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 4th Edition

’
HARRISON S
TM

ENDO CRINO LO GY
 Derived from Harrison’s Principles of Internal Medicine, 19th Edition
Editors
DENNISL. KASPER, md
William Ellery Channing Pro essor o Medicine, Pro essor o
Microbiology and Immunobiology, Department o Microbiology
and Immunobiology, Harvard Medical School; Division o
In ectious Diseases, Brigham and Women’s Hospital
Boston, Massachusetts
STEPHENL. HAUSER, md
Robert A. Fishman Distinguished Pro essor and Chairman,
Department o Neurology, University o Cali ornia, San Francisco
San Francisco, Cali ornia
J. LARRYJAMESON, md, phd
Robert G. Dunlop Pro essor o Medicine;
Dean, Perelman School o Medicine at the University o Pennsylvania;
Executive Vice-President, University o Pennsylvania or the
Health System, Philadelphia, Pennsylvania
ANTHONYS. FAUCI, md
Chie , Laboratory o Immunoregulation; Director, National
Institute o Allergy and In ectious Diseases, National Institutes o
Health, Bethesda, Maryland
DANL. LONGO, md
Pro essor o Medicine, Harvard Medical School; Senior Physician,
Brigham and Women’s Hospital; Deputy Editor, New England
Journal o Medicine, Boston, Massachusetts
JOSEPHLOSCALZO, md, phd
Hersey Pro essor o the T eory and Practice o Medicine, Harvard
Medical School; Chairman, Department o Medicine, and
Physician-in-Chie , Brigham and Women’s Hospital,
Boston, Massachusetts
 4th Edition

’
HARRISON S
TM

ENDO CRINO LO GY

EDITOR
J. Larry Jameson, MD, PhD
Robert G. Dunlop Pro essor o Medicine;
Dean, Perelman School o Medicine at the University o Pennsylvania;
Executive Vice-President, University o Pennsylvania or the
Health System, Philadelphia, Pennsylvania

CONTENTS

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 CONTENTS

Contributors vii 12 esticular Cancer 186

Robert J. Motzer, Darren R. Feldman,
Pre ace ix George J. Bosl
13 Disorders o the Female
SECTION I
Reproductive System 192
INTRODUCTION TO ENDOCRINOLOGY Janet E. Hall
1 Approach to the Patient with 14 In ertility and Contraception 202
Endocrine Disorders 2 Janet E. Hall
J. Larry Jameson
15 Menstrual Disorders and Pelvic Pain 209
2 Mechanisms o Hormone Action 8 Janet E. Hall
J. Larry Jameson
16 Menopause and Postmenopausal
Hormone T erapy 215
SECTION II
JoAnn E. Manson, Shari S. Bassuk
PITUITARY, THYROID, AND ADRENAL
DISORDERS 17 Hirsutism 226
David A. Ehrmann
3 Anterior Pituitary: Physiology o Pituitary
Hormones 18 18 Gynecologic Malignancies 232
Shlomo Melmed, J. Larry Jameson Michael V. Seiden

4 Hypopituitarism 25 19 Sexual Dys unction 241

Shlomo Melmed, J. Larry Jameson Kevin . McVary

5 Anterior Pituitary umor Syndromes 35

Shlomo Melmed, J. Larry Jameson SECTION IV
DIABETES MELLITUS, OBESITY, LIPOPROTEIN
6 Disorders o the Neurohypophysis 55 METABOLISM
Gary L. Robertson
20 Biology o Obesity 252
7 Disorders o the T yroid Gland 68 Je rey S. Flier, Elef heria Maratos-Flier
J. Larry Jameson, Susan J. Mandel,
Anthony P. Weetman 21 Evaluation and Management o Obesity 262
Robert F. Kushner
8 Disorders o the Adrenal Cortex 107
Wiebke Arlt 22 T e Metabolic Syndrome 272
Robert H. Eckel
9 Pheochromocytoma 136
Hartmut P. H. Neumann 23 Diabetes Mellitus: Diagnosis, Classif cation, and
Pathophysiology 280
Alvin C. Powers
SECTION III
REPRODUCTIVE ENDOCRINOLOGY 24 Diabetes Mellitus: Management and T erapies 293
Alvin C. Powers
10 Disorders o Sex Development 146
John C. Achermann, J. Larry Jameson 25 Diabetes Mellitus: Complications 317
Alvin C. Powers
11 Disorders o the estes and Male Reproductive
System 159 26 Hypoglycemia 329
Shalender Bhasin, J. Larry Jameson Philip E. Cryer, Stephen N. Davis

v
 vi Contents

27 Disorders o Lipoprotein Metabolism 339 33 Hypercalcemia and Hypocalcemia 442

Daniel J. Rader, Helen H. Hobbs Sundeep Khosla
34 Disorders o the Parathyroid Gland
SECTION V and Calcium Homeostasis 446
DISORDERS AFFECTING MULTIPLE John . Potts, Jr., Harald Jüppner
ENDOCRINE SYSTEMS
35 Osteoporosis 480
28 Endocrine umors o the Gastrointestinal ract Robert Lindsay, Felicia Cosman
and Pancreas 362
Robert . Jensen 36 Paget’s Disease and Other Dysplasias o Bone 503
Murray J. Favus, amara J. Vokes
29 Multiple Endocrine Neoplasia 390
Appendix
Rajesh V. T akker
Laboratory Values o Clinical Importance . . . . . 515
30 Autoimmune Polyendocrine Syndromes 405 Alexander Kratz, Michael A. Pesce,
Peter A. Gottlieb Robert C. Basner, Andrew J. Einstein

31 Paraneoplastic Syndromes: Endocrinologic/ Review and Sel -Assessment . . . . . . . . . . . . . . . . . . . . 533

Hematologic 413 Charles M. Wiener, Cynthia D. Brown,
J. Larry Jameson, Dan L. Longo Brian Houston
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
SECTION VI
DISORDERS OF BONE AND CALCIUM
METABOLISM
32 Bone and Mineral Metabolism in Health
and Disease 424
F. Richard Bringhurst, Marie B. Demay,
Stephen M. Krane, Henry M. Kronenberg
 CONTRIBUTORS
Numbers in brackets re er to the chapter(s) written or co-written by the contributor.
John C Achermann, MD, PhD, MB
Wellcome rust Senior Research Fellow in Clinical Science,
University College London; Pro essor o Paediatric Endocrinology,
UCL Institute o Child Health, University College London, London,
United Kingdom [10]
Wiebke Arlt, MD, DSc, FRCP, FMedSci
Pro essor o Medicine, Centre or Endocrinology, Diabetes and
Metabolism, School o Clinical and Experimental Medicine,
University o Birmingham; Consultant Endocrinologist, University
Hospital Birmingham, Birmingham, United Kingdom [8]
Robert C Basner, MD
Pro essor o Clinical Medicine, Division o Pulmonary, Allergy, and
Critical Care Medicine, Columbia University College o Physicians
and Surgeons, New York, New York [Appendix]
Shari S Bassuk, ScD
Epidemiologist, Division o Preventive Medicine, Brigham and
Women’s Hospital, Boston, Massachusetts [16]
Shalender Bhasin, MBBS
Pro essor o Medicine, Harvard Medical School; Director, Research
Program in Men’s Health: Aging and Metabolism; Director, Boston
Claude D. Pepper Older Americans Independence Center; Site
Director, Harvard Catalyst Clinical Research Center at BWH,
Brigham and Women’s Hospital, Boston, Massachusetts [11]
George J Bosl, MD
Pro essor o Medicine, Weill Cornell Medical College; Chair,
Department o Medicine; Patrick M. Byrne Chair in Clinical
Oncology, Memorial Sloan-Kettering Cancer Center, New York,
New York [12]
F Richard Bringhurst, MD
Associate Pro essor o Medicine, Harvard Medical School;
Physician, Massachusetts General Hospital, Boston,
Massachusetts [32]
Cynthia D Brown, MD
Associate Pro essor o Clinical Medicine, Division o Pulmonary,
Critical Care, Sleep and Occupational Medicine, Indiana University,
Indianapolis, Indiana [Review and Sel -Assessment]
Felicia Cosman, MD
Pro essor o Medicine, Columbia University College o Physicians
and Surgeons, New York, New York [35]
Philip E Cryer, MD
Pro essor o Medicine Emeritus, Washington University in St.
Louis; Physician, Barnes-Jewish Hospital, St. Louis, Missouri [26]
Stephen N Davis, MBBS, FRCP
T eodore E. Woodward Pro essor and Chairman o the Department
o Medicine, University o Maryland School o Medicine; Physician-
in-Chie , University o Maryland Medical Center, Baltimore,
Maryland [26]
vii
Marie B Demay, MD
Pro essor o Medicine, Harvard Medical School; Physician,
Massachusetts General Hospital, Boston, Massachusetts [32]
Robert H Eckel, MD
Pro essor o Medicine, Division o Endocrinology, Metabolism
and Diabetes, Division o Cardiology; Pro essor o Physiology
and Biophysics, Charles A. Boettcher, II Chair in Atherosclerosis,
University o Colorado School o Medicine, Anschutz Medical
Campus, Director Lipid Clinic, University o Colorado Hospital,
Aurora, Colorado [22]
David A Ehrmann, MD
Pro essor, Department o Medicine, Section o Endocrinology,
Diabetes, and Metabolism, T e University o Chicago Pritzker
School o Medicine, Chicago, Illinois [17]
Andrew J Einstein, MD, PhD
Victoria and Esther Aboodi Assistant Pro essor o Medicine;
Director, Cardiac C Research; Co-Director, Cardiac C and
MRI, Department o Medicine, Cardiology Division, Department
o Radiology, Columbia University College o Physicians and
Surgeons, New York-Presbyterian Hospital, New York, New York
[Appendix]
Murray J Favus, MD
Pro essor o Medicine, Department o Medicine, Section o
Endocrinology, Diabetes and Metabolism, Director Bone
Program, University o Chicago Pritzker School o Medicine,
Chicago, Illinois [36]
Darren R Feldman, MD
Associate Pro essor in Medicine, Weill Cornell Medical Center;
Assistant Attending, Genitourinary Oncology Service, Memorial
Sloan-Kettering Cancer Center, New York, New York [12]
Je rey S Flier, MD
Caroline Shields Walker Pro essor o Medicine and Dean, Harvard
Medical School, Boston, Massachusetts [20]
Peter A Gottlieb, MD
Pro essor o Pediatrics and Medicine, Barbara Davis Center,
University o Colorado School o Medicine, Aurora, Colorado [30]
Janet E Hall, MD, MSc
Pro essor o Medicine, Harvard Medical School and Associate
Chie , Reproductive Endocrine Unit, Massachusetts General
Hospital, Boston, Massachusetts [13–15]
Helen H Hobbs, MD
Pro essor, Internal Medicine and Molecular Genetics, University o
exas Southwestern Medical Center; Investigator, Howard Hughes
Medical Institute, Dallas, exas [27]
Brian Houston, MD
Division o Cardiology, Department o Medicine, Johns Hopkins
Hospital, Baltimore, Maryland [Review and Sel -Assessment]
 viii Contributors
J Larry Jameson
Robert G. Dunlop Pro essor o Medicine;
Dean, Perelman School o Medicine at the University o Pennsylvania;
Executive Vice-President, University o Pennsylvania or the
Health System, Philadelphia, Pennsylvania [1–5, 7, 10, 11, 31]
Robert Jensen, MD
Chie , Cell Biology Section, National Institutes o Diabetes, Diges-
tive and Kidney Diseases, National Institutes o Health, Bethesda,
Maryland [28]
Harald Jüppner, MD
Pro essor o Pediatrics, Endocrine Unit and Pediatric Nephrology
Unit, Massachusetts General Hospital, Boston, Massachusetts [34]
Sundeep Khosla, MD
Pro essor o Medicine and Physiology, College o Medicine, Mayo
Clinic, Rochester, Minnesota [33]
Stephen M Krane, MD
Persis, Cyrus and Marlow B. Harrison Distinguished Pro essor
o Medicine, Harvard Medical School; Massachusetts General
Hospital, Boston, Massachusetts [32]
Alexander Kratz, MD, MPH, PhD
Associate Pro essor o Clinical Pathology and Cell
Biology, Columbia University College o Physicians and Surgeons;
Director, Core Laboratory, Columbia University Medical
Center and the New York Presbyterian Hospital; Director, the Allen
Hospital Laboratory, New York, New York [Appendix]
Henry M Kronenberg, MD
Pro essor o Medicine, Harvard Medical School; Chie , Endocrine
Unit, Massachusetts General Hospital, Boston, Massachusetts [32]
Robert F Kushner, MD, MS
Pro essor o Medicine, Northwestern University Feinberg School o
Medicine, Chicago, Illinois [21]
Robert Lindsay, MD, PhD
Chie , Internal Medicine; Pro essor o Clinical Medicine, Helen
Hayes Hospital, West Haverstraw, New York [35]
Dan L Longo, MD
Pro essor o Medicine, Harvard Medical School; Senior Physician,
Brigham and Women’s Hospital; Deputy Editor, New England
Journal o Medicine, Boston, Massachusetts [31]
Susan J Mandel, MD, MPH
Pro essor o Medicine; Associate Chie , Division o Endocrinology,
Diabetes and Metabolism, Perelman School o Medicine, University
o Pennsylvania, Philadelphia, Pennsylvania [7]
JoAnn E Manson, MD, DrPH
Pro essor o Medicine and the Elizabeth Fay Brigham Pro essor
o Women’s Health, Harvard Medical School; Chie , Division o
Preventive Medicine, Brigham and Women’s Hospital, Boston,
Massachusetts [16]
Elef heria Maratos-Flier, MD
Pro essor o Medicine, Harvard Medical School; Division o
Endocrinology, Beth Israel Deaconess Medical Center, Boston,
Massachusetts [20]
Kevin McVary, MD, FACS
Pro essor and Chairman, Division o Urology, Southern Illinois
University School o Medicine, Spring eld, Illinois [19]
Shlomo Melmed, MD
Senior Vice President and Dean o the Medical Faculty,
Cedars-Sinai Medical Center, Los Angeles, Cali ornia [3–5]
Robert J Motzer, MD
Pro essor o Medicine, Joan and San ord Weill College o Medicine
o Cornell University D. Attending Physician, Genitourinary
Oncology Service, Memorial Sloan-Kettering Cancer Center, New
York, New York [12]
Hartmut P H Neumann, MD
Universitaet Freiburg, Medizinische Universitaetsklinik, Freiburg
im Breisgau, Germany [9]
Michael A Pesce, PhD
Pro essor Emeritus o Pathology and Cell Biology, Columbia
University College o Physicians and Surgeons; Director,
Biochemical Genetics Laboratory, Columbia University Medical
Center, New York Presbyterian Hospital, New York, New York
[Appendix]
John Potts, Jr , MD
Jackson Distinguished Pro essor o Clinical Medicine, Harvard
Medical School; Physician-in-Chie and Director o Research
Emeritus, Massachusetts General Hospital, Boston, Massachusetts [34]
Alvin C Powers, MD
Joe C. Davis Chair in Biomedical Science; Pro essor o Medicine,
Molecular Physiology and Biophysics; Director, Vanderbilt
Diabetes Center; Chie , Division o Diabetes, Endocrinology, and
Metabolism, Vanderbilt University School o Medicine, Nashville,
ennessee [23–25]
Daniel J Rader, MD
Seymour Gray Pro essor o Molecular Medicine; Chair, Department
o Genetics; Chie , Division o ranslational Medicine and Human
Genetics, Department o Medicine, Perelman School o Medicine at
the University o Pennsylvania, Philadelphia, Pennsylvania [27]
Gary L Robertson, MD
Emeritus Pro essor o Medicine, Northwestern University School o
Medicine, Chicago, Illinois [6]
Michael V Seiden, MD, PhD
Chie Medical O cer, McKesson Specialty Health, T e Woodlands,
exas [18]
Rajesh V T akker, MD, FMedSci, FR
May Pro essor o Medicine, Academic Endocrine Unit, University
o Ox ord; O.C.D.E.M., Churchill Hospital, Headington, Ox ord,
United Kingdom [29]
amara J Vokes, MD
Pro essor, Department o Medicine, Section o Endocrinology,
University o Chicago, Chicago, Illinois [36]
Anthony P Weetman, MD, DSc
University o She eld, School o Medicine She eld, She eld,
United Kingdom [7]
Charles M Wiener, MD
Vice President o Academic A airs, Johns Hopkins Medicine Interna-
tional, Pro essor o Medicine and Physiology, Johns Hopkins School o
Medicine, Baltimore, Maryland [Review and Sel -Assessment]
 PREFACE
Harrison’s Principles o Internal Medicine has been a
respected source o medical in ormation or students,
residents, internists, amily physicians, and other health
care providers or many decades. T is book, Harrison’s
Endocrinology, now in its ourth edition, is a compila-
tion o chapters related to the specialty o endocrinol-
ogy, a eld that includes some o the most commonly
encountered diseases such as diabetes mellitus, obesity,
thyroid disorders, and metabolic bone disease.
Our readers consistently note the practical value o
the specialty sections o Harrison’s. Speci cally, these
sections include a rigorous explanation o pathophysiol-
ogy as a background or di erential diagnosis and patient
management. Our goal was to bring this in ormation to
readers in a more compact and usable orm. Because
the topic is more ocused, it is possible to improve the
presentation o the material by enlarging the text and
the tables and providing clearly illustrated gures that
elucidate challenging concepts. We have also included a
Review and Sel -Assessment section that includes ques-
tions and answers to provoke re ection and to provide
additional teaching points.
T e clinical mani estations o endocrine disorders
can usually be explained by considering the physiologic
role o hormones, which are either de cient or exces-
sive. T us, a thorough understanding o hormone action
and principles o hormone eedback arms the clini-
cian with a logical diagnostic approach and a concep-
tual ramework or treating patients. T e rst chapter
o the book, Approach to the Patient with Endocrine
Disorders, provides this type o “systems” overview.
Using numerous examples o translational research, this
introduction links genetics, cell biology, and physiology
with pathophysiology and treatment. T e integration
o pathophysiology with clinical management is a hall-
mark o Harrison’s, and can be ound throughout each
o the subsequent disease-oriented chapters. T e book is
divided into six main sections that re ect the physiologic
roots o endocrinology: (I) Introduction to Endocrinol-
ogy; (II) Pituitary, T yroid, and Adrenal Disorders; (III)
ix
Reproductive Endocrinology; (IV) Diabetes Mellitus,
Obesity, Lipoprotein Metabolism; (V) Disorders A ect-
ing Multiple Endocrine Systems; and (VI) Disorders o
Bone and Calcium Metabolism.
While Harrison’s Endocrinology is classic in its organi-
zation, readers will sense the impact o scienti c advances
as they explore the individual chapters in each section.
In addition to the dramatic discoveries emanating rom
genetics and molecular biology, the introduction o
an unprecedented number o new drugs, particularly
or the management o diabetes, hypogonadism, and
osteoporosis, is trans orming the eld o endocrinology.
Numerous recent clinical studies involving common
diseases like diabetes, obesity, hypothyroidism, hypo-
gonadism, and osteoporosis provide power ul evidence
or medical decision making and treatment. T ese rapid
changes in endocrinology are exciting or new students
o medicine and underscore the need or practicing phy-
sicians to continuously update their knowledge base and
clinical skills.
Our access to in ormation through web-based jour-
nals and databases is remarkably e cient, but also
daunting, creating a need or books that synthesize con-
cepts and highlight important acts. T e preparation o
these chapters is there ore a special craf that requires
distillation o core in ormation rom the ever-expanding
knowledge base. T e editors are indebted to our authors,
a group o internationally recognized authorities who
are masters at providing a comprehensive overview
while being able to distill a topic into a concise and inter-
esting chapter. We are also indebted to our colleagues at
McGraw-Hill. Jim Shanahan is a tireless champion or
Harrison’s, and these books were impeccably produced
by Kim Davis.
We hope you nd this book use ul in your e ort to
achieve continuous learning on behal o your patients.
J. Larry Jameson, MD, PhD
 NOTICE
Medicine is an ever-changing science. As new research and clinical expe-
rience broaden our knowledge, changes in treatment and drug therapy are
required. T e authors and the publisher o this work have checked with
sources believed to be reliable in their e orts to provide in ormation that is
complete and generally in accord with the standards accepted at the time o
publication. However, in view o the possibility o 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 o this work war-
rants that the in ormation contained herein is in every respect accurate or
complete, and they disclaim all responsibility or any errors or omissions or
or the results obtained rom use o the in ormation contained in this work.
Readers are encouraged to con rm the in ormation contained herein with
other sources. For example and in particular, readers are advised to check the
product in ormation sheet included in the package o each drug they plan to
administer to be certain that the in ormation contained in this work is accu-
rate and that changes have not been made in the recommended dose or in the
contraindications or administration. T is recommendation is o particular
importance in connection with new or in requently used drugs.

Review and sel -assessment questions and answers were taken rom Wiener CM,
Brown CD, Houston B (eds). Harrison’s Sel -Assessment and Board Review, 19th ed.
New York, McGraw-Hill, 2017, ISBN 978-1-259-64288-3 .

T e global icons call greater attention to key epidemiologic and clinical di erences in the practice o medicine
throughout the world.

T e genetic icons identi y a clinical issue with an explicit genetic relationship.

 SECTION I

INTRODUCTION TO
ENDOCRINOLOGY
 CH AP TER 1
APPROACH TO THE PATIENT WITH
ENDOCRINE DISORDERS
J. La rry Ja m e so n
T e management o endocrine disorders requires
a broad understanding o intermediary metabo-
lism, reproductive physiology, bone metabolism, and
growth. Accordingly, the practice o endocrinology
is intimately linked to a conceptual ramework or
understanding hormone secretion, hormone action,
and principles o eedback control (Chap. 2). T e
endocrine system is evaluated primarily by measuring
hormone concentrations, arming the clinician with
valuable diagnostic in ormation. Most disorders o the
endocrine system are amenable to e ective treatment
once the correct diagnosis is determined. Endocrine
de ciency disorders are treated with physiologic hor-
mone replacement; hormone excess conditions, which
usually are caused by benign glandular adenomas, are
managed by removing tumors surgically or reducing
hormone levels medically.
SCO P E O F ENDO CRINO LO GY
T e specialty o endocrinology encompasses the study
o glands and the hormones they produce. T e term
endocrine was coined by Starling to contrast the actions
o hormones secreted internally (endocrine) with those
secreted externally (exocrine) or into a lumen, such as
the gastrointestinal tract. T e term hormone, derived
rom a Greek phrase meaning “to set in motion,” aptly
describes the dynamic actions o hormones as they
elicit cellular responses and regulate physiologic pro-
cesses through eedback mechanisms.
Unlike many other specialties in medicine, it is not
possible to de ne endocrinology strictly along anatomic
lines. T e classic endocrine glands—pituitary, thyroid,
parathyroid, pancreatic islets, adrenals, and gonads—
communicate broadly with other organs through the
nervous system, hormones, cytokines, and growth
2
actors. In addition to its traditional synaptic unctions,
the brain produces a vast array o peptide hormones,
and this has led to the discipline o neuroendocrinol-
ogy. T rough the production o hypothalamic releas-
ing actors, the central nervous system (CNS) exerts
a major regulatory in uence over pituitary hormone
secretion (Chap. 3). T e peripheral nervous system
stimulates the adrenal medulla. T e immune and endo-
crine systems are also intimately intertwined. T e adre-
nal hormone cortisol is a power ul immunosuppressant.
Cytokines and interleukins (ILs) have pro ound e ects
on the unctions o the pituitary, adrenal, thyroid, and
gonads. Common endocrine diseases such as autoim-
mune thyroid disease and type 1 diabetes mellitus are
caused by dysregulation o immune surveillance and
tolerance. Less common diseases such as polyglandular
ailure, Addison’s disease, and lymphocytic hypophysitis
also have an immunologic basis.
T e interdigitation o endocrinology with physi-
ologic processes in other specialties sometimes blurs
the role o hormones. For example, hormones play
an important role in maintenance o blood pressure,
intravascular volume, and peripheral resistance in the
cardiovascular system. Vasoactive substances such as
catecholamines, angiotensin II, endothelin, and nitric
oxide are involved in dynamic changes o vascular tone
in addition to their multiple roles in other tissues. T e
heart is the principal source o atrial natriuretic pep-
tide, which acts in classic endocrine ashion to induce
natriuresis at a distant target organ (the kidney). Eryth-
ropoietin, a traditional circulating hormone, is made
in the kidney and stimulates erythropoiesis in bone
marrow. T e kidney is also integrally involved in the
renin-angiotensin axis (Chap. 8) and is a primary target
o several hormones, including parathyroid hormone
(P H), mineralocorticoids, and vasopressin. T e gas-
trointestinal tract produces a surprising number o
peptide hormones, such as cholecystokinin, ghrelin, hormones, are used in numerous physiologic processes, 3
gastrin, secretin, and vasoactive intestinal peptide, including vision, smell, and neurotransmission.
among many others. Carcinoid and islet tumors can
secrete excessive amounts o these hormones, lead-

C
H
ing to speci c clinical syndromes (Chap. 28). Many o

A
PATHO LO GIC MECHANISMS O F

P
T
these gastrointestinal hormones are also produced in

E
ENDO CRINE DISEASE

R
the CNS, where their unctions are poorly understood.

