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3rd Edition

HARRISON’S
TM

Endocrinology
Derived from Harrison’s Principles of Internal Medicine, 18th Edition

Editors
Dan L. Longo, md Anthony S. Fauci, md
Professor of Medicine, Harvard Medical School; Chief, Laboratory of Immunoregulation; Director,
Senior Physician, Brigham and Women’s Hospital; National Institute of Allergy and Infectious Diseases,
Deputy Editor, New England Journal of Medicine, National Institutes of Health, Bethesda, Maryland
Boston, Massachusetts

Dennis L. Kasper, md Stephen L. Hauser, md


William Ellery Channing Professor of Medicine, Robert A. Fishman Distinguished Professor and Chairman,
Professor of Microbiology and Molecular Genetics, Department of Neurology,
Harvard Medical School; Director, Channing Laboratory, University of California, San Francisco,
Department of Medicine, Brigham and Women’s Hospital, San Francisco, California
Boston, Massachusetts

J. Larry Jameson, md, phd Joseph Loscalzo, md, phd


Robert G. Dunlop Professor of Medicine; Hersey Professor of the Theory and Practice of Medicine,
Dean, University of Pennsylvania School of Medicine; Harvard Medical School;
Executive Vice-President of the University of Pennsylvania for the Chairman, Department of Medicine;
Health System, Philadelphia, Pennsylvania Physician-in-Chief, Brigham and Women’s Hospital,
Boston, Massachusetts
3rd Edition

HARRISON’S
TM

Endocrinology

Editor
J. Larry Jameson, MD, PhD
Robert G. Dunlop Professor of Medicine;
Dean, University of Pennsylvania School of Medicine;
Executive Vice-President of the University of Pennsylvania for the
Health System, Philadelphia, Pennsylvania

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Contents

Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii 13 Hirsutism and Virilization . . . . . . . . . . . . . . . . 209


David A. Ehrmann
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
14 Gynecologic Malignancies. . . . . . . . . . . . . . . . 215
  1 Principles of Endocrinology. . . . . . . . . . . . . . . . . 1 Michael V. Seiden
J. Larry Jameson
15 Sexual Dysfunction. . . . . . . . . . . . . . . . . . . . . 224
Kevin T. McVary
section I
Pituitary, Thyroid, and
Adrenal Disorders SECTION III
Diabetes Mellitus, Obesity,
  2 Disorders of the Anterior Pituitary and Lipoprotein Metabolism
Hypothalamus. . . . . . . . . . . . . . . . . . . . . . . . . . 16
Shlomo Melmed, J. Larry Jameson 16 Biology of Obesity . . . . . . . . . . . . . . . . . . . . . 234
Jeffrey S. Flier, Eleftheria Maratos-Flier
  3 Disorders of the Neurohypophysis. . . . . . . . . . . 50
Gary L. Robertson 17 Evaluation and Management of Obesity. . . . . . 244
Robert F. Kushner
  4 Disorders of the Thyroid Gland. . . . . . . . . . . . . 62
J. Larry Jameson, Anthony P. Weetman 18 The Metabolic Syndrome . . . . . . . . . . . . . . . . 253
Robert H. Eckel
  5 Disorders of the Adrenal Cortex. . . . . . . . . . . . 100
Wiebke Arlt 19 Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . . 261
Alvin C. Powers
  6 Pheochromocytoma. . . . . . . . . . . . . . . . . . . . . 127
Hartmut P. H. Neumann 20 Hypoglycemia. . . . . . . . . . . . . . . . . . . . . . . . . 308
Philip E. Cryer, Stephen N. Davis
Section II 21 Disorders of Lipoprotein Metabolism. . . . . . . . 317
Reproductive Endocrinology Daniel J. Rader, Helen H. Hobbs
  7 Disorders of Sex Development. . . . . . . . . . . . . 136
John C. Achermann, J. Larry Jameson SECTION IV
Disorders Affecting Multiple
  8 Disorders of the Testes and Male Reproductive
Endocrine Systems
System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Shalender Bhasin, J. Larry Jameson 22 Endocrine Tumors of the Gastrointestinal
Tract and Pancreas. . . . . . . . . . . . . . . . . . . . . . 342
  9 Testicular Cancer . . . . . . . . . . . . . . . . . . . . . . 172
Robert T. Jensen
Robert J. Motzer, George J. Bosl
23 Disorders Affecting Multiple Endocrine
10 The Female Reproductive System, Infertility,
Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
and Contraception. . . . . . . . . . . . . . . . . . . . . . 178
Camilo Jimenez Vasquez, Robert F. Gagel
Janet E. Hall
24 Endocrine Paraneoplastic Syndromes . . . . . . . . 375
11 Menstrual Disorders and Pelvic Pain. . . . . . . . . 194
J. Larry Jameson
Janet E. Hall
12 The Menopause Transition and
Postmenopausal Hormone Therapy . . . . . . . . . 200
JoAnn E. Manson, Shari S. Bassuk

v
vi Contents

SECTION V 29 Paget’s Disease and Other Dysplasias


Disorders of Bone and of Bone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
Calcium Metabolism Murray J. Favus, Tamara J. Vokes

25 Bone and Mineral Metabolism in Appendix


Health and Disease . . . . . . . . . . . . . . . . . . . . . 384 Laboratory Values of Clinical Importance. . . . . . . . 471
F. Richard Bringhurst, Marie B. Demay, Alexander Kratz, Michael A. Pesce,
Stephen M. Krane, Henry M. Kronenberg Robert C. Basner, Andrew J. Einstein

26 Hypercalcemia and Hypocalcemia . . . . . . . . . . 402 Review and Self-Assessment. . . . . . . . . . . . . . . 487


Sundeep Khosla Charles Wiener, Cynthia D. Brown,
Anna R. Hemnes
27 Disorders of the Parathyroid Gland and
Calcium Homeostasis. . . . . . . . . . . . . . . . . . . . 406
John T. Potts, Jr., Harald Jüppner Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527

28 Osteoporosis. . . . . . . . . . . . . . . . . . . . . . . . . . 439
Robert Lindsay, Felicia Cosman
CONTRIBUTORS

Numbers in brackets refer to the chapter(s) written or co-written by the contributor.


John C. Achermann, MD, PhD Robert H. Eckel, MD
Wellcome Trust Senior Fellow, UCL Institute of Child Health, Professor of Medicine, Division of Endocrinology,
University College London, London, United Kingdom [7] Metabolism, and Diabetes and Division of Cardiology;
Professor of Physiology and Biophysics, Charles A. Boettcher,
Wiebke Arlt, MD, DSc, FRCP, FMedSci II Chair in Atherosclerosis, University of Colorado
Professor of Medicine, Centre for Endocrinology, Diabetes and School of Medicine; Director, Lipid Clinic,
Metabolism, School of Clinical and Experimental Medicine, University of Colorado Hospital, Aurora, Colorado [18]
University of Birmingham; Consultant Endocrinologist,
University Hospital Birmingham, Birmingham, United Kingdom [5] David A. Ehrmann, MD
Professor of Medicine, University of Chicago, Chicago, Illinois [13]
Robert C. Basner, MD
Professor of Clinical Medicine, Division of Pulmonary, Allergy, and Andrew J. Einstein, MD, PhD
Critical Care Medicine, Columbia University College of Physicians Assistant Professor of Clinical Medicine, Columbia University College
and Surgeons, New York, New York [Appendix] of Physicians and Surgeons; Department of Medicine, Division of
Cardiology, Department of Radiology, Columbia University Medical
Shari S. Bassuk, ScD Center and New York-Presbyterian Hospital, New York, New York
Epidemiologist, Division of Preventive Medicine, Brigham and [Appendix]
Women’s Hospital, Boston, Massachusetts [12]
Murray J. Favus, MD
Shalender Bhasin, MD Professor, Department of Medicine, Section of Endocrinology,
Professor of Medicine; Section Chief, Division of Endocrinology, Diabetes, and Metabolism; Director, Bone Program, University of
Diabetes, and Nutrition, Boston University School of Medicine, Chicago Pritzker School of Medicine, Chicago, Illinois [29]
Boston, Massachusetts [8]
Jeffrey S. Flier, MD
George J. Bosl, MD Caroline Shields Walker Professor of Medicine and Dean, Harvard
Professor of Medicine, Weill Cornell Medical College; Chair, Medical School, Boston, Massachusetts [16]
Department of Medicine; Patrick M. Byrne Chair in Clinical
Oncology, Memorial Sloan-Kettering Cancer Center, New York, Robert F. Gagel, MD
New York [9] Professor of Medicine and Head, Division of Internal Medicine,
University of Texas MD Anderson Cancer Center, Houston, Texas [23]
F. Richard Bringhurst, MD
Associate Professor of Medicine, Harvard Medical School; Janet E. Hall, MD, MSc
Physician, Massachusetts General Hospital, Boston, Massachusetts [25] Professor of Medicine, Harvard Medical School; Associate Physician,
Massachusetts General Hospital, Boston, Massachusetts [10, 11]
Cynthia D. Brown, MD
Assistant Professor of Medicine, Division of Pulmonary and Critical Anna R. Hemnes, MD
Care Medicine, University of Virginia, Charlottesville, Virginia Assistant Professor, Division of Allergy, Pulmonary, and Critical
[Review and Self-Assessment] Care Medicine, Vanderbilt University Medical Center, Nashville,
Tennessee [Review and Self-Assessment]
Felicia Cosman, MD
Professor of Clinical Medicine, Columbia University College of Helen H. Hobbs, MD
Physicians and Surgeons, New York [28] Professor of Internal Medicine and Molecular Genetics, University
of Texas Southwestern Medical Center, Dallas, Texas; Investigator,
Philip E. Cryer, MD Howard Hughes Medical Institute, Chevy Chase, Maryland [21]
Irene E. and Michael M. Karl Professor of Endocrinology and
Metabolism in Medicine, Washington University School of Medicine; J. Larry Jameson, MD, PhD
Physician, Barnes-Jewish Hospital, St. Louis, Missouri [20] Robert G. Dunlop Professor of Medicine; Dean, University of
Pennsylvania School of Medicine; Executive Vice President of the
Stephen N. Davis, MBBS, FRCP University of Pennsylvania for the Health System, Philadelphia,
Theodore E. Woodward Professor and Chairman, Pennsylvania [1, 2, 4, 7, 8, 24]
Department of Medicine, University of Maryland
School of Medicine; Physician-in-Chief, University of Maryland Robert T. Jensen, MD
Medical Center, Baltimore, Maryland [20] Digestive Diseases Branch, National Institute of Diabetes;
Digestive and Kidney Diseases, National Institutes of Health,
Marie B. Demay, MD Bethesda, Maryland [22]
Professor of Medicine, Harvard Medical School; Physician,
Massachusetts General Hospital, Boston, Massachusetts [25]

vii
viii Contributors

Harald Jüppner, MD Hartmut P. H. Neumann, MD


Professor of Pediatrics, Endocrine Unit and Pediatric Nephrology Head, Section of Preventative Medicine, Department of Nephrol-
Unit, Massachusetts General Hospital, Boston, Massachusetts [27] ogy and General Medicine, Albert-Ludwigs-University of Freiburg,
Germany [6]
Sundeep Khosla, MD
Professor of Medicine and Physiology, College of Medicine, Michael A. Pesce, PhD
Mayo Clinic, Rochester, Minnesota [26] Professor Emeritus of Pathology and Cell Biology,
Columbia University College of Physicians and Surgeons;
Stephen M. Krane, MD Columbia University Medical Center, New York,
Persis, Cyrus, and Marlow B. Harrison Distinguished Professor of New York [Appendix]
Medicine, Harvard Medical School; Massachusetts General Hospital,
Boston, Massachusetts [25] John T. Potts, Jr., MD
Director of Research, Massachusetts General Hospital,
Alexander Kratz, MD, PhD, MPH Boston, Massachusetts [27]
Associate Professor of Pathology and Cell Biology,
Columbia University College of Physicians and Surgeons; Alvin C. Powers, MD
Director, Core Laboratory, Columbia University Medical Center, Joe C. Davis Chair in Biomedical Science; Professor of Medicine,
New York, New York [Appendix] Molecular Physiology, and Biophysics; Director, Vanderbilt Diabetes
Center; Chief, Division of Diabetes, Endocrinology, and Metabolism,
Henry M. Kronenberg, MD Vanderbilt University School of Medicine, Nashville, Tennessee [19]
Professor of Medicine, Harvard Medical School;
Chief, Endocrine Unit, Massachusetts General Hospital, Daniel J. Rader, MD
Boston, Massachusetts [25] Cooper-McClure Professor of Medicine and Pharmacology, University
of Pennsylvania School of Medicine, Philadelphia, Pennsylvania [21]
Robert F. Kushner, MD, MS
Professor of Medicine, Northwestern University Gary L. Robertson, MD
Feinberg School of Medicine, Chicago, Illinois [17] Senior Research Scientist and Staff Physician, Henry Ford Hospital,
Detroit, Michigan [3]
Robert Lindsay, MD, PhD
Chief, Internal Medicine; Professor of Clinical Medicine, Michael V. Seiden, MD, PhD
Helen Hayes Hospital, West Haverstraw, New York [28] Professor of Medicine; President and CEO,
Fox Chase Cancer Center, Philadelphia, Pennsylvania [14]
JoAnn E. Manson, MD, DrPH
Professor of Medicine and the Michael and Lee Bell Camilo Jimenez Vasquez, MD
Professor of Women’s Health, Harvard Medical School; Assistant Professor, Department of Endocrine Neoplasia and Hormonal
Chief, Division of Preventive Medicine, Brigham and Women’s Disorders, Division of Internal Medicine, University of Texas MD
Hospital, Boston, Massachusetts [12] Anderson Cancer Center, Houston, Texas [23]

Eleftheria Maratos-Flier, MD Tamara J. Vokes, MD, FACP


Associate Professor of Medicine, Harvard Medical School; Professor, Department of Medicine, Section of Endocrinology,
Division of Endocrinology, Beth Israel Deaconess Medical Center, University of Chicago, Chicago, Illinois [29]
Boston, Massachusetts [16]
Anthony P. Weetman, MD
Kevin T. McVary, MD, FACS University of Sheffield School of Medicine, Sheffield,
Professor of Urology, Department of Urology, United Kingdom [4]
Northwestern University Feinberg School of Medicine,
Chicago, Illinois [15] Charles M. Wiener, MD
Dean/CEO Perdana University Graduate School of Medicine,
Shlomo Melmed, MD Selangor, Malaysia; Professor of Medicine and Physiology,
Senior Vice President and Dean of the Medical Faculty, Johns Hopkins University School of Medicine,
Cedars-Sinai Medical Center, Los Angeles, California [2] Baltimore, Maryland [Review and Self-Assessment]

Robert J. Motzer, MD
Professor of Medicine, Weill Cornell Medical College;
Attending Physician, Genitourinary Oncology Service,
Memorial Sloan-Kettering Cancer Center, New York, New York [9]
PREFACE

Harrison’s Principles of Internal Medicine has been a respected Obesity, Lipoprotein Metabolism; (IV) Disorders Affect-
information source for more than 60 years. Over time, ing Multiple Endocrine Systems; and (V) Disorders of
the traditional textbook has evolved to meet the needs of Bone and Calcium Metabolism.
internists, family physicians, nurses, and other health care While Harrison’s Endocrinology is classic in its organiza-
providers. The growing list of Harrison’s products now tion, readers will sense the impact of the scientific re-
includes Harrison’s for the iPad, Harrison’s Manual of Medi- naissance as they explore the individual chapters in each
cine, and Harrison’s Online. This book, Harrison’s Endocrinol- section. In addition to the dramatic advances emanating
ogy, now in its third edition, is a compilation of chapters from genetics and molecular biology, the introduction of
related to the specialty of endocrinology. an unprecedented number of new drugs, particularly for
Our readers consistently note the sophistication of the the management of diabetes and osteoporosis, is trans-
material in the specialty sections of Harrison’s. Our goal forming the field of endocrinology. Numerous recent
was to bring this information to readers in a more com- clinical studies involving common diseases like diabetes,
pact and usable form. Because the topic is more focused, obesity, hypothyroidism, and osteoporosis provide pow-
it was possible to increase the presentation of the mate- erful evidence for medical decision making and treat-
rial by enlarging the text and the tables. We have also ment. These rapid changes in endocrinology are exciting
included a Review and Self-Assessment section that in- for new students of medicine and underscore the need
cludes questions and answers to provoke reflection and for practicing physicians to continuously update their
to provide additional teaching points. knowledge base and clinical skills.
The clinical manifestations of endocrine disorders Our access to information through web-based journals
can usually be explained by considering the physiologic and databases is remarkably efficient. While these sources
role of hormones, which are either deficient or exces- of information are invaluable, the daunting body of data
sive. Thus, a thorough understanding of hormone action creates an even greater need for synthesis and for high-
and principles of hormone feedback arms the clinician lighting important facts. Thus, the preparation of these
with a logical diagnostic approach and a conceptual chapters is a special craft that requires the ability to distill
framework for treatment approaches. The first chapter core information from the ever-expanding knowledge
of the book, Principles of Endocrinology, provides this base. The editors are therefore indebted to our authors,
type of “systems” overview. Using numerous examples a group of internationally recognized authorities who are
of translational research, this introduction links genet- masters at providing a comprehensive overview while
ics, cell biology, and physiology with pathophysiology being able to distill a topic into a concise and interesting
and treatment. The integration of pathophysiology with chapter. We are indebted to our colleagues at McGraw-
clinical management is a hallmark of Harrison’s, and can Hill. Jim Shanahan is a champion for Harrison’s, and these
be found throughout each of the subsequent disease- books were impeccably produced by Kim Davis.
oriented chapters. The book is divided into five main We hope you find this book useful in your effort to
sections that reflect the physiologic roots of endocri- achieve continuous learning on behalf of your patients.
nology: (I) Pituitary, Thyroid, and Adrenal Disorders;
(II) Reproductive Endocrinology; (III) Diabetes Mellitus, J. Larry Jameson, MD, PhD

ix
NOTICE
Medicine is an ever-changing science. As new research and clinical experi-
ence broaden our knowledge, changes in treatment and drug therapy are
required. The authors and the publisher of this work have checked with
sources believed to be reliable in their efforts to provide information that is
complete and generally in accord with the standards accepted at the time of
publication. However, in view of the possibility of human error or changes
in medical sciences, neither the authors nor the publisher nor any other
party who has been involved in the preparation or publication of this work
warrants that the information contained herein is in every respect accurate
or complete, and they disclaim all responsibility for any errors or omissions
or for the results obtained from use of the information contained in this
work. Readers are encouraged to confirm the information contained herein
with other sources. For example and in particular, readers are advised to
check the product information sheet included in the package of each drug
they plan to administer to be certain that the information contained in this
work is accurate and that changes have not been made in the recommended
dose or in the contraindications for administration. This recommendation is
of particular importance in connection with new or infrequently used drugs.

Review and self-assessment questions and answers were taken from Wiener CM,
Brown CD, Hemnes AR (eds). Harrison’s Self-Assessment and Board Review, 18th ed.
New York, McGraw-Hill, 2012, ISBN 978-0-07-177195-5.

The global icons call greater attention to key epidemiologic and clinical differences in the practice of medicine
throughout the world.

The genetic icons identify a clinical issue with an explicit genetic relationship.
cHapter 1
PRINCIPLES OF ENDOCRINOLOGY

J. Larry Jameson

The management of endocrine disorders requires a factors, the central nervous system (CNS) exerts a major
broad understanding of intermediary metabolism, repro- regulatory influence over pituitary hormone secretion
ductive physiology, bone metabolism, and growth. (Chap. 2). The peripheral nervous system stimulates
Accordingly, the practice of endocrinology is intimately the adrenal medulla. The immune and endocrine systems
linked to a conceptual framework for understanding are also intimately intertwined. The adrenal hormone
hormone secretion, hormone action, and principles of cortisol is a powerful immunosuppressant. Cytokines and
feedback control. The endocrine system is evaluated interleukins (ILs) have profound effects on the functions
primarily by measuring hormone concentrations, arm- of the pituitary, adrenal, thyroid, and gonads. Common
ing the clinician with valuable diagnostic information. endocrine diseases such as autoimmune thyroid disease
Most disorders of the endocrine system are amenable to and Type 1 diabetes mellitus are caused by dysregulation
effective treatment once the correct diagnosis is deter- of immune surveillance and tolerance. Less common
mined. Endocrine deficiency disorders are treated with diseases such as polyglandular failure, Addison’s disease,
physiologic hormone replacement; hormone excess and lymphocytic hypophysitis also have an immunologic
conditions, which usually are due to benign glandular basis.
adenomas, are managed by removing tumors surgically The interdigitation of endocrinology with physi-
or reducing hormone levels medically. ologic processes in other specialties sometimes blurs
the role of hormones. For example, hormones play
an important role in maintenance of blood pressure,
scope of eNdocriNology intravascular volume, and peripheral resistance in the
cardiovascular system. Vasoactive substances such as cat-
The specialty of endocrinology encompasses the study of echolamines, angiotensin II, endothelin, and nitric oxide
glands and the hormones they produce. The term endocrine are involved in dynamic changes of vascular tone in
was coined by Starling to contrast the actions of hormones addition to their multiple roles in other tissues. The
secreted internally (endocrine) with those secreted externally heart is the principal source of atrial natriuretic peptide,
(exocrine) or into a lumen, such as the gastrointestinal tract. which acts in classic endocrine fashion to induce natri-
The term hormone, derived from a Greek phrase meaning uresis at a distant target organ (the kidney). Erythropoi-
“to set in motion,” aptly describes the dynamic actions etin, a traditional circulating hormone, is made in the
of hormones as they elicit cellular responses and regulate kidney and stimulates erythropoiesis in bone marrow.
physiologic processes through feedback mechanisms. The kidney is also integrally involved in the renin-
Unlike many other specialties in medicine, it is not angiotensin axis (Chap. 5) and is a primary target of sev-
possible to define endocrinology strictly along anatomic eral hormones, including parathyroid hormone (PTH),
lines. The classic endocrine glands—pituitary, thyroid, mineralocorticoids, and vasopressin. The gastrointesti-
parathyroid, pancreatic islets, adrenals, and gonads— nal tract produces a surprising number of peptide hor-
communicate broadly with other organs through the mones, such as cholecystokinin, ghrelin, gastrin, secretin,
nervous system, hormones, cytokines, and growth fac- and vasoactive intestinal peptide, among many others.
tors. In addition to its traditional synaptic functions, Adipose tissue produces leptin, which acts centrally to
the brain produces a vast array of peptide hormones, control appetite. Carcinoid and islet tumors can secrete
and this has led to the discipline of neuroendocrinol- excessive amounts of these hormones, leading to specific
ogy. Through the production of hypothalamic releasing clinical syndromes (Chap. 22). Many of these gastrointestinal
1
2 hormones are also produced in the CNS, where their Table 1-1
functions are poorly understood. As hormones such as Membrane Receptor Families and Signaling
inhibin, ghrelin, and leptin are discovered, they become Pathways
CHAPTER 1

integrated into the science and practice of medicine on


Signaling
the basis of their functional roles rather than their tissues Receptors Effectors Pathways
of origin.
Characterization of hormone receptors frequently G Protein–Coupled Seven-Transmembrane (GPCR)
reveals unexpected relationships to factors in nonen- b-Adrenergic LH, Gsa, adenylate Stimulation of
docrine disciplines. The growth hormone (GH) and FSH, TSH cyclase cyclic AMP pro-
leptin receptors, for example, are members of the cyto- duction, protein
Principles of Endocrinology

kinase A
kine receptor family. The G protein–coupled receptors Glucagon PTH, Ca2+ channels Calmodulin,
(GPCRs), which mediate the actions of many peptide PTHrP ACTH, Ca2+-dependent
hormones, are used in numerous physiologic processes, MSH GHRH, CRH kinases
including vision, smell, and neurotransmission. a-Adrenergic Giα Inhibition of cyclic
Somatostatin AMP production
Activation of K+,
Ca2+ channels
Nature of Hormones TRH, GnRH Gq, G11 Phospholipase C,
diacylglycerol, IP3,
Hormones can be divided into five major classes:
protein kinase C,
(1) amino acid derivatives such as dopamine, catechol- voltage-dependent
amine, and thyroid hormone; (2) small neuropeptides Ca2+ channels
such as gonadotropin-releasing hormone (GnRH),
Receptor Tyrosine Kinase
thyrotropin-releasing hormone (TRH), somatostatin, and
vasopressin; (3) large proteins such as insulin, luteinizing Insulin, IGF-I Tyrosine MAP kinases, PI
kinases, IRS 3-kinase; AKT,
hormone (LH), and PTH produced by classic endocrine
also known as
glands; (4) steroid hormones such as cortisol and estrogen protein kinase B,
that are synthesized from cholesterol-based precursors; PKB
and (5) vitamin derivatives such as retinoids (vitamin A) EGF, NGF Tyrosine Raf, MAP kinases,
and vitamin D. A variety of peptide growth factors, most of kinases, ras RSK
which act locally, share actions with hormones. As a rule, Cytokine Receptor–Linked Kinase
amino acid derivatives and peptide hormones interact GH, PRL JAK, tyrosine STAT, MAP kinase,
with cell-surface membrane receptors. Steroids, thyroid kinases PI 3-kinase,
hormones, vitamin D, and retinoids are lipid soluble and IRS-1
interact with intracellular nuclear receptors. Serine Kinase
Activin, TGF-b, MIS Serine kinase Smads
Hormone and Receptor Families
Abbreviations: IP3, inositol triphosphate; IRS, insulin receptor sub-
Many hormones and receptors can be grouped into fami- strates; MAP, mitogen-activated protein; MSH, melanocyte-stimulating
lies, reflecting their structural similarities (Table 1-1). hormone; NGF, nerve growth factor; PI, phosphatidylinositol; RSK,
The evolution of these families generates diverse but ribosomal S6 kinase; TGF-b, transforming growth factor b. For all other
abbreviations, see text.
highly selective pathways of hormone action. Recogni-
tion of these relationships allows extrapolation of infor-
mation gleaned from one hormone or receptor to other this family arose from a common ancestral gene, prob-
family members. ably by gene duplication and subsequent divergence to
The glycoprotein hormone family, consisting of evolve new biologic functions.
thyroid-stimulating hormone (TSH), follicle-stimulating As the hormone families enlarge and diverge, their
hormone (FSH), LH, and human chorionic gonado- receptors must co-evolve if new biologic functions
tropin (hCG), illustrates many features of related hor- are to be derived. Related GPCRs, for example, have
mones. The glycoprotein hormones are heterodimers evolved for each of the glycoprotein hormones. These
that have the α subunit in common; the β subunits are receptors are structurally similar, and each is coupled to
distinct and confer specific biologic actions. The overall the Gsα signaling pathway. However, there is minimal
three-dimensional architecture of the β subunits is simi- overlap of hormone binding. For example, TSH binds
lar, reflecting the locations of conserved disulfide bonds with high specificity to the TSH receptor but interacts
that restrain protein conformation. The cloning of the minimally with the LH or the FSH receptor. None-
β-subunit genes from multiple species suggests that theless, there can be subtle physiologic consequences
of hormone cross-reactivity with other receptors. Very effects (sodium retention, potassium wasting). This 3
high levels of hCG during pregnancy stimulate the TSH phenomenon is particularly pronounced in ectopic
receptor and increase thyroid hormone levels, resulting adrenocorticotropic hormone (ACTH) syndromes

CHAPTER 1
in a compensatory decrease in TSH. (Chap. 5). Another example of relaxed nuclear recep-
Insulin and insulin-like growth factor I (IGF-I) and tor specificity involves the estrogen receptor, which can
IGF-II have structural similarities that are most appar- bind an array of compounds, some of which have little
ent when precursor forms of the proteins are compared. apparent structural similarity to the high-affinity ligand
In contrast to the high degree of specificity seen with estradiol. This feature of the estrogen receptor makes
the glycoprotein hormones, there is moderate cross-talk it susceptible to activation by “environmental estro-
among the members of the insulin/IGF family. High gens” such as resveratrol, octylphenol, and many other

Principles of Endocrinology
concentrations of an IGF-II precursor produced by cer- aromatic hydrocarbons. However, this lack of specific-
tain tumors (e.g., sarcomas) can cause hypoglycemia, ity provides an opportunity to synthesize a remarkable
partly because of binding to insulin and IGF-I receptors series of clinically useful antagonists (e.g., tamoxifen)
(Chap. 24). High concentrations of insulin also bind to and selective estrogen response modulators (SERMs)
the IGF-I receptor, perhaps accounting for some of the such as raloxifene. These compounds generate distinct
clinical manifestations seen in severe insulin resistance. conformations that alter receptor interactions with com-
Another important example of receptor cross-talk is ponents of the transcription machinery (see below),
seen with PTH and parathyroid hormone–related pep- thereby conferring their unique actions.
tide (PTHrP) (Chap. 27). PTH is produced by the
parathyroid glands, whereas PTHrP is expressed at high
Hormone Synthesis and Processing
levels during development and by a variety of tumors
(Chap. 24). These hormones have amino acid sequence The synthesis of peptide hormones and their receptors
similarity, particularly in their amino-terminal regions. occurs through a classic pathway of gene expression:
Both hormones bind to a single PTH receptor that is transcription → mRNA → protein → posttranslational
expressed in bone and kidney. Hypercalcemia and hypo- protein processing → intracellular sorting, followed by
phosphatemia therefore may result from excessive produc- membrane integration or secretion.
tion of either hormone, making it difficult to distinguish Many hormones are embedded within larger precur-
hyperparathyroidism from hypercalcemia of malignancy sor polypeptides that are proteolytically processed to yield
solely on the basis of serum chemistries. However, sensi- the biologically active hormone. Examples include pro­
tive and specific assays for PTH and PTHrP now allow opiomelanocortin (POMC) → ACTH; proglucagon →
these disorders to be distinguished more readily. glucagon; proinsulin → insulin; and pro-PTH → PTH,
Based on their specificities for DNA binding sites, among others. In many cases, such as POMC and pro-
the nuclear receptor family can be subdivided into type glucagon, these precursors generate multiple biologically
1 receptors (GR, MR, AR, ER, PR) that bind ste- active peptides. It is provocative that hormone precursors
roids and type 2 receptors (TR, VDR, RAR, PPAR) are typically inactive, presumably adding an additional
that bind thyroid hormone, vitamin D, retinoic acid, level of regulatory control. Prohormone conversion
or lipid derivatives. Certain functional domains in occurs not only for peptide hormones but also for certain
nuclear receptors, such as the zinc finger DNA-binding steroids (testosterone → dihydrotestosterone) and thyroid
domains, are highly conserved. However, selective amino hormone (T4 → T3).
acid differences within this domain confer DNA Hormone precursor processing is intimately linked
sequence specificity. The hormone-binding domains to intracellular sorting pathways that transport proteins
are more variable, providing great diversity in the array to appropriate vesicles and enzymes, resulting in specific
of small molecules that bind to different nuclear recep- cleavage steps, followed by protein folding and trans-
tors. With few exceptions, hormone binding is highly location to secretory vesicles. Hormones destined for
specific for a single type of nuclear receptor. One secretion are translocated across the endoplasmic retic-
exception involves the glucocorticoid and mineralocor- ulum under the guidance of an amino-terminal signal
ticoid receptors. Because the mineralocorticoid recep- sequence that subsequently is cleaved. Cell-surface recep-
tor also binds glucocorticoids with high affinity, an tors are inserted into the membrane via short segments
enzyme (11β-hydroxysteroid dehydrogenase) in renal of hydrophobic amino acids that remain embedded
tubular cells inactivates glucocorticoids, allowing selec- within the lipid bilayer. During translocation through
tive responses to mineralocorticoids such as aldosterone. the Golgi and endoplasmic reticulum, hormones and
However, when very high glucocorticoid concentra- receptors are also subject to a variety of posttranslational
tions occur, as in Cushing’s syndrome, the glucocorti- modifications, such as glycosylation and phosphoryla-
coid degradation pathway becomes saturated, allowing tion, which can alter protein conformation, modify cir-
excessive cortisol levels to exert mineralocorticoid culating half-life, and alter biologic activity.
4 Synthesis of most steroid hormones is based on mod- highly specific for the thyroid gland. Its prolonged half-
ifications of the precursor, cholesterol. Multiple regu- life accounts for relatively constant serum levels even
lated enzymatic steps are required for the synthesis of though TSH is secreted in discrete pulses.
CHAPTER 1

testosterone (Chap. 8), estradiol (Chap. 10), cortisol An understanding of circulating hormone half-life is
(Chap. 5), and vitamin D (Chap. 25). This large num- important for achieving physiologic hormone replace-
ber of synthetic steps predisposes to multiple genetic ment, as the frequency of dosing and the time required
and acquired disorders of steroidogenesis. to reach steady state are intimately linked to rates of
Although endocrine genes contain regulatory DNA hormone decay. T4, for example, has a circulating half-
elements similar to those found in many other genes, life of 7 days. Consequently, >1 month is required
their exquisite control by other hormones also neces- to reach a new steady state, and single daily doses are
Principles of Endocrinology

sitates the presence of specific hormone response ele- sufficient to achieve constant hormone levels. T3, in
ments. For example, the TSH genes are repressed contrast, has a half-life of 1 day. Its administration is
directly by thyroid hormones acting through the thy- associated with more dynamic serum levels, and it must
roid hormone receptor (TR), a member of the nuclear be administered two to three times per day. Similarly,
receptor family. Steroidogenic enzyme gene expression synthetic glucocorticoids vary widely in their half-lives;
requires specific transcription factors, such as steroido- those with longer half-lives (e.g., dexamethasone) are
genic factor-1 (SF-1), acting in conjunction with signals associated with greater suppression of the hypothalamic-
transmitted by trophic hormones (e.g., ACTH or LH). pituitary-adrenal (HPA) axis. Most protein hormones
For some hormones, substantial regulation occurs at [e.g., ACTH, GH, prolactin (PRL), PTH, LH] have
the level of translational efficiency. Insulin biosynthesis, relatively short half-lives (<20 min), leading to sharp
although it requires ongoing gene transcription, is regu- peaks of secretion and decay. The only accurate way to
lated primarily at the translational level in response to profile the pulse frequency and amplitude of these hor-
elevated levels of glucose or amino acids. mones is to measure levels in frequently sampled blood
(every 10 min or less) over long durations (8–24 h).
Because this is not practical in a clinical setting, an alter-
Hormone Secretion, Transport, and
native strategy is to pool three to four samples drawn
Degradation
at about 30-min intervals or interpret the results in the
The circulating level of a hormone is determined by its context of a relatively wide normal range. Rapid hor-
rate of secretion and its circulating half-life. After protein mone decay is useful in certain clinical settings. For
processing, peptide hormones (GnRH, insulin, GH) are example, the short half-life of PTH allows the use of
stored in secretory granules. As these granules mature, they intraoperative PTH determinations to confirm success-
are poised beneath the plasma membrane for imminent ful removal of an adenoma. This is particularly valuable
release into the circulation. In most instances, the stimulus diagnostically when there is a possibility of multicentric
for hormone secretion is a releasing factor or neural sig- disease or parathyroid hyperplasia, as occurs with mul-
nal that induces rapid changes in intracellular calcium con- tiple endocrine neoplasia (MEN) or renal insufficiency.
centrations, leading to secretory granule fusion with the Many hormones circulate in association with serum-
plasma membrane and release of its contents into the extra- binding proteins. Examples include (1) T4 and T3 bind-
cellular environment and bloodstream. Steroid hormones, ing to thyroxine-binding globulin (TBG), albumin,
in contrast, diffuse into the circulation as they are synthe- and thyroxine-binding prealbumin (TBPA); (2) cortisol
sized. Thus, their secretory rates are closely aligned with binding to cortisol-binding globulin (CBG); (3) andro-
rates of synthesis. For example, ACTH and LH induce gen and estrogen binding to sex hormone–binding
steroidogenesis by stimulating the activity of steroidogenic globulin (SHBG) [also called testosterone-binding glob­
acute regulatory (StAR) protein (transports cholesterol into ulin (TeBG)]; (4) IGF-I and -II binding to multiple
the mitochondrion) along with other rate-limiting steps IGF-binding proteins (IGFBPs); (5) GH interactions
(e.g., cholesterol side-chain cleavage enzyme, CYP11A1) with GH-binding protein (GHBP), a circulating frag-
in the steroidogenic pathway. ment of the GH receptor extracellular domain; and
Hormone transport and degradation dictate the (6) activin binding to follistatin. These interactions
rapidity with which a hormonal signal decays. Some provide a hormonal reservoir, prevent otherwise rapid
hormonal signals are evanescent (e.g., somatostatin), degradation of unbound hormones, restrict hormone
whereas others are longer-lived (e.g., TSH). Because access to certain sites (e.g., IGFBPs), and modulate the
somatostatin exerts effects in virtually every tissue, a unbound, or “free,” hormone concentrations. Although
short half-life allows its concentrations and actions to be a variety of binding protein abnormalities have been
controlled locally. Structural modifications that impair identified, most have few clinical consequences aside
somatostatin degradation have been useful for generat- from creating diagnostic problems. For example, TBG
ing long-acting therapeutic analogues such as octreo- deficiency can reduce total thyroid hormone levels
tide (Chap. 2). In contrast, the actions of TSH are greatly, but the free concentrations of T4 and T3 remain
normal. Liver disease and certain medications can also 5
influence binding protein levels (e.g., estrogen increases
Hormone Action through
TBG) or cause displacement of hormones from bind- Receptors

CHAPTER 1
ing proteins (e.g., salsalate displaces T4 from TBG). In Receptors for hormones are divided into two major
general, only unbound hormone is available to inter- classes: membrane and nuclear. Membrane receptors primar-
act with receptors and thus elicit a biologic response. ily bind peptide hormones and catecholamines. Nuclear
Short-term perturbations in binding proteins change receptors bind small molecules that can diffuse across the
the free hormone concentration, which in turn induces cell membrane, such as steroids and vitamin D. Certain
compensatory adaptations through feedback loops. general principles apply to hormone-receptor interac-
SHBG changes in women are an exception to this self-

Principles of Endocrinology
tions regardless of the class of receptor. Hormones bind
correcting mechanism. When SHBG decreases because to receptors with specificity and an affinity that generally
of insulin resistance or androgen excess, the unbound coincides with the dynamic range of circulating hormone
testosterone concentration is increased, potentially lead- concentrations. Low concentrations of free hormone
ing to hirsutism (Chap. 13). The increased unbound (usually 10−12 to 10−9 M) rapidly associate and dissoci-
testosterone level does not result in an adequate com- ate from receptors in a bimolecular reaction such that
pensatory feedback correction because estrogen, not testos- the occupancy of the receptor at any given moment is
terone, is the primary regulator of the reproductive axis. a function of hormone concentration and the receptor’s
An additional exception to the unbound hormone affinity for the hormone. Receptor numbers vary greatly
hypothesis involves megalin, a member of the low-density in different target tissues, providing one of the major
lipoprotein (LDL) receptor family that serves as an determinants of specific cellular responses to circulating
endocytotic receptor for carrier-bound vitamins A and hormones. For example, ACTH receptors are located
D and SHBG-bound androgens and estrogens. After almost exclusively in the adrenal cortex, and FSH recep-
internalization, the carrier proteins are degraded in lyso- tors are found predominantly in the gonads. In contrast,
somes and release their bound ligands within the cells. insulin and TRs are widely distributed, reflecting the
Membrane transporters have also been identified for need for metabolic responses in all tissues.
thyroid hormones.
Hormone degradation can be an important mecha-
nism for regulating concentrations locally. As noted Membrane Receptors
above, 11β-hydroxysteroid dehydrogenase inactivates
glucocorticoids in renal tubular cells, preventing actions Membrane receptors for hormones can be divided into
through the mineralocorticoid receptor. Thyroid hor- several major groups: (1) seven transmembrane GPCRs,
mone deiodinases convert T4 to T3 and can inactivate (2) tyrosine kinase receptors, (3) cytokine receptors,
T3. During development, degradation of retinoic acid and (4) serine kinase receptors (Fig. 1-1). The seven
by Cyp26b1 prevents primordial germ cells in the male transmembrane GPCR family binds a remarkable array of
from entering meiosis, as occurs in the female ovary. hormones, including large proteins (e.g., LH, PTH),

G protein–coupled Insulin/IGF-I
Cytokine/GH/PRL Seven transmembrane Tyrosine kinase

Activin/MIS/BMP Growth factor


TGF-β Serine kinase Tyrosine kinase

Membrane

JAK/STAT G protein
PKA, PKC
Ras/Raf
MAPK Figure 1-1
Smads
Membrane receptor signaling. MAPK,
mitogen-activated protein kinase; PKA, -C,
Nucleus protein kinase A, C; TGF, transforming
growth factor. For other abbreviations,
Target gene
see text.
6 small peptides (e.g., TRH, somatostatin), catechol- intracellular kinases—the Janus kinases (JAKs), which
amines (epinephrine, dopamine), and even minerals phosphorylate members of the signal transduction and
(e.g., calcium). The extracellular domains of GPCRs activators of transcription (STAT) family—as well as
CHAPTER 1

vary widely in size and are the major binding sites for with other signaling pathways (Ras, PI3-K, MAPK).
large hormones. The transmembrane-spanning regions The activated STAT proteins translocate to the nucleus
are composed of hydrophobic α-helical domains that and stimulate expression of target genes.
traverse the lipid bilayer. Like some channels, these The serine kinase receptors mediate the actions of activ-
domains are thought to circularize and form a hydro- ins, transforming growth factor β, müllerian-inhibiting
phobic pocket into which certain small ligands fit. Hor- substance (MIS, also known as anti-müllerian hormone,
mone binding induces conformational changes in these AMH), and bone morphogenic proteins (BMPs). This
Principles of Endocrinology

domains, transducing structural changes to the intracel- family of receptors (consisting of type I and II subunits)
lular domain, which is a docking site for G proteins. signals through proteins termed smads (fusion of terms
The large family of G proteins, so named because for Caenorhabditis elegans sma + mammalian mad). Like
they bind guanine nucleotides [guanosine triphosphate the STAT proteins, the smads serve a dual role of trans-
(GTP), guanosine diphosphate (GDP)], provides great ducing the receptor signal and acting as transcription
diversity for coupling receptors to different signaling factors. The pleomorphic actions of these growth factors
pathways. G proteins form a heterotrimeric complex dictate that they act primarily in a local (paracrine or
that is composed of various α and βγ subunits. The α autocrine) manner. Binding proteins such as follistatin
subunit contains the guanine nucleotide–binding site (which binds activin and other members of this fam-
and hydrolyzes GTP → GDP. The βγ subunits are ily) function to inactivate the growth factors and restrict
tightly associated and modulate the activity of the α their distribution.
subunit as well as mediating their own effector signal-
ing pathways. G protein activity is regulated by a cycle
that involves GTP hydrolysis and dynamic interactions
Nuclear Receptors
between the α and αβ subunits. Hormone binding to
the receptor induces GDP dissociation, allowing Gα to The family of nuclear receptors has grown to nearly
bind GTP and dissociate from the αβ complex. Under 100 members, many of which are still classified as orphan
these conditions, the Gα subunit is activated and medi- receptors because their ligands, if they exist, have not
ates signal transduction through various enzymes, such been identified (Fig. 1-2). Otherwise, most nuclear
as adenylate cyclase and phospholipase C. GTP hydro- receptors are classified on the basis of the nature of their
lysis to GDP allows reassociation with the αβ subunits ligands. Though all nuclear receptors ultimately act to
and restores the inactive state. As described below, a increase or decrease gene transcription, some (e.g., glu-
variety of endocrinopathies result from G protein muta- cocorticoid receptor) reside primarily in the cytoplasm,
tions or from mutations in receptors that modify their whereas others (e.g., thyroid hormone receptor) are
interactions with G proteins. G proteins interact with always located in the nucleus. After ligand binding, the
other cellular proteins, including kinases, channels, G cytoplasmically localized receptors translocate to the nu-
protein–coupled receptor kinases (GRKs), and arrestins, cleus. There is growing evidence that certain nuclear
that mediate signaling as well as receptor desensitization receptors (e.g., glucocorticoid, estrogen) can also act at
and recycling. the membrane or in the cytoplasm to activate or repress
The tyrosine kinase receptors transduce signals for insulin signal transduction pathways, providing a mechanism for
and a variety of growth factors, such as IGF-I, epider- cross-talk between membrane and nuclear receptors.
mal growth factor (EGF), nerve growth factor, platelet- The structures of nuclear receptors have been studied
derived growth factor, and fibroblast growth factor. The extensively, including by x-ray crystallography. The DNA
cysteine-rich extracellular ligand-binding domains con- binding domain, consisting of two zinc fingers, contacts
tain growth factor binding sites. After ligand binding, specific DNA recognition sequences in target genes. Most
this class of receptors undergoes autophosphorylation, nuclear receptors bind to DNA as dimers. Consequently,
inducing interactions with intracellular adaptor proteins each monomer recognizes an individual DNA motif,
such as Shc and insulin receptor substrates. In the case referred to as a “half-site.” The steroid receptors, including
of the insulin receptor, multiple kinases are activated, the glucocorticoid, estrogen, progesterone, and androgen
including the Raf-Ras-MAPK and the Akt/protein receptors, bind to DNA as homodimers. Consistent with
kinase B pathways. The tyrosine kinase receptors play a this twofold symmetry, their DNA recognition half-sites
prominent role in cell growth and differentiation as well are palindromic. The thyroid, retinoid, peroxisome pro-
as in intermediary metabolism. liferator activated, and vitamin D receptors bind to DNA
The GH and PRL receptors belong to the cytokine preferentially as heterodimers in combination with retinoid
receptor family. Analogous to the tyrosine kinase recep- X receptors (RXRs). Their DNA half-sites are arranged as
tors, ligand binding induces receptor interaction with direct repeats.
Homodimer Steroid Heterodimer Receptors Orphan Receptors 7
Receptors
ER, AR, PR, GR TR, VDR, RAR, PPAR SF-1, DAX-1, HNF4α

CHAPTER 1
Ligands

Figure 1-2
Nuclear receptor signaling. ER,
DNA response estrogen receptor; AR, androgen recep-
elements
tor; PR, progesterone receptor; GR,

Principles of Endocrinology
Ligand induces Ligand dissociates corepressors Constitutive activator glucocorticoid receptor; TR, thyroid
coactivator binding and induces coactivator binding or repressor binding
hormone receptor; VDR, vitamin D
Gene Expression

receptor; RAR, retinoic acid receptor;


Activated Activated Activated
PPAR, peroxisome proliferator acti-
Silenced vated receptor; SF-1, steroidogenic
factor-1; DAX, dosage-sensitive sex-
reversal, adrenal hypoplasia congen-
– + Basal – + – + ita, X-chromosome; HNF4α, hepatic
Hormone Hormone Receptor nuclear factor 4α.

The carboxy-terminal hormone-binding domain these are dynamic events that involve relatively rapid
mediates transcriptional control. For type II recep- (e.g., 30–60 min) cycling of transcription complexes
tors such as thyroid hormone receptor (TR) and reti- on any specific target gene.
noic acid receptor (RAR), co-repressor proteins bind
to the receptor in the absence of ligand and silence
gene transcription. Hormone binding induces con- Functions of Hormones
formational changes, triggering the release of co-
repressors and inducing the recruitment of coactiva- The functions of individual hormones are described in
tors that stimulate transcription. Thus, these receptors detail in subsequent chapters. Nevertheless, it is useful
are capable of mediating dramatic changes in the to illustrate how most biologic responses require inte-
level of gene activity. Certain disease states are asso- gration of several different hormone pathways. The
ciated with defective regulation of these events. For physiologic functions of hormones can be divided into
example, mutations in the TR prevent co-repressor three general areas: (1) growth and differentiation,
dissociation, resulting in a dominant form of hor- (2) maintenance of homeostasis, and (3) reproduction.
mone resistance (Chap. 4). In promyelocytic leu-
kemia, fusion of RARα to other nuclear proteins Growth
causes aberrant gene silencing and prevents normal Multiple hormones and nutritional factors mediate the
cellular differentiation. Treatment with retinoic acid complex phenomenon of growth (Chap. 2). Short
reverses this repression and allows cellular differen- stature may be caused by GH deficiency, hypothyroid-
tiation and apoptosis to occur. Most type 1 steroid ism, Cushing’s syndrome, precocious puberty, mal-
receptors interact weakly with co-repressors, but nutrition, chronic illness, or genetic abnormalities that
ligand binding still induces interactions with an array affect the epiphyseal growth plates (e.g., FGFR3 and
of coactivators. X-ray crystallography shows that var- SHOX mutations). Many factors (GH, IGF-I, thyroid
ious SERMs induce distinct estrogen receptor con- hormones) stimulate growth, whereas others (sex ste-
formations. The tissue-specific responses caused by roids) lead to epiphyseal closure. Understanding these
these agents in breast, bone, and uterus appear to hormonal interactions is important in the diagnosis and
reflect distinct interactions with coactivators. The management of growth disorders. For example, delay-
receptor-coactivator complex stimulates gene tran- ing exposure to high levels of sex steroids may enhance
scription by several pathways, including (1) recruit- the efficacy of GH treatment.
ment of enzymes (histone acetyl transferases) that
modify chromatin structure, (2) interactions with Maintenance of Homeostasis
additional transcription factors on the target gene,
Though virtually all hormones affect homeostasis, the
and (3) direct interactions with components of the
most important among them are the following:
general transcription apparatus to enhance the rate of
RNA polymerase II–mediated transcription. Studies 1. Thyroid hormone—controls about 25% of basal
of nuclear receptor–mediated transcription show that metabolism in most tissues
8 2. Cortisol—exerts a permissive action for many hor- during puberty (Chaps. 8 and 10); (3) conception, preg-
mones in addition to its own direct effects nancy, lactation, and child rearing (Chap. 10); and
3. PTH—regulates calcium and phosphorus levels (4) cessation of reproductive capability at menopause
CHAPTER 1

4. Vasopressin—regulates serum osmolality by control- (Chap. 12). Each of these stages involves an orchestrated
ling renal free-water clearance interplay of multiple hormones, a phenomenon well
5. Mineralocorticoids—control vascular volume and illustrated by the dynamic hormonal changes that occur
serum electrolyte (Na+, K+) concentrations during each 28-day menstrual cycle. In the early follic-
6. Insulin—maintains euglycemia in the fed and fasted ular phase, pulsatile secretion of LH and FSH stimulates
states the progressive maturation of the ovarian follicle. This
results in gradually increasing estrogen and progesterone
Principles of Endocrinology

The defense against hypoglycemia is an impressive


levels, leading to enhanced pituitary sensitivity to GnRH,
example of integrated hormone action (Chap. 20). In
which, when combined with accelerated GnRH secre-
response to the fasted state and falling blood glucose,
tion, triggers the LH surge and rupture of the mature fol-
insulin secretion is suppressed, resulting in decreased
licle. Inhibin, a protein produced by the granulosa cells,
glucose uptake and enhanced glycogenolysis, lipoly-
enhances follicular growth and feeds back to the pitu-
sis, proteolysis, and gluconeogenesis to mobilize fuel
itary to selectively suppress FSH without affecting LH.
sources. If hypoglycemia develops (usually from insulin
Growth factors such as EGF and IGF-I modulate follicu-
administration or sulfonylureas), an orchestrated coun-
lar responsiveness to gonadotropins. Vascular endothelial
terregulatory response occurs—glucagon and epineph-
growth factor and prostaglandins play a role in follicle
rine rapidly stimulate glycogenolysis and gluconeogen-
vascularization and rupture.
esis, whereas GH and cortisol act over several hours to
During pregnancy, the increased production of pro-
raise glucose levels and antagonize insulin action.
lactin, in combination with placentally derived steroids
Although free-water clearance is controlled primar-
(e.g., estrogen and progesterone), prepares the breast for
ily by vasopressin, cortisol and thyroid hormone are
lactation. Estrogens induce the production of progester-
also important for facilitating renal tubular responses
one receptors, allowing for increased responsiveness to
to vasopressin (Chap. 3). PTH and vitamin D func-
progesterone. In addition to these and other hormones
tion in an interdependent manner to control calcium
involved in lactation, the nervous system and oxytocin
metabolism (Chap. 25). PTH stimulates renal synthe­
mediate the suckling response and milk release.
sis of 1,25-dihydroxyvitamin D, which increases calcium
absorption in the gastrointestinal tract and enhances
PTH action in bone. Increased calcium, along with
vitamin D, feeds back to suppress PTH, thus maintain- Hormonal Feedback Regulatory
ing calcium balance. Systems
Depending on the severity of a specific stress and Feedback control, both negative and positive, is a funda-
whether it is acute or chronic, multiple endocrine and mental feature of endocrine systems. Each of the major
cytokine pathways are activated to mount an appro- hypothalamic-pituitary-hormone axes is governed by
priate physiologic response. In severe acute stress such negative feedback, a process that maintains hormone
as trauma or shock, the sympathetic nervous system is levels within a relatively narrow range (Chap. 2).
activated and catecholamines are released, leading to Examples of hypothalamic-pituitary negative feedback
increased cardiac output and a primed musculoskeletal include (1) thyroid hormones on the TRH-TSH axis,
system. Catecholamines also increase mean blood pres- (2) cortisol on the CRH-ACTH axis, (3) gonadal ste-
sure and stimulate glucose production. Multiple stress- roids on the GnRH-LH/FSH axis, and (4) IGF-I on
induced pathways converge on the hypothalamus, the growth hormone–releasing hormone (GHRH)-GH
stimulating several hormones, including vasopressin and axis (Fig. 1-3). These regulatory loops include both
corticotropin-releasing hormone (CRH). These hor- positive (e.g., TRH, TSH) and negative (e.g., T4, T3)
mones, in addition to cytokines (tumor necrosis factor α, components, allowing for exquisite control of hormone
IL-2, IL-6), increase ACTH and GH production. levels. As an example, a small reduction of thyroid hor-
ACTH stimulates the adrenal gland, increasing cortisol, mone triggers a rapid increase of TRH and TSH secre-
which in turn helps sustain blood pressure and dampen tion, resulting in thyroid gland stimulation and increased
the inflammatory response. Increased vasopressin acts to thyroid hormone production. When thyroid hormone
conserve free water. reaches a normal level, it feeds back to suppress TRH
and TSH, and a new steady state is attained. Feedback
regulation also occurs for endocrine systems that do not
Reproduction
involve the pituitary gland, such as calcium feedback
The stages of reproduction include (1) sex determination on PTH, glucose inhibition of insulin secretion, and
during fetal development (Chap. 7); (2) sexual maturation leptin feedback on the hypothalamus. An understanding
control are difficult to document because local growth 9
Hypothalamus factor concentrations cannot be measured readily.
CNS Anatomic relationships of glandular systems also

CHAPTER 1
greatly influence hormonal exposure: the physical orga-
Releasing nization of islet cells enhances their intercellular commu-
factors + – nication; the portal vasculature of the hypothalamic-pitu-
itary system exposes the pituitary to high concentrations
of hypothalamic releasing factors; testicular seminiferous
tubules gain exposure to high testosterone levels pro-
duced by the interdigitated Leydig cells; the pancreas

Principles of Endocrinology
Pituitary – receives nutrient information and local exposure to pep-
tide hormones (incretins) from the gastrointestinal tract;
Target hormone
feedback and the liver is the proximal target of insulin action
Trophic
hormones + inhibition because of portal drainage from the pancreas.

