1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 YEN AND JAFFE’S REPRODUCTIVE ENDOCRINOLOGY:   PHYSIOLOGY, PATHOPHYSIOLOGY, AND CLINICAL MANAGEMENT,   6TH EDITION  ISBN: 978-1-4160-4907-4 Copyright © 2009, 2004, 1999, 1991, 1986, 1978 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by   any means, electronic or mechanical, including photocopy, recording, or any information storage   and retrieval system, without permission in writing from the publisher. Permissions may be sought   directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (U.S.) or (+44) 1865   843830 (U.K.); fax: (+44) 1865 853333; e-mail: [email protected]. You may also   complete your request on-line via the Elsevier Web site at http://www.elsevier.com/permissions. Notice Knowledge and best practice in this field are constantly changing. As new research and experience  broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or  appropriate. Readers are advised to check the most current information provided (i) on procedures fea- tured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose  or formula, the method and duration of administration, and contraindications. It is the responsibility of  the practitioner, relying on his or her own experience and knowledge of the patient, to make diagnoses,  to determine dosages and the best treatment for each individual patient, and to take all appropriate  safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assume any  liability for any injury and/or damage to persons or property arising out or related to any use of the  material contained in this book. Library of Congress Cataloging-in-Publication Data Yen and Jaffe’s reproductive endocrinology / [edited by] Jerome F. Strauss, Robert L. Barbieri.—6th ed.     p. ; cm. Includes bibliographical references and index. ISBN 978-1-4160-4907-4 1.  Human reproduction—Endocrine aspects. 2.  Endocrine gynecology.   3.  Generative organs—Diseases—Endocrine aspects.  I. Strauss, Jerome F. (Jerome Frank) II. Barbieri, Robert L. III. Yen, Samuel S. C. Reproductive endocrinology. IV. Title: Reproductive endocrinology. [DNLM: 1.  Reproduction—physiology. 2.  Endocrine Glands—physiology. 3.  Endocrine System Diseases—physiopathology.  WQ 205 Y4467 2009] QP252.Y46 2009 612.6—dc22   2008037592 Acquisitions Editor: Stefanie Jewell-Thomas Developmental Editor: Colleen McGonigal Project Manager: Mary Stermel Marketing Manager: Courtney Ingram Design Direction: Ellen Zanolle Multi-Media Producer: Adrienne Simon Printed in China Last digit is the print number: 9  8  7  6  5  4  3  2  1 remembrance Samuel S. C. Yen, MD, DSc 1927–2006 In 2006, endocrinology in general, and reproductive endocrinology in particular, lost a giant  in clinical and translational reproductive endocrinologic research, Samuel S. C. Yen. He was  insightful and a visionary and demanded excellence from his trainees, but no more so than from  himself. He was arguably the leading clinical reproductive neuroendocrinologist of his time. He and I coedited the first four editions of this textbook, which has since been translated  from English into five languages—including a pirated version from China. The genesis of our  textbook was crystallized during our time at the magnificent, idyllic Rockefeller Foundation  retreat, the Villa Serbelloni, at the nexus of the three legs of Lake Como in Italy. It was there,  surrounded by scholars from a panoply of disciplines and countries (Sam and I were the only  physicians in the group), that we had the time and freedom to finalize the chapters. We mutu- ally selected the authors, most of whom were outstanding investigators and clinicians in the  areas about which they wrote (albeit not all as expeditiously as we had hoped).  Fortunately, our first editor, John Hanley, was a true scholar who shared our passion for  quality and excellence. Our original publisher, W. B. Saunders, shared that same passion. Sam continued his insistence on excellence for each edition, and he cajoled several of our  authors until they did the same. Sam’s chapters on neuroendocrine regulation of the brain and of the hypothalamic-  pituitary-ovarian axis are classic. His extensive and productive collaboration with his very  close friend, the Nobel Laureate Roger Guillemin, who characterized many of the hypotha- lamic secretagogues that Sam used in his clinical studies, enabled him to base many of his  comments in the textbook on his own laboratory’s studies. Sam was hard-driving, yet charming, as demanding of himself and our authors as he was of  the myriad investigators with whom he worked and trained. His was a rich, full, productive,  and creative life. He was a unique and colorful individual.  