1
Adipose tissue produces leptin, which acts centrally to Endocrine diseases can be divided into three major
control appetite, along with adiponectin, resistin, and types o conditions: (1) hormone excess, (2) hormone
other hormones that regulate metabolism. As hormones

A
de ciency, and (3) hormone resistance (Table 1-1).

p
p
such as inhibin, ghrelin, and leptin are discovered, they

r
o
a
become integrated into the science and practice o med-

c
h
icine on the basis o their unctional roles rather than

t
o
CAUSES OF HORMONE EXCESS

t
their tissues o origin.

h
e
P
Characterization o hormone receptors requently Syndromes o hormone excess can be caused by neo-

a
t
i
reveals unexpected relationships to actors in nonen- plastic growth o endocrine cells, autoimmune dis-

e
n
t
docrine disciplines. T e growth hormone (GH) and orders, and excess hormone administration. Benign

w
i
t
leptin receptors, or example, are members o the cyto- endocrine tumors, including parathyroid, pituitary,

h
E
n
kine receptor amily. T e G protein–coupled receptors and adrenal adenomas, o en retain the capacity to pro-

d
o
(GPCRs), which mediate the actions o many peptide duce hormones, perhaps re ecting the act that these

c
r
i
n
e
D
i
s
o
r
d
TABLE 1 -1

e
r
s
CAUSES OF ENDOCRINE DYSFUNCTION
TYPE OF ENDOCRINE DISORDER EXAMPLES

Hyp e r fu n ct io n
Neoplastic
Benign Pituitary adenomas, hyperparathyroidism, autonomous thyroid or adrenal nodules,
pheochromocytoma
Malignant Adrenal cancer, medullary thyroid cancer, carcinoid
Ectopic Ectopic ACTH, SIADH secretion
Multiple endocrine neoplasia (MEN) MEN 1, MEN 2
Autoimmune Graves’disease
Iatrogenic Cushing’s syndrome, hypoglycemia
In ectious/in ammatory Subacute thyroiditis
Activating receptor mutations LH, TSH, Ca 2+, PTH receptors, Gsα
Hyp o fu n ct io n
Autoimmune Hashimoto’s thyroiditis, type 1 diabetes mellitus, Addison’s disease, polyglandular ailure
Iatrogenic Radiation-induced hypopituitarism, hypothyroidism, surgical
In ectious/in ammatory Adrenal insuf ciency, hypothalamic sarcoidosis
Hormone mutations GH, LHβ, FSHβ, vasopressin
Enzyme de ects 21-Hydroxylase de ciency
Developmental de ects Kallmann syndrome, Turner’s syndrome, transcription actors
Nutritional/vitamin de ciency Vitamin D de ciency, iodine de ciency
Hemorrhage/in arction Sheehan’s syndrome, adrenal insuf ciency
Ho rm o n e Re sist a n ce
Receptor mutations
Membrane GH, vasopressin, LH, FSH, ACTH, GnRH, GHRH, PTH, leptin, Ca 2+
Nuclear AR, TR, VDR, ER, GR, PPARγ
Signaling pathway mutations Albright’s hereditary osteodystrophy
Postreceptor Type 2 diabetes mellitus, leptin resistance

Ab brevia tio n s: ACTH, adrenocorticotropic hormone; AR, androgen receptor; ER, estrogen receptor; FSH, ollicle-stimulating hormone; GHRH, growth
hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; GR, glucocorticoid receptor; LH, luteinizing hormone; PPAR, peroxisome proli er-
ator activated receptor; PTH, parathyroid hormone; SIADH, syndrome o inappropriate antidiuretic hormone; TR, thyroid hormone receptor; TSH, thyroid-
stimulating hormone; VDR, vitamin D receptor.
4 tumors are relatively well di erentiated. Many endo- In autoimmune Graves’ disease, antibody interac-
crine tumors exhibit subtle de ects in their “set points” tions with the thyroid-stimulating hormone ( SH)
or eedback regulation. For example, in Cushing’s dis- receptor mimic SH action, leading to hormone over-
ease, impaired eedback inhibition o adrenocortico- production (Chap. 7). Analogous to the e ects o acti-
S
E
tropic hormone (AC H) secretion is associated with vating mutations o the SH receptor, these stimulating
C
T
I
autonomous unction. However, the tumor cells are not autoantibodies induce con ormational changes that
O
N
completely resistant to eedback, as evidenced by AC H release the receptor rom a constrained state, thereby
I
suppression by higher doses o dexamethasone (e.g., triggering receptor coupling to G proteins.
high-dose dexamethasone test) (Chap. 8). Similar set
point de ects are also typical o parathyroid adenomas
I
n
t
r
and autonomously unctioning thyroid nodules. CAUSES OF HORMONE DEFICIENCY
o
d
u
T e molecular basis o some endocrine tumors, such
c
Most examples o hormone de ciency states can be
t
i
o
as the multiple endocrine neoplasia (MEN) syndromes
n
attributed to glandular destruction caused by autoim-
t
(MEN 1, 2A, 2B), have provided important insights
o
munity, surgery, in ection, in ammation, in arction,
E
n
into tumorigenesis (Chap. 29). MEN 1 is characterized
d
hemorrhage, or tumor in ltration ( able 1-1). Auto-
o
primarily by the triad o parathyroid, pancreatic islet,
c
r
immune damage to the thyroid gland (Hashimoto’s
i
n
and pituitary tumors. MEN 2 predisposes to medullary
o
thyroiditis) and pancreatic islet β cells (type 1 diabe-
l
o
thyroid carcinoma, pheochromocytoma, and hyper-
g
tes mellitus) is a prevalent cause o endocrine disease.
y
parathyroidism. T e MEN1 gene, located on chromo-
Mutations in a number o hormones, hormone recep-
some 11q13, encodes a putative tumor-suppressor gene,
tors, transcription actors, enzymes, and channels can
menin. Analogous to the paradigm rst described or
also lead to hormone de ciencies.
retinoblastoma, the a ected individual inherits a mutant
copy o the MEN1 gene, and tumorigenesis ensues a er a
somatic “second hit” leads to loss o unction o the nor-
HORMONE RESISTANCE
mal MEN1 gene (through deletion or point mutations).
In contrast to inactivation o a tumor-suppressor Most severe hormone resistance syndromes are due to
gene, as occurs in MEN 1 and most other inherited can- inherited de ects in membrane receptors, nuclear recep-
cer syndromes, MEN 2 is caused by activating muta- tors, or the pathways that transduce receptor signals.
tions in a single allele. In this case, activating mutations T ese disorders are characterized by de ective hormone
o the RET protooncogene, which encodes a receptor action despite the presence o increased hormone levels.
tyrosine kinase, leads to thyroid C cell hyperplasia in In complete androgen resistance, or example, muta-
childhood be ore the development o medullary thyroid tions in the androgen receptor result in a emale phe-
carcinoma. Elucidation o this pathogenic mechanism notypic appearance in genetic (XY) males, even though
has allowed early genetic screening or RET mutations LH and testosterone levels are increased (Chap. 29). In
in individuals at risk or MEN 2, permitting identi- addition to these relatively rare genetic disorders, more
cation o those who may bene t rom prophylactic common acquired orms o unctional hormone resis-
thyroidectomy and biochemical screening or pheo- tance include insulin resistance in type 2 diabetes mel-
chromocytoma and hyperparathyroidism. litus, leptin resistance in obesity, and GH resistance in
Mutations that activate hormone receptor signal- catabolic states. T e pathogenesis o unctional resis-
ing have been identi ed in several GPCRs. For example, tance involves receptor downregulation and postrecep-
activating mutations o the luteinizing hormone (LH) tor desensitization o signaling pathways; unctional
receptor cause a dominantly transmitted orm o male- orms o resistance are generally reversible.
limited precocious puberty, re ecting premature stimula-
tion o testosterone synthesis in Leydig cells (Chap. 11).
CLINICAL EVALUATION OF ENDOCRINE
Activating mutations in these GPCRs are located pre-
DISORDERS
dominantly in the transmembrane domains and induce
receptor coupling to Gsα even in the absence o hormone. Because most glands are relatively inaccessible, the physi-
Consequently, adenylate cyclase is activated, and cyclic cal examination usually ocuses on the mani estations o
adenosine monophosphate (AMP) levels increase in a hormone excess or de ciency as well as direct examina-
manner that mimics hormone action. A similar phenom- tion o palpable glands, such as the thyroid and gonads.
enon results rom activating mutations in Gsα. When For these reasons, it is important to evaluate patients in
these mutations occur early in development, they cause the context o their presenting symptoms, review o sys-
McCune-Albright syndrome. When they occur only in tems, amily and social history, and exposure to medica-
somatotropes, the activating Gsα mutations cause GH- tions that may a ect the endocrine system. Astute clinical
secreting tumors and acromegaly (Chap. 5). skills are required to detect subtle symptoms and signs
suggestive o underlying endocrine disease. For example,
a patient with Cushing’s syndrome may mani est speci c
ndings, such as central at redistribution, striae, and
proximal muscle weakness, in addition to eatures seen
commonly in the general population, such as obesity,
plethora, hypertension, and glucose intolerance. Simi-
larly, the insidious onset o hypothyroidism—with men-
tal slowing, atigue, dry skin, and other eatures—can be
dif cult to distinguish rom similar, nonspeci c ndings
in the general population. Clinical judgment that is based
on knowledge o disease prevalence and pathophysiology
is required to decide when to embark on more extensive
evaluation o these disorders. Laboratory testing plays an
essential role in endocrinology by allowing quantitative
assessment o hormone levels and dynamics. Radiologic
imaging tests such as computed tomography (C ) scan,
magnetic resonance imaging (MRI), thyroid scan, and
ultrasound are also used or the diagnosis o endocrine
disorders. However, these tests generally are employed
only a er a hormonal abnormality has been established
by biochemical testing.
HORMONE MEASUREMENTS AND
ENDOCRINE TESTING
Immunoassays are the most important diagnostic tool
in endocrinology, as they allow sensitive, speci c, and
quantitative determination o steady-state and dynamic
changes in hormone concentrations. Immunoassays use
antibodies to detect speci c hormones. For many peptide
hormones, these measurements are now con gured to
use two di erent antibodies to increase binding af nity
and speci city. T ere are many variations o these assays;
a common ormat involves using one antibody to cap-
ture the antigen (hormone) onto an immobilized sur ace
and a second antibody, coupled to a chemiluminescent
(immunochemiluminescent assay [ICMA]) or radioac-
tive (immunoradiometric assay [IRMA]) signal, to detect
the antigen. T ese assays are sensitive enough to detect
plasma hormone concentrations in the picomolar to
nanomolar range, and they can readily distinguish struc-
turally related proteins, such as P H rom P H-related
peptide (P HrP). A variety o other techniques are used
to measure speci c hormones, including mass spectros-
copy, various orms o chromatography, and enzymatic
methods; bioassays are now rarely used.
Most hormone measurements are based on plasma or
serum samples. However, urinary hormone determina-
tions remain use ul or the evaluation o some conditions.
Urinary collections over 24 h provide an integrated assess-
ment o the production o a hormone or metabolite, many
o which vary during the day. It is important to assure com-
plete collections o 24-h urine samples; simultaneous mea-
surement o creatinine provides an internal control or the
adequacy o collection and can be used to normalize some
hormone measurements. A 24-h urine ree cortisol mea- 5
surement largely re ects the amount o unbound cortisol,
thus providing a reasonable index o biologically available
hormone. Other commonly used urine determinations
C
H
include 17-hydroxycorticosteroids, 17-ketosteroids, vanillyl-
A
P
T
mandelic acid, metanephrine, catecholamines, 5-hydroxyin-
E
R
doleacetic acid, and calcium.
1
T e value o quantitative hormone measurements lies
in their correct interpretation in a clinical context. T e
normal range or most hormones is relatively broad,
A
p
p
o en varying by a actor o two- to ten old. T e normal
r
o
a
ranges or many hormones are sex- and age-speci c.
c
h
T us, using the correct normative database is an essential
t
o
t
part o interpreting hormone tests. T e pulsatile nature o
h
e
P
hormones and actors that can a ect their secretion, such
a
t
i
as sleep, meals, and medications, must also be consid-
e
n
t
ered. Cortisol values increase ve old between midnight
w
i
t
and dawn; reproductive hormone levels vary dramati-
h
E
n
cally during the emale menstrual cycle.
d
o
For many endocrine systems, much in ormation
c
r
i
n
can be gained rom basal hormone testing, particularly
e
D
when di erent components o an endocrine axis are
i
s
o
r
assessed simultaneously. For example, low testoster-
d
e
r
one and elevated LH levels suggest a primary gonadal
s
problem, whereas a hypothalamic-pituitary disorder is
likely i both LH and testosterone are low. Because SH
is a sensitive indicator o thyroid unction, it is gener-
ally recommended as a rst-line test or thyroid disor-
ders. An elevated SH level is almost always the result
o primary hypothyroidism, whereas a low SH is most
o en caused by thyrotoxicosis. T ese predictions can be
con rmed by determining the ree thyroxine level. In
the less common circumstance when ree thyroxine and
SH are both low, it is important to consider second-
ary hypopituitarism caused by hypothalamic-pituitary
disease. Elevated calcium and P H levels suggest
hyperparathyroidism, whereas P H is suppressed in
hypercalcemia caused by malignancy or granulomatous
diseases. A suppressed AC H in the setting o hyper-
cortisolemia, or increased urine ree cortisol, is seen
with hyper unctioning adrenal adenomas.
It is not uncommon, however, or baseline hormone
levels associated with pathologic endocrine conditions
to overlap with the normal range. In this circumstance,
dynamic testing is use ul to separate the two groups ur-
ther. T ere are a multitude o dynamic endocrine tests,
but all are based on principles o eedback regulation, and
most responses can be rationalized based on principles
that govern the regulation o endocrine axes. Suppres-
sion tests are used in the setting o suspected endocrine
hyper unction. An example is the dexamethasone sup-
pression test used to evaluate Cushing’s syndrome
(Chaps. 5 and 8). Stimulation tests generally are used
to assess endocrine hypo unction. T e AC H stimula-
tion test, or example, is used to assess the adrenal gland
6 TABLE 1 -2
EXAMPLES OF PREVALENT ENDOCRINE AND METABOLIC DISORDERS IN THE ADULT
APPROX.
PREVALENCE IN
S
E
DISORDER ADULTS a SCREENING/TESTING RECOMMENDATIONS b CHAPTER(S)
C
T
I
O
Obesity 34% BMI ≥30 Calculate BMI Ch a p . 21
N
68% BMI ≥25 Measure waist circum erence
I
Exclude secondary causes
Consider comorbid complications
Type 2 diabetes mellitus >7% Beginning at age 45, screen every 3 years, or earlier in high-risk groups: Ch a p . 23
I
n
Fasting plasma glucose (FPG) >126 mg/dL
t
r
o
Random plasma glucose >200 mg/dL
d
u
An elevated HbA1c
c
t
i
Consider comorbid complications
o
n
t
Hyperlipidemia 20–25% Cholesterol screening at least every 5 years; more o ten in high-risk Ch a p . 27
o
E
groups
n
d
Lipoprotein analysis (LDL, HDL) or increased cholesterol, CAD, diabetes
o
c
Consider secondary causes
r
i
n
o
Metabolic syndrome 35% Measure waist circum erence, FPG, BP, lipids Ch a p . 22
l
o
g
Hypothyroidism 5–10%, women TSH; con rm with ree T4 Ch a p . 7
y
0.5–2%, men Screen women a ter age 35 and every 5 years therea ter
Graves’disease 1–3%, women TSH, ree T4 Ch a p . 7
0.1%, men
Thyroid nodules and 2–5% palpable Physical examination o thyroid Ch a p . 7
neoplasia >25% by ultrasound Fine-needle aspiration biopsy
Osteoporosis 5–10%, women Bone mineral density measurements in women >65 years or in post- Ch a p . 35
2–5%, men menopausal women or men at risk
Exclude secondary causes
Hyperparathyroidism 0.1–0.5%, women Serum calcium Ch a p . 34
> men PTH, i calcium is elevated
Assess comorbid conditions
In ertility 10%, couples Investigate both members o couple Ch a p s. 11,
Semen analysis in male 13
Assess ovulatory cycles in emale
Speci c tests as indicated
Polycystic ovarian 5–10%, women Free testosterone, DHEAS Ch a p . 13
syndrome Consider comorbid conditions
Hirsutism 5–10% Free testosterone, DHEAS Ch a p . 17
Exclude secondary causes
Additional tests as indicated
Menopause Median age, 51 FSH Ch a p . 16
Hyperprolactinemia 15% in women with PRL level Ch a p . 5
amenorrhea or MRI, i not medication-related
galactorrhea
Erectile dys unction 10–25% Care ul history, PRL, testosterone Ch a p . 19
Consider secondary causes (e.g., diabetes)
Hypogonadism, male 1–2% Testosterone, LH Ch a p . 11
Gynecomastia 15% O ten, no tests are indicated Ch a p . 11
Consider Kline elter’s syndrome
Consider medications, hypogonadism, liver disease
Kline elter’s syndrome 0.2%, men Karyotype Ch a p . 10
Testosterone
Vitamin D de ciency 10% Measure serum 25-OH vitamin D Ch a p . 32
Consider secondary causes
Turner’s syndrome 0.03%, women Karyotype Ch a p . 10
Consider comorbid conditions

a
The prevalence o most disorders varies among ethnic groups and with aging. Data based primarily on U.S. population.
b
See individual chapters or additional in ormation on evaluation and treatment. Early testing is indicated in patients with signs and symptoms o disease
and in those at increased risk.
Abb revia tio ns: BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; DHEAS, dehydroepiandrosterone; FSH, ollicle-stimulating hor-
mone; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LH, luteinizing hormone; MRI, magnetic resonance imaging; PRL, prolactin; PTH, para-
thyroid hormone; TSH, thyroid-stimulating hormone.
response in patients with suspected adrenal insuf ciency. SCREENING AND ASSESSMENT OF 7
Other stimulation tests use hypothalamic-releasing ac- COMMON ENDOCRINE DISORDERS
tors such as corticotropin-releasing hormone (CRH)
Many endocrine disorders are prevalent in the adult
and growth hormone–releasing hormone (GHRH) to

C
population (Table 1-2) and can be diagnosed and man-

H
evaluate pituitary hormone reserve (Chap. 5). Insulin-

A
aged by general internists, amily practitioners, or other

P
T
induced hypoglycemia also evokes pituitary AC H and

E
primary health care providers. T e high prevalence and

R
GH responses. Stimulation tests based on reduction or

1
clinical impact o certain endocrine diseases justi es
inhibition o endogenous hormones are now used in re-
vigilance or eatures o these disorders during routine
quently. Examples include metyrapone inhibition o
physical examinations; laboratory screening is indicated
cortisol synthesis and clomiphene inhibition o estrogen

A
p
in selected high-risk populations.

p
eedback.

r
o
a
c
h
t
o
t
h
e
P
a
t
i
e
n
t
w
i
t
h
E
n
d
o
c
r
i
n
e
D
i
s
o
r
d
e
r
s
 CH AP TER 2
MECHANISMS OF HORMONE ACTION
J. La rry Ja m e so n
CLASSES O F HO RMO NES
Hormones can be divided into ve major types: (1)
amino acid derivatives such as dopamine, catechol-
amine, and thyroid hormone; (2) small neuropeptides
such as gonadotropin-releasing hormone (GnRH), thy-
rotropin-releasing hormone ( RH), somatostatin, and
vasopressin; (3) large proteins such as insulin, luteiniz-
ing hormone (LH), and parathyroid hormone (P H);
(4) steroid hormones such as cortisol and estrogen that
are synthesized rom cholesterol-based precursors;
and (5) vitamin derivatives such as retinoids (vitamin
A) and vitamin D. A variety o peptide growth factors,
most o which act locally, share actions with hormones.
As a rule, amino acid derivatives and peptide hormones
interact with cell-sur ace membrane receptors. Steroids,
thyroid hormones, vitamin D, and retinoids are lipid-
soluble and interact with intracellular nuclear receptors,
although many also interact with membrane receptors
or intracellular signaling proteins as well.
HORMONE AND RECEPTOR FAMILIES
Hormones and receptors can be grouped into amilies,
re ecting structural similarities and evolutionary ori-
gins (Table 2-1). T e evolution o these amilies gener-
ates diverse but highly selective pathways o hormone
action. Recognition o these relationships has proven
use ul or extrapolating in ormation gleaned rom one
hormone or receptor to other amily members.
T e glycoprotein hormone amily, consisting o thy-
roid-stimulating hormone ( SH), ollicle-stimulating
hormone (FSH), LH, and human chorionic gonado-
tropin (hCG), illustrates many eatures o related hor-
mones. T e glycoprotein hormones are heterodimers
that share the α subunit in common; the β subunits are
distinct and con er speci c biologic actions. T e over-
all three-dimensional architecture o the β subunits is
similar, re ecting the locations o conserved disul de
8
bonds that restrain protein con ormation. T e cloning
o the β-subunit genes rom multiple species suggests
that this amily arose rom a common ancestral gene,
probably by gene duplication and subsequent diver-
gence to evolve new biologic unctions.
As hormone amilies enlarge and diverge, their
receptors must co-evolve to derive new biologic unc-
tions. Related G protein–coupled receptors (GPCRs),
or example, have evolved or each o the glycoprotein
hormones. T ese receptors are structurally similar, and
each is coupled predominantly to the Gsα signaling
pathway. However, there is minimal overlap o hormone
binding. For example, SH binds with high speci city
to the SH receptor but interacts minimally with the
LH or FSH receptors. Nonetheless, there can be subtle
physiologic consequences o hormone cross-reactivity
with other receptors. Very high levels o hCG during
pregnancy stimulate the SH receptor and increase
thyroid hormone levels, resulting in a compensatory
decrease in SH.
Insulin and insulin-like growth actor I (IGF-I) and
IGF-II have structural similarities that are most appar-
ent when precursor orms o the proteins are compared.
In contrast to the high degree o speci city seen with
the glycoprotein hormones, there is moderate cross-talk
among the members o the insulin/IGF amily. High
concentrations o an IGF-II precursor produced by cer-
tain tumors (e.g., sarcomas) can cause hypoglycemia,
partly because o binding to insulin and IGF-I receptors
(Chap. 34). High concentrations o insulin also bind to
the IGF-I receptor, perhaps accounting or some o the
clinical mani estations seen in conditions with chronic
hyperinsulinemia.
Another important example o receptor cross-talk
is seen with P H and parathyroid hormone–related
peptide (P HrP) (Chap. 34). P H is produced by the
parathyroid glands, whereas P HrP is expressed at high
levels during development and by a variety o tumors
(Chap. 31). T ese hormones have amino acid sequence
TABLE 2 -1 receptor, retinoic acid receptor, peroxisome proli erator 9
EXAMPLES OF MEMBRANE RECEPTOR FAMILIES AND activated receptor) that bind thyroid hormone, vitamin
SIGNALING PATHWAYS D, retinoic acid, or lipid derivatives. Certain unctional
domains in nuclear receptors, such as the zinc nger

