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 Shlomo Melmed, MD
Professor of Medicine
Senior Vice President and Dean of the Faculty
Cedars-Sinai Medical Center
Los Angeles, California

Kenneth S. Polonsky, MD
Richard T. Crane Distinguished Service Professor
Dean of the Division of the Biological Sciences
and the Pritzker School of Medicine
Executive Vice President of Medical Affairs
The University of Chicago
Chicago, Illinois

P. Reed Larsen, MD, FACP, FRCP

Professor of Medicine
Harvard Medical School
Senior Physician and Chief
Thyroid Section
Division of Endocrinology, Diabetes, and Metabolism
Brigham and Women’s Hospital
Boston, Massachusetts

Henry M. Kronenberg, MD
Professor of Medicine
Harvard Medical School
Chief, Endocrine Unit
Massachusetts General Hospital
Boston, Massachusetts

Textbook of
WILLIAMS
Endocrinology 12th EDITION
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899

WILLIAMS TEXTBOOK OF ENDOCRINOLOGY ISBN: 978-1-4377-0324-5

Copyright © 2011, 2008, 2003, 1998, 1992, 1985, 1981, 1974, 1968, 1962, 1955 by
Saunders, an imprint of Elsevier Inc. All rights reserved.
Copyright 1950 by Saunders, an imprint of Elsevier Inc.
Copyright renewed 1990 by A.B. Williams, R.I. Williams
Copyright renewed 1983 by William H. Daughaday
Copyright renewed 1978 by Robert H. Williams

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electronic or mechanical, including photocopying, recording, or any information storage and
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This book and the individual contributions contained in it are protected under copyright by
the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional
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Practitioners and researchers must always rely on their own experience and knowledge in
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Library of Congress Cataloging-in-Publication Data

Williams textbook of endocrinology.—12th ed. / Shlomo Melmed ... [et al.].

   p. ; cm.
Textbook of endocrinology
Includes bibliographical references and index.
ISBN 978-1-4377-0324-5 (hardcover : alk. paper) 1. Endocrinology. 2. Endocrine glands—
Diseases. I. Melmed, Shlomo. II. Williams, Robert Hardin. III. Title: Textbook of
endocrinology.
[DNLM: 1. Endocrine Glands. 2. Endocrine System Diseases. WK 100]
RC648.T46 2011
616.4—dc22
2011004321
Acquisitions Editor: Pamela Hetherington
Developmental Editor: Joan Ryan
Publishing Services Manager: Patricia Tannian
Team Manager: Radhika Pallamparthy
Senior Project Manager: Sharon Corell Working together to grow
Project Manager: Jayavel Radhakrishnan libraries in developing countries
Design Direction: Louis Forgione
www.elsevier.com | www.bookaid.org | www.sabre.org
Printed in the United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1
CONTRIBUTORS

John C. Achermann, MD, PhD Lloyd P. Aiello, MD, PhD Andrew Arnold, MD
Wellcome Trust Senior Fellow Associate Professor Murray-Heilig Chair in Molecular
in Clinical Science Harvard Medical School Medicine
UCL Institute of Child Health Director Professor of Medicine
Honorary Consultant in Pediatric Beetham Eye Institute, Chief, Division of Endocrinology
Endocrinology Joslin Diabetes Center and Metabolism
Great Ormond Street Hospital Boston, Massachusetts, USA University of Connecticut
NHS Trust School of Medicine
London, UK Farmington, Connecticut, USA

Jennifer M. Barker, MD Rosemary Basson, MD, FRCP (UK) Shalender Bhasin, MD

Assistant Professor of Pediatrics Clinical Professor Boston University School
University of Colorado Denver Psychiatry of Medicine
Division of Pediatric Endocrinology University of British Columbia Boston Medical Center
The Children’s Hospital Director, Sexual Medicine Boston, Massachusetts, USA
Aurora, Colorado, USA Program Psychiatry
Vancouver General Hospital
Vancouver, British Columbia,
Canada

Andrew J.M. Boulton, MD, FRCP Glenn D. Braunstein, MD William J. Bremner, MD, PhD
Professor of Medicine Professor and Chairman Professor and Chair
University of Manchester Department of Medicine Department of Medicine
Consultant Physician The James R. Klinenberg, MD, Robert G. Petersdorf
Manchester Royal Infirmary Chair in Medicine Cedars-Sinai Endowed Chair
Manchester, UK Medical Center University of Washington
Los Angeles, California, USA School of Medicine
Chair
Department of Medicine
University of Washington
Medical Center
Seattle, Washington, USA
vi Contributors

Gregory A. Brent, MD F. Richard Bringhurst, MD Michael Brownlee, MD

Professor Associate Professor Anita and Jack Saltz Chair in
Departments of Medicine Medicine Diabetes Research and Professor
and Physiology Harvard Medical School Medicine and Pathology
David Geffen School of Medicine Physician Associate Director for Biomedical
at UCLA Medical Service Sciences
Chair, Department of Medicine Massachusetts General Hospital Einstein Diabetes Research Center
VA Greater Los Angeles Healthcare Boston, Massachusetts, USA Albert Einstein College of Medicine
System Bronx, New York, USA
Los Angeles, California, USA

Serdar E. Bulun, MD Charles F. Burant, MD, PhD John B. Buse, MD, PhD
Northwestern Memorial Hospital Professor of Internal Medicine Professor of Medicine
University of Illinois Hospital University of Michigan Chief, Division of Endocrinology
Chicago, Illinois, USA Ann Arbor, Michigan, USA UNC School of Medicine
Chapel Hill, North Carolina, USA

David A. Bushinsky, MD Ernesto Canalis, MD Christin Carter-Su, PhD

Professor Professor of Medicine Professor
Medicine, Pharmacology, and University of Connecticut School Molecular and Integrative Physiology
Physiology of Medicine University of Michigan Medical
University of Rochester School Farmington, Connecticut, USA School
of Medicine Director of Research Associate Director
Rochester, New York, USA St. Francis Hospital and Michigan Diabetes Research and
Medical Center Training Center
Hartford, Connecticut, USA University of Michigan
Ann Arbor, Michigan, USA
 Contributors vii