His like comes along very rarely. Robert B. Jaffe, MD University of California, San Francisco 2008  contributors valerie A. Arboleda enrico carmina, Md Department of Human Genetics, David Geffen School of  Professor of Endocrinology, Department of   Medicine at UCLA, Los Angeles, California Clinical Medicine, University of Palermo,  16: Disorders of Sex Development Palermo, Italy 32: Evaluation of Hormonal Status Mario Ascoli, phd Professor, Department of Pharmacology, Carver College  Alice y. chang, Md, MS of Medicine, The University of Iowa, Iowa City, Iowa Assistant Professor, Department of Internal Medicine,  2: The Gonadotropin Hormones and Their Receptors Division of Endocrinology and Metabolism,   University of Texas Southwestern Medical Center,  richard J. Auchus, Md, phd Dallas, Texas The Charles A. and Elizabeth Ann Sanders Chair in  23: Endocrine Disturbances Affecting Reproduction Translational Research, Professor of Internal Medicine,  Division of Endocrinology and Metabolism, University  r. Jeffrey chang, Md of Texas Southwestern Medical Center, Dallas, Texas Professor and Division Director, University of California  23: Endocrine Disturbances Affecting Reproduction School of Medicine, San Diego, California 20: Polycystic Ovary Syndrome and Hyperandrogenic robert l. Barbieri, Md States Kate Macy Ladd Professor, Department of Obstetrics,  Gynecology and Reproductive Biology, Harvard  charles chapron, Md Medical School; Chair, Department of Obstetrics and  Professor and Chair, Obstetrics and Gynecology II,  Gynecology Brigham and Women’s Hospital, Boston,  Université Descartes GHU Cochin-St. Vincent   Massachusetts de Paul, Paris, France 10: The Breast; 21: Female Infertility 33: Pelvic Imaging in Reproductive Endocrinology Kurt Barnhart, Md, MSce John A. cidlowski, phd Director, Women’s Health Clinical Research Center,  Chief, Laboratory of Signal Transduction, Head,  Assistant Dean, Clinical Trial Operations, University  Molecular Endocrinology Group, National Institute   of Pennsylvania School of Medicine, Philadelphia,  of Environmental Health Science, National   Pennsylvania Institutes of Health, Research Triangle Park,   34: Contraception North Carolina 5: Steroid Hormone Action Breton F. Barrier, Md Assistant Professor, Department of Obstetrics,  donald K. clifton, phd Gynecology and Women’s Health, University of  Professor of Obstetrics and Gynecology, University of  Missouri, Columbia, Columbia, Missouri Washington, Seattle, Washington 13: Reproductive Immunology and Its Disorders 1: Neuroendocrinology of Reproduction iiii iii Contributors Anick de vos, phd Kristin d. Helm, Md Clinical Embryologist, Centre for Reproductive  Fellow, Division of Endocrinology and Metabolism,  Medicine, Universitair Ziekenhuis Brussel, Brussels,  South Shore Hospital, South Weymouth,  Belgium Massachusetts 30: Gamete and Embryo Manipulation 19: Physiologic and Pathophysiologic Alterations of the Neuroendocrine Components of the Reproductive Axis dominique de Ziegler, Md Professor and Head, Reproductive Endocrine and  Mark d. Hornstein, Md Infertility, Obstetrics and Gynecology II, Université  Associate Professor of Obstetrics, Gynecology and  Descartes GHU Cochin-St. Vincent de Paul, Paris,  Reproductive Biology, Harvard Medical School;  France Director, Division of Reproductive Endocrinology and  33: Pelvic Imaging in Reproductive Endocrinology Infertility; Director, Center for Reproductive Medicine,  Brigham and Women’s Hospital, Boston, Massachusetts William S. eans, Md 29: Assisted Reproduction Professor, Departments of Medicine and Obstetrics and  Gynecology, University of Virginia, Charlottesville,  dan i. leboic, Md, MA Virginia Director, Division of Reproductive Endocrinology and  19: Physiologic and Pathophysiologic Alterations of the Infertility, Department of Obstetrics and Gynecology,  Neuroendocrine Components of the Reproductive Axis University of Wisconsin School of Medicine, Madison,  Wisconsin Bart c. J. M. Fauser, Md, phd 24: Endometriosis Professor of Reproductive Medicine; Chair, University  Medical Center Utrecht, Utrecht, The Netherlands charles lee, phd, FAcMg 28: Medical Approaches to Ovarian Stimulation for Director of Cytogenetics, Harvard Cancer Center;  Infertility Associate Professor, Harvard Medical School; Associate  Faculty Member, MIT Broad Institute; Clinical  garret A. Fitzgerald, Md Cytogeneticist, Brigham and Women’s Hospital,  Robert L. McNeil, Jr., Professor in Translational Medicine  Boston, Massachusetts  and Therapeutics, Department of Pharmacology,  31: Cytogenetics in Reproduction University