C
SIGNALING

H
DNA-binding domains, are highly conserved. However,

A
RECEPTORS EFFECTORS PATHWAYS

P
T
selective amino acid di erences within this domain

E
G Pro t e in –Co u p le d Se ve n -Tra n sm e m b ra n e Re ce p t o r

R
(GPCR) con er DNA sequence speci city. T e hormone-binding

2
β-Adrenergic, LH, GSα, adenylate Stimulation o domains are more variable, providing great diversity
FSH, TSH cyclase cyclic AMP pro- in the array o small molecules that bind to di erent
nuclear receptors. With ew exceptions, hormone bind-

M
duction, protein

e
c
kinase A ing is highly speci c or a single type o nuclear recep-

h
a
Ca2+ channels

n
Glucagon, PTH, Calmodulin, tor. One exception involves the glucocorticoid and

i
s
m
PTHrP, ACTH, Ca 2+-dependent mineralocorticoid receptors. Because the mineralo-

s
MSH, GHRH, CRH kinases

o
corticoid receptor also binds glucocorticoids with high

f
H
α-Adrenergic, Giα Inhibition o cyclic
a nity, an enzyme (11β-hydroxysteroid dehydroge-

o
r
somatostatin AMP production

m
nase) in renal tubular cells inactivates glucocorticoids,

o
Activation o K+,

n
allowing selective responses to mineralocorticoids such

e
Ca2+ channels

A
c
TRH, GnRH Gq , G11 Phospholipase C, as aldosterone. However, when very high glucocorticoid

t
i
o
concentrations occur, as in Cushing’s syndrome, the

n
diacyl-glycerol,
IP3, protein glucocorticoid degradation pathway becomes saturated,
kinase C, voltage- allowing excessive cortisol levels to exert mineralocor-
dependent Ca 2+
channels
ticoid e ects (sodium retention, potassium wasting).
T is phenomenon is particularly pronounced in ecto-
Re ce p t o r Tyro sin e Kin a se
pic adrenocorticotropic hormone (AC H) syndromes
Insulin, IGF-I Tyrosine kinases, MAP kinases, PI (Chap. 8). Another example o relaxed nuclear recep-
IRS 3-kinase; AKT tor speci city involves the estrogen receptor, which can
EGF, NGF Tyrosine kinases, Ra , MAP kinases,
ras RSK
bind an array o compounds, some o which have little
apparent structural similarity to the high-a nity ligand
Cyto kin e Re ce p to r–Lin ke d Kin a se
estradiol. T is eature o the estrogen receptor makes
GH, PRL JAK, tyrosine STAT, MAP kinase, it susceptible to activation by “environmental estro-
kinases PI 3-kinase, IRS-1 gens” such as resveratrol, octylphenol, and many other
Se rin e Kin a se aromatic hydrocarbons. However, this lack o speci c-
Activin, TGF-β, MIS Serine kinase Smads ity provides an opportunity to synthesize a remarkable
series o clinically use ul antagonists (e.g., tamoxi en)
Abb revia tio ns: IP3, inositol triphosphate; IRS, insulin receptor substrates; and selective estrogen response modulators (SERMs)
MAP, mitogen-activated protein; MSH, melanocyte-stimulating hormone; such as raloxi ene. T ese compounds generate dis-
NGF, nerve growth actor; PI, phosphatidylinositol; RSK, ribosomal S6
kinase; TGF-β, trans orming growth actor β. For all other abbreviations,
tinct con ormations that alter receptor interactions
see text. Note that most receptors interact with multiple ef ectors and with components o the transcription machinery (see
activate networks o signaling pathways. below), thereby con erring their unique actions.
similarity, particularly in their amino-terminal regions.
Both hormones bind to a single P H receptor that
HORMONE SYNTHESIS AND PROCESSING
is expressed in bone and kidney. Hypercalcemia and
hypophosphatemia there ore may result rom excessive T e synthesis o peptide hormones and their receptors
production o either hormone, making it di cult to occurs through a classic pathway o gene expression:
distinguish hyperparathyroidism rom hypercalcemia transcription → mRNA → protein → posttranslational
o malignancy solely on the basis o serum chemistries. protein processing → intracellular sorting, ollowed by
However, sensitive and speci c assays or P H and membrane integration or secretion.
P HrP now allow these disorders to be distinguished Many hormones are embedded within larger precur-
more readily. sor polypeptides that are proteolytically processed to
Based on their speci cities or DNA binding sites, yield the biologically active hormone. Examples include
the nuclear receptor amily can be subdivided into proopiomelanocortin (POMC) → AC H; progluca-
type 1 receptors (glucocorticoid receptor, mineralo- gon →glucagon; proinsulin →insulin; and pro-P H →
corticoid receptor, androgen receptor, estrogen recep- P H, among others. In many cases, such as POMC and
tor, progesterone receptor) that bind steroids and type proglucagon, these precursors generate multiple bio-
2 receptors (thyroid hormone receptor, vitamin D logically active peptides. It is provocative that hormone
10 precursors are typically inactive, presumably adding an secretion is a releasing actor or neural signal that
additional level o regulatory control. Prohormone con- induces rapid changes in intracellular calcium con-
version occurs not only or peptide hormones but also centrations, leading to secretory granule usion with
or certain steroids (testosterone →dihydrotestosterone) the plasma membrane and release o its contents into
S
E
and thyroid hormone ( 4 → 3). the extracellular environment and bloodstream. Ste-
C
T
I
Peptide precursor processing is intimately linked to roid hormones, in contrast, di use into the circulation
O
N
intracellular sorting pathways that transport proteins to as they are synthesized. T us, their secretory rates are
I
appropriate vesicles and enzymes, resulting in speci c closely aligned with rates o synthesis. For example,
cleavage steps, ollowed by protein olding and trans- AC H and LH induce steroidogenesis by stimulating
location to secretory vesicles. Hormones destined or the activity o the steroidogenic acute regulatory (StAR)
I
n
t
r
secretion are translocated across the endoplasmic retic- protein (transports cholesterol into the mitochondrion)
o
d
u
ulum under the guidance o an amino-terminal sig- along with other rate-limiting steps (e.g., cholesterol
c
t
i
o
nal sequence that subsequently is cleaved. Cell-sur ace side-chain cleavage enzyme, CYP11A1) in the steroido-
n
t
receptors are inserted into the membrane via short genic pathway.
o
E
n
segments o hydrophobic amino acids that remain Hormone transport and degradation dictate the
d
o
embedded within the lipid bilayer. During transloca- rapidity with which a hormonal signal decays. Some
c
r
i
n
tion through the Golgi and endoplasmic reticulum, hormone signals are evanescent (e.g., somatostatin),
o
l
o
hormones and receptors are subject to a variety o post- whereas others are longer-lived (e.g., SH). Because
g
y
translational modi cations, such as glycosylation and somatostatin exerts e ects in virtually every tissue, a
phosphorylation, which can alter protein con ormation, short hal -li e allows its concentrations and actions
modi y circulating hal -li e, and alter biologic activity. to be controlled locally. Structural modi cations that
Synthesis o most steroid hormones is based on impair somatostatin degradation have been use ul or
modi cations o the precursor, cholesterol. Multiple generating long-acting therapeutic analogues such as
regulated enzymatic steps are required or the synthe- octreotide (Chap. 5). In contrast, the actions o SH are
sis o testosterone (Chap. 11), estradiol (Chap. 13), highly speci c or the thyroid gland. Its prolonged hal -
cortisol (Chap. 8), and vitamin D (Chap. 32). T is li e accounts or relatively constant serum levels even
large number o synthetic steps predisposes to multiple though SH is secreted in discrete pulses.
genetic and acquired disorders o steroidogenesis. An understanding o circulating hormone hal -li e is
Endocrine genes contain regulatory DNA elements important or achieving physiologic hormone replace-
similar to those ound in many other genes, but their ment, as the requency o dosing and the time required
exquisite control by hormones re ects the presence o to reach steady state are intimately linked to rates o hor-
speci c hormone response elements. For example, the mone decay. 4, or example, has a circulating hal -li e
SH genes are repressed directly by thyroid hormones o 7 days. Consequently, >1 month is required to reach
acting through the thyroid hormone receptor ( R), a a new steady state, and single daily doses are su cient
member o the nuclear receptor amily. Steroidogenic to achieve constant hormone levels. 3, in contrast, has
enzyme gene expression requires speci c transcription a hal -li e o 1 day. Its administration is associated with
actors, such as steroidogenic actor-1 (SF-1), acting in more dynamic serum levels, and it must be adminis-
conjunction with signals transmitted by trophic hor- tered two to three times per day. Similarly, synthetic glu-
mones (e.g., AC H or LH). For some hormones, sub- cocorticoids vary widely in their hal -lives; those with
stantial regulation occurs at the level o translational longer hal -lives (e.g., dexamethasone) are associated
e ciency. Insulin biosynthesis, although it requires with greater suppression o the hypothalamic-pituitary-
ongoing gene transcription, is regulated primarily at the adrenal (HPA) axis. Most protein hormones (e.g., AC H,
translational and secretory levels in response to elevated GH, prolactin [PRL], P H, LH) have relatively short
levels o glucose or amino acids. hal -lives (<20 min), leading to sharp peaks o secretion
and decay. T e only accurate way to pro le the pulse re-
quency and amplitude o these hormones is to measure
HORMONE SECRETION, TRANSPORT, AND
levels in requently sampled blood (every 10 min or less)
DEGRADATION
over long durations (8–24 h). Because this is not practi-
T e level o a hormone is determined by its rate o cal in a clinical setting, an alternative strategy is to pool
secretion and its circulating hal -li e. Af er protein pro- three to our samples drawn at about 30-min intervals,
cessing, peptide hormones (e.g., GnRH, insulin, growth or interpret the results in the context o a relatively wide
hormone [GH]) are stored in secretory granules. As normal range. Rapid hormone decay is use ul in certain
these granules mature, they are poised beneath the clinical settings. For example, the short hal -li e o P H
plasma membrane or imminent release into the cir- allows the use o intraoperative P H determinations
culation. In most instances, the stimulus or hormone to con rm success ul removal o an adenoma. T is is
particularly valuable diagnostically when there is a pos-
sibility o multicentric disease or parathyroid hyperplasia,
as occurs with multiple endocrine neoplasia (MEN) or
renal insu ciency.
Many hormones circulate in association with serum-
binding proteins. Examples include (1) 4 and 3 bind-
ing to thyroxine-binding globulin ( BG), albumin, and
thyroxine-binding prealbumin ( BPA); (2) cortisol
binding to cortisol-binding globulin (CBG); (3) andro-
gen and estrogen binding to sex hormone–binding
globulin (SHBG); (4) IGF-I and -II binding to multiple
IGF-binding proteins (IGFBPs); (5) GH interactions
with GH-binding protein (GHBP), a circulating rag-
ment o the GH receptor extracellular domain; and (6)
activin binding to ollistatin. T ese interactions provide
a hormonal reservoir, prevent otherwise rapid degrada-
tion o unbound hormones, restrict hormone access to
certain sites (e.g., IGFBPs), and modulate the unbound,
or “ ree,” hormone concentrations. Although a variety
o binding protein abnormalities have been identi ed,
most have little clinical consequence aside rom creat-
ing diagnostic problems. For example, BG de ciency
can reduce total thyroid hormone levels greatly but the
ree concentrations o 4 and 3 remain normal. Liver
disease and certain medications can also in uence
binding protein levels (e.g., estrogen increases BG) or
cause displacement o hormones rom binding proteins
(e.g., salsalate displaces 4 rom BG). In general, only
unbound hormone is available to interact with recep-
tors and thus elicit a biologic response. Short-term per-
turbations in binding proteins change the ree hormone
concentration, which in turn induces compensatory
adaptations through eedback loops. SHBG changes in
women are an exception to this sel -correcting mecha-
nism. When SHBG decreases because o insulin resis-
tance or androgen excess, the unbound testosterone
concentration is increased, potentially leading to hir-
sutism (Chap. 17). T e increased unbound testosterone
level does not result in an adequate compensatory eed-
back correction because estrogen, not testosterone, is
the primary regulator o the reproductive axis.
An additional exception to the unbound hormone
hypothesis involves megalin, a member o the low-
density lipoprotein (LDL) receptor amily that serves
as an endocytotic receptor or carrier-bound vitamins
A and D and SHBG-bound androgens and estrogens.
Af er internalization, the carrier proteins are degraded
in lysosomes and release their bound ligands within the
cells. Membrane transporters have also been identi ed
or thyroid hormones.
Hormone degradation can be an important mecha-
nism or regulating concentrations locally. As noted above,
11β-hydroxysteroid dehydrogenase inactivates glucocorti-
coids in renal tubular cells, preventing actions through the
mineralocorticoid receptor. T yroid hormone deiodinases
convert 4 to 3 and can inactivate 3. During develop- 11
ment, degradation o retinoic acid by Cyp26b1 prevents
primordial germ cells in the male rom entering meiosis,
as occurs in the emale ovary.
C
H
A
P
T
E
R
HORMONE ACTION THROUGH RECEPTORS
2
Receptors or hormones are divided into two major
classes: membrane and nuclear. Membrane receptors
M
e
primarily bind peptide hormones and catecholamines.
c
h
Nuclear receptors bind small molecules that can di use
a
n
i
s
across the cell membrane, such as steroids and vita-
m
s
min D. Certain general principles apply to hormone-
o
f
H
receptor interactions regardless o the class o receptor.
o
r
Hormones bind to receptors with speci city and an
m
o
n
a nity that generally coincides with the dynamic range
e
A
o circulating hormone concentrations. Low concentra-
c
t
i
tions o ree hormone (usually 10−12 to 10−9 M) rapidly
o
n
associate and dissociate rom receptors in a bimolecular
reaction such that the occupancy o the receptor at any
given moment is a unction o hormone concentration
and the receptor’s a nity or the hormone. Receptor
numbers vary greatly in di erent target tissues, pro-
viding one o the major determinants o speci c tissue
responses to circulating hormones. For example, AC H
receptors are located almost exclusively in the adrenal
cortex, and FSH receptors are ound predominantly in
the gonads. In contrast, insulin and Rs are widely dis-
tributed, re ecting the need or metabolic responses in
all tissues.
MEMBRANE RECEPTORS
Membrane receptors or hormones can be divided into
several major groups: (1) seven transmembrane GPCRs,
(2) tyrosine kinase receptors, (3) cytokine receptors,
and (4) serine kinase receptors (Fig. 2-1). T e seven
transmembrane GPCR family binds a remarkable array
o hormones, including large proteins (e.g., LH, P H),
small peptides (e.g., RH, somatostatin), catechol-
amines (epinephrine, dopamine), and even minerals
(e.g., calcium). T e extracellular domains o GPCRs
vary widely in size and are the major binding site or
large hormones. T e transmembrane-spanning regions
are composed o hydrophobic α-helical domains that
traverse the lipid bilayer. Like some channels, these
domains are thought to circularize and orm a hydro-
phobic pocket into which certain small ligands t. Hor-
mone binding induces con ormational changes in these
domains, transducing structural changes to the intracel-
lular domain, which is a docking site or G proteins.
T e large amily o G proteins, so named because
they bind guanine nucleotides (guanosine triphosphate
[G P], guanosine diphosphate [GDP]), provides great
12 G prote in–couple d Ins ulin/IGF-I
Cytokine /GH/P RL S e ve n tra ns me mbra ne Tyros ine kina s e

Activin/MIS /BMP Growth fa ctor

TGF-β S e rine kina s e Tyros ine kina s e
S
E
C
T
I
O
N
I
Me mbra ne
I
n
t
r
G prote in
o
J AK/S TAT
d
P KA, P KC
u
Ra s /Ra f
c
t
i
S ma ds MAP K
o
n
t
o
E
n
d
Nucle us
o
c
r
i
Ta rge t ge ne
n
o
l
o
g
y
FIGURE 2 -1
Me m b ra n e re ce p t o r sig n a lin g . MAPK, mitogen-activated protein kinase; PKA, C, protein kinase A, C; TGF, trans orming growth actor.
For other abbreviations, see text.

diversity or coupling receptors to di erent signaling
pathways. G proteins orm a heterotrimeric complex that
is composed o various α and βγ subunits. T e α subunit
contains the guanine nucleotide–binding site and hydro-
lyzes G P → GDP. T e βγ subunits are tightly associ-
ated and modulate the activity o the α subunit as well
as mediating their own e ector signaling pathways. G
protein activity is regulated by a cycle that involves G P
hydrolysis and dynamic interactions between the α and
αβ subunits. Hormone binding to the receptor induces
GDP dissociation, allowing Gα to bind G P and disso-
ciate rom the αβ complex. Under these conditions, the
Gα subunit is activated and mediates signal transduction
through various enzymes, such as adenylate cyclase and
phospholipase C. G P hydrolysis to GDP allows reas-
sociation with the βγ subunits and restores the inactive
state. As described below, a variety o endocrinopathies
result rom G protein mutations or rom mutations in
receptors that modi y their interactions with G proteins.
G proteins interact with other cellular proteins, including
kinases, channels, G protein–coupled receptor kinases
(GRKs), and arrestins, that mediate signaling as well as
receptor desensitization and recycling.
T e tyrosine kinase receptors transduce signals or
insulin and a variety o growth actors, such as IGF-I,
epidermal growth actor (EGF), nerve growth actor,
platelet-derived growth actor, and broblast growth
actor. T e cysteine-rich extracellular ligand-binding
domains contain growth actor binding sites. Af er ligand
binding, this class o receptors undergoes autophosphor-
ylation, inducing interactions with intracellular adap-
tor proteins such as Shc and insulin receptor substrates
(IRS). In the case o the insulin receptor, multiple kinases
are activated, including the Ra -Ras-MAPK and the Akt/
protein kinase B pathways. T e tyrosine kinase receptors
play a prominent role in cell growth and di erentiation
as well as in intermediary metabolism.
T e GH and PRL receptors belong to the cytokine
receptor amily. Analogous to the tyrosine kinase recep-
tors, ligand binding induces receptor interaction with
intracellular kinases—the Janus kinases (JAKs), which
phosphorylate members o the signal transduction and
activators o transcription (S A ) amily—as well as
with other signaling pathways (Ras, PI3-K, MAPK).
T e activated S A proteins translocate to the nucleus
and stimulate expression o target genes.
T e serine kinase receptors mediate the actions o activ-
ins, trans orming growth actor β, müllerian-inhibiting
substance (MIS, also known as anti-müllerian hormone,
AMH), and bone morphogenic proteins (BMPs). T is
amily o receptors (consisting o type I and II subunits)
signals through proteins termed smads ( usion o terms
or Caenorhabditis elegans sma + mammalian mad). Like
the S A proteins, the smads serve a dual role o trans-
ducing the receptor signal and acting as transcription
actors. T e pleomorphic actions o these growth actors
dictate that they act primarily in a local (paracrine or
autocrine) manner. Binding proteins such as ollistatin
(which binds activin and other members o this amily)
unction to inactivate the growth actors and restrict their
distribution.
NUCLEAR RECEPTORS
T e amily o nuclear receptors has grown to nearly
100 members, many o which are still classi ed as
 Ho mo dime r S te ro id He te ro dime r Re c e pto rs Orphan Re c e pto rs 13
Re c e pto rs
ER, AR, P R, GR TR, VDR, RAR, P P AR S F-1, DAX-1, HNF4α

Liga nds

C
H
A
P
T
E
R
2
DNA re s pons e
e le me nts

M
Liga nd induce s Liga nd dis s ocia te s core pre s s ors Cons titutive a ctiva tor

e
c
coa ctiva tor binding a nd induce s coa ctiva tor binding or re pre s s or binding

h
a
n
n
i
s
o
m
i
Activa te d Activa te d Activa te d
s
s
s
o
e
r
f
S ile nce d
p
H
x
o
E
r
m
e
n
o
e
n
G
e
– + – + – +

