The Center for Population Research of the National Institute of Child Health and Human Development began operations in August 1968 and is engaged in research dealing with health-related popula tion problems. We organize and support projects for the develop ment of new contraceptives and in the broad field of population research in the social sciences o The Center also supports a variety of projects dealing with the mechanism of action and medical effects of contraceptives now in use, particularly oral contraceptives and intrauterine devices. These studies were initiated several years ago at the specific direction of Congresso We were pleased, therefore, with the opportunity to help organize and support this important and timely conference on the "Metabolic Effects of Gonadal Hormones and Contraceptive Steroids," the subject of which forms an integral part of the Center's research program. April, 1969 Philip Ao Corfman Director Center for Population Research National Institute of Child Health and Human Development v PREFACE Progress in science is often associated with either a "sixth sense" or an inevitable timeliness. Both factors, perhaps, led the members of the Endocrinology Study Section of the National Institutes of Health to propose, in 1966, that an expanded view of the effects of gonadal hormones, in general, and the contra ceptive steroids, in particular. was needed. There had been ample evaluations of the clinical symptomatology, contraceptive efficacy, and effects on the reproductive system, but there was a dearth of information on their multiple systemic'metabolic effects."

In the summer of 1969, the first Workshop on Control of Renin Secretion was held at Stanford University. At its completion, it was suggested by many of those who attended that a second Workshop be planned in about two years time. Thus the second Workshop on Control of Renin Secretion took place and from this event the chapters in this book had their origin. The setting of this Work shop was the beautiful J & R Double Arch Ranch in Santa Ynez, California which houses the Kroc Foundation. The Foundation, through the kindness of its President, Dr. Robert L. Kroc, provided us with luxurious accommodations, excellent meeting facilities and an atmosphere extremely conducive to the exchange of scientific knowledge, both formally and informally. In addition, the Founda tion assisted financially in the travel expenses of three of our foreign guests and in the preparation of the manuscripts for this book. I know I speak for all of us who attended the Workshop in expressing our sincere gratitude to the Foundation and to Dr. and Mrs. Kroc and their staff. In addition, I personally, as organizer of the meeting and editor, wish to acknowledge the help of many others who made my job much easier. Drs. Davis, Ganong, Luetscher and Tobian kindly took on the jobs of chairing the four sessions and directing the lively discussions which followed each presentation."

Perinatal problems in thyroid gland physiology are common but complicated and present a diagnostic dilemma for the primary clinician. In December 1990, an international group of basic and clinical investigators gathered in Longboat Key, Florida to address these issues. The participants included internists, obstetricians, pedia tricians, neurologists, pathologists and basic scientists in cellular metabolism, endocrine physiology, and molecular biology. The presentations contained within this book bring together their most current and vital research related to the field of perinatal thyroidology. This book is based on the dynamic and fruitful exchange of the participants at the symposium. We are indebted to these individuals whose valuable insights and efforts are contained within this text. Barry B. Bercu Dorothy I. Shulman vii CONTENTS Session I Mechanism of Thyroid Hormone Action 1 Leslie J. DeGroot Thyroid System Ontogeny in the Sheep: A Model for Precocial Mammalian Species * . . * * 11 Delbert A. Fisher Pathologic Studies of Fetal Thyroid 27 Development * * * * * * * Douglas R. Shanklin Thyroid Hormone Control of Brain and Motor Development: Molecular, Neuroanatomical, 47 and Behavioral Studies * * * * * * * S. A. Stein, P. M. Adams, D. R. Shanklin, G. A. Mihailoff, and M. B. Palnitkar The Thyroidectomized Pregnant Rat: An Animal Model to Study Fetal Effects of Maternal Hypothyroidism 107 Susan P. Porterfield and Chester E.

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.

