"Frontiers In Thyroidology" assembles the prize lectures, symposia, and papers presented during the Ninth International Thyroid Congress in Sao Paulo, Brazil in September, 1985. This book represents the State-of the-Art in thyroid studies with its continuous expansion into the areas of immunology, molecular biology, clinical and environmental medicine. As its name also indicates, the material compiled in this volume defines important questions to be answered in basic and applied aspects of the thyroid. So, this book clearly demonstrates the rewards, excitement, and challenges posed by the thyroid gland. Once again, the thyroid gland, through its unique and important functions and implications in health and disease, has been able to congregate scientists throughout the world to communicate their findings, to share their expertise and experiences, and to strengthen their bonds of friendship and commitment to make a better world through their work. This publication consists of 309 papers in 19 different topics. The prize lectures and symposia review and update our knowledge in basic and clinical aspects of exceptional interest in the thyroid field. "Frontiers in Thyroidology" adds to a series of publications from previous interna tional thyroid meetings which includes: "Advances in Thyroid Research", London, 1960; "Current Topics in Thyroid Research", Rome, 1965; "Further Advances in Thyroid Research", Vienna, 1970; "Thyroid Research", Boston, 1975, and "Thyroid Research VIII", Sydney, 1980. We would like to express our gratitude to Mrs. P. Langford and Drs.

The aim of this book is to provide clear and concise information about the safe prescribing of insulin both subcutaneously and intravenously. It provides information on the different types of insulin, the delivery devices, side effects of insulin and, most importantly, on rational dose adjustment.

The sum of clinical problems caused by diabetic renal disease has been steadily increasing since the first edition of this book was published in 1988. The years since have seen tremendous progress in research activities. Importantly, this also includes improvement in the treatment programs to prevent end-stage renal failure. It has become clear that the diabetic kidney is extremely pressure-sensitive, responding to effective antihypertensive treatment by retarded progression of disease. Some agents may be more beneficial in this respect than others, although effective blood pressure reduction per se is crucial throughout the stages of diabetic renal disease. However, the prime cause of diabetic renal disease is related to poor metabolic control and it is now documented beyond doubt that good metabolic control is able to postpone or perhaps even prevent the development of renal disease. However, in many individuals we are not able to provide such a quality of control that will prevent complications, and therefore non-glycaemic intervention remains important.Maybe in the future non-glycaemic intervention will become the most important research area in diabetic nephropathy. Much information is now available on the exact mechanisms behind poor metabolic control and development of renal disease. It is likely that a combination of genetic predisposition and metabolic and haemodynamic abnormalities explain the progression to renal disease, seen in about 30% of diabetic individuals. Much of this development probably relates to modifiable genetic factors, such as blood pressure elevation or haemodynamic aberrations. However, mechanisms related to the response to hyperglycaemia are also of clear importance, as is the possibility that these metabolic or haemodynamic pathways may be inhibited. This volume reviews older data as well as the progress seen within the research on diabetic nephropathy over the last five years and describes the state of the art of the development.

We have witnessed a rapid development within the field of the kidney and hypertension in diabetes mellitus. A significant amount of work within the traditional areas has been published, and several new dimensions are now being developed, mostly in the experimental setting. These dimensions are discussed in several chapters of this new edition, The Kidney and Hypertension in Diabetes Mellitus, Fourth Edition. This volume endeavors to cover all aspects of renal involvement in diabetes. It is written by colleagues who are themselves active in the many fields of medical research covered in this volume: epidemiology, physiology and pathophysiology, laboratory methodology and renal pathology.

Originally published in 1935, this volume contains the text of the fifth Horsley Memorial Lecture, delivered by Sir Walter Langdon-Brown. This book will be of value to anyone with an interest in medical history, particularly the history of the discovery of the endocrine system.