A
Ba s a l

c
t
Hormone Hormone Re ce ptor

i
o
n
FIGURE 2 -2
Nu cle a r re ce p t o r sig n a lin g . AR, androgen receptor; DAX, dos- activated receptor; PR, progesterone receptor; RAR, retinoic acid
age-sensitive sex-reversal, adrenal hypoplasia congenita, X-chro- receptor; SF-1, steroidogenic actor-1; TR, thyroid hormone recep-
mosome; ER, estrogen receptor; GR, glucocorticoid receptor; tor; VDR, vitamin D receptor.
HNF4α, hepatic nuclear actor 4α; PPAR, peroxisome proli erator

orphan receptors because their ligands, i they exist,
have not been identi ed (Fig. 2-2). Otherwise, most
nuclear receptors are classi ed on the basis o their
ligands. Although all nuclear receptors ultimately act
to increase or decrease gene transcription, some (e.g.,
glucocorticoid receptor) reside primarily in the cyto-
plasm, whereas others (e.g., R) are located in the
nucleus. Af er ligand binding, the cytoplasmically
localized receptors translocate to the nucleus. T ere is
growing evidence that certain nuclear receptors (e.g.,
glucocorticoid, estrogen) can also act at the membrane
or in the cytoplasm to activate or repress signal trans-
duction pathways, providing a mechanism or cross-
talk between membrane and nuclear receptors.
T e structures o nuclear receptors have been stud-
ied extensively, including by x-ray crystallography. T e
DNA binding domain, consisting o two zinc ngers,
contacts speci c DNA recognition sequences in target
genes. Most nuclear receptors bind to DNA as dimers.
Consequently, each monomer recognizes an individ-
ual DNA moti , re erred to as a “hal -site.” T e steroid
receptors, including the glucocorticoid, estrogen, pro-
gesterone, and androgen receptors, bind to DNA as
homodimers. Consistent with this two old symmetry,
their DNA recognition hal -sites are palindromic. T e
thyroid, retinoid, peroxisome proli erator activated,
and vitamin D receptors bind to DNA pre erentially as
heterodimers in combination with retinoid X receptors
(RXRs). T eir DNA hal -sites are typically arranged as
direct repeats.
T e carboxy-terminal hormone-binding domain
mediates transcriptional control. For type II recep-
tors such as R and retinoic acid receptor (RAR), co-
repressor proteins bind to the receptor in the absence o
ligand and silence gene transcription. Hormone bind-
ing induces con ormational changes, triggering the
release o co-repressors and inducing the recruitment
o coactivators that stimulate transcription. T us, these
receptors are capable o mediating dramatic changes
in the level o gene activity. Certain disease states are
associated with de ective regulation o these events. For
example, mutations in the R prevent co-repressor dis-
sociation, resulting in an autosomal dominant orm o
hormone resistance (Chap. 7). In promyelocytic leuke-
mia, usion o RARα to other nuclear proteins causes
aberrant gene silencing that prevents normal cellular
di erentiation. reatment with retinoic acid reverses
this repression and allows cellular di erentiation and
apoptosis to occur. Most type 1 steroid receptors inter-
act weakly with co-repressors, but ligand binding still
induces interactions with an array o coactivators. X-ray
crystallography shows that various SERMs induce dis-
tinct estrogen receptor con ormations. T e tissue-
speci c responses caused by these agents in breast,
bone, and uterus appear to re ect distinct interactions
with coactivators. T e receptor-coactivator complex
stimulates gene transcription by several pathways,
including (1) recruitment o enzymes (histone ace-
tyl trans erases) that modi y chromatin structure, (2)
interactions with additional transcription actors on
14 the target gene, and (3) direct interactions with compo- glucose uptake and enhanced glycogenolysis, lipoly-
nents o the general transcription apparatus to enhance sis, proteolysis, and gluconeogenesis to mobilize uel
the rate o RNA polymerase II–mediated transcrip- sources. I hypoglycemia develops (usually rom insu-
tion. Studies o nuclear receptor-mediated transcription lin administration or sul onylureas), an orchestrated
S
E
show that these are dynamic events that involve rela- counterregulatory response occurs—glucagon and epi-
C
T
I
tively rapid (e.g., 30–60 min) cycling o transcription nephrine rapidly stimulate glycogenolysis and gluco-
O
N
complexes on any speci c target gene. neogenesis, whereas GH and cortisol act over several
I
hours to raise glucose levels and antagonize insulin
action.
Although ree-water clearance is controlled primar-
I
n
t
FUNCTIO NS O F HO RMO NES
r
ily by vasopressin, cortisol and thyroid hormone are
o
d
u
also important or acilitating renal tubular responses
c
T e unctions o individual hormones are described in
t
i
o
to vasopressin (Chap. 6). P H and vitamin D unc-
n
detail in subsequent chapters. Nevertheless, it is use-
t
tion in an interdependent manner to control calcium
o
ul to illustrate how most biologic responses require
E
n
metabolism (Chap. 32). P H stimulates renal synthesis
d
integration o several di erent hormone pathways. T e
o
o 1,25-dihydroxyvitamin D, which increases calcium
c
r
physiologic unctions o hormones can be divided into
i
n
absorption in the gastrointestinal tract and enhances
o
three general areas: (1) growth and di erentiation, (2)
l
o
P H action in bone. Increased calcium, along with vita-
g
maintenance o homeostasis, and (3) reproduction.
y
min D, eeds back to suppress P H, thus maintaining
calcium balance.
GROWTH Depending on the severity o a speci c stress and
whether it is acute or chronic, multiple endocrine and
Multiple hormones and nutritional actors mediate the cytokine pathways are activated to mount an appropri-
complex phenomenon o growth (Chap. 3). Short stat- ate physiologic response. In severe acute stress such as
ure may be caused by GH de ciency, hypothyroidism, trauma or shock, the sympathetic nervous system is
Cushing’s syndrome, precocious puberty, malnutrition, activated and catecholamines are released, leading to
chronic illness, or genetic abnormalities that a ect the increased cardiac output and a primed musculoskel-
epiphyseal growth plates (e.g., FGFR3 and SHOX muta- etal system. Catecholamines also increase mean blood
tions). Many actors (GH, IGF-I, thyroid hormones) pressure and stimulate glucose production. Multiple
stimulate growth, whereas others (sex steroids) lead stress-induced pathways converge on the hypothala-
to epiphyseal closure. Understanding these hormonal mus, stimulating several hormones, including vasopres-
interactions is important in the diagnosis and man- sin and corticotropin-releasing hormone (CRH). T ese
agement o growth disorders. For example, delaying hormones, in addition to cytokines (tumor necrosis
exposure to high levels o sex steroids may enhance the actor α, interleukin [IL] 2, IL-6) increase AC H and
e cacy o GH treatment. GH production. AC H stimulates the adrenal gland,
increasing cortisol, which in turn helps sustain blood
MAINTENANCE OF HOMEOSTASIS pressure and dampen the in ammatory response.
Increased vasopressin acts to conserve ree water.
Although virtually all hormones a ect homeostasis, the
most important among them are the ollowing:
1. T yroid hormone—controls about 25% o basal REPRODUCTION
metabolism in most tissues T e stages o reproduction include (1) sex determina-
2. Cortisol—exerts a permissive action or many hor- tion during etal development (Chap. 10); (2) sexual
mones in addition to its own direct e ects maturation during puberty (Chaps. 11 and 13); (3)
3. P H—regulates calcium and phosphorus levels conception, pregnancy, lactation, and child rearing
4. Vasopressin—regulates serum osmolality by con- (Chap. 13); and (4) cessation o reproductive capability
trolling renal ree-water clearance at menopause (Chap. 16). Each o these stages involves
5. Mineralocorticoids—control vascular volume and an orchestrated interplay o multiple hormones, a phe-
serum electrolyte (Na+, K+) concentrations nomenon well illustrated by the dynamic hormonal
6. Insulin—maintains euglycemia in the ed and asted changes that occur during each 28-day menstrual cycle.
states In the early ollicular phase, pulsatile secretion o LH
T e de ense against hypoglycemia is an impressive and FSH stimulates the progressive maturation o the
example o integrated hormone action (Chap. 26). In ovarian ollicle. T is results in gradually increasing
response to the asting state and alling blood glucose, estrogen and progesterone levels, leading to enhanced
insulin secretion is suppressed, resulting in decreased pituitary sensitivity to GnRH, which, when combined
with accelerated GnRH secretion, triggers the LH surge 15
and rupture o the mature ollicle. Inhibin, a protein Hypotha la mus

produced by the granulosa cells, enhances ollicular CNS

growth and eeds back to the pituitary to selectively

C
H
suppress FSH without a ecting LH. Growth actors

A
Re le a s ing

P
T
such as EGF and IGF-I modulate ollicular responsive- fa ctors + –

E
R
ness to gonadotropins. Vascular endothelial growth

2
actor and prostaglandins play a role in ollicle vascular-
ization and rupture.
During pregnancy, the increased production o pro-

M
e
c
lactin, in combination with placentally derived steroids Pituitary –

h
a
(e.g., estrogen and progesterone), prepares the breast or

n
i
s
Ta rge t hormone

m
lactation. Estrogens induce the production o progester-

s
Trophic fe e dba ck

o
one receptors, allowing or increased responsiveness to inhibition

f
hormone s +

H
progesterone. In addition to these and other hormones

o
r
m
involved in lactation, the nervous system and oxytocin

o
n
mediate the suckling response and milk release.

HO RMO NAL FEEDBACK REGULATO RY
SYSTEMS
Feedback control, both negative and positive, is a unda-
mental eature o endocrine systems. Each o the major
hypothalamic-pituitary-hormone axes is governed
by negative eedback, a process that maintains hor-
mone levels within a relatively narrow range (Chap. 3).
Examples o hypothalamic-pituitary negative eedback
include (1) thyroid hormones on the RH- SH axis,
(2) cortisol on the CRH-AC H axis, (3) gonadal ste-
roids on the GnRH-LH/FSH axis, and (4) IGF-I on the
growth hormone–releasing hormone (GHRH)-GH axis
(Fig. 2-3). T ese regulatory loops include both posi-
tive (e.g., RH, SH) and negative (e.g., 4, 3) compo-
nents, allowing or exquisite control o hormone levels.
As an example, a small reduction o thyroid hormone
triggers a rapid increase o RH and SH secretion,
resulting in thyroid gland stimulation and increased
thyroid hormone production. When thyroid hormone
reaches a normal level, it eeds back to suppress RH
and SH, and a new steady state is attained. Feedback
regulation also occurs or endocrine systems that do not
involve the pituitary gland, such as calcium eedback on
P H, glucose inhibition o insulin secretion, and leptin
eedback on the hypothalamus. An understanding o
eedback regulation provides important insights into
endocrine testing paradigms (see below).
Positive eedback control also occurs but is not well
understood. T e primary example is estrogen-mediated
stimulation o the midcycle LH surge. Although
chronic low levels o estrogen are inhibitory, gradu-
ally rising estrogen levels stimulate LH secretion. T is
e ect, which is illustrative o an endocrine rhythm
(see below), involves activation o the hypothalamic
GnRH pulse generator. In addition, estrogen-primed
e
A
c
t
i
o
n
Adre nal Go nads
Thyro id
FIGURE 2 -3
Fe e d b a ck re g u la t io n o f e n d o crin e a xe s. CNS, central ner-
vous system.
gonadotropes are extraordinarily sensitive to GnRH,
leading to ampli cation o LH release.
PARACRINE AND AUTOCRINE CONTROL
T e previously mentioned examples o eedback control
involve classic endocrine pathways in which hormones
are released by one gland and act on a distant target
gland. However, local regulatory systems, of en involv-
ing growth actors, are increasingly recognized. Para-
crine regulation re ers to actors released by one cell that
act on an adjacent cell in the same tissue. For example,
somatostatin secretion by pancreatic islet δ cells inhibits
insulin secretion rom nearby β cells. Autocrine regula-
tion describes the action o a actor on the same cell rom
which it is produced. IGF-I acts on many cells that pro-
duce it, including chondrocytes, breast epithelium, and
gonadal cells. Unlike endocrine actions, paracrine and
autocrine control are di cult to document because local
growth actor concentrations cannot be measured readily.
Anatomic relationships o glandular systems also
greatly in uence hormonal exposure: the physical
organization o islet cells enhances their intercellular
communication; the portal vasculature o the hypotha-
lamic-pituitary system exposes the pituitary to high con-
centrations o hypothalamic releasing actors; testicular
semini erous tubules gain exposure to high testosterone
levels produced by the interdigitated Leydig cells; the
16 pancreas receives nutrient in ormation and local exposure term. Emerging evidence indicates that circadian clock
to peptide hormones (incretins) rom the gastrointestinal pathways not only regulate sleep-wake cycles but also
tract; and the liver is the proximal target o insulin action play important roles in virtually every cell type. For
because o portal drainage rom the pancreas. example, tissue-speci c deletion o clock genes alters
S
E
rhythms and levels o gene expression, as well as meta-
C
T
I
bolic responses in liver, adipose, and other tissues.
O
N
Other endocrine rhythms occur on a more rapid time
I
HORMONAL RHYTHMS
scale. Many peptide hormones are secreted in discrete
T e eedback regulatory systems described above are bursts every ew hours. LH and FSH secretion are exqui-
superimposed on hormonal rhythms that are used or sitely sensitive to GnRH pulse requency. Intermittent
I
n
t
r
adaptation to the environment. Seasonal changes, the pulses o GnRH are required to maintain pituitary sen-
o
d
u
daily occurrence o the light-dark cycle, sleep, meals, sitivity, whereas continuous exposure to GnRH causes
c
t
i
and stress are examples o the many environmental
o
pituitary gonadotrope desensitization. T is eature o
n
t
events that a ect hormonal rhythms. T e menstrual the hypothalamic-pituitary-gonadotrope axis orms the
o
E
cycle is repeated on average every 28 days, re ecting
n
basis or using long-acting GnRH agonists to treat cen-
d
o
the time required to ollicular maturation and ovu- tral precocious puberty or to decrease testosterone levels
c
r
i
n
lation (Chap. 13). Essentially all pituitary hormone in the management o prostate cancer. It is important to
o
l
o
rhythms are entrained to sleep and to the circadian be aware o the pulsatile nature o hormone secretion and
g
y
cycle, generating reproducible patterns that are repeated the rhythmic patterns o hormone production in relat-
approximately every 24 h. T e HPA axis, or example, ing serum hormone measurements to normal values. For
exhibits characteristic peaks o AC H and cortisol pro- some hormones, integrated markers have been developed
duction in the early morning, with a nadir during the to circumvent hormonal uctuations. Examples include
night. Recognition o these rhythms is important or 24-h urine collections or cortisol, IGF-I as a biologic
endocrine testing and treatment. Patients with Cush- marker o GH action, and HbA1c as an index o long-
ing’s syndrome characteristically exhibit increased term (weeks to months) blood glucose control.
midnight cortisol levels compared with normal indi- Of en, one must interpret endocrine data only in
viduals (Chap. 8). In contrast, morning cortisol levels the context o other hormones. For example, P H lev-
are similar in these groups, as cortisol is normally high els typically are assessed in combination with serum
at this time o day in normal individuals. T e HPA axis calcium concentrations. A high serum calcium level in
is more susceptible to suppression by glucocorticoids association with elevated P H is suggestive o hyper-
administered at night as they blunt the early-morning parathyroidism, whereas a suppressed P H in this situ-
rise o AC H. Understanding these rhythms allows ation is more likely to be caused by hypercalcemia o
glucocorticoid replacement that mimics diurnal pro- malignancy or other causes o hypercalcemia. Similarly,
duction by administering larger doses in the morning SH should be elevated when 4 and 3 concentrations
than in the af ernoon. Disrupted sleep rhythms can are low, re ecting reduced eedback inhibition. When
alter hormonal regulation. For example, sleep depriva- this is not the case, it is important to consider second-
tion causes mild insulin resistance, ood craving, and ary hypothyroidism, which is caused by a de ect at the
hypertension, which are reversible, at least in the short level o the pituitary.
 SECTION II

PITUITARY, THYROID,
AND ADRENAL
DISORDERS
 CH AP TER 3
ANTERIOR PITUITARY: PHYSIOLOGY OF PITUITARY
HORMONES
Sh lo m o Me lm e d
T e nterior pituit ry o en is re erred to s the “ s-
ter gl nd” bec use, together with the hypoth l us, it
orchestr tes the co plex regul tory unctions o ny
other endocrine gl nds. T e nterior pituit ry gl nd
produces six jor hor ones: (1) prol ctin (PRL), (2)
growth hor one (GH), (3) drenocorticotropic hor-
one (AC H), (4) luteinizing hor one (LH), (5)
ollicle-sti ul ting hor one (FSH), nd (6) thyroid-
sti ul ting hor one ( SH) (Table 3-1). Pituit ry hor-
ones re secreted in puls tile nner, re ecting
sti ul tion by n rr y o speci c hypoth l ic rele s-
ing ctors. E ch o these pituit ry hor ones elicits spe-
ci c responses in peripher l t rget tissues. T e hor on l
products o those peripher l gl nds, in turn, exert eed-
b ck control t the level o the hypoth l us nd pitu-
it ry to odul te pituit ry unction (Fig. 3-1). Pituit ry
tu ors c use ch r cteristic hor one excess syndro es.
Hor one de ciency y be inherited or cquired.
Fortun tely, there re e c cious tre t ents or ny
pituit ry hor one excess nd de ciency syndro es.
Nonetheless, these di gnoses re o en elusive; this
e ph sizes the i port nce o recognizing subtle clini-
c l ni est tions nd per or ing the correct l bor tory
di gnostic tests. For discussion of disorders of the pos-
terior pituitary, or neurohypophysis, see Chap. 6.
ANATO MY AND DEVELO PMENT
ANATOMY
T e pituit ry gl nd weighs ~600 g nd is loc ted
within the sell turcic ventr l to the di phr g sell ;
it consists o n to ic lly nd unction lly distinct
nterior nd posterior lobes. T e bony sell is contigu-
ous to v scul r nd neurologic structures, including
the c vernous sinuses, cr ni l nerves, nd optic chi s .
T us, exp nding intr sell r p thologic processes y SH in so totropes, l ctotropes, nd thyrotropes.
■ J. La rry Ja m e so n
h ve signi c nt centr l ss ef ects in ddition to their
endocrinologic i p ct.
Hypoth l ic neur l cells synthesize speci c rele s-
ing nd inhibiting hor ones th t re secreted directly
into the port l vessels o the pituit ry st lk. Blood sup-
ply o the pituit ry gl nd co es ro the superior nd
in erior hypophyse l rteries (Fig. 3-2). T e hypoth -
l ic-pituit ry port l plexus provides the jor blood
source or the nterior pituit ry, llowing reli ble tr ns-
ission o hypoth l ic peptide pulses without signi -
c nt syste ic dilution; consequently, pituit ry cells re
exposed to rele sing or inhibiting ctors nd in turn
rele se their hor ones s discrete pulses into the sys-
te ic circul tion (Fig. 3-3).
T e posterior pituit ry is supplied by the in e-
rior hypophyse l rteries. In contr st to the nterior
pituit ry, the posterior lobe is directly innerv ted by
hypoth l ic neurons (supr opticohypophyse l nd
tuberohypophyse l nerve tr cts) vi the pituit ry st lk
(Chap. 6). T us, posterior pituit ry production o v so-
pressin ( ntidiuretic hor one [ADH]) nd oxytocin
is p rticul rly sensitive to neuron l d ge by lesions
th t f ect the pituit ry st lk or hypoth l us.
PITUITARY DEVELOPMENT
T e e bryonic dif erenti tion nd tur tion o nte-
rior pituit ry cells h ve been elucid ted in consider-
ble det il. Pituit ry develop ent ro R thke’s pouch
involves co plex interpl y o line ge-speci c tr n-
scription ctors expressed in pluripotent precursor
cells nd gr dients o loc lly produced growth ctors
( ble 3-1). T e tr nscription ctor Prop-1 induces
pituit ry develop ent o Pit-1-speci c line ges s
well s gon dotropes. T e tr nscription ctor Pit-1
deter ines cell-speci c expression o GH, PRL, nd
18
 TABLE 3 -1 19
ANTERIOR PITUITARY HORMONE EXPRESSION AND REGULATION
CELL CORTICOTROPE SOMATOTROPE LACTOTROPE THYROTROPE GONADOTROPE

Tissue-speci c- T-Pit Prop-1, Pit-1 Prop-1, Pit-1 Prop-1, Pit-1, TEF SF-1, DAX-1
transcription
actor
Fetal appearance 6 weeks 8 weeks 12 weeks 12 weeks 12 weeks
Hormone POMC GH PRL TSH FSH, LH
Protein Polypeptide Polypeptide Polypeptide Glycoprotein Glycoprotein

C
H
α, βsubunits α, βsubunits

A
P
T
Amino acids 266 (ACTH 1–39) 191 199 211 210, 204

E
R
Stimulators CRH, AVP, gp-130 GHRH, ghrelin Estrogen, TRH, TRH GnRH, activins,

3
cytokines VIP estrogen
Inhibitors Glucocorticoids Somatostatin, IGF-I Dopamine T3, T4, dopamine, soma- Sex steroids, inhibin

A
tostatin, glucocorticoids

n
t
e
Target gland Adrenal Liver, bone, other Breast, other Thyroid Ovary, testis

r
i
o
r
tissues tissues

P
i
t
u
Trophic ef ect Steroid IGF-I production, Milk production T4 synthesis and Sex steroid pro-

i
t
a
production growth induction, secretion duction, ollicle

r
y
:
insulin antagonism growth, germ cell

P
h
maturation

y
s
i
o
Normal range ACTH, 4–22 pg/L <0.5 µg/La M <15 µg/L; 0.1–5 mU/L M, 5–20 IU/L,

l
o
g
F <20 µg/L F (basal), 5–20 IU/L

y
o
f
P
i
t
a
Hormone secretion integrated over 24 h.

u
i
t
Ab brevia tio n s: M, male; F, emale. For other abbreviations, see text.

a
r
So u rce: Adapted rom I Shimon, S Melmed, in S Melmed, P Conn (eds): Endocrinology: Basic and Clinical Principles. Totowa, NJ, Humana, 2005.

y
H
o
r
m
o
n
Expression o high levels o estrogen receptors in cells PROLACTIN

e
s
th t cont in Pit-1 vors PRL expression, where s
Syn th esis
thyrotrope e bryonic ctor ( EF) induces SH
expression. Pit-1 binds to GH, PRL, nd SH gene PRL consists o 198 ino cids nd h s olecul r
regul tory ele ents s well s to recognition sites on ss o 21,500 kD ; it is we kly ho ologous to GH nd
its own pro oter, providing ech nis or in- hu n pl cent l l ctogen (hPL), re ecting the duplic -
t ining speci c pituit ry hor one phenotypic st bil- tion nd divergence o co on GH-PRL-hPL pre-
ity. Gon dotrope cell develop ent is urther de ned cursor gene. PRL is synthesized in l ctotropes, which
by the cell-speci c expression o the nucle r receptors constitute bout 20% o nterior pituit ry cells. L cto-
steroidogenic ctor (SF-1) nd d os ge-sensitive sex tropes nd so totropes re derived ro co on
revers l, a dren l hypopl si critic l region, on chro- precursor cell th t y give rise to tu or th t secretes
oso e X, gene 1 (DAX-1). Develop ent o corti- both PRL nd GH. M rked l ctotrope cell hyperpl si
cotrope cells, which express the proopio el nocortin develops during pregn ncy nd the rst ew onths o
(POMC) gene, requires the -Pit tr nscription ctor. l ct tion. T ese tr nsient unction l ch nges in the l c-
Abnor lities o pituit ry develop ent c used by totrope popul tion re induced by estrogen.
ut tions o Pit-1, Prop-1, SF-1, DAX-1, nd -Pit
result in r re, selective or co bined pituit ry hor-
one de cit syndro es. Se cretio n
Nor l dult seru PRL levels re bout 10–25 µg/L in
wo en nd 10–20 µg/L in en. PRL secretion is puls -
tile, with the highest secretory pe ks occurring during
ANTERIO R P ITUITARY HO RMO NES r pid eye ove ent sleep. Pe k seru PRL levels (up
to 30 µg/L) occur between 4:00 nd 6:00 a .m. T e circu-
E ch nterior pituit ry hor one is under unique con- l ting h l -li e o PRL is bout 50 in.
trol, nd e ch exhibits highly speci c nor l nd dys- PRL is unique ong the pituit ry hor ones in
regul ted secretory ch r cteristics. th t the predo in nt centr l control ech nis is
20
TRH S RIF GHRH

CRH GnRH Third ve ntricle

Ne uroe ndocrine
Dopa mine
ce ll nucle i
Hypotha la mus
Hypotha la mus
–
S
E
S upe rior
C
T
hypophys e a l S ta lk
I
O
a rte ry
N
Infe rior
I
I
Long porta l hypophys e a l
+ + – + – – + ve s s e ls
P ituita ry a rte ry
–
P
Trophic
i
t
u
ACTH hormone
i
t
a
s e cre ting
r
Ta rge t +
y
,
orga ns TS H ce lls
T
h
Po s te rio r
y
r
Cortis ol pituitary
o
GH Ante rio r
i
LH P RL
d
,
Ce ll home os ta s is pituitary
a
Adre na l
a nd function
n
gla nds FS H
d
+ + S hort porta l
A
+
d
ve s s e l
r
Hormone
e
n
T4 /T3
a
s e cre tion
l
D
The rmoge ne s is
i
s
Thyroid FIGURE 3 -2
o
me ta bolis m
r
gla nds +
d
Live r Dia g ra m o f h yp o t h a la m ic p it u it a ry va scu la t u re . The hypo-
e
r
s
Te s tos te rone La cta tion thalamic nuclei produce hormones that traverse the portal sys-
Inhibin tem and impinge on anterior pituitary cells to regulate pituitary
S pe rma toge ne s is hormone secretion. Posterior pituitary hormones are derived
S e conda ry s ex Te s te s
+ rom direct neural extensions.
cha ra cte ris tics