Roger D. Cone, PhD David W. Cooke, MD Mark E. Cooper, MB, BS, PhD
Professor and Chairman Associate Professor Director
Molecular Physiology and Biophysics Pediatries JDRF Centre for Diabetic
Vanderbilt University School of Johns Hopkins University Complications
Medicine School of Medicine Professor of Medicine and
Nashville, Tennessee, USA Baltimore, Maryland, USA Immunology
Monash University
Melbourne, Victoria, Australia

Philip E. Cryer, MD Gilbert H. Daniels, MD Mehul T. Dattani, FRCPCH,

Irene E. and Michael M. Karl Professor of Medicine FRCP, MD
Professor of Endocrinology and Harvard Medical School Professor and Head of Pediatric
Metabolism in Medicine Co-Director Thyroid Clinic Endocrinology
Washington University in St. Louis Medical Director Endocrine Developmental Endocrinology
Physician Tumor Center Research Group, Clinical and
Barnes-Jewish Hospital Thyroid Unit, Department of Molecular Genetics Unit
St. Louis, Missouri, USA Medicine and Cancer Center UCL Institute of Child Health
Massachusetts General Hospital Consultant and Lead in Adolescent
Boston, Massachusetts, USA Endocrinology
University College London Hospitals
London, United Kingdom

Terry F. Davies, MB.BS, MD, Marie B. Demay, MD Sara A. DiVall, MD

FRCP, FACE Professor of Medicine Assistant Professor
Florence and Theodore Baumritter Harvard Medical School Pediatries
Professor of Medicine Physician Johns Hopkins University
Attending Physician Endocrine Unit Baltimore, Maryland, USA
Mount Sinai School of Medicine Department of Medicine
New York, New York, USA Massachusetts General Hospital
Boston, Massachusetts, USA
viii Contributors

Daniel J. Drucker, MD George S. Eisenbarth, MD, PhD Joel K. Elmquist, DVM, PhD
Professor of Medicine Executive Director Professor and Director
University of Toronto Professor of Pediatrics Division of Hypothalamic Research
Toronto, Ontario, Canada Medicine and Immunology Internal Medicine and Pharmacology
Barbara Davis Center for Childhood University of Texas
Diabetes Southwestern Medical
University of Colorado at Denver Center at Dallas
Professor Dallas, Texas, USA
University of Colorado Hospital
Professor, Pediatrics
The Children’s Hospital
Aurora, Colorado, USA

Elisa Fabbrini, MD, PhD Sebastiano Filetti, MD Delbert A. Fisher, MD

Research Assistant Professor Professor of Internal Medicine Professor Emeritus
Center for Human Nutrition Department of Internal Medicine Pediatrics and Medicine
Washington University School of Sapienza Universita’ di Roma David Geffen School of Medicine at
Medicine Chief, Internal Medicine UCLA
St. Louis, Missouri, USA Department of Internal Medicine Los Angeles, California, USA
Policlinico Umberto I
Rome, Italy

Ezio Ghigo, MD Anne C. Goldberg, MD Ira J. Goldberg, MD

Professor of Endocrinology Associate Professor of Medicine Dickinson Richards Jr. Professor
Department of Internal Medicine Division of Endocrinology, Chief, Division of Preventive
University of Turin Faculty of Metabolism, and Lipid Research Medicine and Nutrition
Medicine Department of Internal Medicine Columbia University College of
Chief, Division of Endocrinology, Washington University School of Physicians and Surgeons
Diabetology, and Metabolism Medicine New York, New York, USA
Department of Internal Medicine St. Louis, Missouri, USA
University Hospital
Turin, Italy
 Contributors ix

Peter A. Gottlieb, MD Steven K. Grinspoon, MD Melvin M. Grumbach, MD, DM

Assistant Professor of Pediatrics and Professor of Medicine Edward B. Shaw Professor of
Medicine Harvard Medical School Pediatrics and Emeritus Chairman
The Children’s Hospital Director Department of Pediatrics
University of Colorado Health Neuroendocrine Clinical Center University of California,
Science Center Massachusetts General Hospital San Francisco
Barbara Davis Center for Childhood Boston, Massachusetts, USA Attending Physician
Diabetes Pediatrics
Aurora, Colorado, USA University of California,
San Francisco Medical Center
University of California,
San Francisco Children’s Hospital
San Francisco, California, USA

Joel F. Habener, MD Ian D. Hay, MB, PhD, FACE, FACP, Martha Hickey, BA (Hons), MSc,
Professor of Medicine FRCP (E,G & l), FRCPI (Hon) MBChB, MRCOG, FRANZCOG, MD
Laboratory of Molecular Professor of Medicine and Professor of Gynaecology
Endocrinology Dr. R.F. Emslander Professor of School of Women’s and Infants’
Massachusetts General Hospital Endocrinology Research Health
Boston, Massachusetts, USA Division of Endocrinology and University of Western Australia
Internal Medicine Perth, Western Australia, Australia
Mayo Clinic College of Medicine
Rochester, Minnesota, USA

Peter C. Hindmarsh, BSc, MD, Ken Ho, MD, FRACP, FRCP (UK) Ieuan A. Hughes, MA, MD, FRCP,
FRCP, FRCPCH Professor of Medicine FRCP(C), FRCPCH F Med Sci
Professor of Paediatric Endocrinology University of Queensland Professor of Paediatrics
Developmental Endocrinology Chair University of Cambridge
Research Group Centres for Health Research Honorary Consultant Paedaitrician
Institute of Child Health Princess Alexandra Hospital Cambridge University Hospitals NHS
University College, London Brisbane, Queensland, Australia Foundation Trust
Hon. Consultant Paediatric Cambridge, United Kingdom
Endocrinologist
Great Ormond Street Hospital for
Children
Hon. Consultant Paediatric
Endocrinologist
University College London Hospitals
London, United Kingdom
x Contributors

Andrew M. Kaunitz, MD George G. Klee, MD, PhD Samuel Klein, MD

Professor and Associate Chairman Professor of Laboratory Medicine William H. Danforth Professor of
Obstetrics and Gynecology and Pathology Medicine and Nutritional Science
University of Florida College of Mayo Clinic College of Medicine Center for Human Nutrition
Medicine, Jacksonville Consultant Washington University School of
Jacksonville, Florida, USA Laboratory Medicine and Pathology Medicine
Saint Mary’s Hospital William H. Danforth Professor of
Methodist Hospital Medicine and Nutritional Science
Mayo Clinic Geriatrics and Nutritional Science
Rochester, Minnesota, USA Barnes-Jewish Hospital
St. Louis, Missouri, USA

