Endocrine Pathophysiology 9th Edition

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 To my wife Helena and our children Maranda, Daniel, and Samuel.
—Eric

To my wife Monica and daughters Denise and Erica.

—Guillermo

In addition to our wives and children, together Guillermo and I dedicate this
book to my father, Joel Felner, MD, Professor of Medicine, and Associate Dean
of Clinical Education at Emory University. He is a great parent, grandparent,
mentor, and friend who has inspired and guided the career of Emory students,
residents, fellows, and faculty over the past four decades.
List of Contributors

Student Contributors Eric I. Felner, MD, MSCR

Associate Professor of Pediatrics
Mark H. Adelman (MD 2011) Division of Pediatric Endocrinology
Sarah D. Turbow (MD 2012) Director, Pediatric Endocrinology Fellowship
Bhavya S. Doshi (MD 2012) Program
Director, Pediatric Clerkship
Adva Eisenberg (MD 2013)
Emory University School of Medicine
Kristina M. Cossen (MD 2012)
Raghuveer Halkar, MD
Steven A. Gay (MD 2013)
Associate Professor of Radiology
Robert S. Gerhard (MD 2013) Division of Nuclear Medicine & Molecular
David L. Gutteridge (MD 2012) Imaging
Josh A. Hammel (MD 2011) Emory University School of Medicine
David Kappa (MD 2012) Andrew B. Muir, MD
Geoffrey S. Kelly (MD 2013) Bernard Marcus Professor of Pediatrics
Division Director, Pediatric Endocrinology
Steven C. Kim (MD 2013) Emory University School of Medicine
Anna L. Lipowska (MD 2012)
Briana C. Patterson, MD, MSCR
Meredith MacNamara (MD 2013) Assistant Professor of Pediatrics
Stanislav Polioshenko (MD 2013) Division of Pediatric Endocrinology
Karen E. Schmitz (MD 2013) Emory University School of Medicine
Elicia D. Skelton (MD 2014) Jyotirmay Sharma, MD
Evan T. Tiderington (MD 2012) Assistant Professor of Surgery
Dane Todd (MD 2011) Emory University School of Medicine

Jason Zhu (MD 2013) Guillermo E. Umpierrez, MD, FACP, FACE

Professor of Medicine
Faculty Contributors Division of Endocrinology
Director, Diabetes and Endocrinology
Milton R. Brown, PhD, MHA Section
Assistant Professor of Biochemistry Grady Health Care System
Division of Pediatric Endocrinology Emory University School of Medicine
Emory University School of Medicine
Mary S. Dolan, MD, MPH
Associate Professor of Gynecology/Obstetrics
Division Director, General Gynecology/Obstetrics
Department of Gynecology/Obstetrics
Emory University School of Medicine

All student contributors graduated or are on track to graduate from Emory University School
of Medicine. All faculty contributors are on faculty at Emory University School of Medicine

v
Foreword

O ne of the best ways to learn is to teach. This is almost axiomatic for resident physi-
cians and faculty; however, opportunities for medical students to teach are often lim-
ited. Moreover, the unavoidably large gap in knowledge between faculty members and
those just starting their medical careers often leads to passive transfers of information,
rather than active partnership in learning.
With this textbook of endocrine pathophysiology—the product of collaboration
­between 20 Emory medical students and 8 faculty members—Drs Felner and Umpierrez,
together with their coauthors, have provided a shining example of how to involve medi-
cal students in educating themselves and others. The result is a textbook on a complex
subject that perfectly addresses the needs of early phase learners including medical stu-
dents and house staff. A consistent style is maintained throughout the book. Interest is
maintained with clinical vignettes bracketing each chapter at the beginning and end;
learning objectives are clearly outlined, and subsections are consistently organized. The
learner can assess his or her progress with multiple-choice review questions accompa-
nied by answers that are explained in detail. Reference lists consist mainly of appropri-
ately selected review articles in widely available journals.
Many medical school pathophysiology courses are oriented strongly toward pathology
as it occurs in adults. Yet children are not merely small adults and often are afflicted by
distinct diseases. Moreover, they are far less likely than adults to have multiple medical
problems or to suffer the long-term effects of poor lifestyle choices. Indeed, diseases in
children often provide clearer insights into pathophysiology than can be gleaned by stud-
ying adults. This book strikes a particularly good balance between pediatric and adult
pathophysiology by virtue of being edited by both a pediatric endocrinologist (Felner)
and an adult endocrinologist (Umpierrez). Two additional specific chapters on pediatric
endocrinology further ensure an appropriate balance between diseases of adults and
children.
By integrating physiology, embryology, anatomy, and biochemistry with clinical
­endocrinology, this book is suitable for first- or second-year medical students taking an
endocrinology core course, and for third- or fourth-year medical students on clinical rota-
tions, as well as for residents who need a concise review of the subject to care for their
patients. Medical students and residents have a lot that they need to learn, and Drs Felner
and Umpierrez have greatly facilitated the acquisition of the basics of this complex and
important field.