Es tra diol Chondrocyte s

Proge s te rone
Inhibin Ova rie s Line a r a nd T yrotropin-rele sing hor one ( RH) (pyro Glu-
Ovula tion
orga n growth His-Pro-NH 2) is hypoth l ic tripeptide th t elicits
S e conda ry s ex PRL rele se within 15–30 in er intr venous injec-
cha ra cte ris tics
IGF-1
tion. T e physiologic relev nce o RH or PRL regu-
l tion is uncle r, nd it ppe rs pri rily to regul te
FIGURE 3 -1 SH (Chap. 7). Vasoactive intestinal peptide (VIP) lso
Dia g ra m o f p it u it a ry a xe s. Hypothalamic hormones regulate induces PRL rele se, where s glucocorticoids nd thyroid
anterior pituitary trophic hormones that in turn determine target hor one we kly suppress PRL secretion.
gland secretion. Peripheral hormones eed back to regulate hypo- Seru PRL levels rise tr nsiently er exercise,
thalamic and pituitary hormones. For abbreviations, see text. e ls, sexu l intercourse, inor surgic l procedures,

inhibitory, re ecting dop ine- edi ted suppression

L
m
/
o PRL rele se. T is regul tory p thw y ccounts or
g
p
GnRH puls e s
H
the spont neous PRL hypersecretion th t occurs with
R
n
pituit ry st lk section, o en consequence o co pres-
G
L
sive ss lesions t the skull b se. Pituit ry dop ine
m
/
U
type 2 (D2) receptors edi te inhibition o PRL synthe- LH puls e s
l
m
sis nd secretion. rgeted disruption (gene knockout)
H
L
o the urine D2 receptor in ice results in hyperpro-
l ctine i nd l ctotrope proli er tion. As discussed FIGURE 3 -3
below, dop ine gonists pl y centr l role in the Hyp o t h a la m ic g o n a d o t ro p in re le a sin g h o rm o n e (Gn RH)
n ge ent o hyperprol ctine ic disorders. p u lse s induce secretory pulses o luteinizing hormone (LH).
gener l nesthesi , chest w ll injury, cute yoc r-
di l in rction, nd other or s o cute stress. PRL
levels incre se rkedly ( bout ten old) during preg-
n ncy nd decline r pidly within 2 weeks o p rturi-
tion. I bre st- eeding is initi ted, b s l PRL levels
re in elev ted; suckling sti ul tes tr nsient re ex
incre ses in PRL levels th t l st or bout 30–45 in.
Bre st suckling ctiv tes neur l f erent p thw ys in
the hypoth l us th t induce PRL rele se. With ti e,
suckling-induced responses di inish nd inter eeding
20-kD GH olecule with si il r biologic ctivity. Pl - 21
cent l syncytiotrophobl st cells express GH v ri nt
(hGH-V) gene; the rel ted hor one hu n chorionic
so totropin (HCS) is expressed by distinct e bers o
the gene cluster.
Se cretio n
GH secretion is controlled by co plex hypoth -
l ic nd peripher l ctors. GH-releasing hormone

C
H
PRL levels return to nor l. (GHRH) is 44- ino- cid hypoth l ic peptide

A
P
th t sti ul tes GH synthesis nd rele se. Ghrelin, n

T
E
oct noyl ted g stric-derived peptide, nd synthetic

R
Actio n

3
gonists o the GHS-R induce GHRH nd lso directly
T e PRL receptor is e ber o the type I cytokine sti ul te GH rele se. Somatostatin (so totropin-
receptor ily th t lso includes GH nd interleukin rele se inhibiting ctor [SRIF]) is synthesized in the

A
(IL) 6 receptors. Lig nd binding induces receptor di er-

n
edi l preoptic re o the hypoth l us nd inhibits

t
e
iz tion nd intr cellul r sign ling by J nus kin se (JAK),

r
i
GH secretion. GHRH is secreted in discrete spikes th t

o
r
which sti ul tes tr nsloc tion o the sign l tr nsduction

P
elicit GH pulses, where s SRIF sets b s l GH secre-

i
t
u
nd ctiv tors o tr nscription (S A ) ily to ctiv te tory tone. SRIF lso is expressed in ny extr hypo-

i
t
a
t rget genes. In the bre st, the lobulo lveol r epithe-

r
th l ic tissues, including the centr l nervous syste

y
:
liu proli er tes in response to PRL, pl cent l l ctogens,

P
(CNS), g strointestin l tr ct, nd p ncre s, where it

h
y
estrogen, progesterone, nd loc l p r crine growth c-

s
lso cts to inhibit islet hor one secretion. IGF-I,

i
o
l
tors, including insulin-like growth ctor I (IGF-I).

o
the peripher l t rget hor one or GH, eeds b ck to

g
y
PRL cts to induce nd int in l ct tion, decre se inhibit GH; estrogen induces GH, where s chronic glu-

o
f
reproductive unction, nd suppress sexu l drive. T ese

P
cocorticoid excess suppresses GH rele se.

i
t
u
unctions re ge red tow rd ensuring th t tern l l c- Sur ce receptors on the so totrope regul te GH

i
t
a
t tion is sust ined nd not interrupted by pregn ncy.

r
synthesis nd secretion. T e GHRH receptor is G

y
H
PRL inhibits reproductive unction by suppressing protein–coupled receptor (GPCR) th t sign ls through

o
r
m
hypoth l ic gon dotropin-rele sing hor one (GnRH) the intr cellul r cyclic AMP p thw y to sti ul te

o
n
nd pituit ry gon dotropin secretion nd by i p iring

e
so totrope cell proli er tion s well s GH produc-

gon d l steroidogenesis in both wo en nd en. In the
ov ry, PRL blocks olliculogenesis nd inhibits gr nu-
los cell ro t se ctivity, le ding to hypoestrogenis
nd novul tion. PRL lso h s luteolytic ef ect, gen-
er ting shortened, or in dequ te, lute l ph se o the
enstru l cycle. In en, ttenu ted LH secretion le ds
to low testosterone levels nd decre sed sper togen-
esis. T ese hor on l ch nges decre se libido nd reduce
ertility in p tients with hyperprol ctine i .
GROWTH HORMONE
Syn th esis
GH is the ost bund nt nterior pituit ry hor one,
nd GH-secreting so totrope cells constitute up to
50% o the tot l nterior pituit ry cell popul tion. M -
oso totrope cells, which coexpress PRL with GH,
c n be identi ed by using double i unost ining tech-
niques. So totrope develop ent nd GH tr nscription
re deter ined by expression o the cell-speci c Pit-1
nucle r tr nscription ctor. Five distinct genes encode
GH nd rel ted proteins. T e pituit ry GH gene (hGH-
N) produces two ltern tively spliced products th t give
rise to 22-kD GH (191 ino cids) nd less bund nt
s
tion. In ctiv ting ut tions o the GHRH receptor
c use pro ound dw r s . A distinct sur ce recep-
tor or ghrelin, the g stric-derived GH secret gogue,
is expressed in both the hypoth l us nd pituit ry.
So tost tin binds to ve distinct receptor subtypes
(SS R1 to SS R5); SS R2 nd SS R5 subtypes pre er-
enti lly suppress GH ( nd SH) secretion.
GH secretion is puls tile, with highest pe k lev-
els occurring t night, gener lly correl ting with sleep
onset. GH secretory r tes decline rkedly with ge
so th t hor one levels in iddle ge re bout 15%
o pubert l levels. T ese ch nges re p r lleled by n
ge-rel ted decline in le n uscle ss. GH secretion
is lso reduced in obese individu ls, lthough IGF-I
levels y not be suppressed, suggesting ch nge in
the setpoint or eedb ck control. Elev ted GH lev-
els occur within n hour o deep sleep onset s well
s er exercise, physic l stress, nd tr u nd dur-
ing sepsis. Integr ted 24-h GH secretion is higher in
wo en nd is lso enh nced by estrogen repl ce ent
likely re ective o incre sed peripher l GH-resist nce.
Using st nd rd ss ys, r ndo GH e sure ents re
undetect ble in ~50% o d yti e s ples obt ined
ro he lthy subjects nd re lso undetect ble in ost
obese nd elderly subjects. T us, single r ndo GH
22 e sure ents do not distinguish p tients with dult ctions th t ppe r to be both dependent on nd inde-
GH de ciency ro nor l persons. pendent o GH. T us, GH d inistr tion induces
GH secretion is pro oundly in uenced by nutrition l circul ting IGF-I s well s sti ul ting loc l IGF-I pro-
ctors. Using newer ultr sensitive GH ss ys with duction in ultiple tissues.
sensitivity o 0.002 µg/L, glucose lo d suppresses Both IGF-I nd IGF-II re bound to high- nity cir-
GH to <0.7 µg/L in wo en nd to <0.07 µg/L in en. cul ting IGF-binding proteins (IGFBPs) th t regul te
Incre sed GH pulse requency nd pe k plitudes IGF bio ctivity. Levels o IGFBP3 re GH-dependent,
occur with chronic lnutrition or prolonged sting. nd it serves s the jor c rrier protein or circul ting
GH is sti ul ted by intr venous L- rginine, dop ine, IGF-I. GH de ciency nd lnutrition usu lly re sso-
nd po orphine ( dop ine receptor gonist), s ci ted with low IGFBP3 levels. IGFBP1 nd IGFBP2
S
E
well s by α- drenergic p thw ys. β-Adrenergic block- regul te loc l tissue IGF ction but do not bind ppre-
C
T
I
de induces b s l GH nd enh nces GHRH- nd insu- ci ble ounts o circul ting IGF-I.
O
N
lin-evoked GH rele se. Seru IGF-I concentr tions re pro oundly f ected
I
I
by physiologic ctors. Levels incre se during puberty,
Actio n pe k t 16 ye rs, nd subsequently decline by >80%
during the ging process. IGF-I concentr tions re
P
i
t
T e p ttern o GH secretion y f ect tissue responses.
u
higher in wo en th n in en. Bec use GH is the jor
i
t
a
T e higher GH puls tility observed in en co p red deter in nt o hep tic IGF-I synthesis, bnor lities
r
y
,
with the rel tively continuous b s l GH secretion in o GH synthesis or ction (e.g., pituit ry ilure, GHRH
T
h
y
wo en y be n i port nt biologic deter in nt o receptor de ect, GH receptor de ect or ph r cologic
r
o
i
line r growth p tterns nd liver enzy e induction.
d
GH receptor block de) reduce IGF-I levels. Hypoc lo-
,
a
T e 70-kD peripher l GH receptor protein h s
n
ric st tes re ssoci ted with GH resist nce; IGF-I lev-
d
structur l ho ology with the cytokine/he topoi-
A
els re there ore low with c chexi , lnutrition, nd
d
r
etic super ily. A r g ent o the receptor extr cel-
e
sepsis. In cro eg ly, IGF-I levels re inv ri bly high
n
a
lul r do in gener tes soluble GH binding protein
l
nd re ect log-line r rel tionship with circul ting GH
D
i
(GHBP) th t inter cts with GH in the circul tion. T e
s
concentr tions.
o
r
d
liver nd c rtil ge cont in the gre test nu ber o GH
e
IGF-I p hysio lo g y
r
s
receptors. GH binding to pre or ed receptor di ers is
Injected IGF-I (100 µg/kg) induces hypoglyce i , nd
ollowed by intern l rot tion nd subsequent sign ling
lower doses i prove insulin sensitivity in p tients with
through the JAK/S A p thw y. Activ ted S A pro-
severe insulin resist nce nd di betes. In c chectic
teins tr nsloc te to the nucleus, where they odul te
subjects, IGF-I in usion (12 µg/kg per hour) enh nces
expression o GH-regul ted t rget genes. GH n logues
nitrogen retention nd lowers cholesterol levels. Lon-
th t bind to the receptor but re inc p ble o edi ting
ger-ter subcut neous IGF-I injections enh nce
receptor sign ling re potent nt gonists o GH ction.
protein synthesis nd re n bolic. Although bone or-
A GH receptor nt gonist (pegviso nt) is pproved
tion rkers re induced, bone turnover lso y be
or tre t ent o cro eg ly.
sti ul ted by IGF-I. IGF-I h s only been pproved or
GH induces protein synthesis nd nitrogen reten-
use in p tients with GH-resist nce syndro es.
tion nd i p irs glucose toler nce by nt gonizing
IGF-I side ef ects re dose-dependent, nd over-
insulin ction. GH lso sti ul tes lipolysis, le ding to
dose y result in hypoglyce i , hypotension, uid
incre sed circul ting tty cid levels, reduced o en-
retention, te poro ndibul r j w p in, nd incre sed
t l t ss, nd enh nced le n body ss. GH pro-
intr cr ni l pressure, ll o which re reversible. Av s-
otes sodiu , pot ssiu , nd w ter retention nd
cul r e or l he d necrosis h s been reported. Chronic
elev tes seru levels o inorg nic phosph te. Line r
excess IGF-I d inistr tion presu bly would result in
bone growth occurs s result o co plex hor on l
e tures o cro eg ly.
nd growth ctor ctions, including those o IGF-I. GH
sti ul tes epiphyse l prechondrocyte dif erenti tion.
T ese precursor cells produce IGF-I loc lly, nd their
proli er tion is lso responsive to the growth ctor. ADRENOCORTICOTROPIC HORMONE
(See lso Ch p. 8)
In sulin -like growth fa cto rs
Syn th esis
Although GH exerts direct ef ects in t rget tissues,
ny o its physiologic ef ects re edi ted indirectly AC H-secreting corticotrope cells constitute bout 20%
through IGF-I, potent growth nd dif erenti tion c- o the pituit ry cell popul tion. AC H (39 ino cids)
tor. T e liver is the jor source o circul ting IGF-I. is derived ro the POMC precursor protein (266
In peripher l tissues, IGF-I lso exerts loc l p r crine ino cids) th t lso gener tes sever l other peptides,
including β-lipotropin, β-endorphin, et-enkeph lin,
α- el nocyte-sti ul ting hor one (α-MSH), nd
corticotropin-like inter edi te lobe protein (CLIP).
T e POMC gene is potently suppressed by glucocorti-
coids nd induced by corticotropin-rele sing hor one
(CRH), rginine v sopressin (AVP), nd proin
tory cytokines, including IL-6, s well s leuke i
inhibitory ctor.
CRH, 41- ino- cid hypoth l ic peptide synthe-
sized in the p r ventricul r nucleus s well s in higher
steroidogenesis by sust ining dren l cell proli er tion 23
nd unction. T e receptor or AC H, design ted mela-
nocortin-2 receptor, is GPCR th t induces steroidogen-
esis by sti ul ting c sc de o steroidogenic enzy es
(Chap. 8).
-
GONADOTROPINS: FSH AND LH
Syn th esis a n d se cretio n

C
H
br in centers, is the predo in nt sti ul tor o AC H Gon dotrope cells constitute bout 10% o nterior

A
P
synthesis nd rele se. T e CRH receptor is GPCR th t pituit ry cells nd produce two gon dotropin hor-

T
E
ones—LH nd FSH. Like SH nd hCG, LH nd FSH

R
is expressed on the corticotrope nd sign ls to induce

3
POMC tr nscription. re glycoprotein hor ones th t co prise α nd β sub-
units. T e α subunit is co on to these glycoprotein
hor ones; speci city o hor one unction is con erred

A
Se cretio n

n
by the β subunits, which re expressed by sep r te

t
e
r
i
AC H secretion is puls tile nd exhibits ch r cteristic genes.

o
r
P
circ di n rhyth , pe king t bout 6 a .m. nd re ch- Gon dotropin synthesis nd rele se re dyn ic lly

i
t
u
ing n dir bout idnight. Adren l glucocorticoid

i
regul ted. T is is p rticul rly true in wo en, in who

t
a
r
secretion, which is driven by AC H, ollows p r llel r pidly uctu ting gon d l steroid levels v ry throughout

y
:
P
diurn l p ttern. AC H circ di n rhyth icity is deter- the enstru l cycle. Hypoth l ic GnRH, 10- ino-

h
y
s
ined by v ri tions in secretory pulse plitude r ther cid peptide, regul tes the synthesis nd secretion o both

i
o
l
o
th n ch nges in pulse requency. Superi posed on this LH nd FSH. Br in kisspeptin, product o the KISSI

g
y
endogenous rhyth , AC H levels re incre sed by gene regul tes hypoth l ic GnRH rele se. GnRH is

o
f
P
physic l nd psychologic l stress, exercise, cute illness, secreted in discrete pulses every 60–120 in, nd the

i
t
u
i
nd insulin-induced hypoglyce i . pulses in turn elicit LH nd FSH pulses (Fig. 3-3). T e

t
a
r
Glucocorticoid- edi ted neg tive regul tion o the

y
puls tile ode o GnRH input is essenti l to its ction;

H
o
hypoth l ic-pituit ry- dren l (HPA) xis occurs s pulses pri e gon dotrope responsiveness, where s con-

r
m
consequence o both hypoth l ic CRH suppression tinuous GnRH exposure induces desensitiz tion. B sed

o
n
e
nd direct ttenu tion o pituit ry POMC gene expres- on this pheno enon, long- cting GnRH gonists re

sion nd AC H rele se. In contr st, loss o cortisol
eedb ck inhibition, s occurs in pri ry dren l il-
ure, results in extre ely high AC H levels.
Acute in tory or septic insults ctiv te the
HPA xis through the integr ted ctions o proin
tory cytokines, b cteri l toxins, nd neur l sign ls.
T e overl pping c sc de o AC H-inducing cytokines
(tu or necrosis ctor [ NF]; IL-1, -2, nd -6; nd leu-
ke i inhibitory ctor) ctiv tes hypoth l ic CRH
nd AVP secretion, pituit ry POMC gene expression,
nd loc l pituit ry p r crine cytokine networks. T e
resulting cortisol elev tion restr ins the in tory
response nd en bles host protection. Conco it ntly,
cytokine- edi ted centr l glucocorticoid receptor
resist nce i p irs glucocorticoid suppression o the
HPA. T us, the neuroendocrine stress response re ects
the net result o highly integr ted hypoth l ic, intr -
pituit ry, nd peripher l hor one nd cytokine sign ls
cting to regul te cortisol secretion.
Actio n
T e jor unction o the HPA xis is to int in
et bolic ho eost sis nd edi te the neuroendo-
crine stress response. AC H induces drenocortic l
s
used to suppress gon dotropin levels in children with
precocious puberty nd in en with prost te c ncer
nd re used in so e ovul tion-induction protocols to
reduce levels o endogenous gon dotropins (Chap. 13).
- Estrogens ct t both the hypoth l us nd the pituit ry
to odul te gon dotropin secretion. Chronic estrogen
exposure is inhibitory, where s rising estrogen levels,
s occur during the preovul tory surge, exert positive
eedb ck to incre se gon dotropin pulse requency nd
plitude. Progesterone slows GnRH pulse requency
but enh nces gon dotropin responses to GnRH. estos-
terone eedb ck in en lso occurs t the hypoth l ic
nd pituit ry levels nd is edi ted in p rt by its conver-
sion to estrogens.
Although GnRH is the in regul tor o LH nd
FSH secretion, FSH synthesis is lso under sep r te
control by the gon d l peptides inhibin nd ctivin,
which re e bers o the tr ns or ing growth ctor
β ( GF-β) ily. Inhibin selectively suppresses FSH,
where s ctivin sti ul tes FSH synthesis (Chap. 13).
Actio n
T e gon dotropin hor ones inter ct with their respec-
tive GPCRs expressed in the ov ry nd testis, evoking
24 ger cell develop ent nd tur tion nd steroid hor- T yrotrope cell proli er tion nd SH secretion re
one biosynthesis. In wo en, FSH regul tes ov ri n both induced when neg tive eedb ck inhibition by
ollicle develop ent nd sti ul tes ov ri n estrogen pro- thyroid hor ones is re oved. T us, thyroid d ge
duction. LH edi tes ovul tion nd inten nce o the (including surgic l thyroidecto y), r di tion-induced
corpus luteu . In en, LH induces Leydig cell testoster- hypothyroidis , chronic thyroiditis, nd prolonged goi-
one synthesis nd secretion, nd FSH sti ul tes se ini - trogen exposure re ssoci ted with incre sed SH lev-
erous tubule develop ent nd regul tes sper togenesis. els. Long-st nding untre ted hypothyroidis c n le d
to elev ted SH levels s well s thyrotrope hyperpl si
nd pituit ry enl rge ent, which y be evident on
THYROID-STIMULATING HORMONE gnetic reson nce i ging.
S
E
C
Syn th esis a n d se cretio n
T
I
O
N
SH-secreting thyrotrope cells constitute 5% o the
I
Actio n
I
nterior pituit ry cell popul tion. SH sh res co -
on α subunit with LH nd FSH but cont ins spe- SH is secreted in pulses, lthough the excursions re
ci c SH β subunit. RH is hypoth l ic tripeptide odest in co p rison to other pituit ry hor ones
P
i
t
(pyroglut yl histidylprolin ide) th t cts through bec use o the low plitude o the pulses nd the
u
i
t
a
pituit ry GPCR to sti ul te SH synthesis nd secre- rel tively long h l -li e o SH. Consequently, single
r
y
,
tion; it lso sti ul tes the l ctotrope cell to secrete PRL. deter in tions o SH su ce to precisely ssess its
T
h
y
SH secretion is sti ul ted by RH, where s thyroid circul ting levels. SH binds to GPCR on thyroid ol-
r
o
i
d
hor ones, dop ine, so tost tin, nd glucocorti- licul r cells to sti ul te thyroid hor one synthesis nd
,
a
coids suppress SH by overriding RH induction. rele se (Chap. 7).
n
d
A
d
r
e
n
a
l
D
i
s
o
r
d
e
r
s
 CH AP TER 4
HYPOPITUITARISM
Sh lo m o Me lm e d
Inadequate production o anterior pituitary hormones
leads to eatures o hypopituitarism. Impaired pro-
duction o one or more o the anterior pituitary tro-
phic hormones can result rom inherited disorders;
more commonly, adult hypopituitarism is acquired
and re ects the compressive mass e ects o tumors or
the consequences o local pituitary or hypothalamic
traumatic, in ammatory, or vascular damage. T ese
processes also may impair synthesis or secretion o
hypothalamic hormones, with resultant pituitary ailure
(Table 4-1).
DEVELOPMENTAL AND GENETIC CAUSES
OF HYPOPITUITARISM
Pituita ry dysp la sia
Pituitary dysplasia may result in aplastic, hypoplastic, or
ectopic pituitary gland development. Because pituitary
development ollows midline cell migration rom the
nasopharyngeal Rathke’s pouch, midline cranio acial
disorders may be associated with pituitary dysplasia.
Acquired pituitary ailure in the newborn also can be
caused by birth trauma, including cranial hemorrhage,
asphyxia, and breech delivery.
SEPTO-o p tic d ysp la sia
Hypothalamic dys unction and hypopituitarism may
result rom dysgenesis o the septum pellucidum or
corpus callosum. A ected children have mutations in
the HESX1 gene, which is involved in early develop-
ment o the ventral prosencephalon. T ese children
exhibit variable combinations o cle palate, syndactyly,
ear de ormities, hypertelorism, optic nerve hypoplasia,
micropenis, and anosmia. Pituitary dys unction leads
to diabetes insipidus, growth hormone (GH) de ciency
and short stature, and, occasionally, thyroid-stimulating
hormone ( SH) de ciency.
■ J. La rry Ja m e so n
Tissue-sp e ci c a cto r m uta tio ns
Several pituitary cell–speci c transcription actors, such
as Pit-1 and Prop-1, are critical or determining the
development and committed unction o di erentiated
anterior pituitary cell lineages. Autosomal dominant
or recessive Pit-1 mutations cause combined GH, pro-
lactin (PRL), and SH de ciencies. T ese patients usu-
ally present with growth ailure and varying degrees o
hypothyroidism. T e pituitary may appear hypoplastic
on magnetic resonance imaging (MRI).
Prop-1 is expressed early in pituitary development
and appears to be required or Pit-1 unction. Familial
and sporadic PROP1 mutations result in combined GH,
PRL, SH, and gonadotropin de ciency. Over 80% o
these patients have growth retardation; by adulthood,
all are de cient in SH and gonadotropins, and a small
minority later develop adrenocorticotropic hormone
(AC H) de ciency. Because o gonadotropin de -
ciency, these individuals do not enter puberty spon-
taneously. In some cases, the pituitary gland appears
enlarged on MRI. TPIT mutations result in AC H de -
ciency associated with hypocortisolism.
Develo p m en ta l hyp o th a la m ic d ys u n ctio n
Ka llm a n n syn d ro m e
Kallmann syndrome results rom de ective hypotha-
lamic gonadotropin-releasing hormone (GnRH) syn-
thesis and is associated with anosmia or hyposmia due
to ol actory bulb agenesis or hypoplasia (Chap. 11).
Classically, the syndrome may also be associated with
color blindness, optic atrophy, nerve dea ness, cle
palate, renal abnormalities, cryptorchidism, and neu-
rologic abnormalities such as mirror movements. T e
initial genetic cause was identi ed in the X-linked KAL
gene, mutations o which impair embryonic migra-
tion o GnRH neurons rom the hypothalamic ol ac-
tory placode to the hypothalamus. Based on urther
25
26 TABLE 4 -1 pronounced hypogonadal eatures, including micrope-
ETIOLOGY OF HYPOPITUITARISM a nis, probably the result o low testosterone levels during
Development/structural in ancy. Females present with primary amenorrhea and
Transcription actor de ect ailure o secondary sexual development.
Pituitary dysplasia/aplasia Kallmann syndrome and other causes o congenital
Congenital central nervous system mass, encephalocele GnRH de ciency are characterized by low luteinizing
Primary empty sella hormone (LH) and ollicle-stimulating hormone (FSH)
Congenital hypothalamic disorders (septo-optic dysplasia,
levels and low concentrations o sex steroids (testoster-
Prader-Willi syndrome, Laurence-Moon-Biedl syndrome,
Kallmann syndrome) one or estradiol). In sporadic cases o isolated gonado-
tropin de ciency, the diagnosis is o en one o exclusion
S
Traumatic
E
a er other known causes o hypothalamic-pituitary
C
Surgical resection
T
I
Radiation damage dys unction have been eliminated. Repetitive GnRH
O
N
Head injuries administration restores normal pituitary gonadotropin
I
I
Neoplastic responses, pointing to a hypothalamic de ect in these
Pituitary adenoma
patients.
Parasellar mass (germinoma, ependymoma, glioma)
Long-term treatment o males with human chorionic
P
Rathke’s cyst
i
t
u
gonadotropin (hCG) or testosterone restores pubertal
i
Craniopharyngioma
t
a
development and secondary sex characteristics; women
r
Hypothalamic hamartoma, gangliocytoma
y
,
can be treated with cyclic estrogen and progestin. Fer-
T
Pituitary metastases (breast, lung, colon carcinoma)
h
y
Lymphoma and leukemia tility also may be restored by the administration o
r
o
i
d
Meningioma gonadotropins or by using a portable in usion pump to
,
a
In ltrative/in ammatory
n
deliver subcutaneous, pulsatile GnRH.
d
Lymphocytic hypophysitis
A
d
Hemochromatosis
r
e
Ba rd e t-Bie d l syn d ro m e
n
Sarcoidosis
a
T is very rare genetically heterogeneous disorder is
l
D
Histiocytosis X
i
s
characterized by mental retardation, renal abnormali-
o
Granulomatous hypophysitis
r
d
Transcription actor antibodies ties, obesity, and hexadactyly, brachydactyly, or syn-
e
r
s
Vascular dactyly. Central diabetes insipidus may or may not be
Pituitary apoplexy associated. GnRH de ciency occurs in 75% o males
Pregnancy-related (in arction with diabetes; postpartum
and hal o a ected emales. Retinal degeneration
necrosis)
Sickle cell disease
begins in early childhood, and most patients are blind
Arteritis by age 30. Numerous subtypes o Bardet-Biedl syn-
In ections drome (BBS) have been identi ed, with genetic linkage
Fungal (histoplasmosis) to at least nine di erent loci. Several o the loci encode
Parasitic (toxoplasmosis) genes involved in basal body cilia unction, and this
Tuberculosis may account or the diverse clinical mani estations.
Pneumocystis carinii
a
Trophic hormone ailure associated with pituitary compression or destruc- Le p tin a n d le p tin re ce p to r m u tatio n s
tion usually occurs sequentially: growth hormone > ollicle-stimulating De ciencies o leptin or its receptor cause a broad spec-
hormone > luteinizing hormone > thyroid-stimulating hormone > adreno-
trum o hypothalamic abnormalities, including hyper-
corticotropic hormone. During childhood, growth retardation is o ten the
presenting eature, and in adults, hypogonadism is the earliest symptom. phagia, obesity, and central hypogonadism (Chap. 20).
Decreased GnRH production in these patients results in
attenuated pituitary FSH and LH synthesis and release.

