) and It is incumbent on the clinician to risk stratify
the American College of Radiology (ACR) nodules and thereby enrich the pool of clinically
Thyroid Imaging Reporting and Data System concerning nodules that harbor a higher likelihood
(TI-RADS) sonographic risk stratification of malignancy. Several SRSSs1,2 have been
systems (SRSSs). created to aid in the decision of which nodules
warrant additional evaluation. Uncertainty exists,
• Discuss the strengths and limitations of the however, regarding which SRSS is optimal for
ATA and ACR TI-RADS SRSSs. nodule classification. Ideally an SRSS should
provide both high sensitivity and high specificity.
The ATA system2 provides high sensitivity
but lower specificity, while ACR TI-RADS1
Main Conclusions provides improved specificity at the expense of
Sonographic characterization is an effective means lower sensitivity for detection of malignancy.3
to triage thyroid nodules and provide insight into Nonetheless, both systems perform similarly well
the malignancy risk. Several sonographic features for the identification of intermediate- and high-
are highly predictive of identifying papillary risk nodules. The main difference between these
thyroid carcinoma, including invasive margins, SRSSs lies in the size thresholds for FNA.4
taller-than-wide shape, and punctate echogenic This session will help the clinician understand
foci in a solid nodule. All of the SRSSs identify the pitfalls of each SRSS while also providing
these lesions similarly well. Nodules that have less real-time feedback regarding nodule classification.
specific and/or low-risk findings still harbor a Furthermore, this session will examine the physics
nonnegligible risk of malignancy and may warrant behind ultrasonography and its associated artifacts
further investigation based on their size and the to aid the clinician in diagnosing the underlying
patient’s clinical scenario. pathophysiology seen on bedside ultrasonography.

272  ENDO 2022 • Endocrine Case Management

Barriers to Optimal Practice carefully examine the performance of a given SRSS
in diagnosing follicular tumors.
• Clinician confidence and reference standards An additional limitation of sonographic
to accurately classify nodules. evaluation of thyroid nodules is interobserver
variability of reporting individual sonographic
• Adequate time allotment in a busy clinic
features. The features associated with the highest
for carefully performing ultrasonography
interobserver variability are the presence of
to characterize the nodule and optimize
capsular invasion, microcalcifications, and nodule
image captures.
margins.6 ACR TI-RADS is thus subject to the
• Each SRSS has specific limitations in its usage potential for overscoring or underscoring a
and classification of thyroid nodules. nodule using a summation of nodule features. The
ATA SRSS uses pattern-based recognition in an
attempt to lessen the impact of this potential bias.2
Strategies for Diagnosis, Unfortunately, with this pattern-based system, not
Therapy, and/or Management all types of nodules are currently characterized and
some nodules are unable to be risk stratified.
Ultrasonography is an invaluable tool for the
An additional concern with sonographic
evaluation of thyroid nodules; it helps stratify a
evaluation of thyroid nodules is the relative weight
large proportion of nodules into higher- or lower-
assigned to individual features for malignancy
risk categories. It is also important, however, for
risk prediction. A recent study7 using artificial
clinicians using ultrasonography for nodule triage
intelligence to stratify biopsy-proven thyroid
to familiarize themselves with the strengths and
nodules validated ACR TI-RADS but found that
limitations of this technology.
the assignment of new scores to individual features
Suspicious sonographic features such as
improved the specificity while still maintaining
irregular/infiltrative margins, taller-than-wide
the sensitivity. The findings suggested that
shape, and punctate echogenic foci have a high
hyperechogenicity or isoechogenicity should not
specificity for predicting malignancy. These
be assigned any points and that microcalcifications
features are typically associated with papillary
or coarse calcifications should be the only types of
thyroid carcinoma. Indeed, SRSSs generally
calcifications for which points are given.
perform very well in identifying papillary thyroid
Finally, it is important for clinicians to
carcinomas. Follicular-patterned tumors, however,
approach a thyroid nodule from within the
are more likely to have a less specific appearance;
framework of the clinical scenario, considering
they are often isoechoic, have well-defined
patient age, family history, radiation exposure, and
margins, and typically lack suspicious sonographic
comorbidities. None of the current SRSSs consider
features.5 Thus, many histologically follicular-
the patient’s clinical context when assigning
patterned tumors, such as follicular carcinoma,
malignancy risk. These patient-related factors can
noninvasive follicular tumor with papillary
significantly influence the decision to perform
like nuclear features (NIFTP), and follicular
FNA and/or guide the optimal evaluation strategy.
variant of papillary thyroid cancer fall into lower
Because most thyroid cancers are indolent tumors,
sonographic risk categories (low/intermediate risk
patients with certain comorbid conditions may
with ATA and TR2 or TR3). A major limitation
be more suitable for observation alone rather
of the current literature evaluating the efficacy of
than undergo FNA, even in the setting of a
SRSSs for malignancy risk prediction is that many
sonographically suspicious nodule. However, a
studies eliminate nodules with indeterminate
young, healthy patient with a strong family history
cytology, which disproportionately excludes
of thyroid cancer may be an appropriate candidate
follicular-patterned tumors. Consequently, very
few studies have a sufficient number of nodules to

ENDO 2022 • Thyroid  273

for a lower threshold for FNA if an indeterminate This is a spongiform nodule. These lesions have
or high-risk nodule is identified. a very low risk of malignancy (<3%). The ATA
guidelines recommend either FNA or observation
of these lesions if they are larger than 2.0 cm. The
Clinical Case Vignettes nodule does not meet the size threshold for FNA
Case 1 (Answer C), so reassuring the patient (Answer D)
A 24-year-old nonbinary patient presents to the is correct.
endocrine clinic for evaluation of a thyroid nodule Scintigraphy with 123I or technetium (Answer
incidentally detected during the evaluation of neck B) is not needed in this case unless the TSH
injury after a motor vehicle accident. There are concentration is low. It would be reasonable,
no compressive symptoms, history of radiation however, to measure the patient’s serum TSH
exposure, or family history of thyroid cancer. since it has not yet been done.
The radiologist who performed ultrasonography Ethanol ablation (Answer E) is incorrect
described a 1.4 × 1.2 × 1.6-cm ACR TI-RADS because nodules should be aspirated twice to
4 nodule (5 points) (see Figure). The report definitively rule out malignancy before referral for
indicated a spongiform nodule (0 points) with the procedure.
infiltrative margins (2 points) (asterisk) and linear Elastography (Answer A) can be helpful in the
calcifications (2 points) (arrows). assessment of thyroid nodules for further refining
malignancy risk, but it is not necessary in this
setting, as the nodule is already clearly a very low-
risk lesion. Furthermore, elastography cannot be
used for nodules that are predominantly cystic.
A very important question in this case is how
are the 2 SRSSs so divergent in the malignancy
risk of this nodule? According to the radiology
report that used ACR TI-RADS, this nodule has
an intermediate risk of malignancy. In contrast,
using the ATA SRSS, it is a very low-suspicion
lesion. One of the limitations of ACR TI-RADS
is the potential for overassigning risk in a given
nodule due to the use of individual features.
The one situation where pattern recognition is
recommended for use with ACR TI-RADS is
The patient is referred for consideration of FNA of in the setting of a spongiform nodule. The first
the intermediate-risk nodule. step in evaluating a nodule with ACR TI-RADS
involves determination of the nodule composition.
Which of the following is the best next If a nodule is composed of more than 50% small
step in this patient’s management? cystic spaces, it is classified as spongiform and
A. Evaluate with elastography further points should not be added for the
other categories (echogenicity, shape, margins,
B. Order 123I or technetium scan or echogenic foci). In this case, the radiologist
C. Perform FNA continued to assign points for the individual
D. Reassure the patient nodule features and the malignancy risk was falsely
E. Refer for ethanol ablation elevated. If used appropriately, both systems would
accurately categorize this nodule as low risk. But
Answer: D) Reassure the patient in this scenario, the radiologist inappropriately

274  ENDO 2022 • Endocrine Case Management

continued to assign the ACR TI-RADS point in Which of the following is the ATA
the assessment of this spongiform nodule. risk classification of this nodule?
One final note: the areas of “linear A. Very low suspicion
calcifications” seen in this nodule are not actually B. Low suspicion
calcifications. Rather, these represent linear areas
C. Intermediate suspicion
of posterior acoustic enhancement that are visible
in the septations located posterior to a cystic area. D. High suspicion
These are commonly seen in spongiform nodules. E. Nonclassifiable
It is an artifact due to the change in acoustic
impedance between a cystic area and a solid Answer: E) Nonclassifiable
septation. A strong reflection of waves back to the This nodule is isoechoic, partially cystic, and has
ultrasound occurs when the wave moves from the punctate echogenic foci. It is not spongiform
cystic medium to the solid, resulting in a brighter- because it is less than 50% cystic. This nodule is
than-expected appearance of the septations. nonclassifiable (Answer E) with the ATA SRSS.
It is ACR TI-RADS TR4 (solid [2], isoechoic
Case 2 [1], regular margins [0], wider than tall [0],
microcalcifications [3] = 6 points).
A 75-year-old man is referred for a nodule that
Several types of nodules are currently not
was incidentally noted on 18F-fluorodeoxyglucose
captured with the ATA SRSS. These include
PET done for prostate cancer staging. The nodule
isoechoic or cystic nodules with 1 or more
is metabolically active, with a standard uptake
suspicious sonographic feature(s), including taller-
value of 15. On ultrasonography, the nodule
than-wide shape, infiltrative margins, or punctate
measures 1.6 × 1.5 × 2.2 cm (see Figures).
echogenic foci. Additionally, coarse calcifications
are not captured with the ATA system. In these
scenarios, ACR TI-RADS may be used to classify
the nodule.
The frequency of ATA nonclassifiable lesions
is variably reported in the literature, between
2.7% and 17.9%.8,9 The malignancy risk associated
with ATA nonclassifiable lesions is also variably
reported, between 9.4% and 18.8%,10,11 which
overlaps with risk associated with the intermediate
suspicion category of nodules in the ATA SRSS
(10%-20%).2

ENDO 2022 • Thyroid  275

References
1. Tessler FN, et al. ACR thyroid imaging, reporting and data system (TI- 7. Wildman-Tobriner B, Buda M, Hoang JK, et al. Using artificial intelligence
RADS): white paper of the ACR TI-RADS committee. J Am Coll Radiol. to revise ACR TI-RADS risk stratification of thyroid nodules: diagnostic
2017;14(5):587-595. accuracy and utility. Radiology. 2019;292(1):112-119. PMID: 31112088
2. Haugen BR, et al. 2015 American Thyroid Association management 8. Grani G, Lamartina L, Ascoli V, et al. Reducing the number of unnecessary
guidelines for adult patients with thyroid nodules and differentiated thyroid thyroid biopsies while improving diagnostic accuracy: toward the “right”
cancer: the American Thyroid Association Guidelines Task Force on Thyroid TIRADS. J Clin Endocrinol Metab. 2019;104(1):95-102. PMID: 30299457
Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-133. 9. Gao L, Xi X, Wang J, et al. Ultrasound risk evaluation of thyroid nodules that
3. Kim PH, et al. Unnecessary thyroid nodule biopsy rates under four ultrasound are “unspecified” in the 2015 American Thyroid Association management
risk stratification systems: a systematic review and meta-analysis. Eur Radiol. guidelines: a retrospective study. Medicine (Baltimore). 2018;97(52):e13914.
2021;31(5):2877-2885. PMID: 30593211
4. Yim Y, et al. Concordance of three international guidelines for thyroid 10. Ruan J-L, Yang H-Y, Liu R-B, et al. Fine needle aspiration biopsy indications
nodules classified by ultrasonography and diagnostic performance of biopsy for thyroid nodules: compare a point-based risk stratification system with a
criteria. Korean J Radiol. 2020;21(1):108-116. pattern-based risk stratification system. Eur Radiol. 2019;29(9):4871-4878.
5. Jeh SK, Jung SL, Kim BS, Lee YS. Evaluating the degree of conformity of PMID: 30715590
papillary carcinoma and follicular carcinoma to the reported ultrasonographic 11. Ha EJ, Na DG, Baek JH, Sung JY, Kim J-H, Kang SY. US fine-needle
findings of malignant thyroid tumor. Korean J Radiol. 2007;8(3):192-197. aspiration biopsy for thyroid malignancy: diagnostic performance of
PMID: 17554185 seven society guidelines applied to 2000 thyroid nodules. Radiology.
6. Grani G, Lamartina L, Cantisani V, Maranghi M, Lucia P, Durante C. 2018;287(3):893-900. PMID: 29465333
Interobserver agreement of various thyroid imaging reporting and data
systems. Endocr Connect. 2018;7(1):1-7. PMID: 29196301

276  ENDO 2022 • Endocrine Case Management

Unmet Needs in
Hypothyroidism
Elizabeth A. McAninch, MD. Division of Endocrinology, Gerontology and Metabolism,
Stanford University School of Medicine, Stanford, CA; E-mail: [email protected]

Learning Objectives (supraphysiologic serum peaks and short half-

life). There are potential safety concerns due to
As a result of participating in this session, learners
insufficient long-term outcome data, but many
should be able to:
recent clinical trials have shown no increased
• Identify patients with hypothyroidism who morbidity or mortality. Further longitudinal safety
may benefit from a trial of combination studies are needed. The safety of liothyronine is
therapy and counsel them on the potential unknown in patients with comorbid osteoporosis,
risks and benefits of combination therapy. psychiatric disease, cardiovascular disease, or
atrial fibrillation.
• Perform a trial of combination therapy for
For individuals on levothyroxine with a
eligible patients with hypothyroidism.
normal serum TSH level, combination therapy can
be initiated by decreasing the levothyroxine dosage
by 12 to 25 mcg daily and adding liothyronine,
2.5 to 5 mcg once or twice daily. For monitoring
Main Conclusions peak levels, serum T3 should be assessed 2
The standard of care for treatment of to 4 hours after liothyronine consumption.
hypothyroidism remains levothyroxine at dosages Normalization of serum TSH and optimization
to achieve a normal serum TSH concentration. of symptoms remain the treatment goals. If no
Most patients do well with this approach symptomatic improvement is noted, levothyroxine
with restoration of clinical and biochemical monotherapy can be resumed.
euthyroidism. However, a minority of patients
experience residual hypothyroid symptoms despite
normalization of serum TSH. Evaluation for
other potential etiologies should be performed
Significance of the
in these patients. In more than a dozen clinical Clinical Problem
trials, superiority of combination therapy has In endogenous euthyroidism, the thyroid
not been consistently demonstrated. A roadmap gland secretes about 5 to 6.5 µg of T3 daily.1,2
for designing new, better clinical trials has Most T3 (~20 µg) is produced in the periphery
been outlined, but in the meantime, clinicians by deiodination pathways. The sum of these
can consider a trial of combination therapy contributors results in remarkably stable serum T3
(levothyroxine plus liothyronine) in nonpregnant levels in euthyroid individuals.3 Hypothyroidism
adults with residual symptomatology due to is highly prevalent, affecting about 5% of
hypothyroidism. the population in iodine-sufficient regions.4
Currently available liothyronine formulations Treatment standard of care is levothyroxine,1
exhibit pharmacokinetic properties that do not which is consistently one of the most prescribed
well mimic physiologic, stable serum T3 levels pharmaceuticals in the United States.5 It is

ENDO 2022 • Thyroid  277

increasingly well-recognized that a minority Barriers to Optimal Practice
(about 14% in one study6) of hypothyroid patients
on levothyroxine experience symptoms that • Residual symptoms are often subjective
could be consistent with residual symptoms of and nonspecific.
hypothyroidism. In voluntary patient surveys
• Liothyronine pharmacokinetics are challenging
(subject to sampling bias), dissatisfaction is even
(short half-life, supratherapeutic peak).
more prominent.7,8 Given the high prevalence
of hypothyroidism, the proportion of those • Clinical trial results of combination therapy
struggling with residual symptomatology inconsistently demonstrate “superiority.”
represents a significant number of individuals. It is • More long-term safety data of liothyronine
well-established that hypothyroid patients treated are needed. The safety in individuals with
with levothyroxine exhibit higher serum T4- preexisting comorbidities such as psychiatric
to-T3 ratios.9-12 The acknowledgment of residual disease, cardiovascular disease, atrial
symptomatology and altered T4-to-T3 ratios fibrillation, and osteoporosis is unknown.
exhibited by levothyroxine-treated hypothyroid • Should achieving a physiologic T4-to-T3 ratio
patients has fueled the hypothesis that these be a therapeutic goal? If so, when should T3
symptoms may be due to relative T3 deficiency be measured?
within the peripheral tissues.
In an effort to ameliorate residual
symptomatology and better approximate
physiologic serum T4-to-T3 ratios, combination
Strategies for Diagnosis,
therapy with levothyroxine plus liothyronine Therapy, and/or Management
has been explored with mixed results, failing to Since the 1970s, the standard of care for
demonstrate consistent superiority in clinical hypothyroidism has been levothyroxine
trials.13 However these trials were heterogenous monotherapy at dosages to achieve a normal
in design and recruitment.14 One of the potential serum TSH level.21 That the deiodinases convert
barriers in such trials is the lack of FDA- T4-to-T3 in the periphery22 provided justification
approved sustained-release T3 preparations. for this approach. In more recent years, however,
The American, British, and European Thyroid this dogma has been the subject of intense study,
Associations have outlined proposals for the with many groups of investigators finding that
design of new trials,14 but until those can be levothyroxine-treated hypothyroid patients with
accomplished, clinicians ultimately must balance normal serum TSH levels may not be systemically
the biochemical parameters, symptomatology, euthyroid.9,14,23,24 Even when only considering
and any comorbidities within individual patients. levothyroxine, there is strong evidence if its
Several recent studies have shown no morbidity pervasive overuse25,26 and inadequate/inefficient
or mortality with combination therapy.15-17 dosing,27,28 perhaps suggesting that even its use is
Combination therapy is more complex to not entirely straightforward.
prescribe (multiple doses daily), more costly, and Objectively, despite normal serum TSH,
more complex to monitor than monotherapy. LDL cholesterol and total cholesterol can remain
Despite these complexities, many clinicians are elevated24,29,30 and the metabolic rate is slower23,31,32
prescribing combination therapy.18 Some helpful in population studies. Compared with individuals
prescribing parameters have been proposed with endogenous euthyroidism, hypothyroid
by experts in the field.19,20 Most agree that the patients report lower metabolic equivalents, weigh
treatment goal in hypothyroidism is to restore more, and report more antidepressant and statin
euthyroidism, but exactly how to best achieve this use.9 Subjectively, patients can experience residual
remains controversial. fatigue, “brain fog,”33 and have mood complaints.