Perrin C White, MD
The Audry Newman Rapoport Distinguished Chair in Pediatric Endocrinology
University of Texas Southwestern Medical Center
Dallas, Texas

vii
Preface

T his book provides a comprehensive introduction to the pathophysiology of the

endocrine system that is specifically geared toward medical students and house
­
­officers. Despite an abundance of endocrinology reference books, their content is primar-
ily oriented to the description of their clinical presentation, diagnosis, and management
of endocrine disorders, with limited information on pathophysiology. This can be over-
whelming to a medical student who has yet to start his or her clinical years. This book
aims to integrate physiology, embryology, anatomy, and biochemistry with the clinical
patient encounters in the hospital and in the outpatient settings. It will assist medical
students and trainees to better understand the physiologic and pathophysiologic condi-
tions of the endocrine system. Emphasis is placed primarily on the basic physiology by
which endocrine diseases develop, in order to facilitate understanding of both clinical
diagnosis and therapy.
The motivation for writing this book was a perceived need by our first- and second-
year medical students at Emory University School of Medicine. When our Medical School
underwent a revision of its curriculum in 2007, with reduction of lecture time and greater
emphasis on small group learning, students required a different approach to learning.
This created an opportunity to develop a book that met the needs of our students in a
new paradigm of learning. We realized that the best resource would be a pathophysiol-
ogy textbook with major input from the students themselves. We believed that faculty
guidance would further enhance each chapter and lend credence to the final product.
By the time these young medical students entered the third and fourth years, they were
capable of writing a cogent and easily readable chapter for their younger colleagues, with
the help of an experienced faculty member.
This book is unique for a number of reasons. It is the first comprehensive endocrine
pathophysiology text written by medical students and faculty. The goal for pairing a stu-
dent with a faculty member was to focus on the needs of the student, while providing the
expertise by the faculty. Since learning is enhanced by testing, every chapter concludes
with a series of multiple-choice questions. Each question is annotated in detail, with the
correct answer and each incorrect answer fully explained.
The first chapter is a basic introduction to endocrinology. The next 12 chapters follow
a head-to-toe sequence as follows: hypothalamus and pituitary gland (Chapter 2), thyroid
gland (Chapter 3), parathyroid gland (Chapters 4 and 5), pancreas (Chapters 6 to 8), o
­ besity
(Chapter 9), adrenal gland (Chapters 10 and 11), and reproduction (­Chapters 12 and 13).
The remaining chapters do not follow an anatomical format, but include important ­areas
of endocrinology including pediatric endocrinology (Chapters 14 and 15), the autoimmune
polyglandular syndromes (Chapter 16), multiple endocrine neoplasia (­Chapter 17), endo-
crine biochemical testing (Chapter 18), stimulation and suppression testing (Chapter 19),
radiologic and nuclear medicine approaches to endocrine diseases (Chapter 20), and surgi-
cal approaches to endocrine disorders (Chapter 21).
It has been a great opportunity for these 20 highly motivated medical students and a
privilege for us to collaborate with them that spanned four graduation classes at Emory.
Their enthusiasm, dedication, and attention to detail, while still involved in their medi-
cal school activities, have made this book a labor of love and created an easily readable
and informative text for all of the students who will follow them. We are grateful to our
faculty colleagues who coauthored each chapter for the time, effort, expertise, and com-
mitment to this book.
ix
x Preface

Finally, a project of this magnitude that required more than 3 years to complete could
not have occurred without the support and patience of our families—for whom we are
both extremely grateful.
We hope that readers of this book will expand their understanding of the endocrine
system, specifically the pathophysiology, and the specialty areas that few medical school
textbooks have addressed. We also hope that this book provides a solid foundation for
further learning and clinical care of your patients.