The study of the insulin-like growth factor (IGF) family has become an exciting area of investigation. Initially, this family consisted of ligands (insulin, IGF-I and IGF-m and receptors (the insulin receptor, the type I or IGF-I receptor and the type II or IGF-IYM-6-P receptor). Subsequently, it was discovered that six specific binding proteips (lGFBPs 1-6) playa major role in the actions of this growth factor family. In addition, there are now more potential receptors when one considers the possible roles of the insulin-receptor related receptor (IRR) and hybrid receptor dimers composed of insulin and IGF-I receptor (half-receptors). Another important aspect of this area of research is the realization that the IGFs are not only essential for normal growth and development but, in addition play an important role in the normal specialized function(s) of all tissues of the body, including the nervous system, skeleton, reproductive system, kidney, and the immune system, to name but a few. The development of recombi tant human IGF-I for clinical testing has been a major breakthrough for investigators. Potential uses include wound healing, reversal of catabolic states, diabetes, bone remodeling, recovery from acute renal failure and many others. will determine both its use and its potential hazards.

The Eleventh Midwest Conference on Endocrinology and Metabol ism in September 1975 brought together a number of leading invest igators in the areas of steroid, peptide, acetylcholine, and cate cholamine hormone receptor studies. This book is based upon the reports of investigations into hormone receptor biochemistry and physiology presented at the Conference as well as on the ensuing discussions. However, many of the manuscripts were written after the Conference. Because of this, the reader will find that some literature references and results of i vestigations are more up to-date than the Conference date would suggest. Perusal of this and previous volumes will attest to the high quality of this annual conference, due primarily to the efforts of the Planning Committee. We also acknowledge the superb efforts of the staff of Conferences and Short Courses for their assistance in organizing the Conference, and Mrs. Linda Bennett for expert sec retarial assistance in the typing of the book. Last, but certain ly not least, we express our appreciation to the various organiza tions that provided the necessary financial assistance. Leonard R. Forte John M. Franz David M. Klachko vii Contents The Receptor Concept: Prejudice, Prediction, and Paradox. . . . . Oscar M. Hechter Discussion. . . . . . . . . . . . . . 41 DeGroot, Hechter, Campbell, Freed, Barnawell, Morgan, Siegel Nuclear Receptors for Thyroid Hormone . 45 Leslie J. DeGroot 69 Discussion ............ ."

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."

Since 1948, the date of publication of Hormones and Behavior by Dr. Frank Beach, this hybrid area has received a great deal of attention from scientists representing various allied fields. As a result, the data and publications dealing with hormones and be havior have increased geometrically and on an annual basis. More recently, a number of review articles and short volumes dealing with aspects of hormones and behavior have been published. How ever, there seemed to be an overwhelming need for a synopsis of the major topics in a unified and integrated form. Thus, the reason for this edition. In these two volumes, we hope we have presented a critical assessment of the various interrelated areas dealing with hormones and behavior. In some instances, we have minimized the presenta tion of certain aspects of psychoendocrinology. This was a con scious effort since some areas have received competent coverage in other volumes. In other instances, we have presented hitherto seldom mentioned material. For example, we are presenting coverage of the general areas dealing with hormones and behavior in aging and the aging process, mental illness, early experience, motivation, genetics and personality. In some instances, the available data is overabundant; in others, the data is scarce. However, we hope that an evaluation of this situation stimulates further interest and further collaborative research where needed.

Endocrine disruption is an expanding field due to the numerous chemicals involved and, as evidenced more recently, the variety of homeostatic systems that they can alter throughout life. Also, this field is at the edge of several disciplines with implications of both laboratory scientists and clinicians. This symposium aims at updating mechanisms and consequences of endocrine disruption in three perspectives: neural, metabolic and reproductive. The gathering of experts from all over the world should help the participants to identify health disorders that are possibly or likely related to exposure to endocrine disrupters. The research needs will be discussed as well as recommendations prioritizing target groups and following the precautionary principle.

