The conference represented by this book was made possible by support from NICHD and a planning committee headed by Dr. Richard Sherins. Two general areas of research are included: the first encompasses steroid hormone synthesis, metabolism and transport in the testis; and the second relates to hormonal regula tion of the seminiferous tubule with special emphasis on the con trol of Sertoli cell function. In addition, there are sections on the purification of unique testicular proteins and morpho logical studies with particular emphasis on the Sertoli cell. We would like to express our sincere thanks to Dr. Sherins and his staff at NICHD and to all of the people at the University of North Carolina who participated in the Conference arrangements, to Dr. Judson J. Van Wyk, Chief of the Pediatric Endocrinology Division, and Dr. H. Stanley Bennett, Director of the Laboratories for Reproductive Biology. Our very special thanks to Mrs. Carolyn Jaros for her help in handling the local arrangements. Mrs. Martha Byrd and Mrs. Linda Rollins typed the manuscripts. Miss Leslie Wells and Mr. Albert Smith kindly assisted in proof reading, and Dr. Elizabeth Wilson gave much help with the final editing process. To all of these people, we are most grateful."

Three years ago, most authors contributing to this book gathered at the Heinrich Fabri Institute of the University of Tubingen at Blaubeuren near Ulm in Germany for the third conference on "Pineal Gland and Cancer." In 1987, the late Derek Gupta organized the second meeting and published the first book on the topic, 10 years after Vera Lapin, as part of the 25th anniversary celebrations of the Vienna Cancer Research Institute, had held the first meeting. It was in Vienna during the 1930s and 1940s that W. Bergmann and P. Engel demonstrated that pineal extracts possess growth inhibitory properties on experimental rodent tumors and R. Hofstatter reported favorable results when these extracts were given to cancer patients. In the 1970s, Vera Lapin and others reported that surgical removal of the pineal gland (pinealectomy) stimulates experimental tumor growth rendering fundamental support for an involvement of the pineal gland in malignancy. A focal question of past and present research in this field is whether the pineal gland exerts its tumor inhibitory activity primarily or exclusively via melatonin. Currently, it appears that the action of melatonin on experimental tumor growth criti cally depends on the circadian timing of its administration as weH as on the type and stage of cancer, and that primarily highly differentiated tumor ceHs are controHed. Initial clinical applications of the pineal hormone for incurable cancers raise hopes for a promising future use, particularly when combined with other therapies (e. g."

"Endocrine Pathology" integrates classical diagnostic anatomic pathology with recent developments in immunochemistry and molecular biology in its approach to endocrine disorders. The book discusses not only a wide range of diseases commonly encountered in everyday clinical practice but also those uncommon conditions elucidated by such innovative techniques as ultrastructural immunochemistry and in situ hybridization.

CHARLES Y. c. PAK Major progress has been made in the pathophysiologic elucidation and management of nephrolithiasis during the past two decades. It is now possible to detect the cause of stone disease in more than 95% of patients, to prevent recurrent formation of stones in the majority of patients, and to remove most existing stones less invasively. The assumption of editorship of this book permits me to indulge in the discussion of this progress from my personal perspective. Three somewhat fortuitous events in my academic career dictated my directing major efforts in stone research. The first event occurred in 1963 when, after having completed medical training, I was faced with two years of military service as a participant of the Berry plan. Choices were limited and disconcerting for someone interested in a research career: a staff physician at a military installation or an indian reservation, or a member of a research team in a state penitentiary. An interesting article by Norman Gershfeld on phospholi pid monolayers prompted me to write him seeking a position in his laboratory of Health (NIH) in Bethesda, MD. Partly because of at the National Institutes my rudimentary exposure and publication in surface chemistry, I was offered a position as a staff scientist and a position in the Public Health Service which satisfied the requirements of a military service."