278  ENDO 2022 • Endocrine Case Management

These findings are all supported by rodent The guidelines suggest that patients who
models where animals with hypothyroidism have feel “unwell,” “not benefited,” or who have
a lower metabolic rate and higher serum lipid “persistent complaints” could be considered
profiles despite treatment with levothyroxine for an n-of-1 trial of combination therapy.1,19
monotherapy.34,35 All thyroid professional societies Clinical trial results have been inconsistent,
now acknowledge that some patients with but some trials have shown benefits, including
hypothyroidism can experience residual symptoms improved weight management and preference for
despite treatment with levothyroxine at dosages combination therapy.13,15,16,40
that normalize serum TSH.36 The clinical syndrome of T3 thyrotoxicosis due
Patients may be dissatisfied with therapy to Graves disease has well-defined consequences
and feel that their symptoms are dismissed by that include increased risks of psychosis,
providers.7 The finding that levothyroxine + fracture, osteoporosis, atrial fibrillation, and
liothyronine combination therapy could improve cardiovascular events. Before the development
symptoms was heralded,6 but interestingly, of the TSH radioimmunoassay,41 much higher
this has not been consistently demonstrated in dosages of thyroid hormone replacement in
clinical trials,13 creating major controversy in hypothyroidism were used and such adverse
the field. There are important limitations due effects were not uncommon.21 In the modern
to liothyronine pharmacokinetics: it has a short era, despite a reliable serum TSH assay, concern
half-life and supratherapeutic peak, necessitating for these potentially devastating risks persists.
multiple daily doses to even approach mimicking These concerns are perhaps amplified by the
physiologic replacement. It is not known whether, pharmacokinetic profile of liothyronine, which
if physiologically dosed, the combination therapy results in fluctuating serum levels, often with
trial results would offer more clarity. Although transient hypertriiodothyroninemia at its peak.42
exciting new liothyronine formulations and That being said, there has not been a modern
thyroid transplant technologies are on the study showing serum T3 fluctuations within the
horizon,37-39 clinicians are left dealing with this reference range (while preserving normal serum
highly prevalent clinical dilemma in the present. TSH) to be associated with adverse events19; the
The field currently lacks substantial knowledge of longest of these studies followed patients for 1
exactly what liothyronine’s risks are, ineligibility year. In a large population study conducted over
criteria for combination therapy, treatment 17 years (more than 250,000 person-years total
goals (Serum TSH only? Serum T4-to-T3 ratios? follow-up), individuals on liothyronine therapy
Subjective symptoms/preference?), treatment were found to have double the risk of receiving
monitoring, and the specific dosing ratios and an incident antipsychotic prescription, but no
timing of levothyroxine + liothyronine.14 Thus, increased risk of fracture, atrial fibrillation,
how to best restore thyroid hormone homeostasis or cardiovascular events.17 Further, rigorous
in patients with hypothyroidism is a rapidly exploration of the safety of levothyroxine +
evolving topic. liothyronine combination therapy is needed
before the risks can be fully described to patients
and likely before the routine use of combination
Risk-to-Benefit Ratio
therapy can be recommended by professional
The American, British, and European Thyroid society guidelines. There have been no safety
Association guidelines have recently evolved studies performed in elderly participants or in
in their recognition of the potential limitations those with preexisting cardiovascular disease,
of levothyroxine.36 This shift is reflected in atrial fibrillation, or osteoporosis, so clinicians are
prescribing patterns: physician use of combination unable to adequately describe the risks to patients
therapy is prevalent and possibly increasing.18 and obtain informed consent.

ENDO 2022 • Thyroid  279

Prescribing Levothyroxine adjustments may be needed depending on serum
+ Liothyronine thyroid function tests and symptoms.
The physiologic T4-to-T3 ratio secreted by the
human thyroid is approximately 14:1, of which Anecdotal Experience
about 5 to 6.5 mcg of T3 is secreted daily.1,2 There Since 2014, I have been offering to prescribe
are several combination pills with various fixed levothyroxine + liothyronine to select, dissatisfied
T4-to-T3 ratios in Europe (10:1, 5:1, 4:1).43 In patients struggling with residual hypothyroid
the United States, the only such combination symptoms. In my clinical practice, I have patients
formulation is in desiccated porcine thyroid, whose symptoms do not improve on combination
where the T4-to-T3 ratio is approximately 4:1; therapy after a few dosage adjustments, so they
this is not FDA-approved. In the United States, agree to resume levothyroxine monotherapy. I
liothyronine is available in 5-, 25-, and 50-mcg also have had patients experience palpitations,
tablets, so multiples of 2.5 mcg (half tablet) exacerbation of menopausal hot flashes, insomnia,
or 5 mcg are usually used. Liothyronine to and anxiety while on combination therapy,
levothyroxine dose equivalency is considered to which leads to them to ask to have their regimen
be about 3:1.44 As the guidelines currently state, converted back to levothyroxine monotherapy.
all patients should be prescribed levothyroxine Interestingly, even in these patients, I have
at initial diagnosis, with the dosage titrated to observed that the serum T3 measured at its peak
achieve a normal serum TSH level. Once the to be within the normal range when using doses
clinician has identified an appropriate candidate of 2.5 to 5 mcg liothyronine. There are patients
for an n-of-1 therapeutic trial, in theory, one who feel the extra cost and dosing schedules do
has the advantage of knowing the levothyroxine not justify any benefit, whose regimens are thus
dosage that normalized the patient’s serum TSH. converted back to levothyroxine monotherapy.
Levothyroxine + liothyronine combination Most of my patients (who had residual symptoms
therapy can then be estimated in the context of on levothyroxine and thus opted to embark
these known variables. on a therapeutic trial— selection bias!) prefer
For example, if patient A has a normal levothyroxine + liothyronine combination
serum TSH concentration on levothyroxine, therapy over levothyroxine monotherapy. Most
88 mcg daily, a reasonable first option would of my patients on combination therapy are
be to decrease the levothyroxine dosage to prescribed dosages of 2.5 mcg liothyronine twice
75 mcg and add liothyronine, 2.5 mcg twice daily or 5 mcg liothyronine once or twice daily.
daily or 5 mcg once daily (T4-to-T3 ratio = Anecdotally, among my long-time patients, the
15:1). If patient B has a normal serum TSH dosages of liothyronine that maximize clinical
concentration on levothyroxine, 150 mcg daily, benefit/preference vary from 2.5 mcg liothyronine
a reasonable option would be to decrease the every morning (postmenopausal patient with
levothyroxine dosage to 125 mcg daily and Hashimoto thyroiditis) to 7.5 mcg liothyronine
add liothyronine, 5 mcg twice daily (T4-to-T3 twice daily (athyreotic athlete). Thrice-daily
ratio = 12.5:1). Measuring serum TSH about 6 liothyronine is too burdensome for most of my
weeks after the dosage change is the minimum patients. I take great care to listen to them and
requirement, and if one wishes to evaluate provide the most therapeutic environment that
for hypertriiodothyroninemia, total T3 can be I can, as I believe that the patient-physician
measured within 2 to 4 hours of the morning relationship must be optimized to embark on this
liothyronine dose. As with levothyroxine exploratory journey together to evaluate these
dosing, there is no simple formula that predicts often subjective, je ne sais quoi, symptoms.
the “correct” dose in every patient and dosage

280  ENDO 2022 • Endocrine Case Management

Clinical Case Vignettes C. Offer a therapeutic trial with desiccated thyroid
D. Offer a therapeutic trial with levothyroxine,
Case 1
125 mcg daily, plus liothyronine, 5 mcg
A 57-year-old postmenopausal woman presents twice daily
with large, symptomatic, nontoxic multinodular E. Offer a therapeutic trial with levothyroxine,
goiter. She is otherwise healthy. After several 137 mcg daily, plus liothyronine, 2.5 mcg
FNA biopsies of dominant nodules over the twice daily
years demonstrating benign characteristics,
she opts to proceed with thyroidectomy for Answer: D or E) Offer a therapeutic trial
worsening compressive symptoms. She has with levothyroxine, 125 mcg daily, plus
total thyroidectomy with a high-volume thyroid liothyronine, 5 mcg twice daily or offer a
surgeon and starts levothyroxine replacement at therapeutic trial with levothyroxine, 137 mcg
1.6 mcg/kg per day (150 mcg daily). daily, plus liothyronine, 2.5 mcg twice daily
She has a follow-up appointment 4 weeks
postoperatively. She feels wonderful! She is This healthy, previously hormonally asymptomatic
very pleased that she had surgery, after years of patient presents with acute-onset symptoms
bothersome, progressing, compressive symptoms. after thyroidectomy that could be associated
with hypothyroidism. She has no known cardiac
Laboratory test results: or bone disease. Reassurance that her thyroid
function test results are normal does not address
Serum TSH = 2.01 mIU/L (0.45-4.50 mIU/L)
Serum PTH, normal her symptoms, so continuing levothyroxine at the
Serum calcium, normal same dosage (Answer A) is incorrect.
Increasing the levothyroxine dosage while
One month later (8 weeks postoperatively), the serum TSH remains within reference range
patient sends a message through the electronic has not been shown to improve symptoms in
health record: “My energy has been pretty low. randomized controlled clinical trials (Answer B).23
I’m tired almost all the time. I cannot function at Desiccated thyroid (Answer C) is not FDA-
work. I know my blood work was in the “normal” approved and contains supraphysiologic T3 doses
range, but is there anything that can be done? for humans.
Our next appointment isn’t until the end of next A therapeutic trial with levothyroxine and
month, which seems too long to wait.” Blood liothyronine could be offered, and both dosing
counts and metabolic panel are normal. regimens listed (Answers D and E) are reasonable;
Laboratory test results: they represent more physiologic serum T4-to-T3
ratios.19,20
Serum TSH = 1.8 mIU/L (0.45-4.50 mIU/L)
Free T4 = 1.5 ng/dL (0.82-1.77 ng/dL)
(SI: 19.3 pmol/L [10.6-22.8 pmol/L]) Case 2
Total T3 = 87 ng/dL (71-180 ng/dL)
(SI: 1.34 nmol/L [1.09-2.8 pmol/L])
A 50-year-old woman is a night-shift worker who
has been on long-term thyroid hormone treatment
(about 20 years), after initially presenting with
Which of the following is the weight gain, fatigue, and increased hair shedding.
most appropriate next step in She seeks a third opinion. She recalls that her
this patient’s management? initial diagnostic evaluation yielded thyroid
A. Continue levothyroxine at same dosage function test results that were within the reference
B. Increase the levothyroxine dosage to 175 mcg range but that her reverse T3 was “off.” One
daily, aiming to achieve low-normal serum TSH year ago, she sought a second opinion from an
endocrinologist because of continued symptoms,

ENDO 2022 • Thyroid  281

and that physician recommended changing consistent with hypothyroidism before treatment
to a brand-name, gluten-free levothyroxine can be appropriately initiated. However, many
formulation and adding liothyronine. individuals with endogenous euthyroidism are
She is a single parent to 2 school-aged children inappropriately treated with thyroid hormone
whom she transports and cares for during the supplementation,26 perhaps due to nonspecific
day. During the 2 to 4 hours of sleep she gets symptomatology.1 This patient has a history
per day, she snores. She feels fatigued, reports suggestive of endogenous euthyroidism.
difficultly losing weight, and has noticed that Thyroid hormone supplementation should not
her hair is shedding excessively. Her symptoms be continued (Answers A, B, C, and D) until a
have not improved since thyroid hormone concrete biochemical diagnosis of hypothyroidism
initiation 20 years ago, or since the initiation of can be established. After discontinuation of
combination therapy last year. She has no history thyroid hormone (Answer E), the following
of depression, hopelessness, or suicidal ideation. laboratory values were documented:
Twenty-four–hour urinary free cortisol excretion
Serum TSH = 1.67 mIU/L
is within the reference range. Four hours after Free T4 = 1.21 ng/dL (SI: 15.6 pmol/L)
her levothyroxine (63 mcg daily) and liothyronine Total T3 = 97 ng/dL (SI: 1.5 nmol/L)
(5 mcg every morning) are administered, blood is Free T3 = 2.6 pg/mL (SI: 4.0 pmol/L)
collected for analysis.
She was diagnosed with moderate obstructive
Laboratory test results: sleep apnea and shift-work disorder.
Serum TSH = 0.246 mIU/L (0.45-4.50 mIU/L)
Free T4 = 1.54 ng/dL (0.82-1.77 ng/dL) Case 3
(SI: 19.8 pmol/L [10.6-22.8 pmol/L])
Total T3 = 130 ng/dL (71-180 ng/dL) A 27-year-old G0P0 woman with history of
(SI: 2.0 nmol/L [1.09-2.77 pmol/L]) postsurgical hypothyroidism (benign goiter at
Free T3 = 4.0 pg/mL (2.0-4.4 pg/mL) age 20 years) presents to establish care. She is
(SI: 6.1 pmol/L [3.1-6.8 pmol/L]) otherwise healthy. Her menses are regular, and
she has a copper intrauterine device. She plans to
Which of the following should be advised? remove the intrauterine device in about 5 years
to conceive. Immediately after thyroidectomy,
A. Continue current regimen and evaluate for
her previous physician had prescribed desiccated
other causes of fatigue
porcine thyroid extract, 120 mg every morning.
B. Decrease liothyronine, repeat thyroid function She has never tried another thyroid hormone
tests in 4 to 6 weeks replacement regimen. She has no palpitations,
C. Discontinue liothyronine, repeat thyroid fluctuating energy levels, heat intolerance, anxiety,
function tests in 4 to 6 weeks or weight change. She exercises a few times per
D. Discontinue levothyroxine, repeat thyroid week and has no dyspnea on exertion, muscle
function tests in 4 to 6 weeks aches, or weakness. She feels normal and has
E. Discontinue levothyroxine and liothyronine, no concerns. She is satisfied with her current
repeat thyroid function tests in 4 to 6 weeks regimen. Her physician retired recently, so she is
seeking to establish care.
Answer: E) Discontinue levothyroxine On physical examination, her weight is
and liothyronine, repeat thyroid 125.6 lb (57 kg) (BMI = 21 kg/m2). Her pulse
function tests in 4 to 6 weeks rate is 76 beats/min, and blood pressure is
108/68 mm Hg. Cardiac auscultation reveals no
The symptoms of hypothyroidism are nonspecific;
murmurs, and remaining examination findings
therefore, a biochemical diagnosis must be
are normal.

282  ENDO 2022 • Endocrine Case Management

Laboratory test results: transition to levothyroxine + liothyronine combination
therapy at dosages to achieve normal serum TSH
Serum TSH = 2.0 mIU/L (0.45-4.50 mIU/L)
Free T4 = 0.9 ng/dL (0.82-1.77 ng/dL) Levothyroxine is the standard of care due to
(SI: 11.6 pmol/L [10.6-22.8 pmol/L])
Total T3 (sample collected 3 hours after its efficacy and safety (Answer B). Two grains
ingestion of desiccated thyroid (120 mg) of desiccated thyroid contain about 76
extract) = 160 ng/dL (71-180 ng/dL) mcg T4 and 18 mcg T3. If the pharmacodynamic
(SI: 0.01 nmol/L [1.09-2.77 nmol/L]) equivalence of T4 to T3 is around 3:1,44 then one
could translate her current dosage as equivalent
You counsel her on the goals of therapy in
to about 260 mcg levothyroxine (Answer C).
hypothyroidism for nonpregnant adults, treatment
However, this would be about 4.5 mcg/kg and
options, and pregnancy and hypothyroidism.
would be highly likely to suppress her serum TSH.
After a thorough discussion of the risks Desiccated thyroid extract is not FDA-
and benefits, which of the following approved or regulated (Answer A), but she is
options would be appropriate to offer? asymptomatic, has no contraindications, and has
normal serum T3 level measured near its peak.
A. Continue desiccated thyroid extract, 120 mg daily
If the patient were experiencing fluctuating
B. Discontinue desiccated thyroid extract and symptoms (thyrotoxic at peak and hypothyroid in
initiate levothyroxine, 1.6 mcg/kg daily trough), consideration could be made to splitting
C. Discontinue desiccated thyroid extract and the dose to twice daily (Answer D), but this could
initiate levothyroxine, 200 to 250 mcg daily interfere with her meal schedule.
D. Split desiccated thyroid extract dose into 60 mg Levothyroxine and liothyronine are FDA-
twice daily approved and regulated (Answer E) and would
E. Transition to levothyroxine + liothyronine also provide combination therapy, with established
combination therapy at dosages to achieve efficacy and safety standards.
normal serum TSH However, she opted for Answer A because
she felt well. Continued surveillance over years
Answer: B or E) Discontinue desiccated thyroid extract is notable for stable biochemical parameters and
and initiate levothyroxine, 1.6 mcg/kg daily, or treatment satisfaction.