David Kleinberg, MD Nils P. Krone, MD Henry M. Kronenberg, MD

Chief of Endocrinology Wellcome Trust Clinician Scientist Professor of Medicine
Veterans Administration Fellow Harvard Medical School
Medical Center School of Clinical and Experimental Chief, Endocrine Unit
Department of Medicine Medicine Massachusetts General Hospital
New York University University of Birmingham Boston, Massachusetts, USA
New York, New York, USA Consultant Paediatric
Endocrinologist
Birmingham Children’s Hospital
Birmingham, United Kingdom

Rohit N. Kulkarni, MD, PhD Steven W.J. Lamberts, MD, PhD Fabio Lanfranco, MD, PhD
Investigator Professor Division of Endocrinology,
Cellular and Molecular Physiology Erasmus Medical Center Diabetology, and Metabolism
Joslin Diabetes Center Rotterdam, Neatherlands Department of Internal Medicine
Assistant Professor of Medicine University of Turin
Department of Medicine Turin, Italy
Harvard Medical School
Boston, Massachusetts, USA
 Contributors xi

P. Reed Larsen, MD, FACP, FRCP Mitchell A. Lazar, MD, Ph.D. Joseph A. Lorenzo, MD
Professor of Medicine Professor of Medicine and Genetics Professor of Medicine
Harvard Medical School Chief, Division of Endocrinology, University of Connecticut Health
Senior Physician and Chief Diabetes, and Metabolism Center
Thyroid Section University of Pennsylvania Attending Physician
Division of Endocrinology, Diabetes, Philadelphia, Pennsylvania, USA John Dempsey Hospital
and Metabolism Farmington, Connecticut, USA
Brigham and Women’s Hospital
Boston, Massachusetts, USA

Malcolm J. Low, MD, PhD Susan J. Mandel, MD, MPH Stephen J. Marx, MD
Professor of Physiology and Internal Professor of Medicine and Radiology Branch Chief and Section Chief
Medicine and Associate Chief Metabolic Diseases Branch
Department of Molecular and Division of Endocrinology, Diabetes, and Genetics and Endocrinology
Integrative Physiology and Metabolism Section
University of Michigan School of University of Pennsylvania School of National Institute of Diabetes,
Medicine Medicine Digestive, and Kidney Diseases
Ann Arbor, Michigan, USA Director, Clinical Endocrinology and Bethesda, Maryland, USA
Diabetes
University of Pennsylvania Health
System
Philadelphia, Pennsylvania, USA

Alvin M. Matsumoto, MD Shlomo Melmed, MD Rebeca D. Monk, MD

Professor, Department of Medicine Professor of Medicine Associate Professor of Medicine
University of Washington School of Senior Vice President and Dean of Nephrology
Medicine the Faculty Program Director, Nephrology
Associate Director Cedars-Sinai Medical Center Fellowship
Geriatric Research, Education, and Los Angeles, California, USA University of Rochester
Clinical Center Medical Center
Director, Clinical Research Unit Rochester, New York, USA
VA Puget Sound Health Care System
Seattle, Washington, USA
xii Contributors

Robert D. Murray, MD Richard W. Nesto, MD Kjell Oberg, MD, PhD

Consultant Endocrinologist and Northeast Health System Professor
Honorary Senior Lecturer Beverly Hospital Department of Endocrine Oncology
Department of Endocrinology Beverly, Massachusetts, USA Uppsala University
Leads Teaching Hospitals Lahey Clinic Uppsala, Sweden
NHS Trust Burlington, Massachusetts, USA
Leeds, United Kingdom

Kenneth S. Polonsky, MD Sally Radovick, MD Lawrence G. Raisz, MD

Richard T. Crane Distinguished Johns Hopkins University School of Board of Trustees Distinguished
Service Professor Medicine Professor of Medicine, Emeritus
Dean of the Division of the Johns Hopkins Hospital University of Connecticut
Biological Sciences and the Pritzker Baltimore, Maryland, USA Health Center
School of Medicine Farmington, Connecticut, USA
Executive Vice President of Medical
Affairs
The University of Chicago
Chicago, Illinois, USA

Alan G. Robinson, MD Johannes A. Romijn, MD, PhD Domenico Salvatore, MD, PhD
Associate Vice Chancellor Medical Professor Associate Professor of Endocrinology
Sciences, Executive Associate Dean, Endocrinology Department of Molecular and
and Professor of Medicine Leiden University Medical Center Clinical Endocrinology and
David Geffen School of Medicine Leiden, Netherlands Oncology
at UCLA University of Naples “Federico II”
Los Angeles, California, USA Naples, Italy
 Contributors xiii

Martin-Jean Schlumberger, MD Clay F. Semenkovich, MD Allen M. Spiegel, MD

Professor of Oncology Herbert S. Gasser Professor The Marilyn and Stanley M. Katz
Université Paris Sud. Endocrinology, Metabolism, and Dean
Chair Lipid Research Albert Einstein College of Medicine
Nuclear Medicine and Endocrine Washington University Bronx, New York, USA
Oncology St. Louis, Missouri, USA
Institut Gustave Roussy
Villejuif, France

Paul M. Stewart, MD FRCP, Christian J. Strasburger, MD Dennis M. Styne, MD

FMedSci Professor of Medicine Professor and Rimsey Chair of
Dean of Medicine Chief Pediatric Endocrinology
University of Birmingham Division of Clinical Endocrinology University of California Davis
Consultant Endocrinologist Department of Medicine, CCM Sacramento, California, USA
Queen Elizabeth Hospital Charité Universitätsmedizin
Birmingham, United Kingdom Berlin, Germany

Simeon I. Taylor, MD, PhD Adrian Vella, MD, FRCP (Edin.) Joseph G. Verbalis, MD
Vice President Professor Professor
Discovery Biology Pharmaceutical Division of Endocrinology & Medicine and Physiology
Research Institute Metabolism Georgetown University
Bristol-Myers Squibb Mayo Clinic Chief, Endocrinology and
Hopewell, New Jersey, USA Rochester, Minnesota, USA Metabolism
Georgetown University Hospital
Washington, DC, USA
xiv Contributors