This book is made up of 16 papers delivered during the Paediatric Conference convened by the Royal College of Physicians of London on 20th and 21st October 1983. The main intention of the conference was to allow each contributor to deliver a personal review of his own field, indicating recent develop ments and current practice. This volume, representing the proceedings of that meeting, is not intended as a comprehensive textbook of paedi atric endocrinology but rather as a series of personal narratives. I wish to express my thanks to the Chairmen, who so ably stimulated discussion, and to Miss Gillian Andrew, Conference Secretary of the Royal College of Physicians, and her colleagues, for providing invalu able help in the organization of the conference. I am also grateful to the staff ofMTP Press Limited for their help in producing the book. A. Aynsley-Green IX LIST OF CHAIRMEN Professor R. Hoffenburg PRCP Dr D. I. Johnston MD FRCP President Queen's Medical Centre Royal College of Physicians Nottingham London Dr D. A. Price FRCP Royal Manchester Children's Professor J. W. Farquhar MD FRCP(Ed) Hospital Department of Child Life and Health Pendlebury University of Edinburgh Manchester Edinburgh Dr P. H. W. Rayner FRCP Dr C. C. Forsyth MD FRCP Institute of Child Health Department of Child Health University of Birmingham University of Dundee Birmingham Dundee x LIST OF CONTRIBUTORS Dr D. B. Grant MD FRCP Dr J."

Polycystic ovarian disease, or polyfollicular ovarian disease, as Dr. Fut terweit prefers to call it, is a disease of uncertain etiology and for which numerous modes of therapy have been advanced. Understanding of its pathophysiology should shed light on factors regulating normal ovarian function; the converse is also true. Recent years have brought about great understanding of the neuro endocrine regulation of gonadal function, as well as of factors in the microenvironment of the ovary which affect its function. It is also ap preciated that cases classified as polycystic ovarian disease actually rep resent a clinical and pathological spectrum which may reflect the effects of diverse etiological factors. In the present volume, Dr. Futterweit presents the fruits of his long interest in and extensive experience with this disease. He thoroughly and thoughtfully reviews the vast amount of basic and clinical information that has been garnered with regard to this condition over the past decade. The numerous theories that have been advanced to explain its etiology are presented in balanced fashion, in addition to a hypothesis, which is well formulated and amenable to clinical testing. His clinical interests and judgment are well represented by his presentation of the diverse manifestations of this condition, the approach to proper diagnosis, and the available therapeutic options. Patients with this disease represent diagnostic and therapeutic prob lems in a situation where manifestations of disease may lead to major emotional stress."

This volume describes the proceedings of the Workshop Conference on The Human Testis which was held at Positano, Italy, April 23-25, 1970. The format of the book has been arranged according to topics discussed during the Conference. Each chapter includes individual contributions followed by discussion. Thus, this volume provides a current critical evaluation of the subjects discussed. The Editors assume responsibility for any shortcomings and wish to thank all par~ ticipants for their unprecedented cooperation in making this publi cation possible. The Editors are indebted to Miss Barbara Martin for her able secretarial and administrative assistance and to Mrs. Griff T. Ross who supervised the secretarial staff during the conference. Rec ognition is also due to Mrs. M. Flack for editorial assistance. The Workshop Conference could not have taken place but for the Serono Foundation, which supported this Meeting as well as the pub lication of the Proceedings of this Workshop. The physical as well as the technical arrangements were under the careful direction of Mr. Cesare Florimonte of the Serono Foundation. The support pro vided by the Serono Foundation is another proof of its generosity in stimulating scientific exchanges and a demonstration of its con tinuous efforts to support basic and applied studies in the field of human reproduction. We express our thanks to our Publisher, Plenum Press, for their fine cooperation and for ensuring the rapid publication of this vol ume.

Carole Mendelson has assembled a panel of leading investigators to critically review the various classes of endocrine, paracrine, and neuroendocrine factors that play a role in the regulation of lung development and surfactant production. Special attention is accorded the actions of glucocorticoids in lung development and the synthesis of surfactant glycerophospholipids and proteins. Also extensively treated are the roles of cell-cell interactions and the elaboration of various growth factors and bioactive peptides in pulmonary cell differentiation, gene expression, and pathophysiology. State-of-the-art and comprehensive, Endocrinology of the Lung constitutes a powerful new standard guide that illuminates the complex endocrinology of the lung for all those actively investigating hormone action in pulmonary biology and medicine today.