Leading clinicians review in depth the clinical and molecular aspects of the hormone resistance syndromes caused by receptor mutations. These mutations are involved in a large number of disorders, including dwarfism, Laron syndrome, pseudohypoparathyroidism, insulin resistance, resistance to thyroid hormone, glucocorticoid resistance, hereditary resistance to vitamin D, and estrogen resistance. Throughout, the book's distinguished contributors not only summarize the clinical features of these and related disorders, but also illuminate their molecular bases. Hormone Resistance Syndromes provides an authoritative summary and standard reference for all those clinicians and researchers actively studying these mutations today and affords a unique opportunity to understand hormone action in normal physiology.

Key workers in vascular medicine and biology apply state-of-the-art techniques in cell and molecular biology to study the endothelial and vascular smooth muscle cells. The distinguished scientists and clinicians open a new area of endocrinology, which sees the vasculature and kidney as endocrine organs and sheds new light on the hormonal regulation of the cardiovascular system. They also add significantly to our current understanding of the autocrine, paracrine, and endocrine regulation of vascular function in health and in those vascular disease states that accompany diabetes mellitus, dyslipidemia, and hypertension. Endocrinology of the Vasculature is the first book to comprehensively and systematically explore the vasculature as an endocrine organ.

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.

Jacques Barzun, the noted Columbia University historian of ideas and culture, once described the feeling that some people experience when they come upon a new reference book. He wrote: "Hand over to one of us a new Dictionary, "Companion," or Guide, and our eyes first light up and then turn dreamy: we have seized the volume and are off, arm in arm with the guide i or companion. ..." The book now in your hands made my eyes light up. Thyroid Disorders with Cutaneous Manifestations is that kind of book. Heymann, who has been fascinated by this sometimes controversial subject for decades, has brought not only his own expertise, but that of many experts from the fields of the skin and the thyroid gland. Steven Jay Gould wrote about overlapping and nonoverlapping magisteria-this book demonstrates just how much important overlap there is. But it also covers the basics in such a way that dermatologists can find what they need to know about the thyroid and thyroidologists can find what they need to know about the skin. Thyroid Disorders with Cutaneous Manifestations falls neatly into the tra- tion of medical monographs that become standards. They fulfill the roles of gathering, digesting, and synthesizing current knowledge, and they do so in a way that review articles cannot approach and that the scientific literature is not designed to accomplish.

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."

This has been a year of substantial change for The Year in Endocrinology. The first change, though perhaps only a semantic one, nevertheless represents a landmark. Although last year's volume was designated as the first of an annual series, that seemed to me at the time merely a hope-a realistic hope, perhaps, but a hope, nevertheless. With the publication of this year's volume, however, this can accurately be said to be an annual series, one that we trust will fulfill a need and will therefore continue for years to come. Among other changes from last year's volume are some that were originally intended and others that were unintended. In the former category is the substitution of a chapter on water metabolism and vaso pressin, excellently prepared by Dr. Gary L. Robertson, for the chapter on paraendocrine syndromes that appeared last year. Chapters on these two topics will continue to appear on alternate years. Obviously, the non recurring chapter on a topic of special interest has also changed, and this year's comprises a comprehensive review of autoimmune endocrine dis ease by Drs. Jay Silverberg and Robert Volpe. The unexpected change results from the inability of Dr. Louis Avioli to continue as a member of the Editorial Board. Most fortunately, however, we have persuaded Dr. Charles R. Kleeman to join the Board and to be responsible for the chapter on the parathyroid gland and mineral metabolism. Dr. Kleeman has been assisted on the preparation of this chapter by his daughter, Dr."

In this era of proliferation of synthetic growth hormone in the marketplace, there is a parallel and accentuated interest in growth hormone in the scientific arena. Because many more people can be treated with available growth hormone, clinicians must be prepared to answer hard questions regarding appropriate therapeutic usage and their decisions should be based on substantiated research in growth hormone. In June 1987, an international group of basic and clinical inves tigators gathered in Tampa, Florida, to address these issues and to further explore the very nature of growth hormone. The presentations contained within this book bring together their most current and vital research related to growth hormone. Section I deals with an examination of the molecular and biochemical events which define the growth hormone process. In Section II the neuroregulation of growth hormone secretion is highlighted from contrasting perspectives. The third section emphasizes and defines methods of diagnosis of growth hormone deficiency states. Section IV reviews the physiology, biochemistry and molecular actions of growth hormone and somatomedin. Section V represents an assessment of growth hormone treatment for various disorders, and the sixth section expands current uses of growth hormone therapy as it evolves into the next decade. The symposium upon which this book is based proved to be a dynamic blending of scholarly interaction between basic and clinical scientists. I am indebted to the participants whose worthy contributions are reflected in these pages."