Aaron I. Vinik, MD, PdD Samuel Wells, Jr., MD William F. Young, Jr., MD, MSc
FCP, MACP Senior Investigator Tyson Family Endocrinology Clinical
Professor of Medicine, Pathology, Medical Qncology Branch Professor in Honor of Vahab
Neurobiology National Cancer Institute, NIH Fatourechi, MD
Director of Research and Bethesda, Maryland, USA Professor of Medicine
Neuroendocrine Unit Division of Endocrinology, Diabetes,
Eastern Virginia Medical School, Metabolism, and Nutrition
Strelitz Diabetes Center Mayo Clinic
Norfolk, Virginia, USA Rochester, Minnesota, USA
PREFACE
Welcome to the twelfth edition of Williams Textbook of faculty. A uniform style facilitates identification and ready
Endocrinology. use of clinical algorithms.
Robert Williams inaugurated this enduring textbook We express our deep gratitude to the co-workers in our
more than 50 years ago, and the goals have remained offices: Anita Nichols, Lynn Moulton, Grace Labrado,
essentially unchanged (i.e., to publish “a condensed and Louise Ishibashi, and Sherri Turner, whose energetic efforts
authoritative discussion of the management of clinical have made this work possible. We also thank our colleagues
endocrinopathies based upon the application of funda- at Elsevier—Joan Ryan, Pamela Hetherington, and Dolores
mental information obtained from chemical and physio- Meloni—who skillfully navigated the dynamic world of
logical investigation”). Of course, today we would add medical publishing while assuring achievement of our
results of cellular and genomic investigation, as well as the goals. Their efforts have been essential in ensuring the suc-
wealth of clinical trial data, as aids in clinical management. cessful publication of this high-quality textbook, which
The immense and often overwhelming body of new infor- has become the classic text for all professionals engaged in
mation from multiple disciplines, in fact, makes this syn- caring for patients with endocrine disorders.
thetic endeavor more relevant than ever to help guide Finally, we would like to recognize and congratulate Dr.
endocrinologists in the care of their patients. To encourage Melvin Grumbach for his outstanding contributions to
the goal of both highest quality scientific rigor and knowl- Williams Textbook of Endocrinology, beginning with the
edge synthesis, we continue to ask the most distinguished fourth edition that was published in 1968.
authors to synthesize entire areas of clinical endocrine
science. The mandate for concise yet authoritative and Shlomo Melmed
comprehensive presentations acknowledges both the time
Kenneth S. Polonsky
pressures on today’s physicians and the desire to make the
text affordable and easily navigated. P. Reed Larsen
This edition has involved extensive revisions of the pre-
Henry M. Kronenberg
vious text, and 22 new authors have joined our expert
 The Evolutionary Perspective, 3
Endocrine Glands, 5
Transport of Hormones in Blood, 6
Target Cells as Active Participants, 7
Control of Hormone Secretion, 8
Hormone Measurement, 10
Endocrine Diseases, 11
Therapeutic Strategies, 12

CHAPTER 1
Principles of Endocrinology
HENRY M. KRONENBERG • SHLOMO MELMED • P. REED LARSEN •
KENNETH S. POLONSKY

Roughly 100 years ago, Starling coined the term hormone diverse approaches used by clinicians, physiologists, bio-
to describe secretin, a substance secreted by the small intes- chemists, cell biologists, and geneticists to understand the
tine into the bloodstream to stimulate pancreatic secretion. endocrine system.
In his Croonian Lectures, Starling considered the endo-
crine and nervous systems as two distinct mechanisms for
coordination and control of organ function. Thus, endo- THE EVOLUTIONARY PERSPECTIVE
crinology found its first home in the discipline of mam-
malian physiology. Hormones can be defined as chemical signals secreted into
Work over the next several decades by biochemists, the bloodstream that act on distant tissues, usually in a
physiologists, and clinical investigators led to the charac- regulatory fashion. Hormonal signaling represents a special
terization of many hormones secreted into the bloodstream case of the more general process of signaling between cells.
from discrete glands or other organs. Investigations showed Even unicellular organisms, such as baker’s yeast, Saccharo-
that diseases such as hypothyroidism and diabetes could myces cerevisiae, secrete short peptide mating factors that
be treated successfully, for the first time, by replacing spe- act on receptors of other yeast cells to trigger mating
cific hormones. These initial triumphs formed the founda- between the two cells. These receptors resemble the ubiq-
tion of the clinical specialty of endocrinology. uitous family of mammalian seven-transmembrane span-
Advances in cell biology, molecular biology, and genet- ning receptors that respond to ligands as diverse as photons
ics over the ensuing years began to explain the mecha- and glycoprotein hormones. Because these yeast receptors
nisms of endocrine diseases and of hormone secretion and trigger activation of heterotrimeric G proteins just as mam-
action. Even though these advances have embedded endo- malian receptors do, this conserved signaling pathway
crinology in the framework of molecular cell biology, they must have been present in the common ancestor of yeast
have not changed the essential subject of endocrinology— and humans.
the signaling mechanisms that coordinate and control the Signals from one cell to adjacent cells—so-called para-
functions of multiple organs and processes. Herein we crine signals—often trigger cellular responses that use the
survey the general themes and principles that underpin the same molecular pathways used by hormonal signals. For
3
4   Principles of Endocrinology