Hormonal Rhythms
The feedback regulatory systems described above are
superimposed on hormonal rhythms that are used for
adaptation to the environment. Seasonal changes, the
Adrenal Gonads
daily occurrence of the light-dark cycle, sleep, meals,
Thyroid
and stress are examples of the many environmen-
tal events that affect hormonal rhythms. The menstrual
Figure 1-3 cycle is repeated on average every 28 days, reflecting the
Feedback regulation of endocrine axes. CNS, central ner- time required to follicular maturation and ovulation
vous system. (Chap. 10). Essentially all pituitary hormone rhythms
are entrained to sleep and to the circadian cycle, gener-
of feedback regulation provides important insights into ating reproducible patterns that are repeated approxi-
endocrine testing paradigms (see below). mately every 24 h. The HPA axis, for example, exhibits
Positive feedback control also occurs but is not well characteristic peaks of ACTH and cortisol production in
understood. The primary example is estrogen-mediated the early morning, with a nadir during the night. Rec-
stimulation of the midcycle LH surge. Though chronic ognition of these rhythms is important for endocrine
low levels of estrogen are inhibitory, gradually rising estro- testing and treatment. Patients with Cushing’s syndrome
gen levels stimulate LH secretion. This effect, which is characteristically exhibit increased midnight cortisol
illustrative of an endocrine rhythm (see below), involves levels compared with normal individuals (Chap. 5).
activation of the hypothalamic GnRH pulse generator. In contrast, morning cortisol levels are similar in these
In addition, estrogen-primed gonadotropes are extraor- groups, as cortisol is normally high at this time of day in
dinarily sensitive to GnRH, leading to amplification of normal individuals. The HPA axis is more susceptible
LH release. to suppression by glucocorticoids administered at night
as they blunt the early-morning rise of ACTH. Under-
standing these rhythms allows glucocorticoid replace-
Paracrine and Autocrine Control
ment that mimics diurnal production by administer-
The previously mentioned examples of feedback control ing larger doses in the morning than in the afternoon.
involve classic endocrine pathways in which hormones Disrupted sleep rhythms can alter hormonal regula-
are released by one gland and act on a distant target tion. For example, sleep deprivation causes mild insu-
gland. However, local regulatory systems, often involv- lin resistance, food craving, and hypertension, which are
ing growth factors, are increasingly recognized. Paracrine reversible, at least in the short term.
regulation refers to factors released by one cell that act on Other endocrine rhythms occur on a more rapid
an adjacent cell in the same tissue. For example, soma- time scale. Many peptide hormones are secreted in dis-
tostatin secretion by pancreatic islet δ cells inhibits insulin crete bursts every few hours. LH and FSH secretion
secretion from nearby β cells. Autocrine regulation describes are exquisitely sensitive to GnRH pulse frequency.
the action of a factor on the same cell from which it is Intermittent pulses of GnRH are required to maintain
produced. IGF-I acts on many cells that produce it, pituitary sensitivity, whereas continuous exposure to
including chondrocytes, breast epithelium, and gonadal GnRH causes pituitary gonadotrope desensitization.
cells. Unlike endocrine actions, paracrine and autocrine This feature of the hypothalamic-pituitary-gonadotrope
10 axis forms the basis for using long-acting GnRH ago- Table 1-2
nists to treat central precocious puberty or to decrease Causes of Endocrine Dysfunction
testosterone levels in the management of prostate can-
Type of Endocrine
CHAPTER 1

cer. It is important to be aware of the pulsatile nature Disorder Examples


of hormone secretion and the rhythmic patterns of hor-
mone production in relating serum hormone measure- Hyperfunction
ments to normal values. For some hormones, integrated   Neoplastic
   Benign Pituitary adenomas,
markers have been developed to circumvent hormonal
hyperparathyroidism,
fluctuations. Examples include 24-h urine collections autonomous thyroid or
for cortisol, IGF-I as a biologic marker of GH action,
Principles of Endocrinology

adrenal nodules,
and HbA1c as an index of long-term (weeks to months) pheochromocytoma
blood glucose control.    Malignant Adrenal cancer, medullary
Often, one must interpret endocrine data only in the thyroid cancer, carcinoid
context of other hormones. For example, PTH levels    Ectopic Ectopic ACTH, SIADH
secretion
typically are assessed in combination with serum calcium
   Multiple endocrine MEN 1, MEN 2
concentrations. A high serum calcium level in association   neoplasia
with elevated PTH is suggestive of hyperparathyroidism,   Autoimmune Graves’ disease
whereas a suppressed PTH in this situation is more likely   Iatrogenic Cushing’s syndrome,
to be caused by hypercalcemia of malignancy or other hypoglycemia
causes of hypercalcemia. Similarly, TSH should be ele-   Infectious/inflammatory Subacute thyroiditis
vated when T4 and T3 concentrations are low, reflecting Activating receptor LH, TSH, Ca2+ and PTH
reduced feedback inhibition. When this is not the case, mutations receptors, Gsa
it is important to consider secondary hypothyroidism, Hypofunction
which is caused by a defect at the level of the pituitary.   Autoimmune Hashimoto’s thyroiditis,
Type 1 diabetes mellitus,
Addison’s disease,
polyglandular failure
Pathologic Mechanisms of   Iatrogenic Radiation-induced
Endocrine Disease hypopituitarism,
hypothyroidism, surgical
Endocrine diseases can be divided into three major   Infectious/inflammatory Adrenal insufficiency,
types of conditions: (1) hormone excess, (2) hormone hypothalamic
deficiency, and (3) hormone resistance (Table 1-2). sarcoidosis
  Hormone mutations GH, LHb, FSHb, vasopressin
  Enzyme defects 21-Hydroxylase deficiency
Causes of Hormone Excess   Developmental defects Kallmann syndrome, Turner
syndrome, transcription
Syndromes of hormone excess can be caused by neo- factors
plastic growth of endocrine cells, autoimmune disorders, Nutritional/vitamin Vitamin D deficiency, iodine
and excess hormone administration. Benign endocrine deficiency deficiency
tumors, including parathyroid, pituitary, and adrenal   Hemorrhage/infarction Sheehan’s syndrome,
adrenal insufficiency
adenomas, often retain the capacity to produce hor-
mones, perhaps reflecting the fact that they are relatively Hormone resistance
well differentiated. Many endocrine tumors exhibit sub-   Receptor mutations
   Membrane GH, vasopressin, LH, FSH,
tle defects in their “set points” for feedback regulation. ACTH, GnRH, GHRH,
For example, in Cushing’s disease, impaired feedback PTH, leptin, Ca2+
inhibition of ACTH secretion is associated with autono-    Nuclear AR, TR, VDR, ER, GR,
mous function. However, the tumor cells are not com- PPARg
pletely resistant to feedback, as evidenced by ACTH Signaling pathway Albright’s hereditary
suppression by higher doses of dexamethasone (e.g., mutations osteodystrophy
high-dose dexamethasone test) (Chap. 5). Similar set   Postreceptor Type 2 diabetes mellitus,
point defects are also typical of parathyroid adenomas leptin resistance
and autonomously functioning thyroid nodules.
The molecular basis of some endocrine tumors, Abbreviations: AR, androgen receptor; ER, estrogen receptor; GR,
glucocorticoid receptor; PPAR, peroxisome proliferator activated
such as the MEN syndromes (MEN 1, 2A, 2B),
receptor; SIADH, syndrome of inappropriate antidiuretic hormone;
have provided important insights into tumorigen- TR, thyroid hormone receptor; VDR, vitamin D receptor. For all other
esis (Chap. 23). MEN 1 is characterized primarily by abbreviations, see text.
the triad of parathyroid, pancreatic islet, and pituitary to the thyroid gland (Hashimoto’s thyroiditis) and 11
tumors. MEN 2 predisposes to medullary thyroid car- pancreatic islet β cells (Type 1 diabetes mellitus) is a
cinoma, pheochromocytoma, and hyperparathyroid- prevalent cause of endocrine disease. Mutations in a

CHAPTER 1
ism. The MEN1 gene, located on chromosome 11q13, number of hormones, hormone receptors, transcrip-
encodes a putative tumor-suppressor gene, menin. tion factors, enzymes, and channels can also lead to
Analogous to the paradigm first described for reti- hormone deficiencies.
noblastoma, the affected individual inherits a mutant
copy of the MEN1 gene, and tumorigenesis ensues Hormone Resistance
after a somatic “second hit” leads to loss of function Most severe hormone resistance syndromes are due to
of the normal MEN1 gene (through deletion or point

Principles of Endocrinology
inherited defects in membrane receptors, nuclear recep-
mutations). tors, or the pathways that transduce receptor signals.
In contrast to inactivation of a tumor-suppressor These disorders are characterized by defective hormone
gene, as occurs in MEN 1 and most other inherited action despite the presence of increased hormone levels.
cancer syndromes, MEN 2 is caused by activating muta- In complete androgen resistance, for example, muta-
tions in a single allele. In this case, activating mutations tions in the androgen receptor result in a female phe-
of the RET protooncogene, which encodes a receptor notypic appearance in genetic (XY) males, even though
tyrosine kinase, leads to thyroid C cell hyperplasia in LH and testosterone levels are increased (Chap. 7).
childhood before the development of medullary thyroid In addition to these relatively rare genetic disorders,
carcinoma. Elucidation of this pathogenic mechanism more common acquired forms of functional hormone
has allowed early genetic screening for RET mutations resistance include insulin resistance in Type 2 diabetes
in individuals at risk for MEN 2, permitting identifica- mellitus, leptin resistance in obesity, and GH resistance
tion of those who may benefit from prophylactic thy- in catabolic states. The pathogenesis of functional resis-
roidectomy and biochemical screening for pheochro- tance involves receptor downregulation and postrecep-
mocytoma and hyperparathyroidism. tor desensitization of signaling pathways; functional
Mutations that activate hormone receptor signaling forms of resistance are generally reversible.
have been identified in several GPCRs. For example,
activating mutations of the LH receptor cause a domi- Approach to The
nantly transmitted form of male-limited precocious Patient Endocrine Disease
puberty, reflecting premature stimulation of testosterone
synthesis in Leydig cells (Chap. 8). Activating muta- Because most glands are relatively inaccessible, the
tions in these GPCRs are located predominantly in the examination usually focuses on the manifestations of
transmembrane domains and induce receptor coupling hormone excess or deficiency as well as direct exami-
to Gsα even in the absence of hormone. Consequently, nation of palpable glands, such as the thyroid and
adenylate cyclase is activated, and cyclic adenosine gonads. For these reasons, it is important to evaluate
monophosphate (AMP) levels increase in a manner patients in the context of their presenting symptoms,
that mimics hormone action. A similar phenomenon review of systems, family and social history, and expo-
results from activating mutations in Gsα. When these sure to medications that may affect the endocrine
mutations occur early in development, they cause system. Astute clinical skills are required to detect
McCune-Albright syndrome. When they occur only in subtle symptoms and signs suggestive of underlying
somatotropes, the activating Gsα mutations cause GH- endocrine disease. For example, a patient with Cush-
secreting tumors and acromegaly (Chap. 2). ing’s syndrome may manifest specific findings, such
In autoimmune Graves’ disease, antibody interactions as central fat redistribution, striae, and proximal mus-
with the TSH receptor mimic TSH action, leading to cle weakness, in addition to features seen commonly
hormone overproduction (Chap. 4). Analogous to the in the general population, such as obesity, plethora,
effects of activating mutations of the TSH receptor, hypertension, and glucose intolerance. Similarly, the
these stimulating autoantibodies induce conformational insidious onset of hypothyroidism—with mental slow-
changes that release the receptor from a constrained ing, fatigue, dry skin, and other features—can be dif-
state, thereby triggering receptor coupling to G proteins. ficult to distinguish from similar, nonspecific findings
in the general population. Clinical judgment that is
based on knowledge of disease prevalence and patho-
Causes of Hormone Deficiency physiology is required to decide when to embark on
more extensive evaluation of these disorders. Labora-
Most examples of hormone deficiency states can be attrib-
tory testing plays an essential role in endocrinology by
uted to glandular destruction caused by autoimmunity,
allowing quantitative assessment of hormone levels
surgery, infection, inflammation, infarction, hemorrhage,
and dynamics. Radiologic imaging tests such as CT scan,
or tumor infiltration (Table 1-2). Autoimmune damage
12 MRI, thyroid scan, and ultrasound are also used for the midnight and dawn; reproductive hormone levels vary
diagnosis of endocrine disorders. However, these tests dramatically during the female menstrual cycle.
generally are employed only after a hormonal abnor- For many endocrine systems, much information can
CHAPTER 1

mality has been established by biochemical testing. be gained from basal hormone testing, particularly
when different components of an endocrine axis are
Hormone Measurements and Endo-
assessed simultaneously. For example, low testoster-
crine Testing  Immunoassays are the most
one and elevated LH levels suggest a primary gonadal
important diagnostic tool in endocrinology, as they
problem, whereas a hypothalamic-pituitary disorder is
allow sensitive, specific, and quantitative determina-
likely if both LH and testosterone are low. Because TSH
tion of steady-state and dynamic changes in hormone
Principles of Endocrinology

is a sensitive indicator of thyroid function, it is generally


concentrations. Immunoassays use antibodies to detect
recommended as a first-line test for thyroid disorders.
specific hormones. For many peptide hormones, these
An elevated TSH level is almost always the result of pri-
measurements are now configured to use two differ-
mary hypothyroidism, whereas a low TSH is most often
ent antibodies to increase binding affinity and specific-
caused by thyrotoxicosis. These predictions can be con-
ity. There are many variations of these assays; a com-
firmed by determining the free thyroxine level. Elevated
mon format involves using one antibody to capture
calcium and PTH levels suggest hyperparathyroidism,
the antigen (hormone) onto an immobilized surface
whereas PTH is suppressed in hypercalcemia caused by
and a second antibody, coupled to a chemiluminescent
malignancy or granulomatous diseases. A suppressed
[immunochemiluminescent assay (ICMA)] or radioac-
ACTH in the setting of hypercortisolemia, or increased
tive immunoradiometric assay (IRMA)] signal, to detect
urine free cortisol, is seen with hyperfunctioning adre-
the antigen. These assays are sensitive enough to detect
nal adenomas.
plasma hormone concentrations in the picomolar to
It is not uncommon, however, for baseline hormone
nanomolar range, and they can readily distinguish struc-
levels associated with pathologic endocrine conditions
turally related proteins, such as PTH from PTHrP. A vari-
to overlap with the normal range. In this circumstance,
ety of other techniques are used to measure specific
dynamic testing is useful to separate the two groups
hormones, including mass spectroscopy, various forms
further. There are a multitude of dynamic endocrine
of chromatography, and enzymatic methods; bioassays
tests, but all are based on principles of feedback regula-
are now rarely used.
tion, and most responses can be remembered on the
Most hormone measurements are based on plasma
basis of the pathways that govern endocrine axes. Sup-
or serum samples. However, urinary hormone determi-
pression tests are used in the setting of suspected endo-
nations remain useful for the evaluation of some condi-
crine hyperfunction. An example is the dexamethasone
tions. Urinary collections over 24 h provide an integrated
suppression test used to evaluate Cushing’s syndrome
assessment of the production of a hormone or metabo-
(Chaps. 2 and 5). Stimulation tests generally are used to
lite, many of which vary during the day. It is important
assess endocrine hypofunction. The ACTH stimulation
to assure complete collections of 24-h urine samples;
test, for example, is used to assess the adrenal gland
simultaneous measurement of creatinine provides an
response in patients with suspected adrenal insufficiency.
internal control for the adequacy of collection and can
Other stimulation tests use hypothalamic-releasing
be used to normalize some hormone measurements. A
factors such as CRH and GHRH to evaluate pituitary
24-h urine free cortisol measurement largely reflects the
hormone reserve (Chap. 2). Insulin-induced hypogly-
amount of unbound cortisol, thus providing a reason-
cemia also evokes pituitary ACTH and GH responses.
able index of biologically available hormone. Other com-
Stimulation tests based on reduction or inhibition of
monly used urine determinations include 17-hydroxy-
endogenous hormones are now used infrequently. Exam-
corticosteroids, 17-ketosteroids, vanillylmandelic acid,
ples include metyrapone inhibition of cortisol synthesis
metanephrine, catecholamines, 5-hydroxyindoleacetic
and clomiphene inhibition of estrogen feedback.
acid, and calcium.
The value of quantitative hormone measurements Screening and Assessment of Com-
lies in their correct interpretation in a clinical context. mon Endocrine Disorders  Many endo-
The normal range for most hormones is relatively broad, crine disorders are prevalent in the adult population
often varying by a factor of two- to tenfold. The normal (Table 1-3) and can be diagnosed and managed by
ranges for many hormones are sex and age specific. general internists, family practitioners, or other primary
Thus, using the correct normative database is an essen- health care providers. The high prevalence and clinical
tial part of interpreting hormone tests. The pulsatile impact of certain endocrine diseases justifies vigilance
nature of hormones and factors that can affect their secre- for features of these disorders during routine physi-
tion, such as sleep, meals, and medications, must also be cal examinations; laboratory screening is indicated in
considered. Cortisol values increase fivefold between selected high-risk populations.
Table 1-3 13
Examples of Prevalent Endocrine and Metabolic Disorders in the Adult
Disorder Approx. Prevalence in Adultsa Screening/Testing Recommendationsb Chapter

CHAPTER 1
Obesity 31% BMI ≥30 Calculate BMI 17
65% BMI ≥25 Measure waist circumference
Exclude secondary causes
Consider comorbid complications
Type 2 diabetes >7% Beginning at age 45, screen every 3 years, or earlier 19
mellitus in high-risk groups:

Principles of Endocrinology
Fasting plasma glucose (FPG) >126 mg/dL
Random plasma glucose >200 mg/dL
An elevated HbA1c
Consider comorbid complications
Hyperlipidemia 20–25% Cholesterol screening at least every 5 years; more 21
often in high-risk groups
Lipoprotein analysis (LDL, HDL) for increased
cholesterol, CAD, diabetes
Consider secondary causes
Hypothyroidism 5–10%, women TSH; confirm with free T4 4
0.5–2%, men Screen women after age 35 and every 5 years thereafter
Graves’ disease 1–3%, women TSH, free T4 4
0.1%, men
Thyroid nodules and 2–5% palpable Physical examination of thyroid 4
neoplasia >25% by ultrasound Fine-needle aspiration biopsy
Osteoporosis 5–10%, women Bone mineral density measurements in women 28
2–5%, men >65 years or in postmenopausal women or men at risk
Exclude secondary causes
Hyperparathyroidism 0.1–0.5%, women > men Serum calcium 27
PTH, if calcium is elevated
Assess comorbid conditions
Infertility 10%, couples Investigate both members of couple 8, 10
Semen analysis in male
Assess ovulatory cycles in female
Specific tests as indicated
Polycystic ovarian 5–10%, women Free testosterone, DHEAS 10
syndrome Consider comorbid conditions
Hirsutism 5–10% Free testosterone, DHEAS 13
Exclude secondary causes
Additional tests as indicated
Menopause Median age, 51 FSH 12
Hyperprolactinemia 15% in women with amenorrhea or PRL level 2
galactorrhea MRI, if not medication related
Erectile dysfunction 20–30% Careful history, PRL, testosterone 15
Consider secondary causes (e.g., diabetes)
Gynecomastia 15% Often, no tests are indicated 8
Consider Klinefelter syndrome
Consider medications, hypogonadism, liver disease
Klinefelter syndrome 0.2%, men Karyotype 7
Testosterone
Vitamin D deficiency 40–50% Measure serum 25-OH vitamin D 25
Consider secondary causes
Turner syndrome 0.03%, women Karyotype 7
Consider comorbid conditions

a
The prevalence of most disorders varies among ethnic groups and with aging. Data based primarily on U.S. population.
b
See individual chapters for additional information on evaluation and treatment. Early testing is indicated in patients with signs and symptoms of
disease and in those at increased risk.
Abbreviations: BMI, body mass index; CAD, coronary artery disease; DHEAS, dehydroepiandrosterone; HDL, high-density lipoprotein; LDL,
low-density lipoprotein. For other abbreviations, see text.
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section I

Pituitary, Thyroid,
and Adrenal
Disorders
cHApter 2

DISORDERS OF THE ANTERIOR PITUITARY


AND HYPOTHALAMUS

shlomo Melmed ■ J. larry Jameson

The anterior pituitary often is referred to as the “mas- hormone (ACTH), (4) luteinizing hormone (LH),
ter gland” because, together with the hypothalamus, it (5) follicle-stimulating hormone (FSH), and (6) thyroid-
orchestrates the complex regulatory functions of many stimulating hormone (TSH) (Table 2-1). Pituitary
other endocrine glands. The anterior pituitary gland hormones are secreted in a pulsatile manner, reflect-
produces six major hormones: (1) prolactin (PRL), ing stimulation by an array of specific hypothalamic
(2) growth hormone (GH), (3) adrenocorticotropic releasing factors. Each of these pituitary hormones

Table 2-1
Anterior PituitAry Hormone eXPression AnD reGulAtion
cell corticotroPe somAtotroPe lActotroPe tHyrotroPe GonADotroPe

Tissue-specific T-Pit Prop-1, Pit-1 Prop-1, Pit-1 Prop-1, Pit-1, TEF SF-1, DAX-1
transcription
factor
Fetal appearance 6 weeks 8 weeks 12 weeks 12 weeks 12 weeks
Hormone POMC GH PRL TSH FSH LH
Protein Polypeptide Polypeptide Polypeptide Glycoprotein α, β Glycoprotein α, β
subunits subunits
Amino acids 266 (ACTH 1–39) 191 199 211 210 204
Stimulators CRH, AVP, gp-130 GHRH, ghrelin Estrogen, TRH, TRH GnRH, activins,
cytokines VIP estrogen
Inhibitors Glucocorticoids Somatostatin, Dopamine T3, T4, dopamine, Sex steroids,
IGF-I somatostatin, inhibin
glucocorticoids
Target gland Adrenal Liver, other Breast, other Thyroid Ovary, testis
tissues tissues
Trophic effect Steroid production IGF-I production, Milk production T4 synthesis and Sex steroid pro-
growth induc- secretion duction, follicle
tion, insulin growth, germ cell
antagonism maturation
Normal range ACTH, 4–22 pg/L <0.5 μg/La M <15; F <20 0.1–5 mU/L M, 5–20 IU/L, F
μg/L (basal), 5–20
IU/L

a
Hormone secretion integrated over 24 h.
Abbreviations: M, male; F, female. For other abbreviations, see text.
Source: Adapted from I Shimon, S Melmed, in S Melmed, P Conn (eds): Endocrinology: Basic and Clinical Principles. Totowa, NJ, Humana, 2005.
16
elicits specific responses in peripheral target tissues. disorders of the posterior pituitary, or neurohypophysis, 17
The hormonal products of those peripheral glands, in see Chap. 3.
turn, exert feedback control at the level of the hypo-

CHAPTER 2
thalamus and pituitary to modulate pituitary function
(Fig. 2-1). Pituitary tumors cause characteristic hor-
Anatomy and Development
mone-excess syndromes. Hormone deficiency may be
inherited or acquired. Fortunately, there are efficacious Anatomy
treatments for the various pituitary hormone–excess and
–deficiency syndromes. Nonetheless, these diagnoses are The pituitary gland weighs ∼600 mg and is located
often elusive; this emphasizes the importance of rec- within the sella turcica ventral to the diaphragma sella;

Disorders of the Anterior Pituitary and Hypothalamus


ognizing subtle clinical manifestations and performing it consists of anatomically and functionally distinct ante-
the correct laboratory diagnostic tests. For discussion of rior and posterior lobes. The bony sella is contiguous to
vascular and neurologic structures, including the cav-
ernous sinuses, cranial nerves, and optic chiasm. Thus,
expanding intrasellar pathologic processes may have sig-
TRH SRIF GHRH nificant central mass effects in addition to their endocri-
CRH GnRH nologic impact.
Dopamine Hypothalamic neural cells synthesize specific releasing
Hypothalamus
and inhibiting hormones that are secreted directly into
– the portal vessels of the pituitary stalk. Blood supply of
the pituitary gland comes from the superior and infe-
rior hypophyseal arteries (Fig. 2-2). The hypothalamic-
pituitary portal plexus provides the major blood source
for the anterior pituitary, allowing reliable transmission
of hypothalamic peptide pulses without significant sys-
temic dilution; consequently, pituitary cells are exposed

+ + – + – – +
Pituitary

Third ventricle
ACTH
Neuroendocrine
Target +
cell nuclei
organs TSH Hypothalamus

Cortisol
LH PRL GH
Cell homeostasis
Adrenal
and function
glands FSH
+ + +

T4/T3 Superior
hypophyseal Stalk
Thermogenesis artery
metabolism Thyroid
glands
Inferior
+ Liver Long portal hypophyseal
vessels artery
Testosterone Lactation
Inhibin
Trophic
Spermatogenesis hormone
Secondary sex Testes
+ secreting
characteristics cells
Posterior
Estradiol Chondrocytes
Anterior pituitary
Progesterone
Inhibin Ovaries Linear and pituitary
organ growth
Ovulation Short portal
Secondary sex vessel
characteristics Hormone
IGF-1 secretion

Figure 2-1 Figure 2-2


Diagram of pituitary axes. Hypothalamic hormones regulate Diagram of hypothalamic-pituitary vasculature. The hypo-
anterior pituitary trophic hormones that in turn determine tar- thalamic nuclei produce hormones that traverse the portal
get gland secretion. Peripheral hormones feed back to regu- system and impinge on anterior pituitary cells to regulate
late hypothalamic and pituitary hormones. For abbreviations, pituitary hormone secretion. Posterior pituitary hormones are
see text. derived from direct neural extensions.
18 Hypothalamic and Anterior
LH mlU/mL GnRH pg/mL

Pituitary Insufficiency
GnRH pulses
SECTION I

Hypopituitarism results from impaired production of


one or more of the anterior pituitary trophic hormones.
LH pulses
Reduced pituitary function can result from inherited
disorders; more commonly, hypopituitarism is acquired
and reflects the compressive mass effects of tumors or
the consequences of inflammation or vascular damage.
Figure 2-3
Pituitary, Thyroid, and Adrenal Disorders

These processes also may impair synthesis or secretion


Hypothalamic gonadotropin-releasing hormone (GnRH)
of hypothalamic hormones, with resultant pituitary failure
pulses induce secretory pulses of luteinizing hormone (LH).
(Table 2-2).

to releasing or inhibiting factors and in turn release their Table 2-2


hormones as discrete pulses (Fig. 2-3). Etiology of Hypopituitarisma
The posterior pituitary is supplied by the infe- Development/structural
rior hypophyseal arteries. In contrast to the anterior   Transcription factor defect
pituitary, the posterior lobe is directly innervated by   Pituitary dysplasia/aplasia
hypothalamic neurons (supraopticohypophyseal and   Congenital CNS mass, encephalocele
tuberohypophyseal nerve tracts) via the pituitary stalk   Primary empty sella
(Chap. 3). Thus, posterior pituitary production of vaso- Congenital hypothalamic disorders (septo-optic dyspla-
pressin [antidiuretic hormone (ADH)] and oxytocin is sia, Prader-Willi syndrome, Laurence-Moon-Biedl syn-
drome, Kallmann syndrome)
particularly sensitive to neuronal damage by lesions that
affect the pituitary stalk or hypothalamus. Traumatic
  Surgical resection
  Radiation damage
  Head injuries
Pituitary Development Neoplastic
  Pituitary adenoma
The embryonic differentiation and maturation of anterior
  Parasellar mass (germinoma, ependymoma, glioma)
pituitary cells have been elucidated in considerable detail.   Rathke’s cyst
Pituitary development from Rathke’s pouch involves a   Craniopharyngioma
complex interplay of lineage-specific transcription fac-   Hypothalamic hamartoma, gangliocytoma
tors expressed in pluripotent precursor cells and gradi-   Pituitary metastases (breast, lung, colon carcinoma)
ents of locally produced growth factors (Table 2-1). The   Lymphoma and leukemia
transcription factor Prop-1 induces pituitary develop-   Meningioma
ment of Pit-1–specific lineages as well as gonadotropes. Infiltrative/inflammatory
The transcription factor Pit-1 determines cell-specific   Lymphocytic hypophysitis
expression of GH, PRL, and TSH in somatotropes, lac-   Hemochromatosis
totropes, and thyrotropes. Expression of high levels of   Sarcoidosis
  Histiocytosis X
estrogen receptors in cells that contain Pit-1 favors PRL   Granulomatous hypophysitis
expression, whereas thyrotrope embryonic factor (TEF)
Vascular
induces TSH expression. Pit-1 binds to GH, PRL, and
  Pituitary apoplexy
TSH gene regulatory elements as well as to recogni- Pregnancy related (infarction with diabetes; postpartum
tion sites on its own promoter, providing a mechanism necrosis)
for maintaining specific pituitary phenotypic stability.   Sickle cell disease
Gonadotrope cell development is further defined by   Arteritis
the cell-specific expression of the nuclear receptors ste- Infections
roidogenic factor (SF-1) and dosage-sensitive sex rever-   Fungal (histoplasmosis)
sal, adrenal hypoplasia critical region, on chromosome   Parasitic (toxoplasmosis)
X, gene 1 (DAX-1). Development of corticotrope cells,   Tuberculosis
which express the proopiomelanocortin (POMC) gene,   Pneumocystis carinii
requires the T-Pit transcription factor. Abnormalities
a
of pituitary development caused by mutations of Pit-1, Trophic hormone failure associated with pituitary compression or
destruction usually occurs sequentially: GH > FSH > LH > TSH >
Prop-1, SF-1, DAX-1, and T-Pit result in a series of ACTH. During childhood, growth retardation is often the presenting
rare, selective or combined pituitary hormone deficits. feature, and in adults, hypogonadism is the earliest symptom.
Developmental and Genetic Causes movements. Defects in the X-linked KAL gene impair 19
of Hypopituitarism embryonic migration of GnRH neurons from the hypo-
thalamic olfactory placode to the hypothalamus. Genetic
Pituitary dysplasia

CHAPTER 2
abnormalities, in addition to KAL mutations, also can
Pituitary dysplasia may result in aplastic, hypoplastic, cause isolated GnRH deficiency. Autosomal recessive (i.e.,
or ectopic pituitary gland development. Because pitu- GPR54, KISS1) and dominant (i.e., FGFR1) modes of
itary development follows midline cell migration from transmission have been described, and there is a growing
the nasopharyngeal Rathke’s pouch, midline craniofa- list of genes associated with GnRH deficiency (GNRH1,
cial disorders may be associated with pituitary dysplasia. PROK2, PROKR2, CH7, PCSK1, FGF8, TAC3,
Acquired pituitary failure in the newborn also can be TACR3). GnRH deficiency prevents progression through

Disorders of the Anterior Pituitary and Hypothalamus


caused by birth trauma, including cranial hemorrhage, puberty. Males present with delayed puberty and pro-
asphyxia, and breech delivery. nounced hypogonadal features, including micropenis,
probably the result of low testosterone levels during
Septo-optic dysplasia
infancy. Females present with primary amenorrhea and
Hypothalamic dysfunction and hypopituitarism may failure of secondary sexual development.
result from dysgenesis of the septum pellucidum or cor- Kallmann syndrome and other causes of congeni-
pus callosum. Affected children have mutations in the tal GnRH deficiency are characterized by low LH
HESX1 gene, which is involved in early development and FSH levels and low concentrations of sex steroids
of the ventral prosencephalon. These children exhibit (testosterone or estradiol). In sporadic cases of isolated
variable combinations of cleft palate, syndactyly, ear gonadotropin deficiency, the diagnosis is often one of
deformities, hypertelorism, optic atrophy, micropenis, exclusion after other causes of hypothalamic-pituitary
and anosmia. Pituitary dysfunction leads to diabetes dysfunction have been eliminated. Repetitive GnRH
insipidus, GH deficiency and short stature, and, occa- administration restores normal pituitary gonadotropin
sionally, TSH deficiency. responses, pointing to a hypothalamic defect.
Long-term treatment of men with human chorionic
Tissue-specific factor mutations gonadotropin (hCG) or testosterone restores pubertal
Several pituitary cell–specific transcription factors, such development and secondary sex characteristics; women
as Pit-1 and Prop-1, are critical for determining the can be treated with cyclic estrogen and progestin. Fer-
development and committed function of differentiated tility also may be restored by the administration of
anterior pituitary cell lineages. Autosomal dominant or gonadotropins or by using a portable infusion pump to
recessive Pit-1 mutations cause combined GH, PRL, deliver subcutaneous, pulsatile GnRH.
and TSH deficiencies. These patients usually present Bardet-Biedl syndrome
with growth failure and varying degrees of hypothy- This is a rare genetically heterogeneous disorder char-
roidism. The pituitary may appear hypoplastic on MRI. acterized by mental retardation, renal abnormalities,
Prop-1 is expressed early in pituitary development obesity, and hexadactyly, brachydactyly, or syndactyly.
and appears to be required for Pit-1 function. Familial Central diabetes insipidus may or may not be associ-
and sporadic PROP1 mutations result in combined GH, ated. GnRH deficiency occurs in 75% of males and
PRL, TSH, and gonadotropin deficiency. Over 80% of half of affected females. Retinal degeneration begins in
these patients have growth retardation; by adulthood, early childhood, and most patients are blind by age 30.
all are deficient in TSH and gonadotropins, and a small Numerous subtypes of Bardet-Biedl syndrome (BBS)
minority later develop ACTH deficiency. Because of have been identified, with genetic linkage to at least
gonadotropin deficiency, these individuals do not enter nine different loci. Several of the loci encode genes
puberty spontaneously. In some cases, the pituitary involved in basal body cilia function, and this may
gland is enlarged. TPIT mutations result in ACTH defi- account for the diverse clinical manifestations.
ciency associated with hypocortisolism.
Leptin and leptin receptor mutations
Developmental hypothalamic dysfunction Deficiencies of leptin or its receptor cause a broad spec-
trum of hypothalamic abnormalities, including hyper-
Kallmann syndrome phagia, obesity, and central hypogonadism (Chap. 16).
Kallmann syndrome results from defective hypothalamic Decreased GnRH production in these patients results in
gonadotropin-releasing hormone (GnRH) synthesis and attenuated pituitary FSH and LH synthesis and release.
is associated with anosmia or hyposmia due to olfactory
bulb agenesis or hypoplasia (Chap. 8). The syndrome also
Prader-Willi syndrome
may be associated with color blindness, optic atrophy,
nerve deafness, cleft palate, renal abnormalities, crypt- This is a contiguous gene syndrome that results from
orchidism, and neurologic abnormalities such as mirror deletion of the paternal copies of the imprinted SNRPN
20 gene, the NECDIN gene, and possibly other genes on after whole-brain or head and neck therapeutic irradia-
chromosome 15q. Prader-Willi syndrome is associated tion. The development of hormonal abnormalities cor-
with hypogonadotropic hypogonadism, hyperphagia- relates strongly with irradiation dosage and the time
obesity, chronic muscle hypotonia, mental retardation, interval after completion of radiotherapy. Up to two-
SECTION I

and adult-onset diabetes mellitus. Multiple somatic thirds of patients ultimately develop hormone insuffi-
defects also involve the skull, eyes, ears, hands, and feet. ciency after a median dose of 50 Gy (5000 rad) directed
Diminished hypothalamic oxytocin- and vasopressin- at the skull base. The development of hypopituitarism
producing nuclei have been reported. Deficient GnRH occurs over 5–15 years and usually reflects hypothalamic
synthesis is suggested by the observation that chronic damage rather than primary destruction of pituitary
GnRH treatment restores pituitary LH and FSH release. cells. Although the pattern of hormone loss is variable,
Pituitary, Thyroid, and Adrenal Disorders

GH deficiency is most common, followed by gonado-


tropin and ACTH deficiency. When deficiency of one
Acquired Hypopituitarism or more hormones is documented, the possibility of
diminished reserve of other hormones is likely. Accord-
Hypopituitarism may be caused by accidental or neuro- ingly, anterior pituitary function should be continu-
surgical trauma; vascular events such as apoplexy; pitu- ally evaluated over the long term in previously irradi-
itary or hypothalamic neoplasms, craniopharyngioma, ated patients, and replacement therapy instituted when
lymphoma, or metastatic tumors; inflammatory disease appropriate (see below).
such as lymphocytic hypophysitis; infiltrative disorders
such as sarcoidosis, hemochromatosis, and tuberculosis;
or irradiation. Lymphocytic hypophysitis
Increasing evidence suggests that patients with brain This occurs most often in postpartum women; it usu-
injury, including sports trauma, subarachnoid hemor- ally presents with hyperprolactinemia and MRI evi-
rhage, and irradiation, have transient hypopituitarism dence of a prominent pituitary mass that often resembles
and require intermittent long-term endocrine follow- an adenoma, with mildly elevated PRL levels. Pituitary
up, as permanent hypothalamic or pituitary dysfunction failure caused by diffuse lymphocytic infiltration may be
will develop in 25–40% of these patients. transient or permanent but requires immediate evalua-
tion and treatment. Rarely, isolated pituitary hormone
Hypothalamic infiltration disorders deficiencies have been described, suggesting a selective
autoimmune process targeted to specific cell types. Most
These disorders—including sarcoidosis, histiocytosis X, patients manifest symptoms of progressive mass effects
amyloidosis, and hemochromatosis—frequently involve with headache and visual disturbance. The erythrocyte
both hypothalamic and pituitary neuronal and neuro- sedimentation rate often is elevated. As the MRI image
chemical tracts. Consequently, diabetes insipidus occurs may be indistinguishable from that of a pituitary ade-
in half of patients with these disorders. Growth retar- noma, hypophysitis should be considered in a postpartum
dation is seen if attenuated GH secretion occurs before woman with a newly diagnosed pituitary mass before
pubertal epiphyseal closure. Hypogonadotropic hypo- an unnecessary surgical intervention is undertaken. The
gonadism and hyperprolactinemia are also common. inflammatory process often resolves after several months
of glucocorticoid treatment, and pituitary function may
Inflammatory lesions be restored, depending on the extent of damage.

Pituitary damage and subsequent dysfunction can be


Pituitary apoplexy
seen with chronic infections such as tuberculosis, with
opportunistic fungal infections associated with AIDS, Acute intrapituitary hemorrhagic vascular events can
and in tertiary syphilis. Other inflammatory processes, cause substantial damage to the pituitary and surround-
such as granulomas and sarcoidosis, may mimic the fea- ing sellar structures. Pituitary apoplexy may occur
tures of a pituitary adenoma. These lesions may cause spontaneously in a preexisting adenoma; postpartum
extensive hypothalamic and pituitary damage, leading to (Sheehan’s syndrome); or in association with diabe-
trophic hormone deficiencies. tes, hypertension, sickle cell anemia, or acute shock.
The hyperplastic enlargement of the pituitary, which
occurs normally during pregnancy, increases the risk for
Cranial irradiation hemorrhage and infarction. Apoplexy is an endocrine
Cranial irradiation may result in long-term hypotha- emergency that may result in severe hypoglycemia,
lamic and pituitary dysfunction, especially in children hypotension and shock, central nervous system (CNS)
and adolescents, as they are more susceptible to damage hemorrhage, and death. Acute symptoms may include
severe headache with signs of meningeal irritation, bilat- Laboratory Investigation 21
eral visual changes, ophthalmoplegia, and, in severe
cases, cardiovascular collapse and loss of consciousness. Biochemical diagnosis of pituitary insufficiency is made
by demonstrating low levels of trophic hormones in the

CHAPTER 2
Pituitary CT or MRI may reveal signs of intratumoral
or sellar hemorrhage, with deviation of the pituitary setting of low levels of target hormones. For example,
stalk and compression of pituitary tissue. low free thyroxine in the setting of a low or inappro-
Patients with no evident visual loss or impaired con- priately normal TSH level suggests secondary hypo-
sciousness can be observed and managed conservatively thyroidism. Similarly, a low testosterone level without
with high-dose glucocorticoids. Those with significant elevation of gonadotropins suggests hypogonadotropic
or progressive visual loss or loss of consciousness require hypogonadism. Provocative tests may be required to

Disorders of the Anterior Pituitary and Hypothalamus


urgent surgical decompression. Visual recovery after assess pituitary reserve (Table 2-3). GH responses to
sellar surgery is inversely correlated with the length of insulin-induced hypoglycemia, arginine, l-dopa, growth
time after the acute event. Therefore, severe ophthal- hormone–releasing hormone (GHRH), or growth
moplegia or visual deficits are indications for early sur- hormone–releasing peptides (GHRPs) can be used to
gery. Hypopituitarism is very common after apoplexy. assess GH reserve. Corticotropin-releasing hormone
(CRH) administration induces ACTH release, and
administration of synthetic ACTH (cosyntropin) evokes
Empty sella adrenal cortisol release as an indirect indicator of pitu-
itary ACTH reserve (Chap. 5). ACTH reserve is most
A partial or apparently totally empty sella is often an
reliably assessed by measuring ACTH and cortisol lev-
incidental MRI finding. These patients usually have
els during insulin-induced hypoglycemia. However,
normal pituitary function, implying that the surround-
this test should be performed cautiously in patients with
ing rim of pituitary tissue is fully functional. Hypopi-
suspected adrenal insufficiency because of enhanced sus-
tuitarism, however, may develop insidiously. Pituitary
ceptibility to hypoglycemia and hypotension. Adminis-
masses also may undergo clinically silent infarction and
tering insulin to induce hypoglycemia is contraindicated
involution with development of a partial or totally
in patients with active coronary artery disease or seizure
empty sella by cerebrospinal fluid (CSF) filling the dural
disorders.
herniation. Rarely, small but functional pituitary ade-
nomas may arise within the rim of pituitary tissue, and
they are not always visible on MRI.
Treatment Hypopituitarism

Hormone replacement therapy, including glucocorti-


Presentation and Diagnosis coids, thyroid hormone, sex steroids, growth hormone,
The clinical manifestations of hypopituitarism depend and vasopressin, is usually safe and free of complica-
on which hormones are lost and the extent of the tions. Treatment regimens that mimic physiologic hor-
hormone deficiency. GH deficiency causes growth dis- mone production allow for maintenance of satisfactory
orders in children and leads to abnormal body compo- clinical homeostasis. Effective dosage schedules are
sition in adults (see below). Gonadotropin deficiency outlined in Table 2-4. Patients in need of glucocorticoid
causes menstrual disorders and infertility in women and replacement require careful dose adjustments during
decreased sexual function, infertility, and loss of sec- stressful events such as acute illness, dental procedures,
ondary sexual characteristics in men. TSH and ACTH trauma, and acute hospitalization.
deficiency usually develop later in the course of pitu-
itary failure. TSH deficiency causes growth retardation
in children and features of hypothyroidism in children
and adults. The secondary form of adrenal insufficiency Hypothalamic, Pituitary, and
caused by ACTH deficiency leads to hypocortisolism Other Sellar Masses
with relative preservation of mineralocorticoid produc-
Pituitary Tumors
tion. PRL deficiency causes failure of lactation. When
lesions involve the posterior pituitary, polyuria and poly- Pituitary adenomas are the most common cause of pitu-
dipsia reflect loss of vasopressin secretion. Epidemiologic itary hormone hypersecretion and hyposecretion syn-
studies have documented an increased mortality rate in dromes in adults. They account for ∼15% of all intra-
patients with long-standing pituitary damage, primarily cranial neoplasms and have been identified with a
from increased cardiovascular and cerebrovascular disease. population prevalence of ∼80/100,000. At autopsy, up
Previous head or neck irradiation is also a determinant of to one-quarter of all pituitary glands harbor an unsus-
increased mortality rates in patients with hypopituitarism. pected microadenoma (<10-mm diameter). Similarly,
22 Table 2-3
Tests of Pituitary Sufficiency
Hormone Test Blood Samples Interpretation
SECTION I

Growth Insulin tolerance test: Regular −30, 0, 30, 60, 120 min for glucose Glucose <40 mg/dL; GH should be
hormone insulin (0.05–0.15 U/kg IV) and GH >3 μg/L
GHRH test: 1 μg/kg IV 0, 15, 30, 45, 60, 120 min for GH Normal response is GH >3 μg/L
l-Arginine test: 30 g IV over 0, 30, 60, 120 min for GH Normal response is GH >3 μg/L
30 min
Pituitary, Thyroid, and Adrenal Disorders

l-Dopa test: 500 mg PO 0, 30, 60, 120 min for GH Normal response is GH >3 μg/L
Prolactin TRH test: 200–500 μg IV 0, 20, and 60 min for TSH and PRL Normal prolactin is >2 μg/L and
increase >200% of baseline
ACTH Insulin tolerance test: regular −30, 0, 30, 60, 90 min for glucose Glucose <40 mg/dL
insulin (0.05–0.15 U/kg IV) and cortisol Cortisol should increase by >7 μg/
dL or to >20 μg/dL
CRH test: 1 μg/kg ovine CRH IV 0, 15, 30, 60, 90, 120 min for ACTH Basal ACTH increases 2- to 4-fold
at 8 a.m. and cortisol and peaks at 20–100 pg/mL
Cortisol levels >20–25 μg/dL
Metyrapone test: Metyrapone Plasma 11-deoxycortisol and Plasma cortisol should be <4 μg/dL
(30 mg/kg) at midnight cortisol at 8 a.m.; ACTH can to ensure an adequate response
also be measured Normal response is
11-deoxycortisol >7.5 μg/dL or
ACTH >75 pg/mL
Standard ACTH stimulation test: 0, 30, 60 min for cortisol and Normal response is cortisol >21 μg/dL
ACTH 1-24 (cosyntropin), aldosterone and aldosterone response of
0.25 mg IM or IV >4 ng/dL above baseline
Low-dose ACTH test: ACTH 0, 30, 60 min for cortisol Cortisol should be >21 μg/dL
1-24 (cosyntropin), 1 μg IV
3-day ACTH stimulation test Cortisol >21 μg/dL
consists of 0.25 mg ACTH 1-24
given IV over 8 h each day
TSH Basal thyroid function tests: T4, Basal measurements Low free thyroid hormone levels in
T3, TSH the setting of TSH levels that are
not appropriately increased indi-
cate pituitary insufficiency
TRH test: 200–500 μg IV 0, 20, 60 min for TSH and PRLa TSH should increase by >5 mU/L
unless thyroid hormone levels are
increased
LH, FSH LH, FSH, testosterone, estrogen Basal measurements Basal LH and FSH should be
increased in postmenopausal
women
Low testosterone levels in the
setting of low LH and FSH indicate
pituitary insufficiency
GnRH test: GnRH (100 μg) IV 0, 30, 60 min for LH and FSH In most adults, LH should increase
by 10 IU/L and FSH by 2 IU/L
Normal responses are variable
Multiple Combined anterior pituitary −30, 0, 15, 30, 60, 90, 120 min for Combined or individual releasing
hormones test: GHRH (1 μg/kg), GH, ACTH, cortisol, LH, FSH, and hormone responses must be ele-
CRH (1 μg/kg), GnRH (100 μg), TSH vated in the context of basal target
TRH (200 μg) are given IV gland hormone values and may not
be uniformly diagnostic (see text)

a
Evoked PRL response indicates lactotrope integrity.
Note: For abbreviations, see text.
Table 2-4 Table 2-5 23
Hormone Replacement Therapy for Adult Classification of Pituitary Adenomasa
Hypopituitarisma
Adenoma Cell Hormone

CHAPTER 2
Trophic Origin Product Clinical Syndrome
Hormone Deficit Hormone Replacement
Lactotrope PRL Hypogonadism,
ACTH Hydrocortisone (10–20 mg a.m.; galactorrhea
5–10 mg p.m.) Gonadotrope FSH, LH, Silent or
Cortisone acetate (25 mg a.m.; subunits hypogonadism
12.5 mg p.m.)
Somatotrope GH Acromegaly/gigantism

Disorders of the Anterior Pituitary and Hypothalamus


Prednisone (5 mg a.m.)
TSH l-Thyroxine (0.075–0.15 mg daily) Corticotrope ACTH Cushing’s disease
FSH/LH Males Mixed growth GH, PRL Acromegaly, hypogo-
Testosterone enanthate (200 mg hormone and nadism, galactorrhea
IM every 2 weeks) prolactin cell
Testosterone skin patch (5 mg/d) Other Any Mixed
Females plurihormonal
Conjugated estrogen (0.65–1.25 cell
mg qd for 25 days)
Acidophil stem PRL, GH Hypogonadism,
Progesterone (5–10 mg qd) on
cell galactorrhea,
days 16–25
acromegaly
Estradiol skin patch (0.5 mg,
every other day) Mammosomato- PRL, GH Hypogonadism,
For fertility: Menopausal trope galactorrhea,
gonadotropins, human chorionic acromegaly
gonadotropins Thyrotrope TSH Thyrotoxicosis
GH Adults: Somatotropin Null cell None Pituitary failure
(0.1–1.25 mg SC qd)
Children: Somatotropin Oncocytoma None Pituitary failure
(0.02–0.05 mg/kg per day)
a
Hormone-secreting tumors are listed in decreasing order of fre-
Vasopressin Intranasal desmopressin quency. All tumors may cause local pressure effects, including visual
(5–20 mg twice daily) disturbances, cranial nerve palsy, and headache.
Oral 300–600 mg qd Note: For abbreviations, see text.
Source: Adapted from S Melmed, in JL Jameson (ed): Principles of
a
All doses shown should be individualized for specific patients and Molecular Medicine, Totowa, NJ, Humana Press, 1998.
should be reassessed during stress, surgery, or pregnancy.
Note: For abbreviations, see text.
polysecreting cell type or include cells with mixed func-
tion within the same tumor.
Hormonally active tumors are characterized by
pituitary imaging detects small clinically inapparent autonomous hormone secretion with diminished feed-
pituitary lesions in at least 10% of individuals. back responsiveness to physiologic inhibitory pathways.
Hormone production does not always correlate with
tumor size. Small hormone-secreting adenomas may
Pathogenesis
cause significant clinical perturbations, whereas larger
Pituitary adenomas are benign neoplasms that arise from adenomas that produce less hormone may be clinically
one of the five anterior pituitary cell types. The clini- silent and remain undiagnosed (if no central compres-
cal and biochemical phenotypes of pituitary adenomas sive effects occur). About one-third of all adenomas
depend on the cell type from which they are derived. are clinically nonfunctioning and produce no distinct
Thus, tumors arising from lactotrope (PRL), somato- clinical hypersecretory syndrome. Most of them arise
trope (GH), corticotrope (ACTH), thyrotrope (TSH), from gonadotrope cells and may secrete small amounts
or gonadotrope (LH, FSH) cells hypersecrete their of α- and β-glycoprotein hormone subunits or, very
respective hormones (Table 2-5). Plurihormonal rarely, intact circulating gonadotropins. True pituitary
tumors that express combinations of GH, PRL, TSH, carcinomas with documented extracranial metastases are
ACTH, and the glycoprotein hormone α or β sub- exceedingly rare.
unit may be diagnosed by careful immunocytochemis- Almost all pituitary adenomas are monoclonal in ori-
try or may manifest as clinical syndromes that combine gin, implying the acquisition of one or more somatic
features of these hormonal hypersecretory syndromes. mutations that confer a selective growth advantage.
Morphologically, these tumors may arise from a single Consistent with their clonal origin, complete surgical
24 resection of small pituitary adenomas usually cures hor- Table 2-6
mone hypersecretion. Nevertheless, hypothalamic hor- Familial Pituitary Tumor Syndromes
mones such as GHRH and CRH also enhance mitotic
Gene
activity of their respective pituitary target cells in addi-
SECTION I

Mutated Clinical Features


tion to their role in pituitary hormone regulation. Thus,
patients who harbor rare abdominal or chest tumors that Multiple MEN1 Hyperparathyroidism
endocrine Pancreatic
elaborate ectopic GHRH or CRH may present with
neoplasia 1 neuroendocrine
somatotrope or corticotrope hyperplasia with GH or (MEN 1) (11q13) tumors
ACTH hypersecretion. Foregut carcinoids
Several etiologic genetic events have been implicated
Pituitary, Thyroid, and Adrenal Disorders

Adrenal adenomas
in the development of pituitary tumors. The pathogen- Skin lesions
esis of sporadic forms of acromegaly has been particu- Pituitary adenomas
larly informative as a model of tumorigenesis. GHRH, (40%)
after binding to its G protein–coupled somatotrope Multiple CDKNIB Hyperparathyroidsm
receptor, utilizes cyclic AMP (adenosine monophos- endocrine Pituitary adenomas
phate) as a second messenger to stimulate GH secretion neoplasia 4 Other tumors
(MEN 4) (12p13)
and somatotrope proliferation. A subset (∼35%) of GH-
secreting pituitary tumors contain sporadic mutations in Carney PRKAR1A Pituitary hyperplasia
Gsα (Arg 201 → Cys or His; Gln 227 → Arg). These complex 17q23-24 and adenomas (10%)
Atrial myxomas
mutations attenuate intrinsic GTPase activity, resulting
Schwannomas
in constitutive elevation of cyclic AMP, Pit-1 induc- Adrenal hyperplasia
tion, and activation of cyclic AMP response element Lentigines
binding protein (CREB), thereby promoting somato- Familial AIP Acromegaly/gigantism
trope cell proliferation and GH secretion. pituitary (11q13.3) (15%)
Characteristic loss of heterozygosity (LOH) in vari- adenomas
ous chromosomes has been documented in large or
invasive macroadenomas, suggesting the presence of
putative tumor suppressor genes at these loci. LOH of
chromosome regions on 11q13, 13, and 9 is present in by inactivating germ-line mutations in MENIN, a con-
up to 20% of sporadic pituitary tumors, including GH-, stitutively expressed tumor-suppressor gene located
PRL-, and ACTH-producing adenomas and some non- on chromosome 11q13. Loss of heterozygosity, or a
functioning tumors. somatic mutation of the remaining normal MENIN allele,
Compelling evidence also favors growth factor pro- leads to tumorigenesis. About half of affected patients
motion of pituitary tumor proliferation. Basic fibroblast develop prolactinomas; acromegaly and Cushing’s syn-
growth factor (bFGF) is abundant in the pituitary and drome are less commonly encountered.
has been shown to stimulate pituitary cell mitogenesis. Carney syndrome is characterized by spotty skin pig-
Other factors involved in initiation and promotion of mentation, myxomas, and endocrine tumors, including
pituitary tumors include loss of negative-feedback inhi- testicular, adrenal, and pituitary adenomas. Acromeg-
bition (as seen with primary hypothyroidism or hypo- aly occurs in about 20% of these patients. A subset of
gonadism) and estrogen-mediated or paracrine angio- patients have mutations in the R1α regulatory subunit
genesis. Growth characteristics and neoplastic behavior of protein kinase A (PRKAR1A).
also may be influenced by several activated oncogenes, McCune-Albright syndrome consists of polyostotic
including RAS and pituitary tumor transforming gene fibrous dysplasia, pigmented skin patches, and a variety
(PTTG), or inactivation of growth suppressor genes, of endocrine disorders, including acromegaly, adrenal
including MEG3. adenomas, and autonomous ovarian function (Chap. 10).
Hormonal hypersecretion results from constitutive cyclic
AMP production caused by inactivation of the GTPase
Genetic syndromes associated with pituitary activity of Gsα. The Gsα mutations occur postzygoti-
tumors
cally, leading to a mosaic pattern of mutant expression.
Several familial syndromes are associated with pituitary Familial acromegaly is a rare disorder in which family
tumors, and the genetic mechanisms for some of them members may manifest either acromegaly or gigan-
have been unraveled (Table 2-6). tism. The disorder is associated with LOH at a chro-
Multiple endocrine neoplasia (MEN) 1 is an autoso- mosome 11q13 locus distinct from that of MENIN.
mal dominant syndrome characterized primarily by a A subset of families with a predisposition for famil-
genetic predisposition to parathyroid, pancreatic islet, ial pituitary tumors, especially acromegaly, have been
and pituitary adenomas (Chap. 23). MEN1 is caused found to harbor inactivating mutations in the AIP gene,
which encodes the aryl hydrocarbon receptor interact- Sella chordomas usually present with bony clival ero- 25
ing protein. sion, local invasiveness, and, on occasion, calcification.
Normal pituitary tissue may be visible on MRI, distin-

CHAPTER 2
guishing chordomas from aggressive pituitary adeno-
Other Sellar Masses mas. Mucinous material may be obtained by fine-needle
aspiration.
Craniopharyngiomas are benign, suprasellar cystic masses Meningiomas arising in the sellar region may be diffi-
that present with headaches, visual field deficits, and cult to distinguish from nonfunctioning pituitary adeno-
variable degrees of hypopituitarism. They are derived mas. Meningiomas typically enhance on MRI and may
from Rathke’s pouch and arise near the pituitary stalk, show evidence of calcification or bony erosion. Menin-