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26. Brito JP, Ross JS, El Kawkgi OM, Maraka S, Deng Y, Shah ND, Lipska KJ. 43. Dayan C, Panicker V. Management of hypothyroidism with combination
Levothyroxine use in the United States, 2008-2018. JAMA Internal Med. thyroxine (T4) and triiodothyronine (T3) hormone replacement in clinical
2021;181(10):1402-1405. PMID: 34152370 practice: a review of suggested guidance. Thyroid Res. 2018;11:1. PMID:
27. Miccoli P, Materazzi G, Rossi L. Levothyroxine therapy in thyrodectomized 29375671
patients. Front Endocrinol (Lausanne). 2020;11:626268. PMID: 33584551 44. Celi FS, Zemskova M, Linderman JD, et al. The pharmacodynamic
28. Brun VH, Eriksen AH, Selseth R, et al. Patient-tailored levothyroxine dosage equivalence of levothyroxine and liothyronine: a randomized, double
with pharmacokinetic/pharmacodynamic modeling: a novel approach after blind, cross-over study in thyroidectomized patients. Clin Endocrinol (Oxf).
total thyroidectomy. Thyroid. 2021;31(9):1297-1304. PMID: 33980057 2010;72(5):709-715. PMID: 20447070
29. Lee YK, Lee H, Han S, et al. Association between thyroid-stimulating
hormone level after total thyroidectomy and hypercholesterolemia in female

284  ENDO 2022 • Endocrine Case Management

Management of Hereditary
Medullary Thyroid Cancer
Uriel Clemente-Gutierrez, MD. Department of Surgical Oncology, Section of Surgical
Endocrinology, University of Texas MD Anderson Cancer Center, Houston, TX; E-mail:
[email protected]

Bernice L. Huang, MD. Department of Surgical Oncology, Section of Surgical

Endocrinology, University of Texas MD Anderson Cancer Center, Houston, TX; E-mail:
[email protected]

Danica M. Vodopivec, MD. Department of Endocrine Neoplasia and Hormonal Disorders,

University of Texas MD Anderson Cancer Center, Houston, TX; E-mail: dmvodopivec@
mdanderson.org

Nancy D. Perrier, MD. Department of surgical Oncology, Section of Surgical Endocrinology,

University of Texas MD Anderson Cancer Center, Houston, TX; E-mail: nperrier@
mdanderson.org

Learning Objectives Main Conclusions

As a result of participating in this session, learners MTC is an infrequent cancer arising from the
should be able to: parafollicular cells. This thyroid neoplasia is
hereditary in 25% of affected adults and in 75%
• Identify the clinical manifestations and of affected children, and it is part of multiple
define the appropriate workup for hereditary endocrine neoplasia (MEN) type 2 syndrome.
medullary thyroid carcinoma (MTC). Clinical evaluation must include neck
• Explain the role of specific RET pathogenic inspection and imaging with ultrasonography,
variants and their prognostic implications assessment for signs and symptoms of calcitonin
regarding the timing of prophylactic excess, and investigation for nonendocrine
thyroidectomy based on the American Thyroid manifestations, including cutaneous lichen
Association risk categories. amyloidosis, Hirschsprung disease, and oral/
• Summarize recommended follow-up for eyelid ganglioneuromas. The clinical presentation
patients with MTC. is based on the RET proto-oncogene codon
alteration. As part of the initial workup, basal
• Describe the surgical management of
levels of secretory products of the C cells,
hereditary MTC, including the indications for
calcitonin and carcinoembryonic antigen (CEA),
therapeutic and prophylactic cervical lymph
should be measured. Genetic counseling and
node dissection.
testing are necessary for patients with a new
• Determine the indications of targeted diagnosis of MTC. If a RET gene variant is
therapies in advanced and recurrent MTC. identified, patients should undergo prophylactic
or therapeutic thyroidectomy, depending on the
clinical context.

ENDO 2022 • Thyroid  285

 The timing and indications of prophylactic • Defining the optimal timing and extension of
thyroidectomy are based on the aggressiveness prophylactic surgery for pediatric patients.
of their MTC, which depends on the patient’s • Treatment and follow-up are required in
genotype. In the case of therapeutic thyroidectomy referral centers due to the complexity of
(ie, the patient has preoperative evidence the disease.
of MTC), prophylactic unilateral central
lymphadenectomy is indicated. The management • Targeted therapies have specific indications.
of cervical lateral compartment lymph nodes is
based on the calcitonin level and documented
lymphadenopathy, among other factors. Strategies for Diagnosis,
Follow-up after thyroidectomy consists of Therapy, and/or Management
clinical, radiologic, and laboratory evaluation
Clinical Presentation and
every 6 months for the first year and thereafter on
a yearly basis, adjusted based on the calcitonin and Diagnostic Workup
CEA levels and trends. In case of recurrent disease, Hereditary MTC is one of the main features of
targeted therapies have specific indications. MEN type 2A and MEN type 2B. When this
thyroid neoplasia is diagnosed, it may present
in the index patient as a palpable thyroid nodule
with or without symptoms of calcitonin excess
Significance of the such as diarrhea. In contrast, when MTC is
Clinical Problem diagnosed as a result of screening in a kindred
MTC is a neuroendocrine tumor derived from the with known hereditary MTC, it often presents
C cells in the thyroid gland, and it accounts for as an asymptomatic or nonpalpable thyroid
up to 3% to 4% of all thyroid cancers. MTC has nodule. Surveillance and timing are critical, and
a wide range of clinical behaviors, varying from knowledge of the recommendations to proceed
indolent to invasive tumors, with a reported 10- with prophylactic thyroidectomy is key.
year survival of 69% to 89%. Hereditary MTC has MEN type 2 can present with different
the potential to be treated early with prophylactic phenotypes and thus has different clinical
thyroidectomy, contributing to high cure rates manifestations. MEN type 2A represents 95% of
and low morbidity when appropriately managed MEN type 2 cases, and it is characterized by the
by a high-volume, multidisciplinary thyroid development of MTC, hyperparathyroidism, and
treatment team. Lymph node metastases in MTC pheochromocytoma. Nonendocrine manifestations
depend on the size of the primary lesion in the such as cutaneous lichen amyloidosis and
thyroid, as well as the preoperative calcitonin and Hirschsprung disease are rare and are associated
CEA levels. Timely prophylactic intervention can with pathogenic variants in RET codons 634/804
prevent extrathyroidal spread of the disease and is and 609/611/618/620, respectively. MEN type 2B
associated with surgical remission. accounts for 5% of all MEN type 2 cases. Its clinical
manifestations are early-onset MTC (within
the first year of life); pheochromocytoma; and
Barriers to Optimal Practice nonendocrine physical features, including alacrima
(newborn period), hypotonia, constipation, failure
• Difficulty in diagnosing MTC due to
to thrive, tongue/lip neuromas (first year of life),
heterogeneity of clinical presentation.
elongated/marfanoid facies and body habitus,
• Establishing a correlation between genotype and ganglioneuromas (affecting the aerodigestive
and phenotype in hereditary MTC. tract, lacrimal duct, and eyelids by age 5 years).
These clinical manifestations are highly suggestive

286  ENDO 2022 • Endocrine Case Management

of MEN type 2B and should prompt workup pathologic conditions may lead to falsely elevated
in the pediatric population (Figure). Failure calcitonin, including chronic kidney disease,
to clinically recognize MEN type 2B leads to hypercalcemia, some neuroendocrine tumors
delayed diagnosis with a coincident high rate of (ie, gastrinomas), the presence of heterophilic
patients who have metastatic disease at the time antibodies to calcitonin, and the use of certain
of surgical intervention and failure to achieve medications (eg, glucocorticoids, β-adrenergic
surgical remission. blockers, and proton-pump inhibitors). Basal
Initial workup should be the same as serum calcitonin concentrations in MTC often
with any thyroid nodule and include thyroid correlate with tumor burden; nonetheless, normal
function tests, cervical ultrasonography, and calcitonin levels with high CEA levels could reflect
FNA. Signs and symptoms indicating excess tumor differentiation.
calcitonin secretion or metastatic disease should In adults, 25% of MTC cases are hereditary.
be addressed, especially flushing, diarrhea, In addition, up to 7% of patients with apparently
and bone pain. A biochemical evaluation for sporadic MTC are found to have a RET pathogenic
hyperparathyroidism and pheochromocytoma variant. Hence, genetic counseling and testing
should be performed in all patients, without should be offered to all new patients. In children,
exception. The biochemical workup includes 75% of MTC cases are hereditary with the
measurement of serum levels of secretory products exception of MEN type 2B, which has a higher
of parafollicular C cells, which are used as tumor rate (50% or more) of de novo mutation. The
markers, particularly calcitonin and CEA. Some American Thyroid Association guidelines on

Figure. Genotype-Phenotype Correlations in MEN Type 2

The diagram shows the RET receptor (left) with the reported codons affected in different exons (encoding different domains in the receptor). The
table summarizes the associated endocrine and nonendocrine characteristics and their incidence. The closer the activating pathogenic variant is to
the kinase domain in the RET receptor, the more aggressive MTC could be. Adapted with permission from Kouvaraki MA et al. Thyroid, 2005; 15(6)
© Mary Ann Liebert, Inc.

ENDO 2022 • Thyroid  287

MTC management suggest that patients with summer or school breaks. If calcitonin levels are
suspected hereditary MTC should undergo found to be elevated or there is evidence of a
genetic testing via a tiered approach, beginning rising trend before age 5, thyroidectomy should be
with the most commonly mutated “hotspots” performed earlier. Patients in the moderate-risk
and then proceeding to analysis of other exons if category must be screened on a 6-month to annual
needed. However, more recently, there has been basis, starting at age 5 years. Physical examination,
availability and decreasing cost of next-generation neck ultrasonography, and calcitonin levels are
sequencing technology, allowing some commercial the screening tools. Thyroidectomy is indicated
genetic testing laboratories to offer sequencing based on a proven trend of rising calcitonin levels
of the entire coding region (and certain intronic or identification of any thyroid abnormalities
and noncoding) of the gene.1 More than 100 on ultrasonography. Long-term screening can
pathogenic variants in the RET gene have been be a concerning topic for some parents. If this
identified in patients with hereditary MTC; the is the case, prophylactic thyroidectomy could be
most commonly described pathogenic variants considered based on timing that is appropriate
in MEN type 2A are those affecting the cysteine given input from the family, endocrinologist, and
codons in exons 10 and 11. Ninety-five percent endocrine surgeon.
of patients with MEN type 2B have a pathogenic Studies in patients with MEN type 2A have
variant in exon 16 (M918T); in the remaining 5% demonstrated that lymph node metastases
of cases, there is a variant in exon 15 (A883F). are rare in patients younger than age 11 years
If a RET variant is identified, genetic counseling and in patients with a preoperative calcitonin
should be offered for at risk-risk family members. concentration less than 40 pg/mL (<11.7 pmol/L).
Therefore, for all American Thyroid Association
risk categories, prophylactic central neck
Prophylactic Thyroidectomy: Timing,
dissection, which would place the recurrent
Indications, and Follow-Up laryngeal nerve and parathyroid glands at
The aggressiveness of MTC and, hence, significantly increased risk, is not indicated unless
the recommended timing of prophylactic worrisome lymph nodes are encountered during
thyroidectomy in individuals with MEN type 2 is preoperative assessment or intraoperatively.
largely dependent on the specific RET pathogenic Concomitantly, calcium should always be
variant. The American Thyroid Association has measured during the preoperative workup
designated a classification system for common RET given the risk of primary hyperparathyroidism
variants to predict risk of aggressive MTC.2 The in patients with MEN type 2A. However, MTC
M918T pathogenic variant is considered highest generally presents before parathyroid disease
risk, variants in codons 634 and 883 are considered in these patients. As a rule of thumb, when
high risk, and all other variants are classified as MTC is diagnosed in a patient with MEN
moderate risk. Patients in the American Thyroid type 2A or 2B, pheochromocytoma must be
Association’s highest-risk category should undergo excluded before thyroidectomy and, if detected,
prophylactic thyroidectomy during the first year pheochromocytoma should be medically blocked
of life. Patients within the high-risk category are and surgically removed before the thyroid. In
recommended to have prophylactic thyroidectomy patients with MEN type 2A who have a pathogenic
based on age, RET pathogenic variant, calcitonin variant in codon 634, pheochromocytoma can
levels, and family preference. Thyroidectomy develop as early as 8 years of age.3 In general,
should be offered around age 5 or 6 years, and screening for pheochromocytoma in these patients
factors such as school and family dynamics are is recommended to start at age 11 years.
important for psychologic welfare. Therefore, After prophylactic thyroidectomy has been
surgical procedures are usually scheduled during performed in patients with hereditary MTC, the

288  ENDO 2022 • Endocrine Case Management

suggested follow-up strategy is to evaluate with Factors other than the presence or absence
physical examination, neck ultrasonography, of cervical lymphadenopathy or calcitonin
and biochemical tests (calcitonin and CEA levels have been studied to potentially omit or
measurement) every 6 months for the first recommend prophylactic lymphadenectomy
postoperative year and annually thereafter. in specific population subgroups. The
If serum calcitonin is elevated but less than absence of desmoplastic stromal reaction is a
150 pg/mL (<43.8 pmol/L), doubling times are favorable prognostic factor, and prophylactic
evaluated with measurement of calcitonin and lymphadenectomy might be of poor utility in
CEA every 3 to 6 months. If it is found that this group of patients.6 Interestingly, specific
doubling occurs in less than 6 months or the RET pathogenic variants such as those occurring
calcitonin concentration is greater than 150 pg/mL in exons 11 and 13 have been associated with
(>43.8 pmol/L), imaging studies should be used to elevated risk of cervical lymph node metastases.
evaluate for recurrent and metastatic disease.
Recurrent Disease: Indications for
What Should Be the Extension When to Start Systemic Therapy
of Thyroidectomy and Many patients with distant metastases have
Lymph Node Dissection? indolent disease—with stable to slow-growing
When index family members with hereditary lesions and tumor markers increasing at a slow
MTC presents for medical evaluation, they usually pace—that requires active surveillance without
present with a palpable thyroid nodule. Lymph the need for systemic therapy for years. Systemic
node involvement is found in more than 70% of therapy is reserved for metastatic disease with
affected individuals (this presentation is much at least 1 of the following characteristics: (1)
more similar to that seen in patients with sporadic progressive (by RECIST) within 12 to 14
MTC). In this case, the standard therapeutic months, (2) symptomatic and not treatable
treatment of MTC is total thyroidectomy and, with local or symptom-specific therapies, (3)
depending on preoperative serum calcitonin levels, compromises nearby structures and not treatable
neck ultrasound findings, and intraoperative with localized therapies, (4) calcitonin or CEA
evaluation, compartmental cervical lymph doubling time less than 6 months with structural
node dissection may proceed as well. More evidence of clinically significant disease, and
than 70% of patients with MTC have central (5) severe, intractable MTC-related diarrhea or
compartment involvement,4 and involvement Cushing syndrome with lack of an alternative
of the compartment ipsilateral to the thyroid effective treatment.
lesion is frequently observed. Contralateral FDA-approved tyrosine kinase inhibitors
lymphadenopathy has been documented when for the treatment of MTC are divided into 2
preoperative calcitonin levels are greater than different categories: (1) multikinase inhibitors7:
200 pg/mL (>58.4 pmol/L). For this reason, vandetanib8 and cabozantinib9,10 and (2) selective
prophylactic ipsilateral central compartment RET inhibitors: selpercatinib and pralsetinib.
lymphadenectomy (level VI) is recommended in Selpercatinib11 and pralsetinib12 are considered
all cases, lateral compartment dissection (levels first choice because they are receptor specific and
II, III, IV, and V) is indicated when abnormal hence better tolerated (fewer adverse effects).
lymphadenopathy is documented in preoperative In general, if small-volume oligometastatic
ultrasonography, and contralateral prophylactic disease is stable in all but one area, systemic therapy
lymphadenectomy can be considered if calcitonin should be deferred and localized treatment (to the
levels are above 200 pg/mL (>58.4 pmol/L).2, 5 single area of growth) would be preferred. Localized
treatments include external-beam radiation, surgical