This volume is an outgrowth of a symposium held at the University of Michigan, Ann Arbor, Michigan, October 27-29, 1975. This symposium was organized to bring together basic scientists and clinicians for the purpose of exchanging new ideas and the latest information in the area of Steroid Hormone Action and Cancer. The design of the symposium included both formal plenary sessions and informal roundtable discussion groups, the chapters of this volume being drawn primarily from these proceedings. During the last quarter of a century considerable progress has been made toward understanding the molecular mechanisms in volved in steroid hormone action. It now appears that the mechan sim of action of the four major classes of steroid hormones is qualitatively similar. Research during the past decade has demonstrated steroid hormone receptors in a variety of normal and neoplastic tissues. Receptor-containing neoplasms have been shown to be hormone-dependent and undergo regression when treated with hormone antagonists. Natural and synthetic steroids also have been employed for many years to successfully treat various types of cancer, for example: estrogens, androgens and progestagens for breast cancer; estrogens and progestagens for prostatic carcinoma; progestagens for endometrial carcinoma; and corticoids for leu kemias. All of these neoplasms have now been found to possess receptors for the steroids empirically used in their treatment."

As humans ventured into the twentieth century, the industrialized countries were confronted with the scourge of rickets. Although solariums were becoming common in the early 1900s and phototherapy was gaining popularity as a result of the awarding of a Nobel Prize to Finsen in 1903, it wasn't until 1921 when Hess and Unger demonstrated that rickets could be cured by exposure to sunlight that the healthful benefit of sun exposure appreciated. In 1941, Apperly (Cancer Research; 1: 191-195, 1941) noted that the occasional increased risk of skin cancer was associated with a decreased risk of many other more common and serious cancers. The alarming increase in the number of cases of skin cancer, especially melanoma, has caused great concern about the negative role of sunlight in health. The Sixth International Arnold Rikli Symposium on the Biologic Effects of Light was held in Boston, Massachusetts from June 16th - 18th, 2001. The goal of this Symposium was to focus on the very popular practice of tanning either by sunlight or by artificial light sources and the overall impact this practice has on health and disease. The program was organized by members of the Scientific Advisory Committee and my co-chair emeritus, Professor Ernst G. Jung. The Program Committee organized an outstanding state-of-the-art program that was enthusiastically received by the participants.

The human pancreas consists of two organs in one: the exocrine gland made up of pancreatic acinar cells and duct cells that produce digestive enzymes and sodium bicarbonate, respectively; the endocrine gland made up of four islet cells, namely alpha-, beta-, delta- and PP-cells that produce glucagon, insulin, somatostatin and pancreatic polypeptide, respectively. While the physiological role of exocrine p- creas is to secrete digestive enzyme responsible for our normal digestion, absorption and assimilation of nutrients, the endocrine pancreas is to secrete islet peptide h- mones maintaining our glucose homeostasis. The pancreatic functions are nely regulated by neurocrine, endocrine, paracrine and/or intracrine mechanisms. Thus, dysregulation of these pathways should have signi cant impacts on our health and disease. Nevertheless, the underlying mechanisms by which pancreatic functions are regulated remain poorly understood. Recent basic science and clinical studies con rm myriad physiological and pathophysiological roles of the tissue renin-angiotensin systems (RAS). Of parti- lar interest is the recent identi cation of a local and functional RAS in the pancreas, which in uences both its exocrine and endocrine function. Its role in the pat- genesis of pancreatic diseases including diabetes and pancreatitis is increasingly recognized, as is the therapeutic potential of RAS antagonism: RAS blockade l- its disease progression of type 2 diabetes mellitus and impaired glucose tolerance, and may also protect against pancreatic in ammation.

THIS BOOK collects together papers given at a NATO Advanced Research Workshop held at Il Ciocco (Lucca), Italy, from the 9th to the 15th April, 1989. It sets out to present the current state of understanding of the principles governing the way fluxes and concentrations are maintained and controlled in metabolic systems. Although this is a topic that has held the interest of biochemists for many years, it is only quite recently that the methods of analysing the kinetics of multi-enzyme pathways developed over the past two decades have come to be widely discussed or applied experimentally. Many biochemists remain sceptical that the new methods offer a real advance (except in complexity) over the landmark discoveries of the 1950s and 1960s relating to inhibition of enzymes at branch-points by the end products of metabolic pathways, and the interpretation of allosteric effects and cooperativity. Even those who have become convinced that the classical ideas provide only the starting point for understanding metabolic control have been by no means unanimous in their assess ment of the direction in which one should advance. In this book we have tried to include all of the current points of view, including the view that the classical theories tell us all that we need to know. We have not seen it as our role as editors to paper over the cracks that exist and to pretend that we can speak to the world with one voice."