Calcium plays an enormous and varied role in living systems now widely appreciated by clinicians.
Calcium in Internal Medicine demonstrates the physiological significance of calcium in clinical medicine and discusses the abnormal calcium metabolism in disorders such as renal failure, hypertension, atherosclerosis and osteoporosis.
Hirotoshi Morii (Editor) linked the clinical use of vitamin D analogues in bone diseases, Yoshiki Nishizawa (Editor) researched the connection between calcium metabolism and atherosclerosis and Shaul G. Massry (Editor) was the first to systematize the importance of excess PTH in chronic renal failure. In addition to these areas, Calcium in Internal Medicine covers basic physiology, pathophysiology, nutritional requirements and the role of calcium in the development and treatment of other various diseases. The importance of calcium and its regulatory systems is brought together in one publication providing a useful reference tool for internists, rheumatologists and endocrinologists.

The International Foundation for Biochemical Endocrinology is incorporated as a nonprofit research and educational organization. It is dedicated to the dissemination of knowledge, cooperative research programs, and cultural interaction on an international basis. The Foundation is concerned with both basic research and practical applications of biological knowledge to the betterment of humanity. Among our interests are global resource management, human reproduction, hormonal regulation of normal and cancer cells, study of aging and degenerative diseases, brain peptides, peptide neurotransmitter compounds, mechanism of action of hormones, peptide hormone synthesis, and recombinant DNA techniques. This monograph is the ninth sponsored by the Foundation in the Biochemical Endocrinology series. The previous four have been: Hormonally Active Brain Peptides: Structure and Function (1982), K. W. McKerns and V. Pantie, eds.; Reproductive Processes and Contraception (1981), K. W. McKerns, ed.; Synthesis and Release of Adenohypophyseal Hormones (1980), M. Jutisz and K. W. McKerns, eds.; and Structure and Function of the Gonadotropins (1978), K. W. McKerns, ed. These have all been published by Plenum Press.

Nineteen eighty-six is a most appropriate year in which to be writing about developments in the organ-specific, autoimmune endocrine diseases. It celebrates the publication 30 years ago in 1956 of the classic papers of Roitt and Doniach and their co-workers I , and of Rose and Witebsky2 and Adams 3 and Purves . These three sets of fundamental observations provided the initial building blocks upon which much of what has been established in the field in the last 30 years was built. No publication of this nature on endocrine autoimmune disease can cover every aspect of the subject. I have chosen to highlight the organs (thyroid and pancreeas) which have attracted the most attention, and the areas of work within these fields within which most research effort is currently focused. There are still some gaps; the insulin and TSH receptors are not considered, nor in any detail are the role of cytotoxic mechanisms in mediating gland destruction. Molecular biology will undoubtedly in the next few years clarify once and for all the controversy that surrounds the structure of the TSH receptor and T cell cloning, the role of cell-mediated cytotoxicity. The pathogenetic mechanisms underlying autoimmunity are increasingly well understood and the search for the aetiology has begun.

This 1987 ORPRC Symposium on Primate Reproductive Biology, the third in a series, marked the twenty-fifth anniversary of the Oregon Regional Primate Research Center (ORPRC). In organizing these symposia, we have emphasized the dedication of many ORPRC staff members to research with nonhuman primates as models for human reproduction. The first symposium in this series, organized by William Montagna, was held in May 1981. Appropriately for a beginning series, its topic was fetal endocrinology. The subject of this year's symposium was the primate ovary, and, as in the past, scientists from around the world, including Sweden, Scotland, England, West Germany, and India met in Beaverton, Oregon, to exchange ideas and information on this important "aspect of reproduction. The international scope of the symposium reflects our belief that both the problems and their solutions extend beyond national boundaries. Many of the nonhuman primates that we rely on as models are endangered as civilization, through population pressure, encroaches on their natural habitats. Without a deeper understanding of how primate reproduction is regulated, and without the control over human population that such an understanding can bring, the quality of life for all primate species may well become substantially diminished. Consequently, we dedicate these symposia to the thesis that a deeper understanding of primate reproductive biology will ultimately improve all primate life. Robert M. Brenner Charles H. Phoenix vii PREFACE Today there is renewed interest in the processes controlling the gametogenic and endocrine functions of the ovary.