ENDO 2022 • Thyroid  289

resection, embolization, or cryoablation. Starting as ganglioneuromas described in this case (thus,
systemic therapy should not be taken lightly, as it Answer A is incorrect).
confers toxicities, is not curative, requires long-term This patient has a phenotype consistent with
use for disease control, and loses efficacy over time MEN type 2B, including ganglioneuromas of
due to acquired resistance. In conclusion, the take- the oral cavity and eyelids. These nonendocrine
home message is that the use of systemic treatment manifestations are not seen in patients with MEN
for advanced MTC is reserved for patients with type 2A, who predominantly have pathogenic
progressive, unresectable, locally advanced, or variants in exons 10 and 11 (thus, Answer B is
metastatic disease not amenable to other treatments. incorrect).
The RET M918T pathogenic variant (Answer
D) is identified in 95% of patients with MEN type
Clinical Case Vignettes 2B, and this is the most probable cause of this
Case 1 patient’s condition. The A883F pathogenic variant
A 6-year-old boy with no family history of in exon 15 (Answer C) is found in the remaining
endocrinopathies and who is otherwise healthy 5% of patients with MEN type 2B.
presents to clinic for evaluation. His mother states
that since early in the patient’s life, she has noted Case 2
lesions on his lips and tongue. She points out that,
A 10-year-old girl who is otherwise healthy
peculiarly, similar lesions have appeared on his
presents to clinic for evaluation. Her mother was
eyelids, causing corneal irritation.
recently diagnosed with MEN type 2A, and the
Physical examination confirms what the
patient has tested positive for the same pathogenic
mother has described and reveals a 2-cm anterior
variant in codon 634 of the RET gene that her
cervical mass. After appropriate workup with
mother has. Cervical ultrasonography does not
cervical ultrasonography, FNA, and biochemical
reveal abnormalities of the thyroid gland or
laboratory tests, MTC is diagnosed.
concerning lymph nodes.
Which of the following statements about Laboratory test results:
genetic testing in this patient’s case is correct?
TSH, normal
A. Genetic testing is not indicated in this patient Free T4, normal
because he does not have family history Basal calcitonin = 17 pg/mL (<8 pg/mL)
indicating a hereditary condition (SI: 4.96 pmol/L [<2.34 pmol/L])
Calcium = 9.3 mg/dL (8.2-10.2 mg/dL)
B. Genetic testing with a tiered approach will (SI: 2.3 mmol/L [2.1-2.6 mmol/L])
probably identify pathogenic variants in exons
10 and 11
C. The most common RET pathogenic variant Which of the following is the
causing MEN type 2B is located in exon 15 most appropriate next step in
this patient’s management?
D. The RET M918T pathogenic variant is the
most probable cause of this patient’s condition A. Surveillance
B. Total thyroidectomy
Answer: D) The RET M918T pathogenic variant is
C. Total thyroidectomy with bilateral central
the most probable cause of this patient’s condition
neck dissection
All patients with newly diagnosed MTC should D. Total thyroidectomy with bilateral central neck
undergo genetic counseling and testing, especially dissection and bilateral lateral neck dissection
when syndromic characteristics are identified, such E. Total thyroidectomy with subtotal
parathyroidectomy

290  ENDO 2022 • Endocrine Case Management

Answer: B) Total thyroidectomy C. Physical examination, cervical
ultrasonography, and biochemical studies
For patients with a high-risk pathogenic variant every 6 months for the first year and
(eg, C634 or A883F), MTC often develops annually thereafter
early in life, and annual screening with physical
D. TSH suppression with levothyroxine
examination, cervical ultrasonography, and
biochemical evaluation is recommended to start E. No further treatment or surveillance indicated
at age 3 years, with the timing of prophylactic Answer: C) Physical examination, cervical
thyroidectomy generally considered at age 5 to ultrasonography, and biochemical studies every
6 years. For these reasons, total thyroidectomy 6 months for the first year and annually thereafter
(Answer B) is the correct answer in this case.
If calcitonin levels are noted to be elevated or The suggested follow-up dictated by the American
rising prior to this age, thyroidectomy should be Thyroid Association for patients with a high-
performed earlier. risk pathogenic variant, which is the case of the
Surveillance (Answer A) is incorrect because patient presented in the clinical vignette, is to
in the setting of hereditary MTC, after age 5 or continue postoperative surveillance with physical
6 years, this strategy would be indicated only in examination, ultrasonography of the cervical
patients with a moderate-risk pathogenic variant. region, and measurement of serum levels of
Prophylactic lymph node dissection calcitonin and CEA every 6 months for the first
(Answers C and D) in pediatric patients with year and annually thereafter (Answer C).
hereditary MTC is not routinely performed, and Answers A, B, and E do not satisfy these
lymphadenectomy is only indicated when there are recommendations.
clearly affected lymph nodes. TSH suppression with levothyroxine
Subtotal parathyroidectomy (Answer E) (Answer D) is incorrect because MTC is not a
would only be indicated in case of confirmed follicular neoplasm; postoperative replacement
hyperparathyroidism. therapy with levothyroxine should be
administered with the objective of maintaining
Case 2 (continued) serum TSH levels in the normal range.

The patient’s surgical pathology demonstrates

a medullary microcarcinoma, 0.15 cm in largest Case 3
dimension, with 2 lymph nodes that are negative A 34-year-old woman with a personal and
for carcinoma. Her calcitonin level 3 months after family history of a germline exon 10 RET C620R
surgery is undetectable. pathogenic variant leading to MEN type 2A
(American Thyroid Association level: moderate
What further treatment and surveillance risk) presents to clinic for active surveillance.
for persistent or recurrent disease are Her relevant medical history dates to
recommended for this patient? approximately 1.5 years ago when metastatic MTC
A. Biochemical studies (thyroid function tests, and a pheochromocytoma in the right adrenal
calcitonin and CEA measurement) every gland were diagnosed. Preoperative calcitonin
3 months and CEA measurements are shown in the table.
B. Cervical ultrasonography and biochemical Preoperative staging scans showed metastatic
studies every 6 months indefinitely disease in lateral cervical lymph nodes, bilateral
subcentimeter lung nodules, and a single small
liver metastasis (biopsy-proven MTC). Surgical
resection of the pheochromocytoma was addressed
first through a posterior retroperitoneoscopic

ENDO 2022 • Thyroid  291

 Preoperative (3 months Postoperative (12 months
Preoperative (time of after pheochromocytoma Postoperative (6 months after neck surgery;
Measurement initial diagnosis) resection) after neck surgery) today’s clinic visit)
Calcitonin 4968 pg/mL 4972 pg/mL 1145 pg/mL 1202 pg/mL
(SI: 1451 pmol/L) (SI: 1452 pmol/L) (SI: 334 pmol/L) (SI: 351 pmol/L)
CEA 47.6 ng/mL (SI: 47.6 µg/L) 50.9 ng/mL (SI: 50.9 µg/L) 25.5 ng/mL (SI: 25.5 µg/L) 30.2 ng/mL (SI: 30.2 µg/L)

Reference ranges: calcitonin, ≤7.6 pg/mL (SI: ≤2.2 pmol/L); CEA, ≤3.8 ng/mL (SI: ≤3.8 µg/L).

approach. Three months after adrenalectomy, in major neck vessels in the future. If the 3-month
the absence of biochemical and structural evidence restaging scans after adrenalectomy had shown
of pheochromocytoma, as well as restaging scans rapid metastatic disease progression, a selective
showing stable distant metastatic disease, the RET inhibitor would have been started and
patient underwent total thyroidectomy with the neck surgery deferred. Even though this
bilateral central and lateral neck dissection. patient has metastatic disease, the lesions are not
At today’s clinic visit (12 months after neck rapidly growing and she is asymptomatic. Thus,
surgery), the patient has no concerns, including no continuing to observe (Answer A) is the most
flushing or diarrhea. Her calcitonin and CEA levels appropriate recommendation.
are both rising. Imaging shows stable metastatic Starting intravenous chemotherapy (Answer
lesions in the lungs and a 3-mm increase in the D) is incorrect not only because the patient does
size of the liver lesion over a 12-month interval not meet indications to start systemic treatment,
(1.1 to 1.4 cm). Liver enzymes are within normal but also because with the advent of precision
limits, the liver lesion is not causing any bile oncology, tyrosine kinase inhibitors have
duct obstruction, and it is not located close to the completely replaced cytotoxic chemotherapy.
Glisson capsule. However, starting tyrosine kinase inhibitor
therapy (Answer E) is incorrect because over
Which of the following is the best next a 12-month period, the lung metastases have
step in this patient’s management? not grown and remain subcentimeter in size,
A. Continue to observe the single liver lesion has slightly increased
B. Give external radiotherapy targeting the in size (3 mm), and there are no new lesions.
liver metastasis These findings translate to indolent metastatic
disease—not rapidly progressing—and the patient
C. Start immune check-point inhibitor therapy
is asymptomatic.
D. Start intravenous chemotherapy Immunotherapy (Answer C) has not been
E. Start a tyrosine kinase inhibitor approved for the treatment of MTC and is being
studied in clinical trials.
Answer: A) Continue to observe
External radiotherapy targeting the liver
In patients with MEN type 2 who have metastasis (Answer B) would have been
pheochromocytoma, this tumor must be resected appropriate if in the presence of stable metastatic
first to avoid cardiovascular complications in disease in all other areas, the single liver lesion
future operative interventions. In this case, with was continuing to rapidly grow, cause biliary
known distant metastatic disease at the time obstruction, or cause pain due to its proximity to
of initial diagnosis, the intent of neck surgery the Glisson capsule.
was not to cure but to control disease burden
in the neck to prevent tumor invasion into
the trachea, esophagus, or wrapping around

292  ENDO 2022 • Endocrine Case Management

References
1. Hyde SM, Cote GJ, Grubbs EG. Genetics of multiple endocrine neoplasia type 7. Cabanillas ME, Hu MI, Jimenez C. Medullary thyroid cancer in the era of
1/multiple endocrine neoplasia type 2 syndromes. Endocrinol Metab Clin North tyrosine kinase inhibitors: to treat or not to treat--and with which drug-
Am. 2017;46(2):491-502. PMID: 28476233 -those are the questions. J Clin Endocrinol Metab. 2014;99(12):4390-4396.
2. Wells SA Jr, Asa SL, Dralle H, et al; American Thyroid Association PMID: 25238206
Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American 8. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with
Thyroid Association guidelines for the management of medullary thyroid locally advanced or metastatic medullary thyroid cancer: a randomized,
carcinoma. Thyroid. 2015;25(6):567-610. PMID: 25810047 double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141. PMID: 22025146
3. Rowland KJ, Chernock RD, Moley JF. Pheochromocytoma in an 8-year-old 9. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive
patient with multiple endocrine neoplasia type 2A: implications for screening. medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639-3646. PMID:
J Surg Oncol. 2013;108(4):203-206. PMID: 23868299 24002501
4. Moley JF, DeBenedetti MK. Patterns of nodal metastases in palpable 10. Schlumberger M, Elisei R, Müller S, et al. Overall survival analysis of EXAM,
medullary thyroid carcinoma: recommendations for extent of node dissection. a phase III trial of cabozantinib in patients with radiographically progressive
Ann Surg. 1999;229(6):880-887; discussion 887-888. PMID: 10363903 medullary thyroid carcinoma. Ann Oncol. 2017;28(11):2813-2819. PMID:
5. Machens A, Dralle H. Biomarker-based risk stratification for previously 29045520
untreated medullary thyroid cancer. J Clin Endocrinol Metab. 2010;95(6):2655- 11. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-
2663. PMID: 20339026 altered thyroid cancers. N Engl J Med. 2020;383(9):825-835. PMID: 32846061
6. Niederle MB, Riss P, Selberherr A, et al. Omission of lateral lymph node 12. Subbiah V, Hu MI, Wirth LJ, et al. Pralsetinib for patients with advanced
dissection in medullary thyroid cancer without a desmoplastic stromal or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-
reaction. Br J Surg. 2021;108(2):174-181. PMID: 33704404 label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol. 2021;9(8):491-
501. PMID: 34118198

ENDO 2022 • Thyroid  293

What’s New in the
Treatment of Differentiated
Thyroid Cancer?
Benjamin J. Gigliotti, MD. Department of Medicine, Division of Endocrinology, University of
Rochester, Rochester, NY; E-mail: [email protected]

Learning Objectives lateral nodal stations are radiographically

normal and there is no history of neck
As a result of participating in this session, learners
radiation or family history of thyroid cancer.
should be able to:
• Active surveillance is a reasonable
• Identify appropriate candidates for management option for adults, especially
conservative treatment of low-risk if certain patient factors (accepting of
differentiated thyroid cancer (DTC) and surveillance philosophy, good adherence,
summarize the pros and cons of active high surgical risk) and tumor factors (smaller
surveillance, hemithyroidectomy, and than 1.5 cm with normal surrounding
emerging focally ablative methods. parenchyma, no extrathyroidal extension,
• Develop a personalized approach to treating no nodal or distant metastases, no high-risk
patients with advanced and metastatic thyroid cytopathologic features) are present, along
cancers, including identification of aggressive with access to high-quality ultrasonography
and/or radioiodine-refractory disease, and and willingness of the health care team to
determine when to consider and refer for facilitate surveillance.
“targeted” therapies. • Focal ablative technologies such as percutaneous
radiofrequency, microwave, laser, and ethanol
ablation are being actively studied in the
treatment of papillary thyroid microcarcinomas
Main Conclusions and locoregional nodal disease, although they
are not yet widely available.
• Management of thyroid cancer has been a moving
• Advanced thyroid cancers are uncommon and
target in recent years and has become increasingly
exhibit a wide range of behavior. Defining
personalized and risk-adapted. Treatment of low-
their size, location, and growth trajectory is
risk thyroid carcinoma is becoming increasingly
helpful in management, as is working in or
conservative, and the molecular era has provided
referring to experienced multidisciplinary
new insights and treatment options for patients
teams. For clinically significant disease
with advanced disease.
that is refractory to surgery, radioactive
• Hemithyroidectomy is an attractive iodine (RAI), TSH suppression, and, when
initial surgical approach for patients with appropriate, external-beam radiation, local
indeterminate cytopathology or low-risk ablative therapies, and molecular targeted
intrathyroidal DTC smaller than 4 cm, therapies are invaluable and rapidly evolving
especially if the contralateral lobe and central/ treatment modalities.

294  ENDO 2022 • Endocrine Case Management

 the development of poorly differentiated and
Significance of the undifferentiated (anaplastic) histologies. The
nearly dizzying expansion of available molecular
Clinical Problem targeted therapies has made many of these
The incidence of thyroid cancer has been steadily oncologic alterations “actionable,” dramatically
increasing over the last 3 decades. Small indolent increasing treatment options for patients with
papillary thyroid carcinomas (PTCs) account for aggressive disease. However, the optimal agent
much of the rise, which suggests overdiagnosis, and/or sequence of agents, patient/tumor
most likely due to increasing sensitivity and characteristics, and timing of initiation are not
availability of thyroid ultrasonography and FNA. always clear. In other words, we are left with the
While recent data suggest there may be a small same fundamental questions as for patients with
rise in the incidence of more aggressive thyroid low-risk disease: who and when?
cancers (to which obesity may be contributory), The changing landscape of thyroid cancer
along with a modest increase in mortality, nearly management has made this an equally exciting and
all of these additional cases are not lethal.1,2 bewildering time to care for patients. The purpose
Given widespread recognition that most of this chapter is to briefly review several of these
DTCs are indolent and carry an excellent new and evolving management strategies, focusing
prognosis, coupled with epidemiologic data on low-risk thyroid cancer, which is significantly
that overtreatment increases morbidity, more common and relevant to clinicians in
management of thyroid cancer has become endocrinology, as well as the rarer but more
increasingly conservative. Active surveillance, vexing scenario of advanced disease, through the
hemithyroidectomy rather than total lens of practical clinical application.
thyroidectomy, more judicious use of RAI, and
local ablative technologies have all garnered
significant attention and have expanding evidence
Barriers to Optimal Practice
to support their use. However, thoughtful
• Active surveillance is most successful in
application of conservative strategies requires
the setting of specific patient and tumor
proper identification of appropriate “low-
characteristics and requires local expertise as
risk” patients who are unlikely to be harmed
well as high-quality neck ultrasonography.
from receiving less up-front therapy.3 Most
clinicians have cared for relatively uncommon • Long-term surveillance after
but memorable patients with “low-risk” disease hemithyroidectomy is more challenging than
who experienced poor outcomes. Refining the surveillance after total thyroidectomy followed
definition of “low risk” is an important ongoing by RAI.
effort, including active research to more explicitly • Local ablative therapies continue to benefit
quantify tumor size, volume, and multifocality, from innovation in technology and expanding
define the extent of margin positivity, and handle indications, but they require specialized
increasingly ubiquitous molecular data. equipment and expertise and are not yet
On the opposite end of the disease spectrum, widely available.
a small but clinically significant subset of patients
• Advanced and metastatic thyroid carcinomas
with thyroid cancer experience locoregional
are uncommon and follow a variable course.
recurrence and distant metastasis. Improved
Most systemic therapies are effective, although
understanding of the molecular pathogenesis
they remain palliative and carry the risk of
of thyroid cancer has shed new light on the
significant adverse effects. Tumors eventually
pathogenetic drivers behind more aggressive
develop resistance. Optimal use scenarios and
behavior (including refractoriness to RAI) and
timing of initiation are not always clear.