Cheryl S. Watson University o/Texas Medical Branch Cellular steroid action has been thoroughly studied in the nuclear compartment. However, nuclear steroid receptor mechanisms have been unable to explain some of the rapid activities of steroids, partiCUlarly those which occur in a time frame of seconds to minutes [reviewed in (1;2)]. Based on these and other considerations, an alternative membrane-associated receptor form was long ago proposed to exist (3). Others interpret the location of the steroid receptors mediating these rapid effects as peri membrane or cytoplasmic. New experimental tools have been brought to bear on the topic of receptors for steroids which mediate non-genomic actions, and thus investigative activity and focus regarding this type of steroid receptor has recently increased significantly. However, there may be multiple answers to the question "how do steroids mediate rapid nongenomic effects?" Steroid actions initiated at the cell membrane can impinge on important phases in the lifespan of a cell: proliferation, migration, differentiation, and release of hormones or neurotransmitters functioning as signals to other cells.

The dramatic recent expansion in genomic information has motivated the development of new approaches to characterize gene expression and function. A critical issue for both basic and clinical endocrinologists is the physiological role of genes involved in regulating endocrine functions. Transgenic technologies allow the translation of genotypic information into specific phenotypes by using gene overexpression or loss of specific gene functions. Murine functional genomics is thus of central importance in modem biomedical endocrine research. Although mice are at present, the preferred mammalian species for genetic manipulations because of the availability of pluripotent embryonic. stem cells and inbred strains and the relatively low breeding and maintenance costs, transgenic rats have also been generated and used to study endocrine physiology. The two basic techniques used in the creation of transgenic animal models are integration of foreign DNA into a fertilized oocyte by random chromosomal insertion and homologous recombination in embryonic stem cells that are then introduced into zygotes. Transgenic mice and rats serve as sophisticted tools to probe protein function, as models of human disease, and as hosts for the testing of gene replacement and other therapies. Embryonic stem cell libraries for mouse gene deletion are being developed, which will make it possible to generate knockout mice rapidly and without the need to analyze gene structure, construct targeting vectors, and screen embryonic stem cell clones. A novel approach to transgenesis for the expression of DNA within adult differentiated neuroendocrine cells in vivo is using viral vectors.

The pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) has attracted the interest of our group during the last three decades. As early as 1969, a Nobel Symposium dealing with this topic was organized in Stockholm. This was followed in 1987 by a Nobel Conference devoted to the same subject. The main purpose of these meetings was to bring together the most distinguished scientists from all over the world and present theories on molecular and genetic mechanisms responsible for the development of glucose intolerance in NIDDM. This idea was followed also in the present symposium, "New Concepts in the Pathogenesis of NIDDM," organized with diabetologists from Toronto in Canada. Our purpose is to biannually organize international meetings covering important aspects of dia betes research, hoping that this type of interaction may result in new concepts and treat ment alternatives. For us, participating in this symposium in September 1992, the meeting in Stockholm was very stimulating and innovative. It is a special pleasure that almost all invited lecturers submitted manuscripts. Thus, the publication of the proceedings of the symposium makes it possible for all interested in diabetes research to share new ideas and findings presented at the meeting. Claes-G6ran Ostenson Suad Efendic Mladen V ranic v CONTENTS REGULATION OF INSULIN SECRETION Impaired Glucose-Induced Insulin Secretion: Studies in Animal Models with Spontaneous NIDDM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. -G. Ostenson, A. Khan, and S. Efendic Perturbation ofIslet Metabolism and Insulin Release in NIDDM. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 WJ. Malaisse 2 Regulation of Cytoplasmic Free Ca+ in Insulin-Secreting Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ."