Disorders of the Anterior Pituitary and Hypothalamus


commonly extending into the suprasellar cistern. giomas may cause compressive symptoms.
Craniopharyngiomas are often large, cystic, and locally Histiocytosis X includes a variety of syndromes asso-
invasive. Many are partially calcified, exhibiting a char- ciated with foci of eosinophilic granulomas. Diabetes
acteristic appearance on skull x-ray and CT images. insipidus, exophthalmos, and punched-out lytic bone
More than half of all patients present before age 20, usu- lesions (Hand-Schüller-Christian disease) are associated
ally with signs of increased intracranial pressure, includ- with granulomatous lesions visible on MRI, as well as
ing headache, vomiting, papilledema, and hydrocephalus. a characteristic axillary skin rash. Rarely, the pituitary
Associated symptoms include visual field abnormalities, stalk may be involved.
personality changes and cognitive deterioration, cranial Pituitary metastases occur in ∼3% of cancer patients.
nerve damage, sleep difficulties, and weight gain. Hypo- Bloodborne metastatic deposits are found almost exclu-
pituitarism can be documented in about 90%, and dia- sively in the posterior pituitary. Accordingly, diabetes
betes insipidus occurs in about 10% of patients. About insipidus can be a presenting feature of lung, gastroin-
half of affected children present with growth retardation. testinal, breast, and other pituitary metastases. About
MRI is generally superior to CT for evaluating cystic half of pituitary metastases originate from breast cancer;
structure and tissue components of craniopharyngiomas. about 25% of patients with metastatic breast cancer have
CT is useful to define calcifications and evaluate invasion such deposits. Rarely, pituitary stalk involvement results
into surrounding bony structures and sinuses. in anterior pituitary insufficiency. The MRI diagno-
Treatment usually involves transcranial or trans­ sis of a metastatic lesion may be difficult to distinguish
sphenoidal surgical resection followed by postoperative from an aggressive pituitary adenoma; the diagnosis may
radiation of residual tumor. Surgery alone is curative in require histologic examination of excised tumor tissue.
less than half of patients because of recurrences due to Primary or metastatic lymphoma, leukemias, and plas-
adherence to vital structures or because of small tumor macytomas also occur within the sella.
deposits in the hypothalamus or brain parenchyma. The Hypothalamic hamartomas and gangliocytomas may arise
goal of surgery is to remove as much tumor as possible from astrocytes, oligodendrocytes, and neurons with
without risking complications associated with efforts varying degrees of differentiation. These tumors may
to remove firmly adherent or inaccessible tissue. In overexpress hypothalamic neuropeptides, including
the absence of radiotherapy, about 75% of craniopha- GnRH, GHRH, and CRH. With GnRH-producing
ryngiomas recur, and 10-year survival is less than 50%. tumors, children present with precocious puberty, psy-
In patients with incomplete resection, radiotherapy chomotor delay, and laughing-associated seizures. Med-
improves 10-year survival to 70–90% but is associated ical treatment of GnRH-producing hamartomas with
with increased risk of secondary malignancies. Most long-acting GnRH analogues effectively suppresses
patients require lifelong pituitary hormone replacement. gonadotropin secretion and controls premature puber-
Developmental failure of Rathke’s pouch oblit- tal development. Rarely, hamartomas also are associ-
eration may lead to Rathke’s cysts, which are small ated with craniofacial abnormalities; imperforate anus;
(<5 mm) cysts entrapped by squamous epithelium cardiac, renal, and lung disorders; and pituitary failure
and are found in about 20% of individuals at autopsy. as features of Pallister-Hall syndrome, which is caused by
Although Rathke’s cleft cysts do not usually grow and mutations in the carboxy terminus of the GLI3 gene.
are often diagnosed incidentally, about a third pres- Hypothalamic hamartomas are often contiguous with
ent in adulthood with compressive symptoms, diabetes the pituitary, and preoperative MRI diagnosis may not
insipidus, and hyperprolactinemia due to stalk compres- be possible. Histologic evidence of hypothalamic neu-
sion. Rarely, hydrocephalus develops. The diagnosis is rons in tissue resected at transsphenoidal surgery may be
suggested preoperatively by visualizing the cyst wall on the first indication of a primary hypothalamic lesion.
MRI, which distinguishes these lesions from craniopha- Hypothalamic gliomas and optic gliomas occur mainly in
ryngiomas. Cyst contents range from CSF-like fluid to childhood and usually present with visual loss. Adults
mucoid material. Arachnoid cysts are rare and generate an have more aggressive tumors; about a third are associ-
MRI image that is isointense with cerebrospinal fluid. ated with neurofibromatosis.
26 Brain germ-cell tumors may arise within the sellar Table 2-7
region. They include dysgerminomas, which frequently Features of Sellar Mass Lesionsa
are associated with diabetes insipidus and visual loss.
Impacted Structure Clinical Impact
They rarely metastasize. Germinomas, embryonal carcino-
SECTION I

mas, teratomas, and choriocarcinomas may arise in the para- Pituitary Hypogonadism
sellar region and produce hCG. These germ-cell tumors Hypothyroidism
present with precocious puberty, diabetes insipidus, Growth failure and adult
hyposomatotropism
visual field defects, and thirst disorders. Many patients
Hypoadrenalism
are GH deficient with short stature.
Optic chiasm Loss of red perception
Pituitary, Thyroid, and Adrenal Disorders

Bitemporal hemianopia
Metabolic Effects of Superior or bitemporal field
Hypothalamic Lesions defect
Scotoma
Lesions involving the anterior and preoptic hypo- Blindness
thalamic regions cause paradoxical vasoconstriction, Hypothalamus Temperature dysregulation
tachycardia, and hyperthermia. Acute hyperthermia Appetite and thirst disorders
usually is due to a hemorrhagic insult, but poikilother- Obesity
mia may also occur. Central disorders of thermoregula- Diabetes insipidus
tion result from posterior hypothalamic damage. The Sleep disorders
Behavioral dysfunction
periodic hypothermia syndrome is characterized by episodic
Autonomic dysfunction
attacks of rectal temperatures <30°C (86°F), sweating,
vasodilation, vomiting, and bradycardia. Damage to Cavernous sinus Opthalmoplegia with or without
ptosis or diplopia
the ventromedial hypothalamic nuclei by craniopha- Facial numbness
ryngiomas, hypothalamic trauma, or inflammatory dis-
Frontal lobe Personality disorder
orders may be associated with hyperphagia and obesity.
Anosmia
This region appears to contain an energy-satiety center
where melanocortin receptors are influenced by leptin, Brain Headache
Hydrocephalus
insulin, POMC products, and gastrointestinal peptides
Psychosis
(Chap. 16). Polydipsia and hypodipsia are associated Dementia
with damage to central osmoreceptors located in pre- Laughing seizures
optic nuclei (Chap. 3). Slow-growing hypothalamic
lesions can cause increased somnolence and disturbed a
As the intrasellar mass expands, it first compresses intrasellar pitu-
sleep cycles as well as obesity, hypothermia, and emo- itary tissue, then usually invades dorsally through the dura to lift the
tional outbursts. Lesions of the central hypothalamus may optic chiasm or laterally to the cavernous sinuses. Bony erosion is
rare, as is direct brain compression. Microadenomas may present
stimulate sympathetic neurons, leading to elevated serum with headache.
catecholamine and cortisol levels. These patients are pre-
disposed to cardiac arrhythmias, hypertension, and gastric
erosions. Suprasellar extension can lead to visual loss by sev-
eral mechanisms, the most common being compres-
sion of the optic chiasm, but rarely, direct invasion of
Evaluation the optic nerves or obstruction of CSF flow leading to
secondary visual disturbances also occurs. Pituitary stalk
Local mass effects
compression by a hormonally active or inactive intra-
Clinical manifestations of sellar lesions vary, depend- sellar mass may compress the portal vessels, disrupting
ing on the anatomic location of the mass and the pituitary access to hypothalamic hormones and dopa-
direction of its extension (Table 2-7). The dorsal sel- mine; this results in early hyperprolactinemia and later
lar diaphragm presents the least resistance to soft tissue concurrent loss of other pituitary hormones. This “stalk
expansion from the sella; consequently, pituitary adeno- section” phenomenon may also be caused by trauma,
mas frequently extend in a suprasellar direction. Bony whiplash injury with posterior clinoid stalk compres-
invasion may occur as well. sion, or skull base fractures. Lateral mass invasion may
Headaches are common features of small intrasellar impinge on the cavernous sinus and compress its neural
tumors, even with no demonstrable suprasellar exten- contents, leading to cranial nerve III, IV, and VI pal-
sion. Because of the confined nature of the pituitary, sies as well as effects on the ophthalmic and maxillary
small changes in intrasellar pressure stretch the dural branches of the fifth cranial nerve. Patients may present
plate; however, headache severity correlates poorly with with diplopia, ptosis, ophthalmoplegia, and decreased
adenoma size or extension. facial sensation, depending on the extent of neural
damage. Extension into the sphenoid sinus indicates that of surrounding normal tissue on T1-weighted imag- 27
the pituitary mass has eroded through the sellar floor. ing, and the signal intensity increases with T2-weighted
Aggressive tumors rarely invade the palate roof and images. The high phospholipid content of the posterior

CHAPTER 2
cause nasopharyngeal obstruction, infection, and CSF pituitary results in a “pituitary bright spot.”
leakage. Temporal and frontal lobe involvement may Sellar masses are encountered commonly as inciden-
rarely lead to uncinate seizures, personality disorders, tal findings on MRI, and most of them are pituitary
and anosmia. Direct hypothalamic encroachment by an adenomas (incidentalomas). In the absence of hormone
invasive pituitary mass may cause important metabolic hypersecretion, these small intrasellar lesions can be
sequelae, including precocious puberty or hypogonadism, monitored safely with MRI, which is performed annu-
diabetes insipidus, sleep disturbances, dysthermia, and ally and then less often if there is no evidence of further

Disorders of the Anterior Pituitary and Hypothalamus


appetite disorders. growth. Resection should be considered for incidentally
discovered macroadenomas, as about one-third become
MRI invasive or cause local pressure effects. If hormone
hypersecretion is evident, specific therapies are indi-
Sagittal and coronal T1-weighted MRI imaging before cated. When larger masses (>1 cm) are encountered,
and after administration of gadolinium allows precise they should also be distinguished from nonadenomatous
visualization of the pituitary gland with clear delinea- lesions. Meningiomas often are associated with bony
tion of the hypothalamus, pituitary stalk, pituitary tissue hyperostosis; craniopharyngiomas may be calcified and
and surrounding suprasellar cisterns, cavernous sinuses, are usually hypodense, whereas gliomas are hyperdense
sphenoid sinus, and optic chiasm. Pituitary gland height on T2-weighted images.
ranges from 6 mm in children to 8 mm in adults; during
pregnancy and puberty, the height may reach 10–12 mm.
Ophthalmologic evaluation
The upper aspect of the adult pituitary is flat or slightly
concave, but in adolescent and pregnant individuals, this Because optic tracts may be contiguous to an expand-
surface may be convex, reflecting physiologic pituitary ing pituitary mass, reproducible visual field assessment
enlargement. The stalk should be midline and vertical. using perimetry techniques should be performed on
CT scan is reserved to define the extent of bony erosion all patients with sellar mass lesions that abut the optic
or the presence of calcification. chiasm (Chap. 28). Bitemporal hemianopia or superior
Anterior pituitary gland soft tissue consistency is bitemporal defects are classically observed, reflecting the
slightly heterogeneous on MRI, and signal intensity location of these tracts within the inferior and poste-
resembles that of brain matter on T1-weighted imaging rior part of the chiasm. Homonymous cuts reflect post-
(Fig. 2-4). Adenoma density is usually lower than that chiasmal lesions, and monocular field cuts prechiasmal
lesions. Loss of red perception is an early sign of optic
tract pressure. Early diagnosis reduces the risk of blind-
ness, scotomas, or other visual disturbances.

Laboratory investigation
The presenting clinical features of functional pituitary
adenomas (e.g., acromegaly, prolactinomas, or Cush-
ing’s syndrome) should guide the laboratory studies
(Table 2-8). However, for a sellar mass with no obvi-
ous clinical features of hormone excess, laboratory stud-
ies are geared toward determining the nature of the
tumor and assessing the possible presence of hypopitu-
itarism. When a pituitary adenoma is suspected based
on MRI, initial hormonal evaluation usually includes
(1) basal PRL; (2) insulin-like growth factor (IGF) I;
(3) 24-h urinary free cortisol (UFC) and/or overnight
oral dexamethasone (1 mg) suppression test; (4) α sub-
unit, FSH, and LH; and (5) thyroid function tests.
Figure 2-4 Additional hormonal evaluation may be indicated based
Pituitary adenoma. Coronal T1-weighted postcontrast MR on the results of these tests. Pending more detailed
image shows a homogeneously enhancing mass (arrowheads) assessment of hypopituitarism, a menstrual history,
in the sella turcica and suprasellar region compatible with a measurement of testosterone and 8 a.m. cortisol levels,
pituitary adenoma; the small arrows outline the carotid arteries. and thyroid function tests usually identify patients with
28 Table 2-8
are benign and slow growing. Clinical features result
Screening Tests for Functional Pituitary
from local mass effects and hormonal hypo- or hyper-
Adenomas
secretion syndromes caused directly by the adenoma
SECTION I

Test Comments or occurring as a consequence of treatment. Thus, life-


Acromegaly Serum IGF-I Interpret IGF-I relative long management and follow-up are necessary for
to age- and sex- these patients.
matched controls MRI with gadolinium enhancement for pituitary
Oral glucose Normal subjects visualization, new advances in transsphenoidal surgery
tolerance should suppress and in stereotactic radiotherapy (including gamma-
Pituitary, Thyroid, and Adrenal Disorders

test with GH growth hormone to knife radiotherapy), and novel therapeutic agents have
obtained at 0, <1 μg/L improved pituitary tumor management. The goals of
30, and 60 min pituitary tumor treatment include normalization of
Prolactinoma Serum PRL Exclude medications excess pituitary secretion, amelioration of symptoms
MRI of the sella and signs of hormonal hypersecretion syndromes, and
should be ordered if shrinkage or ablation of large tumor masses with relief
prolactin is elevated of adjacent structure compression. Residual anterior
Cushing’s 24-h urinary free Ensure urine pituitary function should be preserved during treat-
disease cortisol collection is total ment and sometimes can be restored by removing the
and accurate tumor mass. Ideally, adenoma recurrence should be pre-
Dexamethasone Normal subjects vented.
(1 mg) at 11 p.m. suppress to
Transsphenoidal Surgery  Transsphenoi-
and fasting <5 μg/dL
plasma cortisol dal rather than transfrontal resection is the desired surgi-
measured at cal approach for pituitary tumors, except for the rare inva-
8 a.m. sive suprasellar mass surrounding the frontal or middle
ACTH assay Distinguishes adrenal fossa or the optic nerves or invading posteriorly behind
adenoma (ACTH the clivus. Intraoperative microscopy facilitates visual dis-
suppressed) from tinction between adenomatous and normal pituitary tis-
ectopic ACTH or sue as well as microdissection of small tumors that may
Cushing’s disease not be visible by MRI (Fig. 2-5). Transsphenoidal surgery
(ACTH normal or also avoids the cranial invasion and manipulation of brain
elevated)
tissue required by subfrontal surgical approaches. Endo-
scopic techniques with three-dimensional intraoperative
Note: For abbreviations, see text.
localization have also improved visualization and access
to tumor tissue.
pituitary hormone deficiencies that require hormone In addition to correction of hormonal hypersecre-
replacement before further testing or surgery. tion, pituitary surgery is indicated for mass lesions that
impinge on surrounding structures. Surgical decom-
Histologic evaluation pression and resection are required for an expanding
pituitary mass accompanied by persistent headache,
Immunohistochemical staining of pituitary tumor spec- progressive visual field defects, cranial nerve palsies,
imens obtained at transsphenoidal surgery confirms hydrocephalus, and, occasionally, intrapituitary hemor-
clinical and laboratory studies and provides a histologic rhage and apoplexy. Transsphenoidal surgery some-
diagnosis when hormone studies are equivocal and in times is used for pituitary tissue biopsy to establish a
cases of clinically nonfunctioning tumors. Occasion- histologic diagnosis.
ally, ultrastructural assessment by electron microscopy is Whenever possible, the pituitary mass lesion should
required for diagnosis. be selectively excised; normal pituitary tissue should be
manipulated or resected only when critical for effective
mass dissection. Nonselective hemihypophysectomy
 ypothalamic, Pituitary, and Other Sellar
H or total hypophysectomy may be indicated if no hyper-
Treatment
Masses secreting mass lesion is clearly discernible, multifocal
lesions are present, or the remaining nontumorous pitu-
Overview  Successful management of sellar itary tissue is obviously necrotic. This strategy, however,
masses requires accurate diagnosis as well as selection increases the likelihood of hypopituitarism and the
of optimal therapeutic modalities. Most pituitary tumors need for lifelong hormone replacement.
Optic chiasm
29
Pituitary tumor
perforation, or visual disturbances may be encoun-
tered in up to 10% of patients. CSF leaks occur in 4% of
Internal carotid
Oculomotor
patients. Less common complications include carotid

CHAPTER 2
nerve artery
artery injury, loss of vision, hypothalamic damage, and
Trochlear Venus plexus
nerve of cavernous meningitis. Permanent side effects are rare after surgery
Trigeminal
sinus
for microadenomas.
nerve Sphenoid
sinus
Radiation  Radiation is used either as a primary
therapy for pituitary or parasellar masses or, more com-

Disorders of the Anterior Pituitary and Hypothalamus


Sphenoid
monly, as an adjunct to surgery or medical therapy.
Nasal septum
bone Focused megavoltage irradiation is achieved by precise
Surgical curette MRI localization, using a high-voltage linear accelerator
and accurate isocentric rotational arcing. A major deter-
minant of accurate irradiation is reproduction of the
patient’s head position during multiple visits and main-
tenance of absolute head immobility. A total of <50 Gy
(5000 rad) is given as 180-cGy (180-rad) fractions divided
over about 6 weeks. Stereotactic radiosurgery delivers a
large single high-energy dose from a cobalt 60 source
(gamma knife), linear accelerator, or cyclotron. Long-
term effects of gamma-knife surgery are unclear but
appear to be similar to those encountered with conven-
tional radiation.
The role of radiation therapy in pituitary tumor
management depends on multiple factors, including
Pituitary the nature of the tumor, the age of the patient, and the
tumor
availability of surgical and radiation expertise. Because
of its relatively slow onset of action, radiation therapy
is usually reserved for postsurgical management. As an
Sphenoid adjuvant to surgery, radiation is used to treat residual
sinus
tumor and in an attempt to prevent regrowth. Irradia-
Figure 2-5  tion offers the only means for potentially ablating sig-
Transsphenoidal resection of pituitary mass via the endo- nificant postoperative residual nonfunctioning tumor
nasal approach. (Adapted from R Fahlbusch: Endocrinol tissue. In contrast, PRL- and GH-secreting tumor tissues
Metab Clin 21:669, 1992.) are amenable to medical therapy.

Side Effects  In the short term, radiation may cause


Preoperative mass effects, including visual field transient nausea and weakness. Alopecia and loss of
defects and compromised pituitary function, may be taste and smell may be more long lasting. Failure of
reversed by surgery, particularly when the deficits are pituitary hormone synthesis is common in patients
not long-standing. For large and invasive tumors, it is who have undergone head and neck or pituitary-
necessary to determine the optimal balance between directed irradiation. More than 50% of patients develop
maximal tumor resection and preservation of anterior loss of GH, ACTH, TSH, and/or gonadotropin secretion
pituitary function, especially for preserving growth and within 10 years, usually due to hypothalamic damage.
reproductive function in younger patients. Similarly, Lifelong follow-up with testing of anterior pituitary
tumor invasion outside the sella is rarely amenable to hormone reserve is therefore required after radiation
surgical cure; the surgeon must judge the risk-versus- treatment. Optic nerve damage with impaired vision
benefit ratio of extensive tumor resection. due to optic neuritis is reported in about 2% of patients
who undergo pituitary irradiation. Cranial nerve dam-
Side Effects  Tumor size, the degree of invasiveness, age is uncommon now that radiation doses are ≤2 Gy
and experience of the surgeon largely determine the (200 rad) at any one treatment session and the maxi-
incidence of surgical complications. Operative mortality mum dose is <50 Gy (5000 rad). The use of stereotactic
rate is about 1%. Transient diabetes insipidus and hypo- radiotherapy may reduce damage to adjacent struc-
pituitarism occur in up to 20% of patients. Permanent tures. Radiotherapy for pituitary tumors has been
diabetes insipidus, cranial nerve damage, nasal septal associated with adverse mortality rates, mainly from
30 prolactin release within 15–30 min after intravenous
cerebrovascular disease. The cumulative risk of develop- injection. The physiologic relevance of TRH for PRL
ing a secondary tumor after conventional radiation is regulation is unclear, and it appears primarily to regulate
1.3% after 10 years and 1.9% after 20 years. TSH (Chap. 4). Vasoactive intestinal peptide (VIP) also
SECTION I

Medical  Medical therapy for pituitary tumors is induces PRL release, whereas glucocorticoids and thy-
highly specific and depends on tumor type. For pro- roid hormone weakly suppress PRL secretion.
lactinomas, dopamine agonists are the treatment of Serum PRL levels rise transiently after exercise,
choice. For acromegaly, somatostatin analogues and meals, sexual intercourse, minor surgical procedures,
GH receptor antagonists are indicated. For TSH-secret- general anesthesia, chest wall injury, acute myocardial
infarction, and other forms of acute stress. PRL levels
Pituitary, Thyroid, and Adrenal Disorders

ing tumors, somatostatin analogues and occasion-


ally dopamine agonists are indicated. ACTH-secreting increase markedly (about tenfold) during pregnancy and
tumors and nonfunctioning tumors are generally not decline rapidly within 2 weeks of parturition. If breast-
responsive to medications and require surgery and/or feeding is initiated, basal PRL levels remain elevated;
irradiation. suckling stimulates reflex increases in PRL levels that
last for about 30–45 min. Breast suckling activates neu-
ral afferent pathways in the hypothalamus that induce
PRL release. With time, suckling-induced responses
Prolactin diminish and interfeeding PRL levels return to normal.
Synthesis
PRL consists of 198 amino acids and has a molecular Action
mass of 21,500 kDa; it is weakly homologous to GH The PRL receptor is a member of the type I cytokine
and human placental lactogen (hPL), reflecting the receptor family that also includes GH and interleu-
duplication and divergence of a common GH-PRL- kin (IL) 6 receptors. Ligand binding induces receptor
hPL precursor gene. PRL is synthesized in lactotropes, dimerization and intracellular signaling by Janus kinase
which constitute about 20% of anterior pituitary cells. (JAK), which stimulates translocation of the signal trans-
Lactotropes and somatotropes are derived from a com- duction and activators of transcription (STAT) family
mon precursor cell that may give rise to a tumor that to activate target genes. In the breast, the lobuloalveo-
secretes both PRL and GH. Marked lactotrope cell lar epithelium proliferates in response to PRL, placen-
hyperplasia develops during pregnancy and the first few tal lactogens, estrogen, progesterone, and local paracrine
months of lactation. These transient functional changes growth factors, including IGF-I.
in the lactotrope population are induced by estrogen. PRL acts to induce and maintain lactation, decrease
reproductive function, and suppress sexual drive. These
Secretion functions are geared toward ensuring that maternal lac-
tation is sustained and not interrupted by pregnancy.
Normal adult serum PRL levels are about 10–25 μg/L PRL inhibits reproductive function by suppressing
in women and 10–20 μg/L in men. PRL secretion is hypothalamic GnRH and pituitary gonadotropin secre-
pulsatile, with the highest secretory peaks occurring dur- tion and by impairing gonadal steroidogenesis in both
ing rapid eye movement sleep. Peak serum PRL levels women and men. In the ovary, PRL blocks folliculo-
(up to 30 μg/L) occur between 4:00 and 6:00 a.m. The genesis and inhibits granulosa cell aromatase activity,
circulating half-life of PRL is about 50 min. leading to hypoestrogenism and anovulation. PRL also
PRL is unique among the pituitary hormones in that has a luteolytic effect, generating a shortened, or inad-
the predominant central control mechanism is inhibi- equate, luteal phase of the menstrual cycle. In men,
tory, reflecting dopamine-mediated suppression of PRL attenuated LH secretion leads to low testosterone lev-
release. This regulatory pathway accounts for the spon- els and decreased spermatogenesis. These hormonal
taneous PRL hypersecretion that occurs with pituitary changes decrease libido and reduce fertility in patients
stalk section, often a consequence of compressive mass with hyperprolactinemia.
lesions at the skull base. Pituitary dopamine type 2 (D2)
receptors mediate inhibition of PRL synthesis and secre-
tion. Targeted disruption (gene knockout) of the murine Hyperprolactinemia
D2 receptor in mice results in hyperprolactinemia and
Etiology
lactotrope proliferation. As discussed below, dopamine
agonists play a central role in the management of hyper- Hyperprolactinemia is the most common pituitary hor-
prolactinemic disorders. mone hypersecretion syndrome in both men and women.
Thyrotropin-releasing hormone (TRH) (pyro Glu- PRL-secreting pituitary adenomas (prolactinomas)
His-Pro-NH2) is a hypothalamic tripeptide that elicits are the most common cause of PRL levels >200 μg/L
(see below). Less pronounced PRL elevation can also be delivery, or lactotrope responses are associated with 31
seen with microprolactinomas but is more commonly hyperprolactinemia. Thus, hypothalamic tumors, cysts,
caused by drugs, pituitary stalk compression, hypothy- infiltrative disorders, and radiation-induced dam-

CHAPTER 2
roidism, or renal failure (Table 2-9). age cause elevated PRL levels, usually in the range of
Pregnancy and lactation are the important physi- 30–100 μg/L. Plurihormonal adenomas (including GH
ologic causes of hyperprolactinemia. Sleep-associated and ACTH tumors) may hypersecrete PRL directly.
hyperprolactinemia reverts to normal within an hour of Pituitary masses, including clinically nonfunctioning
awakening. Nipple stimulation and sexual orgasm also pituitary tumors, may compress the pituitary stalk to
may increase PRL. Chest wall stimulation or trauma cause hyperprolactinemia.
(including chest surgery and herpes zoster) invoke the Drug-induced inhibition or disruption of dopami-

Disorders of the Anterior Pituitary and Hypothalamus


reflex suckling arc with resultant hyperprolactinemia. nergic receptor function is a common cause of hyper-
Chronic renal failure elevates PRL by decreasing prolactinemia (Table 2-9). Thus, antipsychotics and
peripheral clearance. Primary hypothyroidism is associ- antidepressants are a relatively common cause of mild
ated with mild hyperprolactinemia, probably because of hyperprolactinemia. Most patients receiving risperi-
compensatory TRH secretion. done have elevated prolactin levels, sometimes exceed-
Lesions of the hypothalamic-pituitary region that ing 200 ug/L. Methyldopa inhibits dopamine synthesis
disrupt hypothalamic dopamine synthesis, portal vessel and verapamil blocks dopamine release, also leading to
hyperprolactinemia. Hormonal agents that induce PRL
Table 2-9 include estrogens and TRH.
Etiology of Hyperprolactinemia
I. Physiologic V. Drug-induced Presentation and diagnosis
  hypersecretion   hypersecretion Amenorrhea, galactorrhea, and infertility are the hall-
Pregnancy Dopamine receptor
marks of hyperprolactinemia in women. If hyperprolac-
Lactation   blockers
Chest wall stimulation Atypical tinemia develops before menarche, primary amenorrhea
Sleep antipsychotics: results. More commonly, hyperprolactinemia develops
Stress risperidone later in life and leads to oligomenorrhea and ultimately
II. Hypothalamic–pituitary Phenothiazines: to amenorrhea. If hyperprolactinemia is sustained, ver-
  stalk damage chlorpromazine, tebral bone mineral density can be reduced compared
Tumors perphenazine with age-matched controls, particularly when it is asso-
  Craniopharyngioma Butyrophenones:
ciated with pronounced hypoestrogenemia. Galac-
Suprasellar pituitary haloperidol
mass Thioxanthenes
torrhea is present in up to 80% of hyperprolactinemic
Meningioma Metoclopramide women. Although usually bilateral and spontaneous, it
Dysgerminoma Dopamine synthesis may be unilateral or expressed only manually. Patients
Metastases   inhibitors also may complain of decreased libido, weight gain, and
Empty sella α-Methyldopa mild hirsutism.
Lymphocytic hypophysitis Catecholamine In men with hyperprolactinemia, diminished libido,
Adenoma with stalk   depletors infertility, and visual loss (from optic nerve compres-
  compression Reserpine
Granulomas Opiates
sion) are the usual presenting symptoms. Gonadotropin
Rathke’s cyst H2 antagonists suppression leads to reduced testosterone, impotence,
Irradiation Cimetidine, and oligospermia. True galactorrhea is uncommon in
Trauma ranitidine men with hyperprolactinemia. If the disorder is long-
Pituitary stalk section Imipramines standing, secondary effects of hypogonadism are evi-
Suprasellar surgery Amitriptyline, dent, including osteopenia, reduced muscle mass, and
III. Pituitary hypersecretion amoxapine decreased beard growth.
Prolactinoma Serotonin reuptake
The diagnosis of idiopathic hyperprolactinemia is
Acromegaly   inhibitors
IV. Systemic disorders Fluoxetine made by exclusion of known causes of hyperprolac-
Chronic renal failure Calcium channel tinemia in the setting of a normal pituitary MRI. Some
Hypothyroidism   blockers of these patients may harbor small microadenomas
Cirrhosis Verapamil below visible MRI sensitivity (∼2 mm).
Pseudocyesis Estrogens
Epileptic seizures TRH
Galactorrhea
Note: Hyperprolactinemia >200 μg/L almost invariably is indica-
tive of a prolactin-secreting pituitary adenoma. Physiologic causes,
Galactorrhea, the inappropriate discharge of milk-containing
hypothyroidism, and drug-induced hyperprolactinemia should be fluid from the breast, is considered abnormal if it persists
excluded before extensive evaluation. longer than 6 months after childbirth or discontinuation
32 of breast-feeding. Postpartum galactorrhea associated
Resection of hypothalamic or sellar mass lesions can
with amenorrhea is a self-limiting disorder usually asso-
reverse hyperprolactinemia caused by stalk compres-
ciated with moderately elevated PRL levels. Galactor-
sion and reduced dopamine tone. Granulomatous infil-
rhea may occur spontaneously, or it may be elicited by
SECTION I

trates occasionally respond to glucocorticoid admin-


nipple pressure. In both men and women, galactorrhea
istration. In patients with irreversible hypothalamic
may vary in color and consistency (transparent, milky,
damage, no treatment may be warranted. In up to 30%
or bloody) and arise either unilaterally or bilaterally.
of patients with hyperprolactinemia—usually without
Mammography or ultrasound is indicated for bloody
a visible pituitary microadenoma—the condition may
discharges (particularly from a single nipple), which
may be caused by breast cancer. Galactorrhea is com- resolve spontaneously.
Pituitary, Thyroid, and Adrenal Disorders

monly associated with hyperprolactinemia caused by


any of the conditions listed in Table 2-9. Acromegaly Prolactinoma
is associated with galactorrhea in about one-third of
patients. Treatment of galactorrhea usually involves Etiology and prevalence
managing the underlying disorder (e.g., replacing T4 for Tumors arising from lactotrope cells account for
hypothyroidism, discontinuing a medication, treating about half of all functioning pituitary tumors, with a
prolactinoma). population prevalence of ∼10/100,000 in men and
∼30/100,000 in women. Mixed tumors that secrete
Laboratory investigation combinations of GH and PRL, ACTH and PRL, and
rarely TSH and PRL are also seen. These plurihor-
Basal, fasting morning PRL levels (normally <20 μg/L) monal tumors are usually recognized by immuno-
should be measured to assess hypersecretion. Both histochemistry, sometimes without apparent clinical
false-positive and false-negative results may be manifestations from the production of additional hor-
encountered. In patients with markedly elevated PRL mones. Microadenomas are classified as <1 cm in diam-
levels (>1000 μg/L), reported results may be falsely eter and usually do not invade the parasellar region.
lowered because of assay artifacts; sample dilution Macroadenomas are >1 cm in diameter and may be
is required to measure these high values accurately. locally invasive and impinge on adjacent structures.
Falsely elevated values may be caused by aggregated The female:male ratio for microprolactinomas is 20:1,
forms of circulating PRL, which are usually biologi- whereas the sex ratio is near 1:1 for macroadenomas.
cally inactive (macroprolactinemia). Hypothyroidism Tumor size generally correlates directly with PRL con-
should be excluded by measuring TSH and T4 levels. centrations; values >250 μg/L usually are associated
with macroadenomas. Men tend to present with larger
tumors than women, possibly because the features of
Treatment Hyperprolactinemia male hypogonadism are less readily evident. PRL lev-
els remain stable in most patients, reflecting the slow
Treatment of hyperprolactinemia depends on the growth of these tumors. About 5% of microadenomas
cause of elevated PRL levels. Regardless of the etiol- progress in the long term to macroadenomas.
ogy, however, treatment should be aimed at normal-
izing PRL levels to alleviate suppressive effects on Presentation and diagnosis
gonadal function, halt galactorrhea, and preserve
Women usually present with amenorrhea, infertility,
bone mineral density. Dopamine agonists are effective
and galactorrhea. If the tumor extends outside the sella,
for most causes of hyperprolactinemia (see the treat-
visual field defects or other mass effects may be seen.
ment section for prolactinoma, below) regardless of
Men often present with impotence, loss of libido, infer-
the underlying cause.
tility, or signs of central CNS compression, including
If the patient is taking a medication known to cause
headaches and visual defects. Assuming that physiologic
hyperprolactinemia, the drug should be withdrawn, if
and medication-induced causes of hyperprolactinemia
possible. For psychiatric patients who require neuro-
are excluded (Table 2-9), the diagnosis of prolacti-
leptic agents, supervised dose titration or the addition
noma is likely with a PRL level >200 μg/L. PRL levels
of a dopamine agonist can help restore normoprolac-
<100 μg/L may be caused by microadenomas, other
tinemia and alleviate reproductive symptoms. However,
sellar lesions that decrease dopamine inhibition, or non-
dopamine agonists sometimes worsen the underlying
neoplastic causes of hyperprolactinemia. For this reason,
psychiatric condition, especially at high doses. Hyper-
an MRI should be performed in all patients with hyper-
prolactinemia usually resolves after adequate thyroid
prolactinemia. It is important to remember that hy-
hormone replacement in hypothyroid patients or after
perprolactinemia caused secondarily by the mass effects of
renal transplantation in patients undergoing dialysis. nonlactotrope lesions is also corrected by treatment with
MANAGEMENT OF PROLACTINOMA 33
ELEVATED PROLACTIN LEVELS

CHAPTER 2
Exclude secondary causes of hyperprolactinemia
MRI evidence for pituitary mass

Symptomatic Prolactinoma
Test visual
fields
Macroadenoma

Disorders of the Anterior Pituitary and Hypothalamus


Microadenoma
Test pituitary
reserve function

Titrate Titrate
Drug intolerance
dopamine agonist dopamine agonist

Change Repeat MRI


Serum PRL dopamine agonist within 4 months

,20 20–50 .50 (mg/L) No tumor shrinkage Tumor shrinkage


or tumor growth and prolactin
or persistent normalized
Maintenance Reassess hyperprolactinemia
Rx diagnosis
Increase dose Consider Surgery Monitor PRL
and repeat
MRI annually

Figure 2-6 
Management of prolactinoma. MRI, magnetic resonance imaging; PRL, prolactin.

dopamine agonists despite failure to shrink the underly-


Medical  Oral dopamine agonists (cabergoline and
ing mass. Consequently, PRL suppression by dopamine
agonists does not necessarily indicate that the underlying bromocriptine) are the mainstay of therapy for patients
lesion is a prolactinoma. with micro- or macroprolactinomas. Dopamine agonists
suppress PRL secretion and synthesis as well as lacto-
trope cell proliferation. In patients with microadenomas
Treatment Prolactinoma who have achieved normoprolactinemia and significant
reduction of tumor mass, the dopamine agonist may be
As microadenomas rarely progress to become macroad- withdrawn after 2 years. These patients should be moni-
enomas, no treatment may be needed if fertility is not tored carefully for evidence of prolactinoma recurrence.
desired. Estrogen replacement is indicated to prevent About 20% of patients (especially males) are resistant to
bone loss and other consequences of hypoestrogen- dopaminergic treatment; these adenomas may exhibit
emia and does not appear to increase the risk of tumor decreased D2 dopamine receptor numbers or a postre-
enlargement; these patients should be monitored by ceptor defect. D2 receptor gene mutations in the pitu-
regular serial PRL and MRI measurements. itary have not been reported.
For symptomatic microadenomas, therapeutic goals
include control of hyperprolactinemia, reduction of Cabergoline  An ergoline derivative, cabergoline
tumor size, restoration of menses and fertility, and reso- is a long-acting dopamine agonist with high D2 recep-
lution of galactorrhea. Dopamine agonist doses should tor affinity. The drug effectively suppresses PRL for
be titrated to achieve maximal PRL suppression and >14 days after a single oral dose and induces prolacti-
restoration of reproductive function (Fig. 2-6). A nor- noma shrinkage in most patients. Cabergoline (0.5 to
malized PRL level does not ensure reduced tumor size. 1.0 mg twice weekly) achieves normoprolactinemia
However, tumor shrinkage usually is not seen in those and resumption of normal gonadal function in ∼80% of
who do not respond with lowered PRL levels. For mac- patients with microadenomas; galactorrhea improves or
roadenomas, formal visual field testing should be per- resolves in 90% of patients. Cabergoline normalizes PRL
formed before initiating dopamine agonists. MRI and and shrinks ∼70% of macroprolactinomas. Mass effect
visual fields should be assessed at 6- to 12-month inter- symptoms, including headaches and visual disorders,
vals until the mass shrinks and annually thereafter until usually improve dramatically within days after cabergo-
maximum size reduction has occurred. line initiation; improvement of sexual function requires
34 several weeks of treatment but may occur before com- Surgery  Indications for surgical adenoma debulking
plete normalization of prolactin levels. After initial con- include dopamine resistance or intolerance and the pres-
trol of PRL levels has been achieved, cabergoline should ence of an invasive macroadenoma with compromised
SECTION I

be reduced to the lowest effective maintenance dose. vision that fails to improve after drug treatment. Initial
In ∼5% of treated patients harboring a microadenoma, PRL normalization is achieved in about 70% of micro-
hyperprolactinemia may resolve and not recur when prolactinomas after surgical resection, but only 30% of
dopamine agonists are discontinued after long-term macroadenomas can be resected successfully. Follow-up
treatment. Cabergoline also may be effective in patients studies have shown that hyperprolactinemia recurs in up
resistant to bromocriptine. Adverse effects and drug to 20% of patients within the first year after surgery; long-
Pituitary, Thyroid, and Adrenal Disorders

intolerance are encountered less commonly than with term recurrence rates exceed 50% for macroadenomas.
bromocriptine. Radiotherapy for prolactinomas is reserved for patients
with aggressive tumors that do not respond to maximally
Bromocriptine  The ergot alkaloid bromocrip- tolerated dopamine agonists and/or surgery.
tine mesylate is a dopamine receptor agonist that sup-
presses prolactin secretion. Because it is short acting, Pregnancy  The pituitary increases in size during
the drug is preferred when pregnancy is desired. In pregnancy, reflecting the stimulatory effects of estrogen
microadenomas bromocriptine rapidly lowers serum and perhaps other growth factors on pituitary vascular-
prolactin levels to normal in up to 70% of patients, ity and lactotrope cell hyperplasia. About 5% of micro-
decreases tumor size, and restores gonadal function. In adenomas significantly increase in size, but 15–30% of
patients with macroadenomas, prolactin levels are also macroadenomas grow during pregnancy. Bromocrip-
normalized in 70% of patients and tumor mass shrink- tine has been used for more than 30 years to restore
age (≥50%) is achieved in most patients. fertility in women with hyperprolactinemia, without
Therapy is initiated by administering a low bromocrip- evidence of teratogenic effects. Nonetheless, most
tine dose (0.625–1.25 mg) at bedtime with a snack, fol- authorities recommend strategies to minimize fetal
lowed by gradually increasing the dose. Most patients exposure to the drug. For women taking bromocrip-
are controlled with a daily dose of ≤7.5 mg (2.5 mg tid). tine who desire pregnancy, mechanical contraception
should be used through three regular menstrual cycles
Side Effects  Side effects of dopamine agonists to allow for conception timing. When pregnancy is
include constipation, nasal stuffiness, dry mouth, night- confirmed, bromocriptine should be discontinued and
mares, insomnia, and vertigo; decreasing the dose usu- PRL levels followed serially, especially if headaches or
ally alleviates these problems. Nausea, vomiting, and visual symptoms occur. For women harboring macroad-
postural hypotension with faintness may occur in ∼25% enomas, regular visual field testing is recommended,
of patients after the initial dose. These symptoms may and the drug should be reinstituted if tumor growth is
persist in some patients. In general, fewer side effects apparent. Although pituitary MRI may be safe during
are reported with cabergoline. For the approximately pregnancy, this procedure should be reserved for symp-
15% of patients who are intolerant of oral bromocrip- tomatic patients with severe headache and/or visual
tine, cabergoline may be better tolerated. Intravaginal field defects. Surgical decompression may be indicated
administration of bromocriptine is often efficacious in if vision is threatened. Although comprehensive data
patients with intractable gastrointestinal side effects. support the efficacy and relative safety of bromocriptine-
Auditory hallucinations, delusions, and mood swings facilitated fertility, patients should be advised of poten-
have been reported in up to 5% of patients and may tial unknown deleterious effects and the risk of tumor
be due to the dopamine agonist properties or to the growth during pregnancy. As cabergoline is long acting
lysergic acid derivative of the compounds. Rare reports with a high D2-receptor affinity, it is not recommended
of leukopenia, thrombocytopenia, pleural fibrosis, car- for use in women when fertility is desired.
diac arrhythmias, and hepatitis have been described.
Patients with Parkinson’s disease who receive at least
3 mg of cabergoline daily have been reported to be
Growth Hormone
at risk for development of cardiac valve regurgita-
tion. Studies analyzing over 500 prolactinoma patients Synthesis
receiving recommended doses of cabergoline (up to
2 mg weekly) have shown no evidence for an increased GH is the most abundant anterior pituitary hormone,
incidence of valvular disorders. Nevertheless, as no con- and GH-secreting somatotrope cells constitute up to 50%
trolled prospective studies are available, it is prudent to of the total anterior pituitary cell population. Mammo-
perform echocardiograms before initiating standard- somatotrope cells, which coexpress PRL with GH, can
dose cabergoline therapy. be identified by using double immunostaining tech-
niques. Somatotrope development and GH transcription
are determined by expression of the cell-specific Pit-1 ∼50% of daytime samples obtained from healthy sub- 35
nuclear transcription factor. Five distinct genes encode jects and are also undetectable in most obese and elderly
GH and related proteins. The pituitary GH gene (hGH-N) subjects. Thus, single random GH measurements do not

CHAPTER 2
produces two alternatively spliced products that give distinguish patients with adult GH deficiency from nor-
rise to 22-kDa GH (191 amino acids) and a less abun- mal persons.
dant 20-kDa GH molecule with similar biologic activity. GH secretion is profoundly influenced by nutritional
Placental syncytiotrophoblast cells express a GH variant factors. Using newer ultrasensitive GH assays with a
(hGH-V) gene; the related hormone human chorionic sensitivity of 0.002 μg/L, a glucose load suppresses GH
somatotropin (HCS) is expressed by distinct members of to <0.7 μg/L in women and to <0.07 μg/L in men.
the gene cluster. Increased GH pulse frequency and peak amplitudes

Disorders of the Anterior Pituitary and Hypothalamus


occur with chronic malnutrition or prolonged fasting.
Secretion GH is stimulated by intravenous l-arginine, dopamine,
and apomorphine (a dopamine receptor agonist), as well
GH secretion is controlled by complex hypothalamic as by α-adrenergic pathways. β-Adrenergic blockage
and peripheral factors. GHRH is a 44-amino-acid induces basal GH and enhances GHRH- and insulin-
hypothalamic peptide that stimulates GH synthesis evoked GH release.
and release. Ghrelin, an octanoylated gastric-derived
peptide, and synthetic agonists of the GHS-R induce
GHRH and also directly stimulate GH release. Soma- Action
tostatin [somatotropin-release inhibiting factor (SRIF)] is The pattern of GH secretion may affect tissue responses.
synthesized in the medial preoptic area of the hypothal- The higher GH pulsatility observed in men compared
amus and inhibits GH secretion. GHRH is secreted in with the relatively continuous GH secretion in women
discrete spikes that elicit GH pulses, whereas SRIF sets may be an important biologic determinant of linear
basal GH secretory tone. SRIF also is expressed in many growth patterns and liver enzyme induction.
extrahypothalamic tissues, including the CNS, gastroin- The 70-kDa peripheral GH receptor protein has
testinal tract, and pancreas, where it also acts to inhibit structural homology with the cytokine/hematopoi-
islet hormone secretion. IGF-I, the peripheral target etic superfamily. A fragment of the receptor extracel-
hormone for GH, feeds back to inhibit GH; estrogen lular domain generates a soluble GH-binding protein
induces GH, whereas chronic glucocorticoid excess (GHBP) that interacts with GH in the circulation. The
suppresses GH release. liver and cartilage contain the greatest number of GH
Surface receptors on the somatotrope regulate GH receptors. GH binding to preformed receptor dimers is
synthesis and secretion. The GHRH receptor is a followed by internal rotation and subsequent signaling
G protein–coupled receptor (GPCR) that signals through the JAK/STAT pathway. Activated STAT pro-
through the intracellular cyclic AMP pathway to stimu- teins translocate to the nucleus, where they modulate
late somatotrope cell proliferation as well as GH pro- expression of GH-regulated target genes. GH analogues
duction. Inactivating mutations of the GHRH receptor that bind to the receptor but are incapable of mediating
cause profound dwarfism (see below). A distinct surface receptor signaling are potent antagonists of GH action.
receptor for ghrelin, the gastric-derived GH secreta- A GH receptor antagonist (pegvisomant) is approved for
gogue, is expressed in the hypothalamus and pituitary. treatment of acromegaly.
Somatostatin binds to five distinct receptor subtypes GH induces protein synthesis and nitrogen retention
(SSTR1 to SSTR5); SSTR2 and SSTR5 subtypes pref- and impairs glucose tolerance by antagonizing insulin
erentially suppress GH (and TSH) secretion. action. GH also stimulates lipolysis, leading to increased
GH secretion is pulsatile, with highest peak lev- circulating fatty acid levels, reduced omental fat mass,
els occurring at night, generally correlating with sleep and enhanced lean body mass. GH promotes sodium,
onset. GH secretory rates decline markedly with age potassium, and water retention and elevates serum levels
so that hormone levels in middle age are about 15% of inorganic phosphate. Linear bone growth occurs as a
of pubertal levels. These changes are paralleled by an result of complex hormonal and growth factor actions,
age-related decline in lean muscle mass. GH secretion including those of IGF-I. GH stimulates epiphyseal
is also reduced in obese individuals, though IGF-I lev- prechondrocyte differentiation. These precursor cells
els may not be suppressed, suggesting a change in the produce IGF-I locally, and their proliferation is also
setpoint for feedback control. Elevated GH levels occur responsive to the growth factor.
within an hour of deep sleep onset as well as after exer-
cise, physical stress, and trauma and during sepsis. Inte-
Insulin-Like Growth Factors
grated 24-h GH secretion is higher in women and is
also enhanced by estrogen replacement. Using standard Although GH exerts direct effects in target tissues,
assays, random GH measurements are undetectable in many of its physiologic effects are mediated indirectly
36 through IGF-I, a potent growth and differentiation fac- growth-promoting process also requires caloric energy,
tor. The liver is the major source of circulating IGF-I. amino acids, vitamins, and trace metals and consumes
In peripheral tissues, IGF-I exerts local paracrine actions about 10% of normal energy production. Malnutrition
that appear to be both dependent on and independent impairs chondrocyte activity and reduces circulating
SECTION I

of GH. Thus, GH administration induces circulating IGF-I and IGFBP3 levels.


IGF-I as well as stimulating local IGF-I production in Linear bone growth rates are very high in infancy
multiple tissues. and are pituitary dependent. Mean growth velocity is
Both IGF-I and IGF-II are bound to high-affinity ∼6 cm/year in later childhood and usually is maintained
circulating IGF-binding proteins (IGFBPs) that regulate within a given range on a standardized percentile chart.
IGF bioactivity. Levels of IGFBP3 are GH dependent, Peak growth rates occur during midpuberty when bone
Pituitary, Thyroid, and Adrenal Disorders

and it serves as the major carrier protein for circulating age is 12 (girls) or 13 (boys). Secondary sexual develop-
IGF-I. GH deficiency and malnutrition usually are asso- ment is associated with elevated sex steroids that cause
ciated with low IGFBP3 levels. IGFBP1 and IGFBP2 progressive epiphyseal growth plate closure. Bone age is
regulate local tissue IGF action but do not bind appre- delayed in patients with all forms of true GH deficiency
ciable amounts of circulating IGF-I. or GH receptor defects that result in attenuated GH
Serum IGF-I concentrations are profoundly affected action.
by physiologic factors. Levels increase during puberty, Short stature may occur as a result of constitutive
peak at 16 years, and subsequently decline by >80% intrinsic growth defects or because of acquired extrin-
during the aging process. IGF-I concentrations are sic factors that impair growth. In general, delayed bone
higher in women than in men. Because GH is the age in a child with short stature is suggestive of a hor-
major determinant of hepatic IGF-I synthesis, abnor- monal or systemic disorder, whereas normal bone age
malities of GH synthesis or action (e.g., pituitary failure, in a short child is more likely to be caused by a genetic
GHRH receptor defect, GH receptor defect) reduce cartilage dysplasia or growth plate disorder.
IGF-I levels. Hypocaloric states are associated with GH
resistance; IGF-I levels are therefore low with cachexia, GH deficiency in children
malnutrition, and sepsis. In acromegaly, IGF-I levels are
invariably high and reflect a log-linear relationship with GH deficiency
GH concentrations. Isolated GH deficiency is characterized by short stat-
ure, micropenis, increased fat, high-pitched voice, and
a propensity to hypoglycemia due to relatively unop-
IGF-I physiology posed insulin action. Familial modes of inheritance
IGF-I has been approved for use in patients with GH- are seen in one-third of these individuals and may be
resistance syndromes. Injected IGF-I (100 μg/kg) autosomal dominant, recessive, or X-linked. About
induces hypoglycemia, and lower doses improve insu- 10% of children with GH deficiency have mutations in
lin sensitivity in patients with severe insulin resistance the GH-N gene, including gene deletions and a wide
and diabetes. In cachectic subjects, IGF-I infusion range of point mutations. Mutations in transcription
(12 μg/kg per hour) enhances nitrogen retention and factors Pit-1 and Prop-1, which control somatotrope
lowers cholesterol levels. Longer-term subcutaneous development, result in GH deficiency in combination
IGF-I injections enhance protein synthesis and are ana- with other pituitary hormone deficiencies, which may
bolic. Although bone formation markers are induced, become manifest only in adulthood. The diagnosis of
bone turnover also may be stimulated by IGF-I. idiopathic GH deficiency (IGHD) should be made only
IGF-I side effects are dose dependent, and overdose after known molecular defects have been rigorously
may result in hypoglycemia, hypotension, fluid reten- excluded.
tion, temporomandibular jaw pain, and increased intra- GHRH receptor mutations
cranial pressure, all of which are reversible. Avascular Recessive mutations of the GHRH receptor gene in sub-
femoral head necrosis has been reported. Chronic excess jects with severe proportionate dwarfism are associated
IGF-I administration presumably would result in fea- with low basal GH levels that cannot be stimulated by
tures of acromegaly. exogenous GHRH, GHRP, or insulin-induced hypo-
glycemia, as well as anterior pituitary hypoplasia The
syndrome exemplifies the importance of the GHRH
Disorders of Growth and receptor for somatotrope cell proliferation and hormonal
Development responsiveness.
Skeletal maturation and somatic growth
Growth hormone insensitivity
The growth plate is dependent on a variety of hormonal This is caused by defects of GH receptor structure or
stimuli, including GH, IGF-I, sex steroids, thyroid hor- signaling. Homozygous or heterozygous mutations of
mones, paracrine growth factors, and cytokines. The the GH receptor are associated with partial or complete
GH insensitivity and growth failure (Laron syndrome). of short stature remains cryptic, or when additional clin- 37
The diagnosis is based on normal or high GH levels, ical features suggest a gentic cause.
with decreased circulating GHBP, and low IGF-I levels.

CHAPTER 2
Very rarely, defective IGF-I, IGF-I receptor, or IGF-I
signaling defects are also encountered. STAT5B muta- Treatment Disorders of Growth and Development
tions result in immunodeficiency with abrogated GH
signaling, leading to short stature with normal or ele- Replacement therapy with recombinant GH (0.02–0.05
vated GH levels and low IGF-I levels. mg/kg per day subcutaneously) restores growth veloc-
ity in GH-deficient children to ∼10 cm/year. If pituitary
Nutritional short stature insufficiency is documented, other associated hor-

Disorders of the Anterior Pituitary and Hypothalamus


Caloric deprivation and malnutrition, uncontrolled mone deficits should be corrected—especially adrenal
diabetes, and chronic renal failure represent secondary steroids. GH treatment is also moderately effective for
causes of abrogated GH receptor function. These con- accelerating growth rates in children with Turner syn-
ditions also stimulate production of proinflammatory drome and chronic renal failure.
cytokines, which act to exacerbate the block of GH- In patients with GH insensitivity and growth retar-
mediated signal transduction. Children with these con- dation due to mutations of the GH receptor, treatment
ditions typically exhibit features of acquired short stat- with IGF-I bypasses the dysfunctional GH receptor.
ure with normal or elevated GH, and low IGF-I levels.
Circulating GH receptor antibodies may rarely cause
peripheral GH insensitivity. Adult GH Deficiency (AGHD)
Psychosocial short stature This disorder usually is caused by hypothalamic or pitu-
Emotional and social deprivation lead to growth retar- itary somatotrope damage. Acquired pituitary hormone
dation accompanied by delayed speech, discordant deficiency follows a typical pattern in which loss of
hyperphagia, and an attenuated response to administered adequate GH reserve foreshadows subsequent hormone
GH. A nurturing environment restores growth rates. deficits. The sequential order of hormone loss is usually
GH → FSH/LH → TSH → ACTH.
Presentation and diagnosis
Presentation and diagnosis
Short stature is commonly encountered in clinical prac-
tice, and the decision to evaluate these children requires The clinical features of AGHD include changes in body
clinical judgment in association with auxologic data and composition, lipid metabolism, and quality of life and
family history. Short stature should be evaluated com- cardiovascular dysfunction (Table 2-10). Body com-
prehensively if a patient’s height is >3 standard devia- position changes are common and include reduced lean
tions (SDs) below the mean for age or if the growth rate body mass, increased fat mass with selective deposition
has decelerated. Skeletal maturation is best evaluated by of intraabdominal visceral fat, and increased waist-to-
measuring a radiologic bone age, which is based mainly hip ratio. Hyperlipidemia, left ventricular dysfunction,
on the degree of wrist bone growth plate fusion. Final hypertension, and increased plasma fibrinogen levels
height can be predicted using standardized scales (Bay- also may be present. Bone mineral content is reduced,
ley-Pinneau or Tanner-Whitehouse) or estimated by with resultant increased fracture rates. Patients may
adding 6.5 cm (boys) or subtracting 6.5 cm (girls) from experience social isolation, depression, and difficulty
the midparental height. maintaining gainful employment. Adult hypopituitarism
is associated with a threefold increase in cardiovascular
Laboratory investigation mortality rates in comparison to age- and sex-matched
controls, and this may be due to GH deficiency, as
Because GH secretion is pulsatile, GH deficiency is best patients in these studies were replaced with other defi-
assessed by examining the response to provocative stim- cient pituitary hormones.
uli, including exercise, insulin-induced hypoglycemia,
and other pharmacologic tests that normally increase GH
Laboratory investigation
to >7 μg/L in children. Random GH measurements do
not distinguish normal children from those with true AGHD is rare, and in light of the nonspecific nature
GH deficiency. Adequate adrenal and thyroid hormone of associated clinical symptoms, patients appropriate for
replacement should be assured before testing. Age- and testing should be selected carefully on the basis of well-
sex-matched IGF-I levels are not sufficiently sensitive or defined criteria. With few exceptions, testing should be
specific to make the diagnosis but can be useful to con- restricted to patients with the following predisposing
firm GH deficiency. Pituitary MRI may reveal pituitary factors: (1) pituitary surgery, (2) pituitary or hypotha-
mass lesions or structural defects. Molecular analyses for lamic tumor or granulomas, (3) history of cranial irra-
known mutations should be undertaken when the cause diation, (4) radiologic evidence of a pituitary lesion,
38 Table 2-10 <3 μg/L. Although insulin-induced hypoglycemia is
Features of Adult Growth Hormone safe when performed under appropriate supervision,
Deficiency it is contraindicated in patients with diabetes, isch-
emic heart disease, cerebrovascular disease, or epilepsy
SECTION I

Clinical
  Impaired quality of life and in elderly patients. Alternative stimulatory tests
   Decreased energy and drive include intravenous arginine (30 g), GHRH (1 μg/kg),
   Poor concentration GHRP-6 (90 μg) and glucagon (1 mg). Combinations
   Low self-esteem of these tests may evoke GH secretion in subjects who
   Social isolation are not responsive to a single test.
  Body composition changes
Pituitary, Thyroid, and Adrenal Disorders

   Increased body fat mass


   Central fat deposition
   Increased waist-hip ratio
Treatment Adult GH Deficiency
   Decreased lean body mass
  Reduced exercise capacity Once the diagnosis of AGHD is unequivocally estab-
   Reduced maximum O2 uptake lished, replacement of GH may be indicated. Con-
   Impaired cardiac function traindications to therapy include the presence of an
   Reduced muscle mass active neoplasm, intracranial hypertension, and uncon-
  Cardiovascular risk factors trolled diabetes and retinopathy. The starting dose of
   Impaired cardiac structure and function 0.1–0.2 mg/d should be titrated (up to a maximum of
   Abnormal lipid profile
1.25 mg/d) to maintain IGF-I levels in the mid-normal
   Decreased fibrinolytic activity
   Atherosclerosis range for age- and sex-matched controls (Fig. 2-7).
   Omental obesity Women require higher doses than men, and elderly
patients require less GH. Long-term GH maintenance
Imaging
  Pituitary: mass or structural damage sustains normal IGF-I levels and is associated with per-
  Bone: reduced bone mineral density sistent body composition changes (e.g., enhanced lean
  Abdomen: excess omental adiposity body mass and lower body fat). High-density lipopro-
Laboratory tein cholesterol increases, but total cholesterol and
  Evoked GH <3 ng/mL insulin levels do not change significantly. Lumbar spine
  IGF-I and IGFBP3 low or normal bone mineral density increases, but this response
  Increased LDL cholesterol is gradual (>1 year). Many patients note significant
Concomitant gonadotropin, TSH, and/or ACTH reserve improvement in quality of life when evaluated by stan-
deficits may be present dardized questionnaires. The effect of GH replacement
on mortality rates in GH-deficient patients is currently
Abbreviation: LDL, low-density lipoprotein. For other abbreviations,
the subject of long-term prospective investigation.
see text.