ENDO 2022 • Thyroid  295

Strategies for Diagnosis, It is worth noting that encapsulated follicular
variant PTC were included in the low-risk
Therapy, and/or Management
category at the time the 2015 American Thyroid
Low-Risk DTC Association guidelines were published because
DTC collectively includes PTC and follicular they have long been recognized to be unusually
thyroid carcinoma (FTC); Hürthle-cell carcinoma indolent. Since that time, they have been
and poorly differentiated carcinoma are also reclassified as noninvasive follicular thyroid
included in the 2017 World Health Organization neoplasms with papillary-like nuclear features
classification. While distinct in biology and (NIFTP), rather than carcinoma, although
behavior, PTC and FTC are often grouped “carcinoma in situ” may be a more precise
together because their prognosis is generally description. While NIFTP has relatively strict
very good, and clinical management strategies, diagnostic criteria (eg, no evidence of capsular
including thyroidectomy and RAI, are similar.4 invasion after complete examination of the tumor
Contemporary thyroid cancer management relies capsule), these lesions are definitively treated with
on a risk-adapted approach; the American Thyroid hemithyroidectomy and unequivocally do not
Association Management Guidelines for Adult require additional therapy.5
Patients with Thyroid Nodules and Differentiated
Thyroid Cancer have articulated a shared lexicon Hemithyroidectomy
to stratify “risk of structural disease recurrence” Hemithyroidectomy, or thyroid lobectomy,
using evidence-based clinicopathologic variables, involves removal of the ipsilateral thyroid lobe
supplemented by molecular diagnostics and and isthmus.5 Despite fairly widespread use of
dynamic risk restratification over time.3 According hemithyroidectomy for the treatment of thyroid
to the most recent guidelines, low-risk DTC is cancer in the past, total thyroidectomy followed
defined as follows. by RAI became increasingly common practice
since the 1970s because of several studies showing
• Intrathyroidal PTC with: a reduction in tumor recurrence and mortality.
Since that time, various risk-stratification tools
ԗ No locoregional tissue invasion, local have been designed and validated, enabling better
metastases, or distant metastases on axial prediction of the risk of disease recurrence/
or 131I scanning mortality, and defining who may benefit most
ԗ Conventional or follicular variant histology (and least) from RAI. While the debate about the
and absence of aggressive histology (eg, ideal clinical use of RAI has, and continues to be,
tall-cell variant, hobnail variant, columnar a vibrant one, it is clear that more judicious use
variant) or vascular invasion of RAI in a risk-tailored approach is successful.6
ԗ All macroscopic tumor resected (R0) and The 2009 American Thyroid Association thyroid
no macroscopic or microscopic invasion of cancer management guidelines pioneered the first
perithyroidal soft tissues recurrence-focused risk system and recommended
against routine use of RAI in patients at low risk,
ԗ No suspicious lymph nodes
given convincing data of little-to-no benefit.1 The
on ultrasonography, ≤5 lymph
2015 American Thyroid Association guidelines
node micrometastases <2 mm in
went a step further to refine the definitions of
largest dimension
risk categories and added that hemithyroidectomy
rather than total thyroidectomy may be a
• Intrathyroidal FTC with capsular invasion, but reasonable initial surgical option for low-risk
<4 foci of vascular invasion disease, especially since one of the arguments

296  ENDO 2022 • Endocrine Case Management

for total thyroidectomy is to remove iodine-avid Indications for Completion Thyroidectomy (With
healthy thyroid tissue to facilitate RAI. or Without Compartment-Oriented
Lymph Node Dissection)
Table. Pros and Cons of Hemithyroidectomy
• American Thyroid Association intermediate-
Pros Cons or high-risk histopathologic features
Reduced likelihood of needing Therapeutic RAI and • Development of new abnormal central or
postoperative thyroid hormone diagnostic RAI whole-
(risk factors for replacement body scanning cannot lateral compartment lymph nodes (ideally
include baseline TSH >2-2.5 mIU/L, be performed without after confirming malignancy with FNA and, if
positive antithyroid antibodies completion lobectomy or
or ultrasonographic evidence of residual lobe RAI ablation acellular, thyroglobulin washout)
autoimmunity, smaller thyroid
volume, female sex) • A markedly elevated postoperative
Lower surgical risk of recurrent Potential need for thyroglobulin value, especially if locoregional
laryngeal nerve injury, a second surgery if or distance disease is suspected or found
hypoparathyroidism, hematoma/ pathology reveals higher-
seroma, especially when done by risk features • A positive margin is controversial; a wide
a lower-volume surgeon
rather than focal extent of the margin,
No increased risk of mortality Decreased sensitivity of and posterior more than anterior margin
thyroglobulin in detecting
tumor persistence/ involvement appears to carry higher risk
recurrence due to “noise”
from the residual lobe • Tumor multifocality is controversial; if
Potential savings in cost and At most a small increased contralateral nodules are present, or there are
increased quality-of-life scores recurrence risk additional risk factors (family history, history
of neck radiation), completion thyroidectomy
Ideal Candidates is attractive

• Absence of contralateral nodules/goiter

Active Surveillance
• Absence of abnormal lymph nodes in the Serial ultrasonographic surveillance of biopsy-
central/lateral compartments confirmed or suspected thyroid cancer. Active
• Nodules <4 cm (especially <1 cm) without surveillance was first proposed and implemented
extrathyroidal extension for patients with papillary thyroid microcarcinoma
• Absence of risk factors, including prior head/ (<1 cm) in Japan in the early 1990s, based on
neck radiation and a strong family history of observations that small occult PTCs were common
thyroid cancer and indolent.8 In their landmark study, only 8%
of patients experienced tumor growth of 3 mm
• Bethesda 3 or 4 indeterminate cytopathology or more over 10 years, and the 3.8% of patients
• Strong preference for hemithyroidectomy who required a salvage definitive surgery for new
• Low operative risk, even if 1 or more surgery lymph node metastases had similar outcomes to
is needed those who underwent up-front surgery. These
findings have been corroborated in Korea and
now in the United States, confirming the overall
Reasonable Candidates
safety of the active surveillance strategy and
• Low-risk contralateral nodules (with benign identifying predictors and patterns of tumor
FNA, if indicated by ultrasonographic features progression that continue to undergo active
and size) study. Active surveillance was added to the 2015
American Thyroid Association guidelines as an
• Bethesda 5 or 6 cytopathology
acceptable management strategy for appropriately
selected patients, and a clinical framework was

ENDO 2022 • Thyroid  297

subsequently published to guide adoption for Less Ideal, But Appropriate Characteristics
when the right confluence of patient, tumor, and
medical team characteristics are present.3,9 • Age 18 to 59 years
• Size <1.5 cm (most studies use a 1.5-cm
Ideal Circumstances cutoff, but up to 2 cm may be appropriate; all
• Patient factors numerical thresholds in medicine are informed
by available data, rather than a sacrosanct
ԗ Age >60 years biological cutoff)
ԗ Accepting of the active surveillance • Multifocal papillary thyroid microcarcinoma
philosophy and potential need for • Indistinct tumor margins or a heterogeneous
future surgery or multinodular thyroid parenchyma
ԗ Reliable and adherent to clinical and • Nodule 18F-fluorodeoxyglucose avidity on
ultrasonography follow-up positron emission tomography (if <1 cm)
ԗ High risk of surgery, significant • Subcapsular nodule location, as long as it
comorbidities, and/or limited is away from regions harboring critical
life expectancy anatomy (eg, the recurrent laryngeal nerve,
trachea, esophagus)
• Nodule/tumor factors
ԗ Size <1 cm Suggested Surveillance Protocols
ԗ Solitary well-defined thyroid nodule with • Baseline thyroid ultrasonography with
>2 mm of surrounding normal gland axial dimension measurement and tumor
parenchyma volume calculation
ԗ No evidence of extrathyroidal extension on • Serial thyroid ultrasonography every 6 months
ultrasonography for 2 to 3 years, then annually (if stable)
ԗ Size stability over time
ԗ No clinical evidence of nodal or Indications to Abort Active Surveillance
distant metastases • ≥3 mm or more increase in the axial dimension
ԗ No high-risk cytopathologic or molecular • >50% increase in tumor volume, especially if
features (as of this writing, there are no there is a short doubling time or the tumor is
clear molecular features that preclude adjacent to the thyroid capsule
active surveillance)
• Radiographic evidence of invasion through the
thyroid capsule
• Medical team factors
• Development of cervical lymph node
ԗ Multidisciplinary team with metastasis (or more rarely, distant metastasis)
endocrinologists, high-volume thyroid
surgeons, and sonographers/radiologists
Locally Ablative Technologies
ԗ Physician comfort A cadre of focally delivered ablative therapies
ԗ Availability of high-quality have been used in the treatment of benign
neck ultrasonography and malignant thyroid disease, including
ԗ Robust ancillary support to ensure follow- percutaneous ethanol ablation, radiofrequency,
up and adherence to surveillance protocols or microwave ablation, cryoablation, laser

298  ENDO 2022 • Endocrine Case Management

ablation, chemoembolization, and high-intensity clinical endocrinology in the Williams Textbook of
focused ultrasonography. While varying widely Endocrinology, 12th edition: “With most innocent
in technique, they are often grouped together or nonaggressive thyroid cancers, the rule is to
because of an image-guided minimally invasive think and act like an endocrinologist. With more
approach, compared with conventional surgical aggressive thyroid and other endocrine cancers,
excision. As with any specialized medical a good rule is to think like an oncologist, and to
technology, their study and clinical application refer the patient to one of them if necessary.”16
have been a moving target, including use in the An important first step in the management of
treatment of benign cystic and solid thyroid patients with advanced or dedifferentiated DTC
nodules, oligometastatic disease in neck lymph is to recognize the presence of aggressive features
nodes or distant sites, and salient to the topic of and clinical behavior. Potential characteristics of
low-risk DTC in the nonsurgical management of more aggressive disease include the following:
papillary thyroid microcarcinoma. Percutaneous
radiofrequency, microwave, laser, and ethanol • High-risk of recurrence and/or tumor/node/
ablation have data to support their use in this metastasis stage
setting.10,11 Potential pros of percutaneous ablation • Rapid tumor growth trajectory
include similar outcomes in select patients, lower • Large, locally invasive tumors, especially
cost, an attractive safety profile, and potentially involving or encasing critical structures such
higher quality-of-life scores. Use of these methods as the trachea, esophagus, prevertebral fascia,
is actively being codified into management and carotid artery or mediastinal vessels
guidelines position statements.12,13 Patients who
• Presence of distant metastasis
are interested may be directed to centers within
the United States and abroad that have developed • Multiple recurrent or progressive tumors
expertise and have active clinical programs in the central or lateral neck, especially
and/or trials. if unresectable
• Failure to respond to surgical resection, RAI,
Advanced DTC and TSH suppression
Up to 30% of patients with DTC experience The recognition of failure to respond to our most
locoregional recurrence (or more precisely, widely used and usually successful tools (surgery,
persistence). While most of these patients do RAI, and TSH suppression), is particularly
well, a subset experience repetitive recurrence important. Given the importance of surgery as
with related morbidity, and 1% to 5% of patients first-line management, relying on the expertise
develop distant metastases.14 Poorly differentiated of a skilled and high-volume thyroid surgeon,
and undifferentiated tumors exhibit more and obtaining a second opinion, if necessary,
consistently aggressive behavior, and may arise is important before deciding that surgery is no
de novo or due to dedifferentiation of an existing longer a good option. Defining the clinical utility
DTC.15 While uncommon, these patients are of radioactive iodine, however, often falls to us.
often a source of worry and uncertainty for Unfortunately, no international consensus has
practicing clinicians, especially in the context of been reached on a precise and encompassing
rapidly evolving understanding of the molecular definition of RAI-refractory disease. A recent joint
pathogenesis underlying aggressive behavior, and statement from international experts in the field
an overwhelming cadre of systemic therapies. nicely captures areas of consensus and controversy
My mentor, Dr. Gilbert Daniels from the and articulated the following common clinical
Massachusetts General Hospital Thyroid Unit, scenarios as being suggestive of reduced likelihood
provides us with a guiding axiom in his primer on of response to RAI:

ENDO 2022 • Thyroid  299

• No 131I uptake in tumor foci on a diagnostic • Response rates are variable
(pretreatment) scan or a posttreatment • Treatment is mostly tumoristatic and
131
I scan palliative; most have shown an improvement
• I uptake is present in some but not other
131
in progression-free survival, but not mortality
tumor foci, or is lost over time • Adverse effects can be significant, although
• Presence of metastasis(es) that progress despite newer/more specific therapies such as RET
131
I uptake or a cumulative 131I activity of inhibitors selpercatinib and pralsetinib appear
>600 mCi (>22.2 GBq) to have a gentler adverse effect profile
However, it is important to note that response • Development of resistance is nearly inevitable,
to RAI exists in a spectrum, and no single although mechanisms of resistance and
criterion definitively excludes benefit in every strategies to circumvent them are being
clinical scenario. Therefore, multidisciplinary actively investigated
collaboration with nuclear medicine (and referring To address these limitations, several therapies and
for a second opinion at a high-volume center, strategies are in the research pipeline. There is
if necessary) is critical, especially in light of ongoing identification of driver alterations with
changes on the horizon due to new treatment expanding drug options to target them, application
strategies and emerging “redifferentiation” of immunotherapy and peptide receptor therapy,
protocols aimed at restoration of iodine uptake leveraging of targeted therapies to increase iodine
in recalcitrant tumors through the use of small uptake and retention through restoration of
molecule inhibitors. sodium-iodine symporter function, exploration of
Advances in understanding the genetic sequential or combinatorial treatment protocols
alterations that drive thyroid cancer have shed to attempt to maximize response and minimize
new light on the mechanisms underlying more development of resistance.
aggressive disease. For instance, most thyroid While some endocrinologists have developed
cancers harbor alterations (mostly mutations and particular expertise in the use of targeted
fusions) in the mitogen-activated protein kinase therapies, most notably the Endocrine Neoplasia
(MAPK) pathway, with BRAF V600E representing and Hormonal Disorders Department at MD
the most common alteration in PTC. Certain gain- Anderson, most of us rely on oncology colleagues
of-function pathogenic variants within the MAPK who have more experience with systemic therapies
pathway, including BRAF V600E, can decrease along with a more robust clinical infrastructure to
downstream sodium-iodine symporter expression, procure, prescribe, and monitor them. However,
conveying refractoriness to RAI. The development as the longitudinal providers for most patients
of tyrosine kinase inhibitors that target multiple with thyroid cancer, clinicians in endocrinology
pathways in angiogenesis and cell growth, along are best suited to identify potential candidates for
with inhibitors specific for altered and wild- systemic therapy and to refer to oncology when
type proteins in the MAPK pathway, among needed. Since even recalcitrant or metastatic
others, have become the mainstay for patients thyroid cancer can still be relatively indolent, our
with progressive disease.17 A total of 9 systemic main task is to differentiate clinically significant
therapies (sorafenib, lenvatinib, dabrafenib/ and progressive disease from cancers that are
trametinib, selpercatinib, pralsetinib, larotrectinib, simply detectable (eg. indolent metastases) and
entrectinib, cabozantinib) are currently approved warrant active surveillance. Tumor size, growth
by the US FDA for the treatment of thyroid trajectory, location, and symptoms from organ
cancers of follicular cell origin. However, these involvement are critical variables to consider, as is
therapies have important limitations: whether a disease site is amenable to local-directed
therapies. Consideration of systemic therapy

300  ENDO 2022 • Endocrine Case Management

is most appropriate for patients who exhibit clinicians in endocrinology remain at the heart of
the following: the treatment team, and our role has remained the
same: to lead, coordinate (and occasionally, herd),
• Tumor foci ≥1 to 1.5 cm or in immediate support, and innovate.
adjacency to critical structures
• Rapid growth trajectory over 6 to 12 months
or less (the role of an isolated rise during
Clinical Case Vignettes
biochemical surveillance, eg, thyroglobulin Case 1
doubling without radiographic correlate, is A 78-year-old man presents for evaluation
less clear) of multinodular goiter incidentally identified
• Presence of symptoms related to disease on chest CT during workup for new-onset
burden (eg, shortness of breath or hemoptysis hemoptysis, which is eventually attributed to
associated with lung metastases) chronic bronchitis. His medical history is notable
• Failure to respond to TSH suppression, for chronic obstructive pulmonary disease on
radioactive iodine, and if disease foci are maximal medical therapy and 2 L of oxygen via
oligometastatic and accessible, failure to nasal cannula (40 pack-year smoking history, quit
respond to external-beam radiation and/ after starting oxygen), heart failure with preserved
or focal therapies such as resection and ejection fraction, hypertension, hyperlipidemia,
percutaneous ablation diet-controlled type 2 diabetes mellitus, obesity,
low back pain, and benign prostatic hypertrophy.
If unsure whether to refer, most oncologists are TSH and free T4 concentrations are normal.
happy discuss or see the patient in consultation; Thyroid ultrasonography at an outside imaging
I have found comanagement to be an effective, center reveals a well-demarcated, 1.4-cm, right-
team-building, and educational strategy. sided, hypoechoic, taller-than-wide nodule with
microcalcifications in the anterior/mid aspect of
Conclusion the lobe with at least 4 mm of normal surrounding
parenchyma. There is no sonographic evidence
Management of DTC is increasingly moving of extrathyroidal extension. Additional nodules
towards a personalized and risk-adapted approach, include a nearby right 1.2-cm complex nodule
and active research continues to refine risk and a left 2.5-cm complex nodule, both of which
categories and the most appropriate therapeutic lack suspicious features. Lateral neck lymph nodes
options for each group. While treatment of were not examined. He has no history of radiation
low-risk DTC has become progressively more exposure or family history of thyroid cancer.
conservative, and treatment of advanced disease Ultrasound-guided FNA of the right 1.4-cm
has become more team-based, our options are only nodule reveals Bethesda V “suspicious for PTC,”
increasing in number, and staying abreast of new while the left 2.5-cm nodule is interpreted to be a
changing practice patterns has never been more benign colloid nodule. He lives roughly 10 miles
challenging. The importance of collaborating from your clinic and always attends medical
with each other, as well as with colleagues in appointments. He has a minimalist philosophy to
other specialties cannot be overstated. Working medical care and wants to pursue the least invasive
in a multidisciplinary team with experienced management option, “as long as it’s not going to
thyroid surgeons, nuclear medicine specialists, hurt me.” He has no compressive neck symptoms.
radiologists, pathologist, oncologists, and radiation
oncologists is an effective way to care for patients
across the disease spectrum. However, thanks to
our longitudinal relationships with our patients,