of Pennsylvania School of Medicine,  Philadelphia, Pennsylvania Bruce A. lessey, Md, phd 6: Prostaglandins and Other Lipid Mediators in Greenville Professor, University of South Carolina  Reproductive Medicine School of Medicine; Vice Chair, Research and Division  Director, Reproductive Endocrinology and Infertility,  timothée Fraisse, Md, MSc Greenville Hospital System, Greenville, South Carolina Joint Division Reproductive Endocrine and Infertility,  9: The Structure, Function, and Evaluation of the Female University Hospitals Geneva and Lausanne, Geneva  Reproductive Tract and Lausanne, Switzerland 33: Pelvic Imaging in Reproductive Endocrinology peter y. liu, MBBS, FrAcp, phd Associate Professor and Head, Endocrinology and  colin d. Funk, phd Metabolism, Woolcock Institute of Medical Research  Professor, Departments of Physiology and Biochemistry,  and ANZAC Research Institute, University of Sydney,  Queen’s University, Kingston, Canada Sydney, Australia; Associate Professor and Consultant,  6: Prostaglandins and Other Lipid Mediators in Concord Hospital, Concord, Australia Reproductive Medicine 12: The Hypothalamo-Pituitary Unit, Testes, and Male Accessory Organs Antonio r. gargiulo, Md Assistant Professor, Department of Obstetrics,  rogerio A. lobo, Md Gynecology and Reproductive Biology, Harvard  Professor, Columbia University College of Physicians and  Medical School; Associate Reproductive  Surgeons; Attending Physician, New York Presbyterian  Endocrinologist, Department of Obstetrics,  Hospital; Director, REI Fellowship Program, New  Gynecology and Reproductive Biology,   York, New York Brigham and Women’s Hospital, Boston,   14: Menopause and Aging; 32: Evaluation of Hormonal Massachusetts Status 13: Reproductive Immunology and Its Disorders nicholas S. Macklon, MB, chB, Md, Janet e. Hall, Md Professor and Chair, Department of Reproductive  Professor of Medicine, Harvard Medical School;  Medicine and Gynaecology, University Medical Centre  Reproductive Endocrine Unit, Massachusetts   Utrecht, Utrecht, The Netherlands General Hospital, Boston, Massachusetts 28: Medical Approaches to Ovarian Stimulation for 7: Neuroendocrine Control of the Menstrual Cycle Infertility Contributors ix Sam Mesiano, phd Alex J. polotsky, Md, MSc Assistant Professor, Department of Reproductive Biology,  Assistant Professor of Obstetrics and Gynecology   Case Western Reserve University; Assistant Professor,  and Women’s Health, Albert Einstein College  Department of Obstetrics and Gynecology, University  of Medicine; Attending Physician, Montefiore  Hospitals Case Medical Center, Cleveland, Ohio Medical Center, New York, New York 11: The Endocrinology of Human Pregnancy and 18: Nutrition and the Pubertal Transition Fetoplacental Neuroendocrine Development daid puett, phd Anne elodie Millischer-Belaïche, Md Regents Professor of Biochemistry and Molecular Biology,  Obstetrics and Gynecology II, Université Descartes GHU  University of Georgia, Athens, Georgia Cochin-St. Vincent de Paul, Paris, France 2: The Gonadotropin Hormones and Their Receptors 33: Pelvic Imaging in Reproductive Endocrinology catherine racowsky, phd Mark e. Molitch, Md Associate Professor of Obstetrics, Gynecology and  Professor of Medicine, Division of Endocrinology,  Reproductive Biology, Harvard Medical School;  Metabolism, and Molecular Medicine, Department   Director, Assisted Reproductive Technology  of Medicine, Northwestern University Feinberg   Laboratory, Brigham and Women’s Hospital,   School of Medicine; Attending Physician,  Boston, Massachusetts Northwestern Memorial Hospital, Chicago,   29: Assisted Reproduction Illinois 3: Prolactin in Human Reproduction turk rhen, phd Assistant Professor of Biology, University of North  cynthia c. Morton, phd Dakota, Grand Forks, North Dakota William Lambert Richardson Professor of Obstetrics,  5: Steroid Hormone Action Gynecology and Reproductive Biology, Brigham and  Women’s Hospital, Boston, Massachusetts Jessica rieder, Md, MS 31: Cytogenetics in Reproduction Assistant Professor, Department of Pediatrics,   Division of Adolescent Medicine, Albert Einstein  ralf M. nass, Md College of Medicine; Attending Physician,  Research Assistant Professor, Department of Medicine,  Department of Pediatrics, Division of Adolescent  University of Virginia School of Medicine, University  Medicine, Children’s Hospital at Montefiore,   of Virginia Health System, Charlottesville, Virginia New York, New York 19: Physiologic and Pathophysiologic Alterations 18: Nutrition and the Pubertal Transition of the Neuroendocrine Components of the Reproductive Axis richard J. Santen, Md Professor of