(5) childhood requirement for GH replacement therapy,


and rarely (6) unexplained low age- and sex-matched MANAGEMENT OF ADULT GH DEFICIENCY
IGF-I levels. The transition of a GH-deficient adoles- History of pituitary pathology
cent to adulthood requires retesting to document sub- Clinical features present
Evoked GH <3 µg/L
sequent adult GH deficiency. Up to 20% of patients
previously treated for childhood-onset GH deficiency Exclude contraindications

are found to be GH sufficient on repeat testing as adults. Treat with


A significant proportion (∼25%) of truly GH- GH 0.1–0.3 mg/d
deficient adults have low-normal IGF-I levels. Thus, Check IGF-I after 1 mo
as in the evaluation of GH deficiency in children, valid
age- and sex-matched IGF-I measurements provide a Titrate GH dose
up to 1.25 mg/d
useful index of therapeutic responses but are not suffi-
ciently sensitive for diagnostic purposes. The most vali- 6 mo
dated test to distinguish pituitary-sufficient patients from No
those with AGHD is insulin-induced (0.05–0.1 U/kg) response Response

hypoglycemia. After glucose reduction to ∼40 mg/dL,


Discontinue Rx Monitor
most individuals experience neuroglycopenic symp- IGF-I Levels
toms (Chap. 20), and peak GH release occurs at 60 min
and remains elevated for up to 2 h. About 90% of Figure 2-7 
healthy adults exhibit GH responses >5 μg/L; AGHD Management of adult growth hormone (GH) deficiency.
is defined by a peak GH response to hypoglycemia of IGF, insulin-like growth factor.
GH-secreting somatotrope adenomas, mixed mammo- 39
About 30% of patients exhibit reversible dose-
somatotrope tumors and acidophilic stem-cell adenomas
related fluid retention, joint pain, and carpal tunnel syn-
secrete both GH and PRL. In patients with acidophilic
drome, and up to 40% exhibit myalgias and paresthesia.

CHAPTER 2
stem-cell adenomas, features of hyperprolactinemia
Patients receiving insulin require careful monitoring for
(hypogonadism and galactorrhea) predominate over
dosing adjustments, as GH is a potent counterregula-
the less clinically evident signs of acromegaly. Occa-
tory hormone for insulin action. Patients with Type 2
sionally, mixed plurihormonal tumors are encountered
diabetes mellitus initially develop further insulin resis-
that also secrete ACTH, the glycoprotein hormone α
tance. However, glycemic control improves with the sus-
subunit, or TSH in addition to GH. Patients with par-
tained loss of abdominal fat associated with long-term
tially empty sellas may present with GH hypersecretion

Disorders of the Anterior Pituitary and Hypothalamus


GH replacement. Headache, increased intracranial pres-
due to a small GH-secreting adenoma within the com-
sure, hypertension, and tinnitus occur rarely. Pituitary
pressed rim of pituitary tissue; some of these may reflect
tumor regrowth and progression of skin lesions or other
the spontaneous necrosis of tumors that were previously
tumors are being assessed in long-term surveillance
larger. GH-secreting tumors rarely arise from ectopic
programs. To date, development of these potential side
pituitary tissue remnants in the nasopharynx or midline
effects does not appear significant.
sinuses.
There are case reports of ectopic GH secretion by
Acromegaly tumors of pancreatic, ovarian, lung, or hematopoietic
origin. Rarely, excess GHRH production may cause
Etiology acromegaly because of chronic stimulation of somato-
GH hypersecretion is usually the result of a somatotrope tropes. These patients present with classic features of
adenoma but may rarely be caused by extrapituitary acromegaly, elevated GH levels, pituitary enlarge-
lesions (Table 2-11). In addition to more common ment on MRI, and pathologic characteristics of pitu-
itary hyperplasia. The most common cause of GHRH-
mediated acromegaly is a chest or abdominal carcinoid
Table 2-11 tumor. Although these tumors usually express positive
Causes of Acromegaly GHRH immunoreactivity, clinical features of acro-
megaly are evident in only a minority of patients with
Prevalence, %
carcinoid disease. Excessive GHRH also may be elabo-
Excess Growth Hormone Secretion rated by hypothalamic tumors, usually choristomas or
Pituitary 98 neuromas.
Densely or sparsely granulated GH 60
cell adenoma
Presentation and diagnosis
Mixed GH cell and PRL cell adenoma 25
Mammosomatotrope cell adenoma 10 Protean manifestations of GH and IGF-I hypersecre-
Plurihormonal adenoma tion are indolent and often are not clinically diagnosed
GH cell carcinoma or metastases for 10 years or more. Acral bony overgrowth results in
Multiple endocrine neoplasia 1 (GH
frontal bossing, increased hand and foot size, mandibu-
cell adenoma)
McCune-Albright syndrome lar enlargement with prognathism, and widened space
Ectopic sphenoid or parapharyngeal between the lower incisor teeth. In children and ado-
sinus pituitary adenoma lescents, initiation of GH hypersecretion before epiphy-
Extrapituitary tumor seal long bone closure is associated with development
Pancreatic islet cell tumor <1 of pituitary gigantism (Fig. 2-8). Soft tissue swell-
Lymphoma ing results in increased heel pad thickness, increased
Excess Growth Hormone–Releasing Hormone shoe or glove size, ring tightening, characteristic coarse
Secretion facial features, and a large, fleshy nose. Other commonly
Central <1 encountered clinical features include hyperhidrosis, a
Hypothalamic hamartoma, choris- <1 deep and hollow-sounding voice, oily skin, arthropa-
toma, ganglioneuroma thy, kyphosis, carpal tunnel syndrome, proximal muscle
Peripheral <1 weakness and fatigue, acanthosis nigricans, and skin tags.
Bronchial carcinoid, pancreatic islet
Generalized visceromegaly occurs, including cardio-
cell tumor, small cell lung cancer,
adrenal adenoma, medullary thyroid
megaly, macroglossia, and thyroid gland enlargement.
carcinoma, pheochromocytoma The most significant clinical impact of GH excess
occurs with respect to the cardiovascular system. Cor-
Abbreviations: GH, growth hormone; PRL, prolactin. onary heart disease, cardiomyopathy with arrhyth-
Source: Adapted from S Melmed: N Engl J Med 322:966, 1990. mias, left ventricular hypertrophy, decreased diastolic
40
SECTION I
Pituitary, Thyroid, and Adrenal Disorders

Figure 2-8
Features of acromegaly/gigantism. A 22-year-old man with twin are apparent. Their clinical features began to diverge
gigantism due to excess growth hormone is shown to the at the age of approximately 13 years. (Reproduced from
left of his identical twin. The increased height and progna- R Gagel, IE McCutcheon: N Engl J Med 324:524, 1999; with
thism (A) and enlarged hand (B) and foot (C) of the affected permission.)

function, and hypertension ultimately occur in most disease severity. The diagnosis of acromegaly is con-
patients if untreated. Upper airway obstruction with firmed by demonstrating the failure of GH suppres-
sleep apnea occurs in more than 60% of patients and is sion to <0.4 μg/L within 1–2 h of an oral glucose load
associated with both soft tissue laryngeal airway obstruc- (75 g). When newer ultrasensitive GH assays are used,
tion and central sleep dysfunction. Diabetes mellitus normal nadir GH levels are even lower (<0.05 μg/L).
develops in 25% of patients with acromegaly, and most About 20% of patients exhibit a paradoxical GH rise
patients are intolerant of a glucose load (as GH coun- after glucose. PRL should be measured, as it is elevated
teracts the action of insulin). Acromegaly is associated in ∼25% of patients with acromegaly. Thyroid func-
with an increased risk of colon polyps and mortality tion, gonadotropins, and sex steroids may be attenuated
from colonic malignancy; polyps are diagnosed in up because of tumor mass effects. Because most patients
to one-third of patients. Overall mortality is increased will undergo surgery with glucocorticoid coverage, tests
about threefold and is due primarily to cardiovascular of ACTH reserve in asymptomatic patients are more
and cerebrovascular disorders and respiratory disease. efficiently deferred until after surgery.
Unless GH levels are controlled, survival is reduced by
an average of 10 years compared with an age-matched
control population. Treatment Acromegaly

The goal of treatment is to control GH and IGF-I hyper-


Laboratory investigation secretion, ablate or arrest tumor growth, ameliorate
comorbidities, restore mortality rates to normal, and
Age- and sex-matched serum IGF-I levels are elevated
preserve pituitary function.
in acromegaly. Consequently, an IGF-I level pro-
Surgical resection of GH-secreting adenomas is the
vides a useful laboratory screening measure when clini-
initial treatment for most patients (Fig. 2-9). Somatosta-
cal features raise the possibility of acromegaly. Due to
tin analogues are used as adjuvant treatment for pre-
the pulsatility of GH secretion, measurement of a sin-
operative shrinkage of large, invasive macroadenomas,
gle random GH level is not useful for the diagnosis or
immediate relief of debilitating symptoms, and reduction
exclusion of acromegaly and does not correlate with
MANAGEMENT OF ACROMEGALY 41
GH-Secreting
Adenoma

CHAPTER 2
Likely Assess likelihood Unlikely Somatostatin
of surgical cure analogue

Debulking required
Surgery
for CNS pressure effects

controlled elevated controlled


Measure Measure

Disorders of the Anterior Pituitary and Hypothalamus


GH/IGF-I GH/IGF-I
Somatostatin analogue
Monitor Monitor

controlled Measure
GH/IGF-I

Increase dose/frequency of somatostatin uncontrolled


analogue; add GH receptor antagonist; Figure 2-9 
or add dopamine agonist
Management of acromegaly. GH, growth hor-
• GH receptor mone; CNS, central nervous system; IGF, insulin-
controlled Measure uncontrolled
Monitor antagonist like growth factor. (Adapted from S Melmed et al:
GH/IGF-I • Radiation therapy
• Reoperation J Clin Endocrinol Metab 94:1509–1517, 2009; ©
The Endocrine Society.)

of GH hypersecretion; in frail patients experiencing mor- expressed by GH-secreting tumors. Octreotide acetate
bidity; and in patients who decline surgery or, when is an eight-amino-acid synthetic somatostatin ana-
surgery fails, to achieve biochemical control. Irradiation logue. In contrast to native somatostatin, the analogue
or repeat surgery may be required for patients who can- is relatively resistant to plasma degradation. It has a 2-h
not tolerate or do not respond to adjunctive medical serum half-life and possesses fortyfold greater potency
therapy. The high rate of late hypopituitarism and the than native somatostatin to suppress GH. Octreotide
slow rate (5–15 years) of biochemical response are the is administered by subcutaneous injection, beginning
main disadvantages of radiotherapy. Irradiation is also with 50 μg tid; the dose can be increased gradually
relatively ineffective in normalizing IGF-I levels. Stereo- up to 1500 μg/d. Fewer than 10% of patients do not
tactic ablation of GH-secreting adenomas by gamma- respond to the analogue. Octreotide suppresses inte-
knife radiotherapy is promising, but initial reports sug- grated GH levels and normalizes IGF-I levels in ∼75% of
gest that long-term results and side effects are similar treated patients.
to those observed with conventional radiation. Soma- The long-acting somatostatin depot formulations,
tostatin analogues may be required while awaiting the octreotide and lanreotide, are the preferred medical
full benefits of radiotherapy. Systemic sequelae of acro- treatment for patients with acromegaly. Sandostatin-
megaly, including cardiovascular disease, diabetes, and LAR is a sustained-release, long-acting formulation
arthritis, should be managed aggressively. Mandibular of octreotide incorporated into microspheres that
surgical repair may be indicated. sustain drug levels for several weeks after intramus-
cular injection. GH suppression occurs for as long as
Surgery  Transsphenoidal surgical resection by an
6 weeks after a 30-mg intramuscular injection; long-
experienced surgeon is the preferred primary treatment
term monthly treatment sustains GH and IGF-I sup-
for both microadenomas (cure rate ∼70%) and macroad-
pression and also reduces pituitary tumor size in ∼50%
enomas (<50% cured). Soft tissue swelling improves
of patients. Lanreotide autogel, a slow-release depot
immediately after tumor resection. GH levels return to
somatostatin preparation, is a cyclic somatostatin
normal within an hour, and IGF-I levels are normalized
octapeptide analogue that suppresses GH and IGF-I
within 3–4 days. In ∼10% of patients, acromegaly may
hypersecretion after a 60-mg subcutaneous injec-
recur several years after apparently successful surgery;
tion. Long-term monthly administration controls GH
hypopituitarism develops in up to 15% of patients after
hypersecretion in two-thirds of treated patients and
surgery.
improves patient compliance because of the long inter-
Somatostatin Analogues  Somatostatin val required between drug injections. Rapid relief of
analogues exert their therapeutic effects through SSTR2 headache and soft tissue swelling occurs in ∼75% of
and SSTR5 receptors, both of which invariably are patients within days to weeks of somatostatin analogue
42 initiation. Most patients report symptomatic improve- In summary, surgery is the preferred primary treat-
ment, including amelioration of headache, perspiration, ment for GH-secreting microadenomas (Fig. 2-9). The
obstructive apnea, and cardiac failure. high frequency of GH hypersecretion after macroad-
SECTION I

Side Effects  Somatostatin analogues are well tol-


enoma resection usually necessitates adjuvant or pri-
erated in most patients. Adverse effects are short-lived mary medical therapy for these larger tumors. Patients
and mostly relate to drug-induced suppression of gas- unable to receive or respond to unimodal medical treat-
trointestinal motility and secretion. Nausea, abdominal ment may benefit from combined treatments or can be
discomfort, fat malabsorption, diarrhea, and flatulence offered radiation.
occur in one-third of patients, and these symptoms usu-
Pituitary, Thyroid, and Adrenal Disorders

ally remit within 2 weeks. Octreotide suppresses post-


prandial gallbladder contractility and delays gallblad- Adrenocorticotropic Hormone
der emptying; up to 30% of patients develop long-term
(See also Chap. 5)
echogenic sludge or asymptomatic cholesterol gall-
stones. Other side effects include mild glucose intoler-
ance due to transient insulin suppression, asymptomatic
Synthesis
bradycardia, hypothyroxinemia, and local injection site ACTH-secreting corticotrope cells constitute about
discomfort. 20% of the pituitary cell population. ACTH (39
GH Receptor Antagonist  Pegvisomant amino acids) is derived from the POMC precursor
antagonizes endogenous GH action by blocking periph- protein (266 amino acids) that also generates several
eral GH binding to its receptor. Consequently, serum other peptides, including β-lipotropin, β-endorphin,
IGF-I levels are suppressed, reducing the deleterious met-enkephalin, α-melanocyte-stimulating hormone
effects of excess endogenous GH. Pegvisomant is admin- (α-MSH), and corticotropin-like intermediate lobe pro-
istered by daily subcutaneous injection (10–20 mg) and tein (CLIP). The POMC gene is potently suppressed by
normalizes IGF-I in >90% of patients. GH levels, however, glucocorticoids and induced by CRH, arginine vaso-
remain elevated as the drug does not have antitumor pressin (AVP), and proinflammatory cytokines, includ-
actions. Side effects include reversible liver enzyme ele- ing IL-6, as well as leukemia inhibitory factor.
vation, lipodystrophy, and injection site pain. Tumor size CRH, a 41-amino-acid hypothalamic peptide syn-
should be monitored by MRI. thesized in the paraventricular nucleus as well as in
Combined treatment with monthly somatostatin higher brain centers, is the predominant stimulator of
analogues and weekly or biweekly pegvisomant injec- ACTH synthesis and release. The CRH receptor is a
tions has been used effectively in resistant patients. GPCR that is expressed on the corticotrope and signals
to induce POMC transcription.
Dopamine Agonists  Bromocriptine and cab-
ergoline may modestly suppress GH secretion in some
Secretion
patients. High doses of bromocriptine (≥20 mg/d) or
cabergoline (0.5 mg/d) are usually required to achieve ACTH secretion is pulsatile and exhibits a characteris-
modest GH therapeutic efficacy. Combined treatment tic circadian rhythm, peaking at 6 a.m. and reaching a
with octreotide and cabergoline may induce additive nadir at about midnight. Adrenal glucocorticoid secre-
biochemical control compared with either drug alone. tion, which is driven by ACTH, follows a parallel
diurnal pattern. ACTH circadian rhythmicity is deter-
Radiation  External radiation therapy or high-
mined by variations in secretory pulse amplitude rather
energy stereotactic techniques are used as adjuvant
than changes in pulse frequency. Superimposed on this
therapy for acromegaly. An advantage of radiation is
endogenous rhythm, ACTH levels are increased by
that patient compliance with long-term treatment is
physical and psychological stress, exercise, acute illness,
not required. Tumor mass is reduced, and GH levels are
and insulin-induced hypoglycemia.
attenuated over time. However, 50% of patients require
Loss of cortisol feedback inhibition, as occurs in pri-
at least 8 years for GH levels to be suppressed to
mary adrenal failure, results in extremely high ACTH
<5 μg/L; this level of GH reduction is achieved in about
levels. Glucocorticoid-mediated negative regulation of
90% of patients after 18 years but represents subop-
the hypothalamic-pituitary-adrenal (HPA) axis occurs as
timal GH suppression. Patients may require interim
a consequence of both hypothalamic CRH suppression
medical therapy for several years before attaining maxi-
and direct attenuation of pituitary POMC gene expres-
mal radiation benefits. Most patients also experience
sion and ACTH release.
hypothalamic-pituitary damage, leading to gonado-
Acute inflammatory or septic insults activate the
tropin, ACTH, and/or TSH deficiency within 10 years
HPA axis through the integrated actions of proinflam-
of therapy.
matory cytokines, bacterial toxins, and neural signals.
The overlapping cascade of ACTH-inducing cytokines and impaired cortisol response to insulin-induced hypo- 43
[tumor necrosis factor (TNF); IL-1, -2, and -6; and leu- glycemia, or testing with metyrapone or CRH. For a
kemia inhibitory factor] activates hypothalamic CRH description of provocative ACTH tests, see Chap. 5.

CHAPTER 2
and AVP secretion, pituitary POMC gene expression,
and local pituitary paracrine cytokine networks. The
resulting cortisol elevation restrains the inflammatory Treatment ACTH Deficiency
response and enables host protection. Concomitantly,
cytokine-mediated central glucocorticoid receptor resis- Glucocorticoid replacement therapy improves most fea-
tance impairs glucocorticoid suppression of the HPA. tures of ACTH deficiency. The total daily dose of hydro-
Thus, the neuroendocrine stress response reflects the net

Disorders of the Anterior Pituitary and Hypothalamus


cortisone replacement preferably should not exceed
result of highly integrated hypothalamic, intrapituitary, 25 mg daily, divided into two or three doses. Prednisone
and peripheral hormone and cytokine signals. (5 mg each morning) is longer acting and has fewer
mineralocorticoid effects than hydrocortisone. Some
authorities advocate lower maintenance doses in an
Action effort to avoid cushingoid side effects. Doses should be
The major function of the HPA axis is to maintain increased severalfold during periods of acute illness or
metabolic homeostasis and mediate the neuroendo- stress.
crine stress response. ACTH induces adrenocortical
steroidogenesis by sustaining adrenal cell proliferation
and function. The receptor for ACTH, designated Cushing’s Syndrome
melanocortin-2 receptor, is a GPCR that induces ste- (ACTH-Producing Adenoma)
roidogenesis by stimulating a cascade of steroidogenic
enzymes (Chap. 5). (See also Chap. 5)
Etiology and prevalence
ACTH Deficiency Pituitary corticotrope adenomas account for 70% of
patients with endogenous causes of Cushing’s syn-
Presentation and diagnosis
drome. However, it should be emphasized that iat-
Secondary adrenal insufficiency occurs as a result of rogenic hypercortisolism is the most common cause
pituitary ACTH deficiency. It is characterized by of cushingoid features. Ectopic tumor ACTH pro-
fatigue, weakness, anorexia, nausea, vomiting, and, duction, cortisol-producing adrenal adenomas, adre-
occasionally, hypoglycemia. In contrast to primary adre- nal carcinoma, and adrenal hyperplasia account for the
nal failure, hypocortisolism associated with pituitary fail- other causes; rarely, ectopic tumor CRH production is
ure usually is not accompanied by hyperpigmentation or encountered.
mineralocorticoid deficiency. ACTH-producing adenomas account for about
ACTH deficiency is commonly due to glucocor- 10–15% of all pituitary tumors. Because the clinical fea-
ticoid withdrawal after treatment-associated suppres- tures of Cushing’s syndrome often lead to early diagno-
sion of the HPA axis. Isolated ACTH deficiency may sis, most ACTH-producing pituitary tumors are relatively
occur after surgical resection of an ACTH-secreting small microadenomas. However, macroadenomas also are
pituitary adenoma that has suppressed the HPA axis; seen, while some ACTH-expressing adenomas are clini-
this phenomenon is suggestive of a surgical cure. The cally silent. Cushing’s disease is 5–10 times more com-
mass effects of other pituitary adenomas or sellar lesions mon in women than in men. These pituitary adenomas
may lead to ACTH deficiency, but usually in combina- exhibit unrestrained ACTH secretion, with resultant
tion with other pituitary hormone deficiencies. Partial hypercortisolemia. However, they retain partial suppress-
ACTH deficiency may be unmasked in the presence ibility in the presence of high doses of administered glu-
of an acute medical or surgical illness, when clinically cocorticoids, providing the basis for dynamic testing to
significant hypocortisolism reflects diminished ACTH distinguish pituitary from nonpituitary causes of Cush-
reserve. Rarely, TPIT or POMC mutations result in ing’s syndrome.
primary ACTH deficiency.
Presentation and diagnosis
Laboratory diagnosis
The diagnosis of Cushing’s syndrome presents two great
Inappropriately low ACTH levels in the setting of low challenges: (1) to distinguish patients with pathologic
cortisol levels are characteristic of diminished ACTH cortisol excess from those with physiologic or other dis-
reserve. Low basal serum cortisol levels are associated turbances of cortisol production and (2) to determine
with blunted cortisol responses to ACTH stimulation the etiology of cortisol excess.
44 Typical features of chronic cortisol excess include thin myopathy suggests an ectopic source of ACTH. Hyper-
skin, central obesity, hypertension, plethoric moon facies, tension, hypokalemic alkalosis, glucose intolerance,
purple striae and easy bruisability, glucose intolerance or and edema are also more pronounced in these patients.
diabetes mellitus, gonadal dysfunction, osteoporosis, prox- Serum potassium levels <3.3 mmol/L are evident in
SECTION I

imal muscle weakness, signs of hyperandrogenism (acne, ∼70% of patients with ectopic ACTH secretion but
hirsutism), and psychological disturbances (depression, are seen in <10% of patients with pituitary-dependent
mania, and psychoses) (Table 2-12). Hematopoietic fea- Cushing’s syndrome.
tures of hypercortisolism include leukocytosis, lympho-
penia, and eosinopenia. Immune suppression includes Laboratory investigation
delayed hypersensitivity. These protean yet commonly
Pituitary, Thyroid, and Adrenal Disorders

encountered manifestations of hypercortisolism make The diagnosis of Cushing’s syndrome is based on labo-
it challenging to decide which patients mandate formal ratory documentation of endogenous hypercortisolism.
laboratory evaluation. Certain features make pathologic Measurement of 24-h urinary free cortisol (UFC) is a
causes of hypercortisolism more likely; they include precise and cost-effective screening test. Alternatively,
characteristic central redistribution of fat, thin skin with the failure to suppress plasma cortisol after an overnight
striae and bruising, and proximal muscle weakness. In 1-mg dexamethasone suppression test can be used to
children and in young females, early osteoporosis may identify patients with hypercortisolism. As nadir lev-
be particularly prominent. The primary cause of death is els of cortisol occur at night, elevated midnight sam-
cardiovascular disease, but infections and risk of suicide ples of cortisol are suggestive of Cushing’s syndrome.
are also increased. Basal plasma ACTH levels often distinguish patients
Rapid development of features of hypercortisolism with ACTH-independent (adrenal or exogenous glu-
associated with skin hyperpigmentation and severe cocorticoid) from those with ACTH-dependent (pitu-
itary, ectopic ACTH) Cushing’s syndrome. Mean basal
ACTH levels are about eightfold higher in patients
Table 2-12 with ectopic ACTH secretion than in those with pitu-
Clinical Features of Cushing’s Syndrome itary ACTH-secreting adenomas. However, extensive
(All Ages) overlap of ACTH levels in these two disorders pre-
Symptoms/Signs Frequency, % cludes using ACTH measurements to make the dis-
Obesity or weight gain (>115% ideal 80
tinction. Instead, dynamic testing based on differential
body weight) sensitivity to glucocorticoid feedback or ACTH stimu-
lation in response to CRH or cortisol reduction is used
Thin skin 80
to distinguish ectopic from pituitary sources of excess
Moon facies 75 ACTH (Table 2-13). Very rarely, circulating CRH
Hypertension 75 levels are elevated, reflecting ectopic tumor-derived
Purple skin striae 65 secretion of CRH and often ACTH. For further dis-
Hirsutism 65 cussion of dynamic testing for Cushing’s syndrome, see
Chap. 5.
Menstrual disorders (usually amenorrhea) 60
Most ACTH-secreting pituitary tumors are <5 mm
Plethora 60 in diameter, and about half are undetectable by sensi-
Abnormal glucose tolerance 55 tive MRI. The high prevalence of incidental pituitary
Impotence 55 microadenomas diminishes the ability to distinguish
Proximal muscle weakness 50
ACTH-secreting pituitary tumors accurately from non-
secreting incidentalomas.
Truncal obesity 50
Acne 45
Inferior petrosal venous sampling
Bruising 45
Mental changes 45
Because pituitary MRI with gadolinium enhancement is
insufficiently sensitive to detect small (<2 mm) pituitary
Osteoporosis 40
ACTH-secreting adenomas, bilateral inferior petrosal
Edema of lower extremities 30 sinus ACTH sampling before and after CRH adminis-
Hyperpigmentation 20 tration may be required to distinguish these lesions from
Hypokalemic alkalosis 15 ectopic ACTH-secreting tumors that may have simi-
Diabetes mellitus 15
lar clinical and biochemical characteristics. Simultane-
ous assessment of ACTH in each inferior petrosal vein
Source: Adapted from MA Magiokou et al, in ME Wierman (ed):
and in the peripheral circulation provides a strategy for
Diseases of the Pituitary. Totowa, NJ, Humana, 1997. confirming and localizing pituitary ACTH production.
Table 2-13 Petrosal sinus catheterizations are technically difficult, 45
Differential Diagnosis of ACTH-Dependent and about 0.05% of patients develop neurovascular
Cushing’s Syndromea complications. The procedure should not be performed

CHAPTER 2
ACTH-Secreting Ectopic ACTH in patients with hypertension or in the presence of a
Pituitary Tumor Secretion well-visualized pituitary adenoma on MRI.
Etiology Pituitary Bronchial,
corticotrope abdominal
adenoma carcinoid Treatment Cushing’s Syndrome
Plurihormonal Small cell
adenoma lung cancer

Disorders of the Anterior Pituitary and Hypothalamus


Selective transsphenoidal resection is the treatment of
Thymoma choice for Cushing’s disease (Fig. 2-10). The remission
Sex F>M M>F rate for this procedure is ∼80% for microadenomas but
Clinical features Slow onset Rapid onset <50% for macroadenomas. After successful tumor resec-
Pigmentation tion, most patients experience a postoperative period
Severe myopathy of symptomatic ACTH deficiency that may last up to
Serum potassium <10% 75% 12 months. This usually requires low-dose cortisol
<3.3 μg/L replacement, as patients experience both steroid with-
24-h urinary free High High drawal symptoms and have a suppressed HPA axis.
cortisol (UFC) Biochemical recurrence occurs in approximately 5% of
Basal ACTH level Inappropriately Very high patients in whom surgery was initially successful.
high When initial surgery is unsuccessful, repeat surgery
Dexamethasone
is sometimes indicated, particularly when a pituitary
suppression source for ACTH is well documented. In older patients,
in whom issues of growth and fertility are less impor-
1 mg overnight
tant, hemi- or total hypophysectomy may be neces-
Low dose Cortisol >5 μg/dL Cortisol >5 μg/dL sary if a discrete pituitary adenoma is not recognized.
(0.5 mg q6h)
Pituitary irradiation may be used after unsuccess-
High dose (2 mg Cortisol <5 μg/dL Cortisol >5 μg/dL ful surgery, but it cures only about 15% of patients.
q6h)
Because the effects of radiation are slow and only
UFC >80% Microadenomas: 10%
suppressed 90%
Macroadenomas: MANAGEMENT OF CUSHING’S DISEASE
50%
ACTH-dependent
Inferior petrosal hypercortisolism
sinus sampling
(IPSS) Pituitary MRI
Petrosal sinus
Basal ACTH samplinga
Consider chest/abdomen
IPSS: peripheral >2 <2 imaging
Ectopic ACTH excluded
CRH induced ACTH-secreting
pituitary adenoma
  IPSS: peripheral >3 <3
Transsphenoidal surgical
a
ACTH-independent causes of Cushing’s syndrome are diagnosed by resection
suppressed ACTH levels and an adrenal mass in the setting of hyper-
Pituitary
cortisolism. Iatrogenic Cushing’s syndrome is excluded by history. irradiation
Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin- Biochemical Persistent
releasing hormone; F, female; M, male. cure hypercortisolism and/or
Steroidogenic
Glucocorticoid
inhibitors
replacement,
Sampling is performed at baseline and 2, 5, and 10 min if needed
after intravenous bovine CRH (1 μg/kg) injection. An
?Irradiation
increased ratio (>2) of inferior petrosal:peripheral vein Follow-up: Serial biochemical Adrenalectomy
and MRI Risk of Nelson’s
ACTH confirms pituitary Cushing’s syndrome. After evaluation syndrome
CRH injection, peak petrosal:peripheral ACTH ratios
≥3 confirm the presence of a pituitary ACTH-secreting Figure 2-10 
tumor. The sensitivity of this test is >95%, with very Management of Cushing’s syndrome. ACTH, adrenocorti-
rare false-positive results. False-negative results may be cotropin hormone; MRI, magnetic resonance imaging. aNot
encountered in patients with aberrant venous drainage. usually required.
46 60–120 min, and the pulses in turn elicit LH and FSH
partially effective in adults, steroidogenic inhibitors are
pulses (Fig. 2-3). The pulsatile mode of GnRH input is
used in combination with pituitary irradiation to block
essential to its action; pulses prime gonadotrope respon-
adrenal effects of persistently high ACTH levels.
siveness, whereas continuous GnRH exposure induces
SECTION I

Ketoconazole, an imidazole derivative antimycotic


desensitization. Based on this phenomenon, long-acting
agent, inhibits several P450 enzymes and effectively
GnRH agonists are used to suppress gonadotropin lev-
lowers cortisol in most patients with Cushing’s disease
els in children with precocious puberty and in men with
when administered twice daily (600–1200 mg/d). Ele-
prostate cancer and are used in some ovulation-induction
vated hepatic transaminases, gynecomastia, impotence,
protocols to reduce levels of endogenous gonadotropins
gastrointestinal upset, and edema are common side
(Chap. 10). Estrogens act at both the hypothalamus and
Pituitary, Thyroid, and Adrenal Disorders

effects. Metyrapone (2–4 g/d) inhibits 11β-hydroxylase


the pituitary to modulate gonadotropin secretion. Chronic
activity and normalizes plasma cortisol in up to 75% of
estrogen exposure is inhibitory, whereas rising estrogen
patients. Side effects include nausea and vomiting, rash,
levels, as occur during the preovulatory surge, exert posi-
and exacerbation of acne or hirsutism. Mitotane (o,p′-
tive feedback to increase gonadotropin pulse frequency
DDD; 3–6 g/d orally in four divided doses) suppresses
and amplitude. Progesterone slows GnRH pulse fre-
cortisol hypersecretion by inhibiting 11β-hydroxylase
quency but enhances gonadotropin responses to GnRH.
and cholesterol side-chain cleavage enzymes and by
Testosterone feedback in men also occurs at the hypo-
destroying adrenocortical cells. Side effects of mitotane
thalamic and pituitary levels and is mediated in part by its
include gastrointestinal symptoms, dizziness, gyneco-
conversion to estrogens.
mastia, hyperlipidemia, skin rash, and hepatic enzyme
Although GnRH is the main regulator of LH and FSH
elevation. It also may lead to hypoaldosteronism. Other
secretion, FSH synthesis is also under separate control by
agents include aminoglutethimide (250 mg tid), trilo-
the gonadal peptides inhibin and activin, which are mem-
stane (200–1000 mg/d), cyproheptadine (24 mg/d), and
bers of the transforming growth factor β (TGF-β) family.
IV etomidate (0.3 mg/kg per hour). Glucocorticoid insuf-
Inhibin selectively suppresses FSH, whereas activin stimu-
ficiency is a potential side effect of agents used to block
lates FSH synthesis (Chap. 10).
steroidogenesis.
The use of steroidogenic inhibitors has decreased
the need for bilateral adrenalectomy. Removal of both Action
adrenal glands corrects hypercortisolism but may be
associated with significant morbidity rates and necessi-
The gonadotropin hormones interact with their respec-
tates permanent glucocorticoid and mineralocorticoid
tive GPCRs expressed in the ovary and testis, evoking
replacement. Adrenalectomy in the setting of residual
germ-cell development and maturation and steroid hor-
corticotrope adenoma tissue predisposes to the devel-
mone biosynthesis. In women, FSH regulates ovarian
opment of Nelson’s syndrome, a disorder characterized
follicle development and stimulates ovarian estrogen pro-
by rapid pituitary tumor enlargement and increased
duction. LH mediates ovulation and maintenance of the
pigmentation secondary to high ACTH levels. Radiation
corpus luteum. In men, LH induces Leydig cell testoster-
therapy may be indicated to prevent the development
one synthesis and secretion, and FSH stimulates seminif-
of Nelson’s syndrome after adrenalectomy.
erous tubule development and regulates spermatogenesis.

Gonadotropin Deficiency
Gonadotropins: FSH and LH Hypogonadism is the most common presenting fea-
ture of adult hypopituitarism even when other pituitary
Synthesis and Secretion hormones are also deficient. It is often a harbinger of
Gonadotrope cells constitute about 10% of anterior hypothalamic or pituitary lesions that impair GnRH pro-
pituitary cells and produce two gonadotropins—LH and duction or delivery through the pituitary stalk. As noted
FSH. Like TSH and hCG, LH and FSH are glycopro- above, hypogonadotropic hypogonadism is a common
tein hormones that consist of α and β subunits. The α presenting feature of hyperprolactinemia.
subunit is common to these glycoprotein hormones; A variety of inherited and acquired disorders are
specificity is conferred by the β subunits, which are associated with isolated hypogonadotropic hypogonadism
expressed by separate genes. (IHH) (Chap. 8). Hypothalamic defects associated with
Gonadotropin synthesis and release are dynamically GnRH deficiency include two X-linked disorders,
regulated. This is particularly true in women, in whom Kallmann syndrome (see above) and mutations in the
rapidly fluctuating gonadal steroid levels vary throughout DAX1 gene, as well as dominant mutations in FGFR1.
the menstrual cycle. Hypothalamic GnRH, a 10-amino- Mutations in GPR54, kisspeptin, the GnRH receptor,
acid peptide, regulates the synthesis and secretion of both and the LH β or FSH β subunit genes are additional
LH and FSH. GnRH is secreted in discrete pulses every causes of selective gonadotropin deficiency. Acquired
forms of GnRH deficiency leading to hypogonado- 47
tropism are seen in association with anorexia nervosa, Testosterone may be administered by intramuscular
stress, starvation, and extreme exercise but also may be injections every 1–4 weeks or by using skin patches
that are replaced daily (Chap. 8). Testosterone gels are

CHAPTER 2
idiopathic. Hypogonadotropic hypogonadism in these
disorders is reversed by removal of the stressful stimulus also available. Gonadotropin injections [hCG or human
or by caloric replenishment. menopausal gonadotropin (hMG)] over 12–18 months
are used to restore fertility. Pulsatile GnRH therapy
(25–150 ng/kg every 2 h), administered by a subcuta-
Presentation and diagnosis
neous infusion pump, is also effective for treatment of
In premenopausal women, hypogonadotropic hypogo- hypothalamic hypogonadism when fertility is desired.

Disorders of the Anterior Pituitary and Hypothalamus


nadism presents as diminished ovarian function leading In premenopausal women, cyclical replacement of
to oligomenorrhea or amenorrhea, infertility, decreased estrogen and progesterone maintains secondary sexual
vaginal secretions, decreased libido, and breast atrophy. characteristics and integrity of genitourinary tract mucosa
In hypogonadal adult men, secondary testicular failure is and prevents premature osteoporosis (Chap. 10). Gonado-
associated with decreased libido and potency, infertility, tropin therapy is used for ovulation induction. Follicu-
decreased muscle mass with weakness, reduced beard lar growth and maturation are initiated using hMG or
and body hair growth, soft testes, and characteristic fine recombinant FSH; hCG or human luteinizing hormone
facial wrinkles. Osteoporosis occurs in both untreated (hLH) is subsequently injected to induce ovulation. As in
hypogonadal women and men. men, pulsatile GnRH therapy can be used to treat hypo-
thalamic causes of gonadotropin deficiency.
Laboratory investigation
Central hypogonadism is associated with low or inap- Nonfunctioning and Gonadotropin-
propriately normal serum gonadotropin levels in the Producing Pituitary Adenomas
setting of low sex hormone concentrations (testoster-
Etiology and prevalence
one in men, estradiol in women). Because gonadotro-
pin secretion is pulsatile, valid assessments may require Nonfunctioning pituitary adenomas include those that
repeated measurements or the use of pooled serum sam- secrete little or no pituitary hormones as well as tumors
ples. Men have reduced sperm counts. that produce too little hormone to result in recognizable
Intravenous GnRH (100 μg) stimulates gonadotropes clinical features. They are the most common type of pitu-
to secrete LH (which peaks within 30 min) and FSH itary adenoma and are usually macroadenomas at the time
(which plateaus during the ensuing 60 min). Normal of diagnosis because clinical features are not apparent until
responses vary according to menstrual cycle stage, age, tumor mass effects occur. Based on immunohistochem-
and sex of the patient. Generally, LH levels increase istry, most clinically nonfunctioning adenomas can be
about threefold, whereas FSH responses are less pro- shown to originate from gonadotrope cells. These tumors
nounced. In the setting of gonadotropin deficiency, typically produce small amounts of intact gonadotropins
a normal gonadotropin response to GnRH indicates (usually FSH) as well as uncombined α, LH β, and FSH
intact pituitary gonadotrope function and suggests a β subunits. Tumor secretion may lead to elevated α and
hypothalamic abnormality. An absent response, how- FSH β subunits and, rarely, to increased LH β subunit
ever, cannot reliably distinguish pituitary from hypotha- levels. Some adenomas express α subunits without FSH
lamic causes of hypogonadism. For this reason, GnRH or LH. TRH administration often induces an atypical
testing usually adds little to the information gained increase of tumor-derived gonadotropins or subunits.
from baseline evaluation of the hypothalamic-pituitary-
gonadotrope axis except in cases of isolated GnRH Presentation and diagnosis
deficiency (e.g., Kallmann syndrome). Clinically nonfunctioning tumors often present with
MRI examination of the sellar region and assess- optic chiasm pressure and other symptoms of local expan-
ment of other pituitary functions usually are indicated in sion or may be incidentally discovered on an MRI per-
patients with documented central hypogonadism. formed for another indication (incidentaloma). Rarely,
menstrual disturbances or ovarian hyperstimulation occur
in women with large tumors that produce FSH and LH.
Treatment Gonadotropin Deficiency More commonly, adenoma compression of the pituitary
stalk or surrounding pituitary tissue leads to attenuated
In males, testosterone replacement is necessary to
LH and features of hypogonadism. PRL levels are usu-
achieve and maintain normal growth and development of
ally slightly increased, also because of stalk compression.
the external genitalia, secondary sex characteristics, male
It is important to distinguish this circumstance from true
sexual behavior, and androgenic anabolic effects, includ-
prolactinomas, as nonfunctioning tumors do not shrink in
ing maintenance of muscle function and bone mass. response to treatment with dopamine agonists.
48 Laboratory investigation only be diagnosed by immunostaining of resected tumor
tissue. If PRL levels are <100 μg/L in a patient harbor-
The goal of laboratory testing in clinically nonfunction- ing a pituitary mass, a nonfunctioning adenoma causing
ing tumors is to classify the type of the tumor, identify pituitary stalk compression should be considered.
SECTION I

hormonal markers of tumor activity, and detect possible


hypopituitarism. Free α subunit levels may be elevated
in 10–15% of patients with nonfunctioning tumors. Treatment
 onfunctioning and Gonadotropin-
N
In female patients, peri- or postmenopausal basal FSH Producing Pituitary Adenomas
concentrations are difficult to distinguish from tumor-
Asymptomatic small, nonfunctioning microadenomas
derived FSH elevation. Premenopausal women have
Pituitary, Thyroid, and Adrenal Disorders

adenomas with no threat to vision may be followed


cycling FSH levels, also preventing clear-cut diagnostic
with regular MRI and visual field testing without imme-
distinction from tumor-derived FSH. In men, gonad-
diate intervention. However, for macroadenomas, trans-
otropin-secreting tumors may be diagnosed because
sphenoidal surgery is indicated to reduce tumor size
of slightly increased gonadotropins (FSH > LH) in the
and relieve mass effects (Fig. 2-11). Although it is not
setting of a pituitary mass. Testosterone levels are usu-
usually possible to remove all adenoma tissue surgi-
ally low despite the normal or increased LH level,
cally, vision improves in 70% of patients with preopera-
perhaps reflecting reduced LH bioactivity or the loss
tive visual field defects. Preexisting hypopituitarism that
of normal LH pulsatility. Because this pattern of hor-
results from tumor mass effects may improve or resolve
mone test results is also seen in primary gonadal failure
completely. Beginning about 6 months postoperatively,
and, to some extent, with aging (Chap. 8), the find-
MRI scans should be performed yearly to detect tumor
ing of increased gonadotropins alone is insufficient for
regrowth. Within 5–6 years after successful surgical
the diagnosis of a gonadotropin-secreting tumor. In the
resection, ∼15% of nonfunctioning tumors recur. When
majority of patients with gonadotrope adenomas, TRH
substantial tumor remains after transsphenoidal sur-
administration stimulates LH β subunit secretion; this
gery, adjuvant radiotherapy may be indicated to pre-
response is not seen in normal individuals. GnRH test-
vent tumor regrowth. Radiotherapy may be deferred if
ing, however, is not helpful for making the diagnosis.
no postoperative residual mass is evident.
For nonfunctioning and gonadotropin-secreting tumors,
Nonfunctioning pituitary tumors respond poorly to
the diagnosis usually rests on immunohistochemical
dopamine agonist treatment, and somatostatin ana-
analyses of surgically resected tumor tissue, as the mass
logues are largely ineffective for shrinking these tumors.
effects of these tumors usually necessitate resection.
The selective GnRH antagonist Nal-Glu GnRH sup-
Although acromegaly or Cushing’s syndrome usually
presses FSH hypersecretion but has no effect on ade-
presents with unique clinical features, clinically inappar-
noma size.
ent (silent) somatotrope or corticotrope adenomas may

MANAGEMENT OF A NONFUNCTIONING PITUITARY MASS


Nonfunctioning Pituitary Mass

Differential diagnosis based on MRI and clinical features

Dynamic pituitary reserve testing

Nonfunctioning adenoma Other sellar mass (not adenoma)

Microadenoma Macroadenoma Exclude aneurysm

Low risk of
visual loss Surgery
Histologic diagnosis
Observe Surgery

Follow-up: MRI MRI Trophic hormone MRI May require Trophic hormone
testing and disease-specific testing and
replacement therapy replacement

Figure 2-11 
Management of a nonfunctioning pituitary mass.
Thyroid-replacement therapy should be initiated 49
Thyroid-Stimulating Hormone after adequate adrenal function has been established.
Synthesis and Secretion Dose adjustment is based on thyroid hormone levels

CHAPTER 2
and clinical parameters rather than the TSH level.
TSH-secreting thyrotrope cells constitute 5% of the
anterior pituitary cell population. TSH is structurally
related to LH and FSH. It shares a common α subunit TSH-Secreting Adenomas
with these hormones but contains a specific TSH β sub-
TSH-producing macroadenomas are rare but are often
unit. TRH is a hypothalamic tripeptide (pyroglutamyl
large and locally invasive when they occur. Patients
histidylprolinamide) that acts through a GPCR to stim-

Disorders of the Anterior Pituitary and Hypothalamus


usually present with thyroid goiter and hyperthyroid-
ulate TSH synthesis and secretion; it also stimulates the
ism, reflecting overproduction of TSH. Diagnosis is
lactotrope cell to secrete PRL. TSH secretion is stimu-
based on demonstrating elevated serum free T4 levels,
lated by TRH, whereas thyroid hormones, dopamine,
inappropriately normal or high TSH secretion, and
somatostatin, and glucocorticoids suppress TSH by
MRI evidence of a pituitary adenoma.
overriding TRH induction.
It is important to exclude other causes of inappro-
Thyrotrope growth and TSH secretion are both
priate TSH secretion, such as resistance to thyroid
induced when negative feedback inhibition by thyroid
hormone, an autosomal dominant disorder caused by
hormones is removed. Thus, thyroid damage (including
mutations in the thyroid hormone β receptor (Chap. 4).
surgical thyroidectomy), radiation-induced hypothy-
The presence of a pituitary mass and elevated α subunit
roidism, chronic thyroiditis, and prolonged goitrogen
levels are suggestive of a TSH-secreting tumor. Dysal-
exposure are associated with increased TSH. Long-
buminemic hyperthyroxinemia syndromes, caused by
standing untreated hypothyroidism can lead to thyro-
mutations in serum thyroid hormone binding proteins,
trope hyperplasia and pituitary enlargement, which may
are also characterized by elevated thyroid hormone lev-
be evident on MRI.
els, but with normal rather than suppressed TSH levels.
Moreover, free thyroid hormone levels are normal in
Action these disorders, most of which are familial.
TSH is secreted in pulses, though the excursions are
modest in comparison to other pituitary hormones
because of the low amplitude of the pulses and the rela- Treatment TSH-Secreting Adenomas
tively long half-life of TSH. Consequently, single deter-
minations of TSH suffice to assess its circulating levels. The initial therapeutic approach is to remove or debulk
TSH binds to a GPCR on thyroid follicular cells to stim- the tumor mass surgically, usually using a transsphenoi-
ulate thyroid hormone synthesis and release (Chap. 4). dal approach. Total resection is not often achieved as
most of these adenomas are large and locally invasive.
Normal circulating thyroid hormone levels are achieved
TSH Deficiency in about two-thirds of patients after surgery. Thyroid
Features of central hypothyroidism due to TSH defi- ablation or antithyroid drugs (methimazole and pro-
ciency mimic those seen with primary hypothyroidism pylthiouracil) can be used to reduce thyroid hormone
but are generally less severe. Pituitary hypothyroid- levels. Somatostatin analogue treatment effectively
ism is characterized by low basal TSH levels in the set- normalizes TSH and α subunit hypersecretion, shrinks
ting of low free thyroid hormone. In contrast, patients the tumor mass in 50% of patients, and improves visual
with hypothyroidism of hypothalamic origin (presum- fields in 75% of patients; euthyroidism is restored in
ably due to a lack of endogenous TRH) may exhibit most patients. Because somatostatin analogues mark-
normal or even slightly elevated TSH levels. The TSH edly suppress TSH, biochemical hypothyroidism often
produced in this circumstance appears to have reduced requires concomitant thyroid hormone replacement,
biologic activity because of altered glycosylation. which may also further control tumor growth.
TRH (200 μg) injected intravenously causes a two-
to threefold increase in TSH (and PRL) levels within
30 min. Although TRH testing can be used to assess Diabetes Insipidus
TSH reserve, abnormalities of the thyroid axis usually
can be detected based on basal free T4 and TSH levels, See Chap. 3 for diagnosis and treatment of diabetes
and TRH testing is rarely indicated. insipidus.
chapTer 3

DISORDERS OF THE NEUROHYPOPHYSIS

Gary L. Robertson

The neurohypophysis, or posterior pituitary, is formed processed to AVP, and stored in neurosecretory vesicles
by axons that originate in large cell bodies in the supra- until the hormone and other components are released
optic and paraventricular nuclei of the hypothalamus. by exocytosis into peripheral blood.
It produces two hormones: (1) arginine vasopres- AVP secretion is regulated primarily by the “effec-
sin (AVP), also known as antidiuretic hormone, and tive” osmotic pressure of body fluids. This control is
(2) oxytocin. AVP acts on the renal tubules to reduce mediated by specialized hypothalamic cells known as
water loss by concentrating the urine. Oxytocin stimu- osmoreceptors, which are extremely sensitive to small
lates postpartum milk letdown in response to suckling. changes in the plasma concentration of sodium and
AVP deficiency causes diabetes insipidus (DI), which certain other solutes but normally are insensitive to
is characterized by the production of large amounts of other solutes such as urea and glucose. The osmore-
dilute urine. Excessive or inappropriate AVP produc- ceptors appear to include inhibitory as well as stimu-
tion predisposes to hyponatremia if water intake is not latory components that function in concert to form
reduced in parallel with urine output. a threshold, or set point, control system. Below this
threshold, plasma AVP is suppressed to levels that
permit the development of a maximum water diuresis.
Above it, plasma AVP rises steeply in direct proportion
VasOpressin to plasma osmolarity, quickly reaching levels sufficient
to effect a maximum antidiuresis. The absolute levels
syntHesis AnD secRetion of plasma osmolarity/sodium at which minimally and
AVP is a nonapeptide composed of a six-member disul- maximally effective levels of plasma AVP occur, vary
fide ring and a tripeptide tail (Fig. 3-1). It is synthe- appreciably from person to person, apparently owing
sized via a polypeptide precursor that includes AVP, to genetic influences on the set and sensitivity of the
neurophysin, and copeptin, all encoded by a single gene system. However, the average threshold, or set point,
on chromosome 20. After preliminary processing and for AVP release corresponds to a plasma osmolarity or
folding, the precursor is packaged in neurosecretory sodium of about 280 mosmol/L or 135 meq/L, respec-
vesicles, where it is transported down the axon, further tively; levels only 2–4% higher normally result in max-
imum antidiuresis.
Though it is relatively stable in a healthy adult, the
set point of the osmoregulatory system can be low-
S S ered by pregnancy, the menstrual cycle, estrogen, and
DDAVP –Cys–Tyr–Phe–Gln–Asp–Cys–Pro–D–Arg–Gly–NH2 relatively large, acute reductions in blood pressure or
volume. Those reductions are mediated largely by
S S
AVP NH2–Cys–Tyr–Phe–Gln–Asp–Cys–Pro–L–Arg–Gly–NH2
neuronal afferents that originate in transmural pres-
sure receptors of the heart and large arteries and proj-
S S ect via the vagus and glossopharyngeal nerves to the
Oxytocin NH2–Cys–Tyr–Ile–Gln–Asp–Cys–Pro–L–Leu–Gly–NH2
brainstem, from which postsynaptic projections ascend
Figure 3-1 to the hypothalamus. These pathways maintain a tonic
Primary structures of arginine vasopressin (AVP), oxytocin, inhibitory tone that decreases when blood volume or
and desmopressin. pressure falls by >10–20%. This baroregulatory system
50
is probably of minor importance in the physiology Action 51
of AVP secretion because the hemodynamic changes
required to effect it usually do not occur during nor- The most important, if not the only, physiologic action
of AVP is to reduce water excretion by promoting con-

CHAPTER 3
mal activities. However, the baroregulatory system
undoubtedly plays an important role in AVP secretion centration of urine. This antidiuretic effect is achieved
in patients with large, acute disturbances of hemody- by increasing the hydroosmotic permeability of cells
namic function. that line the distal tubule and medullary collecting ducts
AVP secretion also can be stimulated by nausea, acute of the kidney (Fig. 3-2). In the absence of AVP, these
hypoglycemia, glucocorticoid deficiency, smoking, and, cells are impermeable to water and reabsorb little, if
possibly, hyperangiotensinemia. The emetic stimuli are any, of the relatively large volume of dilute filtrate that

Disorders of the Neurohypophysis


extremely potent since they typically elicit immediate, enters from the proximal nephron. This results in the
50- to 100-fold increases in plasma AVP even when the excretion of very large volumes (as much as 0.2 mL/
nausea is transient and is not associated with vomiting or kg per min) of maximally dilute urine (specific gravity
other symptoms. They appear to act via the emetic cen- and osmolarity ∼1.000 and 50 mosmol/L, respectively),
ter in the medulla and can be blocked completely by a condition known as water diuresis. In the presence of
treatment with antiemetics such as fluphenazine. There is AVP, these cells become selectively permeable to water,
no evidence that pain or other noxious stresses have any allowing the water to diffuse back down the osmotic
effect on AVP unless they elicit a vasovagal reaction with gradient created by the hypertonic renal medulla.
its associated nausea and hypotension. As a result, the dilute fluid passing through the tubules

Glomerulus

Collecting duct
principal cells
180 L/d
(290)

V2 receptor
Na + H2O Collecting
tubule Vesicle AVP

AQP2 cAMP

H2O H2O
24 L/d
AQP3
36 L/d (60)
AQP4
(290)
Na
Henle's loop Tight junctions

H2O Apical Basal

1 L/d
H2O

Figure 3-2
Antidiuretic effect of arginine vasopressin (AVP) in the reg- resulting in the excretion of a much smaller volume of concen-
ulation of urine volume. In a typical 70-kg adult, the kidney trated urine. This antidiuretic effect is mediated via a G protein–
filters ∼180 L/d of plasma. Of this, ∼144 L (80%) is reabsorbed coupled V2 receptor that increases intracellular cyclic AMP,
isosmotically in the proximal tubule and another 8 L (4–5%) is thereby inducing translocation of aquaporin 2 (AQP2) water
reabsorbed without solute in the descending limb of Henle’s channels into the apical membrane. The resultant increase in
loop. The remainder is diluted to an osmolarity of ∼60 mmol/ permeability permits an influx of water that diffuses out of the
kg by selective reabsorption of sodium and chloride in the cell through AQP3 and AQP4 water channels on the basal-
ascending limb. In the absence of AVP, the urine issuing from lateral surface. The net rate of flux across the cell is determined
the loop passes largely unmodified through the distal tubules by the number of AQP2 water channels in the apical mem-
and collecting ducts, resulting in a maximum water diure- brane and the strength of the osmotic gradient between tubu-
sis. In the presence of AVP, solute-free water is reabsorbed lar fluid and the renal medulla. Tight junctions on the lateral
osmotically through the principal cells of the collecting ducts, surface of the cells serve to prevent unregulated water flow.
52 is concentrated and the rate of urine flow decreases. It also may help initiate or facilitate labor by stimulating
The magnitude of this effect varies in direct propor- contraction of uterine smooth muscle, but it is not clear if
tion to the plasma AVP concentration and, at maximum this action is physiologic or necessary for normal delivery.
levels, approximates a urine flow rate as low as 0.35 mL/
SECTION I

min and a urine osmolarity as high as 1200 mosmol/L.