example, the sevenless receptor controls the differentiation speculate that the hormonal actions of vitamin D might
of retinal cells in the Drosophila eye by responding to a have evolved well after the paracrine vitamin D apparatus
membrane-anchored signal from an adjacent cell. Seven- provided the raw materials for the hormonal system.
less is a membrane-spanning receptor with an intracellular Target cells respond similarly to signals that reach them
tyrosine kinase domain that signals in a way that closely from the bloodstream (hormones) or from the cell next
resembles the signaling by hormone receptors such as the door (paracrine factors); the cellular response machinery
insulin receptor tyrosine kinase. does not distinguish the sites of origin of signals. The
Because paracrine factors and hormones can share sig- shared final common pathways used by hormonal and
naling machinery, it is not surprising that hormones can, paracrine signals should not, however, obscure important
in some settings, act as paracrine factors. Testosterone, for differences between hormonal and paracrine signaling
example, is secreted into the bloodstream but also acts systems (Fig.1-1). Paracrine signals do not travel very far;
locally in the testes to control spermatogenesis. Insulin-like consequently, the specific site of origin of a paracrine factor
growth factor 1 (IGF1) is a polypeptide hormone that is determines where it will act and provides specificity to that
secreted into the bloodstream from the liver and other action. When the paracrine factor bone morphogenic
tissues, but it is also a paracrine factor made locally in most protein 4 (BMP4) is secreted by cells in the developing
tissues to control cell proliferation. kidney, BMP4 regulates the differentiation of renal cells;
Furthermore, one receptor can mediate actions of a when the same factor is secreted by cells in bone, it regu-
hormone and a paracrine factor, such as parathyroid lates bone formation. Thus, the site of origin of BMP4
hormone (PTH) and parathyroid hormone–related protein. determines its physiologic role. In contrast, because hor-
In some cases, the paracrine actions of “hormones” have mones are secreted into the bloodstream, their sites of
functions quite unrelated to hormonal functions. For origin are often divorced from their functions. There is
example, macrophages synthesize the active form of nothing about thyroid hormone function, for example,
vitamin D, 1,25-dihydroxyvitamin D3 or calcitriol, which that requires that the thyroid gland be in the neck.
can then bind to vitamin D receptors in the same cells and Because the specificity of paracrine factor action is so
stimulate production of antimicrobial peptides.1 The dependent on its precise site of origin, elaborate mecha-
vitamin D 1α-hydroxylase responsible for activating 25- nisms have evolved to regulate and constrain the diffusion
hydroxyvitamin D (calcidiol) is synthesized in multiple of paracrine factors. Paracrine factors of the hedgehog
tissues in which it has functions not apparently related to family, for example, are covalently bound to cholesterol
the calcium homeostatic actions of calcitriol. One can to constrain the diffusion of these molecules in the

Regulation of signaling: endocrine

Source: gland Distribution: blood stream Non-target organ
• No contribution to • Universal — almost • Metabolism
specificity of target • Importance of dilution
• Synthesis/secretion

Target cell
• Receptor: source of specificity
• Responsiveness:
Number of receptors
Downstream pathways
Other ligands
Metabolism of ligand/receptor
All often regulated by ligand

Regulation of signaling: paracrine

Source: adjacent cell Target cell
• Major determinant of target • Receptor:
• Synthesis/secretion Specificity and sensitivity
Diffusion barrier
Determinant of gradient
• Induced inhibitory pathways,
ligands, and binding proteins

Distribution: matrix
• Diffusion distance
• Binding proteins: BMP, IGF
• Proteases Figure 1-1 Comparison of determinants of endocrine and
• Matrix components paracrine signaling.
 Principles of Endocrinology   5

extracellular milieu. Most paracrine factors interact with which no clear ligand or function is known. The analyses
binding proteins that block their action and control their of these “orphan” receptors have succeeded in broadening
diffusion. For example, chordin, noggin, and many other the current understanding of hormonal signaling. For
distinct proteins bind to various members of the BMP example, the orphan liver X receptor, LXR, was found
family to regulate their action. Proteases such as tolloid during searches for unknown nuclear receptors. Subse-
then destroy the binding proteins at specific sites to liber- quent experiments showed that oxygenated derivatives of
ate BMPs so that they can act on appropriate target cells. cholesterol are the ligands for LXR, which regulates genes
Hormones have rather different constraints. Because involved in cholesterol and fatty acid metabolism.2 LXR
they diffuse throughout the body, they must be synthesized and many other examples raise the question of what
in enormous amounts relative to the amounts of paracrine constitutes a hormone.
factors needed at specific locations. This synthesis usually The classic view of hormones is that they are synthe-
occurs in specialized cells designed for that specific purpose. sized in discrete glands and have no function other than
Hormones must then be able to travel in the bloodstream activating receptors on cell membranes or in the nucleus.
and diffuse in effective concentrations into tissues. Lipo- In contrast, cholesterol, which is converted in cells to oxy-
philic hormones, for example, bind to soluble proteins that genated derivatives that activate the LXR receptor, uses a
allow them to travel in the aqueous medium of blood at hormonal strategy to regulate its own metabolism. Other
relatively high concentrations. The ability of hormones to orphan nuclear receptors similarly respond to ligands such
diffuse through the extracellular space means that the local as bile acids and fatty acids. These “hormones” have impor-
concentration of a hormone at target sites will rapidly tant metabolic roles quite separate from their signaling
decrease when glandular secretion of the hormone stops. properties, although the hormone-like signaling serves to
Because hormones diffuse throughout extracellular fluid allow regulation of the metabolic function. The calcium-
quickly, hormonal metabolism can occur in specialized sensing receptor is an example from the G protein–linked
organs (e.g., liver, kidney) in a manner that determines the receptor family that responds to a nonclassic ligand, ionic
effective hormone concentration in other tissues. calcium. Calcium is released into the bloodstream from
In summary, paracrine factors and hormones use several bone, kidney, and intestine and acts on the calcium-sensing
distinct strategies to control their biosynthesis, sites of receptors on parathyroid cells, renal tubular cells, and
action, transport, and metabolism. These differing strate- other cells to coordinate cellular responses to calcium.
gies probably explain partly why a hormone such as IGF1, Therefore, many important metabolic factors have taken
unlike its close relative, insulin, has multiple binding on hormonal properties as part of a regulatory strategy.
proteins that control its action in tissues. IGF1 exhibits a
double life—it is both a hormone and a paracrine factor.
Presumably, the local actions of IGF1 mandate an elaborate ENDOCRINE GLANDS
binding protein apparatus to enable appropriate hormone
signaling. Hormone formation may occur either in localized collec-
All of the major hormonal signaling programs—G tions of specific cells, the endocrine glands, or in cells that
protein–coupled receptors, tyrosine kinase receptors, have additional roles. Many protein hormones, such as
serine/threonine kinase receptors, ion channels, cytokine growth hormone (GH), PTH, prolactin, insulin, and gluca-
receptors, and nuclear receptors—are also used by para- gon, are produced in dedicated cells by standard protein
crine factors. In contrast, several paracrine signaling pro- synthetic mechanisms common to all cells. These secretory
grams appear to be used only by paracrine factors and not cells usually contain specialized secretory granules designed
by hormones. For example, Notch receptors respond to to store large amounts of hormone and to release the
membrane-based ligands to control cell fate, but no blood- hormone in response to specific signals. Formation of small
borne ligands are known to use Notch-type signaling. hormone molecules begins with commonly found precur-
Perhaps the intracellular strategy used by Notch, which sors, usually located in specific glands such as the adrenals,
involves cleavage of the receptor and subsequent nuclear gonads, or thyroid. In the case of the steroid hormones,
actions of the receptor’s cytoplasmic portion, is too inflex- the precursor is cholesterol, which is modified by various
ible to serve the purposes of hormones. hydroxylations, methylations, and demethylations to form
The analyses of the complete genomes of multiple bac- glucocorticoids, androgens, estrogens, and their biologi-
terial species, the yeast S. cerevisiae, the fruit fly Drosophila cally active derivatives.
melanogaster, the worm Caenorhabditis elegans, the plant However, not all hormones are formed in dedicated and
Arabidopsis thaliana, humans, and many other species have specialized endocrine glands. For example, the protein
allowed a comprehensive view of the signaling machinery hormone, leptin, which regulates appetite and energy
used by various forms of life. As noted earlier, S. cerevisiae expenditure, is formed in adipocytes, providing a
uses G protein–linked receptors; this organism, however, specific signal that reflects the nutritional state to the
lacks tyrosine kinase receptors and nuclear receptors that central nervous system. The cholesterol derivative,
resemble the estrogen/thyroid receptor family. In contrast, 7-dehydrocholesterol, the precursor of vitamin D, is pro-
the worm and fly share with humans the use of each of duced in skin keratinocytes by a photochemical reaction.
these signaling pathways, although with substantial varia- In the unique enteroendocrine hormonal system, peptide
tion in the number of genes committed to each pathway. hormones that regulate metabolic and other responses to
For example, the Drosophila genome encodes 20 nuclear oral nutrients are produced and secreted by specialized
receptors, the C. elegans genome 270, and the human endocrine cells scattered throughout the intestinal
genome (tentatively) more than 50. These patterns suggest epithelium.
that ancient multicellular animals must have already estab- Thyroid hormone synthesis occurs by means of a unique
lished the signaling systems that are the foundation of the pathway. The thyroid cell synthesizes a 660,000-kd homodi-
endocrine system as we know it in mammals. mer, thyroglobulin, which is then iodinated at specific
Even before the sequencing of the human genome was iodotyrosines. Certain of these “couple” to form the iodo-
accomplished, sequence analyses had made clear that thyronine molecule within thyroglobulin, which is then
many receptor genes are found in mammalian genomes for stored in the lumen of the thyroid follicle. For this to occur,
6   Principles of Endocrinology