ENDO 2022 • Thyroid  301

Which of the following is the most efficacy and safety for suspicious nodules larger
appropriate initial management than 10 mm, along limited availability.
strategy for this patient?
A. Measurement of thyroid nodule size and Case 2
volume and locoregional node examination in
anticipation of active surveillance A 59-year-old woman presents for evaluation of
a neck mass after total thyroidectomy 7 years ago.
B. Referral to interventional radiology Medical records document that she had a 4-cm
for radiofrequency ablation of the right “minimally invasive” FTC with fewer than 4 foci
1.4-cm nodule of angioinvasion. She did not receive radioactive
C. Referral to thyroid surgery for consideration iodine and does not recall any recent bloodwork
of right hemithyroidectomy or ultrasound surveillance. Her medical history
D. Referral to thyroid surgery for consideration is otherwise insignificant. Ultrasonography
of total thyroidectomy reveals a 3-cm hypoechoic and hypervascular
nodule in the right thyroid bed, and findings on
Answer: A) Measurement of thyroid nodule size ultrasound-guided FNA are interpreted to be
and volume and locoregional node examination follicular neoplasm.
in anticipation of active surveillance Her TSH concentration is 2.2 mIU/L
This elderly man has a Bethesda V 1.4-cm on levothyroxine, 125 mcg of daily,
thyroid nodule without extrathyroidal extension. and her thyroglobulin concentration is
The nodule is in a favorable location for active 0.24 ng/mL (0.24 ug/L) with negative
surveillance. He is high risk for perioperative antithyroglobulin antibodies.
complications and has a limited life expectancy, She undergoes revision thyroid surgery by
no significant risk factors for thyroid cancer, and a high-volume thyroid surgeon, and pathology
a minimalist philosophy. He engages in reliable reveals a 3-cm angioinvasive FTC; no nodes were
follow-up. The only less ideal (but still reasonable) submitted. Postoperative 131I diagnostic (using
variable is the presence of multinodular goiter, a 3 mCi, 0.111 GBq dose) whole-body scanning
although his suspicious nodule has a distinct border reveals scant central neck uptake but no other
and the other nodules are low risk and the largest sites of iodine avidity. A 100 mCi (3.7 GBq)
has benign findings on FNA. Provided that his adjuvant dose of 131I is given, and the posttreatment
physician is comfortable following him and that scan is unchanged. A postoperative and post RAI
high-quality ultrasonography is available (with thyroglobulin concentration is less than 0.1 ng/mL.
accurate measurements and normal regional lymph One year after revision surgery, she
node morphology), active surveillance (Answer A) develops calf swelling and shortness of breath
is most consistent with the patient’s request. after a long car ride. CT chest reveals a small
Right hemithyroidectomy (Answer C) is not pulmonary embolism, as well as innumerable
unreasonable, although his high operative risk, his small pulmonary nodules, the largest of which
desire for minimal invasiveness, and the presence is 1 cm. Bronchoscopy is performed and FNA is
of a contralateral, albeit asymptomatic, nodule positive for the presence of follicular epithelial
make hemithyroidectomy less attractive. cells. A repeated diagnostic whole-body 131I
Total thyroidectomy (Answer D) is reasonable scan is negative, and no treatment is given. Her
but invasive; the patient should be counseled that shortness of breath resolves with anticoagulation,
it may yet be necessary if significant growth of the and her TSH is suppressed and maintained at a
suspicious nodule is noted. concentration less than 0.10 mIU/L. Over the next
Radiofrequency ablation (Answer B) is 7 years, her pulmonary nodules slowly grow by
inappropriate given limited data to support approximately 1 mm/year until sudden growth

302  ENDO 2022 • Endocrine Case Management

is noted, coinciding with the development of systemic therapy (Answer A). Her relatively low
hemoptysis and shortness of breath. thyroglobulin level despite high tumor burden
and lack of iodine avidity at diagnosis is consistent
Which of the following is the with dedifferentiated RAI-refractory FTC. Given
most appropriate next step in the large size of her original tumor, it is possible
this patient’s management? that more significant angioinvasion was missed
A. Referral to oncology for consideration of due to incomplete sectioning.
systemic therapy Thoracic surgery (Answer C) is incorrect.
B. Referral to radiation oncology for consideration Oligometastatectomy may improve survival in
of external-beam radiation therapy select patients with localized pulmonary metastases.
Repeated 131I whole-body scanning (Answer
C. Referral to thoracic surgery
D) is low yield given lack of uptake on 2 diagnostic
D. Repeated 131I whole-body scanning 131
I whole-body scans, including a post-100 mCi
Answer: A) Referral to oncology for treatment scan.
consideration of systemic therapy Referral for radiation (Answer B) is also not
likely to be fruitful given the widespread pattern
This patient has developed rapidly progressive, of pulmonary metastasis; it would be more
symptomatic, metastatic (lung) angioinvasive FTC reasonable if there were regional oligometastases
after 7 years of indolent growth during active that were not amenable to resection.
surveillance. Thus, she is a good candidate for

References
1. Kitahara CM, Sosa JA. The changing incidence of thyroid cancer. Nat Rev 10. van Dijk SPJ, Coerts HI, Gunput STG, et al. Assessment of radiofrequency
Endocrinol. 2016;12(11):646-653. PMID: 27418023 ablation for papillary microcarcinoma of the thyroid: a systematic review and
2. Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM. Trends in thyroid meta-analysis. JAMA Otolaryngol Head Neck Surg. 2022;148(4):317-325. PMID:
cancer incidence and mortality in the United States, 1974-2013. JAMA. 35142816
2017;317(13):1338-1348. PMID: 28362912 11. Hay ID, Lee RA, Kaggal S, et al. Long-term results of treating with ethanol
3. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid ablation 15 adult patients with cT1aN0 papillary thyroid microcarcinoma. J
Association management guidelines for adult patients with thyroid nodules Endocr Soc. 2020;4(11):bvaa135. PMID: 33073159
and differentiated thyroid cancer: the American Thyroid Association 12. Orloff LA, Noel JE, Stack BC Jr, et al. Radiofrequency ablation and related
Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid ultrasound-guided ablation technologies for treatment of benign and
Cancer. Thyroid. 2016;26(1):1-133. PMID: 26462967 malignant thyroid disease: an international multidisciplinary consensus
4. Schlumberger M, Leboulleux S. Current practice in patients with statement of the American Head and Neck Society Endocrine Surgery Section
differentiated thyroid cancer. Nature Rev Endocrinol. 2021;17(3):176-188. with the Asia Pacific Society of Thyroid Surgery, Associazione Medici
PMID: 33339988 Endocrinologi, British Association of Endocrine and Thyroid Surgeons,
5. Addasi N, Fingeret A, Goldner W. Hemithyroidectomy for thyroid cancer: a European Thyroid Association, Italian Society of Endocrine Surgery Units,
review. Medicina (Kaunas). 2020;56(11):586. PMID: 33153139 Korean Society of Thyroid Radiology, Latin American Thyroid Society, and
6. Hay ID, Kaggal S, Iniguez-Ariza NM, Reinalda MS, Wiseman GA, Thompson Thyroid Nodules Therapies Association. Head Neck. 2022;44(3):633-660.
GB 2021 Inability of radioiodine remnant ablation to improve postoperative PMID: 34939714
outcome in adult patients with low-risk papillary thyroid carcinoma. Mayo 13. Mauri G, Hegedus L, Bandula S, et al. European Thyroid Association and
Clin Proc. 2021;96(7):1727-1745. PMID: 33743997 Cardiovascular and Interventional Radiological Society of Europe 2021
7. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid clinical practice guideline for the use of minimally invasive treatments
Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, in malignant thyroid lesions. Eur Thyroid J. 2021;10(3):185-197. PMID:
et al. Revised American Thyroid Association management guidelines for 34178704
patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 14. Kim WW, Lee J, Jung JH, et al. Predictive risk factors for recurrence or
2009;19(11):1167-1214. PMID: 19860577 metastasis in papillary thyroid cancer. Int J Thyroidology. 2020;13(2):111-117.
8. Lohia S, Hanson M, Tuttle RM, Morris LGT. Active surveillance for 15. Fagin JA, Wells SA, Jr. Biologic and clinical perspectives on thyroid cancer. N
patients with very low-risk thyroid cancer. Laryngoscope Investig Otolaryngol. Engl J Med. 2016;375(11):1054-1067. PMID: 27626519
2020;5(1):175-182. PMID: 32128446 16. Melmed S, Polonsky K, Larsen PR, Kronenberg HM eds. Williams Textbook of
9. Brito JP, Ito Y, Miyauchi A, Tuttle RM. A clinical framework to facilitate Endocrinology. 12th ed. Elsevier Saunders; 2011.
risk stratification when considering an active surveillance alternative 17. Fullmer T, Cabanillas ME, Zafereo M. Novel therapeutics in radioactive
to immediate biopsy and surgery in papillary microcarcinoma. Thyroid. iodine-resistant thyroid cancer. Front Endocrinol (Lausanne). 2021;12:720723.
2016;26(1):144-149. PMID: 26414743 PMID: 34335481

ENDO 2022 • Thyroid  303

MISCELLANEOUS
Doping With Androgens:
Abuse of Androgenic
Performance-Enhancing Drugs
Bradley D. Anawalt, MD. University of Washington School of Medicine, Seattle, WA;
E-mail: [email protected]

Learning Objectives male infertility and requests for testosterone

prescriptions to treat low serum testosterone. In
As a result of participating in this session, learners
men who abuse androgens, serum gonadotropins
should be able to:
are suppressed, and seminal fluid analyses show
• Recognize the clinical presentation of azoospermia or very low sperm concentrations.
androgenic performance-enhancing drug Recovery of gonadal axis function occurs
(PED) abuse (including infertility). spontaneously after discontinuation of androgenic
PEDs; the time to recovery is related to duration
• Recognize the history and physical
of abuse. Treatment consists of encouraging
examination findings and pattern of serum
cessation by respectful and nonjudgmental
hormone results that are consistent with
education about the health consequences of
specific forms of androgenic PED abuse.
androgenic PEDs and management of underlying
• Identify the laboratory studies that are useful anxiety and depressive disorders. For some men
for identifying androgenic PED abuse. who have abused high dosages of PEDs for years,
• Develop a rational approach to the use of there might be a role for adjunctive hormone
psychotherapy and hormone therapy in therapy with a short course of testosterone or
the management of patients who wish to clomiphene to treat anabolic androgenic steroid
discontinue androgenic PED abuse. withdrawal syndrome or a short course of
gonadotropin or clomiphene therapy to hasten
spermatogenic recovery and improve fertility.

Main Conclusions
Androgens and drugs that raise endogenous Significance of the
androgen production are the most commonly Clinical Problem
abused PEDs. In clinical practice, androgenic
Many drugs are used to enhance athletic
PEDs are used almost exclusively by men. The
performance and appearance, including androgens
proven health consequences include infertility,
and drugs that increase serum androgen
acne, and erythrocytosis in men. Other potential
concentrations, insulin, and growth hormone.
adverse effects include increased cardiovascular
Androgens administered at pharmacological
disease, hepatopathy (with oral alkylated
dosages are the most commonly used PEDs, and
androgens), neuropsychopathology, and ruptured
they are the only class of drugs with definitive
upper-extremity tendons. The common clinical
evidence that they enhance strength and athletic
presentations of androgenic PED abuse are
performance. Members of the general public are

306  ENDO 2022 • Endocrine Case Management

much less likely to use growth hormone, insulin, depression and anxiety and are more likely to use
and other nonandrogens as potential PEDs. tobacco and marijuana products, alcohol, illicit
For the purposes of this review and session, the drugs, and high dosages of dietary supplements
focus will be on androgenic PED abuse, and the and nutraceuticals that have not been studied
use of pharmacological dosages of androgens or rigorously for safety. In addition, androgenic PEDs
drugs that increase endogenous androgens will are often purchased on the open market or through
be defined as androgenic PED use. Individuals the internet, and these drugs might contain or be
who are eugonadal and take androgenic PEDs contaminated with unsafe substances.
are abusing them; prescription of androgen
and gonadotropin replacement to hypogonadal
patients is not PED abuse.
Barriers to Optimal Practice
It has been difficult to assess the prevalence of
• Social stigma and laws against androgenic PED
androgenic PED abuse, but the lifetime prevalence
abuse are barriers to disclosure of abuse.
of ever using these PEDs is probably 1% to 5%
in men worldwide.1 There is a trend toward • Many clinicians do not recognize the clues of
decreased incidence in teenagers and young adults, possible androgenic PED abuse.
but there might be a small increasing incidence • Except for disclosure of androgenic abuse by
in middle-aged and older men. The prevalence the patient, there are no methods of making a
of androgenic PED abuse is much higher in men definitive diagnosis of androgenic PED abuse
than in women (>50:1), and long-term abusers are in members of the general public.
almost exclusively male. Most chronic androgenic • There are very limited data on the best
PED abusers begin in their twenties and are therapeutic approach for individuals who abuse
former elite or near-elite athletes or weightlifters androgenic PEDs and want to discontinue.
with a fixation on being more muscular (often
referred to as muscle dysmorphia or bigorexia). • The data about the short-term and long-term
Assessing the short-term and long-term effects of androgenic PED abuse are based on
adverse effects of androgenic PEDs has also case reports, case series, and cross-sectional
been difficult. There are well-described adverse studies with numerous confounders.
effects of androgen therapy, including acne (more
common in younger patients), erythrocytosis
(more common in older patients), and infertility.1,2 Strategies for Diagnosis,
Chronic androgenic PED use accelerates male- Therapy, and/or Management
pattern alopecia and causes hirsutism, alopecia,
and defeminization and virilization in women.
Clinical Presentation of
Hepatopathy occurs with use of oral alkylated Androgenic PED Abuse
androgens only, and there appears to be increased Men who chronically abuse androgenic PEDs
risk of tendinous ruptures, particularly in muscles typically present with infertility or with requests for
of the arms and chest.3,4 There is increasing evaluation for testosterone therapy. These men may
evidence that there is an androgenic PED present with androgenic PED withdrawal syndrome,
withdrawal syndrome of depressed mood, anxiety, with symptoms and signs of hypogonadism,
and low self-esteem after acute cessation.5,6 or with infertility. The use of aromatizable
High dosages of androgenic PEDs might androgenic PEDs can cause gynecomastia, and the
increase the incidence of cardiovascular disease, use of nonaromatizable androgenic PEDs may be
hypertension, and psychiatric disorders.3,7 The causal associated with sexual dysfunction.
relationship is unclear because chronic androgenic Women who chronically abuse androgenic
PED abusers are also more likely to have baseline PEDs are almost exclusively elite athletes and are

ENDO 2022 • Miscellaneous  307

rarely seen by most endocrinologists; they may symptomatic or new-onset gynecomastia. Chronic
present with amenorrhea, infertility, and variable androgenic PED abuse that causes gonadotropin
degrees of defeminization and virilization. This suppression is associated with variably decreased
session will not address this rare endocrine disorder. testicular volumes (typically ~25%-35%), but men
with baseline testicular volumes of 25 mL or more
may not have small testes after chronic androgenic
Diagnosis of Androgenic PED Abuse
PED abuse. Testicular texture (eg, softness or
The diagnosis of androgenic PED abuse should firmness) is not a specific or sensitive physical
be suspected in muscular men who present with examination finding of androgenic PED abuse.
infertility or request an evaluation for testosterone The biochemical evaluation for suspected
therapy. Most men who abuse androgenic PEDs androgenic PED abuse begins with measurement
exercise frequently and many lift weights regularly. of serum testosterone and gonadotropins
These men usually have bigorexia or muscular in a blood sample obtained between 7 and
dysmorphia, a distorted body image that they are 10 AM. Serum testosterone and gonadotropin
not muscular enough.1 They often spontaneously concentrations differ depending on the type
report that their strength and muscle bulk benefit of androgenic PED use (Table). The use of
have plateaued in the weight room. Another clue nontestosterone androgenic anabolic steroids (eg,
that may suggest chronic androgenic PED abuse is nandrolone, oxandrolone, danazol, stanozolol,
a history of use of nutraceuticals and supplements or tetrahydrogestrinone) is associated with low
to build muscles (eg, creatine powder). testosterone and gonadotropin concentrations.
In addition to increased musculature, The standard evaluation for secondary
the physical examination may demonstrate hypogonadism, including sellar imaging and
gynecomastia and small testes, but these findings measurement of serum prolactin, should be done
are not sensitive or specific. The history and in patients with this biochemical profile who
the physical examination may also offer clues to do not report the use of androgenic PEDs. If
the type of androgenic drug being used (Table). androgenic PED use is suspected in a patient with
Androgenic drugs that increase aromatization laboratory evidence of secondary hypogonadism,
of testosterone to estradiol are more likely to it is worthwhile to repeat a respectful and
cause breast growth, breast pain, and tenderness nonjudgmental enquiry about androgenic PED
and gynecomastia. Androgen precursor abuse use. Sometimes, patients will report androgenic
increases the serum estradiol concentration PED use if they understand that further evaluation
disproportionately to the serum testosterone for other secondary causes of hypogonadism will
concentration and is also more likely to cause cost them time and money.