This action is mediated via binding to G protein–coupled Deficiencies of Vasopressin
V2 receptors on the serosal surface of the cell, activation Secretion and Action
of adenyl cyclase, and insertion into the luminal surface of
water channels composed of a protein known as aquaporin Diabetes Insipidus
2 (AQP2). The V2 receptors and aquaporin 2 are encoded
Pituitary, Thyroid, and Adrenal Disorders

Clinical characteristics
by genes on chromosomes Xq28 and 12q13, respectively.
At high concentrations, AVP also causes contraction of Decreased secretion or action of AVP usually mani-
smooth muscle in blood vessels and in the gastrointestinal fests as diabetes insipidus, a syndrome characterized by
tract, induces glycogenolysis in the liver, and potentiates the production of abnormally large volumes of dilute
adrenocorticotropic hormone (ACTH) release by corti- urine. The 24-hour urine volume is >50 mL/kg body
cotropin-releasing factor. These effects are mediated by weight, and the osmolarity is <300 mosmol/L. The
V1a or V1b receptors that are coupled to phospholipase C. polyuria produces symptoms of urinary frequency,
Their role, if any, in human physiology/pathophysiology enuresis, and/or nocturia, which may disturb sleep and
is uncertain. cause mild daytime fatigue or somnolence. It also results
in a slight rise in plasma osmolarity that stimulates thirst
and a commensurate increase in fluid intake (polydip-
Metabolism sia). Overt clinical signs of dehydration are uncommon
unless fluid intake is impaired.
AVP distributes rapidly into a space roughly equal to
the extracellular fluid volume. It is cleared irrevers-
ibly with a t1/2 of 10–30 minutes. Most AVP clearance Etiology
is due to degradation in the liver and kidneys. During
Deficient secretion of AVP can be primary or second-
pregnancy, the metabolic clearance of AVP is increased
ary. The primary form usually results from agenesis or
three- to fourfold due to placental production of an
irreversible destruction of the neurohypophysis and is
N-terminal peptidase.
referred to variously as neurohypophyseal DI, pituitary DI,
or central DI. It can be caused by a variety of congeni-
tal, acquired, or genetic disorders, but in about one-half
Thirst of all adult patients it is idiopathic (Table 3-1). The
surgically induced forms of pituitary DI usually appear
Because AVP cannot reduce water loss below a certain within 24 hours and then go through a 2- to 3-week
minimum level obligated by urinary solute load and interim period of inappropriate antidiuresis, after which
evaporation from skin and lungs, a mechanism for ensur- they may or may not recur. The genetic form usually
ing adequate intake is essential for preventing dehy- is transmitted in an autosomal dominant mode and is
dration. This vital function is performed by the thirst caused by diverse mutations in the coding region of
mechanism. Like AVP, thirst is regulated primarily by an the AVP–neurophysin II (or AVP-NPII) gene. All the
osmostat that is situated in the anteromedial hypothala- mutations alter one or more amino acids known to
mus and is able to detect very small changes in the plasma be critical for correct folding of the prohormone, thus
concentration of sodium and certain other effective sol- interfering with its processing and trafficking through
utes. The thirst osmostat appears to be “set” about 5% the endoplasmic reticulum. The AVP deficiency and
higher than the AVP osmostat. This arrangement ensures DI develop gradually several months to years after birth,
that thirst, polydipsia, and dilution of body fluids do not progressing from partial to severe and permanent DI.
occur until plasma osmolarity/sodium start to exceed the They appear to result from accumulation of misfolded
defensive capacity of the antidiuretic mechanism. mutant precursor followed by selective degeneration of
AVP-producing magnocellular neurons. An autosomal
recessive form due to an inactivating mutation in the
Oxytocin AVP portion of the gene, an X-linked recessive form
due to an unidentified gene on Xq28, and an autoso-
Oxytocin is also a nonapeptide, and it differs from AVP mal recessive form due to mutations of the WFS 1 gene
only at positions 3 and 8 (Fig. 3-1). However, it has rela- responsible for Wolfram’s syndrome [diabetes insipi-
tively little antidiuretic effect and seems to act mainly on dus, diabetes mellitus, optic atrophy, and neural deaf-
mammary ducts to facilitate milk letdown during nursing. ness (DIDMOAD)] have also been described. A primary
Table 3-1 53
Causes of Diabetes Insipidus
  Pituitary diabetes insipidus Nephrogenic diabetes insipidus

CHAPTER 3
  Acquired Acquired
  Head trauma (closed and penetrating) including   Drugs
  pituitary surgery    Lithium
   Neoplasms    Demeclocycline
    Primary    Methoxyflurane
     Craniopharyngioma    Amphotericin B
     Pituitary adenoma (suprasellar)    Aminoglycosides

Disorders of the Neurohypophysis


     Dysgerminoma    Cisplatin
     Meningioma    Rifampin
    Metastatic (lung, breast)    Foscarnet
    Hematologic (lymphoma, leukemia)   Metabolic
   Granulomas    Hypercalcemia, hypercalciuria
    Sarcoidosis    Hypokalemia
    Histiocytosis   Obstruction (ureter or urethra)
    Xanthoma disseminatum   Vascular
   Infectious    Sickle cell disease and trait
    Chronic meningitis    Ischemia (acute tubular necrosis)
    Viral encephalitis   Granulomas
    Toxoplasmosis    Sarcoidosis
   Inflammatory   Neoplasms
    Lymphocytic infundibuloneurohypophysitis    Sarcoma
    Granulomatosis with polyangiitis (Wegener’s)   Infiltration
    Lupus erythematosus    Amyloidosis
    Scleroderma   Pregnancy
   Chemical toxins   Idiopathic
    Tetrodotoxin Genetic
    Snake venom   X-linked recessive (AVP receptor-2 gene)
   Vascular   Autosomal recessive (AQP2 gene)
    Sheehan’s syndrome   Autosomal dominant (AQP2 gene)
    Aneurysm (internal carotid) Primary polydipsia
    Aortocoronary bypass Acquired
    Hypoxic encephalopathy   Psychogenic
   Pregnancy (vasopressinase)    Schizophrenia
   Idiopathic    Obsessive compulsive disorder
   Congenital malformations   Dipsogenic (abnormal thirst)
    Septo-optic dysplasia    Granulomas
    Midline craniofacial defects     Sarcoidosis
    Holoprosencephaly    Infectious
    Hypogenesis, ectopia of pituitary     Tuberculous meningitis
   Genetic    Head trauma (closed and penetrating)
    Autosomal dominant (AVP-neurophysin gene)    Demyelination
    Autosomal recessive (AVP-neurophysin gene)     Multiple sclerosis
    Autosomal recessive-Wolfram-(4p − WFS 1 gene)    Drugs
    X-linked recessive (Xq28)     Lithium
    Deletion chromosome 7q     Carbamazepine
   Idiopathic
  Iatrogenic

deficiency of plasma AVP also can result from increased three subcategories. One of them, dipsogenic DI, is char-
metabolism by an N-terminal aminopeptidase produced acterized by inappropriate thirst caused by a reduction
by the placenta. It is referred to as gestational DI since in the set of the osmoregulatory mechanism. It some-
the signs and symptoms manifest during pregnancy and times occurs in association with multifocal diseases of
usually remit several weeks after delivery. the brain such as neurosarcoid, tuberculous meningi-
Secondary deficiencies of AVP result from inhibi- tis, and multiple sclerosis but is often idiopathic. The
tion of secretion by excessive intake of fluids. They are second subtype, psychogenic polydipsia, is not associated
referred to as primary polydipsia and can be divided into with thirst, and the polydipsia seems to be a feature of
54 psychosis or obsessive compulsive disorder. The third or clinically appreciable overhydration is uncommon
subtype, iatrogenic polydipsia, results from recommen- unless the polydipsia is very severe or the compensatory
dations to increase fluid intake for its presumed health water diuresis is impaired by a drug or disease that stim-
benefits. ulates or mimics endogenous AVP.
SECTION I

Primary deficiencies in the antidiuretic action of In the dipsogenic form of primary polydipsia, fluid
AVP result in nephrogenic DI (Table 3-1). They can be intake is excessive because the osmotic threshold for
genetic, acquired, or drug induced. The genetic form thirst appears to be reset to the left, often well below
usually is transmitted in a semirecessive X-linked man- that for AVP release. When deprived of fluids or sub-
ner and is caused by mutations in the coding region jected to another acute osmotic or nonosmotic stimu-
of the V2 receptor gene that impair trafficking and/ lus, these individuals invariably increase plasma AVP
Pituitary, Thyroid, and Adrenal Disorders

or ligand binding of the mutant receptor. Autosomal normally, but the resultant increase in urine concentra-
recessive or dominant forms are caused by AQP2 gene tion is usually subnormal because the individuals’ renal
mutations that result in complete or partial defects in capacities to concentrate the urine also are blunted tem-
trafficking and function of the water channels in distal porarily by chronic polyuria. Thus, the maximum level
and collecting tubules of the kidney. of urine osmolarity achieved is usually indistinguishable
Secondary deficiencies in the antidiuretic response from that in patients with partial pituitary, partial ges-
to AVP result from polyuria per se. They are caused by tational, or partial nephrogenic DI. Patients with psy-
washout of the medullary concentration gradient and/ chogenic or iatrogenic polydipsia respond similarly to
or suppression of aquaporin function. They usually fluid restriction but do not complain of thirst and usu-
resolve 24–48 hours after the polyuria is corrected but ally offer other explanations for their high fluid intake.
can complicate interpretation of some acute tests used
for differential diagnosis. Differential diagnosis
When symptoms of urinary frequency, enuresis, noc-
Pathophysiology
turia, and/or persistent thirst are present, the possibility
When the secretion or action of AVP falls below of DI should be evaluated after excluding glucosuria by
80–85% of normal, urine concentration ceases and the collecting a 24-hour urine on ad libitum fluid intake.
rate of urine output rises to symptomatic levels. If the If the volume exceeds 50 mL/kg per day (3500 mL in a
defect is due to pituitary, gestational, or nephrogenic 70-kg male) and the osmolarity is <300 mosmol/L, DI
DI, the polyuria results in a small (1–2%) decrease in is confirmed and the patient should be evaluated further
body water and a commensurate increase in plasma to determine the type.
osmolarity and sodium concentration that stimulate In differentiating among the various types of DI, the
thirst and a compensatory increase in water intake. As history alone may be sufficient if it reveals a likely ante-
a result, hypernatremia and other overt physical or laboratory cedent such as pituitary surgery. Usually, however, that
signs of dehydration do not develop unless the patient also has type of indicator is absent, ambiguous, or misleading and
a defect in thirst or fails to drink for some other reason. other approaches are needed. Except in the rare patient
The severity of the antidiuretic defect varies markedly with hypertonic dehydration under basal conditions, dif-
from patient to patient. In some, the deficiencies in AVP ferentiation should begin with a fluid deprivation test. It
secretion or action are so severe that even an intense can be performed on an outpatient basis if the necessary
stimulus such as nausea or severe dehydration does not staff and facilities are available. To minimize patient dis-
raise plasma AVP enough to concentrate the urine. In comfort, avoid excessive dehydration, and maximize the
others, the deficiency is incomplete, and a modest stim- information obtained, the test should be started in the
ulus such as a few hours of fluid deprivation, smoking, morning and continued with hourly monitoring of body
or a vasovagal reaction increases plasma AVP sufficiently weight, plasma osmolarity and/or sodium concentration,
to raise urine osmolarity as high as 800 mosmol/L. The urine volume, and urine osmolarity until either of two
maximum achieved is usually less than normal, but that is endpoints is reached. If fluid deprivation does not result
the case largely because maximal concentrating capacity in urine concentration (osmolarity >300 mosmol/L, spe-
is temporarily impaired by chronic polyuria. cific gravity >1.010) before body weight decreases by
In primary polydipsia, the pathogenesis of the poly- 5% or plasma osmolarity/sodium rise above the upper
dipsia and polyuria is the reverse of that in pituitary, limit of normal, the patient has severe pituitary or severe
nephrogenic, and gestational DI. Thus, the excessive nephrogenic DI. These disorders usually can be distin-
intake of fluids slightly increases body water, thereby guished by administering desmopressin (0.03 μg/kg SC
reducing plasma osmolarity, AVP secretion, and uri- or IV) and repeating the measurement of urine osmolar-
nary concentration. The latter results in a compensa- ity 1–2 hours later. An increase of >50% indicates severe
tory increase in urinary free-water excretion that varies pituitary DI, whereas a smaller or absent response is
in direct proportion to intake. Therefore, hyponatremia strongly suggestive of nephrogenic DI.
1000 60 55
40

Plasma vasopressin, pg/mL


Urine osmolarity, mosmol/L

800

CHAPTER 3
20
600 Figure 3-3
15
Relationship of plasma AVP to urine
400 osmolarity (left) and plasma osmolarity
10
(right) before and during fluid deprivation–
200 hypertonic saline infusion test in patients
5
who are normal or have primary poly-

Disorders of the Neurohypophysis


dipsia (blue zones), pituitary diabetes
0 0
0.1 0.5 1 3 10 30 60 270 280 290 300 310 insipidus (green zones), or nephrogenic
Plasma vasopressin, pg/mL Plasma osmolarity, mosmol/L diabetes insipidus (pink zones).

Conversely, if fluid deprivation results in concentra- Thus, a normal bright spot virtually excludes pituitary
tion of the urine, severe defects in AVP secretion and DI, argues against nephrogenic DI, and strongly suggests
action are excluded and the question becomes whether primary polydipsia. Lack of the bright spot is less help-
the patient has partial pituitary DI, partial nephro- ful, however, because it is absent not only in pituitary
genic DI, or primary polydipsia. The maximum levels and nephrogenic DI but also in some healthy adults and
of urine osmolarity achieved before and after desmo- patients with empty sella who do not have DI or AVP
pressin injection are of no help in this regard because deficiency.
the values in the three groups vary widely and overlap The other way to distinguish among the three basic
owing to impairment of renal concentrating capacity types of DI is a closely monitored trial of desmopressin
caused by polyuria per se. Therefore, another approach therapy.
is needed to differentiate among them. The easiest
and least expensive method is to measure plasma AVP
before and during the fluid deprivation test and ana- Treatment Diabetes Insipidus
lyze the results in relation to the concurrent plasma and
The signs and symptoms of uncomplicated pituitary DI
urine osmolarity (Fig. 3-3). This approach invariably
can be eliminated completely by treatment with desmo-
differentiates partial nephrogenic DI from partial pitu-
pressin (DDAVP), a synthetic analogue of AVP (Fig. 3-1).
itary DI and primary polydipsia. It also differentiates
DDAVP acts selectively at V2 receptors to increase urine
partial pituitary DI from primary polydipsia if plasma
concentration and decrease urine flow in a dose-depen-
osmolarity and/or sodium are clearly above the nor-
dent manner (Fig. 3-4). It is also more resistant to deg-
mal range when the hormone is measured. However,
radation than is AVP and has a three- to fourfold longer
the requisite level of hypertonic dehydration may be
duration of action. Desmopressin can be given by IV or
difficult to produce by fluid deprivation alone when
SC injection, nasal inhalation, or oral tablet. The doses
urine concentration occurs. Therefore, it is usually
required to control pituitary DI completely vary widely,
necessary to continue the fluid deprivation and infuse
depending on the patient and the route of administra-
hypertonic (3%) saline at a rate of 0.1 mL/kg per min
tion. However, they usually range from 1–2 μg qd or
until plasma osmolarity/sodium measured every 20 to
bid by injection, 10–20 μg bid or tid by nasal spray, or
30 minutes reach or slightly exceed the upper limit of
100–400 μg bid or tid orally. The onset of action is rapid,
normal. At that point, the measurement of plasma AVP
ranging from as little as 15 minutes after injection to
should be repeated and the result related to the plasma
60 minutes after oral administration. When given in
osmolarity/sodium.
doses sufficient to normalize urinary osmolarity and
An alternative method of differential diagno-
flow completely, desmopressin produces a slight
sis is MRI of the pituitary and hypothalamus. In most
(1–3%) increase in total body water and a commensu-
healthy adults and children, the posterior pituitary
rate decrease in plasma osmolarity and sodium con-
emits a hyperintense signal in T1-weighted midsagittal
centration that rapidly eliminates thirst and polydipsia.
images. This “bright spot” is almost always present in
Consequently, water balance is maintained and hypo-
patients with primary polydipsia but is invariably absent
natremia does not develop unless the osmoregula-
or abnormally small in patients with pituitary DI. It is
tion of thirst is also impaired or fluid intake is exces-
usually also small or absent in nephrogenic DI presum-
sive for another reason such as a misconception about
ably because of high secretion and turnover of AVP.
56 Desmopressin 20 µg IN
of desmopressin. If resistance is partial, it may be over-
600 come by tenfold higher doses, but this treatment is
Urine too expensive and inconvenient to be useful chroni-
SECTION I

osmolarity, 300
mosmol/L cally. However, treatment with conventional doses of a
thiazide diuretic and/or amiloride in conjunction with a
0
low-sodium diet and a prostaglandin synthesis inhibitor
12 12
(e.g., indomethacin) usually reduces the polyuria and
9 9
Urine Fluid polydipsia by 30–70% and may eliminate them com-
volume, intake,
6 6 pletely in some patients. Side effects such as hypokale-
Pituitary, Thyroid, and Adrenal Disorders

L/d L/d
3 3 mia and gastric irritation can be minimized by the use
0 0 of amiloride or potassium supplements and by taking
Body
71 medications with meals.
weight, 70
kg
69
Adipsic Hypernatremia
296 143

Plasma 294 142 Plasma


Clinical characteristics
osmolarity, 292 141 sodium,
mosmol/L meq/L A defect in the thirst mechanism results in adipsic
290 140 hypernatremia, a syndrome characterized by chronic
288 139 or recurrent hypertonic dehydration. The hypernatre-
0 1 2 3 4 5 6 mia varies widely in severity and usually is associated
Day with signs of hypovolemia such as tachycardia, postural
Figure 3-4  hypotension, azotemia, hyperuricemia, and hypokale-
Effect of desmopressin therapy on water balance in a mia. Muscle weakness, pain, rhabdomyolysis, hypergly-
patient with uncomplicated pituitary diabetes insipidus. cemia, hyperlipidemia, and acute renal failure may also
Note that treatment rapidly reduces thirst and fluid intake occur. DI usually does not exist at presentation but may
as well as urine output to normal, with only a slight increase develop during rehydration.
in body water (weight) and a decrease in plasma osmolarity/
sodium. (From P Felig, L Frohman [eds]: Endocrinology and
Etiology
Metabolism, 4th ed. New York, McGraw-Hill, 2001, with
permission.) Deficient thirst is usually due to hypogenesis or destruc-
tion of the osmoreceptors in the anterior hypothalamus.
Because of their proximity, the osmoreceptors that
the need to prevent dehydration. Fortunately, thirst regulate AVP secretion also are usually impaired.
abnormalities are rare in pituitary DI, and other moti- These defects can result from various congenital malfor-
vations to drink excessively usually can be eliminated mations of midline brain structures or may be acquired
by patient education. Therefore, desmopressin usu- due to diseases such as occlusions of the anterior com-
ally can be given safely in doses sufficient to normalize municating artery, primary or metastatic tumors in the
urine output completely, thereby avoiding the inconve- hypothalamus, head trauma, surgery, granulomatous
nience and discomfort of intermittent escape otherwise diseases such as sarcoidosis and histiocytosis, AIDS, and
needed to prevent water intoxication. cytomegalovirus encephalitis.
Primary polydipsia cannot be treated safely with
desmopressin or any other antidiuretic drug because Pathophysiology
eliminating the polyuria does not eliminate the urge to A deficiency of thirst results in a failure to drink enough
drink. Therefore, it produces hyponatremia and/or other water to replenish obligatory renal and extrarenal losses,
signs of water intoxication, usually within 24 to 48 hours causing hypertonic dehydration. In most patients, the
if urine output is normalized completely. Patient educa- response of AVP to osmotic stimulation is also deficient
tion may eliminate iatrogenic polydipsia, but it is largely (Fig. 3-5). If the deficiency is partial, it may not be
ineffective in psychogenic or dipsogenic DI. In these clinically apparent at first because the hypertonicity and
patients, the only help currently available is to try to hypovolemia are severe enough to stimulate the release
prevent water intoxication by warning about the use of AVP in the small amounts necessary to concen-
of drugs that can impair urinary free-water excretion trate the urine. However, when the hypertonicity and
directly or indirectly. hypovolemia are reduced, plasma AVP falls and poly-
The polyuria and polydipsia of nephrogenic DI uria develops, often before the dehydration is corrected
are not affected by treatment with standard doses fully. Patients with a complete lack of osmoregulation
20 Normal range if rehydration is excessive. In most patients, the neu- 57
rohypophysis and the AVP response to hemodynamic
18
or emetic stimuli are normal. In a few, however, the

CHAPTER 3
16
neurohypophysis is also destroyed, resulting in a com-
Plasma vasopressin, pg/mL

14
a bination of chronic pituitary DI and hypodipsia that is
12 particularly difficult to manage.
10
8 Differential diagnosis
6
Adipsic hypernatremia usually can be distinguished clin-

Disorders of the Neurohypophysis


Partial AH
4 b
P
ically from other causes of inadequate fluid intake (e.g.,
2 c T coma, paralysis, restraints, absence of fresh water) that
0 d Total AH can also result in hypertonic dehydration. Previous epi-
sodes and/or denial of thirst and failure to drink sponta-
240 260 280 300 320 340 360 380 neously when the patient is conscious, unrestrained, and
Plasma osmolarity, mosmol/L hypernatremic are virtually diagnostic of adipsia. The
Figure 3-5 hypernatremia caused by excessive oral or intravenous
Heterogeneity of osmoregulatory dysfunction in adipsic intake of sodium can also be distinguished by the his-
hypernatremia (AH) and the syndrome of inappropri- tory and/or physical examination and laboratory signs of
ate antidiuresis (SIAD). Each line depicts schematically volume expansion rather than contraction.
the relationship of plasma arginine vasopressin (AVP) to
plasma osmolarity during water loading and/or infusion
of 3% saline in a patient with either AH (open symbols) or
SIAD (closed symbols). The shaded area indicates the nor-
Treatment Adipsic Hypernatremia
mal range of the relationship. The horizontal broken line
Adipsic hypernatremia should be treated by administer-
indicates the plasma AVP level below which the hormone
ing water orally if the patient is alert and cooperative or
is undetectable and urinary concentration usually does
not occur. Lines P and T represent patients with a selec-
by using hypotonic fluids (0.45% saline or 5% dextrose
tive deficiency in the osmoregulation of thirst and AVP that and water) via IV if the patient is not. The amount of
is either partial ( ) or total ( ). In the latter, plasma AVP free water in liters required to correct the deficit (ΔFW)
does not change in response to increases or decreases can be estimated from body weight in kg (BW) and the
in plasma osmolarity but remains within a range sufficient serum sodium concentration in mmol/L (SNa) by the
to concentrate the urine even if overhydration produces formula ΔFW = 0.5BW × [(SNa − 140)/140]. If serum glu-
hypotonic hyponatremia. In contrast, if the osmoregula- cose (SGlu) is elevated, the measured SNa should be cor-
tory deficiency is partial ( ), rehydration of the patient sup- rected (SNa*) by the formula SNa* = SNa + [(SGlu − 90)/36].
presses plasma AVP to levels that result in urinary dilution This amount plus an allowance for continuing insensible
and polyuria before plasma osmolarity and sodium are and urinary losses should be given over a 24- to 48-hour
reduced to normal. Lines a–d represent different defects period. Close monitoring of serum sodium as well as
in the osmoregulation of plasma AVP observed in patients fluid intake and urinary output is essential because,
with SIAD. In a ( ), plasma AVP is markedly elevated and depending on the extent of osmoreceptor deficiency
fluctuates widely without relation to changes in plasma (Fig. 3-5), some patients will develop AVP-deficient DI,
osmolarity, indicating complete loss of osmoregulation. In requiring desmopressin therapy to complete rehydra-
b ( ), plasma AVP remains fixed at a slightly elevated level tion; others will develop hyponatremia and a syndrome
until plasma osmolarity reaches the normal range, at which of inappropriate antidiuresis (SIAD)-like picture if over-
point it begins to rise appropriately, indicating a selective hydrated. If hyperglycemia and/or hypokalemia are
defect in the inhibitory component of the osmoregulatory present, insulin and/or potassium supplements should
mechanism. In c ( ), plasma AVP rises in close correlation
be given with the expectation that both can be dis-
with plasma osmolarity before the latter reaches the nor-
continued soon after rehydration is complete. Plasma
mal range, indicating downward resetting of the osmostat.
urea/creatinine should be monitored closely for signs of
In d ( ), plasma AVP appears to be osmoregulated nor-
acute renal failure.
mally, suggesting that the inappropriate antidiuresis is
Once the patient has been rehydrated, an MRI of the
caused by some other abnormality.
brain and tests of anterior pituitary function should be
performed to look for the cause and collateral defects
do not develop DI at any level of hydration because in other hypothalamic functions. A long-term manage-
they cannot osmotically suppress or stimulate AVP ment plan to prevent or minimize recurrence of the fluid
secretion. Therefore, a hyponatremic syndrome indis- and electrolyte imbalance also should be developed.
tinguishable from inappropriate antidiuresis may develop
58 Table 3-2
This should include a practical method that can be
Causes of Syndrome of Inappropriate
used to regulate fluid intake in accordance with day-
Antidiuresis (SIAD)
to-day variations in water balance. The most effective
SECTION I

way to do this is to prescribe desmopressin to con- Neoplasms Neurologic


  Carcinomas   Guillain-Barré syndrome
trol DI if it is present, and teach the patient how to
   Lung   Multiple sclerosis
adjust daily fluid intake in accordance with day-to-day    Duodenum   Delirium tremens
changes in body weight or serum sodium as deter-    Pancreas Amyotrophic lateral
mined by home monitoring analyzers. Prescribing a    Ovary sclerosis
constant fluid intake is ineffective and potentially dan-    Bladder, ureter   Hydrocephalus
Pituitary, Thyroid, and Adrenal Disorders

gerous because it does not take into account the large, Other neoplasms   Psychosis
uncontrolled variations in insensible loss that inevita-   Thymoma   Peripheral neuropathy
bly result from changes in ambient temperature and   Mesothelioma Congenital malformations
  Bronchial adenoma   Agenesis corpus callosum
physical activity.
  Carcinoid   Cleft lip/palate
  Gangliocytoma Other midline defects
  Ewing’s sarcoma Metabolic
Head trauma (closed and Acute intermittent
Excess Vasopressin Secretion penetrating) porphyria
and Action Infections   Pulmonary
Pneumonia, bacterial or   Asthma
Hyponatremia viral   Pneumothorax
  Abscess, lung or brain Positive-pressure
Clinical characteristics
  Cavitation (aspergillosis) respiration
Excessive secretion or action of AVP results in the   Tuberculosis, lung or brain Drugs
production of decreased volumes of more highly Meningitis, bacterial or Vasopressin or desmo-
concentrated urine. If not accompanied by a com- viral pressin
  Encephalitis   Chlorpropamide
mensurate reduction in fluid intake or an increase in   AIDS   Oxytocin, high dose
insensible loss, the reduction in urine output results Vascular   Vincristine
in excess water retention with expansion and dilution Cerebrovascular   Carbamazepine
of all body fluids. In some patients, excessive intake occlusions, hemorrhage   Nicotine
results from inappropriate thirst. If the hyponatremia Cavernous sinus   Phenothiazines
develops gradually or has been present for more than a thrombosis   Cyclophosphamide
few days, it may be largely asymptomatic. However, if Genetic   Tricyclic antidepressants
X-linked recessive Monoamine oxidase
it develops acutely, it usually is accompanied by symp-
(V2 receptor gene) inhibitors
toms and signs of water intoxication that may include Serotonin reuptake
mild headache, confusion, anorexia, nausea, vomiting, inhibitors
coma, and convulsions. Severe hyponatremia may be
lethal. Other clinical signs and symptoms vary greatly,
depending on the pathogenesis of the defect in antidi-
uretic function.
In this case, the SIAD is usually self-limited and remits
spontaneously within 2–3 weeks, but about 10% of
Etiology
cases are chronic. The mechanisms by which these dis-
Hyponatremia and impaired urinary dilution can be eases disrupt osmoregulation are not known. The defect
caused by either a primary or a secondary defect in the in osmoregulation can take any of four distinct forms
regulation of AVP secretion or action. The primary (Fig. 3-5). In one of the most common (reset osmo-
forms are generally referred to as the syndrome of inap- stat), AVP secretion remains fully responsive to changes
propriate antidiuresis. They have many different causes, in plasma osmolarity/sodium, but the threshold, or set
including ectopic production of AVP by lung cancer or point, of the osmoregulatory system is abnormally low.
other neoplasms; eutopic release by various diseases or These patients differ from those with the other types
drugs; and exogenous administration of AVP, desmo- of osmoregulatory defect in that they are able to maxi-
pressin, or large doses of oxytocin (Table 3-2). The mally suppress plasma AVP and dilute their urine if
ectopic forms result from abnormal expression of the their fluid intake is high enough to reduce their plasma
AVP-NPII gene by primary or metastatic malignancies. osmolarity/sodium to the new set point. Another,
The eutopic forms occur most often in patients with smaller subgroup (∼10% of the total) has inappropriate
acute infections or strokes but have also been associ- antidiuresis without a demonstrable defect in the osmo-
ated with many other neurologic diseases and injuries. regulation of plasma AVP (Fig. 3-5). In some of them,
all young boys, the inappropriate antidiuresis has been In both types, the increased AVP secretion appears to 59
traced to a constitutively activating mutation of the V2 be due to downward resetting of the osmostat. Type III
receptor gene. This unusual variant may be referred is due to nonosmotic, nonhemodynamic AVP stimuli

CHAPTER 3
to as familial nephrogenic SIAD to distinguish it from such as nausea or isolated glucocorticoid deficiency that
other possible causes of the syndrome. produce a form of euvolemic hyponatremia similar to
The secondary forms of osmotically inappropriate SIAD (Table 3-3). They are differentiated because the
antidiuresis also have multiple causes. They usually are cause of excess AVP secretion in type III can be cor-
subdivided into three types, depending on the nature of rected quickly and completely by treatments (antiemet-
the abnormal stimulus and the state of extracellular fluid ics or glucocorticoids) that are not useful in SIAD.
volume. Type I occurs in sodium-retaining, edema-

Disorders of the Neurohypophysis


forming states such as congestive heart failure, cirrho-
Pathophysiology
sis, and nephrosis. It is associated with markedly exces-
sive retention of water and sodium that is thought to When osmotic suppression of antidiuresis is impaired
be stimulated by a large reduction in “effective” blood for any reason, retention of water and dilution of body
volume caused by low cardiac output and/or redistribu- fluids occur only if intake exceeds the rate of obligatory
tion of plasma from the intravascular space to the inter- and insensible urinary losses. The excess water intake
stitial space. Type II occurs in sodium-depleted states sometimes is due to an associated defect in the osmo-
such as severe gastroenteritis, diuretic abuse, and miner- regulation of thirst (dipsogenic) but also can be psy-
alocorticoid deficiency. It is due to stimulation of AVP chogenic or iatrogenic, including IV administration of
by a large reduction in blood volume and/or pressure. hypotonic fluids.

Table 3-3
Differential Diagnosis of Hyponatremia Based on Clinical Assessment of Extracellular Fluid
Volume (ECFV)
Clinical Findings Type I, Hypervolemic Type II, Hypovolemic Type III, Euvolemic SIAD Euvolemic

History
 CHF, cirrhosis, or nephrosis Yes No No No
  Salt and water loss No Yes No No
 ACTH–cortisol No No Yes No
 deficiency and/or nausea
and vomiting
Physical examination
 Generalized edema, ascites Yes No No No
  Postural hypotension Maybe Maybe Maybea No
Laboratory
  BUN, creatinine High-normal High-normal Low-normal Low-normal
  Uric acid High-normal High-normal Low-normal Low-normal
  Serum potassium Low-normal Low-normalb Normalc Normal
  Serum albumin Low-normal High-normal Normal Normal
  Serum cortisol Normal-high Normal-highd Lowe Normal
  Plasma renin activity High High Lowf Low
 Urinary sodium Low Lowh Highi Highi
  (meq unit of time)g

a
Postural hypotension may occur in secondary (ACTH-dependent) adrenal insufficiency even though extracellular fluid volume and aldosterone
are usually normal.
b
Serum potassium may be high if hypovolemia is due to aldosterone deficiency.
c
Serum potassium may be low if vomiting causes alkalosis.
d
Serum cortisol is low if hypovolemia is due to primary adrenal insufficiency (Addison’s disease).
e
Serum cortisol will be normal or high if the cause is nausea and vomiting rather than secondary (ACTH-dependent) adrenal insufficiency.
f
Plasma renin activity may be high if the cause is secondary (ACTH) adrenal insufficiency.
g
Urinary sodium should be expressed as the rate of excretion rather than the concentration. In a hyponatremic adult, an excretion
rate >25 meq/d (or 25 μeq/mg of creatinine) could be considered high.
h
The rate of urinary sodium excretion may be high if the hypovolemia is due to diuretic abuse, primary adrenal insufficiency, or other causes of
renal sodium wasting.
i
The rate of urinary sodium excretion may be low if intake is curtailed by symptoms or treatment.
Abbreviations: ACTH, adrenocorticotropic hormone; BUN, blood urea nitrogen; CHF, congestive heart failure; SIAD, syndrome of inappropriate
antidiuresis.
60 In SIAD, the excessive retention of water expands provided that the hyponatremia is not in the recovery
extracellular and intracellular volume, increases glomer- phase or due to a primary defect in renal conservation
ular filtration and atrial natriuretic hormone, suppresses of sodium, diuretic abuse, or hyporeninemic hypoaldo-
plasma renin activity, and increases urinary sodium steronism. The latter may be suspected if serum potas-
SECTION I

excretion. This natriuresis reduces total body sodium, sium is elevated instead of low, as it usually is in types I
and this serves to counteract the extracellular hypervol- and II hyponatremia. Measurements of plasma AVP are
emia but aggravates the hyponatremia. The osmotically currently of no value in differentiating among the three
driven increase in intracellular volume results in swell- types of hyponatremia since the abnormalities are simi-
ing of brain cells and increases intracranial pressure; this lar. In patients who fulfill the clinical criteria for type
is probably responsible for the symptoms of acute water III (euvolemic) hyponatremia, morning plasma cortisol
Pituitary, Thyroid, and Adrenal Disorders

intoxication. Within a few days, this swelling may be should also be measured to exclude secondary adrenal
counteracted by inactivation or elimination of intra- insufficiency. If it is normal and there is no history of
cellular solutes, resulting in the remission of symptoms nausea/vomiting, the diagnosis of SIAD is confirmed
even though the hyponatremia persists. The pathophys- and a careful search for occult lung cancer or other
iology of type III (euvolemic) hyponatremia is probably common causes of the syndrome (Table 3-2) should be
similar to that of SIAD. undertaken. If an activating mutation of the V2 recep-
In type I (hypervolemic) or type II (hypovolemic) tor gene is suspected, plasma AVP should be measured
hyponatremia, the antidiuretic effect of hemodynami- while the hyponatremia and antidiuresis are present. If it
cally induced AVP release is enhanced by decreased is undetectable, DNA should be collected for analysis of
distal delivery of glomerular filtrate that results from the V2 receptor gene.
increased reabsorption of sodium in proximal nephrons.
If the marked reduction in urine output is not associ-
ated with a commensurate reduction in water intake or
Treatment Hyponatremia
an increase in insensible loss, body fluids are expanded
and diluted, resulting in hyponatremia. Unlike SIAD, The management of hyponatremia differs depending
however, glomerular filtration is reduced and plasma not only on the type but also on the severity and dura-
renin activity and aldosterone are elevated due to either tion of symptoms. In a patient with SIAD and few symp-
effective hypovolemia (type I) or absolute hypovolemia toms, the objective is to reduce body water gradually
(type II). Thus, urinary sodium excretion is low (unless by restricting total fluid intake to less than the sum of
sodium reabsorption is impaired by a diuretic), and the urinary and insensible losses. Because the water derived
hyponatremia is usually accompanied by hypokalemia, from food (300–700 mL/d) usually approximates basal
azotemia, and hyperuricemia. The sodium retention is insensible losses in adults, total discretionary intake
an appropriate compensatory response to severe volume (all liquids) should be at least 500 mL less than urinary
and sodium depletion in type II but is inappropriate and output. If achievable, this usually reduces body water
deleterious in type I since body sodium and extracellular and increases serum sodium by about 1–2% per day.
volume are already markedly increased, as evidenced by If the symptoms or signs of water intoxication are more
the presence of generalized edema. severe, the hyponatremia can be corrected more rap-
idly by supplementing the fluid restriction with IV infu-
Differential diagnosis sion of hypertonic (3%) saline. This treatment also has
the advantage of correcting the sodium deficiency that
SIAD is a diagnosis of exclusion that usually can be
is partly responsible for the hyponatremia in SIAD and
made from the history, physical examination, and basic
produces a solute diuresis that serves to remove some
laboratory data. The possibility that hyponatremia is due
of the excess water. However, if plasma sodium is raised
to an osmotically driven shift of water from the intracel-
too rapidly or too much and the hyponatremia has
lular space to the extracellular space can be excluded if
been present for >24–48 hours, it also has the poten-
plasma glucose is not high enough to account for the
tial to produce central pontine myelinolysis, an acute,
hyponatremia [serum sodium decreases ∼1 meq/L for
potentially fatal neurologic syndrome characterized by
each rise in glucose of 2 mmol/L (36 mg/dL)] and/or
quadriparesis, ataxia, and abnormal extraocular move-
plasma osmolarity is reduced in proportion to sodium
ments. The risk of this complication can be minimized
(each decrease in serum sodium of 1 meq/L should
by observing several precautions: 3% saline should be
reduce plasma osmolarity by ∼2 mosmol/L). The type
infused at a rate ≥0.05 mL/kg body weight per min; the
of hypotonic hyponatremia can then be determined
effect should be monitored continuously by STAT mea-
by standard clinical indicators of the extracellular fluid
surements of serum sodium at least once every 2 hours;
volume (Table 3-3). If these findings are ambiguous
and the infusion should be stopped as soon as serum
or contradictory, measuring the rate of urinary sodium
sodium increases by 12 mmol/L or to 130 mmol/L,
excretion or plasma renin activity may be helpful
whichever comes first. Urinary output should be moni- and edema and may precipitate cardiovascular decom-
61
tored continuously since SIAD can remit spontaneously pensation. Preliminary studies with antagonists of V2
at any time, resulting in an acute water diuresis that receptors indicate that they are almost as effective in

CHAPTER 3
greatly accelerates the rate of rise in serum sodium pro- type I hyponatremia as they are in SIAD.
duced by fluid restriction and 3% saline infusion. In type II hyponatremia, the defect in AVP secretion
In chronic SIAD, the hyponatremia can be corrected and water balance usually can be corrected easily and
by treatment with demeclocycline, 150–300 mg PO quickly by stopping the loss of sodium and water and/
tid or qid, or fludrocortisone, 0.05–0.2 mg PO bid. The or replacing the deficits by mouth or IV infusion of nor-
effect of the demeclocycline manifests in 7–14 days mal or hypertonic saline. As with the treatment of other

Disorders of the Neurohypophysis


and is due to production of a reversible form of neph- forms of hyponatremia, care must be taken to ensure
rogenic DI. Potential side effects include phototoxicity that plasma sodium does not increase too rapidly. Fluid
and azotemia. The effect of fludrocortisone also requires restriction and administration of AVP antagonists are
1–2 weeks and is partly due to increased retention of contraindicated in type II as they would only aggravate
sodium and possibly inhibition of thirst. It also increases the underlying volume depletion and could result in
urinary potassium excretion, which may require replace- hemodynamic collapse.
ment through dietary adjustments or supplements and In euvolemic hyponatremia due to protracted nausea
may induce hypertension, occasionally necessitating and vomiting or isolated glucocorticoid deficiency (type
discontinuation of the treatment. III), all abnormalities can be corrected quickly and com-
Nonpeptide AVP antagonists that block the antidi- pletely by giving an antiemetic or stress doses of hydro-
uretic effect of AVP have been used experimentally to cortisone. As with other treatments, care must be taken
treat SIAD. They produce a dose-dependent increase in to ensure that serum sodium does not rise too quickly
urinary free-water excretion, that, if combined with a or too far.
modest restriction of fluid intake, reduces body water Global Perspectives  The incidence,
and corrects the hyponatremia. The antagonists appear clinical characteristics, etiology, pathophysiology,
to have no adverse side effects, but, like hypertonic differential diagnosis, and treatments of fluid
saline, they probably carry the risk of inducing osmotic and electrolyte disorders in tropical and nonindustrial-
demyelinization if the hyponatremia is corrected too ized countries differ in some respects from those in the
rapidly. One of them, a combined V2/V1a antagonist United States and other industrialized parts of the
(Conivaptan), has been approved for short-term in- world. Hyponatremia, for example, appears to be more
hospital IV treatment of SIAD and the hyponatremia common and is more likely to be due to infectious dis-
of congestive heart failure. It is a substrate and inhibitor of eases such as cholera, shigellosis, and other diarrheal
cyto­chrome P450 and should not be used in conjunction disorders. In these circumstances, hyponatremia is prob-
with other drugs metabolized by these pathways. Other ably due to gastrointestinal losses of salt and water
V2 receptor antagonists are currently in phase III trials. (hypovolemia type II), but other abnormalities, includ-
In type I hyponatremia, fluid restriction is also appro- ing undefined infectious toxins, also may contribute.
priate and somewhat effective if it can be maintained. The causes of DI are similar worldwide except in regions
However, infusion of hypertonic saline is contraindi- where malaria and venoms from snake or insect bites
cated because it further increases total body sodium are more common.
chapteR 4

DISORDERS OF THE THYROID GLAND

J. Larry Jameson ■ Anthony P. Weetman

The thyroid gland produces two related hormones, hormone, are located posterior to each pole of the thy-
thyroxine (T4) and triiodothyronine (T3) (Fig. 4-1). roid. The recurrent laryngeal nerves traverse the lat-
Acting through thyroid hormone receptors α and β, eral borders of the thyroid gland and must be identified
these hormones play a critical role in cell differentiation during thyroid surgery to avoid injury and vocal cord
during development and help maintain thermogenic and paralysis.
metabolic homeostasis in the adult. Autoimmune disor- The thyroid gland develops from the floor of the
ders of the thyroid gland can stimulate overproduction primitive pharynx during the third week of gestation.
of thyroid hormones (thyrotoxicosis) or cause glandular The developing gland migrates along the thyroglossal
destruction and hormone deficiency (hypothyroidism). duct to reach its final location in the neck. This feature
In addition, benign nodules and various forms of thyroid accounts for the rare ectopic location of thyroid tissue
cancer are relatively common and amenable to detec- at the base of the tongue (lingual thyroid) as well as the
tion by physical examination. occurrence of thyroglossal duct cysts along this devel-
opmental tract. Thyroid hormone synthesis normally
begins at about 11 weeks’ gestation.
Neural crest derivatives from the ultimobranchial
anatomy and deVelopment body give rise to thyroid medullary C cells that produce
calcitonin, a calcium-lowering hormone. The C cells
The thyroid (Greek thyreos, shield, plus eidos, form) are interspersed throughout the thyroid gland, although
consists of two lobes connected by an isthmus. It is their density is greatest in the juncture of the upper
located anterior to the trachea between the cricoid car- one-third and lower two-thirds of the gland. Calcitonin
tilage and the suprasternal notch. The normal thyroid is plays a minimal role in calcium homeostasis in humans
12–20 g in size, highly vascular, and soft in consistency. but the C cells are important because of their involve-
Four parathyroid glands, which produce parathyroid ment in medullary thyroid cancer.

I I NH2
3' 3
HO 5' O 5 CH2 CH COOH

I I
Thyroxine (T4)
3,5,3',5'-Tetraiodothyronine
Deiodinase 1 or 2 Deiodinase 3>2
(5'-Deiodination) (5-Deiodination)

I I NH2 I I NH2
Figure 4-1
HO O CH2 CH COOH HO O CH2 CH COOH structures of thyroid hormones. Thyroxine (T4)
I I contains four iodine atoms. Deiodination leads to
Triiodothyronine (T3) Reverse T3 (rT3) production of the potent hormone triiodothyronine
3,5,3'-Triiodothyronine 3,3',5'-Triiodothyronine (T3), or the inactive hormone reverse T3.
62
Table 4-1 63
Genetic Causes of Congenital Hypothyroidism
Defective Gene Protein Inheritance Consequences

CHAPTER 4
PROP-1 Autosomal recessive Combined pituitary hormone
deficiencies with preservation of
adrenocorticotropic hormone
PIT-1 Autosomal recessive Combined deficiencies of growth
Autosomal dominant hormone, prolactin, thyroid-
stimulating hormone (TSH)

Disorders of the Thyroid Gland


TSHβ Autosomal recessive TSH deficiency
TTF-1 (TITF-1) Autosomal dominant Variable thyroid hypoplasia,
choreoathetosis, pulmonary
problems
TTF-2 (FOXE-1) Autosomal recessive Thyroid agenesis, choanal atresia,
spiky hair
PAX-8 Autosomal dominant Thyroid dysgenesis
TSH-receptor Autosomal recessive Resistance to TSH
Gsα (Albright hereditary osteodystrophy) Autosomal dominant Resistance to TSH
Na+/I− symporter Autosomal recessive Inability to transport iodide
THOX2 Autosomal dominant Organification defect
Thyroid peroxidase Autosomal recessive Defective organification of iodide
Thyroglobulin Autosomal recessive Defective synthesis of thyroid
hormone
Pendrin Autosomal recessive Pendred syndrome: sensorineural
deafness and partial organification
defect in thyroid
Dehalogenase 1 Autosomal recessive Loss of iodide reutilization

Thyroid gland development is orchestrated by the amounts of thyroglobulin, the protein precursor of thy-
coordinated expression of several developmental tran- roid hormones (Fig. 4-2). The thyroid follicular cells
scription factors. Thyroid transcription factor (TTF)-1, are polarized—the basolateral surface is apposed to the
TTF-2, and paired homeobox-8 (PAX-8) are expressed bloodstream and an apical surface faces the follicular
selectively, but not exclusively, in the thyroid gland. In lumen. Increased demand for thyroid hormone is reg-
combination, they dictate thyroid cell development and ulated by thyroid-stimulating hormone (TSH), which
the induction of thyroid-specific genes such as thyroglob- binds to its receptor on the basolateral surface of the
ulin (Tg), thyroid peroxidase (TPO), the sodium iodide follicular cells, leading to Tg reabsorption from the follic-
symporter (Na+/I, NIS), and the thyroid-stimulating hor- ular lumen, and proteolysis within the cytoplasm, yield-
mone receptor (TSH-R). Mutations in these develop- ing thyroid hormones for secretion into the bloodstream.
mental transcription factors or their downstream target
genes are rare causes of thyroid agenesis or dyshormono-
genesis, though the causes of most forms of congenital Regulation of the Thyroid Axis
hypothyroidism remain unknown (Table 4-1). Because
congenital hypothyroidism occurs in approximately 1 in TSH, secreted by the thyrotrope cells of the anterior
4000 newborns, neonatal screening is now performed in pituitary, plays a pivotal role in control of the thyroid
most industrialized countries (see below). Transplacental axis and serves as the most useful physiologic marker
passage of maternal thyroid hormone occurs before the of thyroid hormone action. TSH is a 31-kDa hor-
fetal thyroid gland begins to function and provides par- mone composed of α and β subunits; the α subunit is
tial hormone support to a fetus with congenital hypothy- common to the other glycoprotein hormones [lutein-
roidism. Early thyroid hormone replacement in newborns izing hormone, follicle-stimulating hormone, human
with congenital hypothyroidism prevents potentially chorionic gonadotropin (hCG)], whereas the TSH β
severe developmental abnormalities. subunit is unique to TSH. The extent and nature of
The thyroid gland consists of numerous spherical fol- carbohydrate modification are modulated by thyrotropin-
licles composed of thyroid follicular cells that surround releasing hormone (TRH) stimulation and influence the
secreted colloid, a proteinaceous fluid containing large biologic activity of the hormone.
64 hormone levels rapidly and directly suppress TSH gene
Hypothalamus T3 T4 expression secretion and inhibit TRH stimulation of

TSH-R
TSH, indicating that thyroid hormones are the domi-
nant regulator of TSH production. Like other pitu-
SECTION I

Basal
NIS
I- itary hormones, TSH is released in a pulsatile manner
and exhibits a diurnal rhythm; its highest levels occur
I- at night. However, these TSH excursions are modest
TRH cAMP in comparison to those of other pituitary hormones, in
+ – part, because TSH has a relatively long plasma half-life
(50 minutes). Consequently, single measurements of
Pituitary, Thyroid, and Adrenal Disorders

Tg
Pituitary Apical TSH are adequate for assessing its circulating level. TSH
DIT
TPO is measured using immunoradiometric assays that are
Follicular
cell
highly sensitive and specific. These assays readily distin-
Tg-MIT
TSH
Tg + I- guish between normal and suppressed TSH values; thus,
Co

+
up
lin g Iodination TSH can be used for the diagnosis of hyperthyroidism
(low TSH) as well as hypothyroidism (high TSH).

Thyroid
Thyroid follicle
Thyroid Hormone Synthesis,
Metabolism, and Action
T4 T3
Thyroid Hormone Synthesis
Peripheral Thyroid hormones are derived from Tg, a large iodinated
actions glycoprotein. After secretion into the thyroid follicle,
Figure 4-2 Tg is iodinated on tyrosine residues that are subse-
Regulation of thyroid hormone synthesis. Left. Thyroid quently coupled via an ether linkage. Reuptake of Tg
hormones T4 and T3 feed back to inhibit hypothalamic pro- into the thyroid follicular cell allows proteolysis and the
duction of thyrotropin-releasing hormone (TRH) and pituitary release of newly synthesized T4 and T3.
production of thyroid-stimulating hormone (TSH). TSH stimu-
lates thyroid gland production of T4 and T3. Right. Thyroid Iodine metabolism and transport
follicles are formed by thyroid epithelial cells surrounding
proteinaceous colloid, which contains thyroglobulin. Follicu- Iodide uptake is a critical first step in thyroid hormone
lar cells, which are polarized, synthesize thyroglobulin and synthesis. Ingested iodine is bound to serum proteins,
carry out thyroid hormone biosynthesis (see text for details). particularly albumin. Unbound iodine is excreted in
TSH-R, thyroid-stimulating hormone receptor; Tg, thyroglob- the urine. The thyroid gland extracts iodine from the
ulin; NIS, sodium iodide symporter; TPO, thyroid peroxidase; circulation in a highly efficient manner. For example,
DIT, diiodotyrosine; MIT, monoiodotyrosine. 10–25% of radioactive tracer (e.g., 123I) is taken up
by the normal thyroid gland over 24 hours; this value
can rise to 70–90% in Graves’ disease. Iodide uptake is
The thyroid axis is a classic example of an endocrine mediated by NIS, which is expressed at the basolateral
feedback loop. Hypothalamic TRH stimulates pituitary membrane of thyroid follicular cells. NIS is most highly
production of TSH, which, in turn, stimulates thyroid expressed in the thyroid gland, but low levels are pres-
hormone synthesis and secretion. Thyroid hormones, ent in the salivary glands, lactating breast, and placenta.
acting predominantly through thyroid hormone recep- The iodide transport mechanism is highly regulated,
tor β2 (TRβ2), feed back to inhibit TRH and TSH allowing adaptation to variations in dietary supply. Low
production (Fig. 4-2). The “set-point” in this axis is iodine levels increase the amount of NIS and stimulate
established by TSH. TRH is the major positive regu- uptake, whereas high iodine levels suppress NIS expres-
lator of TSH synthesis and secretion. Peak TSH secre- sion and uptake. The selective expression of NIS in the
tion occurs ∼15 min after administration of exogenous thyroid allows isotopic scanning, treatment of hyperthy-
TRH. Dopamine, glucocorticoids, and somatostatin roidism, and ablation of thyroid cancer with radioisotopes
suppress TSH but are not of major physiologic impor- of iodine, without significant effects on other organs.
tance except when these agents are administered in Mutation of the NIS gene is a rare cause of congenital
pharmacologic doses. Reduced levels of thyroid hor- hypothyroidism, underscoring its importance in thyroid
mone increase basal TSH production and enhance hormone synthesis. Another iodine transporter, pen-
TRH-mediated stimulation of TSH. High thyroid drin, is located on the apical surface of thyroid cells and
mediates iodine efflux into the lumen. Mutation of the of IQ. Oversupply of iodine, through supplements or 65
pendrin gene causes Pendred syndrome, a disorder charac- foods enriched in iodine (e.g., shellfish, kelp), is associ-
terized by defective organification of iodine, goiter, and ated with an increased incidence of autoimmune thy-

CHAPTER 4
sensorineural deafness. roid disease. The recommended average daily intake
Iodine deficiency is prevalent in many moun- of iodine is 150–250 μg/d for adults, 90–120 μg/d
tainous regions and in central Africa, central for children, and 250 μg/d for pregnant and lactating
South America, and northern Asia (Fig. 4-3). women. Urinary iodine is >10 μg/dL in iodine-suffi-
Europe remains mildly iodine deficient, and health sur- cient populations.
veys indicate that iodine intake has been falling in the
United States and Australia. The World Health Orga-

Disorders of the Thyroid Gland


Organification, coupling, storage, release
nization (WHO) estimates that about 2 billion people
are iodine deficient, based on urinary excretion data. In After iodide enters the thyroid, it is trapped and trans-
areas of relative iodine deficiency, there is an increased ported to the apical membrane of thyroid follicular cells,
prevalence of goiter and, when deficiency is severe, where it is oxidized in an organification reaction that
hypothyroidism and cretinism. Cretinism is characterized involves TPO and hydrogen peroxide. The reactive
by mental and growth retardation and occurs when iodine atom is added to selected tyrosyl residues within
children who live in iodine-deficient regions are not Tg, a large (660-kDa) dimeric protein that consists of
treated with iodine or thyroid hormone to restore nor- 2769 amino acids. The iodotyrosines in Tg are then
mal thyroid hormone levels during early life. These coupled via an ether linkage in a reaction that is also
children are often born to mothers with iodine defi- catalyzed by TPO. Either T4 or T3 can be produced
ciency, and it is likely that maternal thyroid hormone by this reaction, depending on the number of iodine
deficiency worsens the condition. Concomitant sele- atoms present in the iodotyrosines. After coupling, Tg
nium deficiency may also contribute to the neurologic is taken back into the thyroid cell, where it is processed
manifestations of cretinism. Iodine supplementation in lysosomes to release T4 and T3. Uncoupled mono-
of salt, bread, and other food substances has markedly and diiodotyrosines (MIT, DIT) are deiodinated by the
reduced the prevalence of cretinism. Unfortunately, enzyme dehalogenase, thereby recycling any iodide that
how­ever, iodine deficiency remains the most com- is not converted into thyroid hormones.
mon cause of preventable mental deficiency, often Disorders of thyroid hormone synthesis are rare
because of societal resistance to food additives or the causes of congenital hypothyroidism. The vast major-
cost of supplementation. In addition to overt cretin- ity of these disorders are due to recessive mutations in
ism, mild iodine deficiency can lead to subtle reduction TPO or Tg, but defects have also been identified in

Status unknown Sufficiency


Moderate-severe deficiency Likely sufficiency
Mild deficiency Excess
Likely deficiency Likely excess

Figure 4-3
Worldwide iodine nutrition. Data are from the WHO and the International Council for the Control of Iodine Deficiency Disorders
(http://indorgs.virginia.edu/iccidd/mi/cidds.html ).
66 the TSH-R, NIS, pendrin, hydrogen peroxide gen- action of high iodide may persist, however, in patients
eration, and dehalogenase. Because of the biosynthetic with underlying autoimmune thyroid disease.
defect, the gland is incapable of synthesizing adequate
amounts of hormone, leading to increased TSH and a
SECTION I

large goiter. Thyroid Hormone Transport


and Metabolism
TSH action Serum binding proteins
TSH regulates thyroid gland function through the T4 is secreted from the thyroid gland in about twenty-
Pituitary, Thyroid, and Adrenal Disorders

TSH-R, a seven-transmembrane G protein–coupled fold excess over T3 (Table 4-2). Both hormones are
receptor (GPCR). The TSH-R is coupled to the α bound to plasma proteins, including thyroxine-binding
subunit of stimulatory G protein (Gsα), which acti- globulin (TBG), transthyretin (TTR, formerly known
vates adenylyl cyclase, leading to increased production as thyroxine-binding prealbumin, or TBPA), and albu-
of cyclic AMP. TSH also stimulates phosphatidylinosi- min. The plasma-binding proteins increase the pool of
tol turnover by activating phospholipase C. The func- circulating hormone, delay hormone clearance, and may
tional role of the TSH-R is exemplified by the conse- modulate hormone delivery to selected tissue sites. The
quences of naturally occurring mutations. Recessive concentration of TBG is relatively low (1–2 mg/dL),
loss-of-function mutations cause thyroid hypoplasia and but because of its high affinity for thyroid hormones
congenital hypothyroidism. Dominant gain-of-function (T4 > T3), it carries about 80% of the bound hormones.
mutations cause sporadic or familial hyperthyroidism Albumin has relatively low affinity for thyroid hor-
that is characterized by goiter, thyroid cell hyperpla- mones but has a high plasma concentration (∼3.5 g/dL),
sia, and autonomous function. Most of these activat- and it binds up to 10% of T4 and 30% of T3. TTR car-
ing mutations occur in the transmembrane domain of ries about 10% of T4 but little T3.
the receptor. They mimic the conformational changes When the effects of the various binding proteins are
induced by TSH binding or the interactions of thyroid- combined, approximately 99.98% of T4 and 99.7% of
stimulating immunoglobulins (TSI) in Graves’ disease. T3 are protein bound. Because T3 is less tightly bound
Activating TSH-R mutations also occur as somatic than T4, the fraction of unbound T3 is greater than
events, leading to clonal selection and expansion of the unbound T4, but there is less unbound T3 in the cir-
affected thyroid follicular cell and autonomously func- culation because it is produced in smaller amounts and
tioning thyroid nodules (see below). cleared more rapidly than T4. The unbound or “free”
concentrations of the hormones are ∼2 × 10−11 M for
T4 and ∼6 × 10−12 M for T3, which roughly correspond
Other factors that influence hormone to the thyroid hormone receptor binding constants for
synthesis and release these hormones (see below). The unbound hormone is
Although TSH is the dominant hormonal regula-
tor of thyroid gland growth and function, a variety of
Table 4-2
growth factors, most produced locally in the thyroid
gland, also influence thyroid hormone synthesis. These Characteristics of Circulating T4 and T3
include insulin-like growth factor 1 (IGF-1), epidermal Hormone Property T4 T3
growth factor, transforming growth factor β (TGF-β),
Serum concentrations
endothelins, and various cytokines. The quantitative
roles of these factors are not well understood, but they   Total hormone 8 μg/dL 0.14 μg/dL
are important in selected disease states. In acromegaly, Fraction of total hormone 0.02% 0.3%
for example, increased levels of growth hormone and in the free form
IGF-1 are associated with goiter and predisposition to Free (unbound) hormone 21 × 10−12 M 6 × 10−12 M
multinodular goiter (MNG). Certain cytokines and Serum half-life 7d 0.75 d
interleukins (ILs) produced in association with autoim-
Fraction directly from the 100% 20%
mune thyroid disease induce thyroid growth, whereas thyroid
others lead to apoptosis. Iodine deficiency increases thy-
Production rate, including 90 μg/d 32 μg/d
roid blood flow and upregulates the NIS, stimulating
peripheral conversion
more efficient iodine uptake. Excess iodide transiently
inhibits thyroid iodide organification, a phenomenon Intracellular hormone fraction ∼20% ∼70%
known as the Wolff-Chaikoff effect. In individuals with a Relative metabolic potency 0.3 1
normal thyroid, the gland escapes from this inhibitory Receptor binding 10 −10
M 10−11 M
effect and iodide organification resumes; the suppressive
thought to be biologically available to tissues. Nonethe- replacement as TBG levels are increased by pregnancy 67
less, the homeostatic mechanisms that regulate the thy- or estrogen treatment. Mutations in TBG, TTR, and
roid axis are directed toward maintenance of normal albumin may increase the binding affinity for T4 and/or

CHAPTER 4
concentrations of unbound hormones. T3 and cause disorders known as euthyroid hyperthyrox-
inemia or familial dysalbuminemic hyperthyroxinemia (FDH)
(Table 4-3). These disorders result in increased total
Abnormalities of thyroid hormone T4 and/or T3, but unbound hormone levels are normal.
binding proteins
The familial nature of the disorders, and the fact that
A number of inherited and acquired abnormalities affect TSH levels are normal rather than suppressed, should
thyroid hormone binding proteins. X-linked TBG defi- suggest this diagnosis. Unbound hormone levels (ideally

Disorders of the Thyroid Gland


ciency is associated with very low levels of total T4 and measured by dialysis) are normal in FDH. The diagnosis
T3. However, because unbound hormone levels are can be confirmed by using tests that measure the affini-
normal, patients are euthyroid, and TSH levels are nor- ties of radiolabeled hormone binding to specific trans-
mal. It is important to recognize this disorder to avoid port proteins or by performing DNA sequence analyses
efforts to normalize total T4 levels, as this leads to thy- of the abnormal transport protein genes.
rotoxicosis and is futile because of rapid hormone clear- Certain medications, such as salicylates and salsalate,
ance in the absence of TBG. TBG levels are elevated can displace thyroid hormones from circulating binding
by estrogen, which increases sialylation and delays TBG proteins. Although these drugs transiently perturb the
clearance. Consequently, in women who are preg- thyroid axis by increasing free thyroid hormone levels,
nant or taking estrogen-containing contraceptives, ele- TSH is suppressed until a new steady state is reached,
vated TBG increases total T4 and T3 levels; however, thereby restoring euthyroidism. Circulating factors asso-
unbound T4 and T3 levels are normal. These features ciated with acute illness may also displace thyroid
are part of the explanation for why women with hypo- hormone from binding proteins (see “Sick Euthyroid
thyroidism require increased amounts of l-thyroxine Syndrome,” below).