Since the late 1960s, there has been an acceleration of research focused on understanding how the efferent ducts, the epididymis, and the vas deferens function with respect to the maturation and storage of spermatozoa and as hormone dependent tissues. Another major interest in the epididymis is that it is an attractive target for the development of male contraceptives. There are well over 16,000 peer reviewed articles in the literature on these tissues, their structure, gene expression, protein synthesis and function. Regular international meetings have been initiated that are dedicated to this field. Thus, there is an urgent need for a comprehensive reference volume that spans every facet of epididymal biology, from historical background to the most current results, from basic cell and molecular biology to clinical issues. Well-established experts from every part of the world have contributed to this volume. By necessity, each author was given page limitations so that many topics are not dealt with exhaustively. Whenever possible, references to more comprehensive discussion of specific topics are included.

It is remarkable how much we take for granted the tremendous energy and vitality that the sun provides earth's inhabitants. As we enter the new millennium, it is worthwhile to review how our ancestors perceived the biologic effects of sunlight, and how science and medicine have advanced our knowledge about the biologic effects of light. At the turn of the century, a multitude of investigators explored the use of sunlight and artificial radiation for treating a multitude of diseases. These explorations gave rise to photodynamic therapy, phototherapy, and chemophototherapy. However, enthusiasm for using sunlight and artificial radiation to treat disease was dampened with the birth of pharmacology. It was the goal of the Fifth International Arnold Rikli Symposium on the Biologic Effects of Light, held in Basel, Switzerland, on November 1-3, 1998, to review the history of phototherapy and have some of the world's leading experts on the biologic effects of light provide new perspectives on the positive and negative effects of light. The general topics included a broad range of biologic effects of sunlight, artificial ultraviolet radiation and electromagnetic radiation. Special sessions on radiation and vitamin D and bone health, photoimmunology, biopositive effects of UV radiation, effects of electromagnetic currents and fields, and ocular and non-ocular regulation of circadian rhythms and melatonin, should be of particular interest to readers of Biologic Effects of Light.

Recent Developments in Graves' Ophthalmopathy offers an overview of the pathogenesis, assessment and management of patients with thyroid-associated eye disease. Each chapter is written by an expert and truly represents the current state of the art on the particular topic. This book can therefore almost be considered a textbook on this enigmatic disorder. Recent Developments in Graves' Ophthalmopathy is designed for all those interested in this disease, including basic scientists, clinical endocrinologists, ophthalmologists, radiotherapists, and orbital surgeons. The book gives a comprehensive overview of all aspects of Graves' ophthalmopathy. Subjects covered include the pathology of Graves' eye disease and the controversial views on its autoimmune pathogenesis; assessment of the eye changes using reliable measurements; medical management of Graves' eye disease with an overview of the many treatment options available to the clinician, including orbital radiotherapy and other immunosuppressive treatments; management of the thyroid disease; and finally, the techniques for performing various surgical procedures, which are explained and illustrated.

The idea for this book developed as an outcome of a multidisciplinary sym posium entitled "Pituitary Adenoma Update" that was held at Tufts-New En gland Medical Center in April 1977. The purpose of that symposium was to put together our current knowledge of the cause of pituitary tumors and discuss the diagnostic evaluation and management that was now appropriate, in light of the rapid advances that had taken place so recently in this area. Those of our colleagues who had presented papers at the symposium, as well as a number of others, were invited to contribute to this volume, which should serve as a presentation of the "state of the art" on all aspects of pitu itary tumors. We felt that such a book would be of value to endocrinologists, neurosurgeons, neuroradiologists, and pathologists who are involved in the investigation or care of patients with pituitary disorders. For a number of reasons, a review of pituitary adenomas seems particu larly timely. Rapid advances have taken place coincidentally in the fields of neurosurgery, neuroendocrinology, neuroradiology, neuropathology, and neuropharmacology. Seven major developments in these areas have occurred independently and almost simultaneously that have virtually revolutionized our approach to pituitary adenomas.

