The study of prenatal development provides many clues for understanding the physiology as well as the pathogeny of malformations and many diseases. I became interested in the analysis of human development as a young medical student more than 30 years ago, and I have stayed in this field all my life. In my studies, I always tried to compare the events of different disciplines such as genetics, anatomy, bio chemistry and physiology. I learned that the development of a structure is, under normal circumstances, strictly determined and that the development of structures always precedes their proper function. There are no changes in function without changes in structure. The life of every cell is genetically preprogrammed and the program may be modified by complicated interactions with environment. Recent progress in our knowledge is basicly related to technology. However, using all the tools of today's technology, we are still unable to understand the basic normal development. After almost thirty years of work, I am trying to present a subjective review of the development of the human endocrine glands. I am presenting an image emerging from my experience. I personally studied several hundred human embryos using mostly anatomical, histochemical and some biochemical techniques. I found much additional information in the literature."

Five years ago, a new system of classification of the various types of diabetes was proposed. This publication provides an inte grated picture of the latest information on the similarities and dissimilarites of two types of diabetes. It contains contributions from morphologists, physiologists, biochemists, immunologists, pathologists, geneticists, clinicians and epidemiologists. In the first section, the basis for the present classification and its limitations are discussed. In addition, there is a discussion of gestational diabetes and heterogeneity of some sub-classes of diabetes. The next section deals with genetics and immunology. The third section discusses abnormalities of insulin secretion and act ion on both the receptor and post . . . receptor levels. The role of gastrointestinal peptides in Type I and Type II diabetes is also considered. In the last section, both types of diabetes are compared with respect to diabetic complications. The closing sec tion summarizes the present status and offers a stimulating view of future development. We hope that this book will be a useful source of information for both researchers and practicing clinicians. M. Vranic G. steiner C. H. Hollenberg v ACKNOWLEDGEMENTS The symposium from which this volume arose (June 28-29, 1984) was organized by the Banting and Best Diabetes Centre, University of Toronto. We would like to express our appreciation to the following sponsors: Ames Educational Institute, Ayerst Laboratories, Becton Dickinson Canada Inc. , Canadian Soft Drink Association, Connaught Laboratories Limited, Connaught Novo Ltd. , Eli Lilly Canada Inc.

The Twelfth Annual Midwest Conference on Endocrinology and Metabolism continued the tradition of selecting a topic of inter- est to a wide variety of scientists with interests in biology. The conference an "Hormones and Energy Metabolism" was dedicated appro- priately to Dr. Samuel A. Brody, a leader in research in this field as described by Professor Johnson in this volume. A particular feature of these conferences has been the large proportion of time devoted to discussion of each paper and the pub- lished proceedings have included edited transcripts of these dis- cussions. Unfortunately, due to malfunction of the recording sys- tem, major portians of the discussions were lost and, despite much effort, insufficient was salvageable tobe meaningful and helpful. Consequently, the editors decided to omit completely the discus- sions except for a communication provided by Dr. Woodside. We again express our appreciation to the staff of Conferences and Short Courses, University of r~issouri-Columbia Extension Divi- sion and especially to Dr. John Swanson who helped organize the multitude of administrative details; to ~lrs. Linda Bennett, CPS, for her continuing excellent efforts in typing the manuscripts for publication; and particularly to the sponsors, without whom there would have been no conference. Ralph R. Anderson f*1urray Heimberg David r~. Klachko vii CONTENTS Dedication: Dr. Samuel A. Brody xi Brody Memorial Lecture: Same Aspects of Energy Coupling by Mitochondria ...

This book contains contributions presented at the last of the Alcuin Symposia, held in April 2000, as a Festschrift to honour Prof. Axel Wollmer on the occasion of his retirement from the Rheinisch-Westfalische Technische Hochschule (RWTH) Aachen. The Alcuin Symposia were initially held alternatively in York and Aachen, in recent years in Aachen only, as joint workshops on insulin between the groups of Prof. Guy Dodson in York and the groups of Profs Dietrich Brandenburg and Axel Wollmer in Aachen. The Symposium was named after Alcuin, an Anglo-Latin poet, educator and cleric from York, who was invited to join the court of Charlemagne at Aachen. Alcuin's first 50 years were spent in Yorkshire, were he was first a pupil, later headmaster of the cathedral school of York, the most renowned of its day. Charlemagne was gathering at Aachen the leading Irish, English and Italian scholars of the age. Alcuin was appointed head of the Palatine school, where Charlemagne himself, his family, his friends, and his friends's sons were taught. Alcuin introduced the traditions of Anglo-Saxon humanism into Western Europe and was the foremost scholar of the revival of learning known as the Carolingian Renaissance. He also promoted the use of the beautiful Carolingian minuscule script, the ancestor of modern Roman typefaces."