Medicine, University of Virginia Health  errol r. norwitz, Md, phd Sciences System, Charlottesville, Virginia Professor, Yale University School of Medicine;   27: Breast Cancer Co-Director, Division of Maternal-Fetal Medicine;  Director, Maternal-Fetal Medicine Fellowship Program;  nanette Santoro, Md Director, Obstetrics and Gynecology Residency  Professor and Director, Division of Reproductive  Program, Department of Obstetrics, Gynecology   Endocrinology, Department of Obstetrics and  and Reproductive Sciences, Yale-New Haven Hospital,  Gynecology and Women’s Health, Albert Einstein  New Haven, Connecticut College of Medicine/Montefiore Medical Center,   26: Endocrine Diseases of Pregnancy New York, New York 18: Nutrition and the Pubertal Transition tony M. plant, phd Professor, DDeeppaarrttmmeennttss ooff CCCeeellllll BBBiiiooolllooogggyyy aaannnddd PPPhhhyyysssiiiooolllooogggyyy  courtney A. Schreiber, Md, MpH and Obstetrics, Gynecology and Reproductive  Assistant Professor of Obstetrics and Gynecology,  Sciences, University of Pittsburgh School of Medicine,  University of Pennsylvania, Philadelphia,   Pittsburgh, Pennsylvania Pennsylvania 17: Puberty: Gonadarche and Adrenarche 34: Contraception Staci pollack, Md danny J. Schust, Md Assistant Professor of Obstetrics and Gynecology  Associate Professor of Obstetrics, Gynecology and  and Women’s Health, Associate Reproductive  Women’s Health; Chief, Division of Reproductive  Endocrinology and Infertility Fellowship Director,  Endocrinolgy and Infertility, Department of Obstetrics,  Albert Einstein College of Medicine, New York,   Gynecology and Women’s Health, University of  New York Missouri, Columbia, Missouri 18: Nutrition and the Pubertal Transition 13: Reproductive Immunology and Its Disorders x Contributors peter J. Snyder, Md paul J. turek, Md, FAcS, FrSM Professor of Medicine, University of Pennsylvania,  Former Professor and Endowed Chair in Urologic  Philadelphia, Pennsylvania Education, Department of Urology, Obstetrics,  15: Male Reproductive Aging Gynecology and Reproductive Sciences, University  of San Fransiscco; Director, The Turek Clinic, San  Wen-chao Song, phd Francisco, California Professor, Department of Pharmacology, Institute for  22: Male Infertility Translational Medicine and Therapeutics, University  of Pennsylvania School of Medicine, Philadelphia,  André van Steirteghem, Md, phd Pennsylvania Emeritus Professor, Faculty of Medicine, Vrije  6: Prostaglandins and Other Lipid Mediators in Universiteit Brussel; Honorary Consultant, Centre  Reproductive Medicine for Reproductive Medicine, Universitair Ziekenhuis  Brussel, Brussels, Belgium robert A. Steiner, phd 30: Gamete and Embryo Manipulation Professor, Departments of Obstetrics and Gynecology and  Physiology and Biophysics, University of Washington,  Johannes d. veldhuis, Md Seattle, Washington Professor of Medicine and Clinical Investigator, Mayo  1: Neuroendocrinology of Reproduction Clinic College of Medicine; Consultant, Division  of Endocrinology, Diabetes, Metabolism, Nutrition,  elizabeth A. Stewart, Md Department of Internal Medicine, Mayo Clinic,  Professor, Department of Obstetrics and Gynecology,  Rochester, Minnesota Mayo Clinic College of Medicine; Senior Associate  12: The Hypothalamo-Pituitary Unit, Testes, and Male Consultant, Mayo Clinic, Rochester, Minnesota Accessory Organs 25: Benign Uterine Disorders eric vilain, Md, phd Jerome F. Strauss iii, Md, phd Professor of Human Genetics, Pediatrics, and Urology;  Executive Vice President for Medical Affairs, VCU Health  Chief, Medical Genetics, Department of Pediatrics,  System; Dean, School of Medicine and Professor of  David Geffen School of Medicine at UCLA, Los  Obstetrics and Gynecology, Virginia Commonwealth  Angeles, California University, Richmond, Virginia 16: Disorders of Sex Development 4: The Synthesis and Metabolism of Steroid Hormones; 8: The Ovarian Life Cycle; 9: The Structure, Function, carmen J. Williams, Md, phd and Evaluation of the Female Reproductive Tract Clinical Investigator, Laboratory of Reproductive and  Developmental Toxicology, National Institute of  robert n. taylor, Md, phd Environmental Health Sciences, Research Triangle  Willaford Leach-Armand Hendee Professor and Vice  Park, North Carolina Chair for Research, Department of Gynecology and  8: The Ovarian Life Cycle Obstetrics, Emory University School of Medicine,  Atlanta, Georgia Selma Feldman Witchel, Md 24: Endometriosis Associate Professor, Department of Pediatrics, University  of Pittsburgh School of Medicine; Associate Professor,  Stephen F. thung, Md, MSci Division of Endocrinology, Children’s Hospital of  