Dr. Robert L. Jackson, Professor of Child Health at the Uni versity of Missouri-Columbia, decided to retire from clinical practice in 1977 and the Department of Child Health planned a con ference in his honor. The Thirteenth Annual MidweSt Conference on Endocrinology and Metabolism also was in the planning stages and scheduled for two days in the fall. It seemed appropriate to com bine the two into an expanded three-day conference. In view of Dr. Jackson's international reputation in the study and care of children with diabetes mellitus, the conference topic was not dif ficult to find. Experts in this field were delighted to be asked to speak at a conference in Dr. Jackson's honor. We selected a number of excellent speakers to survey the physiology and pathophy siology of pancreatic hormones and their effects in diabetes mel litus, to discuss current knowledge of the microvascular complica tions of the disease, and to put it all into the proper historical perspective of where we have been and where we are going. We think the conference achieved its objective to pay meaningful trib ute to a distinguished member of the scientific community. As with any conference, the conversion of the presentations and discussions to the printed page is a long and arduous process. Many manuscripts were completed well after the conference and references often are more recent than the date of the conference."

Leading medical specialists critically review for the general practitioner the latest techniques for the clinical management of diabetic neuropathy. These authoritative contributors focus on the practical aspects of diabetic neuropathy and describe in detail the treatments that are currently available or expected to become available in the near future. They also include concise discussions of the causes of diabetic neuropathy and highlight the relatively unknown features of neuropathy that can significantly impact a patient's life. Comprehensive, up-to-date bibliographies at the end of each chapter provide an opportunity for the interested physician to gain a more detailed picture of a particular topic. This book offers family physicians, internists, endocrinologists, podiatrists, cardiologists, neurologists, and gastroenterologists an authoritative practical guide and a vital day-to-day reference source for the management of their neuropathic diabetic patients.

After a decade or longer, approximately one-third of individuals with either type 1 or type 2 diabetes commence a downhill course in which decreasing renal function and failing vision define a Renal-Retinal Syndrome, dominating all aspects of life and presaging early death. Only a generation ago, survival after onset of end-stage renal disease (ESRD) in diabetes was limited because rehabilitation was preempted by blindness, limb amputation, stroke, and heart disease. By 1998, however, team management has improved the outlook, with preserved sight and return to work and home responsibilities, usually for a decade or longer, following kidney transplantation and laser photocoagulation. Recognition of the critical requirement for blood pressure regulation and metabolic control are central themes in management. In this unique book, the accomplishments of ophthalmologists, nephrologists, diabetologists, transplant surgeons, and basic scientists are blended into a strategic approach that may be readily applied by all those caring for diabetic patients. Each of twenty-one presentations suitable for primary care physicians, as well as for subspecialists concerned with macrovascular and microvascular complications of diabetes, is placed in perspective by an introductory editorial analysis. Promising near-term innovative therapies, including insertion of genetically engineered beta cells or polymer-coated islets of Langerhans, interdiction of kinins that promote retinal angiogenesis, and prevention of synthesis of advanced glycosylated endproducts (AGEs), are presented in detail. While comprehensive care of diabetic patients reflects multiple incremental advances that in sum afford major benefit, this text envisions further remarkable changes likely to suppress and possibly entirely prevent the Diabetic Renal-Retinal Syndrome.

This volume contains the edited proceedings of the Totts Gap Colloquium on Diabetes Mellitus, DILEMMAS IN DIABETES. The Collo- quium, lasting two and a half days, was organized mainly as a dia- logue among experts in the field with different disciplinary back- grounds and, to some extent, differing points of view. The effort was to synthesize existing knowledge, reconciling disparate data and interpretation, and pointing up important areas of ignorance. Thus, the book should serve not only as a summary of recent information on diabetes, but as a reliable guide to the practicing physician as he wades through often conflicting etiologic dogmas and therapeutic practices. The Colloquium was made possible through the generous support of the Geigy Pharmaceutical Company and the conscientious and expert coordination of Mr. Oscar Swarth. The participants were: Dr. George F. Cahill, Boston, Massachusetts Dr. Harvey C. Knowles, Cincinnati, Ohio Dr. Rachmiel Levine, Duarte, California Dr. Lelio Orci, Geneva, Switzerland Dr. Norton Spritz, New York, New York Dr. Roger Unger, Dallas, Texas Dr. Robert Williams, Seattle, Washington Dr. Stewart Wolf, Galveston, Texas Dr. Arnold Lazarow and Dr. I. Arthur Mirsky were to have partici- pated, but unfortunately were ill at the time of the meeting. Others in attendance included five medical students, especially selected from medical schools in the Philadelphia/New York area.