the thyroid cell must concentrate the trace quantities of programmed increases and decreases in hormone secretion
iodide from the blood and oxidize it via a specific peroxi- or activation also occur through neuroendocrine pathways.
dase. Release of thyroxine (T4) from the thyroglobulin Examples include the circadian variation in secretion of
requires its phagocytosis and cathepsin-catalyzed digestion ACTH that directs the synthesis and release of cortisol. The
by the same cells. monthly menstrual cycle exemplifies a system with much
Hormones are synthesized in response to biochemical longer periodicity that requires a complex synergism
signals generated by various modulating systems. Many of between central and peripheral axes of the endocrine
these systems are specific to the effects of the hormone glands. Disruption of hormonal homeostasis due to
product. For example, PTH synthesis is regulated by the glandular or central regulatory system dysfunction has
concentration of ionized calcium, and insulin synthesis is both clinical and laboratory consequences. Recognition
regulated by the concentration of glucose. For others, such and correction of these effects are the essence of clinical
as gonadal, adrenal, and thyroid hormones, control of endocrinology.
hormone synthesis is achieved by the hormonostatic func-
tion of the hypothalamic-pituitary axis. Cells in the hypo-
thalamus and pituitary monitor the circulating hormone TRANSPORT OF HORMONES
concentration and secrete tropic hormones, which activate IN BLOOD
specific pathways for hormone synthesis and release.
Typical examples are luteinizing hormone (LH), follicle- Protein hormones and some small molecules, such as the
stimulating hormone (FSH), thyroid-stimulating hormone catecholamines, are water soluble and readily transported
(TSH), and adrenocorticotropic hormone (ACTH). via the circulatory system. Others, such as the steroid and
These trophic hormones increase rates of hormone syn- thyroid hormones, are almost insoluble in water, and their
thesis and secretion, and they may induce target cell divi- distribution presents special problems. Such molecules are
sion, resulting in enlargement of the various target glands. bound to 50- to 60-kd carrier plasma glycoproteins such as
For example, in hypothyroid individuals living in iodine- thyroxine-binding globulin (TBG), sex hormone–binding
deficient areas of the world, TSH secretion causes a marked globulin (SHBG), and corticosteroid-binding globulin, as
hyperplasia of thyroid cells. In such regions, the thyroid well as to albumin. The ligand-protein complexes serve as
gland may be 20 to 50 times its normal size. Adrenal hyper- reservoirs of these hormones, ensure ubiquitous distribu-
plasia occurs in patients with genetic deficiencies in corti- tion of their water-insoluble ligands, and protect the small
sol formation. Hypertrophy and hyperplasia of parathyroid molecules from rapid inactivation or excretion in the urine
cells, in this case initiated by an intrinsic response to the or bile. Without these proteins, it is unlikely that hydro-
stress of hypocalcemia, occurs in patients with renal insuf- phobic molecules would be transported much beyond the
ficiency or calcium malabsorption. veins draining the glands in which they are formed.
Hormones may be fully active when they are released The protein-bound hormones exist in rapid equilibrium
into the bloodstream (e.g., GH, insulin), or they may with the often minute quantities of hormone in the
require activation in specific cells to produce their biologic aqueous plasma. It is this “free” fraction of the circulating
effects. These activation steps are often highly regulated. hormone that is taken up by the cell. For example, if tracer
For example, the T4 released from the thyroid cell is a pro- thyroid hormone is injected into the portal vein in a
hormone that must undergo a specific deiodination to protein-free solution, it becomes bound to hepatocytes at
form the active 3,5,3′-triiodothyronine (T3). This deiodin- the periphery of the hepatic sinusoid. When the same
ation reaction can occur in target tissues (e.g., in the central experiment is repeated with a protein-containing solution,
nervous system); in the thyrotrophs, where T3 provides there is a uniform distribution of tracer hormone through-
feedback regulation of TSH production; or in hepatic and out the hepatic lobule.3
renal cells, from which it is released into the circulation for Despite the very high affinity of some of the binding
uptake by all tissues. A similar postsecretory activation proteins for their ligands, a specific protein may not be
step, catalyzed by a 5αα-reductase, causes tissue-specific essential for hormone distribution. For example, in humans
activation of testosterone to dihydrotestosterone in target with a congenital deficiency of TBG, other proteins, namely
tissues including the male urogenital tract and genital skin, transthyretin (TTR) and albumin, subsume its role. Because
as well as in liver. Vitamin D undergoes hydroxylation at the affinity of these secondary thyroid hormone transport
the 25 position in the liver and at the 1 position in the proteins is several orders of magnitude lower than that of
kidney. Both hydroxylations must occur to produce the TBG, it is possible for the hypothalamic-pituitary feedback
active hormone, calcitriol. The activity of 1α-hydroxylase, system to maintain free thyroid hormone in the normal
but not that of 25-hydroxylase, is stimulated by PTH and range at a much lower total hormone concentration. The
reduced plasma phosphate but inhibited by calcium, fact that the level of “free” hormone concentration is
calcitriol, and fibroblast growth factor 23 (FGF23). normal in subjects with TBG deficiency indicates that it is
Hormones are synthesized as required on a daily, hourly, this free moiety that is defended by the hypothalamic-
or minute-to-minute basis with minimal storage, but there pituitary axis and is the active hormone.4
are significant exceptions. One is the thyroid gland, which The availability of gene targeting techniques has allowed
contains enough stored hormone to last for about 2 specific tests of the physiologic roles of several hormone-
months. This permits a constant supply despite significant binding proteins. For example, mice with targeted inactiva-
variations in the availability of iodine. However, if iodine tion of the vitamin D–binding protein (DBP) have been
deficiency is prolonged, the normal reservoirs of T4 can be generated.5 Although the absence of DBP markedly reduces
depleted. the circulating concentration of vitamin D, the mice are
The various feedback signaling systems already described otherwise normal. However, they do show enhanced sus-
enable the hormonal homeostasis that is characteristic of ceptibility to a vitamin D–deficient diet because of the
virtually all endocrine systems. Regulation may include the reduced reservoir of this sterol. In addition, the absence of
central nervous system or local signal recognition mecha- DBP markedly reduces the half-life of calcidiol by accelerat-
nisms in the glandular cells, such as the calcium-sensing ing its hepatic uptake, making the mice less susceptible to
receptor of the parathyroid cell. Superimposed, centrally vitamin D intoxication.
 Principles of Endocrinology   7