studies, at least a dozen other genetic abnormalities, in Pra d e r-Willi syn d ro m e

addition to KAL mutations, have been ound to cause
isolated GnRH de ciency. Autosomal recessive (i.e.,
GPR54, KISS1) and dominant (i.e., FGFR1) modes
o transmission have been described, and there is a
growing list o genes associated with GnRH de ciency
(GNRH1, PROK2, PROKR2, CH7, PCSK1, FGF8, NELF,
WDR11, TAC3, TACR3). A raction o patients have
digenic mutations. Associated clinical eatures, in addi-
tion to GnRH de ciency, vary depending on the genetic
cause. GnRH de ciency prevents progression through
puberty. Males present with delayed puberty and
T is is a contiguous gene syndrome that results rom
deletion o the paternal copies o the imprinted SNRPN
gene, the NECDIN gene, and possibly other genes on
chromosome 15q. Prader-Willi syndrome is associated
with hypogonadotropic hypogonadism, hyperphagia-
obesity, chronic muscle hypotonia, mental retardation,
and adult-onset diabetes mellitus. Multiple somatic
de ects also involve the skull, eyes, ears, hands, and
eet. Diminished hypothalamic oxytocin- and vaso-
pressin-producing nuclei have been reported. De -
cient GnRH synthesis is suggested by the observation
that chronic GnRH treatment restores pituitary LH and
FSH release.
ACQUIRED HYPOPITUITARISM
Hypopituitarism may be caused by accidental or neuro-
surgical trauma; vascular events such as apoplexy; pitu-
itary or hypothalamic neoplasms, craniopharyngioma,
lymphoma, or metastatic tumors; in ammatory disease
such as lymphocytic hypophysitis; in ltrative disorders
such as sarcoidosis, hemochromatosis, and tuberculosis;
or irradiation.
Increasing evidence suggests that patients with brain
injury, including contact sports trauma, subarachnoid
hemorrhage, and irradiation, have transient hypopi-
tuitarism and require intermittent long-term endo-
crine ollow-up, because permanent hypothalamic or
pituitary dys unction will develop in 25–40% o these
patients.
Hyp o tha la m ic in ltra tio n d iso rd ers
T ese disorders—including sarcoidosis, histiocytosis X,
amyloidosis, and hemochromatosis— requently involve
both hypothalamic and pituitary neuronal and neuro-
chemical tracts. Consequently, diabetes insipidus occurs
in hal o patients with these disorders. Growth retar-
dation is seen i attenuated GH secretion occurs be ore
puberty. Hypogonadotropic hypogonadism and hyper-
prolactinemia are also common.
In f a m m a to ry lesio n s
Pituitary damage and subsequent secretory dys unction
can be seen with chronic site in ections such as tuber-
culosis, with opportunistic ungal in ections associated
with AIDS, and in tertiary syphilis. Other in amma-
tory processes, such as granulomas and sarcoidosis,
may mimic the eatures o a pituitary adenoma. T ese
lesions may cause extensive hypothalamic and pituitary
damage, leading to trophic hormone de ciencies.
Cra n ia l irra d ia tio n
Cranial irradiation may result in long-term hypotha-
lamic and pituitary dys unction, especially in children
and adolescents, as they are more susceptible to dam-
age a er whole-brain or head and neck therapeutic
irradiation. T e development o hormonal abnormali-
ties correlates strongly with irradiation dosage and
the time interval a er completion o radiotherapy. Up
to two-thirds o patients ultimately develop hormone
insuf ciency a er a median dose o 50 Gy (5000 rad)
directed at the skull base. T e development o hypopi-
tuitarism occurs over 5–15 years and usually re ects
hypothalamic damage rather than primary destruction
o pituitary cells. Although the pattern o hormone loss 27
is variable, GH de ciency is most common, ollowed by
gonadotropin and AC H de ciency. When de ciency
o one or more hormones is documented, the possibil-
ity o diminished reserve o other hormones is likely.
Accordingly, anterior pituitary unction should be
continually evaluated over the long term in previously
irradiated patients, and replacement therapy instituted
when appropriate (see below).
C
H
A
Lym p h o cytic hyp o p hysitis
P
T
E
T is occurs most o en in postpartum women; it usually
R
4
presents with hyperprolactinemia and MRI evidence
o a prominent pituitary mass that o en resembles an
adenoma, with mildly elevated PRL levels. Pituitary ail-
H
y
ure caused by di use lymphocytic in ltration may be
p
o
p
transient or permanent but requires immediate evalua-
i
t
u
tion and treatment. Rarely, isolated pituitary hormone
i
t
a
r
de ciencies have been described, suggesting a selec-
i
s
m
tive autoimmune process targeted to speci c cell types.
Most patients mani est symptoms o progressive mass
e ects with headache and visual disturbance. T e eryth-
rocyte sedimentation rate o en is elevated. Because
the MRI image may be indistinguishable rom that o a
pituitary adenoma, hypophysitis should be considered
in a postpartum woman with a newly diagnosed pitu-
itary mass be ore an unnecessary surgical intervention
is undertaken. T e in ammatory process o en resolves
a er several months o glucocorticoid treatment, and
pituitary unction may be restored, depending on the
extent o damage.
Pituita ry a p o p lexy
Acute intrapituitary hemorrhagic vascular events can
cause substantial damage to the pituitary and surround-
ing sellar structures. Pituitary apoplexy may occur
spontaneously in a preexisting adenoma; postpartum
(Sheehan’s syndrome); or in association with diabetes,
hypertension, sickle cell anemia, or acute shock. T e
hyperplastic enlargement o the pituitary, which occurs
normally during pregnancy, increases the risk or
hemorrhage and in arction. Apoplexy is an endocrine
emergency that may result in severe hypoglycemia,
hypotension and shock, central nervous system (CNS)
hemorrhage, and death. Acute symptoms may include
severe headache with signs o meningeal irritation,
bilateral visual changes, ophthalmoplegia, and, in severe
cases, cardiovascular collapse and loss o conscious-
ness. Pituitary computed tomography (C ) or MRI may
reveal signs o intratumoral or sellar hemorrhage, with
pituitary stalk deviation and compression o pituitary
tissue.
Patients with no evident visual loss or impaired con-
sciousness can be observed and managed conservatively
28 with high-dose glucocorticoids. T ose with signi cant trophic hormones in the setting o low levels o target
or progressive visual loss, cranial nerve palsy, or loss hormones. For example, low ree thyroxine in the setting
o consciousness require urgent surgical decompres- o a low or inappropriately normal SH level suggests
sion. Visual recovery a er sellar surgery is inversely secondary hypothyroidism. Similarly, a low testosterone
correlated with the length o time a er the acute event. level without elevation o gonadotropins suggests hypo-
T ere ore, severe ophthalmoplegia or visual de cits are gonadotropic hypogonadism. Provocative tests may be
indications or early surgery. Hypopituitarism is com- required to assess pituitary reserve (Table 4-2). GH
mon a er apoplexy. responses to insulin-induced hypoglycemia, arginine,
L-dopa, growth hormone–releasing hormone (GHRH),
or growth hormone–releasing peptides (GHRPs) can be
S
Em p ty sella
E
used to assess GH reserve. Corticotropin-releasing hor-
C
T
I
A partial or apparently totally empty sella is o en an mone (CRH) administration induces AC H release,
O
N
incidental MRI nding, and may be associated with and administration o synthetic AC H (cosyntropin)
I
I
intracranial hypertension. T ese patients usually have evokes adrenal cortisol release as an indirect indicator
normal pituitary unction, implying that the surround- o pituitary AC H reserve (Chap. 8). AC H reserve is
ing rim o pituitary tissue is ully unctional. Hypopi- most reliably assessed by measuring AC H and cortisol
P
i
t
u
tuitarism, however, may develop insidiously. Pituitary levels during insulin-induced hypoglycemia. However,
i
t
a
masses also may undergo clinically silent in arction this test should be per ormed cautiously in patients with
r
y
,
and involution with development o a partial or totally suspected adrenal insuf ciency because o enhanced sus-
T
h
y
empty sella by cerebrospinal uid (CSF) lling the dural ceptibility to hypoglycemia and hypotension. Adminis-
r
o
i
d
herniation. Rarely, small but unctional pituitary adeno- tering insulin to induce hypoglycemia is contraindicated
,
a
n
mas may arise within the rim o normal pituitary tissue, in patients with active coronary artery disease or known
d
A
and they are not always visible on MRI. seizure disorders.
d
r
e
n
a
l
D
TREATMENT Hypopituitarism
i
PRESENTATION AND DIAGNOSIS
s
o
r
d
e
T e clinical mani estations o hypopituitarism depend Hormone replacement therapy, including glucocorticoids,
r
s
on which hormones are lost and the extent o the thyroid hormone, sex steroids, growth hormone, and vaso-
hormone de ciency. GH de ciency causes growth pressin, is usually sa e and ree o complications. reatment
disorders in children and leads to abnormal body com- regimens that mimic physiologic hormone production allow
position in adults (see below). Gonadotropin de ciency or maintenance o satis actory clinical homeostasis. E ective
causes menstrual disorders and in ertility in women dosage schedules are outlined in Table 4-3. Patients in need
and decreased sexual unction, in ertility, and loss o glucocorticoid replacement require care ul dose adjust-
o secondary sexual characteristics in men. SH and ments during stress ul events such as acute illness, dental
AC H de ciency usually develop later in the course o procedures, trauma, and acute hospitalization.
pituitary ailure. SH de ciency causes growth retar-
dation in children and eatures o hypothyroidism
in children and adults. T e secondary orm o adre-
DISORDERS OF GROWTH AND
nal insuf ciency caused by AC H de ciency leads to
DEVELOPMENT
hypocortisolism with relative preservation o mineralo-
corticoid production. PRL de ciency causes ailure o Skeleta l m a tu ra tio n a n d so m a tic g ro wth
lactation. When lesions involve the posterior pituitary, T e growth plate is dependent on a variety o hormonal
polyuria and polydipsia re ect loss o vasopressin secre- stimuli, including GH, insulin-like growth actor (IGF)
tion. In patients with long-standing pituitary damage, I, sex steroids, thyroid hormones, paracrine growth
epidemiologic studies document an increased mortal- actors, and cytokines. T e growth-promoting process
ity rate, primarily rom increased cardiovascular and also requires caloric energy, amino acids, vitamins, and
cerebrovascular disease. Previous head or neck irradia- trace metals and consumes about 10% o normal energy
tion is also a determinant o increased mortality rates in production. Malnutrition impairs chondrocyte activity,
patients with hypopituitarism, especially rom cerebro- increases GH resistance, and reduces circulating IGF-I
vascular disease. and IGFBP3 levels.
Linear bone growth rates are very high in in ancy and
are pituitary-dependent. Mean growth velocity is ~6 cm/
LABORATORY INVESTIGATION
year in later childhood and usually is maintained within
Biochemical diagnosis o pituitary insuf ciency is made a given range on a standardized percentile chart. Peak
by demonstrating low levels o respective pituitary growth rates occur during midpuberty when bone age is

TABLE 4 -2
TESTS OF PITUITARY SUFFICIENCY
HORMONE TEST
Growth hor- Insulin tolerance test: Regular
mone (GH) insulin (0.05–0.15 U/kg IV)
GHRH test: 1 µg/kg IV
l -Arginine
test: 30 g IV
over 30 min
l -Dopa test: 500 mg PO
Prolactin TRH test: 200–500 µg IV
ACTH Insulin tolerance test: regular
insulin (0.05–0.15 U/kg IV)
CRH test: 1 µg/kg ovine CRH IV
at 8 a .m.
Metyrapone test: Metyrapone
(30 mg/kg) at midnight
Standard ACTH stimulation
test: ACTH 1-24 (cosyntropin),
0.25 mg IM or IV
Low-dose ACTH test: ACTH 1-24
(cosyntropin), 1 µg IV
3-day ACTH stimulation test
consists o 0.25 mg ACTH 1-24
given IV over 8 h each day
TSH Basal thyroid unction tests:
T4, T3, TSH
TRH test: 200–500 µg IV
LH, FSH LH, FSH, testosterone, estrogen
GnRH test: GnRH (100 µg) IV
Multiple Combined anterior pitu-
hormones itary test: GHRH (1 g/kg),
CRH (1 µg/kg), GnRH (100 g),
TRH (200 µg) are given IV
a
Evoked PRL response indicates lactotrope integrity.
Abbrevia tions: T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone. For other abbreviations, see text.
BLOOD SAMPLES
−30, 0, 30, 60, 120 min or glucose
and GH
0, 15, 30, 45, 60, 120 min or GH
0, 30, 60, 120 min or GH
0, 30, 60, 120 min or GH
0, 20, and 60 min or TSH and PRL
−30, 0, 30, 60, 90 min or glucose
and cortisol
0, 15, 30, 60, 90, 120 min or ACTH
and cortisol
Plasma 11-deoxycortisol and cor-
tisol at 8 a .m.; ACTH can also be
measured
0, 30, 60 min or cortisol and
aldosterone
0, 30, 60 min or cortisol
Basal measurements
0, 20, 60 min or TSH and PRLa
Basal measurements
0, 30, 60 min or LH and FSH
−30, 0, 15, 30, 60, 90, 120 min or
GH, ACTH, cortisol, LH, FSH, and
TSH
29
INTERPRETATION
Glucose <40 mg/dL; GH should be >3
µg/L
Normal response is GH >3 µg/L
Normal response is GH >3 µg/L
C
H
Normal response is GH >3 µg/L
A
P
T
Normal prolactin is >2 µg/L and
E
R
increase >200% o baseline
4
Glucose <40 mg/dL
Cortisol should increase by >7 µg/dL or
to >20 µg/dL
H
y
p
Basal ACTH increases 2- to 4- old and
o
p
i
peaks at 20–100 pg/mL
t
u
i
t
Cortisol levels >20–25 µg/dL
a
r
i
s
Plasma cortisol should be <4 g/dL to
m
assure an adequate response
Normal response is 11-deoxycortisol
>7.5 µg/dL or ACTH >75 pg/mL
Normal response is cortisol >21 g/
dL and aldosterone response o
>4 ng/dL above baseline
Cortisol should be >21 g/dL
Cortisol >21 g/dL
Low ree thyroid hormone levels in
the setting o TSH levels that are not
appropriately increased indicate pitu-
itary insuf ciency
TSH should increase by >5 mU/L unless
thyroid hormone levels are increased
Basal LH and FSH should be increased
in postmenopausal women
Low testosterone levels in the setting
o low LH and FSH indicate pituitary
insuf ciency
In most adults, LH should increase by
10 IU/L and FSH by 2 IU/L
Normal responses are variable
Combined or individual releasing hor-
mone responses must be elevated
in the context o basal target gland
hormone values and may not be uni-
ormly diagnostic (see text)
30 TABLE 4 -3
HORMONE REPLACEMENT THERAPY FOR ADULT HYPOPITUITARISM a
TROPHIC HORMONE DEFICIT HORMONE REPLACEMENT

ACTH Hydrocortisone (10–20 mg a .m.; 5–10 mg p.m.)

Cortisone acetate (25 mg a .m.; 12.5 mg p.m.)
Prednisone (5 mg a .m.)
TSH l -Thyroxine (0.075–0.15 mg daily)
FSH/LH Males
Testosterone gel (5–10 g/d)
S
Testosterone skin patch (5 mg/d)
E
C
T
Testosterone enanthate (200 mg IM every 2 weeks)
I
O
Females
N
Conjugated estrogen (0.65–1.25 mg qd or 25 days)
I
I
Progesterone (5–10 mg qd) on days 16–25
Estradiol skin patch (0.025–0.1 mg every week), adding progesterone on
days 16–25 i uterus intact
P
i
t
For ertility: menopausal gonadotropins, human chorionic gonadotropins
u
i
t
a
GH Adults: Somatotropin (0.1–1.25 mg SC qd)
r
y
,
Children: Somatotropin (0.02–0.05 mg/kg per day)
T
h
y
r
Vasopressin Intranasal desmopressin (5–20 g twice daily)
o
i
d
Oral 300–600 µg qd
,
a
n
d
A
a
All doses shown should be individualized or speci c patients and should be reassessed during stress, surgery, or pregnancy.
d
r
Male and emale ertility requirements should be managed as discussed in Chaps. 11 and 13.
e
n
No te: For abbreviations, see text.
a
l
D
i
s
o
r
d
12 (girls) or 13 (boys). Secondary sexual development is a er known molecular de ects have been rigorously
e
r
s
associated with elevated sex steroids that cause progres- excluded.
sive epiphyseal growth plate closure. Bone age is delayed
GHRH re ce p to r m u tatio n s
in patients with all orms o true GH de ciency or GH
Recessive mutations o the GHRH receptor gene in sub-
receptor de ects that result in attenuated GH action.
jects with severe proportionate dwar sm are associated
Short stature may occur as a result o constitutive
with low basal GH levels that cannot be stimulated by
intrinsic growth de ects or because o acquired extrin-
exogenous GHRH, GHRP, or insulin-induced hypo-
sic actors that impair growth. In general, delayed bone
glycemia, as well as anterior pituitary hypoplasia T e
age in a child with short stature is suggestive o a hor-
syndrome exempli es the importance o the GHRH
monal or systemic disorder, whereas normal bone age
receptor or somatotrope cell proli eration and hor-
in a short child is more likely to be caused by a genetic
monal responsiveness.
cartilage dysplasia or growth plate disorder.
GH in se n sitivit y
GH d e cien cy in ch ild ren T is is caused by de ects o GH receptor structure or
signaling. Homozygous or heterozygous mutations o
GH d e f cie n cy
the GH receptor are associated with partial or com-
Isolated GH de ciency is characterized by short stat- plete GH insensitivity and growth ailure (Laron’s syn-
ure, micropenis, increased at, high-pitched voice, and drome). T e diagnosis is based on normal or high GH
a propensity to hypoglycemia due to relatively unop- levels, with decreased circulating GH-binding protein
posed insulin action. Familial modes o inheritance are (GHBP), and low IGF-I levels. Very rarely, de ective
seen in at least one-third o these individuals and may IGF-I, IGF-I receptor, or IGF-I signaling de ects are also
be autosomal dominant, recessive, or X-linked. About encountered. STAT5B mutations result in both immu-
10% o children with GH de ciency have mutations in node ciency as well as abrogated GH signaling, leading
the GH-N gene, including gene deletions and a wide to short stature with normal or elevated GH levels and
range o point mutations. Mutations in transcription low IGF-I levels. Circulating GH receptor antibodies
actors Pit-1 and Prop-1, which control somatotrope may rarely cause peripheral GH insensitivity.
development, result in GH de ciency in combination
with other pituitary hormone de ciencies, which may Nu tritio n a l sh o rt statu re
become mani est only in adulthood. T e diagnosis o Caloric deprivation and malnutrition, uncontrolled
idiopathic GH def ciency (IGHD) should be made only diabetes, and chronic renal ailure represent secondary
causes o abrogated GH receptor unction. T ese con-
ditions also stimulate production o proin ammatory
cytokines, which act to exacerbate the block o GH-
mediated signal transduction. Children with these con-
ditions typically exhibit eatures o acquired short stature
with normal or elevated GH and low IGF-I levels.
Psych o so cia l sh o rt statu re
Emotional and social deprivation lead to growth retarda-
tion accompanied by delayed speech, discordant hyper-
may reveal pituitary mass lesions or structural de ects. 31
Molecular analyses or known mutations should be
undertaken when the cause o short stature remains
cryptic, or when additional clinical eatures suggest a
genetic cause.
ADULT GH DEFICIENCY (AGHD)
T is disorder usually is caused by acquired hypothalamic

C
phagia, and an attenuated response to administered GH. or pituitary somatotrope damage. Acquired pituitary

H
A
A nurturing environment restores growth rates. hormone de ciency ollows a typical pattern in which