In a rapidly evolving and extremely important area of medical science, it is often difficult for the student, teacher, and researcher to keep abreast of all the important advances. The purpose of Molecular Biology ofDiabetes, Parts I and II is to bring to these individuals the latest knowledge of diabetes-related research in a comprehensive, yet concise manner. To this end, we have assembled chapters, written by most of the world's experts in the field, that we believe compre hensively survey and synthesize a coherent understanding of the subject. Studies of the etiology of type I and type II diabetes are extremely exciting and essential, since we hope to one day prevent the disease using gene therapy. These aspects are covered in Molecular Biology of Diabetes: I. Autoimmunity and Genetics; Insulin Synthesis and Secretion. In type II diabetes, an abnormality in pancreatic secretion exists concomitantly with peripheral insulin resistance. This abnor mality of insulin secretion is believed to be related to a defect(s) in glucose sensing. Uncoupling of glucose sensing from insulin secre tion may be the crucial step in the pathogenesis of noninsulin-depen dent diabetes. In this volume, we have invited authors to describe their studies on all known factors affecting ~-cell function, including autoimmunity and genetics of diabetes, as well as molecular mecha nisms of insulin synthesis and secretion. In the last few years, the most rapidly advancing area of research in diabetes has been, in fact, related to insulin action.

Growth Hormone is a fitting addition to the Endocrine Updates Series. The aim of these publications is to provide the clinician with cutting-edge, yet succinct, access to the latest advances in endocrinology. Current interest in this rapidly evolving area of endocrinology makes this a timely and important update. Growth Hormone joins Dr. Fagin's Thyroid Cancer in continuing the standard of excellence as the fourth volume in this series of topical updates. Shlomo Melmed, MD, Series Editor, Endocrine Updates Ten years ago, many endocrinologists were still skeptical that growth hormone (GH) played an active role in adult metabolism. This is, perhaps, surprising given that GH deficiency (GHD) in adulthood had been `recognized' as long ago as the 1960s. During the last ten years studies have shown that GHD in adulthood is a far-reaching syndrome associated with abnormal body composition, reduced bone mineral density with an increased fracture rate, increased cardiovascular morbidity and impaired cardiac function, as well as reduced exercise performance and decreased psychological well-being. Importantly, it is also clear, from placebo-controlled trials, that GH replacement therapy can normalize body composition, increase bone mineral content and improve the cardiovascular risk factor profile. GH replacement therapy also improves cardiac performance and exercise capacity, increases muscle strength and improves well-being and quality of life. The aim of Growth Hormone is to provide a critical update of current knowledge about adult GHD and the future role of GH/IGF-1 in adult medicine. For this purpose, contributions from a number of research groups have been invited. It is my hope that the book may not only serve as an introduction to the field, but also stimulate further research within this exciting area.

It is an authentic privilege to have the opportunity to assemble and edit a new volume on "Prolactin," the first in several decades to be devoted to this fascinating hormone in all its aspects. The obvious clinical rationale for understanding prolactin (PRL) is the frequent occurrence of prolactinomas, the most common type of pituitary tumor. Fortunately, medical management of prolactinomas can be based on our under standing of the physiology of hypothalamic control of the lactotroph. Armed with this knowledge, therapies for proiactinomas are highly successful and well tolerated. Be cause of the historical and practical importance of knowledge regarding the hypothala mus-Iactotroph axis, the first chapters of this volume are dedicated to reviewing the physiology, development, and cell biology of lactotroph regulation. Chapters focusing on prolactinomas and related clinical issues follow these. PRL is the primary hormone that is responsible for "parental care" in many verte brate species. This reproductive strategy is not unique to mammals, but it has devel oped through evolution to be the central distinguishing feature of the mammalian life cycle. Among the mammals, mice have become the most effective research species in recent years. This can be traced to the development of a wide range of methods for manipulating mouse genetics, and thereby influencing development, physiology and behavior. Mice also provide a profound illustration of the physiological challenges faced in maternity. Female mice undergo a post-partum estrous, and often are both pregnant and lactating simultaneously.

