Second Edition HARRISON’S Endocrinology Derived from Harrison’s Principles of Internal Medicine, 17th Edition Editors ANTHONY S. FAUCI, EUGENE BRAUNWALD, MD MD Chief,Laboratory of Immunoregulation; Distinguished Hersey Professor of Medicine, Director,National Institute of Allergy and Infectious Diseases, Harvard Medical School;Chairman,TIMI Study Group, National Institutes of Health,Bethesda Brigham and Women’s Hospital,Boston DENNIS L. KASPER, STEPHEN L. HAUSER, MD MD William Ellery Channing Professor of Medicine,Professor of Robert A.Fishman Distinguished Professor and Chairman, Microbiology and Molecular Genetics,Harvard Medical School; Department of Neurology,University of California,San Francisco Director,Channing Laboratory,Department of Medicine, Brigham and Women’s Hospital,Boston J. LARRY JAMESON, , MD PhD Professor of Medicine; DAN L. LONGO, MD Vice President for Medical Affairs Scientific Director,National Institute on Aging, and Lewis Landsberg Dean, National Institutes of Health, Northwestern University Feinberg Bethesda and Baltimore School of Medicine,Chicago JOSEPH LOSCALZO, , MD PhD Hersey Professor ofTheory and Practice of Medicine, Harvard Medical School;Chairman,Department of Medicine; Physician-in-Chief,Brigham and Women’s Hospital,Boston Second Edition HARRISON’S Endocrinology Editor J. Larry Jameson, MD, PhD Professor of Medicine; Vice President for Medical Affairs and Lewis Landsberg Dean, Northwestern University Feinberg School of Medicine,Chicago New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto Copyright © 2010 by The McGraw-Hill Companies, Inc. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-0-07-174147-7 MHID: 0-07-174147-X The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-174144-6, MHID: 0-07-174144-5. All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefi t of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs. To contact a representative please e-mail us at [email protected]. This book was set in Bembo by Glyph International.The editors were James F. Shanahan and Kim J. Davis. The production supervisor was Catherine H. Saggese. Project management was provided by Arushi Chawla of Glyph International. The cover design was by Thomas DePierro. TERMS OF USE This is a copyrighted work and The McGraw-Hill Companies, Inc. (“McGrawHill”) and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise. CONTENTS Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii 12 The Menopause Transition and Postmenopausal Hormone Therapy . . . . . . . . . 207 Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix JoAnn E.Manson,Shari S.Bassuk 1 Principles of Endocrinology . . . . . . . . . . . . . . . . 1 13 Hirsutism and Virilization . . . . . . . . . . . . . . . . 216 J.Larry Jameson David A.Ehrmann SECTION I 14 Gynecologic Malignancies. . . . . . . . . . . . . . . . 222 PITUITARY, THYROID, AND Robert C.Young ADRENAL DISORDERS 15 Sexual Dysfunction. . . . . . . . . . . . . . . . . . . . . 232 2 Disorders of the Anterior Pituitary and Kevin T.McVary Hypothalamus. . . . . . . . . . . . . . . . . . . . . . . . . . 16 Shlomo Melmed, J.Larry Jameson SECTION III DIABETES MELLITUS, OBESITY, 3 Disorders of the Neurohypophysis . . . . . . . . . . . 50 LIPOPROTEIN METABOLISM Gary L.Robertson 16 Biology of Obesity . . . . . . . . . . . . . . . . . . . . . 242 4 Disorders of the Thyroid Gland . . . . . . . . . . . . . 62 Jeffrey S.Flier,Eleftheria Maratos-Flier J.Larry Jameson,Anthony P.Weetman 17 Evaluation and Management of Obesity . . . . . 251 5 Disorders of the Adrenal Cortex. . . . . . . . . . . . . 99 Robert F.Kushner Gordon H.Williams,Robert G.Dluhy 18 The Metabolic Syndrome . . . . . . . . . . . . . . . . 259 6 Pheochromocytoma . . . . . . . . . . . . . . . . . . . . 133 Robert H.Eckel Hartmut P.H.Neumann 19 Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . . 267 Alvin C.Powers SECTION II REPRODUCTIVE ENDOCRINOLOGY 20 Hypoglycemia. . . . . . . . . . . . . . . . . . . . . . . . . 314 Philip E.Cryer 7 Disorders of Sex Development. . . . . . . . . . . . . 144 John C.Achermann,J.Larry Jameson 21 Disorders of Lipoprotein Metabolism. . . . . . . . 323 Daniel J.Rader,Helen H.Hobbs 8 Disorders of the Testes and Male Reproductive System. . . . . . . . . . . . . . . . . . . . 