Table 4-3
Conditions Associated With Euthyroid Hyperthyroxinemia
Disorder Cause Transmission Characteristics

Familial dysalbuminemic Albumin mutations, usually AD Increased T4


hyperthyroxinemia (FDH) R218H Normal unbound T4
Rarely increased T3
TBG
  Familial excess Increased TBG production XL Increased total T4, T3
Normal unbound T4, T3
  Acquired excess Medications (estrogen), Acquired Increased total T4, T3
pregnancy, cirrhosis, hepatitis Normal unbound T4, T3
Transthyretina
  Excess Islet tumors Acquired Usually normal T4, T3
  Mutations Increased affinity for T4 or T3 AD Increased total T4, T3
Normal unbound T4, T3
Medications: propranolol, Decreased T4 → T3 conversion Acquired Increased T4
ipodate, iopanoic acid, Decreased T3
amiodarone Normal or increased TSH
Sick euthyroid syndrome Acute illness, especially Acquired Transiently increased unbound T4
psychiatric disorders Decreased TSH
T4 and T3 may also be decreased
(see text)
Resistance to thyroid Thyroid hormone receptor β AD Increased unbound T4, T3
hormone (RTH) mutations Normal or increased TSH
Some patients clinically thyrotoxic

a
Also known as thyroxine-binding prealbumin, TBPA.
Abbreviations: AD, autosomal dominant; TBG, thyroxine-binding globulin; TSH, thyroid-stimulating hormone; XL, X-linked.
68 Deiodinases
T4 may be thought of as a precursor for the more potent Nucleus
T3
T3. T4 is converted to T3 by the deiodinase enzymes
SECTION I

(Fig. 4-1). Type I deiodinase, which is located primar- T4


ily in thyroid, liver, and kidneys, has a relatively low T3 CoR
1
affinity for T4. Type II deiodinase has a higher affin- 2
ity for T4 and is found primarily in the pituitary gland, T3
CoA

brain, brown fat, and thyroid gland. Expression of type RXR TR


CoA 3
II deiodinase allows it to regulate T3 concentrations Cytoplasm
Pituitary, Thyroid, and Adrenal Disorders

locally, a property that may be important in the context TRE Gene


of levothyroxine (T4) replacement. Type II deiodinase 4
is also regulated by thyroid hormone; hypothyroidism Gene expression
induces the enzyme, resulting in enhanced T4 → T3
conversion in tissues such as brain and pituitary. T4 →
T3 conversion is impaired by fasting, systemic illness or
acute trauma, oral contrast agents, and a variety of medi- Figure 4-4
cations (e.g., propylthiouracil, propranolol, amiodarone, Mechanism of thyroid hormone receptor action. The thy-
glucocorticoids). Type III deiodinase inactivates T4 and roid hormone receptor (TR) and retinoid X receptor (RXR)
T3 and is the most important source of reverse T3 (rT3). form heterodimers that bind specifically to thyroid hormone
Massive hemangiomas that express type III deiodinase response elements (TREs) in the promoter regions of target
are a rare cause of hypothyroidism in infants. genes. In the absence of hormone, TR binds co-repressor
(CoR) proteins that silence gene expression. The numbers
refer to a series of ordered reactions that occur in response to
thyroid hormone: (1) T4 or T3 enters the nucleus; (2) T3 binding
Thyroid Hormone Action
dissociates CoR from TR; (3) coactivators (CoA) are recruited
Thyroid hormone transport to the T3-bound receptor; (4) gene expression is altered.
Circulating thyroid hormones enter cells by passive dif-
fusion and via specific transporters such as the mono-
carboxylate 8 (MCT8) transporter. Mutations in the
MCT8 gene have been identified in patients with (TREs), in the promoter regions of target genes
X-linked psychomotor retardation and thyroid function (Fig. 4-4). The receptors bind as homodimers or,
abnormalities (low T4, high T3, and high TSH). After more commonly, as heterodimers with retinoic acid X
entering cells, thyroid hormones act primarily through receptors (RXRs) (Chap. 1). The activated receptor can
nuclear receptors, although they also have nongenomic either stimulate gene transcription (e.g., myosin heavy
actions through stimulating plasma membrane and chain α) or inhibit transcription (e.g., TSH β-subunit
mitochondrial enzymatic responses. gene), depending on the nature of the regulatory ele-
ments in the target gene.
Thyroid hormones (T3 and T4) bind with similar
Nuclear thyroid hormone receptors affinities to TRα and TRβ. However, structural dif-
Thyroid hormones bind with high affinity to nuclear ferences in the ligand-binding domains provide the
thyroid hormone receptors (TRs) α and β. Both TRα and potential for developing receptor-selective agonists or
TRβ are expressed in most tissues, but their relative antagonists. T3 is bound with 10–15 times greater affin-
expression levels vary among organs; TRα is particu- ity than T4, which explains its increased hormonal
larly abundant in brain, kidneys, gonads, muscle, and potency. Though T4 is produced in excess of T3, recep-
heart, whereas TRβ expression is relatively high in the tors are occupied mainly by T3, reflecting T4 → T3
pituitary and liver. Both receptors are variably spliced conversion by peripheral tissues, greater T3 bioavail-
to form unique isoforms. The TRβ2 isoform, which ability in the plasma, and receptors’ greater affinity for
has a unique amino terminus, is selectively expressed in T3. After binding to TRs, thyroid hormone induces
the hypothalamus and pituitary, where it plays a role in conformational changes in the receptors that modify its
feedback control of the thyroid axis (see above). The interactions with accessory transcription factors. Impor-
TRα2 isoform contains a unique carboxy terminus that tantly, in the absence of thyroid hormone binding, the
precludes thyroid hormone binding; it may function to aporeceptors bind to co-repressor proteins that inhibit
block the action of other TR isoforms. gene transcription. Hormone binding dissociates the
The TRs contain a central DNA-binding domain co-repressors and allows the recruitment of coactiva-
and a C-terminal ligand-binding domain. They bind to tors that enhance transcription. The discovery of TR
specific DNA sequences, termed thyroid response elements interactions with co-repressors explains the fact that
TR silences gene expression in the absence of hormone especially when nodules are small. The patient’s neck 69
binding. Consequently, hormone deficiency has a pro- should be slightly flexed to relax the neck muscles. After
found effect on gene expression because it causes gene locating the cricoid cartilage, the isthmus can be iden-

CHAPTER 4
repression as well as loss of hormone-induced stimula- tified and followed laterally to locate either lobe (nor-
tion. This concept has been corroborated by the find- mally, the right lobe is slightly larger than the left). By
ing that targeted deletion of the TR genes in mice has asking the patient to swallow sips of water, thyroid con-
a less-pronounced phenotypic effect than hormone sistency can be better appreciated as the gland moves
deficiency. beneath the examiner’s fingers.
Features to be noted include thyroid size, consis-
Thyroid hormone resistance tency, nodularity, and any tenderness or fixation. An

Disorders of the Thyroid Gland


estimate of thyroid size (normally 12–20 g) should be
Resistance to thyroid hormone (RTH) is an autosomal
made, and a drawing is often the best way to record
dominant disorder characterized by elevated thyroid
findings. However, ultrasound is the method of choice
hormone levels and inappropriately normal or elevated
when it is important to determine thyroid size accu-
TSH. Individuals with RTH do not, in general, exhibit
rately. The size, location, and consistency of any nodules
signs and symptoms that are typical of hypothyroidism
should also be defined. A bruit over the gland indicates
because hormone resistance is partial and is compen-
increased vascularity, as occurs in hyperthyroidism. If
sated by increased levels of thyroid hormone. The clini-
the lower borders of the thyroid lobes are not clearly
cal features of RTH can include goiter, attention deficit
felt, a goiter may be retrosternal. Large retrosternal goi-
disorder, mild reduction in IQ, delayed skeletal matura-
ters can cause venous distention over the neck and dif-
tion, tachycardia, and impaired metabolic responses to
ficulty breathing, especially when the arms are raised
thyroid hormone.
(Pemberton’s sign). With any central mass above the
RTH is caused by mutations in the TRβ receptor
thyroid, the tongue should be extended, as thyroglos-
gene. These mutations, located in restricted regions of
sal cysts then move upward. The thyroid examination is
the ligand-binding domain, cause loss of receptor func-
not complete without assessment for lymphadenopathy
tion. However, because the mutant receptors retain the
in the supraclavicular and cervical regions of the neck.
capacity to dimerize with RXRs, bind to DNA, and
recruit co-repressor proteins, they function as antago-
nists of the remaining normal TRβ and TRα recep- Laboratory Evaluation
tors. This property, referred to as “dominant negative” Measurement of thyroid hormones
activity, explains the autosomal dominant mode of
transmission. The diagnosis is suspected when unbound The enhanced sensitivity and specificity of TSH assays
thyroid hormone levels are increased without suppres- have greatly improved laboratory assessment of thyroid
sion of TSH. Similar hormonal abnormalities are found function. Because TSH levels change dynamically in
in other affected family members, although the TRβ response to alterations of T4 and T3, a logical approach
mutation arises de novo in about 20% of patients. DNA to thyroid testing is to first determine whether TSH is
sequence analysis of the TRβ gene provides a defini- suppressed, normal, or elevated. With rare exceptions
tive diagnosis. RTH must be distinguished from other (see below), a normal TSH level excludes a primary
causes of euthyroid hyperthyroxinemia (e.g., FDH) and abnormality of thyroid function. This strategy depends
inappropriate secretion of TSH by TSH-secreting pitu- on the use of immunochemiluminometric assays
itary adenomas (Chap. 2). In most patients, no treatment (ICMAs) for TSH that are sensitive enough to discrimi-
is indicated; the importance of making the diagnosis is nate between the lower limit of the reference range and
to avoid inappropriate treatment of mistaken hyperthy- the suppressed values that occur with thyrotoxicosis.
roidism and to provide genetic counseling. Extremely sensitive (fourth-generation) assays can detect
TSH levels ≤0.004 mU/L, but, for practical purposes,
assays sensitive to ≤0.1 mU/L are sufficient. The wide-
Physical Examination
spread availability of the TSH ICMA has rendered the
In addition to the examination of the thyroid itself, the TRH stimulation test obsolete, because the failure of
physical examination should include a search for signs TSH to rise after an intravenous bolus of 200–400 μg TRH
of abnormal thyroid function and the extrathyroidal fea- has the same implications as a suppressed basal TSH mea-
tures of ophthalmopathy and dermopathy (see below). sured by ICMA.
Examination of the neck begins by inspecting the seated The finding of an abnormal TSH level must be fol-
patient from the front and side and noting any surgical lowed by measurements of circulating thyroid hormone
scars, obvious masses, or distended veins. The thyroid levels to confirm the diagnosis of hyperthyroidism
can be palpated with both hands from behind or while (suppressed TSH) or hypothyroidism (elevated TSH).
facing the patient, using the thumbs to palpate each Radioimmunoassays are widely available for serum total
lobe. It is best to use a combination of these methods, T4 and total T3. T4 and T3 are highly protein bound,
70 and numerous factors (illness, medications, genetic fac- first trimester of pregnancy (due to hCG secretion), after
tors) can influence protein binding. It is useful, there- treatment of hyperthyroidism (because TSH can remain
fore, to measure the free, or unbound, hormone levels, suppressed for several months), and in response to cer-
which correspond to the biologically available hormone tain medications (e.g., high doses of glucocorticoids or
SECTION I

pool. Two direct methods are used to measure unbound dopamine). Importantly, secondary hypothyroidism,
thyroid hormones: (1) unbound thyroid hormone compe- caused by hypothalamic-pituitary disease, is associated
tition with radiolabeled T4 (or an analogue) for binding with a variable (low to high-normal) TSH level, which
to a solid-phase antibody, and (2) physical separation of is inappropriate for the low T4 level. Thus, TSH should
the unbound hormone fraction by ultracentrifugation or not be used as an isolated laboratory test to assess thyroid func-
equilibrium dialysis. Though early unbound hormone tion in patients with suspected or known pituitary disease.
Pituitary, Thyroid, and Adrenal Disorders

immunoassays suffered from artifacts, newer assays cor- Tests for the end-organ effects of thyroid hormone
relate well with the results of the more technically excess or depletion, such as estimation of basal meta-
demanding and expensive physical separation methods. bolic rate, tendon reflex relaxation rates, or serum cho-
An indirect method to estimate unbound thyroid hor- lesterol, are not useful as clinical determinants of thyroid
mone levels is to calculate the free T3 or free T4 index function.
from the total T4 or T3 concentration and the thyroid
hormone binding ratio (THBR). The latter is derived from Tests to determine the etiology of
the T3-resin uptake test, which determines the distribution thyroid dysfunction
of radiolabeled T3 between an absorbent resin and
the unoccupied thyroid hormone–binding proteins in the Autoimmune thyroid disease is detected most easily by
sample. The binding of the labeled T3 to the resin is measuring circulating antibodies against TPO and Tg.
increased when there is reduced unoccupied protein As antibodies to Tg alone are uncommon, it is reason-
binding sites (e.g., TBG deficiency) or increased total able to measure only TPO antibodies. About 5–15% of
thyroid hormone in the sample; it is decreased under euthyroid women and up to 2% of euthyroid men have
the opposite circumstances. The product of THBR and thyroid antibodies; such individuals are at increased risk
total T3 or T4 provides the free T3 or T4 index. In effect, the of developing thyroid dysfunction. Almost all patients
index corrects for anomalous total hormone values caused with autoimmune hypothyroidism, and up to 80% of
by abnormalities in hormone-protein binding. those with Graves’ disease, have TPO antibodies, usually
Total thyroid hormone levels are elevated when TBG at high levels.
is increased due to estrogens (pregnancy, oral contra- TSI are antibodies that stimulate the TSH-R in
ceptives, hormone therapy, tamoxifen), and decreased Graves’ disease. They can be measured in bioassays or
when TBG binding is reduced (androgens, nephrotic indirectly in assays for TSH-binding inhibiting immu-
syndrome). Genetic disorders and acute illness can also noglobulins (TBII) that detect antibody binding to the
cause abnormalities in thyroid hormone–binding pro- receptor. The main use of these assays is to predict neo-
teins, and various drugs [phenytoin, carbamazepine, natal thyrotoxicosis caused by high maternal levels of
salicylates, and nonsteroidal anti-inflammatory drugs TSI in the last trimester of pregnancy.
(NSAIDs)] can interfere with thyroid hormone binding. Serum Tg levels are increased in all types of thyrotox-
Because unbound thyroid hormone levels are normal icosis except thyrotoxicosis factitia caused by self-admin-
and the patient is euthyroid in all of these circumstances, istration of thyroid hormone. Tg levels are particularly
assays that measure unbound hormone are preferable to increased in thyroiditis, reflecting thyroid tissue destruc-
those for total thyroid hormones. tion and release of Tg. The main role for Tg measure-
For most purposes, the unbound T4 level is sufficient ment, however, is in the follow-up of thyroid cancer
to confirm thyrotoxicosis, but 2–5% of patients have patients. After total thyroidectomy and radioablation,
only an elevated T3 level (T3 toxicosis). Thus, unbound Tg levels should be undetectable; in the absence of anti-
T3 levels should be measured in patients with a sup- Tg antibodies, measurable levels indicate incomplete
pressed TSH but normal unbound T4 levels. ablation or recurrent cancer.
There are several clinical conditions in which the use
Radioiodine uptake and thyroid scanning
of TSH as a screening test may be misleading, particu-
larly without simultaneous unbound T4 determinations. The thyroid gland selectively transports radioisotopes of
Any severe nonthyroidal illness can cause abnormal TSH iodine (123I, 125I, 131I) and 99mTc pertechnetate, allowing
levels (see below). Although hypothyroidism is the most thyroid imaging and quantitation of radioactive tracer
common cause of an elevated TSH level, rare causes fractional uptake.
include a TSH-secreting pituitary tumor (Chap. 2), thy- Nuclear imaging of Graves’ disease is characterized
roid hormone resistance, and assay artifact. Conversely, by an enlarged gland and increased tracer uptake that is
a suppressed TSH level, particularly <0.1 mU/L, usually distributed homogeneously. Toxic adenomas appear as
indicates thyrotoxicosis but may also be seen during the focal areas of increased uptake, with suppressed tracer
uptake in the remainder of the gland. In toxic MNG, in ultrasound technology. Using 10-MHz instruments, 71
the gland is enlarged—often with distorted architec- spatial resolution and image quality are excellent, allow-
ture—and there are multiple areas of relatively increased ing the detection of nodules and cysts >3 mm. In addi-

CHAPTER 4
or decreased tracer uptake. Subacute thyroiditis is asso- tion to detecting thyroid nodules, ultrasound is useful for
ciated with very low uptake because of follicular cell monitoring nodule size and for the aspiration of nod-
damage and TSH suppression. Thyrotoxicosis factitia is ules or cystic lesions. Ultrasound-guided FNA biopsy of
also associated with low uptake. thyroid lesions lowers the rate of inadequate sampling.
Although the use of fine-needle aspiration (FNA) Ultrasonography is also used in the evaluation of recur-
biopsy has diminished the use of thyroid scans in the rent thyroid cancer, including possible spread to cervical
evaluation of solitary thyroid nodules, the functional lymph nodes.

Disorders of the Thyroid Gland


features of thyroid nodules have some prognostic signif-
icance. So-called cold nodules, which have diminished
tracer uptake, are usually benign. However, these nod-
Hypothyroidism
ules are more likely to be malignant (∼5–10%) than so-
called hot nodules, which are almost never malignant. Iodine deficiency remains the most common cause of
Thyroid scanning is also used in the follow-up of hypothyroidism worldwide. In areas of iodine suffi-
thyroid cancer. After thyroidectomy and ablation using ciency, autoimmune disease (Hashimoto’s thyroiditis)
131
I, there is diminished radioiodine uptake in the thy- and iatrogenic causes (treatment of hyperthyroidism) are
roid bed, allowing the detection of metastatic thyroid most common (Table 4-4).
cancer deposits that retain the ability to transport iodine.
Whole-body scans using 111–185 MBq (3–5 mCi) 131I
are typically performed after thyroid hormone with- Congenital Hypothyroidism
drawal to raise the TSH level or after the administration Prevalence
of recombinant human TSH.
Hypothyroidism occurs in about 1 in 4000 newborns.
It may be transient, especially if the mother has TSH-R
Thyroid ultrasound blocking antibodies or has received antithyroid drugs,
Ultrasonography is used increasingly to assist in the diag- but permanent hypothyroidism occurs in the majority.
nosis of nodular thyroid disease, a reflection of the limi- Neonatal hypothyroidism is due to thyroid gland dysgen-
tations of the physical examination and improvements esis in 80–85%, and to inborn errors of thyroid hormone

Table 4-4
Causes of Hypothyroidism
Primary
Autoimmune hypothyroidism: Hashimoto’s thyroiditis, atrophic thyroiditis
Iatrogenic: 131I treatment, subtotal or total thyroidectomy, external irradiation of neck for lymphoma or cancer
Drugs: iodine excess (including iodine-containing contrast media and amiodarone), lithium, antithyroid drugs, p-aminosalicylic
acid, interferon-α and other cytokines, aminoglutethimide, sunitinib
Congenital hypothyroidism: absent or ectopic thyroid gland, dyshormonogenesis, TSH-R mutation
Iodine deficiency
Infiltrative disorders: amyloidosis, sarcoidosis, hemochromatosis, scleroderma, cystinosis, Riedel’s thyroiditis
Overexpression of type 3 deiodinase in infantile hemangioma
Transient
Silent thyroiditis, including postpartum thyroiditis
Subacute thyroiditis
Withdrawal of thyroxine treatment in individuals with an intact thyroid
After 131I treatment or subtotal thyroidectomy for Graves’ disease
Secondary
Hypopituitarism: tumors, pituitary surgery or irradiation, infiltrative disorders, Sheehan’s syndrome, trauma, genetic forms of
combined pituitary hormone deficiencies
Isolated TSH deficiency or inactivity
Bexarotene treatment
Hypothalamic disease: tumors, trauma, infiltrative disorders, idiopathic

Abbreviations: TSH, thyroid-stimulating hormone; TSH-R, TSH receptor.


72 synthesis in 10–15%, and is TSH-R antibody mediated Autoimmune Hypothyroidism
in 5% of affected newborns. The developmental abnor-
Classification
malities are twice as common in girls. Mutations that
cause congenital hypothyroidism are being increas- Autoimmune hypothyroidism may be associated with
SECTION I

ingly identified, but the vast majority remain idiopathic a goiter (Hashimoto’s, or goitrous thyroiditis) or, at the
(Table 4-1). later stages of the disease, minimal residual thyroid tis-
sue (atrophic thyroiditis). Because the autoimmune pro-
Clinical manifestations cess gradually reduces thyroid function, there is a phase
of compensation when normal thyroid hormone levels
The majority of infants appear normal at birth, and <10% are maintained by a rise in TSH. Though some patients
Pituitary, Thyroid, and Adrenal Disorders

are diagnosed based on clinical features, which include may have minor symptoms, this state is called sub-
prolonged jaundice, feeding problems, hypotonia, clinical hypothyroidism. Later, unbound T4 levels fall and
enlarged tongue, delayed bone maturation, and umbili- TSH levels rise further; symptoms become more read-
cal hernia. Importantly, permanent neurologic damage ily apparent at this stage (usually TSH >10 mIU/L),
results if treatment is delayed. Typical features of adult which is referred to as clinical hypothyroidism or overt
hypothyroidism may also be present (Table 4-5). Other hypothyroidism.
congenital malformations, especially cardiac, are four
times more common in congenital hypothyroidism.
Prevalence

Diagnosis and treatment The mean annual incidence rate of autoimmune hypo-
thyroidism is up to 4 per 1000 women and 1 per 1000 men.
Because of the severe neurologic consequences of It is more common in certain populations, such as
untreated congenital hypothyroidism, neonatal screen- the Japanese, probably because of genetic factors and
ing programs have been established. These are gen- chronic exposure to a high-iodine diet. The mean age
erally based on measurement of TSH or T4 levels in at diagnosis is 60 years, and the prevalence of overt
heel-prick blood specimens. When the diagnosis is con- hypothyroidism increases with age. Subclinical hypo-
firmed, T4 is instituted at a dose of 10–15 μg/kg per thyroidism is found in 6–8% of women (10% over the
day, and the dose is adjusted by close monitoring of age of 60) and 3% of men. The annual risk of devel-
TSH levels. T4 requirements are relatively great during oping clinical hypothyroidism is about 4% when sub-
the first year of life, and a high circulating T4 level is clinical hypothyroidism is associated with positive TPO
usually needed to normalize TSH. Early treatment with antibodies.
T4 results in normal IQ levels, but subtle neurodevelop-
mental abnormalities may occur in those with the most
severe hypothyroidism at diagnosis or when treatment is Pathogenesis
delayed or suboptimal. In Hashimoto’s thyroiditis, there is a marked lympho-
cytic infiltration of the thyroid with germinal center
formation, atrophy of the thyroid follicles accompanied
Table 4-5 by oxyphil metaplasia, absence of colloid, and mild to
Signs and Symptoms of Hypothyroidism moderate fibrosis. In atrophic thyroiditis, the fibrosis
(Descending Order of Frequency) is much more extensive, lymphocyte infiltration is less
Symptoms Signs pronounced, and thyroid follicles are almost completely
Tiredness, weakness Dry, coarse skin; cool absent. Atrophic thyroiditis likely represents the end
Dry skin peripheral extremities stage of Hashimoto’s thyroiditis rather than a distinct
Feeling cold Puffy face, hands, and feet disorder.
Hair loss (myxedema)
Difficulty concentrating and Diffuse alopecia
As with most autoimmune disorders, susceptibility to
poor memory Bradycardia autoimmune hypothyroidism is determined by a com-
Constipation Peripheral edema bination of genetic and environmental factors, and the
Weight gain with poor Delayed tendon reflex risk of either autoimmune hypothyroidism or Graves’
appetite relaxation disease is increased among siblings. HLA-DR polymor-
Dyspnea Carpal tunnel syndrome phisms are the best documented genetic risk factors for
Hoarse voice Serous cavity effusions autoimmune hypothyroidism, especially HLA-DR3,
Menorrhagia (later
-DR4, and -DR5 in Caucasians. A weak association also
oligomenorrhea or
amenorrhea)
exists between polymorphisms in CTLA-4, a T cell–
Paresthesia regulatory gene, and autoimmune hypothyroidism. Both
Impaired hearing of these genetic associations are shared by other auto-
immune diseases, which may explain the relationship
between autoimmune hypothyroidism and other autoim- antibodies, therefore, cause hypothyroidism and, especially 73
mune diseases, especially type 1 diabetes mellitus, Addi- in Asian patients, thyroid atrophy. Their transplacental
son’s disease, pernicious anemia, and vitiligo (Chap.  23). passage may induce transient neonatal hypothyroidism.

CHAPTER 4
HLA-DR and CTLA-4 polymorphisms account for Rarely, patients have a mixture of TSI- and TSH-R–
approximately half of the genetic susceptibility to auto- blocking antibodies, and thyroid function can oscillate
immune hypothyroidism. Other contributory loci remain between hyperthyroidism and hypothyroidism as one
to be identified. A gene on chromosome 21 may be or the other antibody becomes dominant. Predicting
responsible for the association between autoimmune the course of disease in such individuals is difficult, and
hypothyroidism and Down syndrome. The female pre- they require close monitoring of thyroid function. Bio-
ponderance of thyroid autoimmunity is most likely due assays can be used to document that TSH-R–blocking

Disorders of the Thyroid Gland


to sex steroid effects on the immune response, but an X antibodies reduce the cyclic AMP–inducing effect of
chromosome–related genetic factor is also possible and TSH on cultured TSH-R–expressing cells, but these
may account for the high frequency of autoimmune assays are difficult to perform. TBII assays that measure
hypothyroidism in Turner’s syndrome. Environmen- the binding of antibodies to the receptor by competi-
tal susceptibility factors are poorly defined at present. tion with radiolabeled TSH do not distinguish between
A high iodine intake may increase the risk of autoim- TSI- and TSH-R–blocking antibodies, but a positive
mune hypothyroidism by immunologic effects or direct result in a patient with spontaneous hypothyroidism is
thyroid toxicity. There is no convincing evidence for a strong evidence for the presence of blocking antibodies.
role of infection except for the congenital rubella syn- The use of these assays does not generally alter clinical
drome, in which there is a high frequency of autoim- management, although it may be useful to confirm the
mune hypothyroidism. Viral thyroiditis does not induce cause of transient neonatal hypothyroidism.
subsequent autoimmune thyroid disease.
The thyroid lymphocytic infiltrate in autoimmune Clinical manifestations
hypothyroidism is composed of activated CD4+ and
CD8+ T cells as well as B cells. Thyroid cell destruction The main clinical features of hypothyroidism are sum-
is primarily mediated by the CD8+ cytotoxic T cells, marized in Table 4-5. The onset is usually insidious,
which destroy their targets by either perforin-induced and the patient may become aware of symptoms only
cell necrosis or granzyme B–induced apoptosis. In addi- when euthyroidism is restored. Patients with Hashimo-
tion, local T-cell production of cytokines, such as tumor to’s thyroiditis may present because of goiter rather than
necrosis factor (TNF), IL-1, and interferon γ (IFN-γ), symptoms of hypothyroidism. The goiter may not be
may render thyroid cells more susceptible to apopto- large, but it is usually irregular and firm in consistency.
sis mediated by death receptors, such as Fas, which are It is often possible to palpate a pyramidal lobe, normally
activated by their respective ligands on T cells. These a vestigial remnant of the thyroglossal duct. Rarely is
cytokines also impair thyroid cell function directly and uncomplicated Hashimoto’s thyroiditis associated with
induce the expression of other proinflammatory mole- pain.
cules by the thyroid cells themselves, such as cytokines, Patients with atrophic thyroiditis or the late stage
HLA class I and class II molecules, adhesion molecules, of Hashimoto’s thyroiditis present with symptoms and
CD40, and nitric oxide. Administration of high con- signs of hypothyroidism. The skin is dry, and there is
centrations of cytokines for therapeutic purposes (espe- decreased sweating, thinning of the epidermis, and
cially IFN-α) is associated with increased autoimmune hyperkeratosis of the stratum corneum. Increased der-
thyroid disease, possibly through mechanisms similar to mal glycosaminoglycan content traps water, giving rise
those in sporadic disease. to skin thickening without pitting (myxedema). Typical
Antibodies to TPO and Tg are clinically useful features include a puffy face with edematous eyelids and
markers of thyroid autoimmunity, but any pathogenic nonpitting pretibial edema (Fig. 4-5). There is pallor,
effect is restricted to a secondary role in amplifying an often with a yellow tinge to the skin due to carotene
ongoing autoimmune response. TPO antibodies fix accumulation. Nail growth is retarded, and hair is dry,
complement, and complement membrane-attack com- brittle, difficult to manage, and falls out easily. In addi-
plexes are present in the thyroid in autoimmune hypo- tion to diffuse alopecia, there is thinning of the outer
thyroidism. However, transplacental passage of Tg third of the eyebrows, although this is not a specific sign
or TPO antibodies has no effect on the fetal thyroid, of hypothyroidism.
which suggests that T cell–mediated injury is required Other common features include constipation and
to initiate autoimmune damage to the thyroid. weight gain (despite a poor appetite). In contrast to
Up to 20% of patients with autoimmune hypothy- popular perception, the weight gain is usually mod-
roidism have antibodies against the TSH-R, which, est and due mainly to fluid retention in the myxede-
in contrast to TSI, do not stimulate the receptor but matous tissues. Libido is decreased in both sexes,
prevent the binding of TSH. These TSH-R–blocking and there may be oligomenorrhea or amenorrhea in
74 problems include reversible cerebellar ataxia, dementia,
psychosis, and myxedema coma. Hashimoto’s encephalop-
athy has been defined as a steroid-responsive syndrome
associated with TPO antibodies, myoclonus, and slow-
SECTION I

wave activity on electroencephalography, but the rela-


tionship with thyroid autoimmunity or hypothyroidism
is not established. The hoarse voice and occasionally
clumsy speech of hypothyroidism reflect fluid accumu-
lation in the vocal cords and tongue.
The features described above are the consequence of
Pituitary, Thyroid, and Adrenal Disorders

thyroid hormone deficiency. However, autoimmune


hypothyroidism may be associated with signs or symp-
toms of other autoimmune diseases, particularly vitiligo,
pernicious anemia, Addison’s disease, alopecia areata,
and type 1 diabetes mellitus. Less-common associations
include celiac disease, dermatitis herpetiformis, chronic
active hepatitis, rheumatoid arthritis, systemic lupus
erythematosus (SLE), myasthenia gravis, and Sjögren’s
syndrome. Thyroid-associated ophthalmopathy, which
usually occurs in Graves’ disease (see below), occurs in
about 5% of patients with autoimmune hypothyroidism.
Autoimmune hypothyroidism is uncommon in chil-
Figure 4-5
dren and usually presents with slow growth and delayed
Facial appearance in hypothyroidism. Note puffy eyes and facial maturation. The appearance of permanent teeth
thickened skin. is also delayed. Myopathy, with muscle swelling, is
more common in children than in adults. In most cases,
puberty is delayed, but precocious puberty sometimes
long-standing disease, but menorrhagia is also common. occurs. There may be intellectual impairment if the
Fertility is reduced, and the incidence of miscarriage is onset is before 3 years and the hormone deficiency is
increased. Prolactin levels are often modestly increased severe.
(Chap.  2) and may contribute to alterations in libido
and fertility and cause galactorrhea.
Laboratory evaluation
Myocardial contractility and pulse rate are reduced,
leading to a reduced stroke volume and bradycardia. A summary of the investigations used to determine the
Increased peripheral resistance may be accompanied existence and cause of hypothyroidism is provided in
by hypertension, particularly diastolic. Blood flow is Fig. 4-6. A normal TSH level excludes primary (but
diverted from the skin, producing cool extremities. not secondary) hypothyroidism. If the TSH is elevated,
Pericardial effusions occur in up to 30% of patients but an unbound T4 level is needed to confirm the pres-
rarely compromise cardiac function. Though alterations ence of clinical hypothyroidism, but T4 is inferior to
in myosin heavy chain isoform expression have been TSH when used as a screening test, because it will not
documented, cardiomyopathy is unusual. Fluid may also detect subclinical hypothyroidism. Circulating unbound
accumulate in other serous cavities and in the middle T3 levels are normal in about 25% of patients, reflect-
ear, giving rise to conductive deafness. Pulmonary func- ing adaptive deiodinase responses to hypothyroidism. T3
tion is generally normal, but dyspnea may be caused by measurements are, therefore, not indicated.
pleural effusion, impaired respiratory muscle function, Once clinical or subclinical hypothyroidism is con-
diminished ventilatory drive, or sleep apnea. firmed, the etiology is usually easily established by dem-
Carpal tunnel and other entrapment syndromes are onstrating the presence of TPO antibodies, which are
common, as is impairment of muscle function with stiff- present in >90% of patients with autoimmune hypothy-
ness, cramps, and pain. On examination, there may be roidism. TBII can be found in 10–20% of patients, but
slow relaxation of tendon reflexes and pseudomyoto- these determinations are not needed routinely. If there
nia. Memory and concentration are impaired. Experi- is any doubt about the cause of a goiter associated with
mentally, PET scans examining glucose metabolism in hypothyroidism, FNA biopsy can be used to confirm
hypothyroid subjects show lower regional activity in the the presence of autoimmune thyroiditis. Other abnor-
amygdala, hippocampus, and perigenual anterior cin- mal laboratory findings in hypothyroidism may include
gulated cortex, among other regions, and this activity increased creatine phosphokinase, elevated cholesterol
corrects after thyroxine replacement. Rare neurologic and triglycerides, and anemia (usually normocytic or
EVALUATION OF HYPOTHYROIDISM 75
Measure TSH

CHAPTER 4
Elevated Normal

Measure unbound T4 Pituitary disease suspected?

Normal Low No Yes

Disorders of the Thyroid Gland


Mild Primary No further Measure unbound T4
hypothyroidism hypothyroidism tests

TPOAb+ TPOAb– Low Normal


TPOAb+ or TPOAb–, no
symptomatic symptoms
No further
Autoimmune Rule out other tests
hypothyroidism causes of
hypothyroidism
Rule out drug effects, sick
euthyroid syndrome,
T4 treatment Annual follow-up T4 treatment then evaluate anterior
pituitary function

Figure 4-6
Evaluation of hypothyroidism. TPOAb+, thyroid peroxidase antibodies present; TPOAb–, thyroid peroxidase antibodies not
present; TSH, thyroid-stimulating hormone.

macrocytic). Except when accompanied by iron defi- Iodine deficiency is responsible for endemic goi-
ciency, the anemia and other abnormalities gradually ter and cretinism but is an uncommon cause of adult
resolve with thyroxine replacement. hypothyroidism unless the iodine intake is very low or
there are complicating factors, such as the consump-
tion of thiocyanates in cassava or selenium deficiency.
Differential diagnosis Though hypothyroidism due to iodine deficiency can
An asymmetric goiter in Hashimoto’s thyroiditis may be be treated with thyroxine, public health measures to
confused with a multinodular goiter or thyroid carci- improve iodine intake should be advocated to elimi-
noma, in which thyroid antibodies may also be present. nate this problem. Iodized salt or bread or a single bolus
Ultrasound can be used to show the presence of a soli- of oral or intramuscular iodized oil have all been used
tary lesion or a multinodular goiter rather than the het- successfully.
erogeneous thyroid enlargement typical of Hashimoto’s Paradoxically, chronic iodine excess can also induce
thyroiditis. FNA biopsy is useful in the investigation of goiter and hypothyroidism. The intracellular events
focal nodules. Other causes of hypothyroidism are dis- that account for this effect are unclear, but individuals
cussed below and in Table 4-4, but rarely cause diag- with autoimmune thyroiditis are especially susceptible.
nostic confusion. Iodine excess is responsible for the hypothyroidism that
occurs in up to 13% of patients treated with amiodarone
(see below). Other drugs, particularly lithium, may also
Other Causes of Hypothyroidism cause hypothyroidism. Transient hypothyroidism caused
Iatrogenic hypothyroidism is a common cause of hypothy- by thyroiditis is discussed below.
roidism and can often be detected by screening before Secondary hypothyroidism is usually diagnosed in the
symptoms develop. In the first 3–4 months after radio- context of other anterior pituitary hormone deficien-
iodine treatment, transient hypothyroidism may occur cies; isolated TSH deficiency is very rare (Chap. 2).
due to reversible radiation damage. Low-dose thyrox- TSH levels may be low, normal, or even slightly
ine treatment can be withdrawn if recovery occurs. increased in secondary hypothyroidism; the latter is
Because TSH levels are suppressed by hyperthyroid- due to secretion of immunoactive but bioinactive
ism, unbound T4 levels are a better measure of thyroid forms of TSH. The diagnosis is confirmed by detect-
function than TSH in the months following radioiodine ing a low unbound T4 level. The goal of treatment is
treatment. Mild hypothyroidism after subtotal thyroid- to maintain T4 levels in the upper half of the reference
ectomy may also resolve after several months, as the range, because TSH levels cannot be used to monitor
gland remnant is stimulated by increased TSH levels. therapy.
76
Treatment Hypothyroidism to consider variable adherence, because this pattern of
thyroid function tests is otherwise suggestive of disor-
Clinical Hypothyroidism  If there is no ders associated with inappropriate TSH secretion (Table
SECTION I

residual thyroid function, the daily replacement dose 4-3). Because T4 has a long half-life (7 days), patients
of levothyroxine is usually 1.6 μg/kg body weight (typi- who miss a dose can be advised to take two doses of
cally 100–150 μg). In many patients, however, lower the skipped tablets at once. Other causes of increased
doses suffice until residual thyroid tissue is destroyed. levothyroxine requirements must be excluded, particu-
In patients who develop hypothyroidism after the treat- larly malabsorption (e.g., celiac disease, small-bowel
ment of Graves’ disease, there is often underlying auton- surgery), estrogen therapy, and drugs that interfere with
Pituitary, Thyroid, and Adrenal Disorders

omous function, necessitating lower replacement doses T4 absorption or clearance such as cholestyramine, fer-
(typically 75–125 μg/d). rous sulfate, calcium supplements, lovastatin, aluminum
Adult patients under 60 without evidence of heart hydroxide, rifampicin, amiodarone, carbamazepine, and
disease may be started on 50–100 μg levothyroxine (T4) phenytoin.
daily. The dose is adjusted on the basis of TSH levels,
with the goal of treatment being a normal TSH, ideally Subclinical Hypothyroidism  By defini-
in the lower half of the reference range. TSH responses tion, subclinical hypothyroidism refers to biochemical
are gradual and should be measured about two months evidence of thyroid hormone deficiency in patients who
after instituting treatment or after any subsequent have few or no apparent clinical features of hypothy-
change in levothyroxine dosage. The clinical effects of roidism. There are no universally accepted recommen-
levothyroxine replacement are slow to appear. Patients dations for the management of subclinical hypothy-
may not experience full relief from symptoms until roidism, but the most recently published guidelines do
3–6 months after normal TSH levels are restored. Adjust- not recommend routine treatment when TSH levels are
ment of levothyroxine dosage is made in 12.5- or 25-μg below 10 mU/L. It is important to confirm that any ele-
increments if the TSH is high; decrements of the same vation of TSH is sustained over a 3-month period before
magnitude should be made if the TSH is suppressed. treatment is given. As long as excessive treatment is
Patients with a suppressed TSH of any cause, including avoided, there is no risk in correcting a slightly increased
T4 overtreatment, have an increased risk of atrial fibrilla- TSH. Moreover, there is a risk that patients will progress
tion and reduced bone density. to overt hypothyroidism, particularly when the TSH level
Although dessicated animal thyroid preparations is elevated and TPO antibodies are present. Treatment
(thyroid extract USP) are available, they are not recom- is administered by starting with a low dose of levothy-
mended because the ratio of T3 to T4 is nonphysiologic. roxine (25–50 μg/d) with the goal of normalizing TSH. If
The use of levothyroxine combined with liothyronine thyroxine is not given, thyroid function should be evalu-
(triiodothyronine, T3) has been investigated, but benefit ated annually.
has not been confirmed in prospective studies. There
is no place for liothyronine alone as long-term replace- Special Treatment Considerations
ment, because the short half-life necessitates three or Rarely, levothyroxine replacement is associated with
four daily doses and is associated with fluctuating T3 pseudotumor cerebri in children. Presentation appears
levels. to be idiosyncratic and occurs months after treatment
Once full replacement is achieved and TSH levels has begun. Women with a history or high risk of hypo-
are stable, follow-up measurement of TSH is recom- thyroidism should ensure that they are euthyroid prior
mended at annual intervals and may be extended to to conception and during early pregnancy as maternal
every 2–3 years if a normal TSH is maintained over sev- hypothyroidism may adversely affect fetal neural devel-
eral years. It is important to ensure ongoing adherence, opment and cause preterm delivery. The presence of
however, as patients do not feel any symptomatic differ- thyroid autoantibodies alone, in a euthyroid patient, is
ence after missing a few doses of levothyroxine, and this also associated with preterm delivery, and outcome may
sometimes leads to self-discontinuation. be improved by levothyroxine treatment. Thyroid func-
In patients of normal body weight who are tak- tion should be evaluated immediately after pregnancy
ing ≥200 μg of levothyroxine per day, an elevated TSH is confirmed and at the beginning of the second and
level is often a sign of poor adherence to treatment. third trimesters. The dose of levothyroxine may need to
This is also the likely explanation for fluctuating TSH be increased by ≥50% during pregnancy and returned
levels, despite a constant levothyroxine dosage. Such to previous levels after delivery. Elderly patients may
patients often have normal or high unbound T4 levels, require 20% less thyroxine than younger patients. In the
despite an elevated TSH, because they remember to elderly, especially patients with known coronary artery
take medication for a few days before testing; this is suf- disease, the starting dose of levothyroxine is 12.5–25 μg/d
ficient to normalize T4, but not TSH levels. It is important with similar increments every 2–3 months until TSH
is normalized. In some patients, it may be impossible to should be avoided because they may exacerbate water
77
achieve full replacement despite optimal antianginal retention secondary to reduced renal perfusion and
treatment. Emergency surgery is generally safe in patients inappropriate vasopressin secretion. The metabolism of

CHAPTER 4
with untreated hypothyroidism, although routine sur- most medications is impaired, and sedatives should be
gery in a hypothyroid patient should be deferred until avoided if possible or used in reduced doses. Medica-
euthyroidism is achieved. tion blood levels should be monitored, when available,
Myxedema coma still has a high mortality rate, to guide dosage.
despite intensive treatment. Clinical manifestations
include reduced level of consciousness, sometimes

Disorders of the Thyroid Gland


associated with seizures, as well as the other features
Thyrotoxicosis
of hypothyroidism (Table 4-5). Hypothermia can reach
23°C (74°F). There may be a history of treated hypo- Thyrotoxicosis is defined as the state of thyroid hormone
thyroidism with poor compliance, or the patient may excess and is not synonymous with hyperthyroidism,
be previously undiagnosed. Myxedema coma almost which is the result of excessive thyroid function. How-
always occurs in the elderly and is usually precipitated ever, the major etiologies of thyrotoxicosis are hyper-
by factors that impair respiration, such as drugs (espe- thyroidism caused by Graves’ disease, toxic MNG, and
cially sedatives, anesthetics, antidepressants), pneu- toxic adenomas. Other causes are listed in Table 4-6.
monia, congestive heart failure, myocardial infarction,
gastrointestinal bleeding, or cerebrovascular accidents.
Sepsis should also be suspected. Exposure to cold may Graves’ Disease
also be a risk factor. Hypoventilation, leading to hypoxia Epidemiology
and hypercapnia, plays a major role in pathogenesis;
hypoglycemia and dilutional hyponatremia also contrib- Graves’ disease accounts for 60–80% of thyrotoxicosis.
ute to the development of myxedema coma. The prevalence varies among populations, reflecting
Levothyroxine can initially be administered as a sin- genetic factors and iodine intake (high iodine intake is
gle IV bolus of 500 μg, which serves as a loading dose. associated with an increased prevalence of Graves’ dis-
Although further levothyroxine is not strictly neces- ease). Graves’ disease occurs in up to 2% of women but
sary for several days, it is usually continued at a dose of
50–100 μg/d. If suitable IV preparation is not available, Table 4-6
the same initial dose of levothyroxine can be given by Causes of Thyrotoxicosis
nasogastric tube (though absorption may be impaired
Primary hyperthyroidism
in myxedema). An alternative is to give liothyronine (T3)
intravenously or via nasogastric tube, in doses ranging Graves’ disease
from 10 to 25 μg every 8–12 h. This treatment has been Toxic multinodular goiter
Toxic adenoma
advocated because T4 → T3 conversion is impaired in
Functioning thyroid carcinoma metastases
myxedema coma. However, excess liothyronine has the Activating mutation of the TSH receptor
potential to provoke arrhythmias. Another option is to Activating mutation of Gsα (McCune-Albright syndrome)
combine levothyroxine (200 μg) and liothyronine (25 μg) Struma ovarii
as a single, initial IV bolus followed by daily treatment Drugs: iodine excess (Jod-Basedow phenomenon)
with levothyroxine (50–100 μg/d) and liothyronine Thyrotoxicosis without hyperthyroidism
(10 μg every 8 h). Subacute thyroiditis
Supportive therapy should be provided to correct Silent thyroiditis
any associated metabolic disturbances. External warm- Other causes of thyroid destruction: amiodarone, radia-
ing is indicated only if the temperature is <30°C, as it tion, infarction of adenoma
can result in cardiovascular collapse. Space blankets Ingestion of excess thyroid hormone (thyrotoxicosis facti-
should be used to prevent further heat loss. Parenteral tia) or thyroid tissue
hydrocortisone (50 mg every 6 h) should be admin- Secondary hyperthyroidism
istered, because there is impaired adrenal reserve in TSH-secreting pituitary adenoma
profound hypothyroidism. Any precipitating factors Thyroid hormone resistance syndrome: occasional
should be treated, including the early use of broad- patients may have features of thyrotoxicosis
spectrum antibiotics, pending the exclusion of infec- Chorionic gonadotropin-secreting tumorsa
tion. Ventilatory support with regular blood gas analysis Gestational thyrotoxicosisa
is usually needed during the first 48 hours. Hypertonic
a
Circulating TSH levels are low in these forms of secondary hyper-
saline or IV glucose may be needed if there is severe
thyroidism.
hyponatremia or hypoglycemia; hypotonic IV fluids Abbreviation: TSH, thyroid-stimulating hormone.
78 is one-tenth as frequent in men. The disorder rarely association with autoimmune thyroid disease. Increased
begins before adolescence and typically occurs between fat is an additional cause of retrobulbar tissue expansion.
20 and 50 years of age; it also occurs in the elderly. The increase in intraorbital pressure can lead to propto-
sis, diplopia, and optic neuropathy
SECTION I

Pathogenesis
As in autoimmune hypothyroidism, a combination of Clinical manifestations
environmental and genetic factors, including polymor-
phisms in HLA-DR, CTLA-4, CD25, PTPN22 (a T- Signs and symptoms include features that are common
cell regulatory gene) and TSH-R, contribute to Graves’ to any cause of thyrotoxicosis (Table 4-7) as well as
Pituitary, Thyroid, and Adrenal Disorders

disease susceptibility. The concordance for Graves’ dis- those specific for Graves’ disease. The clinical presenta-
ease in monozygotic twins is 20–30%, compared to <5% tion depends on the severity of thyrotoxicosis, the dura-
in dizygotic twins. Indirect evidence suggests that stress tion of disease, individual susceptibility to excess thyroid
is an important environmental factor, presumably oper- hormone, and the patient’s age. In the elderly, features
ating through neuroendocrine effects on the immune of thyrotoxicosis may be subtle or masked, and patients
system. Smoking is a minor risk factor for Graves’ dis- may present mainly with fatigue and weight loss, a con-
ease and a major risk factor for the development of dition known as apathetic thyrotoxicosis.
ophthalmopathy. Sudden increases in iodine intake Thyrotoxicosis may cause unexplained weight loss,
may precipitate Graves’ disease, and there is a threefold despite an enhanced appetite, due to the increased met-
increase in the occurrence of Graves’ disease in the post- abolic rate. Weight gain occurs in 5% of patients, how-
partum period. Graves’ disease may occur during the ever, because of increased food intake. Other prominent
immune reconstitution phase after highly active antiret- features include hyperactivity, nervousness, and irritabil-
roviral therapy (HAART) or alemtuzumab treatment. ity, ultimately leading to a sense of easy fatigability in
The hyperthyroidism of Graves’ disease is caused by some patients. Insomnia and impaired concentration are
TSI that are synthesized in the thyroid gland as well as common; apathetic thyrotoxicosis may be mistaken for
in bone marrow and lymph nodes. Such antibodies can depression in the elderly. Fine tremor is a frequent finding,
be detected by bioassays or by using the more widely best elicited by having patients stretch out their fingers
available TBII assays. The presence of TBII in a patient while feeling the fingertips with the palm. Common
with thyrotoxicosis implies the existence of TSI, and neurologic manifestations include hyperreflexia, muscle
these assays are useful in monitoring pregnant Graves’ wasting, and proximal myopathy without fasciculation.
patients in whom high levels of TSI can cross the pla- Chorea is rare. Thyrotoxicosis is sometimes associated
centa and cause neonatal thyrotoxicosis. Other thyroid with a form of hypokalemic periodic paralysis; this dis-
autoimmune responses, similar to those in autoimmune order is particularly common in Asian males with thy-
hypothyroidism (see above), occur concurrently in rotoxicosis, but it occurs in other ethnic groups as well.
patients with Graves’ disease. In particular, TPO anti- The most common cardiovascular manifestation is
bodies occur in up to 80% of cases and serve as a readily sinus tachycardia, often associated with palpitations, occa-
measurable marker of autoimmunity. Because the coex- sionally caused by supraventricular tachycardia. The high
isting thyroiditis can also affect thyroid function, there
is no direct correlation between the level of TSI and
Table 4-7
thyroid hormone levels in Graves’ disease. In the long
term, spontaneous autoimmune hypothyroidism may Signs and Symptoms of Thyrotoxicosis
(Descending Order of Frequency)
develop in up to 15% of patients with Graves’ disease.
Cytokines appear to play a major role in thyroid- Symptoms Signsa
Hyperactivity, irritability, Tachycardia; atrial
associated ophthalmopathy. There is infiltration of the
dysphoria fibrillation in the elderly
extraocular muscles by activated T cells; the release Heat intolerance and   Tremor
of cytokines such as IFN-γ, TNF, and IL-1 results in sweating   Goiter
fibroblast activation and increased synthesis of glycos-   Palpitations   Warm, moist skin
aminoglycans that trap water, thereby leading to charac-   Fatigue and weakness Muscle weakness,
teristic muscle swelling. Late in the disease, there is irre- Weight loss with proximal myopathy
versible fibrosis of the muscles. Orbital fibroblasts may increased appetite   Lid retraction or lag
  Diarrhea   Gynecomastia
be particularly sensitive to cytokines, perhaps explain-
  Polyuria
ing the anatomic localization of the immune response. Oligomenorrhea, loss of
Though the pathogenesis of thyroid-associated oph- libido
thalmopathy remains unclear, there is mounting evi-
dence that the TSH-R may be a shared autoantigen that a
Excludes the signs of ophthalmopathy and dermopathy specific for
is expressed in the orbit; this would explain the close Graves’ disease.
cardiac output produces a bounding pulse, widened pulse 79
pressure, and an aortic systolic murmur and can lead to
worsening of angina or heart failure in the elderly or

CHAPTER 4
those with preexisting heart disease. Atrial fibrillation is
more common in patients >50 years of age. Treatment
of the thyrotoxic state alone converts atrial fibrillation
to normal sinus rhythm in about half of patients, sug-
gesting the existence of an underlying cardiac problem
in the remainder.
The skin is usually warm and moist, and the patient

Disorders of the Thyroid Gland


may complain of sweating and heat intolerance, particu-
larly during warm weather. Palmar erythema, onychol-
ysis, and, less commonly, pruritus, urticaria, and diffuse
hyperpigmentation may be evident. Hair texture may
become fine, and a diffuse alopecia occurs in up to 40%
of patients, persisting for months after restoration of
euthyroidism. Gastrointestinal transit time is decreased,
leading to increased stool frequency, often with diar-
rhea and occasionally mild steatorrhea. Women fre-
quently experience oligomenorrhea or amenorrhea; in
men, there may be impaired sexual function and, rarely, Figure 4-7
gynecomastia. The direct effect of thyroid hormones Features of Graves’ disease. A. Ophthalmopathy in Graves’
on bone resorption leads to osteopenia in long-standing disease; lid retraction, periorbital edema, conjunctival injec-
thyrotoxicosis; mild hypercalcemia occurs in up to 20% tion, and proptosis are marked. B. Thyroid dermopathy over
of patients, but hypercalciuria is more common. There the lateral aspects of the shins. C. Thyroid acropachy.
is a small increase in fracture rate in patients with a pre-
vious history of thyrotoxicosis.
In Graves’ disease, the thyroid is usually diffusely proptosis, best detected by visualization of the sclera
enlarged to two to three times its normal size. The con- between the lower border of the iris and the lower
sistency is firm, but less so than in MNG. There may be eyelid, with the eyes in the primary position. Proptosis
a thrill or bruit due to the increased vascularity of the can be measured using an exophthalmometer. In severe
gland and the hyperdynamic circulation. cases, proptosis may cause corneal exposure and dam-
Lid retraction, causing a staring appearance, can age, especially if the lids fail to close during sleep. Peri-
occur in any form of thyrotoxicosis and is the result orbital edema, scleral injection, and chemosis are also
of sympathetic overactivity. However, Graves’ dis- frequent. In 5–10% of patients, the muscle swelling is
ease is associated with specific eye signs that comprise so severe that diplopia results, typically, but not exclu-
Graves’ ophthalmopathy (Fig. 4-7A). This condition is sively, when the patient looks up and laterally. The
also called thyroid-associated ophthalmopathy, as it occurs most serious manifestation is compression of the optic
in the absence of Graves’ disease in 10% of patients. nerve at the apex of the orbit, leading to papilledema,
Most of these individuals have autoimmune hypothy- peripheral field defects, and, if left untreated, permanent
roidism or thyroid antibodies. The onset of Graves’ loss of vision.
ophthalmopathy occurs within the year before or after Many scoring systems have been used to gauge the
the diagnosis of thyrotoxicosis in 75% of patients but extent and activity of the orbital changes in Graves’ dis-
can sometimes precede or follow thyrotoxicosis by ease. The “NO SPECS” scheme is an acronym derived
several years, accounting for some cases of euthyroid from the following eye changes:
ophthalmopathy.
Some patients with Graves’ disease have little clini- 0 = No signs or symptoms
1 = Only signs (lid retraction or lag), no symptoms
cal evidence of ophthalmopathy. However, the enlarged
2 = Soft-tissue involvement (periorbital edema)
extraocular muscles typical of the disease, and other
3 = Proptosis (>22 mm)
subtle features, can be detected in almost all patients
4 = Extraocular muscle involvement (diplopia)
when investigated by ultrasound or CT imaging of
5 = Corneal involvement
the orbits. Unilateral signs are found in up to 10% of
6 = Sight loss
patients. The earliest manifestations of ophthalmopa-
thy are usually a sensation of grittiness, eye discomfort, Although useful as a mnemonic, the NO SPECS
and excess tearing. About one-third of patients have scheme is inadequate to describe the eye disease fully,
80 EVALUATION OF THYROTOXICOSIS
Measure TSH, unbound T4
SECTION I

TSH low, unbound TSH low, unbound TSH normal or increased, TSH and unbound
T4 high T4 normal high unbound T4 T4 normal

Primary Measure TSH-secreting


thyrotoxicosis unbound T3 pituitary adenoma
or thyroid hormone
resistance syndrome
Pituitary, Thyroid, and Adrenal Disorders

High Normal

T3 toxicosis Subclinical No further tests


hyperthyroidism

Features of Follow up in
Graves’ diseasea? 6-12 weeks

Yes No

Graves’ disease Multinodular goiter or toxic adenomab?