Table. Serum Hormone Concentrations During Androgenic PED Use

Androgenic PED New-onset or tender gynecomastia Testes <15 cc Serum testosterone Serum FSH Serum LH
Testosterone Uncommon More common ↑ ↓ ↓
Testosterone precursors* More common More common ↑ ↓ ↓
Nontestosterone More common** More common ↓ ↓ ↓
androgenic steroids
hCG Common No ↑ ↓ ↓
Aromatase inhibitor alone Uncommon No ↑ ↑ ↑
Clomiphene ? No ↑ ↑ ↑
* Very high dosages are required.
** If an aromatizable androgen.

308  ENDO 2022 • Endocrine Case Management

 Androgens increase serum hematocrit and After all, scientists disputed the benefits of
decrease serum HDL cholesterol, SHBG, and androgenic PEDs decades after athletes empirically
thyroxine-binding globulin. In patients with proved the performance-enhancing effects; why
suspected androgenic PED use, it is useful should androgenic PED abusers believe scientists
to measure hematocrit and often helpful and clinicians about potential adverse effects?
to measure HDL cholesterol, SHBG, and/ All androgenic PED users must be queried about
or thyroxine-binding globulin. Seminal fluid anxiety and depression and abuse of alcohol or
analyses generally show azoospermia or very low illicit drugs and offered a referral for treatment
sperm concentrations. if appropriate.
There are methods for detecting androgenic Some men are not prepared to stop using
PEDs and their metabolites in urine samples of androgenic PEDs. The endocrinologist should
elite athletes, but these methods are not available counsel patients about the known adverse effects
in most commercial laboratories.8 In addition, (including reduced fertility that might take 1
there are many ways to create spurious results, to 2 years to normalize after discontinuation
including dilution, substitution of someone else’s of androgenic PEDs, erythrocytosis, and
sample, and submitting a sample at a time when dyslipidemia) and potential adverse effects with
the patient is not using androgenic PEDs. For elite a focus on the cardiovascular system. Some men
athletes, urine samples are obtained under very who are not willing to discontinue androgenic
strict circumstances, including random times and PEDs are willing to “convert” to prescription
observed micturition into a sample container. testosterone. Conversion to intramuscular
Thus, methods to accurately measure androgenic testosterone formulations at up to 2 to 3 times
PEDs and their metabolites in urine are not the usual replacement dosage with a tapering of
relevant diagnostic studies in clinical practice. the dosage over several months is likely to be
safer than very high dosages of androgenic PEDs
of unknown safety and purity purchased from
Treatment of Androgenic PED
unregulated sources. High dosages of testosterone
Abuse and Withdrawal Syndrome are initially required because androgenic PED
There are no clinical trials or guidelines on the users generally use high dosages of various
management of patients who abuse androgenic androgens simultaneously (“stacking”), and
PEDs or the management of cessation of they will experience symptoms of withdrawal
androgenic PEDs and androgenic PED withdrawal if immediately converted directly to typical
syndrome. Therefore, care of patients who abuse testosterone replacement dosages used for
androgenic PEDs is based on the following: (1) treatment of male hypogonadism. This approach
readiness to cease androgenic PEDs; (2) duration permits the establishment of a relationship
and intensity of androgenic PED abuse; (3) near- between the patient and clinician over time;
team goals for fertility; and (4) a risk-benefit this might facilitate eventual discontinuation of
analysis of the treatment options compared androgenic PED use.
with continuation or resumption of androgenic For men who are ready to quit androgenic
PED use.1 PED use, there are the following options: (1)
A key principle for the care of androgenic PED immediate discontinuation without medical
users is the establishment a relationship of trust therapy; (2) conversion to testosterone therapy
based on respectful and nonjudgmental behavior. with a tapering dosage over many months (see
While this principle guides all patient-clinician above); (3) discontinuation with initiation of a
relationships, it is particularly important for this limited course of subcutaneous hCG therapy, or
group of patients. They are often distrustful of (4) discontinuation with initiation of a limited
traditional health care providers and scientists. course of oral clomiphene therapy.

ENDO 2022 • Miscellaneous  309

 Immediate discontinuation of androgenic On physical examination, his blood
PEDs without additional medical therapy is pressure is 135/85 mm Hg, pulse rate is
the best choice for men who have used these 80 beats/min, respiratory rate is 12 breaths/min,
drugs for 1 year or less. Based on limited, low- and BMI is 21 kg/m2. He is muscular. There is no
quality data, it appears that after androgenic gynecomastia, and testes are 12 mL bilaterally. No
PED discontinuation, serum gonadotropin acne is observed.
concentrations spontaneously normalize within
3 to 6 months, followed by recovery of serum Laboratory test results:
testosterone to normal serum concentrations Hematocrit = 46% (38%-48%)
within 6 months in most men who report a year Serum total testosterone = 110 ng/dL (264-870 ng/dL)
or less of androgenic PED use. Spermatogenesis (SI: 3.8 nmol/L [9.2-30.2 nmol/L])
Serum FSH = 0.2 mIU/mL (1.0-7.0 mIU/mL)
typically returns to normal 3 to 6 months after (SI: 0.2 IU/L [1.0-7.0 IU/L])
serum testosterone normalizes.1,9 Serum LH = 0.1 mIU/mL (1.0-9.0 mIU/mL)
For men who report chronic androgenic (SI: 0.1 IU/L [1.0-9.0 IU/L]
PED use longer than 1 year, there is a higher risk
of withdrawal syndrome, and the gonadal axis You advise him to abstain from using androgenic
may take years to recover.1,10-12 Intramuscular steroids. You also inform him that he might feel
testosterone that is tapered over many months sluggish and tired for several weeks while his
might be a good option for many of these men, but hypothalamic-pituitary-testicular axis recovers
this approach is not an option for men who are within 3 to 6 months.
interested in conceiving. Exogenous testosterone The patient returns 6 months later with
therapy will continue to suppress spermatogenesis his wife. He reports that he has felt tired and
and fertility. For men who are infertile because despondent since stopping androgenic PEDs. He
of androgenic PED use for more than 1 year has low libido and low sexual satisfaction. He now
and who want to have a child within the next 2 reports that he has been taking androgenic PEDs
years, the best options may be hCG therapy or for many years. His wife confirms these symptoms
clomiphene therapy. Clinical experience and safety and reports that they have been trying to conceive
data are much more robust for hCG therapy than for the past 6 months. She confirms that he took
for clomiphene, but there are scanty data on the testosterone for “about a year” and that he had a
effectiveness for improving spermatogenesis and marked increase in libido during that year.
fertility in this setting for either drug. Laboratory test results at this clinic visit:
Hematocrit = 37% (38%-48%)
Clinical Case Vignettes Serum total testosterone = 80 ng/dL (264-870 ng/dL)
(SI: 2.8 nmol/L [9.2-30.2 nmol/L])
Case 1 Serum FSH = 0.3 mIU/mL (1.0-7.0 mIU/mL)
A 32-year-old man requests evaluation for (SI: 0.3 IU/L [1.0-7.0 IU/L])
testosterone or clomiphene therapy. He confides Serum LH = 0.2 mIU/mL (1.0-9.0 mIU/mL)
(SI: 0.2 IU/L [1.0-9.0 IU/L])
that he has been taking anabolic androgenic Seminal fluid analysis, no sperm
steroids for the past year. He reports taking a
combination of several at once (“stacking”) and
rotating the combination (“cycling”). His wife has
been urging him to stop taking them because she
is concerned about his health. He is under the care
of a mental health professional for treatment of
anxiety and depression.

310  ENDO 2022 • Endocrine Case Management

Which of the following would Case 2
you recommend?
A 21-year-old man seeks evaluation of breast
A. Anastrozole therapy growth and tenderness for the past 3 months.
B. Evaluation for hypothalmic or pituitary causes He reports that he does not get the same “cut”
of hypogonadism look (increased muscles) that his friends at the
C. hCG therapy gym do. He reports no change in libido. He has
D. Intramuscular testosterone taper no weight loss. He went through puberty at age
13 years. He reports no history of medical illness
E. Reassurance
and no surgeries. He states that he does not take
Answer: B) Evaluation for hypothalmic any medications or anabolic androgenic steroids
or pituitary causes of hypogonadism (“steroids”), opioids, or other illicit drugs. He does
not drink alcohol.
This man continues to be significantly On physical examination, his blood pressure
hypogonadal 6 months after cessation of is 110/70 mm Hg, pulse rate is 72 beats/min,
androgenic PED abuse. His decline in hematocrit respiratory rate is 12 breaths/min, and BMI is
supports that he has discontinued PEDs. It 21 kg/m2. He has a beard and normal musculature.
is unusual to have no sign of recovery the There is 2.5 cm of slightly tender gynecomastia,
hypothalamic-pituitary-testicular axis after 6 and testes are 15 mL bilaterally. There are no
months of abstinence from androgen use. Most scrotal masses. Findings on skin examination are
men younger than 50 years regain normal serum normal with no striae or ecchymoses. He has mild
gonadotropin and testosterone concentrations acne on his back.
within 1 to 3 months of discontinuing androgen
use of 1 year or less.1 With the use of longer- Laboratory test results (ordered by the
acting formulations, recovery might take a little referring clinician):
longer, but there should be significant recovery Hematocrit = 48% (38%-48%)
or normalization of serum testosterone 6 months Serum total testosterone = 880 ng/dL
after discontinuing androgen use of 1 year or less. (264-916 ng/dL) (SI: 30.6 nmol/L
His wife’s comments suggest that the patient [9.2-30.2 nmol/L])
might have had underlying hypogonadism prior Serum DHEA-S = 556 µg/dL (211-494 µg/dL)
(SI: 15.1 µmol/L [5.72-13.39 µmol/L])
to using illicit androgenic steroids; his sustained Serum FSH = 0.2 mIU/mL (1.0-7.0 mIU/mL)
increase of libido after initiating androgenic (SI: 0.2 IU/L [1.0-7.0 IU/L])
steroids is unusual in normal eugonadal men Serum LH = 0.1 mIU/mL (1.0-9.0 mIU/mL)
because there is a ceiling effect for testosterone (SI: 0.1 IU/L [1.0-9.0 IU/L])
on sexual function. There might be a transient
placebo effect to increase libido with the initiation Which of the following is the
of androgens in eugonadal men, but that most likely diagnosis?
effect does not generally persist except in men
A. Adrenal cortical carcinoma
with hypogonadism.
This man should be evaluated for causes B. hCG use
of pituitary dysfunction (Answer B), including C. Leydig-cell tumor
hyperprolactinemia, iron overload, and pituitary D. Nandrolone use
macroadenoma. Gonadotropin replacement E. Testosterone use
therapy should be considered for this couple that is
trying to conceive. Answer: B) hCG use

ENDO 2022 • Miscellaneous  311

This man is in the demographic that is most nontestosterone androgens suppress serum
likely to abuse androgens (male, age ~16-25 years, testosterone and gonadotropins.
weightlifter or body builder). Testosterone A Leydig-cell tumor (Answer C) can produce
(Answer E) and hCG (Answer B) abuse are testosterone or estradiol and could explain this
both consistent with the presentation of a high patient’s presentation, but these tumors are
serum testosterone concentration and low serum uncommon and occur mostly in prepubertal boys.
gonadotropin concentrations, but hCG abuse is This patient’s presentation is inconsistent
much more likely to cause acute breast growth with adrenal cortical carcinoma (Answer A),
and tenderness. Because hCG has LH activity that which generally does not present with evidence
increases aromatase activity and conversion of of excess production of androgens or estrogens
testosterone to estradiol, hCG is more likely to until the tumor is large (might be palpable) and
cause gynecomastia. symptomatic with weight loss, abdominal pain,
The high serum testosterone concentration anorexia, and/or nausea. Although his serum
excludes abuse with a nontestosterone DHEA-S is elevated, modest elevations are usually
androgenic PED such as nandrolone (Answer D); idiopathic and not due to adrenal pathology
(eg, adrenal carcinoma).

References
1. Anawalt BD. Diagnosis and management of anabolic androgenic steroid use. J 7. Baggish AL, Weiner RB, Kanayama G, et al. Cardiovascular toxicity of illicit
Clin Endocrinol Metab. 2019;104(7):2490-2500. PMID: 30753550 anabolic-androgenic steroid use. Circulation. 2017;135(21):1991-2002. PMID:
2. Christou MA, Christou PA, Markozannes G, Tsatsoulis A, Mastorakos 28533317
G, Tigas S. Effects of anabolic androgenic steroids on the reproductive system 8. Anawalt BD. Detection of anabolic androgenic steroid use by elite athletes
of athletes and recreational users: a systematic review and meta-analysis. and by members of the general public. Mol Cell Endocrinol. 2018;464:21-27.
Sports Med. 2017;47(9):1869-1883. PMID: 28258581 PMID: 28943276
3. Pope HG Jr, Wood RI, Rogol A, Nyberg F, Bowers L, Bhasin S. Adverse 9. Liu PY, Swerdloff RS, Christenson PD, Handelsman DJ, Wang C; Hormonal
health consequences of performance-enhancing drugs: an Endocrine Society Male Contraception Summit Group. Rate, extent, and modifiers of
scientific statement. Endocr Rev. 2014;35(3):341-375. PMID: 24423981 spermatogenic recovery after hormonal male contraception: an integrated
4. Kanayama G, DeLuca J, Meehan WP 3rd, et al. Ruptured tendons in analysis. Lancet. 2006;367(9520):1412-1420. PMID: 16650651
anabolic-androgenic steroid users: a cross-sectional cohort study. Am J Sports 10. Kanayama G, Hudson JI, DeLuca J, et al. Prolonged hypogonadism in
Med. 2015;43(11):2638-2644. PMID: 26362436 males following withdrawal from anabolic-androgenic steroids: an under-
5. Onakomaiya MM, Henderson LP. Mad men, women and steroid cocktails: a recognized problem. Addiction. 2015;110(5):823-831. PMID: 25598171
review of the impact of sex and other factors on anabolic androgenic steroids 11. Rasmussen JJ, Selmer C, Østergren PB, et al. Former abusers of anabolic
effects on affective behaviors. Psychopharmacology (Berl). 2016;233(4):549-569. androgenic steroids exhibit decreased testosterone levels and hypogonadal
PMID: 26758282  symptoms years after cessation: a case-control study. PLoS One.
6. Piacentino D, Kotzalidis GD, Del Casale A, et al. Anabolic-androgenic 2016;11:e0161208. PMID: 275532478
steroid use and psychopathology in athletes. A systematic review. Curr 12. Anawalt BD. Male fertility after androgenic steroid use: how little we know. J
Neuropharmacol. 2015;13(1):101-121. PMID: 26074746 Clin Endocrinol Metab. 2021;106(7):e2813-e2815. PMID: 33861859

312  ENDO 2022 • Endocrine Case Management

E-Consults: An Evolving
Area of Endocrine Care
David Saxon, MD. Division of Endocrinology, Metabolism, and Diabetes, University of
Colorado School of Medicine and Rocky Mountain Regional VA Medical Center, Aurora,
Colorado; E-mail: [email protected]

Varsha Vimalananda, MD. Center for Healthcare Organization and Implementation

Research (CHOIR), Bedford VA Medical Center, Bedford, Massachusetts; Section of
Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston,
Massachusetts; E-mail: [email protected]

Learning Objectives e-consults have shown benefit are also reported

in the literature. Reimbursement for e-consults
As a result of participating in this session, learners
is improving but remains a concern for those
should be able to:
who practice in fee-for-service systems. “High-
• Explain the use and benefits of electronic quality” e-consult responses are specific, practical,
consultations (e-consults), as well as barriers to educational, and often give anticipatory guidance, so
their use, in the field of endocrinology. that the patient can remain under the care of their
primary care clinician.
• Recognize various e-consult models that have
been used for endocrine care and describe how
these models might be used to a greater extent
to improve endocrine care in the future. Significance of the
• Describe considerations related to Clinical Problem
reimbursement for e-consults. Timely access to specialty care is a longstanding
• Identify the elements of a high-quality and worsening challenge. Endocrinology as a field
e-consult response. faces a clinical workforce shortage, exacerbating
access challenges for our specialty. E-consults offer
an approach to overcoming problems of access
while improving use of health care resources and
Main Conclusions maintaining high patient and provider satisfaction.
E-consults are asynchronous, consultative,
E-consult use is growing within the United States
provider-to-provider communications within a
and internationally. As a lab-based specialty with
shared electronic medical record (or web-based
expertise in many common diseases, endocrinology
platform). Patients are not directly involved in this
is one of the most popular subspecialties for
mode of care delivery. Many diabetes and endocrine
e-consults. Various models of e-consult care
questions can be answered in a useful and succinct
have been used. E-consults across specialties
way by endocrinologists without the need for a
increase access to care (ie, more appropriate use of
face-to-face patient visit. This session will review
specialist visits) and improve management of some
the growing use and utility of e-consults with a
conditions (at the individual patient and population
specific focus on use in the endocrine space.
levels). Endocrine disease-specific scenarios where