Those who are familiar with the two volumes of The Year in Endocrinology may, at first glance, fail to recognize their relationship to the present volume, Contemporary Endocrinology. The name is different and the cover design different, but nonetheless the admonition against judging a book by its cover is very well taken in this instance. In fact, Contemporary Endocrinology is not only the direct linear descendant of The Year in Endocrinology, it is a purposeful clone thereof-the topics are unchanged, the talented group of authors is unchanged, and most importantly, both the objective of the work and the manner in which that objective is approached are unchanged. The objective is, of course, to assist the reader in maintaining currency with respect to important developments, both basic and clinical, in the major areas of endocrinology. We are all much too familiar, unfortunately, with the difficulty of maintaining currency these days. Our approach to dealing with the informational inflation that we are suffering is similar to that used by economists in dealing with monetary inflation, that is, to increase interest. This we have attempted to do by providing for the reader an easy-to-read group of essays in which advances in individual areas of endocrinology are re viewed broadly, synthesized, and placed into perspective by a group of authors who are authorities in their individual fields. They serve, not as guest artists, but as members of a stable Editorial Board that provides continuity by contributing to successive volumes."

The secretion of bioactive products by tumors of the gastroenteropancreatic system results in the development of watery diarrhea that can lead to death in a very short period if not brought under control. Even if the consequences are less dramatic, the patients' ability to lead a normal daily life is seriously impaired, and they may become severely depressed. SandostatinR alleviates the condition by inhibiting peptide release, and its long duration of action makes it an effective and rational adjunct to therapy at all stages. Last year a consensus Round Table Meeting was held in Scottsdale, Arizona, to discuss the optimal use of SandostatinR in this indication. These guidelines offer the results of clinical research and the dosage recommendations arising from them, together with a critical summary of the points of view presented.

During the last decade, circadian and episodic fluctuations of the plasma levels of pituitary hormones have been demon~ trated in man. The interest in the time dependence of the pituitary secretions partially originates from their close functional relation with the neuroendocrine mechanisms pre- sumably responsible for the control of the circadian.rhyth- micity in man. High frequency blood sampling techniques and specific radio- immunoassays have allowed to describe in detail the varia- tions over the 24-h cycle of the hormonal concentrations in healthy individuals under basal conditions as well as after manipulation of external synchronizers such as the sleep- wake cycle, the dark-light cycle and the feeding schedule. Alterations in normal hormonal var~ions have been sugges- ted to play a role in the etiopathogeny of several metabo- lic and mental diseases, such as obesity or manic-depressio~ Important clinical implications regarding treatment and pre- vention are expected to be developed in the near future. However, so far, data obtained in different groups are dif- ficult to compare because different hormones were studied using different protocols and statistical methods. As a result, unclear or controversial issues are not uncommon.

We had the pleasure and the great opportunity to organize a symposium on "Molecular Biology of Brain and Endocrine Peptidergic Systems" under the auspices of the Canadian Biochemical society and the International Foundation for Biochemical Endocrinology. We were indeed very happy to ass ble a series of first rate speakers who delivered excellent papers on a variety of subjects from the synthesis of complicated peptide analogs, to the creation of trangenic mice, site-directed mutagenesis, enzyme characterization and DNA binding sites. One hundred and seventy-five participants attended the 40 conferences while having the opportunity to look at 24 posters presented by senior scientists as well as students. We, of the organizing committee, feel extremely pleased to have received an overwhelming response from such a group of scholars. We wish to express our sincere gratitude to Mrs. Diane Marcil who arranged most aspects of the meeting with efficiency. We also thank the different organizations and companies for their generous grants which made the reunion possible. We hope that the participants have gained scientifically while having a pleasant sojourn in beautiful Montreal. The organizing committee was made up of a group of dedicated people, particularly its secretary, Dr. Philippe Crine. To all speakers and sessions chairpersons, we are indebted for the excellence of their participation.

Relaxin, perhaps more than any other hormone, has a varied history of eliciting enthusiasm, rejection, skepticism, and long lapses of neglect. Long after its discovery, it was a hormone in search of a physiological role in humans. Today, relaxin is implicated in mammary growth, development and function, ionotropic and chronotropic action on the heart, and angiogenic activity in both the peripheral tissues and the endometrium. It is best known for its effect on the uterus and the symphysis pubis in preparation for parturition. However, the literature suggests that not all functions occur in one species. This book describes how to obtain the necessary molecules or derivatives for research, reaching right into the design of new molecules for specific applications.