Assistant Professor, DDeeppaarrttmmeenntt ooff OObbsstteettrriiccss,,  Pittsburgh, Pittsburgh, Pennsylvania Gynecology and Reproductive Sciences, Yale  17: Puberty: Gonadarche and Adrenarche University School of Medicine; DDiirreeccttoorr,, YYaallee MMaatteerrnnaall-- Fetal Medicine Practice; Director, Yale Diabetes during  Pregnancy Program, New Haven, Connecticut 26: Endocrine Diseases of Pregnancy preface The year 2008 marked the 30th anniversary of the clinical success of in vitro fertilization  and embryo transfer, a technology that has revolutionized the treatment of infertility. This  landmark event came about through the marriage of reproductive biology, endocrinology, and  gynecology, in what was at the time a new model of translational science. Today, the field of  reproductive endocrinology continues to be broad-based with contributions from the fields  of developmental and reproductive biology, neuroscience, genetics and genomics, endocri- nology, gynecology, obstetrics, andrology, pediatrics, pathology and laboratory medicine, and  diagnostic imaging, among others. The multiple disciplines and their respective perspectives  have brought forth what can arguably be considered the greatest medical advance in the past  century: the capacity of humans to master the process of reproduction. The 6th edition of Yen and Jaffe’s Reproductive Endocrinology has been expanded to reflect the position of our field as  the nexus of basic and clinical research, and as a source of innovation that shapes the scientific   foundations of physiology and medicine. The editors thank the chapter authors, both old  and new, for delivering the insightful synthesis of their topics. In many instances, advances  in research and clinical practice have resulted in substantial changes in scope and direction  that necessitated critical appraisal of information offered in the 5th edition. Since the previous edition of this text, we lost Samuel S. C. Yen, one of the founders of  contemporary reproductive endocrinology and one half of the brilliant team that birthed  this text. As noted in the remembrance, his legacy is profound, and the editors once again  acknowledge his transformative influence on the field. Jerome F. Strauss III, MD, PhD Richmond, Virginia Robert L. Barbieri, MD Boston, Massachusetts xxii 1 C H A P T E R Neuroendocrinology of Reproduction Donald K. Clifton and Robert A. Steiner Historical Perspective work of Harvey Cushing, Bernard Aschner, and others es- tablished that the pituitary was indeed important and that experimental manipulations or tumors of the pituitary ENDOCRINOLOGY TAKES FLIGHT were associated with disorders of growth, metabolism, ad- In 1849, A. A. Berthold conducted the first known experi- renal function, and reproduction. Also in the 19th century, ment in endocrinology—long before the word endocrinol- Ramón y Cajal described a neural tract that led from the ogy was invented. He castrated roosters and showed that brain to the neural lobe of the pituitary, and in the mid after the surgery, the animals lost the ability to crow, their 1920s, it was recognized that the supraoptic and paraven- combs drooped, and they stopped chasing hens. Berthold tricular nuclei in the hypothalamus were the origins of went on to show that if he transplanted testes from other this neural tract. Cushing observed that the anterior lobe roosters into the castrated animals, the newly transplanted of the pituitary was highly vascularized, and he postulated organs would survive and the roosters became sexually that this organ was anatomically and physiologically rejuvenated—crowing, strutting, and mounting the hens, distinct from the pars intermedia, which he incorrectly as they did before castration. Berthold observed that the thought was part of the “neural lobe.” Confusion about transplanted testes became revascularized and thus revi- the anatomy of the pituitary persisted until the mid 1930s, talized—despite having no obvious regeneration of nerve when G. B. Wislocki and L. S. King finally got it right. supply to the organ. Berthold deduced correctly that with- out the action of nerves, the testes must release blood- ANTERIOR PITUITARY AS A SOURCE borne substances that are transported to distant target sites FOR GONADOTROPINS in the body and thus support the secondary sex character- istics of the rooster and its behavior. The turn of the 20th century brought with it the first clue that the gonads were somehow physiologically linked to the pituitary gland. In 1905, Fichera reported that castra- THE ANTERIOR PITUITARY tion produced a gross enlargement of the pituitary gland AND NEUROHYPOPHYSIS and