P
T
E
loss o adequate GH reserve oreshadows subsequent

R
PRESENTATION AND DIAGNOSIS

4
hormone de cits. T e sequential order o hormone loss
is usually GH →FSH/LH → SH →AC H. Patients pre-
Short stature is commonly encountered in clinical
viously diagnosed with childhood-onset GH de ciency
practice, and the decision to evaluate these children

H
should be retested as adults to af rm the diagnosis.

y
p
requires clinical judgment in association with auxologic

o
p
data and amily history. Short stature should be evalu-

i
t
u
PRESENTATION AND DIAGNOSIS

i
ated comprehensively i a patient’s height is >3 standard

t
a
r
i
deviations (SD) below the mean or age or i the growth

s
m
T e clinical eatures o AGHD include changes in
rate has decelerated. Skeletal maturation is best evalu- body composition, lipid metabolism, and quality o
ated by measuring a radiologic bone age, which is based li e and cardiovascular dys unction (Table 4-4). Body
mainly on the degree o wrist bone growth plate usion.
Final height can be predicted using standardized scales TABLE 4 -4
(Bayley-Pinneau or anner-Whitehouse) or estimated FEATURES OF ADULT GROWTH HORMONE
by adding 6.5 cm (boys) or subtracting 6.5 cm (girls) DEFICIENCY
rom the midparental height. Clinical
Impaired quality o li e
LABORATORY INVESTIGATION Decreased energy and drive
Poor concentration
Because GH secretion is pulsatile, GH de ciency is Low sel -esteem
best assessed by examining the response to provoca- Social isolation
tive stimuli, including exercise, insulin-induced hypo- Body composition changes
glycemia, and other pharmacologic tests that normally Increased body at mass
increase GH to >7 µg/L in children. Random GH mea- Central at deposition
surements do not distinguish normal children rom Increased waist-to-hip ratio
those with true GH de ciency. Adequate adrenal and Decreased lean body mass
Reduced exercise capacity
thyroid hormone replacement should be assured be ore Reduced maximum O2uptake
testing. Age- and sex-matched IGF-I levels are not su - Impaired cardiac unction
ciently sensitive or speci c to make the diagnosis but Reduced muscle mass
can be use ul to con rm GH de ciency. Pituitary MRI Cardiovascular risk actors
Impaired cardiac structure and unction
Abnormal lipid pro le
Decreased brinolytic activity
TREATMENT Disorders o Growth and Development Atherosclerosis
Omental obesity
Replacement therapy with recombinant GH (0.02–0.05 Imaging
mg/kg per day SC) restores growth velocity in GH-de cient Pituitary: mass or structural damage
children to ~10 cm/year. I pituitary insuf ciency is docu- Bone: reduced bone mineral density
mented, other associated hormone de cits should be cor- Abdomen: excess omental adiposity
Laboratory
rected, especially adrenal steroids. GH treatment is also
Evoked GH <3 ng/mL
moderately e ective or accelerating growth rates in children IGF-I and IGFBP3 low or normal
with urner’s syndrome and chronic renal ailure. Increased LDL cholesterol
In patients with GH insensitivity and growth retardation Concomitant gonadotropin, TSH, and/or ACTH reserve de -
due to mutations o the GH receptor, treatment with IGF-I cits may be present
bypasses the dys unctional GH receptor. Abbrevia tion: LDL, low-density lipoprotein. For other abbreviations, see
text.
32 composition changes are common and include reduced MANAGEMENT OF ADULT GH DEFICIENCY
lean body mass, increased at mass with selective depo-
His tory of pituita ry pa thology
sition o intraabdominal visceral at, and increased Clinica l fe a ture s pre s e nt
waist-to-hip ratio. Hyperlipidemia, le ventricular dys- Evoke d GH < 3 g/L
unction, hypertension, and increased plasma brino-
Exclude contra indica tions
gen levels also may be present. Bone mineral content is
reduced, with resultant increased racture rates. Patients Tre a t with
may experience social isolation, depression, and di - GH 0.1–0.3 mg/d
culty maintaining gain ul employment. Adult hypo-
Che ck IGF-I a fte r 1 mo
pituitarism is associated with a three old increase in
S
E
cardiovascular mortality rates in comparison to age-
C
Titra te GH dos e
T
I
and sex-matched controls, and this may be due to GH up to 1.25 mg/d
O
N
de ciency, as patients in these studies were replaced
I
I
6 mo
with other de cient pituitary hormones.
No
re s pons e Re s pons e
P
i
t
u
LABORATORY INVESTIGATION
i
t
Dis continue Rx Monitor
a
r
y
IGF-I Le ve ls
,
AGHD is rare, and in light o the nonspeci c nature o
T
h
y
associated clinical symptoms, patients appropriate or
r
o
i
testing should be selected care ully on the basis o well-
d
FIGURE 4 -1
,
a
de ned criteria. With ew exceptions, testing should be
n
Management o adult growth hormone (GH) def ciency. IGF,
d
restricted to patients with the ollowing predisposing
A
insulin-like growth actor; Rx, Treatment.
d
r
actors: (1) pituitary surgery, (2) pituitary or hypotha-
e
n
a
lamic tumor or granulomas, (3) history o cranial irra-
l
D
i
diation, (4) radiologic evidence o a pituitary lesion, (5)
s
o
r
childhood requirement or GH replacement therapy,
d
TREATMENT Adult GHDef ciency
e
r
and rarely (6) unexplained low age- and sex-matched
s
IGF-I levels. T e transition o a GH-de cient adolescent Once the diagnosis o AGHD is unequivocally established,
to adulthood requires retesting to document subsequent replacement o GH may be indicated. Contraindications to
adult GH de ciency. Up to 20% o patients previously therapy include the presence o an active neoplasm, intracra-
treated or childhood-onset GH de ciency are ound to nial hypertension, and uncontrolled diabetes and retinopathy.
be GH-suf cient on repeat testing as adults. T e starting dose o 0.1–0.2 mg/d should be titrated (up to a
A signi cant proportion (~25%) o truly GH-de - maximum o 1.25 mg/d) to maintain IGF-I levels in the mid-
cient adults have low-normal IGF-I levels. T us, as normal range or age- and sex-matched controls (Fig. 4-1).
in the evaluation o GH de ciency in children, valid Women require higher doses than men, and elderly patients
age- and sex-matched IGF-I measurements provide a require less GH. Long-term GH maintenance sustains nor-
use ul index o therapeutic responses but are not su - mal IGF-I levels and is associated with persistent body com-
ciently sensitive or diagnostic purposes. T e most position changes (e.g., enhanced lean body mass and lower
validated test to distinguish pituitary-suf cient patients body at). High-density lipoprotein cholesterol increases, but
rom those with AGHD is insulin-induced (0.05–0.1 total cholesterol and insulin levels may not change signi -
U/kg) hypoglycemia. A er glucose reduction to ~40 cantly. Lumbar spine bone mineral density increases, but this
mg/dL, most individuals experience neuroglycopenic response is gradual (>1 year). Many patients note signi cant
symptoms (Chap. 26), and peak GH release occurs at improvement in quality o li e when evaluated by standard-
60 min and remains elevated or up to 2 h. About 90% ized questionnaires. T e e ect o GH replacement on mortal-
o healthy adults exhibit GH responses >5 µg/L; AGHD ity rates in GH-de cient patients is currently the subject o
is de ned by a peak GH response to hypoglycemia o long-term prospective investigation.
<3 µg/L. Although insulin-induced hypoglycemia is About 30% o patients exhibit reversible dose-related uid
sa e when per ormed under appropriate supervision, it retention, joint pain, and carpal tunnel syndrome, and up
is contraindicated in patients with diabetes, ischemic to 40% exhibit myalgias and paresthesia. Patients receiving
heart disease, cerebrovascular disease, or epilepsy and insulin require care ul monitoring or dosing adjustments,
in elderly patients. Alternative stimulatory tests include as GH is a potent counterregulatory hormone or insulin
intravenous arginine (30 g), GHRH (1 µg/kg), GHRP-6 action. Patients with type 2 diabetes mellitus initially develop
(90 µg), and glucagon (1 mg). Combinations o these urther insulin resistance. However, glycemic control usu-
tests may evoke GH secretion in subjects who are not ally improves with the sustained loss o abdominal at asso-
responsive to a single test. ciated with long-term GH replacement. Headache, increased
intracranial pressure, hypertension, and tinnitus occur rarely.
Pituitary tumor regrowth and progression o skin lesions or
other tumors are being assessed in long-term surveillance
programs. o date, development o these potential side e ects
does not appear signi cant.
ACTH DEFICIENCY
PRESENTATION AND DIAGNOSIS
Secondary adrenal insuf ciency occurs as a result
o pituitary AC H de ciency. It is characterized by
atigue, weakness, anorexia, nausea, vomiting, and,
occasionally, hypoglycemia. In contrast to primary
adrenal ailure, hypocortisolism associated with pitu-
itary ailure usually is not accompanied by hyperpig-
mentation or mineralocorticoid de ciency.
AC H de ciency is commonly due to glucocorticoid
withdrawal a er treatment-associated suppression o
the hypothalamic-pituitary-adrenal (HPA) axis. Isolated
AC H de ciency may occur a er surgical resection o an
AC H-secreting pituitary adenoma that has suppressed
the HPA axis; this phenomenon is in act suggestive o a
surgical cure. T e mass e ects o other pituitary adeno-
mas or sellar lesions may lead to AC H de ciency, but
usually in combination with other pituitary hormone
de ciencies. Partial AC H de ciency may be unmasked
in the presence o an acute medical or surgical illness,
when clinically signi cant hypocortisolism re ects
diminished AC H reserve. Rarely, TPIT or POMC muta-
tions result in primary AC H de ciency.
LABORATORY DIAGNOSIS
Inappropriately low AC H levels in the setting o low
cortisol levels are characteristic o diminished AC H
reserve. Low basal serum cortisol levels are associ-
ated with blunted cortisol responses to AC H stimula-
tion and impaired cortisol response to insulin-induced
hypoglycemia, or testing with metyrapone or CRH. For
a description of provocative ACTH tests, see Chap. 8.
TREATMENT ACTHDef ciency
Glucocorticoid replacement therapy improves most ea-
tures o AC H de ciency. T e total daily dose o hydro-
cortisone replacement pre erably should not exceed 25 mg
daily, divided into two or three doses. Prednisone (5 mg
each morning) is longer acting and has ewer mineralocorti-
coid e ects than hydrocortisone. Some authorities advocate
lower maintenance doses in an e ort to avoid cushingoid side
e ects. Doses should be increased several old during periods
o acute illness or stress.
33
GO NADOTRO P IN DEFICIENCY
Hypogonadism is the most common presenting ea-
ture o adult hypopituitarism even when other pituitary
hormones are also de cient. It is o en a harbinger o
hypothalamic or pituitary lesions that impair GnRH
production or delivery through the pituitary stalk. As
noted below, hypogonadotropic hypogonadism is a
common presenting eature o hyperprolactinemia.
A variety o inherited and acquired disorders are
C
H
A
associated with isolated hypogonadotropic hypogonad-
P
T
ism (IHH) (Chap. 11). Hypothalamic de ects associated
E
R
with GnRH de ciency include Kallmann syndrome
4
and mutations in more than a dozen genes that regulate
GnRH neuron migration, development, and unction
H
(see above). Mutations in GPR54, DAX1, kisspeptin,
y
p
the GnRH receptor, and the LHβ or FSHβ subunit
o
p
i
genes also cause pituitary gonadotropin de ciency.
t
u
i
t
Acquired orms o GnRH de ciency leading to hypogo-
a
r
i
s
nadotropism are seen in association with anorexia ner-
m
vosa, stress, starvation, and extreme exercise but also
may be idiopathic. Hypogonadotropic hypogonadism
in these disorders is reversed by removal o the stress ul
stimulus or by caloric replenishment.
PRESENTATION AND DIAGNOSIS
In premenopausal women, hypogonadotropic hypogo-
nadism presents as diminished ovarian unction leading
to oligomenorrhea or amenorrhea, in ertility, decreased
vaginal secretions, decreased libido, and breast atrophy.
In hypogonadal adult men, secondary testicular ailure
is associated with decreased libido and potency, in er-
tility, decreased muscle mass with weakness, reduced
beard and body hair growth, so testes, and character-
istic ne acial wrinkles. Osteoporosis occurs in both
untreated hypogonadal women and men.
LABORATORY INVESTIGATION
Central hypogonadism is associated with low or inap-
propriately normal serum gonadotropin levels in the
setting o low sex hormone concentrations (testoster-
one in men, estradiol in women). Because gonadotro-
pin secretion is pulsatile, valid assessments may require
repeated measurements or the use o pooled serum
samples. Men have reduced sperm counts.
Intravenous GnRH (100 µg) stimulates gonado-
tropes to secrete LH (which peaks within 30 min) and
FSH (which plateaus during the ensuing 60 min). Nor-
mal responses vary according to menstrual cycle stage,
age, and sex o the patient. Generally, LH levels increase
about three old, whereas FSH responses are less pro-
nounced. In the setting o gonadotropin de ciency,
a normal gonadotropin response to GnRH indicates
34 intact pituitary gonadotrope unction and suggests a therapy (25–150 ng/kg every 2 h), administered by a subcuta-
hypothalamic abnormality. An absent response, how- neous in usion pump, is also e ective or treatment o hypo-
ever, does not reliably distinguish pituitary rom hypo- thalamic hypogonadism when ertility is desired.
thalamic causes o hypogonadism. For this reason, In premenopausal women, cyclical replacement o estro-
GnRH testing usually adds little to the in ormation gen and progesterone maintains secondary sexual charac-
gained rom baseline evaluation o the hypothalamic- teristics and integrity o genitourinary tract mucosa and
pituitary-gonadotrope axis except in cases o isolated prevents premature osteoporosis (Chap. 13). Gonadotropin
GnRH de ciency (e.g., Kallmann syndrome). therapy is used or ovulation induction. Follicular growth
and maturation are initiated using hMG or recombinant FSH;
hCG or human luteinizing hormone (hLH) is subsequently
S
E
injected to induce ovulation. As in men, pulsatile GnRH
C
T
I
therapy can be used to treat hypothalamic causes o gonado-
O
N
tropin de ciency.
I
I
TREATMENT Gonadotropin Def ciency

In males, testosterone replacement is necessary to achieve

P
MRI examination o the sellar region and assessment
i
t
and maintain normal growth and development o the exter-
u
i
o other pituitary unctions usually are indicated in
t
a
nal genitalia, secondary sex characteristics, male sexual
r
y
patients with documented central hypogonadism.
,
behavior, and androgenic anabolic e ects, including mainte-
T
h
y
nance o muscle unction and bone mass. estosterone may
r
o
i
be administered by intramuscular injections every 1–4 weeks
d
,
a
or by using skin patches that are replaced daily (Chap. 11). DIABETES INSIP IDUS
n
d
estosterone gels are also available. Gonadotropin injections
A
d
See Chap. 6 for diagnosis and treatment of diabetes
r
(hCG or human menopausal gonadotropin [hMG]) over
e
n
a
12–18 months are used to restore ertility. Pulsatile GnRH insipidus.
l
D
i
s
o
r
d
e
r
s
Another random document with
no related content on Scribd:
human misfortunes, leading, by a natural step, to the plot itself. So,
in Don Juan, only one canto—the second—begins with the tale itself;
266
every other has a preliminary discussion of one sort or another. It
was also Berni’s custom to take formal leave of his readers at the
267
end of each canto, and to add a promise of what was to come.
This habit, all but universal with the Italian narrative poets, Byron
followed, although his farewell occurs sometimes even before the
very last stanza. A typical example may be quoted:

“It is time to ease

This Canto, ere my Muse perceives fatigue.
The next shall ring a peal to shake all people,
268
Like a bob-major from a village steeple.”

Berni’s style and diction are far superior to Pulci’s. Count

Giammaria Mazzuchelli, in the edition of Berni in Classici Italiani,
says of this feature of his work: “La, facilita della rima congiunta alia
naturallezza dell’ espressione, e la vivacita de’ pensieri degli scherzi
uniti a singolare coltura nello stile sono in lui si maravigliose, che
viene egli considerate come il capo di si fatta poesia, la quale percio
ha presa da lui la denominazione, e suol chimarsi Bernesca.” He
alone of the three Italian burlesque writers considered, succeeded in
269
creating a masterpiece of literary art. In this respect, then, his
influence on Byron may have been salutary.
Henri Beyle (1783–1842), the self-styled M. Stendhal, is
responsible for the theory, since repeated by other critics, that
Byron’s Italian satires owe much to the work of the Venetian dialect
poet, Pietro Buratti (1772–1832). When Beyle was with Byron in
Milan in November, 1816, he heard Silvio Pellico speak to Byron of
Buratti as a charming poet, who, every six months, by the governor’s
orders, paid a visit to the prisons of Venice. Beyle’s account of the
ensuing events runs as follows: “In my opinion, this conversation
with Silvio Pellico gave the tone to Byron’s subsequent poetical
career. He eagerly demanded the name of the bookseller who sold
M. Buratti’s works; and as he was accustomed to the expression of
Milanese bluntness, the question excited a hearty laugh at his
expense. He was soon informed that if Buratti wished to pass his
whole life in prison, the appearance of his works in print would
infallibly lead to the gratification of his desires; and besides, where
could a printer be found hardy enough to run his share of the risk?—
The next day, the charming Contessina N. was kind enough to lend
her collection to one of our party. Byron, who imagined himself an
adept in the language of Dante and Ariosto, was at first rather
puzzled by Buratti’s manuscripts. We read over with him some of
Goldoni’s comedies, which enabled him at last to comprehend
Buratti’s satires. I persist in thinking, that for the composition of
Beppo, and subsequently of Don Juan, Byron was indebted to the
270
reading of Buratti’s poetry.”
A statement so plain by a man of Beyle’s authority deserves
some attention. The first question which arises in connection with his
assertion is naturally, what work Buratti had done before 1817, when
271
Byron began the composition of Beppo. After a dissipated
boyhood, Buratti had become a member of the Corte dei Busoni, a
pseudo-Academy which devoted its attention chiefly to satire.
Although he was the author of several early lampoons, his first
political satire was recited in 1813 among a party of friends at the
home of Counsellor Galvagna in Venice. It is, in substance, a
lamentation over the fate of Venice, with invective directed against
the French army of occupation; Malamani styles it “a masterpiece of
subtle sarcasm.” Eventually, through the treachery of apparent
friends, the verses came to French ears, and Buratti was imprisoned
for thirty days, his punishment, however, being somewhat lightened
by powerful patrons. Shortly after this episode, he circulated some
quatrains of a scurrilous nature on Filippo Scolari, a pedantic youth
who had criticised contemporary literary men in a supercilious way.
For these insults, Scolari tried to have Buratti apprehended again,
but the latter, although he was forced to sign an agreement to write
no more satires, received only a reprimand. During this period he
had also directed several pasquinades at an eccentric priest, Don
Domenico Marienis, who seems to have been a general object of
ridicule in Venice.
Such, according to Malamani, was the extent of Buratti’s work up
to 1816. His masterpiece, the Storia dell’ Elefante, was not written
until 1819, too late to have been a strong influence even on Don
Juan. Of this early satiric verse, no one important poem was
composed in ottava rima. The poems, all short and of no especial
value as literature, used the Venetian dialect, as far removed from
pure Tuscan as Scotch is from English. Their most noticeable
characteristic is their prevailing irony, a method of satire of which
Byron only occasionally availed himself. With these facts in mind,
and with the additional knowledge that Byron was unquestionably
influenced by the burlesque writers, it is improbable that Beyle’s
theory deserves any credence. Beyle has made it clear that Byron,
at one time, read Buratti’s work with interest; but he has failed to
show how the English poet could have acquired anything, either in
272
matter or in style, from the Italian satirist.
Of other Italian poems sometimes mentioned as possibly
contributing something to Don Juan, no one is worth more than a
cursory notice. La Secchia Rapita, by Tassoni (1565–1635), is a
genuine mock-heroic, the model for Boileau’s Lutrin and, to some
extent, for Pope’s Rape of the Lock. So far as can be ascertained,
Byron has no reference either to the author or to his poem; and since
La Secchia Rapita preserves consistently the grand style, applying it
273
to trivial subjects, it has little in common with Byron’s satires.
With Il Ricciardetto, by Forteguerri (1675–1735), Byron was
better acquainted. Indeed Foscolo, without giving proof for his
conclusion, suggested that it might have offered some ideas to the
English writer. The Italian poem, completed about 1715, after having
been composed, according to tradition, at the rate of a canto a day,
contains thirty cantos in ottava rima. It is an avowed burlesque, in
which heroes of Carolingian romance are degraded to buffoons,
Rinaldo becoming a cook and Ricciardetto a barber. In it, as Foffano
says, “the marvellous becomes absurd, the sublime, grotesque, and
the heroic, ridiculous.” Forteguerri’s design, however, was not
directly satiric, and he was seldom a destructive critic. His mission
was solely to divert his readers. Byron refers to Lord Glenbervie’s
rendering of the first canto of Il Ricciardetto (1822) as most
274
amusing, but he seems to have had no great interest in the
original.
A point has now been reached where it is practicable to frame
some generalizations as to the extent and nature of Byron’s
indebtedness to the Italians. For his subject-matter, he owed them
something. The Catharine II episode in Don Juan may have been
suggested by Il Poema Tartaro; an occasional unimportant incident
or situation may have been taken or modified from the work of Casti
or Pulci. On the whole, however, Byron’s material was either original
or drawn from other sources than the Italians. Even though Byron
and Casti so frequently satirize the same institutions and theories, it
is improbable that this is more than coincidence, the result of the
natural opposition which similar abuses aroused in men so alike in
temperament and intellect.
In his manner, however, Byron was profoundly affected, so much
so that his own statement about Beppo—“The style is not English, it
275
is Italian”— is in exact accordance with the impression which
Beppo, as well as Don Juan, makes on the reader. He learned, in
part from Casti, and later from Berni and Pulci, the use of the
burlesque method; he adopted their discursive style, with its
opportunities for digression and self-assertion, and made it a
channel for voicing his own beliefs as well as for speaking out
against his enemies. Accepting the hint offered by their tendency to
colloquial speech, he lowered the tone of his diction and addressed
himself often directly to his readers. Moreover, he acquired the habit
of shifting suddenly from seriousness to absurdity, from the pathetic
to the grotesque, in the compass of a single stanza. His wrath, at
first untempered, was now softened by a new attitude of skepticism
which turned him more to irony and mockery than to violent rage.
In utilizing the octave for his own satires, he gave it a freedom of
which it had never before been made capable in English; and, by a
clever employment of double and triple rhymes, and by the constant
use of run-on lines and stanzas, he adjusted the measure to the
conversational flow of his verse.
At a time, then, when his youthful narrowness was developing
into the maturity that comes only from experience, and when,
therefore, he was most susceptible to broadening influences, Byron,
fortunately for his satire, was brought into contact with the Italian
spirit. The result was that Don Juan joined many of the most
powerful features of English Bards with the lighter elements of Berni
and Casti.
The beauty of Byron’s satire at its finest in Don Juan and The
Vision of Judgment, lies in the welding of the direct and indirect
methods, in the interweaving of invective with burlesque, in such a
way that the poems seem to link the spirit of Juvenal with the spirit of
Pulci. The consequence is a variety of tone, a widening of scope,
and a considerable increase in effectiveness. Byron’s general
attacks are relieved from the charge of futility; his vindictiveness is
mitigated by humor and a touch of the ridiculous; and his
aggressiveness, though it does not disappear, is sometimes
changed to a cynical tolerance.
 CHAPTER VIII
“DON JUAN”

With the exception of The Ring and the Book, Don Juan,
containing approximately 16,000 lines, is probably the longest
original poem in English since the Faerie Queene; moreover, if we
exclude the Canterbury Tales, no other work in verse in our literature
attempts an actual “criticism of life” on so broad a scale. It is Byron’s
deliberate and exhaustive characterization of his age, the book in
which he divulges his opinions with the least reticence and the most
finality. With all their occasional brilliance and power, his earlier
satires had been essentially imitative and could be judged by pre-
existing standards. Later, in composing Beppo, Byron discovered
that he had found a kind of verse capable of free and varied
treatment and therefore especially suited to his improvising and
discursive genius; accordingly, in Don Juan, which is a longer and
more elaborate Beppo, he produced a masterpiece which, besides
being an adequate revelation of his complex personality, is unique in
276
English, anomalous in its manner and method.
Because it reflects nearly every side of Byron’s variable
individuality, Don Juan, though satirical in main intent, combines
satire with many other elements. It is tragic, sensuous, humorous,
melancholy, cynical, realistic, and exalted, with words for nearly
every emotion and temper. It contains a romantic story, full of
sentiment and tenderness; it rises into passages of lyric and
descriptive beauty, evidently heart-felt; yet these serious and
imaginative details are imbedded in a sub-stratum of satire.
Furthermore, its range in substance and style is very great; it
discusses matters in politics, in society, in literature, and in religion; it
shifts in a stanza from grave to gay, from the commonplace to the
sublime. It is a poem of freedom; free in thought and free in speech,
unrestricted by the ordinary laws of metre. “The soul of such writing
is its license,” wrote Byron to Murray in 1819.
The plot of Don Juan, dealing, like the picaresque romances of
Le Sage and Smollett, with a series of adventures in the life of a
wandering hero, and interrupted constantly by the comments of the
author, has little real unity. Considered as a satire, however, the
poem becomes unified through the personality behind the stanzas. It
is a colossal monument of egotism; wherever we read, we meet the
inevitable “I.” The poet’s interest in the progress of his characters is
so obviously subordinated to his desire for gossiping with his readers
that the plot seems, at times, to be almost forgotten. Thus Don Juan
is as subjective as Byron’s correspondence; indeed ideas were often
transferred directly from his letters to his verses. There are lines in
the poem which restate, sometimes in the same phraseology, the
confessions and the criticisms recorded by Lady Blessington in her
Conversations with Lord Byron. Autobiographical references are very
277
common, sometimes merely casual, sometimes used as a text for
278
satire. The powerful personality of the writer, expressed thus in
his work, furnishes it with a unity which is lacking in the plot.
It is probable that Byron himself had only a vague conception of
the structure and limits of his poem. His conflicting assertions,
usually half-jocular, concerning his plan or scheme are proof that he
cared little about adhering to a closely knit form. He is most to be
trusted when he says:

“Note or text,
279
I never know the word which will come next.”

or when he confesses to Murray: “You ask me for the plan of Donny

280
Juan: I have no plan—I had no plan; but I had or have materials.”
The inconsistent statements in the body of the poem are, of course,
merely quizzical: thus in the first canto Byron says decidedly,
 “My poem’s epic, and is meant to be
281
Divided in twelve books”;

when the twelfth canto is reached, he has an apology ready:

“I thought, at setting off, about two dozen

Cantos would do; but at Apollo’s pleading,
If that my Pegasus should not be foundered,
282
I hope to canter gently through a hundred.”