The flow of information in neuroendocrinology and related disciplines is vigorous, favored by the availability of sensitive and specific biochemical and histochemical techniques that advance our knowledge of CNS neurotransmitter and neuropeptide systems. Volume 8 of Neuroendocrine Perspectives illuminates new findings inthis areawhich add complexity to the traditional view ofthe hypothalamo- pituitary control, and to established concepts ofthe modulation ofbrain function by target hormones. In the first chapter, Ben-Jonathan exhaustively reviews evidence derived from her own work that demonstrates the importance of the posterior lobe as a regulator of prolactin secretion via two opposing influences, i. e. , dopamine released by the tuberohypophyseal dopaminergic system into the short portal vessels and a prolactin-releasing factor which is produced locally, though the identity of its innervating neurons is still unclear. Despite the wealth of information on prolactin and its cell of origin, little is known about the manner in which the hormone exerts its effects on target cells. Frawley and coworkers thoroughlyexamine the direct actions ofprolactin on a broad spectrum ofmammalian tissues, dealing extensivelywith prolactin receptors and the putative second messengers. They also review new evidence, based on their original findings, for an indirect action ofprolactin exerted through the livervia synlactin and liver lactogenic factor, two extracellular modulators ofthe biological functions ofthe hormone. The relationships among the CNS, neuroendocrine and immune systems are bidirectional and constitute an integrated loop.

It is unclear, and really no longer relevant, whether the information explosion that we now contend with has been fostered by the growth of specialization and subspecialization in medicine, or vice versa. What is clear is that the two are mutually supportive and constitute what would be in endocrine parlance a short-loop positive feedback system. As a result, for most areas of medicine, even the subspecialist in that area has a problem in maintaining currency, the more general specialist has substan tial difficulty in doing so, and the generalist is tempted to abandon the effort altogether. Nevertheless, for all, both the internal pressures of conscience and self-esteem and the external pressures generated by peer review, recertifi cation, and subspecialty boards create the need for continuous self-educa tion. We are, therefore, in an era in which the means of dissemination of new information deserves as much creative attention as does its acquisition.

For many years now, our understanding of the somatotrophic and reproduc tive axes has evolved essentially independently, both fields of study reaching a highly advanced, although far from complete, level of under standing. Along the way, however, it became apparent that in some circumstances the reproductive and somatotrophic axes may be inter dependent. Inklings to this effect were at times feeble and at other times more convincing. Among those inklings are the clinical recognition by pediatric endocrinologists of the apparent association between isolated GH deficiency and delayed puberty, as well as of the apparent permissive, pUberty-promoting property of GH. Equally important is a body of experi mental studies establishing the ovary of multiple species as a site of GH reception and action. Arguing against an essential role for GH in the reproductive process is the observation that individuals who have GH resistance of the Laron variety are fertile arid that isolated GH deficiency does not constitute an absolute barrier to the attainment of sexual maturation and fertility. The intraovarian insulin-like growth factor (IGF) hypothesis proposes that IGFs may serve as amplifiers of gonadotropin action. Although the dependence of intraovarian IGFs on systemic GH action has never been unequivocally demonstrated, that leap of faith has often been made. The intraovarian IGF hypothesis serves as the rationale for the adjunctive use of GH in the induction of ovulation."

The beautiful town of Cavtat near Dubvronic, Yugoslavia was the site of the twelfth meeting of the International Foundation for Biochemical Endocrinology. It was sponsored by the Serbian Academy for Sciences and Arts and by the Foundation. The Croatia Hotel in Cavtat was a splendid place for a meeting. The presentation of the subject matter relating to "Neuroendocrine Correlates of Stress" was interesting and informa tive. The topics included many forms of stress, their mediators and responses. They included: releasing factors; neurotransmitters in the hypothalamus; role of noradrenal ine; the reaction of the hypothalamo-pituitary-adrenocortical axis to stress; immunological stress; thermal stress; immobil ization stress; peptides in shock; stress-induced prolactin; stress and acupuncture; stress and behavior; spinal cord transection and stress; electroconvulsive stress; neuroendocrine cells and stress; protein kinase as a signal transducer; the effects of constant 1 ight and darkness on the pineal; sleep, stress and ovarian function; and finally, hormonal response to exercise. Subsequently, the papers presented were rewritten for inclusion in this monograph. The Chairmen for the sessions at Cavtat were K. McKerns and Stefan Manolov, V. Chong-Li and L. Rakic, S. Feldman and R. Mil in, M. Lee and V. Liposits. The next meeting of the Foundation will be held in Edinburgh near the end of September, 1985. The topic will be "Neuroendocrine Molecular Biology" with Professor George Fink as Honorary Chairman of the local organizing committee."