the appearance of large vacuolated cells—“castration The thought that the pituitary gland serves some physi- cells.” In 1926, working independently, Philip Smith and ologic function can be traced to the first century AD, when Bernard Zondek showed that daily injections of fresh pi- Galen postulated that the pituitary was a sump for wastes tuitary glands into immature mice and rats would induce distilled from the brain—an idea that was also champi- precocious puberty in recipient animals. In 1927, Smith oned by the Belgian physician and anatomist Andreas Vesa- and E. T. Engle showed that hypophysectomy would pre- lius in the middle of the 16th century. However, the true vent sexual maturation, thus establishing a critical role for physiologic significance of the pituitary traces its roots to the pituitary in reproduction. In the early 1930s, Zondek the late 19th and early 20th century with early attempts also proposed that the pituitary produced two “gonado- of physiologists to perform hypophysectomies and study tropic” hormones, which he termed Prolan A (FSH) and the outcome on survival, growth, and reproduction. The Prolan B (LH), and shortly thereafter, H. L. Fevold and   PART I Endocrinology of Reproduction F. L. Hisaw, working at the University of Wisconsin, suc- cyclicity. By the late 1940s, experiments conducted by cessfully isolated and purified these two hormones, which J. W. Everett, C. H. Sawyer, and J. E. Markee clearly came to be known as luteinizing hormone (LH) and follicle- showed in the rat and rabbit that ovulation could be ei- stimulating hormone (FSH). ther blocked or induced by drugs that act on the central nervous system, thus reinforcing the idea that the brain plays a central role in the events that trigger ovulation. PROLACTIN AND LACTATION Although it had also become evident that communication In the late 1920s, the idea that the pituitary gland plays between the brain and the pituitary was essential for pi- some role in lactation grew from observations that daily tuitary function, the anatomic basis for this communica- injections of extracts from the anterior pituitary would tion (later discovered to be the pituitary portal vessels) re- stimulate mammary gland development in rabbits. In the mained unappreciated for many years. In fact, it remained early 1930s, Oscar Riddle conducted experiments in pi- dogmatic that the brain–pituitary connection must be geons and ring doves, showing that secretion of crop milk “neural,” notwithstanding the anatomic observations of in birds was stimulated by the same hormone that induced A. T. Rasmussen, who had reported finding very few nerve milk secretion in mammals, and Riddle named this hor- fibers in the anterior pituitary. mone prolactin. A spate of experimental work over the next In the early 1930s, G. T. Popa and U. Fielding reported several decades would establish that prolactin has compli- finding blood vessels that connected the basal forebrain to cated effects on the reproductive axis in mammals—acting the anterior pituitary gland. However, they incorrectly de- as a luteotropic factor in some species, but inhibiting FSH duced that blood flowed from the pituitary to the brain— secretion (and thus estrous cyclicity) in others. The isola- not the other way around. In 1935, using microscopy, tion of prolactin from growth hormone would not come B. Houssay visualized the blood vessels along the pituitary until 1962, when R. W. Bates and his colleagues finally stalk in the toad and observed blood flowing from the separated these closely related molecules and thus helped brain to the pituitary. One year later, G. B. Wislocki and to explain 30 years of confusing experimental results L. S. King performed careful histologic studies of the involving studies of “pituitary extracts” on growth, repro- median eminence and pituitary and described a dense cap- duction, and lactation. illary bed that drained blood from the median eminence, which collected into the large portal vessels along the infundibular stalk, and in turn fed a secondary capillary THE HYPOTHALAMIC–PITUITARY–GONADAL bed in the pars distalis (anterior pituitary). This came to (HPG) AXIS be known as the hypothalamo-hypophysial portal system. As early as 1901, Alfred Frohlich had described a clinical The notion that there is a humoral (instead of neural) syndrome termed urogenital dystrophy, which was associ- connection between the hypothalamus and the anterior pi- ated with damage to the pituitary gland and basal fore- tuitary was seeded by the early observations of J. C. Hinsey brain, but for the next 40 years, it remained controversial and J. E. Markee in the