ENDO 2022 • Miscellaneous  313

Barriers to Optimal Practice medical subspecialties.1-3 Endocrinologists can
reasonably anticipate that e-consults will become
• Lack of or unpredictable reimbursement for a routine aspect of their clinical practice at some
this type of care. point during their career.
• Concern about the legal ramifications
of providing e-consult care without Endocrinology Is Well-
physically seeing the patient whose issue is Suited to E-Consults
being addressed.
Studies at both single institutions and large
• Insufficient technological support to create and health care systems have consistently shown that
maintain a robust e-consult platform. endocrinology is one of the more commonly
• Lack of clarity and agreement across services e-consulted specialties. Certainly, the lab-
about elements of a good e-consult request based nature of our specialty is one of the main
and response. drivers of this popularity. In the Veterans Health
Administration from 2012 to 2018, more than
• Added work for the primary care provider
3 million e-consults were completed across 41
and specialist.
specialties. Endocrinology ranked as the third most
used specialty overall.1
Use and Benefits of E-Consults
Benefits of E-Consults
E-Consult Systems Are
E-consults allow primary care clinicians to access
Increasingly Common specialty expertise through chart review and often
Historically, “curbside consults” have been result in avoiding a face-to-face patient visit.
commonplace in medicine. However, face-to- Even if the consultant decides a face-to-face visit
face and phone communication among clinicians is ultimately needed, an e-consult beforehand
has decreased as the electronic medical record can guide the primary care clinician in a previsit
has taken over as the primary channel by which workup (eg, laboratory tests and imaging) that
colleagues in large hospital systems interact. could be completed in time for review at the initial
Furthermore, in many health care settings, limited endocrinology visit. This preparatory work results
access to timely specialty care has necessitated the in a more efficient face-to-face consultation and
development of clinical workflows that address potentially avoids at least 1 visit.
this issue. It is within this changing nature of Compared with face-to-face visits, e-consults
medical practice that e-consults have arisen as a result in faster access to specialty input, allow
model for clinical care. specialists to triage and prioritize patients for face-
E-consults are now used in many health care to-face care, and reduce wait times for face-to-face
systems in the United States and internationally. visits. E-consults have been shown to reduce the
Additionally, since 2014 the American Association total cost of care by 36% to 83%, including for
of Medical Colleges has partnered with more endocrinology.4 Patient, primary care clinician,
than 40 academic medical centers, children’s and specialist satisfaction with e-consults is high
hospitals, and health care organizations to across studies. There are limited data on safety
implement e-consults as a part of Project CORE and clinical outcomes, but the existing literature
(Coordinating Optimal Referral Experiences). suggests that e-consults are safe and not associated
There are also national network, third-party with worse clinical quality of care.5
contractors who provide e-consult services.
Studies of e-consult use have consistently shown
that endocrinology is one of the most highly used

314  ENDO 2022 • Endocrine Case Management

Benefits of E-Consults Especially if the goal of the e-consult is
for Endocrine Care to avoid a face-to-face visit, the primary
care clinician should discuss the e-consult
Benefits of e-consults that are applicable to with the patient prior to requesting it.
endocrine practice include their feasibility and Patient consent is a required component for
flexibility across a variety of settings, as well Medicare reimbursement.
their ability to facilitate timely specialty advice
(while reducing unnecessary or inappropriate
consultations).6 Also, e-consults present an Figure. Optional Pathway Model
opportunity for the endocrinologist to provide
succinct (often templated) education to their
primary care colleagues on commonly encountered
endocrine problems, an experience that many find
to be enjoyable.
Several experiences in endocrine-related
e-consult care have been published. In one series,
the most common reasons for endocrinology
e-consults were thyroid diseases, osteoporosis, and
adrenal insufficiency.7 The majority of answered
e-consults suggested the need for further testing,
and nearly 95% of the consults were answered
within 3 or fewer business days. When thyroid
fine-needle aspirations were preceded by an
endocrinology e-consult, there were timelier
workups and similar guideline concordance as
compared with fine-needle aspirations preceded
by endocrinology face-to-face visits.8 In the
inpatient setting, use of targeted automatic
e-consults (referred to as a “virtual glucose
Reprinted from Vimalananda VG et al. Journal of Telemedicine and
management service”) to manage diabetes at 3 Telecare, 2015;21(6) © SAGE Publications.

University of California San Francisco hospitals

over a 12-month period was shown to decrease
the proportion of patients with hyperglycemia or
hypoglycemia by 39% and 36%, respectively.9 2. E-consult first—single pathway model:
In this model, specialists make the judgment
E-Consult Models about an e-consult vs face-to-face care. The
E-consults are flexible in their application. e-consult is reviewed by a specialty clinician
Common models include: who then either recommends that the patient
be seen in person or resolves the e-consult
1. E-consult option—optional pathway request without a visit by providing needed
model: information regarding management of the
condition. When this model was deployed in
In this model (see Figure), primary care
the Los Angeles County Department of Health
clinicians request an e-consult up front.
Services, the average e-consult response time
In many systems, specialists retain the
was 1 day and 25% of all e-consults were
option to convert e-consults to face-to-face
resolved without a specialist visit.10
referrals or request additional information.

ENDO 2022 • Miscellaneous  315

3. Targeted automatic e-consults: Guidance on Reimbursement
Patients are prospectively identified using In many integrated health care systems, clinicians
electronic medical record data. Relevant are not reimbursed directly for responding
clinical information is then presented on a to e-consults. Other arrangements include
dashboard to consultants who provide written reimbursement per e-consult completed or time
recommendations as a “virtual consult” spent completing an e-consult. Another option is
without the request being initiated by the to reimburse e-consults as a mode of care delivery.
primary care clinician. This model has been In 2019, the Centers for Medicare and Medicaid
used to identify and improve care for patients adopted 2 new codes for interprofessional internet
with hip fractures who may be candidates for consultation, and these are used for e-consults.
medical therapy and to optimize treatment for
patients with uncontrolled diabetes.9,11 Consulting Clinician
99451: “Interprofessional telephone/internet/
The Potential Future of electronic health record assessment and
Endocrine E-Consult Care management service provided by a consultative
physician including a written report to the
• There are many scenarios where targeted patient’s treating/requesting physician or other
e-consults could be used in the outpatient qualified health care professional, 5 or more
setting to triage care, improve the minutes of medical consultative time”
appropriateness of care rendered at a
• Can be reported for new or
population level, and address some clinical
established patients
issues that may have gone ignored. Some
examples include providing guidance on • Can be reported for a new or
hormonal workup of radiological endocrine exacerbated problem
incidentalomas, suggesting appropriate • Are reported only by a consultant when
next laboratory tests and imaging for requested by another physician/qualified
newly identified thyroid disorders, health professional
improving the clinical diagnosis of familial
• Cannot be reported more than once per 7 days
hypercholesterolemia, or providing advice on
for the same patient
next steps for optimizing diabetes medication
prior to a primary care visit. • Are reported based on cumulative time spent,
even if that time occurs on subsequent days
• Greater use of specialty-to-specialty
e-consults could be deployed, such as direct • Are not reported if a transfer of care or request
e-consultation between endocrinology and for a face-to-face consultation occurs because
urology regarding use of testosterone in a man of the consultation within the next 14 days
with a history of prostate cancer. • Are not reported if the patient was seen by the
• Systematic incorporation of e-consults as part consultant within the past 14 days
of an “expanding spectrum of modalities of • Require that the request and the reason for
care” that includes both patient-involved (eg, the request for the consult be documented in
synchronous video, remote patient monitoring) the record
and clinician-clinician (eg, teleconsultation by
• Require verbal consent for the
email or phone, Project ECHO).
interprofessional consultation from the
• With wider reimbursement, e-consults are patient/family documented in the patient’s
likely to spread even more broadly. medical record

316  ENDO 2022 • Endocrine Case Management

 Code Reported by: Concluded with: Time required How time is spent 2021 wRVU
99451 Consultant Written report required ≥5 min Review pertinent medical records, 0.7
to treating/requesting laboratory tests/imaging studies,
physician/qualified medication profile, etc, and medical
health professional consultative verbal or internet discussion
99452 Requestor NA ≥16 min Preparing for the consult and/or the 0.7
actual time spent communicating with
the consultant

Features of High-Quality Response

E-Consult Responses Endocrinologist’s chart review:
In endocrinology, e-consults are perhaps best used A 70-year-old woman with a history of
for clinical scenarios where there are either minor hypertension and osteopenia was found to have
laboratory abnormalities or where the primary a TSH value of 0.33 mIU/L (reference range,
care clinician is already managing the endocrine 0.45-5.30 mIU/L) on routine laboratory tests
condition but needs advice about the best next step in March 2021. No previous TSH values are
in the patient’s management. documented in the electronic medical record.
Excellent e-consult responses reduce the Follow-up testing performed in April 2021
likelihood that patients will ultimately need a included normal free T4 and free T3 levels
face-to-face visit. Rigorous consensus methods (TSH and total T3 were not measured). Current
identify the features of a “high-quality” e-consult medications include amlodipine, 5 mg daily;
correspondence: specific, up-to-date, patient- lisinopril, 5 mg daily; and vitamin D3, 2000 units
individualized, and practical advice (with daily. There is no prior neck imaging in her
anticipatory guidance) that a primary care record. A recent primary care clinical note states
provider can effectively implement.12 Anticipatory that the patient has been in good health and
guidance is critical given that management of does not mention any symptoms concerning
the condition is intended to remain with the for hyperthyroidism or neck discomfort. There
primary care clinician. Thus, it is helpful to list is no mention of herbal or over-the-counter
any indications for face-to-face referral. Responses medications or supplements.
are enhanced when they are educational for the
Endocrinologist’s recommendation(s):
consulting clinician; this may include pertinent
This patient has a mildly low TSH value
professional society guidelines and other relevant
documented on one occasion. The clinical
literature. Endocrinologists might consider
significance of this finding is unknown, and
developing templates for common questions
many patients with such an abnormality
that can be tailored for the individual patient.
have normalization of TSH on repeated
Templates can ease the burden of responding to
testing. TSH values that are fully suppressed
the same question repeatedly while ensuring all
(ie, TSH <0.1 mIU/L) merit a more extensive
relevant components of a response are covered.
workup. In the case of an only slightly low TSH
value, the best next step is to ensure this is not a
Clinical Case Vignettes spurious result. When subclinical hyperthyroidism
is present (ie, fully suppressed TSH, but normal
Case 1
free T4 and total T3 values), treatment is
Question from primary care provider recommended for older patients because this
“Does this patient with subclinical situation poses an increased risk of bone loss
hyperthyroidism need further evaluation or can and atrial fibrillation. Please perform a thorough
these labs just be monitored?”

ENDO 2022 • Miscellaneous  317

physical examination to assess for palpable thyroid Response
nodules or signs of Graves disease. Also, FYI, we
generally avoid measuring free T3 levels because Endocrinologist’s chart review:
the assay is thought to be unreliable. Please send a Laboratory test results from 3/22/2021:
follow-up e-consult or refer the patient for a clinic Calcium = 11.6 mg/dL (SI: 2.9 mmol/L)
visit if repeated thyroid testing or physical exam PTH = 193 pg/mL (SI: 193 ng/L)
warrants further assessment and management. 25-Hydroxyvitamin D = 13 ng/mL (SI: 32.4 nmol/L)
Creatinine = 1.35 mg/dL (SI: 119.3 µmol/L)
Evidence supporting e-consult response: Estimated glomerular filtration rate =
58 mL/min per 1.73 m2
• Ross DS, Burch HB, Cooper DS, et al. 2016 Hemoglobin A1c = 5.7% (39 mmol/mol)
American Thyroid Association Guidelines for
On 4/9/2021, DXA documents lowest T-score
diagnosis and management of hyperthyroidism
is –1.2 at left femoral neck, and findings are
and other causes of thyrotoxicosis. Thyroid.
otherwise normal.
2016;26(10):1343-1421.
Endocrinologist’s recommendation(s):
E-consult outcome: This patient very likely has primary
Following this e-consult, the primary care hyperparathyroidism. The only other test to order
physician measured TSH again 5 and 8 months is a 24-hour urinary calcium with creatinine just
later. Both TSH values fell within the normal to make sure that he does not have FHH (familial
range and no further workup was performed. hypocalciuric hypercalcemia), which is a genetic
disorder that runs in families and can mimic
primary hyperparathyroidism. In patients with
Case 2 FHH, the urinary calcium is very low, whereas in
Question from primary care provider primary hyperparathyroidism the urinary calcium
A 53-year-old man presents with asymptomatic is generally normal or high. FHH is very rare
hypercalcemia. He reports that his calcium has but needs to be ruled out because missing that
been high in the past, but we do not have copies diagnosis can result in a patient going to surgery
of previous lab results. Current laboratory who does not need it. If the urine test result
test results: is not concerning for FHH, then the best and
Calcium = 11.6 mg/dL (SI: 2.9 mmol/L) most appropriate treatment option for primary
Calcium (ionized) = 6.1 mg/dL (SI: 1.5 mmol/L) hyperparathyroidism is parathyroidectomy
PTH = 193 pg/mL (SI: 193 ng/L) because it is definitive. He meets guideline criteria
25-Hydroxyvitamin D = 32 ng/mL (SI: 79.9 nmol/L) for parathyroidectomy given that his calcium level
Creatinine = 1.35 mg/dL (SI: 119.3 µmol/L) is a full point above the upper limit of normal.
Estimated glomerular filtration rate =
58 mL/min per 1.73 m2 Please write back with questions or concerns.

DXA shows the lowest T-score is –1.2 at the left Evidence supporting e-consult response:
femoral neck. No history of kidney stones. Do Primary hyperparathyroidism is diagnosed by
you recommend that I observe patient, send to finding an elevated serum calcium level associated
endocrine, or send to surgery? with a serum PTH level that is elevated or in
the mid- to high-normal range >20 pg/mL
[>20 ng/L]). Serum PTH levels are less than
10 pg/mL (<10 ng/L) or undetectable in all other
causes of hypercalcemia except one rare genetic
syndrome. For asymptomatic patients, indications
for surgery include the following: serum calcium

318  ENDO 2022 • Endocrine Case Management

greater than 1 mg/dL above the upper limit of • Zhu CY, Sturgeon C, Yeh MW. Diagnosis and
normal, bone mineral density T-score less than management of primary hyperparathyroidism.
–2.5 or a fragility fracture, creatinine clearance JAMA. 2020;323(12):1186-1187.
less than 60 mL/min, 24-hour urinary calcium • Bilezikian J. Guidelines for the management of
greater than 400 mg/24 h, kidney stones, or age asymptomatic primary hyperparathyroidism:
younger than 50 years. Surgery should be offered summary statement from the Fourth
to symptomatic patients and to asymptomatic International Workshop. J Clin Endocrinol
patients who meet 1 or more of these criteria. Metab. 2014;99(10):3561-3569.
For asymptomatic patients who don’t meet any
of these criteria, surgery is still an option, but it is
E-consult outcome:
also reasonable to monitor such patients without
The patient was referred directly to endocrine
surgery with measurement of serum calcium and
surgery without need for a face-to-face
creatinine every 6 to 12 months and DXA every 1
endocrinology consultation and underwent
to 2 years. When low bone mineral density is the
successful single-gland parathyroidectomy for a
only criterion met, an alternative is to treat with a
parathyroid adenoma.
bisphosphonate or other osteoporosis medication.

References
1. Saxon DR, Kaboli PJ, Haraldsson B, Wilson C, Ohl M, Augustine MR. 8. Yoon SS, Wong DH, Wormwood JB, Reisman JI, Vimalananda VG. Impact
Growth of electronic consultations in the Veterans Health Administration. of electronic consultation on timeliness and guideline concordance of
Am J Manag Care. 2021;27(1):12-19. PMID: 33471457 workups leading to thyroid nodule fine-needle aspiration biopsy. Endocr Pract.
2. Leyton C, Zhang C, Rikin S. Evaluation of the effects of the COVID-19 2021;27(10):1011–1016. PMID: 33766654
pandemic on electronic consultation use in primary care. Telemed J E Health. 9. Rushakoff RJ, Sullivan MM, MacMaster HW, et al. Association between a
2022;28(1):66-72. PMID: 33794114 virtual glucose management service and glycemic control in hospitalized adult
3. Kirsh S, Carey E, Aron DC, et al. Impact of a national specialty e-consultation patients: an observational study. Ann Intern Med. 2017;166(9):621-627. PMID:
implementation project on access. Am J Manag Care. 2015;21(12):e648-e654. 28346946
PMID: 26760427 10. Barnett ML, Yee HF Jr, Mehrotra A, Giboney P. Los Angeles safety-net
4. Thielke A, King V. Electronic consultations (eConsults): a triple win for program eConsult system was rapidly adopted and decreased wait times to see
patients, clinicians, and payers. Milbank Memorial Fund. 2020. Available at: specialists. Health Aff (Millwood). 2017;36(3):492-499. PMID: 28264951
http://resource.nlm.nih.gov/101775057 11. Lee RH, Pearson M, Lyles KW, Jenkins PW, Colon-Emeric C. Geographic
5. Vimalananda VG, Orlander JD, Afable MK, et al. Electronic consultations scope and accessibility of a centralized, electronic consult program for
(E-consults) and their outcomes: a systematic review. J Am Med Inform Assoc. patients with recent fracture. Rural Remote Health. 2016;16(1):3440. PMID:
2020;27(3):471-479. PMID: 31621847 26745338
6. Vimalananda VG, Gupte G, Seraj SM, et al. Electronic consultations 12. Tran C, Liddy C, Pinto N, Keely E. Impact of question content on
(e-consults) to improve access to specialty care: a systematic review and e-consultation outcomes. Telemed J E Health. 2016;22(3):216-222. PMID:
narrative synthesis. J Telemed Telecare. 2015;21(6):323-330. PMID: 25995331 26281010
7. Wasfy JH, Rao SK, Essien UR, et al. Initial experience with endocrinology
e-consults. Endocrine. 2017;55(2):640-642. PMID: 27507674

ENDO 2022 • Miscellaneous  319

 2022 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
you to evaluate your endocrine knowledge and gain insight into the
strategies used by clinical experts.

Features of 2022 Endocrine Case Management:

Meet the Professor include:

• Significance of the Clinical Problem

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