Almost every aspect of energy and nutrient metabolism is altered by hormonal and other physiological changes during pregnancy and lactation. While it is evident that hormonal adjustments affect nutrient requirements, these are rarely considered when nutrient recommen dations are made for pregnant or lactating women, and often neglected during evaluation of nutritional status. In addition, changes in nutrient metabolism during the stages of pregnancy and oflactation are usually considered separately, while in reality events during pregnancy can have a major influence on nutritional status and nutrient requirements during lactation. The purpose of this volume is to describe changes in the metabolism of important nutrients during pregnancy and lactation, including the physiological basis for these changes and their implications for nutrient requirements and assessment. Authors have considered such issues as inter-relationships between endocrine changes and nutrient metabolism at the tissue, cellular and molecular level; alterations in nutrient binding proteins; the efficiency of nutrient absorp tion and retention; and the impact on maternal as well as fetal nutritional status. Another unique aspect of this book is the focus on pregnancy and lactation as a continuum."

Recent progress in recombinant DNA technology and the availability of a number of nonpeptide subtype-specific receptor antagonists and of specific antibodies to components of prorenin-renin-angiotensin system (PRAS) have led to rapid advances in the under standing of the multifaceted role of angiotensin II, classically known as a peptide hormone of cardiovascular homeostasis. Accumulating evidence sug responsible for the regulation gests that, in addition to its role in salt and water metabolism, PRAS may control other physiological functions including neurosecretion, cellular proliferation, hypertrophy and/or differentiation, angiogenesis and gonadal function. At the same time, it is becoming evident that the specialized functions of endocrine glands are not only regulated by trophic hormones but also by locally produced paracrine/autocrine factors. The concept is emerging that tissue PRAS is one such locally active regulatory system. With more and more reproductive and endocrine organs being added to the list of tissues that contain a local tissue PRAS, questions are being raised by the reproductive biologists and endocrinologists as to the role of such systems in the tissues of their interest. On the other hand, the cardiovascular and renovascular physiologists are wondering about the relevance of PRAS in various peripheral tissues compared to those of the classical cardiovascular organs. It appeared, therefore, that the time was ripe for a meeting to consider a merger of interest in these two important but heretofore distinct areas of physiology."

This volume presents the proceedings of a symposium on the "Control of the thyroid gland~ regulation of its normal function and growth," held at the National Insti- tutes of Health, Bethesda, Maryland on March 20 and 21, 1989. Our motivation for the organization of this symposium was the fast development in re cent years of our understan- ding of the regulation of the thyroid - and the progress in the field of cell regulation in general - which have led to profound modifications of our view of the control of the thyroid. Not so many years aga the thyroid was thought to be controlled by one regulator, the pituitary TSH, which with cyclic AMP in the role of second messen- ger was considered to express or regulate most or all processes in the gland. In the last several years it has been weIl documented that hormones other than TSH and various growth factors are involved in thyroid growth con- trol and it has been increasingly clear that several hor- mones and neurogenic agents are obligate participants in the regulation of thyroid function. In addition, not only new agonists acting on the thyroid have been revealed, but new transducer and second messenger systems have been discovered. In particular the interest has been - and is- focused on the signals emanating from the hydrolysis of the inositol phospholipids, comprising the inositol tris- phosphate/Ca2~ pathway and the diacylglycerol/protein kinase C pathway.