Eric I. Felner, MD, MSCR

Guillermo E. Umpierrez, MD, FACP, FACE
Contents

List of Contributors v CHAPTER 4

Foreword vii Hypocalcemia 71
Preface ix David L. Gutteridge and Eric I. Felner
Physiology: Calcium and Phosphorus
Homeostasis 72
CHAPTER 1 Hypocalcemia 77
Basic Endocrinology and Hypocalcemia with low or normal
Function 1 parathyroid hormone levels 78
Eric I. Felner and Guillermo Hypocalcemia with Elevated Parathyroid
E. Umpierrez Hormone Levels 84
Endocrine System 2 CHAPTER 5
Endocrine Homeostasis and Feedback
Regulation 8 Hypercalcemia 97
David L. Gutteridge and Eric I. Felner
Hormone Excess, Deficiency, and
Resistance 9 Overview 98
Clinical Endocrinology 9 Hypercalcemia with Normal or Elevated
Parathyroid Hormone 100
CHAPTER 2 Hypercalcemia with Low Parathyroid
Hypothalamic and Pituitary Hormone 105
Disorders 13 Hypercalcemia Associated with other
Sara D. Turbow and Briana C. Patterson Endocrine Conditions 107
Hypercalcemia Associated with
Hypothalamic and Pituitary Gland
Nonendocrine Conditions 108
Physiology 14
Hypopituitarism 19 CHAPTER 6
Pituitary Hormone Excess States 29
Glucose Metabolism and
CHAPTER 3 Hypoglycemia 115
Anna L. Lipowska and Eric I. Felner
Thyroid Pathophysiology 39
Karen E. Schmitz and Eric I. Felner Physiology 116
Hypoglycemia 122
Thyroid Gland Anatomy and Nonketotic Hypoglycemia 123
Embryology 40 Ketotic Hypoglycemia 130
Thyroid Gland Physiology 41
Hypothyroidism 45 CHAPTER 7
Primary Hypothyroidism: Congenital Type 1 Diabetes Mellitus 140
Causes 48 Dane Todd and Guillermo E. Umpierrez
Primary Hypothyroidism: Acquired
Causes 49 Overview 141
Central Hypothyroidism: Congenital CHAPTER 8
Causes 52
Central Hypothyroidism: Acquired Type 2 Diabetes Mellitus 158
Evan T. Tiderington and Guillermo
Causes 52
E. Umpierrez
Hyperthyroidism 53
Thyroid Nodules 62 Overview 159
Thyroid Cancer 63 Metabolic Syndrome 171
xi
xii Contents

CHAPTER 9 CHAPTER 12
Obesity 177 Female Reproductive Disorders 253
Adva Eisenberg, Jason Zhu, Steven A. Gay and Mary S. Dolan
and Andrew B. Muir
Anatomy 254
Epidemiology 178 Embryology 255
Classification 179 Physiology 255
Physiology 179 Menstrual Cycle Abnormalities 262
Causes of Obesity 185 Female Hypogonadism 266
Endocrinologic Complications Congenital Outflow Tract
of Obesity 193 Abnormalities 271
Nonendocrinologic Complications Acquired Outflow Tract
of Obesity 194 Abnormalities 272
Assessment of Obesity 194 Ovarian Disorders 275
Management of Obesity 197 Adrenal Gland Disorders 276

CHAPTER 10 CHAPTER 13
Adrenal Gland Disorders 205 Male Reproductive Disorders 283
Josh A. Hammel and Guillermo David Kappa and Eric I. Felner
E. Umpierrez Physiology 284
Physiology 206 Hypogonadism 287
Adrenal Insufficiency 208 Primary Hypogonadism (Congenital) 289
Primary Adrenal Gland Insufficiency Primary Hypogonadism (Acquired) 293
(Congenital) 211 Central Hypogonadism
Primary Adrenal Gland Insufficiency (Congenital) 295
(Acquired) 215 Central Hypogonadism (Acquired) 297
Central Adrenal Gland Insufficiency Mixed Primary and Central
(Congenital) 218 Hypogonadism 298
Central Adrenal Gland Insufficiency
CHAPTER 14
(Acquired) 219
Acute Adrenal Crisis 220 Pediatric Growth and
Adrenal Gland Excess 220 Development 304
Geoffrey S. Kelly and Eric I. Felner
CHAPTER 11 Physiology 305
Endocrine Hypertension 229 Short Stature: Physiologic Causes 317
Mark H. Adelman and Eric I. Felner Short Stature: Pathologic Causes
(Endocrine) 318
Physiology 230 Short Stature: Pathologic Causes
Adrenal Cortex and Medulla 234 (Nonendocrine) 323
Endocrine States of Hypertension 234 Precocious Puberty 326
Adrenal Cortex Mineralocorticoid
Hormones 234 CHAPTER 15
Adrenal Cortex Glucocorticoid Pediatrics II: Disorders of Sexual
Hormones 239
Differentiation and Ambiguous
Adrenocorticotropic Hormone–
Genitalia 333
Dependent Disorders 240 Robert S. Gerhard and Eric I. Felner
Sodium-Reabsorption Disorders 242
Mutations of the Mineralocorticoid Embryology and Physiology 334
Receptor 243 Ambiguous Genitalia (Virilized
Adrenal Medullary Hormones 243 Females) 336
 Contents xiii