156 Shalender Bhasin,J.Larry Jameson SECTION IV DISORDERS AFFECTING MULTIPLE 9 Testicular Cancer. . . . . . . . . . . . . . . . . . . . . . . 180 ENDOCRINE SYSTEMS Robert J.Motzer,George J.Bosl 22 Endocrine Tumors of the Gastrointestinal 10 The Female Reproductive System: Tract and Pancreas. . . . . . . . . . . . . . . . . . . . . . 348 Infertility and Contraception . . . . . . . . . . . . . . 186 Robert T.Jensen Janet E.Hall 23 Multiple Endocrine Neoplasias and 11 Menstrual Disorders and Pelvic Pain. . . . . . . . . 201 Autoimmune Endocrinopathies. . . . . . . . . . . . 367 Janet E.Hall Camilo Jimenez,Robert F.Gagel v vi Contents 24 Endocrine Paraneoplastic Syndromes . . . . . . . . 379 28 Osteoporosis. . . . . . . . . . . . . . . . . . . . . . . . . . 443 J.Larry Jameson Robert Lindsay,Felicia Cosman SECTION V 29 Paget’s Disease and Other Dysplasias of Bone . . 462 DISORDERS OF BONE AND CALCIUM Murray J.Favus,Tamara J.Vokes METABOLISM Appendix Laboratory Values of Clinical Importance . . . . . 475 25 Bone and Mineral Metabolism in Alexander Kratz,Michael A.Pesce,Daniel J.Fink Health and Disease . . . . . . . . . . . . . . . . . . . . . 388 F.Richard Bringhurst,Marie B.Demay, Stephen M.Krane,Henry M.Kronenberg Review and Self-Assessment. . . . . . . . . . . . . . . 491 Charles Wiener,Gerald Bloomfield, 26 Approach to Hypercalcemia and Cynthia D.Brown,Joshua Schiffer,Adam Spivak Hypocalcemia. . . . . . . . . . . . . . . . . . . . . . . . . 406 Sundeep Khosla Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525 27 Diseases of the Parathyroid Gland. . . . . . . . . . . 411 John T.Potts,Jr. CONTRIBUTORS Numbers in brackets refer to the chapter(s) written or co-written by the contributor. JOHN C.ACHERMANN,MD MURRAY J.FAVUS,MD Lecturer in Endocrinology,UCL Institute of Child Health, Professor of Medicine,Interim Head,Endocrine Section;Director, University College,London,United Kingdom [7] Bone Section,University of Chicago Pritzker School of Medicine, Chicago [29] SHARI S.BASSUK,ScD Epidemiologist,Division of Preventive Medicine, DANIEL J.FINK,†MD,MPH Brigham and Women’s Hospital,Boston [12] Associate Professor of Clinical Pathology,College of Physicians and Surgeons,Columbia University,New York [Appendix] SHALENDER BHASIN,MD Chief and Professor,Department of Endocrinology, JEFFREY S.FLIER,MD Diabetes,& Nutrition,Boston University,Boston [8] Caroline Shields Walker Professor of Medicine, Harvard Medical School;Dean of the Faculty of Medicine, GERALD BLOOMFIELD,MD,MPH Harvard School of Medicine,Boston [16] Department of Internal Medicine,The Johns Hopkins University School of Medicine,Baltimore [Review and Self-Assessment] ROBERT F.GAGEL,MD Professor of Medicine and Head,Division of Internal Medicine, GEORGE J.BOSL,MD University of Texas MD Anderson Cancer Center,Houston [23] Chairman,Department of Medicine,Memorial Sloan-Kettering Cancer Center;Professor of Medicine,Joan and Sanford I.Weill JANET E.HALL,MD Medical College of Cornell University,New York [9] Associate Professor of Medicine,Harvard Medical School;Associate Physician,Massachusetts General Hospital,Boston [10,11] F.RICHARD BRINGHURST,MD Senior Vice President for Medicine and Research Management, HELEN H.HOBBS,MD Massachusetts General Hospital;Associate Professor of Medicine, Investigator,Howard Hughes Medical Institute;Professor of Internal Harvard Medical School,Boston [25] Medicine and Molecular Genetics,University of Texas Southwestern Medical Center,Dallas [21] CYNTHIA D.BROWN,MD Department of Internal Medicine,The Johns Hopkins University J.LARRY JAMESON,MD,PhD School of Medicine,Baltimore [Review and Self-Assessment] Professor of Medicine;Vice President for Medical Affairs and Lewis Landsberg Dean,Northwestern University Feinberg School of FELICIA COSMAN,MD Medicine,Chicago [1,2,4,7,8,24] Associate Professor of Clinical Medicine,Columbia University College of Physicians and Surgeons;Medical Director,Clinical Research ROBERT T.JENSEN,MD Center,Helen Hayes Hospital,West Haverstraw,New York [28] Chief,Digestive Diseases Branch,National Institute of Diabetes, Digestive and Kidney Diseases,National Institutes of Health, PHILIP E.CRYER,MD Bethesda [22] Irene E.and Michael M.Karl Professor of Endocrinology and Metabolism in Medicine,Washington University,St.Louis [20] CAMILO JIMENEZ,MD Assistant Professor,Department of Endocrine Neoplasia & Hormonal MARIE