rabbit, showing that coitally in- whether the condition was caused by damage to either the duced ovulation persists in rabbits with severed cervical hypothalamus or the pituitary. Nevertheless, by 1930, it sympathetic nerves. They deduced that some substances had become clear that experimental manipulations of the must somehow diffuse from the posterior lobe (neurohy- anterior pituitary gland (e.g., hypophysectomy) could in- pophysis) into the anterior pituitary to control its func- fluence gonadal function and likewise that alterations in tion. The exact method by which the brain communicates gonadal function (i.e., castration) would influence the cel- with the pituitary remained controversial (and unproven) lular architecture of the pituitary. These observations led until an elegant series of investigations by J. D. Green, Dorothy Price and Carl Moore to postulate that there was a G. W. Harris, and D. Jacobsohn provided compelling evi- reciprocal relationship between the pituitary and gonads, dence that humeral agents must be released by the brain such that pituitary hormones stimulate gonadal function, into the hypophysial portal system, which then spews whereas gonadal hormones inhibit “gonadotropin” secre- “hypophysiotropic factors” into the anterior pituitary to tion—a concept that has come to be known as gonadal regulate its function. However, it still was not clear pre- steroid negative feedback. The idea that the brain might cisely how the brain could control all aspects of pituitary also be involved in this process was presaged by studies function—i.e., the secretion not only of the gonadotro- in the late 1920s of coitally induced ovulation in rabbits, pins, but also of growth hormone, prolactin, thyroid- but Walter Holweg and Karl Junkmann were the first to stimulating hormone (TSH), and adrenocorticotropic argue that the brain serves as an intermediary target for hormone (ACTH). Although it had been postulated by gonadal hormones, and then in turn controls the activity J. D. Green, G. W. Harris, and S. M. McCann that the brain of the anterior pituitary. Later in the 1930s, F. H. Marshall, produces separate excitatory and inhibitory factors that G. W. Harris, and others went on to show that stimula- regulate the various pituitary hormones, proof of the exis- tion of the brain and hypothalamus, in particular, could tence of such factors (e.g., thyrotropin-releasing hormone induce ovulation in the rabbit. In the early 1940s, Fred- [TRH], somatostatin, gonadotropin-releasing hormone erick Dey, working at Northwestern University, showed [GnRH], corticotropin-releasing hormone [CRH]) was that discrete lesions placed in the hypothalamus could not forthcoming until the final isolation, characterization, induce either constant estrus or diestrus in the rat. This and purification of these “hypophysiotropic hormones” in work established the idea that different areas of the hy- the early 1970s by R. Guillemin, A. Schally, and their co- pothalamus coordinate particular aspects of reproductive workers, for which they received the Nobel Prize in 1977. CHAPTER 1 Neuroendocrinology of Reproduction  PRIMATES ARE PHYSIOLOGICALLY UNIQUE2 NEUROTRANSMITTERS, NEUROMODULATORS, AND THEIR RECEPTORS Until the early 1970s, the foundation of modern reproduc- tive neuroendocrinology had been built on studies of infra Communication in the brain is mediated through synap- primate species—most notably, the rabbit, rat, mouse, tic transmission involving three classes of neurotransmit- and sheep. Classical studies in these nonprimate species ters—amino acids, biogenic amines, and neuropeptides. established basic principles that apply to all mammals— Examples of amino acid transmitters include acetylcholine such as the negative feedback regulation of gonadotropin (excitatory), glutamate and aspartate (excitatory), glycine secretion by sex steroids and the stimulatory action of (inhibitory), and γ-aminobutyric acid (GABA), which is GnRH on pituitary gonadotropes. However, there are fun- predominantly inhibitory but may also be excitatory. The damental aspects of the neuroendocrine regulation of re- biogenic amines include the catecholamines (e.g., norepi- production that are dramatically different among species nephrine, epinephrine, dopamine) and the indoleamine and several that are unique to higher primates, such as serotonin. There are many neuropeptides that act as neu- Old World monkeys, the great apes, and humans. These rotransmitters, neuromodulators, or hypophysiolotropic include the cellular and molecular mechanisms that gov- factors in the brain. These include proopiomelanocortin ern the onset of