Yes No

Toxic nodular hyperthyroidism Low radionuclide uptake?

Yes No

Destructive thyroiditis, iodine excess Rule out other causes including stimulation
or excess thyroid hormone by chorionic gonadotropin

Figure 4-8
Evaluation of thyrotoxicosis. aDiffuse goiter, positive confirmed by radionuclide scan. TSH, thyroid-stimulating
TPO antibodies, ophthalmopathy, dermopathy; bCan be hormone.

and patients do not necessarily progress from one class Laboratory evaluation
to another. When Graves’ eye disease is active and
severe, referral to an ophthalmologist is indicated and Investigations used to determine the existence and
objective measurements are needed, such as lid-fissure cause of thyrotoxicosis are summarized in Fig. 4-8. In
width; corneal staining with fluorescein; and evaluation Graves’ disease, the TSH level is suppressed and total
of extraocular muscle function (e.g., Hess chart), intra- and unbound thyroid hormone levels are increased.
ocular pressure and visual fields, acuity, and color vision. In 2–5% of patients (and more in areas of borderline
Thyroid dermopathy occurs in <5% of patients with iodine intake), only T3 is increased (T3 toxicosis). The
Graves’ disease (Fig. 4-7B), almost always in the pres- converse state of T4 toxicosis, with elevated total and
ence of moderate or severe ophthalmopathy. Although unbound T4 and normal T3 levels, is occasionally seen
most frequent over the anterior and lateral aspects when hyperthyroidism is induced by excess iodine, pro-
of the lower leg (hence the term pretibial myxedema), viding surplus substrate for thyroid hormone synthesis.
skin changes can occur at other sites, particularly after Measurement of TPO antibodies or TBII may be use-
trauma. The typical lesion is a noninflamed, indurated ful if the diagnosis is unclear clinically but is not needed
plaque with a deep pink or purple color and an “orange routinely. Associated abnormalities that may cause diag-
skin” appearance. Nodular involvement can occur, and nostic confusion in thyrotoxicosis include elevation of
the condition can rarely extend over the whole lower bilirubin, liver enzymes, and ferritin. Microcytic anemia
leg and foot, mimicking elephantiasis. Thyroid acropachy and thrombocytopenia may occur.
refers to a form of clubbing found in <1% of patients
Differential diagnosis
with Graves’ disease (Fig. 4-7C). It is so strongly asso-
ciated with thyroid dermopathy that an alternative cause Diagnosis of Graves’ disease is straightforward in a
of clubbing should be sought in a Graves’ patient with- patient with biochemically confirmed thyrotoxicosis,
out coincident skin and orbital involvement. diffuse goiter on palpation, ophthalmopathy, and often
a personal or family history of autoimmune disorders. 81
For patients with thyrotoxicosis who lack these features, drugs, or reducing the amount of thyroid tissue with
the most reliable diagnostic method is to measure TBII radioiodine (131I) treatment or by thyroidectomy. Anti-
thyroid drugs are the predominant therapy in many

CHAPTER 4
or TSI. An alternative is to undertake a radionuclide
(99mTc, 123I, or 131I) scan of the thyroid, which will dis- centers in Europe and Japan, whereas radioiodine is
tinguish the diffuse, high uptake of Graves’ disease from more often the first line of treatment in North Amer-
nodular thyroid disease, destructive thyroiditis, ectopic ica. These differences reflect the fact that no single
thyroid tissue, and factitious thyrotoxicosis. In second- approach is optimal, and that patients may require mul-
ary hyperthyroidism due to a TSH-secreting pituitary tiple treatments to achieve remission.
tumor, there is also a diffuse goiter. The presence of a The main antithyroid drugs are the thionamides, such

Disorders of the Thyroid Gland


nonsuppressed TSH level and the finding of a pituitary as propylthiouracil, carbimazole, and the active metab-
tumor on CT or MRI scan readily identify such patients. olite of the latter, methimazole. All inhibit the func-
Clinical features of thyrotoxicosis can mimic cer- tion of TPO, reducing oxidation and organification of
tain aspects of other disorders, including panic attacks, iodide. These drugs also reduce thyroid antibody levels
mania, pheochromocytoma, and weight loss associated by mechanisms that remain unclear, and they appear
with malignancy. The diagnosis of thyrotoxicosis can to enhance rates of remission. Propylthiouracil inhibits
be easily excluded if the TSH and unbound T4 and T3 deiodination of T4 → T3. However, this effect is of minor
levels are normal. A normal TSH also excludes Graves’ benefit, except in the most severe thyrotoxicosis, and is
disease as a cause of diffuse goiter. offset by the much shorter half-life of this drug (90 min)
compared to methimazole (6 h).
There are many variations of antithyroid drug regi-
Clinical course mens. The initial dose of carbimazole or methimazole is
Clinical features generally worsen without treatment; usually 10–20 mg every 8 or 12 h, but once-daily dosing
mortality was 10–30% before the introduction of satis- is possible after euthyroidism is restored. Propylthioura-
factory therapy. Some patients with mild Graves’ dis- cil is given at a dose of 100–200 mg every 6–8 h, and
ease experience spontaneous relapses and remissions. divided doses are usually given throughout the course.
Rarely, there may be fluctuation between hypo- and Lower doses of each drug may suffice in areas of low
hyperthyroidism due to changes in the functional activ- iodine intake. The starting dose of antithyroid drugs can
ity of TSH-R antibodies. About 15% of patients who be gradually reduced (titration regimen) as thyrotoxi-
enter remission after treatment develop hypothyroidism cosis improves. Alternatively, high doses may be given
10–15 years later as a result of the destructive autoim- combined with levothyroxine supplementation (block-
mune process. replace regimen) to avoid drug-induced hypothyroid-
The clinical course of ophthalmopathy does not fol- ism. Initial reports suggesting superior remission rates
low that of the thyroid disease. Ophthalmopathy typi- with the block-replace regimen have not been repro-
cally worsens over the initial 3–6 months, followed duced in several other trials. The titration regimen is
by a plateau phase over the next 12–18 months, with often preferred to minimize the dose of antithyroid drug
spontaneous improvement, particularly in the soft tis- and provide an index of treatment response.
sue changes. However, the course is more fulminant Thyroid function tests and clinical manifestations
in up to 5% of patients, requiring intervention in the are reviewed 3–4 weeks after starting treatment, and
acute phase if there is optic nerve compression or cor- the dose is titrated based on unbound T4 levels. Most
neal ulceration. Diplopia may appear late in the disease patients do not achieve euthyroidism until 6–8 weeks
due to fibrosis of the extraocular muscles. Some studies after treatment is initiated. TSH levels often remain
suggest that radioiodine treatment for hyperthyroidism suppressed for several months and therefore do not
worsens the eye disease in a small proportion of patients provide a sensitive index of treatment response. The
(especially smokers). Antithyroid drugs or surgery have usual daily maintenance doses of antithyroid drugs in
no adverse effects on the clinical course of ophthal- the titration regimen are 2.5–10 mg of carbimazole or
mopathy. Thyroid dermopathy, when it occurs, usu- methimazole and 50–100 mg of propylthiouracil. In the
ally appears 1–2 years after the development of Graves’ block-replace regimen, the initial dose of antithyroid
hyperthyroidism; it may improve spontaneously. drug is held constant, and the dose of levothyroxine is
adjusted to maintain normal unbound T4 levels. When
TSH suppression is alleviated, TSH levels can also be
Treatment Graves’ Disease used to monitor therapy.
Maximum remission rates (up to 30–50% in some pop-
The hyperthyroidism of Graves’ disease is treated by ulations) are achieved by 18–24 months for the titration
reducing thyroid hormone synthesis, using antithyroid regimen and by 6 months for the block-replace regimen.
82 For unclear reasons, remission rates appear to vary features, such as the severity of thyrotoxicosis, the size
in different geographic regions. Patients with severe of the goiter (increases the dose needed), and the level
hyperthyroidism and large goiters are most likely to of radioiodine uptake (decreases the dose needed). 131I
SECTION I

relapse when treatment stops, but outcomes are dif- dosage generally ranges between 185 MBq (5 mCi) to
ficult to predict. All patients should be followed closely 555 MBq (15 mCi). Incomplete treatment or early relapse
for relapse during the first year after treatment and at is more common in males and in patients <40 years of
least annually thereafter. age. Many authorities favor an approach aimed at thy-
The common side effects of antithyroid drugs are roid ablation (as opposed to euthyroidism), given that
rash, urticaria, fever, and arthralgia (1–5% of patients). levothyroxine replacement is straightforward, and most
Pituitary, Thyroid, and Adrenal Disorders

These may resolve spontaneously or after substitut- patients ultimately progress to hypothyroidism over
ing an alternative antithyroid drug. Rare but major side 5–10 years, frequently with some delay in the diagnosis
effects include hepatitis; an SLE-like syndrome; and, of hypothyroidism.
most important, agranulocytosis (<1%). It is essential Certain radiation safety precautions are necessary in
that antithyroid drugs are stopped and not restarted if the first few days after radioiodine treatment, but the
a patient develops major side effects. Written instruc- exact guidelines vary depending on local protocols. In
tions should be provided regarding the symptoms of general, patients need to avoid close, prolonged con-
possible agranulocytosis (e.g., sore throat, fever, mouth tact with children and pregnant women for several days
ulcers) and the need to stop treatment pending a com- because of possible transmission of residual isotope and
plete blood count to confirm that agranulocytosis is not excessive exposure to radiation emanating from the
present. It is not useful to monitor blood counts pro- gland. Rarely, there may be mild pain due to radiation
spectively, because the onset of agranulocytosis is idio- thyroiditis 1–2 weeks after treatment. Hyperthyroidism
syncratic and abrupt. can persist for 2–3 months before radioiodine takes full
Propranolol (20–40 mg every 6 h) or longer-acting effect. For this reason, β-adrenergic blockers or antithy-
beta blockers such as atenolol, may be helpful to con- roid drugs can be used to control symptoms during this
trol adrenergic symptoms, especially in the early stages interval. Persistent hyperthyroidism can be treated with
before antithyroid drugs take effect. Beta blockers are a second dose of radioiodine, usually 6 months after the
also useful in patients with thyrotoxic periodic paraly- first dose. The risk of hypothyroidism after radioiodine
sis, pending correction of thyrotoxicosis. The need for depends on the dosage but is at least 10–20% in the first
anticoagulation with coumadin should be considered year and 5% per year thereafter. Patients should be
in all patients with atrial fibrillation. If digoxin is used, informed of this possibility before treatment and require
increased doses are often needed in the thyrotoxic close follow-up during the first year and annual thyroid
state. function testing.
Radioiodine causes progressive destruction of thyroid Pregnancy and breast-feeding are absolute contra-
cells and can be used as initial treatment or for relapses indications to radioiodine treatment, but patients can
after a trial of antithyroid drugs. There is a small risk of conceive safely 6 months after treatment. The presence
thyrotoxic crisis (see below) after radioiodine, which can of severe ophthalmopathy requires caution, and some
be minimized by pretreatment with antithyroid drugs authorities advocate the use of prednisone, 40 mg/d,
for at least a month before treatment. Antecedent treat- at the time of radioiodine treatment, tapered over
ment with antithyroid drugs should be considered for 2–3 months to prevent exacerbation of ophthalmopathy.
all elderly patients or for those with cardiac problems to The overall risk of cancer after radioiodine treatment
deplete thyroid hormone stores before administration in adults is not increased. Although many physicians
of radioiodine. Carbimazole or methimazole must be avoid radioiodine in children and adolescents because
stopped at least 2 days before radioiodine administra- of the theoretical risks of malignancy, emerging evi-
tion to achieve optimum iodine uptake. Propylthiouracil dence suggests that radioiodine can be used safely in
has a prolonged radioprotective effect and should be older children.
stopped several weeks before radioiodine is given, or a Subtotal or near-total thyroidectomy is an option for
larger dose of radioiodine will be necessary. patients who relapse after antithyroid drugs and they
Efforts to calculate an optimal dose of radioiodine prefer this treatment to radioiodine. Some experts rec-
that achieves euthyroidism without a high incidence ommend surgery in young individuals, particularly
of relapse or progression to hypothyroidism have not when the goiter is very large. Careful control of thyro-
been successful. Some patients inevitably relapse after toxicosis with antithyroid drugs, followed by potassium
a single dose because the biologic effects of radiation iodide (3 drops SSKI orally tid), is needed prior to sur-
vary between individuals, and hypothyroidism cannot gery to avoid thyrotoxic crisis and to reduce the vascu-
be uniformly avoided even using accurate dosimetry. larity of the gland. The major complications of surgery—
A practical strategy is to give a fixed dose based on clinical bleeding, laryngeal edema, hypoparathyroidism, and
damage to the recurrent laryngeal nerves—are unusual every 6 h, is an alternative but is not generally avail-
83
when the procedure is performed by highly experi- able.) Propranolol should also be given to reduce tachy-
enced surgeons. Recurrence rates in the best series are cardia and other adrenergic manifestations (40–60 mg

CHAPTER 4
<2%, but the rate of hypothyroidism is only slightly less PO every 4 h; or 2 mg IV every 4 h). Although other
than that following radioiodine treatment. β-adrenergic blockers can be used, high doses of pro-
The titration regimen of antithyroid drugs should be pranolol decrease T4 → T3 conversion, and the doses
used to manage Graves’ disease in pregnancy, as block- can be easily adjusted. Caution is needed to avoid acute
ing doses of these drugs produce fetal hypothyroidism. negative inotropic effects, but controlling the heart rate
Propylthiouracil is usually used because of relatively is important, as some patients develop a form of high-

Disorders of the Thyroid Gland


low transplacental transfer and its ability to block T4 → output heart failure. Additional therapeutic measures
T3 conversion. Also, carbimazole and methimazole have include glucocorticoids (e.g., dexamethasone, 2 mg
been associated with rare cases of fetal aplasia cutis and every 6 h), antibiotics if infection is present, cooling,
other defects, such as choanal atresia. The lowest effec- oxygen, and intravenous fluids.
tive dose of propylthiouracil should be given, and it is Ophthalmopathy requires no active treatment when
often possible to stop treatment in the last trimester it is mild or moderate, because there is usually sponta-
because TSI tend to decline in pregnancy. Nonetheless, neous improvement. General measures include meticu-
the transplacental transfer of these antibodies rarely lous control of thyroid hormone levels, cessation of
causes fetal or neonatal thyrotoxicosis. Poor intrauter- smoking, and an explanation of the natural history of
ine growth, a fetal heart rate of >160 beats/min, and ophthalmopathy. Discomfort can be relieved with arti-
high levels of maternal TSI in the last trimester may ficial tears (e.g., 1% methylcellulose), eye ointment, and
herald this complication. Antithyroid drugs given to the use of dark glasses with side frames. Periorbital
the mother can be used to treat the fetus and may be edema may respond to a more upright sleeping posi-
needed for 1–3 months after delivery, until the maternal tion or a diuretic. Corneal exposure during sleep can
antibodies disappear from the baby’s circulation. The be avoided by using patches or taping the eyelids shut.
postpartum period is a time of major risk for relapse of Minor degrees of diplopia improve with prisms fitted to
Graves’ disease. Breast-feeding is safe with low doses of spectacles. Severe ophthalmopathy, with optic nerve
antithyroid drugs. Graves’ disease in children is usually involvement or chemosis resulting in corneal damage,
managed with antithyroid drugs, often given as a pro- is an emergency requiring joint management with an
longed course of the titration regimen. Surgery or radio- ophthalmologist. Short-term benefit can be gained in
iodine may be indicated for severe disease. about two-thirds of patients by the use of high-dose
Thyrotoxic crisis, or thyroid storm, is rare and presents glucocorticoids (e.g., prednisone, 40–80 mg daily),
as a life-threatening exacerbation of hyperthyroidism, sometimes combined with cyclosporine. Glucocorti-
accompanied by fever, delirium, seizures, coma, vomit- coid doses are tapered by 5 mg every 2 weeks, but the
ing, diarrhea, and jaundice. The mortality rate due to taper often results in reemergence of congestive symp-
cardiac failure, arrhythmia, or hyperthermia is as high toms. Pulse therapy with IV methylprednisolone (e.g.,
as 30%, even with treatment. Thyrotoxic crisis is usu- 500–1000 mg of methylprednisolone in 250 mL of saline
ally precipitated by acute illness (e.g., stroke, infection, infused over 2 h daily for 1 week) followed by an oral
trauma, diabetic ketoacidosis), surgery (especially on the regimen is also used. When glucocorticoids are ineffec-
thyroid), or radioiodine treatment of a patient with par- tive, orbital decompression can be achieved by remov-
tially treated or untreated hyperthyroidism. Management ing bone from any wall of the orbit, thereby allowing
requires intensive monitoring and supportive care, displacement of fat and swollen extraocular muscles.
identification and treatment of the precipitating cause, The transantral route is used most often, because it
and measures that reduce thyroid hormone synthesis. requires no external incision. Proptosis recedes an aver-
Large doses of propylthiouracil (600 mg loading dose age of 5 mm, but there may be residual or even wors-
and 200–300 mg every 6 h) should be given orally or ened diplopia. Once the eye disease has stabilized,
by nasogastric tube or per rectum; the drug’s inhibi- surgery may be indicated for relief of diplopia and cor-
tory action on T4 → T3 conversion makes it the anti- rection of the appearance. External beam radiotherapy
thyroid drug of choice. One hour after the first dose of of the orbits has been used for many years, but the
propylthiouracil, stable iodide is given to block thyroid efficacy of this therapy remains unclear, and it is best
hormone synthesis via the Wolff-Chaikoff effect (the reserved for those who have failed or are not candidates
delay allows the antithyroid drug to prevent the excess for glucocorticoid therapy.
iodine from being incorporated into new hormone). Thyroid dermopathy does not usually require treat-
A saturated solution of potassium iodide (5 drops SSKI ment, but it can cause cosmetic problems or interfere
every 6 h), or ipodate or iopanoic acid (500  mg per with the fit of shoes. Surgical removal is not indicated.
12  h), may be given orally. (Sodium iodide, 0.25 g IV If necessary, treatment consists of topical, high-potency
84 Table 4-8
glucocorticoid ointment under an occlusive dressing.
Octreotide may be beneficial in some cases. Causes of Thyroiditis
Acute
Other Causes of Thyrotoxicosis
SECTION I

Bacterial infection: especially Staphylococcus,


Destructive thyroiditis (subacute or silent thyroiditis) Streptococcus, and Enterobacter
typically presents with a short thyrotoxic phase due to Fungal infection: Aspergillus, Candida, Coccidioides,
the release of preformed thyroid hormones and catabo- Histoplasma, and Pneumocystis
lism of Tg (see “Subacute Thyroiditis,” below). True hyper- Radiation thyroiditis after 131I treatment
thyroidism is absent, as demonstrated by a low radionu-   Amiodarone (may also be subacute or chronic)
clide uptake. Circulating Tg levels are usually increased.
Pituitary, Thyroid, and Adrenal Disorders

Subacute
Other causes of thyrotoxicosis with low or absent thy- Viral (or granulomatous) thyroiditis
roid radionuclide uptake include thyrotoxicosis facti- Silent thyroiditis (including postpartum thyroiditis)
tia, iodine excess, and, rarely, ectopic thyroid tissue, Mycobacterial infection
particularly teratomas of the ovary (struma ovarii); and Chronic
functional metastatic follicular carcinoma. Whole-body Autoimmunity: focal thyroiditis, Hashimoto’s thyroiditis,
radionuclide studies can demonstrate ectopic thyroid atrophic thyroiditis
tissue, and thyrotoxicosis factitia can be distinguished Riedel’s thyroiditis
from destructive thyroiditis by the clinical features Parasitic thyroiditis: echinococcosis, strongyloidiasis,
cysticercosis
and low levels of Tg. Amiodarone treatment is associ-
Traumatic: after palpation
ated with thyrotoxicosis in up to 10% of patients, par-
ticularly in areas of low iodine intake (see below).
TSH-secreting pituitary adenoma is a rare cause of
thyrotoxicosis. It can be identified by the presence
of an inappropriately normal or increased TSH level erythema over the thyroid are common, as are systemic
in a patient with hyperthyroidism, diffuse goiter, and symptoms of a febrile illness and lymphadenopathy.
elevated T4 and T3 levels (Chap. 2). Elevated levels of The differential diagnosis of thyroid pain includes sub-
the α-subunit of TSH, released by the TSH-secreting acute or, rarely, chronic thyroiditis; hemorrhage into a
adenoma, support this diagnosis, which can be con- cyst; malignancy including lymphoma; and, rarely, ami-
firmed by demonstrating the pituitary tumor on MRI or odarone-induced thyroiditis or amyloidosis. However,
CT scan. A combination of transsphenoidal surgery, sella the abrupt presentation and clinical features of acute
irradiation, and octreotide may be required to normalize thyroiditis rarely cause confusion. The erythrocyte sedi-
TSH, because many of these tumors are large and locally mentation rate (ESR) and white cell count are usually
invasive at the time of diagnosis. Radioiodine or antithy- increased, but thyroid function is normal. FNA biopsy
roid drugs can be used to control thyrotoxicosis. shows infiltration by polymorphonuclear leukocytes;
Thyrotoxicosis caused by toxic MNG and hyperfunc- culture of the sample can identify the organism. Cau-
tioning solitary nodules is discussed below. tion is needed in immunocompromised patients as fun-
gal, mycobacterial, or Pneumocystis thyroiditis can occur
in this setting. Antibiotic treatment is guided initially by
Gram stain and, subsequently, by cultures of the FNA
Thyroiditis biopsy. Surgery may be needed to drain an abscess,
which can be localized by CT scan or ultrasound. Tracheal
A clinically useful classification of thyroiditis is based on obstruction, septicemia, retropharyngeal abscess, medi-
the onset and duration of disease (Table 4-8). astinitis, and jugular venous thrombosis may complicate
acute thyroiditis but are uncommon with prompt use of
antibiotics.
Acute Thyroiditis
Acute thyroiditis is rare and due to suppurative infec-
Subacute Thyroiditis
tion of the thyroid. In children and young adults, the
most common cause is the presence of a piriform sinus, This is also termed de Quervain’s thyroiditis, granuloma-
a remnant of the fourth branchial pouch that connects tous thyroiditis, or viral thyroiditis. Many viruses have been
the oropharynx with the thyroid. Such sinuses are implicated, including mumps, coxsackie, influenza, ade-
predominantly left-sided. A long-standing goiter and noviruses, and echoviruses, but attempts to identify the
degeneration in a thyroid malignancy are risk factors virus in an individual patient are often unsuccessful and
in the elderly. The patient presents with thyroid pain, do not influence management. The diagnosis of sub-
often referred to the throat or ears, and a small, tender acute thyroiditis is often overlooked because the symp-
goiter that may be asymmetric. Fever, dysphagia, and toms can mimic pharyngitis. The peak incidence occurs
at 30–50 years, and women are affected three times precede the thyroid-related features by several weeks. 85
more frequently than men. In other patients, the onset is acute, severe, and without
obvious antecedent. The patient typically complains of

CHAPTER 4
Pathophysiology a sore throat, and examination reveals a small goiter that
is exquisitely tender. Pain is often referred to the jaw or
The thyroid shows a characteristic patchy inflamma- ear. Complete resolution is the usual outcome, but per-
tory infiltrate with disruption of the thyroid follicles and manent hypothyroidism can occur, particularly in those
multinucleated giant cells within some follicles. The fol- with coincidental thyroid autoimmunity. A prolonged
licular changes progress to granulomas accompanied by course over many months, with one or more relapses,
fibrosis. Finally, the thyroid returns to normal, usually occurs in a small percentage of patients.

Disorders of the Thyroid Gland


several months after onset. During the initial phase of
follicular destruction, there is release of Tg and thyroid Laboratory evaluation
hormones, leading to increased circulating T4 and T3
and suppression of TSH (Fig. 4-9). During this destruc- As depicted in Fig. 4-9, thyroid function tests character-
tive phase, radioactive iodine uptake is low or unde- istically evolve through three distinct phases over about
tectable. After several weeks, the thyroid is depleted 6 months: (1) thyrotoxic phase, (2) hypothyroid phase,
of stored thyroid hormone and a phase of hypothy- and (3) recovery phase. In the thyrotoxic phase, T4 and
roidism typically occurs, with low unbound T4 (and T3 levels are increased, reflecting their discharge from
sometimes T3) and moderately increased TSH levels. the damaged thyroid cells, and TSH is suppressed. The
Radioactive iodine uptake returns to normal or is T4/T3 ratio is greater than in Graves’ disease or thy-
even increased as a result of the rise in TSH. Finally, roid autonomy, in which T3 is often disproportionately
thyroid hormone and TSH levels return to normal as increased. The diagnosis is confirmed by a high ESR
the disease subsides. and low radioiodine uptake. The white blood cell count
may be increased, and thyroid antibodies are negative.
If the diagnosis is in doubt, FNA biopsy may be useful,
Clinical manifestations
particularly to distinguish unilateral involvement from
The patient usually presents with a painful and enlarged bleeding into a cyst or neoplasm.
thyroid, sometimes accompanied by fever. There
may be features of thyrotoxicosis or hypothyroid-
ism, depending on the phase of the illness. Malaise and Treatment Subacute Thyroiditis
symptoms of an upper respiratory tract infection may
Relatively large doses of aspirin (e.g., 600 mg every 4–6 h)
or NSAIDs are sufficient to control symptoms in many
100 40 50
cases. If this treatment is inadequate, or if the patient
ESR
TSH has marked local or systemic symptoms, glucocorticoids
30
UT4
should be given. The usual starting dose is 40–60 mg
5 prednisone, depending on severity. The dose is gradu-
UT4 (pmol/L)

TSH (mU/L)
ESR (mm/h)

50 20 ally tapered over 6–8 weeks, in response to improve-


ment in symptoms and the ESR. If a relapse occurs during
10 0.5 glucocorticoid withdrawal, treatment should be started
again and withdrawn more gradually. In these patients,
0 0 0.01
it is useful to wait until the radioactive iodine uptake
0 6 12 18 normalizes before stopping treatment. Thyroid function
Time (weeks)
should be monitored every 2–4 weeks using TSH and
Thyrotoxic Hypothyroid Recovery unbound T4 levels. Symptoms of thyrotoxicosis improve
Clinical Phases spontaneously but may be ameliorated by β-adrenergic
blockers; antithyroid drugs play no role in treatment of
Figure 4-9
the thyrotoxic phase. Levothyroxine replacement may
Clinical course of subacute thyroiditis. The release of thy-
roid hormones is initially associated with a thyrotoxic phase
be needed if the hypothyroid phase is prolonged, but
and suppressed thyroid-stimulating hormone (TSH). A hypo- doses should be low enough (50 to 100 μg daily) to allow
thyroid phase then ensues, with low T4 and TSH levels that TSH-mediated recovery.
are initially low but gradually increase. During the recovery
phase, increased TSH levels combined with resolution of Silent Thyroiditis
thyroid follicular injury leads to normalization of thyroid func-
tion, often several months after the beginning of the illness. Painless thyroiditis, or “silent” thyroiditis, occurs in patients
ESR, erythrocyte sedimentation rate; FT4, free or unbound T4. with underlying autoimmune thyroid disease. It has
86 a clinical course similar to that of subacute thyroiditis, to suspicion of a malignancy. Diagnosis requires open
except that there is little or no thyroid tenderness. The biopsy as FNA biopsy is usually inadequate. Treatment
condition occurs in up to 5% of women 3–6 months is directed to surgical relief of compressive symptoms.
after pregnancy and is then termed postpartum thyroiditis. Tamoxifen may also be beneficial. There is an associa-
SECTION I

Typically, patients have a brief phase of thyrotoxico- tion between Riedel’s thyroiditis and idiopathic fibro-
sis lasting 2–4 weeks, followed by hypothyroidism for sis at other sites (retroperitoneum, mediastinum, biliary
4–12 weeks, and then resolution; often, however, only tree, lung, and orbit).
one phase is apparent. The condition is associated with
the presence of TPO antibodies antepartum, and it is
three times more common in women with type 1 dia- Sick Euthyroid Syndrome
Pituitary, Thyroid, and Adrenal Disorders

betes mellitus. As in subacute thyroiditis, the radioac-


tive iodine uptake is initially suppressed. In addition Any acute, severe illness can cause abnormalities of cir-
to the painless goiter, silent thyroiditis can be distin- culating TSH or thyroid hormone levels in the absence
guished from subacute thyroiditis by a normal ESR and of underlying thyroid disease, making these measure-
the presence of TPO antibodies. Glucocorticoid treat- ments potentially misleading. The major cause of these
ment is not indicated for silent thyroiditis. Severe thy- hormonal changes is the release of cytokines such as
rotoxic symptoms can be managed with a brief course IL-6. Unless a thyroid disorder is strongly suspected, the
of propranolol, 20–40 mg three or four times daily. routine testing of thyroid function should be avoided in
Thyroxine replacement may be needed for the hypothy- acutely ill patients.
roid phase but should be withdrawn after 6–9 months, The most common hormone pattern in sick euthy-
as recovery is the rule. Annual follow-up thereafter is roid syndrome (SES) is a decrease in total and unbound
recommended, because a proportion of these individu- T3 levels (low T3 syndrome) with normal levels of T4
als develop permanent hypothyroidism. The condition and TSH. The magnitude of the fall in T3 correlates
may recur in subsequent pregnancies. with the severity of the illness. T4 conversion to T3 via
peripheral deiodination is impaired, leading to increased
reverse T3 (rT3). Despite this effect, decreased clearance
Drug-Induced Thyroiditis rather than increased production is the major basis for
Patients receiving cytokines such as IFN-α or IL-2 may increased rT3. Also, T4 is alternately metabolized to the
develop painless thyroiditis. IFN-α, which is used to hormonally inactive T3 sulfate. It is generally assumed
treat chronic hepatitis B or C and hematologic and skin that this low T3 state is adaptive, because it can be
malignancies, causes thyroid dysfunction in up to 5% induced in normal individuals by fasting. Teleologi-
of treated patients. It has been associated with painless cally, the fall in T3 may limit catabolism in starved or ill
thyroiditis, hypothyroidism, and Graves’ disease, and is patients.
most common in women with TPO antibodies prior to Very sick patients may exhibit a dramatic fall in total
treatment. For discussion of amiodarone, see “Amioda- T4 and T3 levels (low T4 syndrome). This state has a
rone Effects on Thyroid Function,” later. poor prognosis. A key factor in the fall in T4 levels is
altered binding to TBG. T4 assays usually demonstrate
a normal unbound T4 level in such patients, depending
Chronic Thyroiditis on the assay method used. Fluctuation in TSH levels also
Focal thyroiditis is present in 20–40% of euthyroid creates challenges in the interpretation of thyroid func-
autopsy cases and is associated with serologic evidence tion in sick patients. TSH levels may range from <0.1
of autoimmunity, particularly the presence of TPO to >20 mIU/L; these alterations reverse after recovery,
antibodies. These antibodies are 4–10 times more com- confirming the absence of underlying thyroid disease. A
mon in otherwise healthy women than men. The most rise in cortisol or administration of glucocorticoids may
common clinically apparent cause of chronic thyroid- provide a partial explanation for decreased TSH levels.
itis is Hashimoto’s thyroiditis, an autoimmune disorder The exact mechanisms underlying the subnormal TSH
that often presents as a firm or hard goiter of variable seen in 10% of sick patients and the increased TSH seen
size (see above). Riedel’s thyroiditis is a rare disorder that in 5% remain unclear but may be mediated by cytokines
typically occurs in middle-aged women. It presents including IL-12 and IL-18.
with an insidious, painless goiter with local symptoms Any severe illness can induce changes in thyroid hor-
due to compression of the esophagus, trachea, neck mone levels, but certain disorders exhibit a distinctive
veins, or recurrent laryngeal nerves. Dense fibrosis dis- pattern of abnormalities. Acute liver disease is associ-
rupts normal gland architecture and can extend outside ated with an initial rise in total (but not unbound) T3
the thyroid capsule. Despite these extensive histologic and T4 levels, due to TBG release; these levels become
changes, thyroid dysfunction is uncommon. The goiter subnormal with progression to liver failure. A transient
is hard, nontender, often asymmetric, and fixed, leading increase in total and unbound T4 levels, usually with a
normal T3 level, is seen in 5–30% of acutely ill psychi- thereafter, most individuals escape from iodide-dependent 87
atric patients. TSH values may be transiently low, nor- suppression of the thyroid (Wolff-Chaikoff effect), and
mal, or high in these patients. In the early stage of HIV the inhibitory effects on deiodinase activity and thyroid

CHAPTER 4
infection, T3 and T4 levels rise, even if there is weight hormone receptor action become predominant. These
loss. T3 levels fall with progression to AIDS, but TSH events lead to the following pattern of thyroid func-
usually remains normal. Renal disease is often accompa- tion tests: increased T4, decreased T3, increased rT3,
nied by low T3 concentrations, but with normal rather and a transient TSH increase (up to 20 mIU/L). TSH
than increased rT3 levels, due to an unknown factor that levels normalize or are slightly suppressed within 1–3
increases uptake of rT3 into the liver. months.
The diagnosis of SES is challenging. Historic infor- The incidence of hypothyroidism from amiodarone

Disorders of the Thyroid Gland


mation may be limited, and patients often have multi- varies geographically, apparently correlating with iodine
ple metabolic derangements. Useful features to consider intake. Hypothyroidism occurs in up to 13% of amioda-
include previous history of thyroid disease and thyroid rone-treated patients in iodine-replete countries, such as
function tests, evaluation of the severity and time course the United States, but is less common (<6% incidence)
of the patient’s acute illness, documentation of medica- in areas of lower iodine intake, such as Italy or Spain.
tions that may affect thyroid function or thyroid hor- The pathogenesis appears to involve an inability of the
mone levels, and measurements of rT3 together with thyroid gland to escape from the Wolff-Chaikoff effect
unbound thyroid hormones and TSH. The diagno- in autoimmune thyroiditis. Consequently, amiodarone-
sis of SES is frequently presumptive, given the clinical associated hypothyroidism is more common in women
context and pattern of laboratory values; only resolu- and individuals with positive TPO antibodies. It is usu-
tion of the test results with clinical recovery can clearly ally unnecessary to discontinue amiodarone for this side
establish this disorder. Treatment of SES with thyroid effect, because levothyroxine can be used to normal-
hormone (T4 and/or T3) is controversial, but most ize thyroid function. TSH levels should be monitored,
authorities recommend monitoring the patient’s thyroid because T4 levels are often increased for the reasons
function tests during recovery, without administering described above.
thyroid hormone, unless there is historic or clinical evi- The management of amiodarone-induced thyrotoxi-
dence suggestive of hypothyroidism. Sufficiently large cosis (AIT) is complicated by the fact that there are dif-
randomized controlled trials using thyroid hormone are ferent causes of thyrotoxicosis and because the increased
unlikely to resolve this therapeutic controversy in the thyroid hormone levels exacerbate underlying arrhyth-
near future, because clinical presentations and outcomes mias and coronary artery disease. Amiodarone treatment
are highly variable. causes thyrotoxicosis in 10% of patients living in areas
of low iodine intake and in 2% of patients in regions of
high iodine intake. There are two major forms of AIT,
Amiodarone Effects although some patients have features of both. Type 1
on Thyroid Function AIT is associated with an underlying thyroid abnormal-
ity (preclinical Graves’ disease or nodular goiter). Thy-
Amiodarone is a commonly used type III antiarrhyth- roid hormone synthesis becomes excessive as a result of
mic agent. It is structurally related to thyroid hormone increased iodine exposure (Jod-Basedow phenomenon).
and contains 39% iodine by weight. Thus, typical doses Type 2 AIT occurs in individuals with no intrinsic thy-
of amiodarone (200 mg/d) are associated with very high roid abnormalities and is the result of drug-induced
iodine intake, leading to greater than fortyfold increases lysosomal activation leading to destructive thyroiditis
in plasma and urinary iodine levels. Moreover, because with histiocyte accumulation in the thyroid; the inci-
amiodarone is stored in adipose tissue, high iodine levels dence rises as cumulative amiodarone dosage increases.
persist for >6 months after discontinuation of the drug. Mild forms of type 2 AIT can resolve spontaneously or
Amiodarone inhibits deiodinase activity, and its metab- can occasionally lead to hypothyroidism. Color-flow
olites function as weak antagonists of thyroid hormone Doppler thyroid scanning shows increased vascularity
action. Amiodarone has the following effects on thy- in type 1 AIT but decreased vascularity in type 2 AIT.
roid function: (1) acute, transient suppression of thyroid Thyroid scintiscans are difficult to interpret in this set-
function; (2) hypothyroidism in patients susceptible to ting because the high endogenous iodine levels dimin-
the inhibitory effects of a high iodine load; and (3) thy- ish tracer uptake. However, the presence of normal or
rotoxicosis that may be caused by either a Jod-Basedow rarely increased uptake favors type 1 AIT.
effect from the iodine load, in the setting of MNG or In AIT, the drug should be stopped, if possible,
incipient Graves’ disease, or a thyroiditis-like condition. although this is often impractical because of the under-
The initiation of amiodarone treatment is associ- lying cardiac disorder. Discontinuation of amiodarone
ated with a transient decrease of T4 levels, reflect- will not have an acute effect because of its storage and
ing the inhibitory effect of iodine on T4 release. Soon prolonged half-life. High doses of antithyroid drugs
88 can be used in type 1 AIT but are often ineffective. In hormone requirements are increased by 25–50 μg/d
type 2 AIT, oral contrast agents, such as sodium ipodate during pregnancy.
(500 mg/d) or sodium tyropanoate (500 mg, 1–2 doses/d),
rapidly reduce T4 and T3 levels, decrease T4 → T3 con-
SECTION I

version, and may block tissue uptake of thyroid hor-


mones. Potassium perchlorate, 200 mg every 6 h, has
Goiter and Nodular
been used to reduce thyroidal iodide content. Perchlo- Thyroid Disease
rate treatment has been associated with agranulocytosis, Goiter refers to an enlarged thyroid gland. Biosynthetic
though the risk appears relatively low with short-term defects, iodine deficiency, autoimmune disease, and
use. Glucocorticoids, as administered for subacute thy-
Pituitary, Thyroid, and Adrenal Disorders

nodular diseases can each lead to goiter, though by dif-


roiditis, have modest benefit in type 2 AIT. Lithium ferent mechanisms. Biosynthetic defects and iodine
blocks thyroid hormone release and can also pro- deficiency are associated with reduced efficiency of
vide some benefit. Near-total thyroidectomy rapidly thyroid hormone synthesis, leading to increased TSH,
decreases thyroid hormone levels and may be the most which stimulates thyroid growth as a compensatory
effective long-term solution if the patient can undergo mechanism to overcome the block in hormone syn-
the procedure safely. thesis. Graves’ disease and Hashimoto’s thyroiditis are
also associated with goiter. In Graves’ disease, the goi-
ter results mainly from the TSH-R–mediated effects
of TSI. The goitrous form of Hashimoto’s thyroiditis
Thyroid Function in Pregnancy occurs because of acquired defects in hormone synthe-
Five factors alter thyroid function in pregnancy: sis, leading to elevated levels of TSH and its consequent
(1) the transient increase in hCG during the first tri- growth effects. Lymphocytic infiltration and immune
mester, which stimulates the TSH-R; (2) the estrogen- system–induced growth factors also contribute to thyroid
induced rise in TBG during the first trimester, which is enlargement in Hashimoto’s thyroiditis. Nodular disease
sustained during pregnancy; (3) alterations in the immune is characterized by the disordered growth of thyroid
system, leading to the onset, exacerbation, or amelioration cells, often combined with the gradual development of
of an underlying autoimmune thyroid disease (see above); fibrosis. Because the management of goiter depends on the
(4) increased thyroid hormone metabolism by the pla- etiology, the detection of thyroid enlargement on phys-
centa; and (5) increased urinary iodide excretion, which ical examination should prompt further evaluation to
can cause impaired thyroid hormone production in areas identify its cause.
of marginal iodine sufficiency. Women with a precarious Nodular thyroid disease is common, occurring in
iodine intake (<50 μg/d) are most at risk of developing about 3–7% of adults when assessed by physical exami-
a goiter during pregnancy, and iodine supplementation nation. Using more sensitive techniques, such as ultra-
should be considered to prevent maternal and fetal hypo- sound, it is present in >25% of adults. Thyroid nodules
thyroidism and the development of neonatal goiter. may be solitary or multiple, and they may be functional
The rise in circulating hCG levels during the first tri- or nonfunctional.
mester is accompanied by a reciprocal fall in TSH that
persists into the middle of pregnancy. This appears to
reflect weak binding of hCG, which is present at very Diffuse Nontoxic (Simple) Goiter
high levels, to the TSH-R. Rare individuals have been
Etiology and pathogenesis
described with variant TSH-R sequences that enhance
hCG binding and TSH-R activation. Human chori- When diffuse enlargement of the thyroid occurs in the
onic gonadotropin-induced changes in thyroid function absence of nodules and hyperthyroidism, it is referred
can result in transient gestational hyperthyroidism and/ to as a diffuse nontoxic goiter. This is sometimes called
or hyperemesis gravidarum, a condition characterized by simple goiter, because of the absence of nodules, or colloid
severe nausea and vomiting and risk of volume deple- goiter, because of the presence of uniform follicles that
tion. Antithyroid drugs are rarely needed, and parenteral are filled with colloid. Worldwide, diffuse goiter is most
fluid replacement usually suffices until the condition commonly caused by iodine deficiency and is termed
resolves. endemic goiter when it affects >5% of the population. In
Maternal hypothyroidism occurs in 2–3% of women nonendemic regions, sporadic goiter occurs, and the cause
of child-bearing age and is associated with increased risk is usually unknown. Thyroid enlargement in teenag-
of developmental delay in the offspring. Consequently, ers is sometimes referred to as juvenile goiter. In general,
TSH screening for hypothyroidism is indicated in early goiter is more common in women than men, probably
pregnancy and should be considered in women who are because of the greater prevalence of underlying autoim-
planning pregnancy, particularly if they have a goiter or mune disease and the increased iodine demands associ-
strong family history of autoimmune thyroid disease. Thyroid ated with pregnancy.
In iodine-deficient areas, thyroid enlargement reflects risk of atrial fibrillation and bone loss. TPO antibod- 89
a compensatory effort to trap iodide and produce suf- ies may be useful to identify patients at increased risk of
ficient hormone under conditions in which hormone autoimmune thyroid disease. Low urinary iodine levels
(<10 μg/dL) support a diagnosis of iodine deficiency.

CHAPTER 4
synthesis is relatively inefficient. Somewhat surprisingly,
TSH levels are usually normal or only slightly increased, Thyroid scanning is not generally necessary but will
suggesting increased sensitivity to TSH or activation reveal increased uptake in iodine deficiency and most
of other pathways that lead to thyroid growth. Iodide cases of dyshormonogenesis. Ultrasound is not gener-
appears to have direct actions on thyroid vasculature and ally indicated in the evaluation of diffuse goiter unless a
may indirectly affect growth through vasoactive sub- nodule is palpable on physical examination.
stances such as endothelins and nitric oxide. Endemic

Disorders of the Thyroid Gland


goiter is also caused by exposure to environmental goi-
trogens such as cassava root, which contains a thiocya- Treatment Diffuse Nontoxic (Simple) Goiter
nate; vegetables of the Cruciferae family (known as cru-
ciferous vegetables) (e.g., brussels sprout, cabbage, and Iodine or thyroid hormone replacement induces vari-
cauliflower); and milk from regions where goitrogens able regression of goiter in iodine deficiency, depend-
are present in grass. Though relatively rare, inherited ing on how long it has been present and the degree of
defects in thyroid hormone synthesis lead to a diffuse fibrosis that has developed. Because of the possibility of
nontoxic goiter. Abnormalities at each step in hormone underlying thyroid autonomy, caution should be exer-
synthesis, including iodide transport (NIS), Tg synthesis, cised when instituting suppressive thyroxine therapy
organification and coupling (TPO), and the regenera- in patients with goiter, particularly if the baseline TSH
tion of iodide (dehalogenase), have been described. is in the low to normal range. In younger patients, the
dose of levothyroxine can be started at 100 mg/d and
adjusted to suppress the TSH into the low to normal,
Clinical Manifestations but detectable, range. Treatment of elderly patients
and Diagnosis should be initiated at 50 mg/d. The efficacy of suppres-
If thyroid function is preserved, most goiters are asymp- sive treatment is greater in younger patients and for
tomatic. Spontaneous hemorrhage into a cyst or nod- those with soft goiters. Significant regression is usually
ule may cause the sudden onset of localized pain and seen within 3–6 months of treatment; after this time, it
swelling. Examination of a diffuse goiter reveals a sym- is unlikely to occur. In older patients and in those with
metrically enlarged, nontender, generally soft gland some degree of nodular disease or fibrosis, fewer than
without palpable nodules. Goiter is defined, some- one-third demonstrate significant shrinkage of the goiter.
what arbitrarily, as a lateral lobe with a volume greater Surgery is rarely indicated for diffuse goiter. Exceptions
than the thumb of the individual being examined. If include documented evidence of tracheal compression
the thyroid is markedly enlarged, it can cause tracheal or obstruction of the thoracic outlet, which are more
or esophageal compression. These features are unusual, likely to be associated with substernal multinodular goi-
however, in the absence of nodular disease and fibro- ters (see below). Subtotal or near-total thyroidectomy
sis. Substernal goiter may obstruct the thoracic inlet. Pem- for these or cosmetic reasons should be performed by
berton’s sign refers to symptoms of faintness with evi- an experienced surgeon to minimize complication rates.
dence of facial congestion and external jugular venous Surgery should be followed by replacement with levo-
obstruction when the arms are raised above the head, a thyroxine, with the aim of keeping the TSH level at the
maneuver that draws the thyroid into the thoracic inlet. lower end of the reference range to prevent regrowth
Respiratory flow measurements and CT or MRI should of the goiter. Radioiodine reduces goiter size by about
be used to evaluate substernal goiter in patients with 50% in the majority of patients over 6–12 months. It is
obstructive signs or symptoms. rarely associated with transient acute swelling of the
Thyroid function tests should be performed in all thyroid, which is usually inconsequential unless there
patients with goiter to exclude thyrotoxicosis or hypo- is severe tracheal narrowing. If they are not treated
thyroidism. It is not unusual, particularly in iodine with levothyroxine, patients should be followed after
deficiency, to find a low total T4, with normal T3 and radioiodine treatment for the possible development of
TSH, reflecting enhanced T4 → T3 conversion. A low hypothyroidism.
TSH with a normal free T3 and free T4, particularly in
older patients, suggests the possibility of thyroid auton- Nontoxic Multinodular Goiter
omy or undiagnosed Graves’ disease, and is termed sub-
Etiology and pathogenesis
clinical thyrotoxicosis. The benefit of treatment (typically
with radioiodine) in subclinical thyrotoxicosis, versus Depending on the population studied, MNG occurs
follow-up and implementing treatment if free T3 or free in up to 12% of adults. MNG is more common in
T4 levels become abnormal, is unclear, but treatment is women than men and increases in prevalence with age.
increasingly recommended in the elderly to reduce the It is more common in iodine-deficient regions but also
90 occurs in regions of iodine sufficiency, reflecting multi- suggestive of malignancy (e.g., microcalcifications,
ple genetic, autoimmune, and environmental influences hypoechogenicity, increased vascularity).
on the pathogenesis.
There is typically wide variation in nodule size. His-
SECTION I

tology reveals a spectrum of morphologies ranging from Treatment Nontoxic Multinodular Goiter
hypercellular regions to cystic areas filled with colloid.
Fibrosis is often extensive, and areas of hemorrhage or Most nontoxic MNGs can be managed conservatively.
lymphocytic infiltration may be seen. Using molecular T4 suppression is rarely effective for reducing goiter
techniques, most nodules within a MNG are polyclonal size and introduces the risk of subclinical or overt thy-
in origin, suggesting a hyperplastic response to locally rotoxicosis, particularly if there is underlying autonomy
Pituitary, Thyroid, and Adrenal Disorders

produced growth factors and cytokines. TSH, which or if it develops during treatment. If levothyroxine is
is usually not elevated, may play a permissive or con- used, it should be started at low doses (50 μg) and
tributory role. Monoclonal lesions also occur within a advanced gradually while monitoring the TSH level
MNG, reflecting mutations in genes that confer a selec- to avoid excessive suppression. Contrast agents and
tive growth advantage to the progenitor cell. other iodine-containing substances should be avoided
because of the risk of inducing the Jod-Basedow effect,
characterized by enhanced thyroid hormone produc-
Clinical manifestations tion by autonomous nodules. Radioiodine is used with
Most patients with nontoxic MNG are asymptomatic increasing frequency because it can decrease goiter size
and euthyroid. MNG typically develops over many and may selectively ablate regions of autonomy. Dos-
years and is detected on routine physical examination or age of 131I depends on the size of the goiter and radio-
when an individual notices an enlargement in the neck. iodine uptake but is usually about 3.7 MBq (0.1 mCi)
If the goiter is large enough, it can ultimately lead to per gram of tissue, corrected for uptake [typical dose
compressive symptoms including difficulty swallowing, 370–1070 MBq (10 to 29 mCi)]. Repeat treatment may
respiratory distress (tracheal compression), or plethora be needed and effectiveness may be increased by con-
(venous congestion), but these symptoms are uncom- current administration of recombinant TSH. It is pos-
mon. Symptomatic MNGs are usually extraordinarily sible to achieve a 40–50% reduction in goiter size in
large and/or develop fibrotic areas that cause compres- most patients. Earlier concerns about radiation-induced
sion. Sudden pain in a MNG is usually caused by hem- thyroid swelling and tracheal compression have dimin-
orrhage into a nodule but should raise the possibility of ished; studies have shown this complication to be rare.
invasive malignancy. Hoarseness, reflecting laryngeal When acute compression occurs, glucocorticoid treat-
nerve involvement, also suggests malignancy. ment or surgery may be needed. Radiation-induced
hypothyroidism is less common than after treatment for
Graves’ disease. However, posttreatment autoimmune
Diagnosis thyrotoxicosis may occur in up to 5% of patients treated
On examination, thyroid architecture is distorted, and for nontoxic MNG. Surgery remains highly effective but
multiple nodules of varying size can be appreciated. is not without risk, particularly in older patients with
Because many nodules are deeply embedded in thyroid underlying cardiopulmonary disease.
tissue or reside in posterior or substernal locations, it is
not possible to palpate all nodules. A TSH level should
Toxic Multinodular Goiter
be measured to exclude subclinical hyper- or hypothy-
roidism, but thyroid function is usually normal. Tracheal The pathogenesis of toxic MNG appears to be similar
deviation is common, but compression must usually to that of nontoxic MNG; the major difference is the
exceed 70% of the tracheal diameter before there is sig- presence of functional autonomy in toxic MNG. The
nificant airway compromise. Pulmonary function testing molecular basis for autonomy in toxic MNG remains
can be used to assess the functional effects of compres- unknown. As in nontoxic goiters, many nodules are
sion and to detect tracheomalacia, which characteristi- polyclonal, while others are monoclonal and vary in
cally causes inspiratory stridor. CT or MRI can be used their clonal origins. Genetic abnormalities known to
to evaluate the anatomy of the goiter and the extent of confer functional autonomy, such as activating TSH-R
substernal extension, which is often much greater than or Gsα mutations (see below), are not usually found in
is apparent on physical examination. A barium swal- the autonomous regions of toxic MNG goiter.
low may reveal the extent of esophageal compression. In addition to features of goiter, the clinical presen-
The risk of malignancy in MNG is similar to that in soli- tation of toxic MNG includes subclinical hyperthy-
tary nodules. Ultrasonography can be used to identify roidism or mild thyrotoxicosis. The patient is usually
which nodules should be biopsied, including large, domi- elderly and may present with atrial fibrillation or palpita-
nant nodules or those with sonographic characteristics tions, tachycardia, nervousness, tremor, or weight loss.
Recent exposure to iodine, from contrast dyes or other 91
sources, may precipitate or exacerbate thyrotoxicosis.
The TSH level is low. The T4 level may be normal or
Extracellular domain

CHAPTER 4
minimally increased; T3 is often elevated to a greater
degree than T4. Thyroid scan shows heterogeneous
uptake with multiple regions of increased and decreased TSH-R
uptake; 24-hour uptake of radioiodine may not be
increased.