The German land of Hesse (Bundesland Hessen) is well known for its excellent wines (Rheinhessen), for its financial centre and for its airport (FrankfurtlMain). It is, unjustifiably, far less well known for its importance to thennoregulation. Within the small area of Bad Nauheim, Giessen and Marburg (in alphabetical order) a greater concentration of students of thenno regulation has been trained or worked or is working than probably in any other single area of Europe, if not the world. It is thus most appropriate to hold the Ninth International Symposium on the Pharmacology of Thennoregulation in Giessen, from August 7 to 12, 1994. The community of students of thennoregulation was extremely grateful that Professor Kurt Bruck and the lustus-Liebig-University of Giessen had extended this invitation. The same community was even more saddened that Kurt Bruck died on April 27, 1992 and thus could not participate in this event that had been planned to honour his achievements. As a small token of friendship and affection, the many friends of Kurt Bruck from all over the world who will participate in this event dedicate this symposium to the memory of Kurt Bruck. Another staunch friend, researcher of temperature regulation and supporter of this series of symposia died in October 1993: Professor Wilhelm Siegmund Feldberg. We feel fortunate to be able to start this volume with two brief infonnal and personal accounts of professors Bruck and Feldberg."

Physical activity exerts an important influence on the endocrine system, modulating synthesis and secretion of several hormones. Almost every organ and system in the body is affected by physical activity and exercise, mainly through the endocrine and neuroendocrine system. Mode, intensity, and duration of the exercise bout, age, gender and fitness level of the individual as well as environmental and psychological factors may affect the endocrine response to physical activity.

On the other hand, several hormones are able to influence physical performance and body composition. Thus, a bi-univocal interrelationship between exercise and hormones exists.

In this book new developments on metabolic and endocrine response to exercise are revised and introduce the "hot topic" of hormonal doping in sports. In the past decades, hormone abuse has become a widespread habit among professional and most of all and more frequently recreational athletes. A substantial part of this volume is devoted to the effects of exogenous hormones on performance. Anabolic steroids, growth hormone and erythropoietin properties, use and misuse in sports are widely described. Specific methods to detect hormone abuse are presented and discussed.

The contributors to this volume are well-known experts and dedicated researchers in the fields of sports medicine and endocrinology, endocrine physiology, pharmacology, and doping detection.

The purpose of this volume is to provide all professionals involved in sports medicine and endocrinology a state-of-the-art overview of the complex interactions between physical activity and the endocrine system and to focus on hormone abuse in sports at competitive and recreational level highlighting its negative consequences for long-term health."

Biological order in all living creatures is a fascinating phenomenon. Biochemical reactions and biophysical processes including enormous amount of various entities and structures are coordinated in space and time resulting in highly organized dynamic system with self control. The book consists of analysis of biophysical mechanism of long range interactions based on polar vibrations in microtubules and in actin filaments in cytoskeleton, spectral energy transfer in non-linear systems, excitation of a state far from the thermodynamic equilibrium in systems with energy supply, transition from incoherent to coherent vibration states, generation of endogenous electromagnetic field, information transfer between vibration systems, and interaction energy of vibration systems. The Frohlich vibration system is used."

Cell biology has made an appreciable impact on the evaluation of physiological and pathophysiological processes leading to a more detailed understanding of the signaling mechanisms by which cells communicate in vivo and in vitro and modify adaptively. By using cell culture models in addition to animal experiments we are now able to better define the overall and the selective potential of drugs. This book is designed to give information on the advantages and limitations and on new aspects and the meaning of cell culture models in pharmaceutical research.

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."

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.

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.