puberty, the circuitry that triggers the (POMC) and its derivatives, including α-melanocyte- preovulatory surge of gonadotropins, and circadian in- stimulating hormone and β-endorphin); neuropeptide puts to GnRH neurons. The neuroendocrine mechanisms Y (NPY); growth hormone–releasing hormone (GHRH); that control these processes are different in higher pri- TRH; CRH; somatostatin; vasoactive intestinal peptide mates compared with rodent and ovine species. Thus, (VIP); vasopressin; oxytocin; cholecystokinin; peptide caution must be exercised when making generalizations PYY; neurotensin; angiotensin II; galanin-like peptide and drawing inferences based on work performed in cer- (GALP); kisspeptin (and other RF amides, including tain laboratory animals because the data may or may not gonadotropin-inhibitory peptide); galanin; neurokinin B; apply to humans. This fact has implications that extend dynorphin; enkephalin; GnRH; and others. In some cas- beyond physiology into the realms of pathophysiology es, the function of these neurotransmitters is clear—e.g., and the translational relevance of the various models of GnRH stimulates the release of the gonadotropins—but disorders of reproduction. in other (most) cases, the physiologic function of a par- ticular factor either is unknown or is complex and diverse (e.g., NPY, which has functions in feeding behavior and Neuroendocrine Anatomy reproduction, but is likely to play other physiologic roles as well). These various neurotransmitters have multiple NEURONS AND GLIA receptors and cellular mechanisms of action (e.g., five re- ceptor subtypes for NPY), which adds layers of complexity The brain has two predominant cell types—neurons, which to their divergent and diverse functions. constitute approximately 10% of the brain, and glia, which make up the other 90%. Neurons represent a highly differ- entiated and phenotypically diverse array of excitable cells HYPOTHALAMIC NEUROANATOMY that receive, transduce, and relay information through ac- AND LIMBIC INPUTS tion potentials and the release of neurotransmitters and neuromodulators at synaptic junctions. Glia comprise The hypothalamus is part of the diencephalon. It lies ros- several general types of non-neuronal cells, the most nu- tral to the midbrain and caudal to the forebrain. The hypo- merous of which are astrocytes. Astrocytes can respond to thalamus is bounded dorsally by the thalamus, posteriorly neurotransmitters, neuromodulators, and hormones, and by the mammillary bodies, and anteriorly by the lamina they may provide substrates and signals to neurons and terminalis and optic chiasm, and the third ventricle splits thus regulate their activity and metabolism (e.g., insulin- the hypothalamus bilaterally (Figs. 1-1 and 1-2). The hy- like growth factor-1, transforming growth factor α and β). pothalamus receives rich input from the autonomic areas Changes in the activity of astrocytes have been linked to and reticular nuclei of the brain stem, particularly the cat- the mechanisms that control the onset of puberty. Astro- echolaminergic cell groups (many of which have neuro- cytes have highly motile processes that may cover nerve peptides as cotransmitters, such as galanin and NPY). The terminals (and thus restrict secretion) or retract to expose hypothalamus also receives dense innervation from the nerve terminals and allow unrestricted neurosecretion. Pi- limbic areas of the forebrain, including the hippocampus, tuicytes are modified glial cells that reside in the neural amygdala, septum, and orbitofrontal cortex. lobe of the pituitary, and their movable processes either The hypothalamus serves as the primary site for the ensheath or expose nerve terminals that release oxytocin integration and regulation of many important physiologic or vasopressin. Oligodendocytes are cells that form the processes. These include homeostatic control of tempera- myelin sheaths around axons, allowing neurons to con- ture, metabolism, and body weight, aspects of cardiovas- duct action potentials rapidly across long distances with- cular function, physiologic adaptation to stress, regulation out decrement. Ependymal cells are epithelial cells (often of growth, reproduction (including sexual behavior), and ciliated), which line the third ventricle. The end feet pro- lactation. Although the regulation of these complex pro- cesses of these cells govern exchange between the paren- cesses depends on the circuitry of the hypothalamus (and chyma of the brain and the fluid-filled ventricular cavities its afferent inputs), the control of these systems cannot be of the brain. defined on the basis of strict anatomic criteria.