For out of olde hokes, in good feyth, Cometh all this newe science that men lere. Geoffrey Chaucer The Parliament of Fowls During the past two decades knowledge of the human menstrual cycle and of normal and abnormal reproduc- tive function has increased at a dramatic rate. As rec- ognized in this volume, this explosion of knowledge is due in large measure to the development of radio- immunoassays for the measurement of the minute quantities of reproductive hormones found in the cir- culation. Yet the foundations for the many recent developments were laid well in advance. The concepts and hypotheses tested were often suggested even be- fore the hormones involved were identified and iso- lated. A consideration of the historic aspects of re- search in this field places recent research in the appropriate perspective. Moreover, as presented by Drs. vii viii FOREWORD Gruhn and Kazer, the history of progress in this field makes fascinating reading. A review of the history of reproductive endocri- nology should be required reading for all students of the subject and reproductive endocrinologists in train- ing. Dr. Griff T. Ross, a noted reproductive endocri- nologist, often instructed his students that every hy- pothesis he tested could be found in some form in the publications of previous scientists. The answers to present and future questions are often hidden in the lessons of the past.

This work, Essential Endocrinology: A Primer for Nonspecialists, is written with dual purposes in mind: first, to provide a framework of basic endocrinology and diabetology to the medical student, and second, to provide a quick, con cise, and handy "guide" to the junior residents in their early years of training who wish to obtain a working knowledge about endocrine disorders that affect their patients. One of the outstanding advantages of being a teacher of en docrinology to students and junior residents is that it bestows a perspective from a unique vantage point. Books written for the junior members of our profession have suffered from extremes of caliber, ranging from excellence beyond their comprehension to insufferable mediocrity. Textbooks in en docrinology that are simple enough to cover the principles of that speciality and yet comprehensive enough without treading into controversial quicksand are few and far between. This book is aimed at filling that gap and is written with no other criterion than simplifying a complex subject matter. From this touchstone, the work has never really departed. A decade of experience as a teacher and physician in the field of endo crinologyhas impressed on me that the process of "simplification" rests on four basic principles: an understanding of endocrine concepts, the application of these concepts to the understanding of diseases, the transference of knowl edge to clinical situations, and the integration of the patient with the labo ratory, the ultimate testing ground where clinical diagnoses stand or fall."

The disorders induced by iodine deficiency affect at least one billion people. Because ofits effects on brain development, iodinedeficiency is the single most preventable cause of mental retardation in the world. Therefore, the United Nations and the Heads of State of almost all the world's countries represented at the Summit for Children in 1990 adopted resolutions to eradicate the disorders induced by iodine deficiency (IDD) by the year 2000. For geological and socio-economic reasons, most of the populations affected by iodine deficiency disorders live in isolated and usually mountainous areas, in pre industrialized parts ofthe world. The problem of iodine deficiency in Europe has been greatly underestimated in the last decades. After the remarkable studies on the effects of iodine deficiency and their prevention and correction in Switzerland, IDD was generally considered no longer a significant public health problem in Europe. However, surveys carried out in the early 1980's under the auspices of the European Thyroid Association, clearly demonstrated the persistence of moderately or even severely affected areas. These surveys also highlighted the lack ofinformation about large parts ofEurope, especially its eastern part. It is only quite recently, following major changes in international relations and thanks to the support of UNICEF, WHO, the International Council for the Control of Iodine Deficiency Disorders and the European Thyroid Association, that more extensive surveys have been conducted in several parts of Europe hitherto almost unexplored. These surveys showed that most European countries were iodine deficient."

Diabetic nephropathy is a tragic illness. Its often insidious onset in the insulin dependent (type I) diabetic, typically a young adult, heralds the last act in the course of a disease that will increasingly become the dominant preoccupation in the patient's shortened life. For most type II diabetics, the beginning of clinical renal insufficiency is but a phase in a continuous deterioration that affects the integrity ofjob, marriage, and family. The nephropathic diabetic is hypertensive, has worsening retinopathy, and more often than not, is also plagued by peripheral vascular insufficiency, heart disease, gastrointestinal malfunction, and deepening depression. Until the 1980's, few type I diabetics who became uremic (because ofdiabetic nephropathy) lived for more than two years. Hardly any attained true rehabilitation. This dismal prognosis is changing substantially for the better. Research in diabetes has resulted in striking advances at both ends of the type I diabetic's natural history. In one exciting clinical trial now underway in London, Ontario, halfofchildhood diabetics treated with cyclosporine within six weeks of onset evince"permanent" disappearanceofhyperglycemia and the need for insulin. At the otherendofthe natural historyofdiabetes for the nephropathic patientwith worsening eye disease (renal-retinal syndrome), who receives a kidney transplant, patient and graft survival, two years after cadaveric kidney transplantation in type I diabetics is now equal to that of the nondiabetic."