In rodents, TTR carries retinol-binding protein and is it is the hormone bound to SHBG, rather than the “free”
also the principal thyroid hormone–binding protein. This hormone, that is the active moiety that enters cells. It is
protein is synthesized in the liver and in choroid plexus. unclear how generally this apparent exception to the “free
It is the major thyroid hormone–binding protein in the hormone” hypothesis occurs.
cerebrospinal fluid of both rodents and humans and was
previously thought to possibly serve an important role in
thyroid hormone transport into the central nervous system. TARGET CELLS AS ACTIVE
This hypothesis was later disproved by the fact that mice PARTICIPANTS
without TTR have normal concentrations of T4 in the brain
in addition to free T4 in the plasma.6,7 To be sure, the serum Hormones determine cellular target actions by binding
concentrations of vitamin A and total T4 are decreased, but with high specificity to receptor proteins. Whether a
the knockout mice have no signs of vitamin A deficiency peripheral cell is hormonally responsive depends to a large
or hypothyroidism. Such studies suggest that these pro- extent on the presence and function of specific and selec-
teins primarily serve distributive and reservoir functions. tive hormone receptors. Receptor expression determines
Protein hormones and some small ligands (e.g., cate- which cells will respond as well as the nature of the intra-
cholamines) produce their effects by interacting with cell cellular effector pathways activated by the hormone signal.
surface receptors. Others, such as the steroid and thyroid Receptor proteins may be localized to the cell membrane,
hormones, must enter the cell to bind to cytosolic or cytoplasm, or nucleus. Broadly, polypeptide hormone
nuclear receptors. In the past, it was thought that much of receptors are associated with cell membranes, whereas
the transmembrane transport of hormones was passive. steroid hormones selectively bind soluble intracellular pro-
Evidence has now demonstrated that specific transporters teins (Fig. 1-2). However, exceptions do occur. For example,
are involved in cellular uptake of thyroid hormone.8 This epidermal growth factor (EGF) may signal directly to recep-
may be found to be the case for other small ligands as well, tors located within the nucleus.
revealing yet another mechanism for ensuring the distribu- Membrane-associated receptor proteins usually consist
tion of a hormone to its site of action. Studies in mice of extracellular sequences that recognize and bind ligand,
missing megalin, a large cell surface protein in the low- transmembrane anchoring hydrophobic sequences, and
density lipoprotein (LDL) receptor family, have suggested intracellular sequences that initiate intracellular signaling.
that estrogen and testosterone uses megalin to enter certain Intracellular signaling is mediated by covalent modifica-
tissues while still bound to SHBG.9 In this case, therefore, tion and activation of intracellular signaling molecules

Progesterone

O R

O RR O
XTyr

Figure 1-2 Hormonal signaling by cell surface and intracel- TF P TFTyr P

R ss
lular receptors. The receptors for the water-soluble poly- PKA s
peptide hormones, luteinizing hormone (LH), and insulin-like Target gene
growth factor 1 (IGF-1), are integral membrane proteins IGF-1
XTyr P
located at the cell surface. They bind the hormone-utilizing cAMP
extracellular sequences and transduce a signal through the
generation of second messengers: cyclic adenosine mono-
phosphate (cAMP) for the LH receptor and tyrosine-
AC

phosphorylated substrates for the IGF-1 receptor. Although ATP AAAAA

effects on gene expression are indicated, direct effects on G mRNAs
cellular proteins (e.g., ion channels) are also observed. In R
s ss

contrast, the receptor for the lipophilic steroid hormone,

progesterone, resides in the cell nucleus. It binds the LH
hormone and becomes activated and capable of directly
modulating target gene transcription.) AC, Adenylate cyclase; Proteins
G, heterotrimeric G protein; mRNAs, messenger RNAs;
PKA, protein kinase A; R, receptor molecule;TF, transcription
factor; Tyr, tyrosine found in protein X; X, unknown protein
substrate. (Reproduced from Mayo K. Receptors: molecular
mediators of hormone action. In: Conn PM, Melmed S, eds.
Endocrinology: Basic and Clinical Principles. Totowa, NJ: Humana
Press, 1997:11.) Biological responses
8   Principles of Endocrinology