B.DEMAY,MD Disorders,The University of Texas MD Cancer Center,Houston [23] Associate Professor of Medicine,Harvard Medical School; Associate Physician,Massachusetts General Hospital,Boston [25] SUNDEEP KHOSLA,MD Professor of Medicine and Physiology,Mayo Clinic College of ROBERT G.DLUHY,MD Medicine,Rochester [26] Program Director,Fellowship in Endocrinology;Professor of Medicine,Brigham and Women’s Hospital,Harvard Medical School; STEPHEN M.KRANE,MD Associate Editor,New England Journal of Medicine,Boston [5] Persis,Cyrus and Marlow B.Harrison Distinguished Professor of Medicine,Harvard Medical School,Massachusetts General Hospital, ROBERT H.ECKEL,MD Boston [25] Professor of Medicine,Division of Endocrinology,Metabolism and Diabetes,Division of Cardiology;Professor of Physiology and ALEXANDER KRATZ,MD,PhD,MPH Biophysics;Charles A.Boettcher II Chair in Atherosclerosis; Assistant Professor of Clinical Pathology,Columbia University Program Director,Adult General Clinical Research Center, College of Physicians and Surgeons;Associate Director, University of Colorado at Denver and Health Sciences Center; Core Laboratory,Columbia University Medical Center, Director,Lipid Clinic,University Hospital,Aurora [18] New York-Presbyterian Hospital;Director, Allen Pavilion Laboratory,New York [Appendix] DAVID A.EHRMANN,MD Professor of Medicine;Associate Director,University of Chicago HENRY M.KRONENBERG,MD General Clinical Research Center,Chicago [13] Chief,Endocrine Unit,Massachusetts General Hospital; Professor of Medicine,Harvard Medical School,Boston [25] †Deceased. vii viii Contributors ROBERT F.KUSHNER,MD ALVIN C.POWERS,MD Professor of Medicine,Northwestern University Feinberg Joe C.Davis Chair in Biomedical Science;Professor of Medicine, School of Medicine,Chicago [17] Molecular Physiology and Biophysics;Director,Vanderbilt Diabetes Research and Training Center;Director,Vanderbilt Diabetes Center, ROBERT LINDSAY,MD,PhD Nashville [19] Professor of Clinical Medicine,Columbia University College of Physicians and Surgeons;Chief,Internal Medicine,Helen Hayes DANIEL J.RADER,MD Hospital,West Havershaw,New York [28] Cooper-McClure Professor of Medicine,University of Pennsylvania School of Medicine,Philadelphia [21] JOANN E.MANSON,MD,DrPH Professor of Medicine and the Elizabeth Fay Brigham Professor of GARY L.ROBERTSON,MD Women’s Health,Harvard Medical School;Chief,Division of Emeritus Professor of Medicine,Northwestern University Feinberg Preventive Medicine,Brigham and Women’s Hospital,Boston [12] School of Medicine,Chicago [3] ELEFTHERIA MARATOS-FLIER,MD JOSHUA SCHIFFER,MD Associate Professor of Medicine,Harvard Medical School; Department of Internal Medicine,The Johns Hopkins University Chief,Obesity Section,Joslin Diabetes Center,Boston [16] School of Medicine,Baltimore [Review and Self-Assessment] KEVIN T.MCVARY,MD ADAM SPIVAK,MD Associate Professor of Urology,Northwestern University Feinberg Department of Internal Medicine,The Johns Hopkins University School of Medicine,Chicago [15] School of Medicine,Baltimore [Review and Self-Assessment] SHLOMO MELMED,MD TAMARA J.VOKES,MD Senior Vice President,Academic Affairs;Associate Dean, Associate Professor,Section of Endocrinology,University of Cedars Sinai Medical Center,David Geffen School of Chicago,Chicago [29] Medicine at UCLA,Los Angeles [2] ANTHONY P.WEETMAN,MD,DSc ROBERT J.MOTZER,MD Professor of Medicine and Dean of the School of Medicine and Attending Physician,Department of Medicine,Memorial Biomedical Sciences,University of Sheffield,Sheffield,United Sloan-Kettering Cancer Center;Professor of Medicine, Kingdom [4] Weill Medical College of Cornell University,New York [9] CHARLES WIENER,MD HARTMUT P.H.NEUMANN,MD Professor of Medicine and Physiology;Vice Chair,Department of Head,Section Preventative Medicine,Department of Nephrology Medicine;Director,Osler Medical Training Program,The Johns and General Medicine,Albert-Ludwigs-University of Freiburg, Hopkins University School of Medicine,Baltimore [Review and Germany [6] Self-Assessment] MICHAEL A.PESCE,PhD GORDON H.WILLIAMS,MD Clinical Professor of Pathology,Columbia University College of Professor of Medicine,Harvard Medical School;Chief, Physicians and Surgeons;Director of Specialty Laboratory,New York Cardiovascular Endocrinology Section,Brigham and Women’s Presbyterian