It has been ten years since the National Hormone and Pituitary Program (then called the National Pituitary Agency) sponsored a symposium on human growth hormone (hGH). Numerous advances have occurred during this period. This book does not attempt to summarize past achievements. Rather, it deals with the contemporary issues in hGH research. A discussion of the present state of the art, of necessity, includes a review of the past. Some of the topics herein discussed include the following: 1. Growth hormone releasing factor (GRF). In 1973, the growth hormone inhibitory factor (somatostatin) had recently been discovered. The search for a releasing factor in humans led to its discovery not in the pituitary but in a pancreatic tumor that secreted growth hormone. The advances are discussed in this book. The current hope is that GRF will eventually become an effective therapeutic agent for idiopathic hypopituitarism in childhood and adolescence. 2. Biosynthesis of hGR by recombinant DNA technology. Current advances are discussed. Although hGH is not yet an approved drug, it will eventually become one. This will broaden our horizons in terms of hGH effectiveness in disorders other than hypopituitary dwarfism. The current experience with this type of hGH in both the Vnited States and Europe is reviewed by several authors.

Proceedings of the First International Meeting of the Pancreatic Islet Study Group held in the Alicante, Spain, November 25-28 1994

Proceedings of the Third Hans Selye Symposium on Neuroendocrinology and Stress held in Budapest, Hungary, August 17-21, 1992.

The discovery of hypothalamic factors that inhibited growth hormone secretion and of pancreatic factors that inhibited insulin secretion were the first clues to the existence of somatostatin. During the course of efforts to isolate growth hormone releasing factor, Krulich, McCann and Dhariwal found that hypothalamic extracts contained a potent inhibitor of growth hormone secretion. They postulated that growth hormone secretion was under a dual control system, one inhibitory and the other excitatory (I) . In studies being carried out at about the same time, Hellman and Lernmark found a factor in pancreatic extracts that inhibited insulin secretion (2). They postulated that islet cell function was regulated by local hormonal factors. With the isolation and chemical characterization of somatostatin by Brazeau and colleagues (3), and the availability of relatively large amounts of the synthetic peptide for research, it has been possible to demonstrate that both predictions were true. Subsequent work revealed that somatostatin, as initially isolated (somatostatin 14), was but one of several related peptides, part of a multigene family, with tissue specific processing. Many of the details of biosynthesis and genetic control have been worked out, and this molecule has served many workers as a model gut-brain peptide for detailed study. The peptides are widely distributed in tissues and exert an extraordinary range of effects on most glandular secretions, both internal and external.

In the forty years since melatonin's isolation and characterization, a large and multifaceted database has accrued. This book documents the diverse research contributions of most of the major laboratories in the field of melatonin research, as presented in a special conference to mark the 40 year anniversary of the isolation and chemical identification of this hormone. In addition, many chapters by younger scientists provide an exciting glimpse of where melatonin research is heading in the future.

Male Reproductive Function gives an up-to-date review on the physiology and disease processes associated with the male reproductive system. The first few chapters describe the regulation of the functions of the testis and the integration of its components: germ cells, Sertoli cells and Leydig cells. This is followed by a description of puberty and aging, and the disorders or dysfunction that may be associated with these physiological processes. Discussions on the current methods for the diagnosis and treatment of male hypogonadism, male infertility and male sexual dysfunction follow, with detailed descriptions of types of androgen replacement and the benefits and risks of such treatment. The book concludes with the development of male contraception and the possible influence of the environment on the male reproductive system. Male Reproductive Function represents a conglomeration of the efforts of experts in andrology from all over the world, both in basic cellular/molecular biology as well as in clinical science and practice. This book is suitable for endocrinologists, urologists, general internists, gynecologists and other students in the field of male reproduction.

"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 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.

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 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 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."