(e.g., STAT proteins) or by generation of small molecule may be induced by activating mutations (e.g., TSH recep-
second messengers (e.g., cyclic adenosine monophosphate) tor) leading to endocrine organ hyperfunction, even in the
through activation of heterotrimeric G proteins. The α-, β-, absence of hormone. Conversely, inactivating receptor
and γ-subunits of these G proteins activate or suppress mutations may lead to endocrine hypofunction (e.g., tes-
effector enzymes and ion channels that generate the second tosterone receptor, vasopressin receptor). These syndromes
messengers. Some of these receptors may in fact exhibit are well characterized and are well described in other chap-
constitutive activity and have been shown to signal in the ters of this text (Fig. 1-3).
absence of added ligand. The functional diversity of receptor signaling also results
Several growth factors and hormone receptors (e.g., for in overlapping or redundant intracellular pathways. For
insulin) behave as intrinsic tyrosine kinases or activate example, both GH and cytokines activate JAK-STAT signal-
intracellular protein tyrosine kinases. Ligand activation ing, whereas the distal effects of these stimuli clearly differ.
may cause receptor dimerization (e.g., GH) or heterodimer- Therefore, despite common signaling pathways, hormones
ization (e.g., interleukin-6), followed by activation of intra- elicit highly specific cellular effects. Tissue or cell-type
cellular phosphorylation cascades. These activated proteins genetic programs or receptor-receptor interactions at the
ultimately determine specific nuclear gene expression. cell surface (e.g., dopamine D2 hetero-oligomerization with
Both the number of receptors expressed per cell and somatotropin release–inhibiting factor [SRIF]) may also
their responses are regulated, providing a further level of confer specific cellular response to a hormone and provide
control for hormone action. Several mechanisms account an additive cellular effect.10
for altered receptor function. Receptor endocytosis causes
internalization of cell surface receptors; the hormone-
receptor complex is subsequently dissociated, resulting in
abrogation of the hormone signal. Receptor trafficking may CONTROL OF HORMONE SECRETION
then result in recycling back to the cell surface (e.g.,
as for insulin), or the internalized receptor may undergo Anatomically distinct endocrine glands are composed of
lysosomal degradation. Both of these mechanisms, trig- highly differentiated cells that synthesize, store, and secrete
gered by activation of receptors, effectively lead to impaired hormones. Circulating hormone concentrations are a func-
hormone signaling by downregulation of these receptors. tion of glandular secretory patterns and hormone clearance
The hormone signaling pathway may also be downregu- rates. Hormone secretion is tightly regulated to attain cir-
lated by receptor desensitization (e.g., as for epinephrine); culating levels that are most conducive to eliciting the
ligand-mediated receptor phosphorylation leads to a revers- appropriate target tissue response. For example, longitudi-
ible deactivation of the receptor. Desensitization mecha- nal bone growth is initiated and maintained by exquisitely
nisms can be activated by a receptor’s ligand (homologous regulated levels of circulating GH: mild GH hypersecretion
desensitization) or by another signal (heterologous desen- results in gigantism, and GH deficiency causes growth
sitization), which attenuates receptor signaling in the con- retardation. Ambient circulating hormone concentrations
tinued presence of ligand. Receptor function may also be are not uniform, and the secretion patterns determine
limited by the action of specific phosphatases (e.g., SHP) appropriate physiologic function. For example, insulin
or by intracellular negative regulation of the signaling secretion occurs in short pulses elicited by nutrient intake
cascade (e.g., suppressor of cytokine signaling [SOCS] pro- and other signals; gonadotropin secretion is episodic,
teins inhibiting JAK-STAT signaling). determined by a hypothalamic pulse generator; and pro-
Mutational changes in receptor structure can also deter- lactin secretion appears to be relatively continuous with
mine hormone action. Constitutive receptor activation secretory peaks elicited during suckling.

Diseases caused by mutations in G-protein-coupled receptors

Condition Receptor Inheritance ∆ Function
Retinitis pigmentosa Rhodopsin AD/AR Loss
Nephrogenic diabetes insipidus Vasopressin V2 X-linked Loss
Isolated glucocorticoid deficiency ACTH AR Loss
Color blindness Red/green opsins X-linked Loss
Familial precocious puberty LH AD (male) Gain
Familial hypercalcemia Ca2+ sensing AD Loss
Neonatal severe parathyroidism Ca2+ sensing AR Loss
Dominant form hypocalcemia Ca2+ sensing AD Gain
Congenital hyperthyroidism TSH AD Gain
Resistance to thyroid hormone TSH AR (comp het) Loss
Hyperfunctioning thyroid adenoma TSH Somatic Gain
Metaphyseal chondrodysplasia PTH-PTHrP Somatic Gain
Hirschsprung’s disease Endothelin-B Multigenic Loss
Coat color alteration (E locus, mice) MSH AD/AR Loss and gain
Dwarfism (little locus, mice) GHRH AR Loss

Figure 1-3 Diseases caused by mutations in G-protein–coupled receptors. All are human conditions with the exception of the final two entries, which refer
to the mouse. Loss of function refers to inactivating mutations of the receptor, and gain of function to activating mutations. ACTH, adrenocorticotropic
hormone; AD, autosomal dominant; AR, autosomal recessive; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; PTH-PTHrP, parathyroid hormone
and parathyroid hormone–related peptide; MSH, melanocyte-stimulating hormone; GHRH, growth hormone–releasing hormone; FSH, follicle-stimulating
hormone. (Reproduced from Mayo K. Receptors: molecular mediators of hormone action. In Conn PM, Melmed S, eds. Endocrinology: Basic and Clinical Principles.
Totowa, NJ: Humana Press, 1997:27.)
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