Lipids and Women's Health is an up-to-date critical review of pertinent scientific and clinical issues connected with lipid disorders in women. Topics discussed include the public health significance of cardiovascular disease in women, lipoprotein and lipid metabolism, effects of estrogens and progestins on lipid metabolism, metabolic changes of menopause, and the paradox of obesity, a curable disease that is rarely cured, as well as those conceptual advances in our understanding of diabetes mellitus that have clarified diagnosis and may have improved treatment. The relationship of diet and lipid intake to the development of breast and uterine cancer; dietary and drug treatment of lipid disorders; effects of exercise, smoking, and stress; and repercussions of lipid disorders on the family are explored. The volume should prove of use to gynecologists, internists, family practitioners, and pediatricians, as well as to all other professionals with a major concern for the health of female patients.

A central concept in the evolutionary theory of senescence is the idea that ageing results from life-history trade-offs. In particular, the disposable soma theory suggests that longevity is determined through the setting of longevity assurance mechanisms so as to provide an optimal compromise between investments in somatic maintenance (including stress resistance) and in reproduction. Comparative studies among mammalian species confirm that cells from long-lived species appear to have a greater intrinsic capacity to withstand stresses than cells from short-lived species. Childbearing at older ages has become increasingly common in modern societies because of demographic changes, medical progress and personal choice. While the detrimental effects of late reproduction on infant mortality and genetic diseases have been well documented, little is known about the possible postponed detrimental effects of late parenting.

The traditional concept of a neuroendocrine mechanism for regulation of growth hormone (GH) secretion is based in large part on the work of Roger Guillemin. The work of Dr. Guillemin, who was awarded the 1977 Nobel Prize in Physiology and Medicine, supported the view that quantita tive change in GH secretion was the net result of pituitary stimulation and inhibition by the hypothalamic neurohormones, GH releasing hormone (GHRH), and somatostatin (somatotropin release inhibiting factor; SRIF), respectively. During the 1970s, another endocrine research pioneer, Dr. Cyril Bowers, discovered that structural modification of enkephalin re sulted in a family of peptides with GH releasing properties. These com pounds, simply called GH releasing peptide (GHRP), were originally thought to mimic GHRH. However, upon subsequent investigation they were found to supplement the activity of the natural hormone through a different mechanism. Nearly two decades after their discovery, the differ ences between GHRP and GHRH have been described by many different laboratories throughout the world. The complementary GH secretagogues have different binding sites, second messengers, and effects on gene expres sion. Based on these differences, it has been suggested that expansion of the original two hormone mechanisms for GH regulation to include a third molecule may be appropriate, even though the naturally occurring ana logue of GHRP has not yet been identified. Despite our lack of knowledge concerning the natural product mimicked by GHRP, clinical development of the new family of GH secretagogues for diagnostic and therapeutic purposes has begun in earnest."

In the words of Disraeli, "To be conscious that you are ignorant of the facts is a great step to knowledge. " For most of us, the conscious awareness of relative ignorance is an uncomfortable aspect of daily life. New data appear in such inexorable profusion that the necessity for continuous retooling has joined death and taxes as an inescapable component of our destinies. Perhaps it is this "consciousness of ignorance" that accounts for the success of the preceding volumes of this new series. The Year in Metabolism and The Year in Endocrinology series were introduced with the avowed intention of "providing an efficient and enjoyable bridge between those who are creating new knowledge at the bedside and the professional consciousness of those for whom such knowledge is ultimately intended. " That objective seems particularly appropriate at a time when the award of the 1977 Nobel Prize in Medicine or Physiology to Guillemin, Schally, and Yalow has served to emphasize the epoch-making advances that have characterized the recent course of endocrinology and me bolism. For the 1977 volume of The Year in Metabolism, the previous formula has been preserved. The same internationally recognized authorities again have contributed commentaries about the progress in their areas of expertise. They have been joined by Drs. Jack W. Coburn, David L. Hartenbower, and Charles R. Kleeman, who have provided a new section on Divalent Ion Metabolism.