Ambiguous Genitalia (Undervirilized Disorders of the Hypothalamic-

Males) 342 Pituitary-Adrenal Axis 407
Ovotesticular Disease 345 Disorders of Growth Hormone 415
Disorders of the Hypothalamic-
CHAPTER 16 Pituitary-Thyroid Axis 417
Autoimmune Polyglandular Disorders of the Hypothalamic-
Syndromes 352 Pituitary-Gonadal Axis 417
Elicia D. Skelton, Kristina M. Cossen, Disorders of Water Regulation 419
and Eric I. Felner Combined Anterior Pituitary
Testing 420
Autoimmune Polyglandular
Syndromes 353 CHAPTER 20
Physiology: Immune System 353 Nuclear Medicine Approaches
Physiology: Autoimmunity 355 to Endocrinology 426
Autoantibodies in Organ-Specific Stanislav Polioshenko
Autoimmune Diseases 357 and Raghuveer Halkar

CHAPTER 17 Nuclear Medicine 427

Multiple Endocrine Neoplasia Radiation 428
Syndromes 371 Radionuclides 429
Kristina M. Cossen and Eric I. Felner Clinical Applications 431

Multiple Endocrine Neoplasia 372 CHAPTER 21

Surgical Approaches to Endocrine
CHAPTER 18 Disorders 444
Endocrine Assays 389 Meredith Macnamara
Steven C. Kim and Milton R. Brown and Jyotirmay Sharma
Assay Basics 390 Pituitary Gland 445
Factors that Interfere with Thyroid Gland 450
Immunoassays 400 Parathyroid Gland 453
Pancreas 456
CHAPTER 19 Adrenal Gland 458
Stimulation and Suppression
Testing 406 Index 467
Bhavya S. Doshi and Eric I. Felner

Dynamic Endocrine Testing

Overview 407
 Basic Endocrinology and Function 1

Basic Endocrinology and

Function
Eric I. Felner
1
Guillermo E. Umpierrez

CASE
You are called to see a 27-year-old previously healthy man who is in the local emergency
center because he was involved in a motor vehicle accident 1 hour ago. He is conscious but
not completely alert. He is afebrile and his blood pressure is 95/42 mmHg. He is able to move
all of his extremities but complains of significant pain over his right thigh. He is wearing a
medical identification bracelet, but the information has worn off. Due to concern for certain
life-threatening conditions, a series of laboratory tests are ordered. After receiving intrave-
nous fluids, his blood pressure improves to 125/75 mmHg, and he is now alert and oriented.
A radiograph of his right leg shows a midfemur fracture. Prior to entering the operating room,
he informs you that he wears the bracelet because he has a penicillin allergy. He receives pain
medication, and, shortly prior to undergoing surgical reduction of his femur, the operating
room nurse states that his electrolyte panel, blood count, liver function, and kidney function
are normal. He does, however, have an elevated cortisol of 35 mcg/dL (normal = 8 to 22).
Should the surgeon be concerned about operating on a man with an elevated cortisol level?

K nowledge of the anatomy and normal function

of the endocrine glands is crucial to understand-
ing and evaluating the diseases that affect the endo-
CHAPTER OUTLINE
Endocrine System
Endocrine Glands
Hormone–Receptor Interactions
crine system. This chapter reviews the physiology of
Hormone Classification
the endocrine system to help the learner recognize Peptides
appropriate hormone responses to the above clinical Steroid Hormones
scenario. We summarize the appropriate responses to Amine Hormones
a stressful event at the end of the chapter to give the Endocrine Homeostasis and
Feedback Regulation
learner a better understanding of endocrine physiology.
Hormone Excess, Deficiency, and
The remaining chapters focus on pathophysiology.
Resistance
Clinical Endocrinology
OBJECTIVES
1. Define endocrinology.
2. Recognize the components of the endocrine system.
3. Compare and contrast the two major classes of
hormones.
4. List the hormones and the glands that produce them.
2 Chapter 1