Growth Hormone and the Heart endeavors to bring together knowledge that has been accumulated in the area of GH and the heart, from basic to clinical studies, by research groups working on this topic throughout the world. Lessons from different experimental models and from several human diseases (acromegaly, adult GH deficiency, heart failure) suggest to endocrinologists and cardiologists that GH may not only have a role in the physiology and pathophysiology of heart function, but that GH itself may have a place in the treatment of primary heart diseases (such as dilated cardiomyopathy) or of cardiac complications of hypopituitarism. Growth Hormone and the Heart will be a useful update of the research produced in the field of cardiovascular endocrinology. The Editors also hope that this book will serve as the primary step in the recognition of the wide physiological and clinical significance of GH and heart interactions.

Genetics of Diabetes Mellitus is intended to be a resource for both researchers in the field as well as endocrinologists, diabetologists, and geneticists who seek to learn more about this rapidly changing and important field. The text contains chapters from experts in the area who review aspects of the genetics of both type 1 and 2 diabetes mellitus as well as various syndromic forms of diabetes. The chapters are approachable for those who are not experts in the field of genetics but also comprehensive, so as to serve as an important resource for researchers interested in the genetics of diabetes mellitus. A description of basic concepts of the genetics of complex diseases like type 1 and type 2 diabetes is provided as background. Type 1 diabetes is addressed in chapters exploring genetic determinants that affect the autoimmune process characteristic of type 1 diabetes, the role of the insulin gene in the pathogenesis of type 1 diabetes and additional genes that may impact upon the risk of type 1 diabetes. The impact of genetic determinants on the pathophysiology of type 2 diabetes is covered, as are chapters that address specific genes that are important for the development of type 2 diabetes. Finally, syndromic forms of diabetes, including Maturity Onset Diabetes of the Young and mitochondrial diabetes, and the insight that these disorders provide into more common forms of diabetes are reviewed. Thus, this comprehensive and up-to-date text will serve as an important resource for those actively engaged in research in this area and clinicians treating these patients to provide an up-to-date entree for those seeking to become more knowledgeable in the area.

This volume is a collection of the most significant contributions to the 4th International Symposium on MULTIPLE RISK FACTORS IN CARDIOVASCULAR DISEASE: STRATEGIES OF PREVENTION OF CORONARY HEART DISEASE, CARDIAC F AlLURE, AND STROKE held in Washington, D. C. in April 1997. The meeting focused on the risk factors for cardiovascular disease and their interactions. The need for this symposium is based on the epidemiological, clinical, and biological evidence that individuals from industrialized countries often possess two or more risk factors which synergistically increase the global risk profile. This has become more evident in recent years with the increase in life expectancy of populations in the industrialized countries. The evidence that a combination of risk factors confers a very high risk of developing cardiovascular diseases, is of pivotal interest in the process of detection of patients who will benefit the most from pharmacological treatment. Many recent epidemiological data identifying the intrinsic and environmental factors contributing to the development of atherosclerosis are discussed. These results, in parallel with basic and clinical research, underline atherosclerosis as a complex and multifactorial process involving the influences of lipids, including lipoprotein subfractions, blood pressure rheologic forces, carbohydrate tolerance, and thrombogenic factors, including fibrinogen, tissue factor, PAl-I, and homocysteine. Furthennore, the risk associated with anyone of these risk factors varies widely depending on the level of the associated atherogenic risk factors. Hyper cholesterolemia and hypertriglyceridemia, for instance, are more common than would be expected by chance among hypertensive patients.