Hospital,Columbia University Medical Center, Hospital,Boston [5] New York [Appendix] ROBERT C.YOUNG,MD JOHN T.POTTS,JR.,MD Chancellor,Fox Chase Cancer Center,Philadelphia [14] Jackson Distinguished Professor of Clinical Medicine,Harvard Medical School;Director of Research and Physician-in-Chief Emeritus,Massachusetts General Hospital,Charlestown [27] PREFACE The editors of Harrison’s Principles of Internal Medicine refer Endocrine Systems;and (V) Disorders of Bone and Cal- to it as the “mother book,” a description that confers cium Metabolism. respect but also acknowledges its size and its ancestral sta- While Harrison’s Endocrinology is classic in its organiza- tus among the growing list of Harrison’s products,which tion,readers will sense the impact of the scientific renais- now include Harrison’s Manual of Medicine, Harrison’s sance as they explore the individual chapters in each section. Online,and Harrison’s Practice,an online highly structured In addition to the dramatic advances emanating from reference for point-of-care use and continuing educa- genetics and molecular biology, the introduction of an tion.This book, Harrison’s Endocrinology, second edition, unprecedented number of new drugs,particularly for the is a compilation of chapters related to the specialty of management of diabetes and osteoporosis,is transforming endocrinology. the field of endocrinology. Numerous recent clinical Our readers consistently note the sophistication of studies involving common diseases like diabetes, obesity, the material in the specialty sections of Harrison’s. Our hypothyroidism, osteoporosis, and polycystic ovarian goal was to bring this information to readers in a more syndrome provide powerful evidence for medical decision- compact and usable form. Because the topic is more making and treatment.These rapid changes in endocrinology focused, it was possible to increase the presentation of are exciting for new students of medicine and underscore the material by enlarging the text and the tables.We the need for practicing physicians to continuously update have also included a Review and Self-Assessment section their knowledge base and clinical skills. that includes questions and answers to provoke reflec- Our access to information through web-based jour- tion and to provide additional teaching points. nals and databases is remarkably efficient.While these The clinical manifestations of endocrine disorders can sources of information are invaluable,the daunting body usually be explained by considering the physiologic role of data creates an even greater need for synthesis and for of hormones, which are either deficient or excessive. highlighting important facts. Thus, the preparation of Thus,a thorough understanding of hormone action and these chapters is a special craft that requires the ability principles of hormone feedback arms the clinician with to distill core information from the ever-expanding a logical diagnostic approach and a conceptual frame- knowledge base.The editors are therefore indebted to our work for treatment approaches.The first chapter of the authors, a group of internationally recognized authori- book,Principles of Endocrinology,provides this type of ties who are masters at providing a comprehensive “systems”overview.Using numerous examples of trans- overview while being able to distill a topic into a concise lational research, this introduction links genetics, cell and interesting chapter.We are grateful to Emily Cowan biology,and physiology with pathophysiology and treat- for assisting with research and preparation of this book. ment.The integration of pathophysiology with clinical Our colleagues at McGraw-Hill continue to innovate in management is a hallmark of Harrison’s,and can be found health care publishing.This new product was champi- throughout each of the subsequent disease-oriented oned by Jim Shanahan and impeccably produced by chapters.The book is divided into five main sections Kim Davis. that reflect the physiologic roots of endocrinology: (I) We hope you find this book useful in your effort to Pituitary, Thyroid, and Adrenal Disorders; (II) Repro- achieve continuous learning on behalf of your patients. ductive Endocrinology;(III) Diabetes Mellitus,Obesity, Lipoprotein Metabolism;(IV) Disorders Affecting Multiple J.Larry Jameson,MD,PhD ix