ENDOCRINE SYSTEM
The endocrine and nervous systems are the two major organ systems by which cells and
tissues communicate. From a simple perspective, endocrinology can be defined as the
study of glands, the hormones they produce, and the effects of the hormones. Hormones
are secreted directly into circulation and exert their effects by binding to receptors in or
on target cells. Hormones may act within the same cell (autocrine action), on neighbor-
ing cells (paracrine action), or on distal cells (endocrine action).
A more in-depth study of endocrinology encompasses the following: 1) regulation
of hormone synthesis and secretion; 2) hormone–receptor interaction; 3) interaction
between endocrine organs and target tissues; 4) hormone deficiency, excess, or ­resistance;
and 5) regulation of energy metabolism, reproduction, and growth.

Endocrine Glands
The major glands that make up the endocrine system include the hypothalamus, pitu-
itary, thyroid, parathyroid, pancreas, adrenal, ovary, testis, and placenta (Figure 1-1).
Most of these glands produce hormones with a variety of effects. Under physiologic
conditions, hormones are secreted from their glands, bind to a receptor, and initiate their
action. In addition to these glands, nonendocrine organs (i.e., lungs and stomach) as
well as a number of solid tumors can produce hormones.

Pineal

Pituitary
(hypophysis)

Thyroid
Parathyroids
(posterior)

Thymus

Adrenals

Pancreatic
islets

Ovaries

Testes

Figure 1-1. Location of the major endocrine glands. (Cohen BJ, Taylor JJ. Memmler’s The Human Body
in Health and Disease. 11th ed. Baltimore, MD: Wolters Kluwer Health; 2009.)
 Basic Endocrinology and Function 3

Hormone–Receptor Interactions
Hormone receptors are proteins that bind hormones with high affinity and specificity.
Each receptor has a domain that recognizes a specific hormone and a domain that gener-
ates a signal once the hormone is bound (Figure 1-2).
Receptors in the cell membrane, known as cell surface receptors, are usually present
in excess of the amount actually needed for maximum biologic response. Hormones are
present in low concentration in the circulation so that the maximum biologic response of
cell surface receptors is determined by hormone concentration.
Nuclear, or intracellular, receptors, on the other hand, are usually present in low
concentration in the cell, and the number of receptors, rather than the hormone concen-
tration, determines the extent of the biologic response.
Events at the postreceptor level are necessary for normal hormone action. Therefore,
the cells must have a mechanism for release of bound hormone or the destruction of the
hormone–receptor complex to turn off the action of the hormone.

Hormone Classification
Hormones are divided into three major classes: peptides, steroids, and amines. Peptide
hormones include hormones secreted from the hypothalamus, pituitary gland, pancreas,
and placenta (Table 1-1). Steroid hormones include hormones secreted from the adrenal
cortex and gonad (Table 1-2). Amine hormones are synthesized from amino acids and are

Hormone
Second
messenger Surface receptor

Enzyme activity

Cell
response

A
Nucleus

Hormone

Protein
synthesis
Hormone–receptor
complex

Figure 1-2. General mechanisms of hormone action for (A) peptide hormones and (B) steroid hormones.
(Porth CM. Pathophysiology Concepts of Altered Health States. 7th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2005.)
4 Chapter 1

TABLE 1-1. Peptide Hormones

Location/Number of Hormones Names and Abbreviations
Hypothalamus (4) Corticotropin-releasing hormone (CRH),
growth hormone–releasing hormone (GHRH),
gonadotropin-releasing hormone (GnRH),
thyrotropin-releasing hormone (TRH)
Anterior pituitary (6) Adrenocorticotropic hormone (ACTH), ­follicle-
stimulating hormone (FSH), luteinizing hormone
(LH), growth hormone (GH), thyroid-stimulating
hormone (TSH), prolactin (Prl)
Posterior pituitary (2) Antidiuretic hormone (ADH), oxytocin
Pancreatic islets (3) Glucagon, insulin, somatostatin
Calcium-regulating hormones (2) Calcitonin, parathyroid hormone (PTH)
Placenta (2) Human chorionic gonadotropin (hCG), human
placental lactogen (hPL)
Gonad (1) Inhibin
Liver (1) Insulin-like growth factor-1 (IGF-1)

TABLE 1-2. Steroid Hormones

Location/Number of Hormones Names and Abbreviations
Adrenal cortex (4) Aldosterone, cortisol, dehydroepiandrosterone
(DHEA), progesterone
Gonad (5) Dehydroepiandrosterone (DHEA), progesterone,
testosterone, dihydrotestosterone (DHT), estradiol
Kidney (1) Calcitriol (1,25-(OH)2-vitamin D)

TABLE 1-3. Amine Hormones

Location/Number of Hormones Names and Abbreviations
Adrenal medulla (2) Epinephrine, norepinephrine
Thyroid (2) Triiodothyronine (T3), thyroxine (T4)

secreted from the adrenal medulla, hypothalamus, thyroid gland, pineal gland, central
nervous system (CNS), and gastrointestinal (GI) tract (Table 1-3). The characteristics of
these hormones are shown in Table 1-4.