Disorders of the Thyroid Gland


Treatment Toxic Multinodular Goiter
4 7
The management of toxic MNG is challenging. Antithy- 5 6

roid drugs, often in combination with beta blockers, Transmembrane


can normalize thyroid function and address clinical fea- domains GSα
tures of thyrotoxicosis. This treatment, however, often AC
Activating mutations
stimulates the growth of the goiter, and in contrast to
Graves’ disease, spontaneous remission does not occur.
Radioiodine can be used to treat areas of autonomy as
well as to decrease the mass of the goiter. Usually, how- Cell growth, differentiation
ever, some degree of autonomy remains, presumably cyclic AMP
Hormone synthesis
because multiple autonomous regions emerge as soon
Figure 4-10
as others are treated. Nonetheless, a trial of radioiodine
Activating mutations of the TSH-R. Mutations (✸) that acti-
should be considered before subjecting patients, many
vate the thyroid-stimulating hormone receptor (TSH-R) reside
of whom are elderly, to surgery. Surgery provides defini-
mainly in transmembrane 5 and intracellular loop 3, though
tive treatment of underlying thyrotoxicosis as well as
mutations have occurred in a variety of different locations.
goiter. Patients should be rendered euthyroid using an The effect of these mutations is to induce conformational
antithyroid drug before operation. changes that mimic TSH binding, thereby leading to coupling
to stimulatory G protein (GSα) and activation of adenylate
Hyperfunctioning Solitary Nodule cyclase (AC), an enzyme that generates cyclic AMP.

A solitary, autonomously functioning thyroid nodule


is referred to as toxic adenoma. The pathogenesis of this provides a definitive diagnostic test, demonstrating focal
disorder has been unraveled by demonstrating the func- uptake in the hyperfunctioning nodule and diminished
tional effects of mutations that stimulate the TSH-R uptake in the remainder of the gland, as activity of the
signaling pathway. Most patients with solitary hyper- normal thyroid is suppressed.
functioning nodules have acquired somatic, activating
mutations in the TSH-R (Fig. 4-10). These muta-
tions, located primarily in the receptor transmembrane Treatment Hyperfunctioning Solitary Nodule
domain, induce constitutive receptor coupling to GSα,
increasing cyclic AMP levels and leading to enhanced Radioiodine ablation is usually the treatment of choice.
thyroid follicular cell proliferation and function. Less Because normal thyroid function is suppressed, 131I is
commonly, somatic mutations are identified in GSα. concentrated in the hyperfunctioning nodule with
These mutations, which are similar to those seen in minimal uptake and damage to normal thyroid tissue.
McCune-Albright syndrome (Chap. 10) or in a sub- Relatively large radioiodine doses [e.g., 370–1110 MBq
set of somatotrope adenomas (Chap. 2), impair GTP (10–29.9 mCi)131I] have been shown to correct thyrotoxi-
hydrolysis, also causing constitutive activation of the cosis in about 75% of patients within 3 months. Hypothy-
cyclic AMP signaling pathway. In most series, activat- roidism occurs in <10% of those patients over the next
ing mutations in either the TSH-R or the GSα subunit 5 years. Surgical resection is also effective and is usually
genes are identified in >90% of patients with solitary limited to enucleation of the adenoma or lobectomy,
hyperfunctioning nodules. thereby preserving thyroid function and minimizing risk
Thyrotoxicosis is usually mild. The disorder is sug- of hypoparathyroidism or damage to the recurrent laryn-
gested by the presence of the thyroid nodule, which geal nerves. Medical therapy using antithyroid drugs
is generally large enough to be palpable, and by the and beta blockers can normalize thyroid function but is
absence of clinical features suggestive of Graves’ dis- not an optimal long-term treatment. Using ultrasound
ease or other causes of thyrotoxicosis. A thyroid scan guidance, repeated ethanol injections, or percutaneous
92 fluid (colloid). Many are mixed cystic/solid lesions, in
radiofrequency thermal ablation have been used suc-
which case it is desirable to aspirate cellular components
cessfully in some centers to ablate hyperfunctioning
under ultrasound or harvest cells after cytospin of cyst
nodules, and these techniques have also been used
fluid. Cysts frequently recur, even after repeated aspira-
SECTION I

to reduce the size of nonfunctioning thyroid nodules.


tion, and may require surgical excision if they are large
or if the cytology is suspicious. Sclerosis has been used
Benign Neoplasms with variable success but is often painful and may be
complicated by infiltration of the sclerosing agent.
The various types of benign thyroid nodules are listed in The treatment approach for benign nodules is similar
Table 4-9. These lesions are common (5–10% adults), to that for MNG. TSH suppression with levothyroxine
Pituitary, Thyroid, and Adrenal Disorders

particularly when assessed by sensitive techniques such as decreases the size of about 30% of nodules and may pre-
ultrasound. The risk of malignancy is very low for macro- vent further growth. If a nodule has not decreased in
follicular adenomas and normofollicular adenomas. Microfollicular, size after 6–12 months of suppressive therapy, treatment
trabecular, and Hürthle cell variants raise greater concern, should be discontinued because little benefit is likely to
and the histology is more difficult to interpret. About accrue from long-term treatment; the risk of iatrogenic
one-third of palpable nodules are thyroid cysts. These may subclinical thyrotoxicosis should also be considered.
be recognized by their ultrasound appearance or based
on aspiration of large amounts of pink or straw-colored
Thyroid Cancer

Table 4-9 Thyroid carcinoma is the most common malignancy of


the endocrine system. Malignant tumors derived from
Classification of Thyroid Neoplasms
the follicular epithelium are classified according to his-
Benign tologic features. Differentiated tumors, such as papillary
Follicular epithelial cell adenomas thyroid cancer (PTC) or follicular thyroid cancer (FTC),
  Macrofollicular (colloid) are often curable, and the prognosis is good for patients
  Normofollicular (simple) identified with early-stage disease. In contrast, anaplastic
  Microfollicular (fetal) thyroid cancer (ATC) is aggressive, responds poorly to
  Trabecular (embryonal)
treatment, and is associated with a bleak prognosis.
  Hürthle cell variant (oncocytic)
The incidence of thyroid cancer (∼9/100,000 per
Approximate year) increases with age, plateauing after about age 50
Malignant Prevalence, %
(Fig. 4-11). Age is also an important prognostic factor—
Follicular epithelial cell thyroid cancer at a young age (<20) or in older per-
  Well-differentiated carcinomas
sons (>45) is associated with a worse prognosis. Thy-
   Papillary carcinomas 80–90
    Pure papillary
roid cancer is twice as common in women as men, but
    Follicular variant male gender is associated with a worse prognosis. Addi-
    Diffuse sclerosing variant tional important risk factors include a history of child-
    Tall cell, columnar cell variants hood head or neck irradiation, large nodule size (≥4 cm),
   Follicular carcinomas 5–10 evidence for local tumor fixation or invasion into lymph
    Minimally invasive nodes, and the presence of metastases (Table 4-10).
    Widely invasive Several unique features of thyroid cancer facilitate its
    Hürthle cell carcinoma
management: (1) thyroid nodules are readily palpable,
    (oncocytic)
    Insular carcinoma allowing early detection and biopsy by FNA; (2) iodine
  Undifferentiated (anaplastic) radioisotopes can be used to diagnose (123I) and treat
  carcinomas (131I) differentiated thyroid cancer, reflecting the unique
C cell (calcitonin producing) uptake of this anion by the thyroid gland; and (3) serum
  Medullary thyroid cancer <10 markers allow the detection of residual or recurrent dis-
   Sporadic ease, including the use of Tg levels for PTC and FTC
   Familial
and calcitonin for medullary thyroid cancer (MTC).
   MEN 2
Other malignancies
  Lymphomas 1–2 Classification
  Sarcomas
  Metastases Thyroid neoplasms can arise in each of the cell types
  Others that populate the gland, including thyroid follicular
cells, calcitonin-producing C cells, lymphocytes, and
Abbreviation: MEN, multiple endocrine neoplasia. stromal and vascular elements, as well as metastases from
Table 4-11 93
10
Thyroid Cancer Classificationa
Papillary or follicular thyroid cancers

CHAPTER 4
8
<45 years >45 years
Rate per 100,000/year

  Stage I Any T, any N, M0 T1, N0, M0


6   Stage II Any T, any N, M1 T2 or T3, N0, M0
  Stage III — T4, N0, M0
4
Any T, N1, M0
  Stage IV — Any T, any N, M1
Anaplastic thyroid cancer

Disorders of the Thyroid Gland


2   Stage IV All cases are
stage IV
Medullary thyroid cancer
0
0 20 40 60 80   Stage I T1, N0, M0
Age (year)
  Stage II T2–T4, N0, M0
  Stage III Any T, N1, M0
Figure 4-11   Stage IV Any T, any N, M1
Age-associated incidence (—♦—) and mortality (—•—)
rates for invasive thyroid cancer. (Adapted from LAG a
Criteria include: T, the size and extent of the primary tumor (T1 ≤ 1 cm;
Ries et al [eds]: SEER Cancer Statistics Review, 1973–1996, 1 cm < T2 ≤ 4 cm; T3 > 4 cm; T4 direct invasion through the thy-
Bethesda, National Cancer Institute, 1999.) roid capsule); N, the absence (N0) or presence (N1) of regional node
involvement; M, the absence (M0) or presence (M1) of metastases.
Source: American Joint Committee on Cancer staging system for
Table 4-10 thyroid cancers using the TNM classification.
Risk Factors for Thyroid Carcinoma in
Patients With Thyroid Nodule the risk of benign and malignant thyroid nodules, is
History of head and neck irradiation associated with multicentric cancers, and shifts the
Age <20 or >45 years incidence of thyroid cancer to an earlier age group.
Bilateral disease Radiation from nuclear fallout also increases the risk
Increased nodule size (>4 cm)
of thyroid cancer. Children seem more predisposed to
New or enlarging neck mass
Male gender the effects of radiation than adults. Of note, radiation
Family history of thyroid cancer or MEN 2 derived from 131I therapy appears to contribute minimal
Vocal cord paralysis, hoarse voice increased risk of thyroid cancer.
Nodule fixed to adjacent structures
Extrathyroidal extension
Suspected lymph node involvement
TSH and growth factors
Iodine deficiency (follicular cancer) Many differentiated thyroid cancers express TSH recep-
tors and therefore remain responsive to TSH. This
Abbreviation: MEN, multiple endocrine neoplasia. observation provides the rationale for T4 suppression of
TSH in patients with thyroid cancer. Residual expres-
other sites (Table 4-9). The American Joint Committee sion of TSH receptors also allows TSH-stimulated
on Cancer (AJCC) has designated a staging system using uptake of 131I therapy (see below).
the TNM classification (Table 4-11). Several other
classification and staging systems are also widely used,
Oncogenes and tumor-suppressor genes
some of which place greater emphasis on histologic fea-
tures or risk factors such as age or gender. Thyroid cancers are monoclonal in origin, consistent
with the idea that they originate as a consequence of
Pathogenesis and Genetic Basis mutations that confer a growth advantage to a single cell.
In addition to increased rates of proliferation, some thy-
Radiation roid cancers exhibit impaired apoptosis and features that
Early studies of the pathogenesis of thyroid cancer enhance invasion, angiogenesis, and metastasis. Thyroid
focused on the role of external radiation, which predis- neoplasms have been analyzed for a variety of genetic
poses to chromosomal breaks, leading to genetic rear- alterations, but without clear evidence of an ordered
rangements and loss of tumor-suppressor genes. Exter- acquisition of somatic mutations as they progress from
nal radiation of the mediastinum, face, head, and neck the benign to the malignant state. On the other hand, cer-
region was administered in the past to treat an array of tain mutations are relatively specific for thyroid neopla-
conditions, including acne and enlargement of the thy- sia, some of which correlate with histologic classification
mus, tonsils, and adenoids. Radiation exposure increases (Table 4-12).
94 Table 4-12
Genetic Alterations in Thyroid Neoplasia
Chromosomal Genetic
SECTION I

Gene/Protein Type of Gene Location Abnormality Tumor

TSH receptor GPCR receptor 14q31 Point mutations Toxic adenoma, differentiated
carcinomas
GSα G protein 20q13.2 Point mutations Toxic adenoma, differentiated
carcinomas
RET/PTC Receptor tyrosine kinase 10q11.2 Rearrangements PTC
Pituitary, Thyroid, and Adrenal Disorders

PTC1: (inv(10)
q11.2q21)
PTC2: (t(10;17)
(q11.2;q23))
PTC3: ELE1/TK
RET Receptor tyrosine kinase 10q11.2 Point mutations MEN 2, medullary thyroid cancer
BRAF MEK kinase 7q24 Point mutations, PTC, ATC
rearrangements
TRK Receptor tyrosine kinase 1q23-24 Rearrangements Multinodular goiter, papillary
thyroid cancer
RAS Signal transducing p21 Hras 11p15.5Kras Point mutations Differentiated thyroid carcinoma,
12p12.1; Nras adenomas
1p13.2
p53 Tumor suppressor, cell 17p13 Point mutations Anaplastic cancer
cycle control, apoptosis Deletion, insertion
APC Tumor suppressor, 5q21-q22 Point mutations Anaplastic cancer, also associ-
adenomatous polyposis ated with familial polyposis coli
coli gene
p16 (MTS1, Tumor suppressor, cell 9p21 Deletions Differentiated carcinomas
CDKN2A) cycle control
p21/WAF Tumor suppressor, cell 6p21.2 Overexpression Anaplastic cancer
cycle control
MET Receptor tyrosine kinase 7q31 Overexpression Follicular thyroid cancer
c-MYC Receptor tyrosine kinase 8q24.12-13 Overexpression Differentiated carcinoma
PTEN Phosphatase 10q23 Point mutations PTC in Cowden’s syndrome
(multiple hamartomas, breast
tumors, gastrointestinal polyps,
thyroid tumors)
CTNNB1 β-Catenin 3p22 Point mutations Anaplastic cancer
Loss of hetero- ?Tumor suppressors 3p; 11q13, other Deletions Differentiated thyroid carcino-
zygosity (LOH) loci mas, anaplastic cancer
PAX8-PPARγ 1 Transcription factor t(2;3)(q13;p25) Translocation Follicular adenoma or carcinoma
Nuclear receptor fusion

Abbreviations: APC, adenomatous polyposis coli; BRAF, v-raf homologue, B1; CDKN2A, cyclin-dependent kinase inhibitor 2A; c-MYC, cellular
homologue of myelocytomatosis virus proto-oncogene; ELE1/TK, RET-activating gene ele1/tyrosine kinase; GPCR, G protein–coupled recep-
tor; GSα, G-protein stimulating α-subunit; MEK, mitogen extracellular signal-regulated kinase; MEN 2, multiple endocrine neoplasia-2; MET, met
proto-oncogene (hepatocyte growth factor receptor); MTS, multiple tumor suppressor; p53, p53 tumor suppressor gene; PAX8, paired domain
transcription factor; PPARγ1, peroxisome-proliferator activated receptor γ1; PTC, papillary thyroid cancer; PTEN, phosphatase and tensin homo-
logue; RAS, rat sarcoma proto-oncogene; RET, rearranged during transfection proto-oncogene; TRK, tyrosine kinase receptor; TSH, thyroid-
stimulating hormone; p21, p21 tumor suppressor; WAF, wild-type p53 activated fragment.
Source: Adapted with permission from P Kopp, JL Jameson, in JL Jameson (ed): Principles of Molecular Medicine. Totowa, NJ, Humana Press,
1998.

As described above, activating mutations of the heterogeneous. A variety of rearrangements involving


TSH-R and the GSα subunit are associated with auton- the RET gene on chromosome 10 brings this recep-
omously functioning nodules. Though these mutations tor tyrosine kinase under the control of other promoters,
induce thyroid cell growth, this type of nodule is almost leading to receptor overexpression. RET rearrange-
always benign. ments occur in 20–40% of PTCs in different series
Activation of the RET-RAS-BRAF signaling pathway and were observed with increased frequency in tumors
is seen in most PTCs, though the types of mutations are developing after the Chernobyl radiation accident.
Rearrangements in PTC have also been observed for of thyroid glands at autopsy, but most of these lesions 95
another tyrosine kinase gene, TRK1, which is located are very small (several millimeters) and are not clinically
on chromosome 1. To date, the identification of PTC significant. Characteristic cytologic features of PTC

CHAPTER 4
with RET or TRK1 rearrangements has not proven help make the diagnosis by FNA or after surgical resec-
useful for predicting prognosis or treatment responses. tion; these include psammoma bodies, cleaved nuclei
BRAF mutations appear to be the most common with an “orphan-Annie” appearance caused by large
genetic alteration in PTC. These mutations activate the nucleoli, and the formation of papillary structures.
kinase, which stimulates the mitogen-activated protein PTC tends to be multifocal and to invade locally
MAP kinase (MAPK) cascade. RAS mutations, which within the thyroid gland as well as through the thyroid
also stimulate the MAPK cascade, are found in about capsule and into adjacent structures in the neck. It has

Disorders of the Thyroid Gland


20–30% of thyroid neoplasms, including both PTC and a propensity to spread via the lymphatic system but can
FTC. Of note, simultaneous RET, BRAF, and RAS metastasize hematogenously as well, particularly to bone
mutations do not occur in the same tumor, suggest- and lung. Because of the relatively slow growth of the
ing that activation of the MAPK cascade is critical for tumor, a significant burden of pulmonary metastases
tumor development, independent of the step that initi- may accumulate, sometimes with remarkably few symp-
ates the cascade. toms. The prognostic implication of lymph node spread
RAS mutations also occur in FTCs. In addition, a is debated. Lymph node involvement by thyroid cancer
rearrangement of the thyroid developmental transcrip- can be well tolerated but appears to increase the risk of
tion factor PAX8 with the nuclear receptor PPARγ is recurrence and mortality, particularly in older patients.
identified in a significant fraction of FTCs. Loss of het- The staging of PTC by the TNM system is outlined in
erozygosity of 3p or 11q, consistent with deletions of Table 4-11. Most papillary cancers are identified in the
tumor-suppressor genes, is also common in FTCs. early stages (>80% stages I or II) and have an excellent
Most of the mutations seen in differentiated thy- prognosis, with survival curves similar to expected sur-
roid cancers have also been detected in ATCs. BRAF vival (Fig. 4-12A). Mortality is markedly increased in
mutations are seen in up to 50% of ATCs. Mutations stage IV disease (distant metastases), but this group com-
in CTNNB1, which encodes β-catenin, occur in about prises only about 1% of patients. The treatment of PTC
two-thirds of ATCs, but not in PTC or FTC. Muta- is described below.
tions of the tumor suppressor p53 also play an important
role in the development of ATC. Because p53 plays a
role in cell cycle surveillance, DNA repair, and apop- Follicular
tosis, its loss may contribute to the rapid acquisition of The incidence of FTC varies widely in different parts
genetic instability as well as poor treatment responses of the world; it is more common in iodine-deficient
(Table 4-12). regions. FTC is difficult to diagnose by FNA because
The role of molecular diagnostics in the clinical man- the distinction between benign and malignant follicu-
agement of thyroid cancer is under investigation. In lar neoplasms rests largely on evidence of invasion into
principle, analyses of specific mutations might aid in vessels, nerves, or adjacent structures. FTC tends to
classification, prognosis, or choice of treatment. How- spread by hematogenous routes leading to bone, lung,
ever, there is no clear evidence to date that this infor- and central nervous system metastases. Mortality rates
mation alters clinical decision making. associated with FTC are less favorable than those for
MTC, when associated with multiple endocrine neo- PTC, in part because a larger proportion of patients
plasia (MEN) type 2, harbors an inherited mutation of present with stage IV disease (Fig. 4-12B). Poor prog-
the RET gene. Unlike the rearrangements of RET seen nostic features include distant metastases, age >50 years,
in PTC, the mutations in MEN 2 are point mutations primary tumor size >4 cm, Hürthle cell histology, and
that induce constitutive activity of the tyrosine kinase the presence of marked vascular invasion.
(Chap. 23). MTC is preceded by hyperplasia of the C cells,
raising the likelihood that as-yet-unidentified “second
hits” lead to cellular transformation. A subset of sporadic
Treatment Well-Differentiated Thyroid Cancer
MTC contain somatic mutations that activate RET.
Surgery  All well-differentiated thyroid cancers
should be surgically excised. In addition to removing
Well-Differentiated Thyroid Cancer the primary lesion, surgery allows accurate histologic
Papillary diagnosis and staging, and multicentric disease is com-
monly found in the contralateral thyroid lobe. Lymph
PTC is the most common type of thyroid cancer,
node spread can also be assessed at the time of surgery,
accounting for 70–90% of well-differentiated thyroid
and involved nodes can be removed. Recommendations
malignancies. Microscopic PTC is present in up to 25%
96 100 Stage I
Stage II TSH Suppression Therapy  As most tumors
are still TSH responsive, levothyroxine suppression of
Surviving papillary thyroid

80
Stage III TSH is a mainstay of thyroid cancer treatment. Though
SECTION I

carcinoma, %

60 TSH suppression clearly provides therapeutic benefit,


there are no prospective studies that identify the opti-
40 mal level of TSH suppression. A reasonable goal is to
suppress TSH as much as possible without subjecting
20 the patient to unnecessary side effects from excess
Stage IV
thyroid hormone, such as atrial fibrillation, osteope-
Pituitary, Thyroid, and Adrenal Disorders

0
0 5 10 15 20 25 nia, anxiety, and other manifestations of thyrotoxico-
A Years after initial treatment sis. For patients at low risk of recurrence, TSH should
be suppressed into the low but detectable range
100
Stage I
(0.1–0.5 mIU/L). For patients at high risk of recurrence
or with known metastatic disease, complete TSH sup-
Surviving follicular thyroid

80 Stage II pression is indicated if there are no strong contra-


indications to mild thyrotoxicosis. In this instance,
carcinoma, %

60
unbound T4 must also be monitored to avoid exces-
Stage III
sive treatment.
40
Radioiodine Treatment  Well-differentiated
20 Stage IV thyroid cancer still incorporates radioiodine, though less
efficiently than normal thyroid follicular cells. Radioio-
0
0 5 10 15 20 25 dine uptake is determined primarily by expression of
B Years after initial treatment the NIS and is stimulated by TSH, requiring expression
of the TSH-R. The retention time for radioactivity is influ-
Figure 4-12 enced by the extent to which the tumor retains differ-
Survival rates in patients with differentiated thyroid can-
entiated functions such as iodide trapping and organi-
cer. A. Papillary cancer, cohort of 1851 patients. I, 1107
fication. After near-total thyroidectomy, substantial
(60%); II, 408 (22%); III, 312 (17%); IV, 24 (1%); n = 1185.
thyroid tissue often remains, particularly in the thyroid
B. Follicular cancer, cohort of 153 patients. I, 42 (27%); II, 82
bed and surrounding the parathyroid glands. Conse-
(54%); III, 6 (4%); IV, 23 (15%); n = 153. (Adapted from PR
quently, 131I ablation is necessary to eliminate remain-
Larsen et al: William’s Textbook of Endocrinology, 9th ed,
JD Wilson et al [eds]. Philadelphia, Saunders, 1998, pp 389–
ing normal thyroid tissue and to treat residual tumor
575, with permission.) cells.
Indications  The use of therapeutic doses of radio-
iodine remains an area of controversy in thyroid cancer
management. However, postoperative thyroid ablation
about the extent of surgery vary for stage I disease,
and radioiodine treatment of known residual PTC or
as survival rates are similar for lobectomy and near-
FTC clearly reduces recurrence rates but has a smaller
total thyroidectomy. Lobectomy is associated with a
impact on mortality, particularly in patients at relatively
lower incidence of hypoparathyroidism and injury to
low risk. This low-risk group includes most patients with
the recurrent laryngeal nerves. However, it is not pos-
stage 1 PTC with primary tumors <1.5 cm in size. For
sible to monitor Tg levels or to perform whole-body 131I
patients with larger papillary tumors, spread to the adja-
scans in the presence of the residual lobe. Moreover,
cent lymph nodes, FTC, or evidence of metastases, thy-
if final staging or subsequent follow-up indicates the
roid ablation and radioiodine treatment are generally
need for radioiodine scanning or treatment, repeat sur-
indicated.
gery is necessary to remove the remaining thyroid tis-
sue. Therefore, near-total thyroidectomy is preferable 131
I Thyroid Ablation and Treatment  As
in almost all patients; complication rates are acceptably noted above, the decision to use 131I for thyroid abla-
low if the surgeon is highly experienced in the proce- tion should be coordinated with the surgical approach,
dure. Postsurgical radioablation of the remnant thyroid as radioablation is much more effective when there
tissue is increasingly being used because it may destroy is minimal remaining normal thyroid tissue. A typical
remaining or multifocal thyroid carcinoma, and it facili- strategy is to treat the patient for several weeks postop-
tates the use of Tg determinations and radioiodine scan- eratively with liothyronine (25 μg bid or tid), followed
ning for long-term follow-up by eliminating residual by thyroid hormone withdrawal. Ideally, the TSH level
normal or neoplastic tissue. should increase to >50 mU/L over 3–4 weeks. The level
to which TSH rises is dictated largely by the amount rhTSH IN FOLLOW UP OF PTS WITH THYROID CANCER 97
of normal thyroid tissue remaining postoperatively. Thyroidectomy
131I Ablation
Recombinant human TSH (rhTSH) has also been used to

CHAPTER 4
T4 suppression
enhance 131I uptake for postsurgical ablation. It appears Postablation or follow-up scan
to be at least as effective as thyroid hormone with-
drawal and should be particularly useful as residual thy- Likely residual disease Low disease risk
roid tissue prevents an adequate endogenous TSH rise. Tg >2 ng/mL Tg <2 ng/mL
A pretreatment scanning dose of 131I [usually 111–
T4 withdrawal rhTSH (Thyrogen)
185 MBq (3–5 mCi)] can reveal the amount of residual protocol protocol

Disorders of the Thyroid Gland


tissue and provides guidance about the dose needed
Discontinue T4 Continue
to accomplish ablation. However, because of concerns T3, 25 µg 2–3×/d T4 suppression
about radioactive “stunning” that impairs subsequent
Discontinue T3 after rhTSH
treatment, there is a trend to avoid pretreatment scan- 2–3 weeks 0.9 mg IM qd × 2
ning and to proceed directly to ablation, unless there
Off T4 & T3 Day 3
is suspicion that the amount of residual tissue will alter 2–3 weeks 4 mCi 131I
therapy. A maximum outpatient 131I dose is 1110 MBq TSH >25 mU/L Day 5
(29.9 mCi) in the United States, though ablation is often Measure Tg Body scan;
Measure Tg
more complete using greater doses [1850–3700 MBq 4 mCi 131I
(50–100 mCi)]. Patients should be placed on a low- Whole-body scan
iodine diet (<50 μg/d urinary iodine) to increase radioio- No apparent
disease
dine uptake. In patients with known residual cancer, the Continue
No apparent Residual disease
larger doses ensure thyroid ablation and may destroy disease metastases, ↑Tg
follow-up
measure
remaining tumor cells. A whole-body scan following Continue Therapeutic 131I
the high-dose radioiodine treatment is useful to identify follow-up
measure
possible metastatic disease.
Follow-Up Whole-Body Thyroid Scanning Figure 4-13 
and Thyroglobulin Determinations  An ini- Use of recombinant human thyroid-stimulating hormone
tial whole-body scan should be performed about (TSH) in the follow-up of patients with thyroid cancer.
6 months after thyroid ablation. The strategy for follow- rhTSH, recombinant human TSH; Tg, thyroglobulin.
up management of thyroid cancer has been altered by
the availability of rhTSH to stimulate 131I uptake and by
the improved sensitivity of Tg assays to detect residual
or recurrent disease. A scheme for using either rhTSH
can be managed with suppressive therapy and mea-
or thyroid hormone withdrawal for thyroid scanning is
surements of unstimulated Tg every 6–12 months. The
summarized in Fig. 4-13. After thyroid ablation, rhTSH
absence of Tg antibodies should be confirmed in these
can be used in follow-up to stimulate Tg and 131I uptake
patients. On the other hand, patients with residual dis-
without subjecting patients to thyroid hormone with-
ease on whole-body scanning or those with elevated
drawal and its associated symptoms of hypothyroidism
Tg levels require additional 131I therapy. In addition,
as well as the risk of tumor growth after prolonged TSH
most authorities advocate radioiodine treatment for
stimulation. Alternatively, in patients who are likely to
scan-negative, Tg-positive (Tg >5–10 ng/mL) patients,
require 131I treatment, the traditional approach of thy-
as many derive therapeutic benefit from a large dose
roid hormone withdrawal can be used to increase TSH.
of 131I.
This involves switching patients from levothyroxine (T4)
In addition to radioiodine, external beam radiother-
to the more rapidly cleared hormone liothyronine (T3),
apy is also used to treat specific metastatic lesions,
thereby allowing TSH to increase more quickly. Because
particularly when they cause bone pain or threaten
TSH stimulates Tg levels, Tg measurements should be
neurologic injury (e.g., vertebral metastases).
obtained after administration of rhTSH or when TSH lev-
els have risen after thyroid hormone withdrawal. New Potential Therapies  Kinase inhibitors are
In low-risk patients who have no clinical evidence of being explored as a means to target pathways known
residual disease after ablation and a basal Tg <1 ng/ml, to be active in thyroid cancer, including the Ras, BRAF,
increasing evidence supports the use of rhTSH-stimu- EGFR, VEGFR, and angiogenesis pathways. Partial
lated Tg levels one year after ablation, without the need responses have been seen in small trials using mote-
for radioiodine scanning. If stimulated Tg levels are low saniv, sorafenib, and other agents, but the efficacy of
(<2 ng/ml) and, ideally, undetectable, these patients these agents awaits larger studies.
98 Anaplastic and Other Forms of
commonly identify thyroid nodules. The main goal of
Thyroid Cancer
this evaluation is to identify, in a cost-effective manner,
Anaplastic thyroid cancer the small subgroup of individuals with malignant lesions.
SECTION I

As noted above, ATC is a poorly differentiated and Nodules are more common in iodine-deficient areas,
aggressive cancer. The prognosis is poor, and most in women, and with aging. Most palpable nodules are
patients die within 6 months of diagnosis. Because of >1 cm in diameter, but the ability to feel a nodule is
the undifferentiated state of these tumors, the uptake influenced by its location within the gland (superficial
of radioiodine is usually negligible, but it can be used versus deeply embedded), the anatomy of the patient’s
therapeutically if there is residual uptake. Chemotherapy neck, and the experience of the examiner. More sensi-
Pituitary, Thyroid, and Adrenal Disorders

has been attempted with multiple agents, including tive methods of detection, such as CT, thyroid ultra-
anthracyclines and paclitaxel, but it is usually ineffective. sound, and pathologic studies, reveal thyroid nodules in
External beam radiation therapy can be attempted and >20% of glands. The presence of these thyroid inciden-
continued if tumors are responsive. talomas has led to much debate about how to detect
nodules and which nodules to investigate further. Most
Thyroid lymphoma authorities still rely on physical examination to detect
thyroid nodules, reserving ultrasound for monitoring
Lymphoma in the thyroid gland often arises in the nodule size or as an aid in thyroid biopsy.
background of Hashimoto’s thyroiditis. A rapidly An approach to the evaluation of a solitary nodule is
expanding thyroid mass suggests the possibility of this outlined in Fig. 4-14. Most patients with thyroid nod-
diagnosis. Diffuse large-cell lymphoma is the most ules have normal thyroid function tests. Nonetheless,
common type in the thyroid. Biopsies reveal sheets of thyroid function should be assessed by measuring a TSH
lymphoid cells that can be difficult to distinguish from level, which may be suppressed by one or more autono-
small-cell lung cancer or ATC. These tumors are often mously functioning nodules. If the TSH is suppressed, a
highly sensitive to external radiation. Surgical resec- radionuclide scan is indicated to determine if the iden-
tion should be avoided as initial therapy because it may tified nodule is “hot,” as lesions with increased uptake
spread disease that is otherwise localized to the thyroid. are almost never malignant and FNA is unnecessary.
If staging indicates disease outside of the thyroid, treat- Otherwise, FNA biopsy, ideally performed with ultra-
ment should follow guidelines used for other forms of sound guidance, should be the first step in the evalua-
lymphoma. tion of a thyroid nodule. FNA has good sensitivity and
specificity when performed by physicians familiar with
Medullary Thyroid Carcinoma the procedure and when the results are interpreted by
experienced cytopathologists. The technique is particu-
MTC can be sporadic or familial and accounts for about
larly useful for detecting PTC. The distinction of benign
5% of thyroid cancers. There are three familial forms of
and malignant follicular lesions is often not possible
MTC: MEN 2A, MEN 2B, and familial MTC without
using cytology alone.
other features of MEN (Chap. 23). In general, MTC
In several large studies, FNA biopsies yielded the fol-
is more aggressive in MEN 2B than in MEN 2A, and
lowing findings: 70% benign, 10% malignant or suspi-
familial MTC is more aggressive than sporadic MTC.
cious for malignancy, and 20% nondiagnostic or yielding
Elevated serum calcitonin provides a marker of residual
insufficient material for diagnosis. Characteristic features
or recurrent disease. It is reasonable to test all patients
of malignancy mandate surgery. A diagnosis of follicular
with MTC for RET mutations, as genetic counseling
neoplasm also warrants surgery, as benign and malig-
and testing of family members can be offered to those
nant lesions cannot be distinguished based on cytopa-
individuals who test positive for mutations.
thology or frozen section. The management of patients
The management of MTC is primarily surgical.
with benign lesions is more variable. Many authorities
Unlike tumors derived from thyroid follicular cells,
these tumors do not take up radioiodine. External radia- advocate TSH suppression, whereas others monitor
tion treatment and chemotherapy may provide pallia- nodule size without suppression. With either approach,
tion in patients with advanced disease (Chap. 23). thyroid nodule size should be monitored, ideally using
ultrasound. Repeat FNA is indicated if a nodule enlarges,
and a second biopsy should be performed within
APPROACH TO THE
PATIENT A Thyroid Nodule 2–5 years to confirm the benign status of the nodule.
Nondiagnostic biopsies occur for many reasons,
Palpable thyroid nodules are found in about 5% of including a fibrotic reaction with relatively few cells
adults, but the prevalence varies considerably world- available for aspiration, a cystic lesion in which cellular
wide. Given this high prevalence rate, practitioners components reside along the cyst margin, or a nodule
APPROACH TO PT WITH THYROID NODULE 99
Solitary or suspicious
nodulea

CHAPTER 4
Normal TSH Low TSH Thyroid scan
“Hot” nodule Ablate, resect,
or Rx medically
“Cold” or
FNA, consider indeterminate
US-guided

Cytopathology

Disorders of the Thyroid Gland


17% 69% 10% 4%
Nondiagnostic Benign Suspicious or Malignant
follicular neoplasm
Repeat bx
inadequate
Monitor by US
Consider “Cold” or
indeterminate Surgery
thyroid scan

“Hot” nodule

Surgery if further growth or suspicious cytology

Figure 4-14 
Approach to the patient with a thyroid nodule. See text cystic or mixed solid-cystic. US, ultrasound; TSH, thyroid-
and references for details. aAbout one-third of nodules are stimulating hormone; FNA, fine-needle aspiration.

that may be too small for accurate aspiration. For these The evaluation of a thyroid nodule is stressful for
reasons, ultrasound-guided FNA is indicated when the most patients. They are concerned about the possibility
FNA is repeated. Ultrasound characteristics are also of thyroid cancer, whether verbalized or not. It is con-
useful for deciding which nodules to biopsy when mul- structive, therefore, to review the diagnostic approach
tiple nodules are present. Sonographic characteristics and to reassure patients when no malignancy is found.
suggestive of malignancy include microcalcifications, When a suspicious lesion or thyroid cancer is identified,
increased vascularity, and hypoechogenicity within the the generally favorable prognosis and available treat-
nodule. ment options can be reassuring.
CHAPTER 5

DISORDERS OF THE ADRENAL CORTEX

Wiebke Arlt

The adrenal cortex produces three classes of corticosteroid from gonads and kidneys about the sixth week of gesta-
hormones: glucocorticoids (e.g., cortisol), mineralocorti- tion. Concordant with the time of sexual differentiation
coids (e.g., aldosterone), and adrenal androgen precursors (seventh to ninth week of gestation, see Chap. 7), the
(e.g., dehydroepiandrosterone, DHEA) (Fig. 5-1). Glu- adrenal cortex starts to produce cortisol and the adre-
cocorticoids and mineralocorticoids act through specific nal sex steroid precursor DHEA. The orphan nuclear
nuclear receptors, regulating aspects of the physiologic receptors SF1 (steroidogenic factor 1) and DAX1 (dos-
stress response as well as blood pressure and electrolyte age-sensitive sex reversal gene 1), among others, play
homeostasis. Adrenal androgen precursors are converted in a crucial role during this period of development, as
the gonads and peripheral target cells to sex steroids that act they regulate a multitude of adrenal genes involved in
via nuclear androgen and estrogen receptors. steroidogenesis.
Disorders of the adrenal cortex are characterized
by deficiency or excess of one or several of the three
major corticosteroid classes. Hormone deficiency can RegulAtoRy contRol
be caused by inherited glandular or enzymatic disor- of SteRoidogeneSiS
ders or by destruction of the pituitary or adrenal gland Production of glucocorticoids and adrenal androgens
by autoimmune disorders, infection, infarction, or by is under the control of the hypothalamic-pituitary-
iatrogenic events such as surgery or hormonal suppres- adrenal (HPA) axis, whereas mineralocorticoids are
sion. Hormone excess is usually the result of neoplasia, regulated by the renin-angiotensin-aldosterone (RAA)
leading to increased production of adrenocorticotropic system.
hormone (ACTH) by the pituitary or neuroendocrine Glucocorticoid synthesis is under inhibitory feedback
cells (ectopic ACTH), or increased production of glu- control by the hypothalamus and the pituitary (Fig. 5-2).
cocorticoids or mineralocorticoids by adrenal nodules. Hypothalamic release of corticotropin-releasing hormone
Adrenal nodules are increasingly identified inciden- (CRH) occurs in response to endogenous or exog-
tally during abdominal imaging performed for other enous stress. CRH stimulates the cleavage of the 241–
reasons. amino acid polypeptide pro opiomelanocortin (POMC)
by pituitary-specific prohormone convertase, yielding
ACTH. ACTH is released by the corticotrope cells of
AdRenAl AnAtomy And develoPment
the anterior pituitary and acts as the pivotal regulator of
The normal adrenal glands weigh 6–11 g each. They cortisol synthesis, with additional short-term effects on
are located above the kidneys and have their own blood mineralocorticoid and adrenal androgen synthesis. The
supply. Arterial blood flows initially to the subcapsular release of CRH, and subsequently ACTH, occurs in a
region and then meanders from the outer cortical zona pulsatile fashion that follows a circadian rhythm under
glomerulosa through the intermediate zona fasciculata the control of the hypothalamus, specifically its supra-
to the inner zona reticularis and eventually to the adre- chiasmatic nucleus (SCN), with additional regulation
nal medulla. The right suprarenal vein drains directly by a complex network of cell-specific clock genes.
into the vena cava while the left suprarenal vein drains Reflecting the pattern of ACTH secretion, adrenal cor-
into the left renal vein. tisol secretion exhibits a distinct circadian rhythm, with
During early embryonic development, the adrenals peak levels in the morning and low levels in the evening
originate from the urogenital ridge and then separate (Fig. 5-3).
100
H3C
H 3C

H
101
CH3
H3C H
H3C
H H

CHAPTER 5
HO

Cholesterol

CYP11A1 Glucocorticoid Mineralocorticoid Mineralocorticoids


ADX precursors precursors
O O O O O O
CH3 HO
CH3 CHO
H3C H3C H3C H3C
HO HO HO
OH OH OH OH

Disorders of the Adrenal Cortex


H3C H H3C H H3C H H3C H H3C H H3C H

H H H H H H H H H H H H

O O O
HO POR O ADX O ADX ADX
HSD3B2 CYP21A2 CYP11B2 CYP11B2 CYP11B2
Pregnenolone Progesterone Deoxycortico- Cortico- 18OH-Cortico- Aldosterone
sterone CYP11B1 sterone sterone
POR POR
CYP17A1 CYP17A1
O O O O O
CH3 CH3
H3C H3C H3C H3C H3C
OH OH OH OH HO OH OH O OH OH
H3C H H3C H H3C H H3C H H3C H

H H H H H H H H H H

HO O O O O
POR ADX H6PDH
17-hydroxy- HSD3B2 17-hydroxy- CYP21A2 11- CYP11B1 HSD11B1
pregnenolone progesterone Deoxycortisol Cortisol Cortisone
(17OHP) HSD11B2
POR
CYP17A1
POR Glucocorticoids
O
CYP17A1 O O OH
H3C H3C H3C H3C

H3C H H3C H H3C H H3C H

H H H H H H H H

HO HSD3B2 O O O
H
HSD17B SRD5A
DHEA Andro- Testosterone 5-Dihydrotestosterone
stenedione
PAPSS2
SULT2A1 Adrenal Androgen Androgens
precursors
O
H3C

H3C H

H H

HO
DHEAS

Figure 5-1
Adrenal steroidogenesis. CYP11A1, side chain cleavage 11β-hydroxysteroid dehydrogenase type 2; H6PDH, hexose-
enzyme; CYP17A1, 17α-hydroxylase/17,20 lyase; POR, P450 6-phosphate dehydrogenase; HSD17B, 17β-hydroxysteroid
oxidoreductase; ADX, adrenodoxin; HSD3B2, 3β-hydroxysteroid dehydrogenase; SRD5A, 5α-reductase; SULT2A1, DHEA
dehydrogenase type 2; CYP21A2, 21-hydroxylase; CYP11B1, sulfotransferase; DHEA, dehydroepiandrosterone; DHEAS,
11β-hydroxylase; CYP11B2, aldosterone synthase; HSD11B1, dehydroepiandrosterone sulfate; PAPSS2, PAPS synthase
11β-hydroxysteroid dehydrogenase type 1; HSD11B2, type 2.

Diagnostic tests assessing the HPA axis make use of If cortisol production is driven by an ectopic source of
the fact that it is regulated by negative feedback. Glu- ACTH, the tumors are usually resistant to dexametha-
cocorticoid excess is diagnosed by employing a dexa- sone suppression. Thus, the dexamethasone suppression
methasone suppression test. Dexamethasone, a potent test is useful to establish the diagnosis of Cushing’s syn-
glucocorticoid, suppresses CRH/ACTH and, therefore, drome and to assist with the differential diagnosis of
endogenous cortisol. Various versions of the dexa- cortisol excess.
methasone suppression test are described in detail in Conversely, to assess glucocorticoid deficiency, ACTH
Chap. 2. If cortisol production is autonomous (e.g., stimulation of cortisol production is used. The ACTH pep-
adrenal nodule), ACTH is already suppressed and dexa- tide contains 39 amino acids, but the first 24 are suf-
methasone has little additional effect. If cortisol pro- ficient to elicit a physiologic response. The standard
duction is driven by an ACTH-producing pituitary ACTH stimulation test involves administration of
adenoma, dexamethasone suppression is ineffective at cosyntropin (ACTH 1-24), 0.25 mg IM or IV, and col-
low doses but usually induces suppression at high doses. lection of blood samples at 0, 30, and 60 minutes for
102 cortisol. A normal response is defined as a cortisol level
Stressors
Circadian
(physical, emotional, including >20 μg/dL or an increment of >10 μg/dL over base-
rhythm
fever, hypoglycemia, hypotension) line. A low-dose (1 μg cosyntropin IV) version of this
test has been advocated to avoid overstimulation of
SECTION I

the adrenal gland. Alternatively, an insulin tolerance


test (ITT) can be used to assess adrenal insufficiency.
Neurotransmitters It involves injection of insulin to induce hypoglyce-
mia, which represents a strong stress signal that triggers
hypothalamic CRH release and activation of the entire
HPA axis. The ITT involves administration of regular
Pituitary, Thyroid, and Adrenal Disorders

Hypothalamus
insulin 0.1 U/kg IV (dose should be lower if hypopi-
tuitarism is likely) and collection of blood samples at
0, 30, 60, and 120 minutes for glucose, cortisol, and
– growth hormone (GH), if also assessing the GH axis.
CRH + Oral or IV glucose is administered after the patient has
achieved symptomatic hypoglycemia (usually glucose
<40 mg/dL). A normal response is defined as a cortisol
>20 μg/dL and GH >5.1 μg/L. The ITT requires care-
Anterior
– ful clinical monitoring and sequential measurements of
pituitary
glucose. It is contraindicated in patients with coronary
disease, cerebrovascular disease, or seizure disorders,
which has made the short cosyntropin test the com-
ACTH + Circulating monly accepted first-line test.
Cortisol Mineralocorticoid production is controlled by the
RAA regulatory cycle, which is initiated by the release
of renin from the juxtaglomerular cells in the kidney,
resulting in cleavage of angiotensinogen to angiotensin I
in the liver (Fig. 5-4). Angiotensin-converting enzyme
Adrenal Cortex (ACE) cleaves angiotensin I to angiotensin II, which
Figure 5-2 binds and activates the angiotensin II receptor type 1
Regulation of the hypothalamic-pituitary-adrenal (HPA) (AT1 receptor), resulting in increased aldosterone produc-
axis. CRH, corticotropin-releasing hormone; ACTH, adreno- tion and vasoconstriction. Aldosterone enhances sodium
corticotropic hormone. retention and potassium excretion, and increases the

600

500
Acrophase: 0830 h

400
Cortisol (nmol/L)

300

200
Nadir: 0015 h

100
MESOR: 5.25 µg/dL (145 nmol/L)

0
22 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Clock time

Figure 5-3
Physiologic cortisol circadian rhythm. Circulating corti- levels are observed ∼8:30 a.m. (acrophase). (Modified after
sol concentrations drop under the rhythm-adjusted mean Debono M et al: Modified-release hydrocortisone to provide
(MESOR) in the early evening hours, with nadir levels circadian cortisol profiles. J Clin Endocrinol Metab 94:1548,
around midnight and a rise in the early morning hours; peak 2009.)
103
Circulating blood volume
Kidney

CHAPTER 5
Renal sodium
retention (and
potassium excretion) Renal perfusion
pressure

Disorders of the Adrenal Cortex


Vasoconstriction
Adrenal
Juxtaglomerular
Aldosterone release
cells

Activation of Angiotensinogen
Angiotensin II receptor
type 1 (AT1 receptor)
Renin release

Angiotensin II

Angiotensin I

Angiotensin-
converting
enzyme (ACE)

Figure 5-4
Regulation of the renin-angiotensin-aldosterone (RAA) system.

arterial perfusion pressure, which in turn regulates renin of hormone-sensitive lipase, which cleaves cholesterol
release. Because mineralocorticoid synthesis is primarily esters to cholesterol for import into the mitochondrion;
under the control of the RAA system, hypothalamic- and (3) increases the availability and phosphorylation of
pituitary damage does not significantly impact the capacity CREB (cAMP response element binding), a transcrip-
of the adrenal to synthesize aldosterone. tion factor that enhances transcription of CYP11A1 and
Similar to the HPA axis, the assessment of the RAA other enzymes required for glucocorticoid synthesis.
system can be used for diagnostic purposes. If mineralo- Adrenal steroidogenesis occurs in a zone-specific
corticoid excess is present, there is a counter-regulatory fashion, with mineralocorticoid synthesis occurring in
downregulation of plasma renin (see below for testing). the outer zona glomerulosa, glucocorticoid synthesis
Conversely, in mineralocorticoid deficiency, plasma in the zona fasciculata, and adrenal androgen synthesis
renin is markedly increased. Physiologically, oral or IV in the inner zona reticularis (Fig. 5-1). All steroidogenic
sodium loading results in suppression of aldosterone, pathways require cholesterol import into the mitochon-
a response that is attenuated or absent in patients with drion, a process initiated by the action of the steroido-
autonomous mineralocorticoid excess. genic acute regulatory (StAR) protein, which shuttles
cholesterol from the outer to the inner mitochondrial
membrane. The majority of steroidogenic enzymes
Steroid Hormone Synthesis,
are cytochrome P450 (CYP) enzymes, which are
Metabolism, and Action
either located in the mitochondrion (side chain cleav-
ACTH stimulation is required for the initiation of ste- age enzyme, CYP11A1; 11β-hydroxylase, CYP11B1;
roidogenesis. The ACTH receptor MC2R (melanocortin aldosterone synthase, CYP11B2) or in the endoplasmic
2 receptor) interacts with the MC2R-accessory protein reticulum membrane (17α-hydroxylase, CYP17A1;
MRAP, and the complex is transported to the adre- 21-hydroxylase, CYP21A2; aromatase, CYP19A1).
nocortical cell membrane, where it binds to ACTH These enzymes require electron donation via specific
(Fig. 5-5). ACTH stimulation generates cyclic AMP redox cofactor enzymes, P450 oxidoreductase (POR),
(cAMP), which upregulates the protein kinase A and adrenodoxin/adrenodoxin reductase (ADX/ADR)
(PKA) signaling pathway. PKA activation impacts ste- for the microsomal and mitochondrial CYP enzymes,
roidogenesis in three distinct ways: (1) increases the respectively. In addition, the short-chain dehydrogenase
import of cholesterol esters; (2) increases the activity 3β-hydroxysteroid dehydrogenase type 2 (3β-HSD2),
104 Adrenal cortex cell
Cholesterol
ester
Cell membrane
SECTION I

ACTH Scavenger
receptor B1
ATP Cytosol

ACTH Adenylate cAMP Protein


cyclase Kinase A Cholesterol
γ
β ester
Gsα N
Hormone-
MC2R sensitive
N lipase Cholesterol
Pituitary, Thyroid, and Adrenal Disorders

C C CREB StAR
N
C Mitochondrion
C
N
N C
N Endoplasmic
MRAP reticulum
C
P Nucleus CYP11A1
CREB
CRE Pregnenolone

Transcription of CYP11A1
and other steroidogenic
enzymes

Figure 5-5
ACTH effects on adrenal steroidogenesis. ACTH, adreno- binding; MRAP, MC2R-accessory protein; StAR, steroido-
corticotropic hormone; ATP, adenosine triphosphate; CRE, genic acute regulatory (protein).
cAMP response element; CREB, cAMP response element

also termed Δ4,Δ5 isomerase, plays a major role in adre- unbound hormone. Free cortisol is thought to enter
nal steroidogenesis. cells directly, not requiring active transport. In addi-
The cholesterol side chain cleavage enzyme CYP11A1 tion, in a multitude of peripheral target tissues of glu-
generates pregnenolone. Glucocorticoid synthesis requires cocorticoid action, including adipose, liver, muscle,
conversion of pregnenolone to progesterone by 3β-HSD2, and brain, cortisol is generated from inactive cortisone
followed by conversion to 17-hydroxyprogesterone within the cell by the enzyme 11β-hydroxysteroid
by CYP17A1, further hydroxylation at carbon 21 by dehydrogenase type 1 (11β-HSD1) (Fig. 5-6). Thereby,
21-hydroxylase, and eventually, 11β-hydroxylation by 11β-HSD1 functions as a tissue-specific prereceptor
CYP11B1 to generate active cortisol (Fig. 5-1). Miner- regulator of glucocorticoid action. For the conver-
alocorticoid synthesis also requires progesterone, which sion of inactive cortisone to active cortisol, 11β-HSD1
is first converted to deoxycorticosterone by CYP21A2 requires nicotinamide adenine dinucleotide phosphate
and then converted via corticosterone and 18-hydroxy- [NADPH (reduced form)], which is provided by the
corticosterone to aldosterone in three steps catalyzed by enzyme hexose-6-phosphate dehydrogenase (H6PDH).
CYP11B2. For adrenal androgen synthesis, pregnenolone Like the catalytic domain of 11β-HSD1, H6PDH is
undergoes conversion by CYP17A1, which uniquely located in the lumen of the endoplasmic reticulum,
catalyzes two enzymatic reactions. Via its 17α-hydroxylase and converts glucose-6-phosphate (G6P) to 6-phos-
activity, CYP17A1 converts pregnenolone to 17-hydroxy­ phogluconate (6PGL), thereby regenerating NADP+
pregnenolone, followed by generation of the universal to NADPH, which drives the activation of cortisol
sex steroid precursor DHEA via CYP17A1 17,20 lyase from cortisone by 11β-HSD1.
activity. The majority of DHEA is secreted by the adre- In the cytosol of target cells, cortisol binds and
nal in the form of its sulfate ester, DHEAS, generated by activates the glucocorticoid receptor (GR), which
DHEA sulfotransferase (SULT2A1). results in dissociation of heat shock proteins (HSPs) from
Following its release from the adrenal, cortisol the receptor and subsequent dimerization (Fig. 5-6).
circulates in the bloodstream mainly bound to corti- Cortisol-bound GR dimers translocate to the nucleus
sol-binding globulin (CBG) and to a lesser extent to and activate glucocorticoid response elements (GREs)
albumin, with only a minor fraction circulating as free, in the DNA sequence, thereby enhancing transcription
Glucocorticoid target cell 105
Cytosol

CHAPTER 5
GR
Cortisone

Cortisol
GR HSP

11β-HSD1 Coactivator
Endoplasmic complex

Disorders of the Adrenal Cortex


reticulum
NADPH NADP+ Nucleus
Nucleus
GR AP-1 GR GR
G6P or GRE

H6PDH 6PGL No Transcription Transcription

GR Transrepression GR Transactivation

Figure 5-6
Prereceptor activation of cortisol and glucocorticoid HSP, heat shock protein; NADPH, nicotinamide adenine
receptor (GR) action. GRE, glucocorticoid response element; dinucleotide phosphate (reduced form).

of glucocorticoid-regulated genes (GR transactivation). Analogous to cortisol action via the GR, aldoste-
However, cortisol-bound GR can also form heterodi- rone (or cortisol) binding to the MR dissociates the
mers with transcription factors such as AP-1 or NF-κB, HSP–receptor complex, allowing homodimerization
resulting in transrepression of proinflammatory genes, of the MR, and translocation of the hormone-bound
a mechanism of major importance for the anti-inflam- MR dimer to the nucleus (Fig. 5-7). The activated MR
matory action of glucocorticoids. It is important to note enhances transcription of the epithelial sodium chan-
that corticosterone also exerts glucocorticoid activity, nel (ENaC) and serum glucocorticoid-inducible kinase
albeit much weaker than cortisol itself. However, in 1 (SGK-1). In the cytosol, interaction of ENaC with
rodents corticosterone is the major glucocorticoid and Nedd4 prevents cell surface expression of ENaC. How-
in patients with 17-hydroxylase deficiency, lack of cor- ever, SGK-1 phosphorylates serine residues within the
tisol can be compensated for by higher concentrations Nedd4 protein, reduces the interaction between Nedd4
of corticosterone that accumulates as a consequence of and ENaC, and consequently enhances the trafficking
the enzymatic block. of ENaC to the cell surface, where it mediates sodium
Cortisol is inactivated to cortisone by the microsomal retention.
enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-
HSD2) (Fig. 5-7), mainly in the kidney, but also in the
Cushing’S Syndrome
colon, salivary glands, and other target tissues. Cortisol
and aldosterone bind the mineralocorticoid receptor (See also Chap. 2) Cushing’s syndrome reflects a con-
(MR) with equal affinity; however, cortisol circulates in stellation of clinical features that result from chronic
the bloodstream at about a thousandfold higher concen- exposure to excess glucocorticoids of any etiology.
tration. Thus, only rapid inactivation of cortisol to cor- The disorder can be ACTH dependent (e.g., pituitary
tisone by 11β-HSD2 prevents MR activation by excess corticotrope adenoma, ectopic secretion of ACTH by
cortisol, thereby acting as a tissue-specific modulator nonpituitary tumor) or ACTH independent (e.g., adre-
of the MR pathway. In addition to cortisol and aldo- nocortical adenoma, adrenocortical carcinoma, nodular
sterone, deoxycorticosterone (DOC) (Fig. 5-1) also adrenal hyperplasia), as well as iatrogenic (e.g., admin-
exerts mineralocorticoid activity. DOC accumulation istration of exogenous glucocorticoids to treat various
due to 11β-hydroxylase deficiency or due to tumor- inflammatory conditions). The term Cushing’s disease
related excess production can result in mineralocorti- refers specifically to Cushing’s syndrome caused by a
coid excess. pituitary corticotrope adenoma.
106 Kidney distal convoluted tubule cell

Blood Lumen
(basal site) (apical site)
SECTION I

Cytosol
Aldosterone

Cortisol
MR HSP
Cortisone MR
11β_HSD2
NAD+ MR
Pituitary, Thyroid, and Adrenal Disorders

MR
NADH
MR SGK-1
MR
ENaC Na+
ER Lumen Nedd4
Nucleus ENaC Na+

aC
EN
MR MR
HRE

Transcription Nedd4
of ENaC and
ENaC
SGK-1

Figure 5-7