As it lengthened Don Juan developed more and more into a verse

diary, bound, from the looseness of its design, to remain
uncompleted at Byron’s death.
But whatever may have actuated Byron in beginning Don Juan
and however uncertain he may have been at first about its ultimate
purpose, it soon grew to be primarily satirical. He himself perceived
this in describing it to Murray in 1818 as “meant to be a little quietly
283
facetious upon everything” and in characterizing it in 1822 as “a
284
Satire on abuses of the present states of society.” Despite the
intermingling of other elements, the poem is exactly what Byron
285
called it—an “Epic Satire.” His remark “I was born for opposition”
indicates how much at variance with his age he felt himself to be;
and his inclination to pick flaws in existing institutions and to indulge
in destructive criticism of his time had become so strong that any
poem which expressed fully his attitude towards life was bound to be
satirical. Just as the cosmopolitan outlook of the poem is due partly
to Byron’s long-continued residence in a foreign country, so its varied
moods, its diverse methods, and its wide range of subject matter are
to be attributed, to a large extent, to the fact that the composition of
Don Juan extended over several years during a period when he was
286
growing intellectually and responding eagerly to new ideas. The
work is a fair representation of Byron’s theories and beliefs during
the period of his maturity, when he was developing into an
enlightened advocate of progressive and liberal doctrines. It is an
attack on political inertia and retrogression, on social conventionality,
on cant and sham and intolerance. The intermittent, erratic, and
somewhat imitative radicalism of a few of his earlier poems has
changed into a persistent hostility to all the reactionary conservation
of the time. Don Juan is satiric, then, in that it is a protest against all
that hampers individual freedom and retards national independence.
The pervasive satiric spirit of Don Juan has varied
manifestations. In a few passages there are examples of rancor and
spite, of direct personal denunciation and furious invective, that
recall the satire of English Bards. The attacks on Castlereagh and
Southey, on Brougham and Lady Byron are in deadly earnest, with
hardly a touch of mockery. At the same time Byron relies mainly on
the more playful and less savage method which he had learned from
the Italians and used in Beppo. He himself expressed this alteration
in mood by saying,

“Methinks the older that one grows,

287
Inclines us more to laugh than scold.”

It is noticeable, too, that in Don Juan petulant fury is much less

conspicuous than philosophic satire. Byron is assailing institutions
and theories as well as men and women. To some extent the poem
is a medium for satisfying a quarrel or a prejudice; but to a far
greater degree it is a summary of testimony hostile to the reactionary
early nineteenth century. The poet still prefers, in many cases, to
make specific persons responsible for intolerable systems; but he is
gradually forsaking petty aims and rising to a far nobler position as a
critic of his age.
The satire in Don Juan is still more remarkable when we
consider the field which it surveys. Byron is no longer dealing with
local topics, but with subjects of momentous interest to all humanity.
He is assailing, not a small coterie of editors or an immodest dance,
but a bigoted and absolute government, a hypocritical society, and, a
false idealism, wherever they exist. More than this, he so succeeds
in uniting his satire, through the force of his personality, with the
eternal elements of realism and romance, that the combination,
complex and intricate though it is, seems to represent an undivided
purpose.
Perhaps the loftiest note in Byron’s protest is struck in dealing
with the political situation of his day. Despite his noble birth and his
aristocratic tastes, he had become, partly through temperamental
inclination, partly through association with Moore and Hunt, a fairly
consistent republican, though he took care to make it clear, as Nichol
points out, that he was “for the people, not of them.” Impatient of
restraint on his own actions, he extended his belief in personal liberty
until it included the advocacy of any democratic movement. It is to
his credit, moreover, that he was no mere closet theorist; in Italy he
espoused the cause of freedom in a practical way by abetting and
joining the revolutionary Carbonari; and he died enrolled in the ranks
of the liberators of Greece. In Don Juan he declares himself
resolutely opposed to tyranny in any form, asserting his hatred of
despotism in memorable lines:

“I will teach, if possible, the stones

To rise against earth’s tyrants. Never let it
288
Be said that we still truckle unto thrones.”

Such doctrine was, of course, not new in Byron’s poetry. He had

already spoken eloquently and mournfully of the loss of Greek
289
independence ; he had prophesied the downfall of monarchs and
290
the triumph of democracy ; and he had inserted in Childe Harold
that vigorous apostrophe to liberty:

“Yet, Freedom, yet thy banner, torn but flying,

291
Streams like the thunder-storm against the wind.”
In Don Juan, however, Byron is less rhetorical and more direct. In
expressing his

“Plain sworn downright detestation

292
Of every despotism in every nation,”

he does not hesitate to condemn all absolute monarchs; moreover

he displays a sincere faith in the ultimate success of popular
government:

“I think I hear a little bird, who sings

293
The people by and by will be the stronger.”

Such lines as these show a maturity and an earnestness that mark

the evolution of Byron’s satiric spirit from the hasty petulance of
English Bards to the humanitarian breadth of his thoughtful
manhood. Like “Young Azim” in Moore’s Veiled Prophet of
Khorassan, he is eager to march and command under the banner on
which is emblazoned “Freedom to the World.”
It is characteristic of Byron’s later satire that he applied his
theory of liberty to the current problems of British politics by assailing
the obnoxious domestic measures instituted by the Tory ministry of
Lord Liverpool, by condemning the English foreign policy of
acquiescence in the legitimist doctrines of Metternich and the
continental powers, and by attacking the characters of the ministers
whom he considered responsible for England’s position at home and
abroad. The England of the time of Don Juan was the country which
Shelley so graphically pictured in his Sonnet: England in 1819:—

“An old, mad, blind, despised, and dying king, ...

Rulers who neither see, nor feel, nor know,
But leech-like to their fainting country cling,
 Till they drop, blind in blood, without a blow, ...
A people starved and stabbed in the untilled field.”

It was a nation exhausted by war, burdened with debt, and

seething with discontent. The Luddite outbreaks, the “Manchester
Massacre,” which so excited the wrath of Shelley, and the “Cato
Street Conspiracy” showed the temper of the poor and disaffected
classes. Unfortunately the cabinet saw the solution of these
difficulties not in reform but in repression, and preferred to put down
the uprisings by force rather than to remove their causes. For these
conditions Byron blamed Castlereagh, the Foreign Secretary.
Byron had never met Castlereagh and had never suffered a
personal injury from him; his rage, therefore, was directed solely at
the statesman, not at the man. The Secretary had long been
294
detestable to Irish Whigs like Moore and English radicals like
295
Shelley ; it remained for Byron to track him through life with
venomous hatred and to pursue him beyond the grave with scathing
epigrams. For anything comparable aimed at a man in high position
we must go back to Marvell’s satires on Charles II and the Duke of
York or to the contemporary satire in 1762 on Lord Bute. Byron’s
Castlereagh has no virtues; the portrait, like Gifford’s sketch of Peter
Pindar, is all in dark colors. The satire is vehement and personal,
without malice and without pity.
Byron also attacked Wellington, but in manner ironic and
scornful, as a leader who had lost all claim to the gratitude of the
people by allying himself with their oppressors. For George, who as
Regent and King, had done nothing to redeem himself with his
subjects, Byron had little but contempt. In satirizing these men,
however, Byron was perhaps less effective than Moore, over whose
imitations of Castlereagh’s orations and “best-wigged Prince in
Christendom,” people smiled when Byron’s tirades seemed too
vicious.
Through the method commonly called dramatic, or indirect,
Byron assailed English politicians in his portrayal of Lord Henry
Amundeville, the statesman who is “always a patriot—and
sometimes a placeman,” and who is representative of the
unemotional, just, yet altogether selfish British minister. The type is
drawn with considerable skill and with much less rancor than would
have been possible with Byron ten years before. Indeed the satire
resembles Dryden’s in that it admits of a wide application and is not
limited to the individual described.
Nothing in Byron’s political creed redounds more to his credit
than his persistent opposition to all war except that carried on in the
“defence of freedom, country, or of laws.” Neglecting the pride and
pomp of war, he depicted the Siege of Ismail with ghastly realism,
laying emphasis on the blood and carnage of the battle and
condemning especially mercenary soldiers, “those butchers in large
business.” Though this attitude towards warfare was not original with
296
him, Byron spoke out with a firmness and pertinacity that marked
him as far ahead of his age.
Though Byron, in Don Juan, was almost entirely a destructive
critic of the political situation in England and in Europe, his ideas
were exceedingly influential. In spite of the fact that he had no
definite remedy to offer for intolerable conditions, his daring
championship of oppressed peoples affected European thought, not
only during his lifetime, but also for years after his death. He was
revered in Greece as more than mortal; he was an inspiration for
Mazzini and Cavour; he seemed to Lamartine an apostle of liberty. It
is probably to his insistence on the rights of the people and to his
sweeping indictment of autocratic rule that he owes the greatest part
of his international recognition.
Byron’s iconoclastic tendencies showed themselves also in his
attack on English society, in which he aimed to expose the
selfishness, stupidity, and affectation of the small class that
represented the aristocratic circle of the nation. In dealing with this
subject he knew of what he was speaking, for he had been a
member and a close observer of “that Microcosm on stilts yclept the
Great World.” His picture of this upper class is humorous and ironic,
but seldom vehement. In a series of vivid and often brilliant character
sketches he delineates the personages that Juan, Ambassador of
Russia, meets in London, touching cleverly on their defects and
vices, and unveiling the sensuality, jealousy, and deceit which their
outward decorum covers. Though the figures are types rather than
individuals, they were in many cases suggested by men and women
whom Byron knew. Possibly the most effective satire occurs in the
description of the gathering at Lady Adeline’s country-seat, Norman
Abbey, where some thirty-three guests, “the Brahmins of the Ton,”
297
meet at a fashionable house party.
For these social parasites and office seekers Byron felt nothing
but contempt. His advice to Juan moving among them is:

“Be hypocritical, be cautious, be

298
Not what you seem, but always what you see.”

He describes their life as dull and uninteresting, a gay masquerade

which palls when all its delights have been tried. Its prudery conceals
scandal, treachery, and lust; its great vices are hypocrisy and cant
299
—“cant political, cant religious, cant moral.” Indeed the satire of
Don Juan, from Canto XI to the point where the poem is broken off,
is an attack on pretence and sham, and a vindication of the free and
natural man. Byron’s motive may have been, in part, the desire for
revenge on the circle which had cast him out; but certainly he was
disgusted with the narrowness and conventionality of his London life,
and his newly acquired jesting manner found in it a suitable object
for satire.
While Byron’s liberalism and democracy were doing effective
service in pointing out flaws in existing political and social systems,
he was still maintaining, not without many inconsistencies, his old
conservative doctrines in literature, and doggedly insisting on the
virtue of his literary commandments:

“Thou shalt believe in Milton, Dryden, Pope;

 300
Thou shalt not set up Wordsworth, Coleridge, Southey.”

While he was being hailed as a leader of the romantic school of

poetry, he was still defending the principles of Pope, praising the
work of Crabbe, Rogers, and Campbell, and disapproving of the
verses of the members of the Lake School. He dedicated Don Juan,
in a mocking and condescending fashion, to Southey, and described
him in the sketch of the bard “paid to satirise or flatter” who sang to
301
Haidée and Juan the beautiful lyric, The Isles of Greece. He
ridiculed The Waggoner and Peter Bell, treating Wordsworth with an
hostility which is almost inexplicable in view of Byron’s indebtedness
in Childe Harold, III and IV to the older poet’s feeling for nature. Only
in minor respects had Byron’s position changed; he was more
appreciative of Scott and less vindictive towards Jeffrey; and he had
found at least one new literary enemy in the poetaster, William
Sotheby. In general there was little for him to add to what he had
already said in English Bards. His otherwise progressive spirit had
not extended into the field of literary criticism.
It is not at all surprising that a large portion of Don Juan should
be devoted to two subjects in which Byron had always been deeply
interested—woman and love. Nor is it at all remarkable, in view of
his singularly complex and variable nature, that the poem should
contain not only the exquisite idyll of Haidée but also line after line of
cynical satire on her sex. Though Byron’s opinion of women was
usually not complimentary, sentiment, and even sentimentality of a
certain sort, had a powerful attraction for him. If many of his love
affairs were followed and even accompanied by cynicism, it was
because the passion in such cases was sensual, and in reaction, he
went to the other extreme. The influence of the Guiccioli, however,
manifest in his descriptions of Haidée and Aurora Raby, was
beneficial to Byron’s character, and his ideas of love were somewhat
altered through his relations with her. At the same time the
conventional assertions of woman’s inconstancy and treachery so
common in his earlier work recur frequently in Don Juan.
 Love, according to Byron’s philosophy, can exist only when it is
free and untrammelled. The poet’s too numerous amours and the
general laxity of Italian morals had joined in exciting in him a
prejudice against English puritanism; while his own unfortunate
marital experience had convinced him that “Love and Marriage rarely
302
can combine.” The remembrance of his married life and his
observation in the land of his adoption were both instrumental in
forming his conclusion:

“There’s doubtless something in domestic doings,

303
Which forms, in fact, true love’s antithesis.”

When marriage, then, is so unalluring, the logical refuge is an honest

friendship with a married lady, “of all connections the most
304
steady.” When Byron does speak of women with apparent
respect, it is always well to search for irony behind. If he says,
evidently with emotion:

“All who have loved, or love, will still allow

Life has nought like it. God is love, they say,
305
And love’s a god,”

he qualifies his ecstacy elsewhere by asserting that Love is “the very

306 307
God of evil.” Although he protests that he loves the sex, he
308 309 310
must add that they are deceitful, hypocritical, and fickle.
Nothing in the first two cantos of Don Juan was more offensive to
Hobhouse and the “Utican Senate” to which Murray submitted them
than the poorly disguised portrayal of Lady Byron in the character of
Donna Inez. Though Byron explicitly disavowed all intention of
satirising his wife directly, no one familiar with the facts could
possibly have doubted that this lady “whose favorite science was the
mathematical,” who opened her husband’s trunks and letters, and
tried to prove her loving lord mad, and who acted under all
circumstances like “Morality’s prim personification” was intended to
represent the former Miss Milbanke and present Lady Byron.
Doubtless there is something artificial and affected in much of
Byron’s cynical comment on women and love; but if we are inclined
to distrust this man of many amours who delights in flaunting his past
before the eyes of his shocked compatriots, we must remember that
there is probably no conscious insincerity in his words. Byron
frequently deludes not only his readers but himself, and his satire on
women, when it is not a kind of bravado, is merely part of his worldly
philosophy.
The philosophical conceptions on which Don Juan rests are, in
their general trend, not uncommonly satirical; that is, they are
destructive rather than constructive, skeptical rather than idealistic,
founded on doubt rather than on faith. It is the object of the poem to
overturn tottering institutions, to upset traditions, and to unveil
illusions. Byron’s attitude is that so often taken by a thorough man of
the world who has tasted pleasure to the point of satiety, and who
has arrived at early middle age with his enthusiasms weakened and
his faith sunk in pessimism. This accounts for much of the realism in
the poem. Sometimes the poet, in the effort to portray things as they
311
are, merely transcribes the prose narratives of others into verse,
just as Shakspere borrowed passages from North’s Plutarch for
Julius Cæsar. More often he undertakes to detect and reveal the
incongruity between actuality and pretence, and to expose weakness
and folly under its mask of sham. The realism of this sort closely
resembles the more modern work of Zola, attributing as it does even
good actions to low motives and degrading deliberately the better
impulses of mankind. In Byron’s case it seems to be the result partly
of a wish to avoid carrying sentiment and romance to excess, partly
of a distorted or partial view of life. Whatever romance there is in
Don Juan—and the amount is not inconsiderable—is invariably
followed by a drop into bathos or absurdity. The deservedly famous
312
“Ave Maria,” with its exquisite sentiment and melody, is closed by
a stanza harsh and grating, which calls the reader with a shock back
to a lower level. This juxtaposition of tenderness and mockery,
tending by contrast to accentuate both moods, is highly
characteristic of the spirit of the poem. Juan’s lament for Donna Julia
313
is interrupted by sea-sickness, and his rhetorical address on
London, “Freedom’s chosen station,” is broken off by “Damn your
314
eyes! your money or your life.” Byron never overdoes the
emotional element in Don Juan; he draws us back continually to the
315
commonplace, and sometimes to the mean and vulgar.
Byron’s materialistic and skeptical habit of mind is often put into
phraseology that recalls the “Que sais-je?” of Montaigne. Rhetorical
disquisitions on the vanity of human knowledge and of worldly
316
achievement had appeared in Childe Harold ; in Don Juan the
poet dismisses the great problems of existence with a jest:

“What is soul, or mind, their birth and growth,

317
Is more than I know—the deuce take them both.”

In the words of the British soldier, Johnson, to Juan, we have,

perhaps, a summary of the position which Byron himself had
reached:

“There are still many rainbows in your sky,

But mine have vanished. All, when Life is new,
Commence with feelings warm and prospects high;
But Time strips our illusions of their hue,
And one by one in turn, some grand mistake
318
Casts off its bright skin yearly like the snake.”

As a corollary to this recognition of the futility of human endeavor,

the doctrine of mutability, so common in Shelley’s poetry, appears
319
frequently in Don Juan, ringing in the note of sadness which
Byron would have us believe was his underlying mood. Curiously
enough, though he cynically classed together “rum and true religion”
320
as calming to the spirit, he was chary of assailing Christian
theology or orthodox creeds. He preserved a kind of respect for the
Church; and even Dr. Kennedy was obliged to admit that on religious
questions Byron was a courteous and fair, as well as an acute,
antagonist. Perhaps the half-faith which led him to say once “The
trouble is I do believe” may account for the fact that, at a time when
William Hone and other satirists were making the Church of England
a target for their wit, Don Juan contained no reference to that
institution.
Byron, then, refused to accept any of the creeds and idealisms
of his day. His own position, however, was marked by doubt and
vacillation, and he took no positive attitude towards any of the great
problems of existence. Experience led him to nothing but uncertainty
and indecision, with the result that he became content to destroy,
since he was unable to construct.
This is no place for discussing the fundamental morality or
immorality of Don Juan. The British public of Byron’s day, basing
their judgment largely upon the voluptuousness of certain love
scenes and upon some coarse phrases scattered here and there
through the poem, charged him with “brutally outraging all the best
feeling of humanity.” There can be no doubt that Byron did ignore the
ordinary standards of conduct among average people; though he
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asserted “My object is Morality,” no one knew better than he that
he was constantly running counter to the conventional code of
behavior. Nor can any one doubt, after a study of his letters to
Murray and Moore, that he felt a sardonic glee in acting as an agent
of disillusion and pretending to be a very dangerous fellow. This spirit
led him to employ profanity in Don Juan until his friend Hobhouse
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protested: “Don’t swear again—the third ‘damn.’” By assailing
many things that his time held sacred, by calling love “selfish in its
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beginning as its end,” and maintaining that the desire for money
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is “the only sort of pleasure that requites,” Byron drew upon
himself the charge of immorality. The poem, however, does not
attempt to justify debauchery or to defend vicious practices; Byron is
attacking not virtue, but false sentiment, false idealism, and false
faith. His satiric spirit is engaged in analyzing and exposing the
strange contradictions and contrasts in human life, in tearing down
what is sham and pretence and fraud. Judged from this standpoint,
Don Juan is profoundly moral.
Fortunately, in this poem the design of which was to exploit the
doctrine of personal freedom, Byron had discovered a medium
through which he could make his individuality effective, in which he
could speak in the first person, leave off his story when he chose,
digress and comment on current events, and voice his every mood
and whim. The colloquial tone of the poem strikes the reader at
once. He censures himself in a jocular way for letting the tale slip
forever through his fingers, and confesses with mock humility,
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“If I have any fault, it is digression.”
The habit of calling himself back to the narrative becomes almost as
much of an idiosyncrasy as Mr. Kipling’s “But that is another
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story.” Obviously Byron’s words are really no more than half-
apologetic; he knew perfectly well what he was doing and why he
was doing it. Without insisting too much on the value of a
mathematical estimate it is still safe to say that Don Juan is fully half-
concerned with that sort of gossipy chat with which Byron’s visitors
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at Venice or Pisa were entertained, and as the poem lengthened,
his tendency was to neglect the plot more and more. Indeed the
justification for treating Don Juan as a satire lies mainly in these
side-remarks in which Byron discloses his thoughts and opinions
with so little reserve. The digressions in the poem are used
principally for two purposes: to satirize directly people, institutions, or
theories; to gossip about the writer himself. In either case we may
imagine Byron as a monologist, telling us what he has done and
what he is going to do, what he has seen and heard, what he thinks
on current topics, and illustrating points here and there by a short
anecdote or a compact maxim. In such a series of observations,
extending as they do over a number of years and written as they