Peptides
Peptide hormone synthesis follows the typical sequence for protein synthesis: gene activa-
tion, DNA transcription, formation of messenger RNA (mRNA), and translation of mRNA
 Basic Endocrinology and Function 5

TABLE 1-4. Hormone Characteristics

Characteristic Peptides Steroids
Hormone synthesis Typical sequence Derived from cholesterol
Travel in circulation Unbound Bound to carrier proteins
Half-life Short Long
Solubility Water Lipid
Delivery Injection or nasal Oral
Membrane permeability No Yes
Receptor binding Cell surface receptors Intracellular receptors
Postreceptor binding action Second messengers Hormone–receptor complex

into protein. In general, an initial large preprohormone enters the endoplasmic reticulum.
A signal sequence is cleaved; the remaining prohormone or hormone undergoes further
modification, is packaged into vesicles, and delivered to the Golgi apparatus. Most of
these hormones are stored in the gland in granules awaiting the appropriate stimulus for
release. Occasionally, peptide hormones are altered further while in the ­storage granules.
Once released into the circulation, most peptide hormones travel unbound to carrier
proteins. As these unbound hormones are subject to degradation by proteases, they tend
to have short half-lives. Glycoproteins are peptides with one or more carbohydrate moi-
eties. They are generally more stable and last longer in circulation than peptides. Due to
the stomach acid and intestinal peptidases in the human GI system, most peptides are
not given orally.
Peptide hormones are water soluble and cannot cross cell membranes easily. They bind
to cell surface receptors, and most activate guanosine triphosphate (GTP)-binding pro-
teins, which serve as on/off switches. Coupling of peptide hormones (first messengers)
to cell surface receptors generates second messengers that set off a cascade of reactions,
leading to changes in the phosphorylation state. For example, a combination of a peptide
hormone with its cell surface receptor activates a GTP-binding protein. This results in
increased or decreased adenylyl cyclase activity, which, in turn, increases or decreases
the cyclic adenosine monophosphate (cAMP) formation. cAMP activates protein kinase
A that initiates a phosphorylation cascade mediated by other kinases (Figure 1-3).
Another second messenger system involves the activation of phospholipase C via
activation from the GTP-binding protein. Phospholipase C generates diacylglycerol that
activates protein kinase C and initiates a phosphorylation cascade mediated by other
kinases. Finally, activation of phospholipase C also generates inositol trisphosphate
(IP3) that increases cytosolic calcium by increasing calcium release from intracellular
­membranes (Figure 1-4).

Steroid Hormones
The basic steroid structure is derived from cholesterol. Steroid and steroid-type hor-
mones are lipid soluble and must be carried in circulation attached to carrier proteins.
They can be given orally, and, because they are lipid soluble, they can cross membranes
and enter all cells.
6 Chapter 1

Effector Receptor
protein 2

Membrane

γ
β α
Effector
G-protein protein 1

A
Transmitter
Effector
protein 2

γ
β α

Activated Gα binds GTP

γ
α
β

Gβγ-stimulated Gα (GTP)-stimulated
effector protein effector protein

γ
α
β

+ PO4
D
Figure 1-3. The basic mode of operation of G proteins. (A) In its inactive state, the α subunit of the
G protein binds GDP. (B) When activated by a G protein–coupled receptor, the GDP is exchanged for GTP.
(C) The activated G protein splits, and both the G (GTP) subunit and the G subunit become available
to activate effector proteins. (D) The G subunit slowly removes phosphate (PO4) from GTP, converting
GTP to GDP and terminating its own activity. (From Bear MF, Connors BW, Parasido, MA. Neuroscience—
Exploring the Brain. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.)

Steroid hormones bind to intracellular receptors that are located in the cytoplasm or
nucleus. The intracellular receptors all have the same basic structure that includes hor-
mone-binding and DNA-binding domains. These domains allow the h ­ ormone–receptor