The use of cells for the treatment of a variety of diseases is no longer a dream. Today, blood transfusion, bone marrow transplantation, the use of ex vivo cultured skin in wound healing, and peripheral stern cell transplantation, including the ex vivo expansion of hematopoietic stern cells after high-dose chemo/radiation therapy, are routine. This high standard of knowledge and skills in cell transplantation might also re sult in tackling hitherto untreatable diseases. Organ transplantation is presently the only life-saving treatment for a variety of conditions. Important findings in cell and molecular biol ogy, the identification of hematopoietic, mesenchymal and neuronal stern cells, together with breakthroughs in the methodology for isolat ing, purifying, expanding, and storing human cells could make cellular therapy an alternative to organ transplantation in certain diseases within the next decade. Placental blood may be the source of choice in isolating naive progenitor cells for allogeneic transplantation. Immunotherapy is the most hopeful strategy to date for the treat ment of tumors resistant to chemotherapy, radiation therapy, or hor mone therapy. It includes the use of tumor-infiltrating lymphocytes, ex vivo activated memory T lymphocytes, and cell-based vaccines."

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.

This volume provides a brief resume of the history of testosterone research, from the early pioneers through to the most recent advances in the field. We discover how steroid hormones were first identified and how testosterone was shown to be essential for male development. Moving forward we explore how and where testosterone is produced, and how the body controls testosterone production. We then investigate the impact testosterone has on different body systems both during their development and function, and how perturbation of testosterone action is associated with disease. We complete our story with an exploration of the emerging roles of testosterone in clinical therapy, and the future potential for manipulation of the testosterone signaling system for human health benefit.

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."

Proceedings of the 2nd World Conference - Hormonal and Genetic Basis of Sexual Differentiation Disorders and Hot Topics in Endocrinology. The meeting took place at The Eden Roc Hotel in Miami Beach, Florida, 1/15/10 - 1/17-10. Endocrinology and more specifically, the area of sexual differentiation disorders is an evolving field of medicine. The diagnosis and treatment of Disorders of Sex Development (DSD) is multi-faceted.

The molecular era ushered in the cloning of the growth hormone (GH) gene and the production of unlimited amounts of GH through recombinant technology. The continuing momentum of research from basic science to clinical evaluation has brought unprecedented advances to the understanding of GH biology for the clinical endocrinologist. Growth Hormone Related Diseases and Therapy: A Molecular and Physiological Perspective for the Clinician distills all the new information of relevance to the endocrinologist over the last 20 years by offering five sections: physiology, molecular genetics, GH deficiency, acromegaly and pharmacotherapy. The first section on physiology focuses on GH action.

A review on the structure and function of the GH receptor is followed by a perspective on the regulatory role of ghrelin on GH secretion. The second section on genetics covers pituitary function and adenomas, including new and fascinating information on familial pituitary adenomas, their genotype and phenotype. The adult GH deficiency section spans the epidemiology and diagnosis of GH deficiency with a strong reminder for the clinician that the transition period represents a critical time of somatic maturation, which continues for years after cessation of liner growth. The section on acromegaly focuses on management, giving practical guides to the value of GH and IGF-1 measurements, the place of somatostatin analogues and of radiotherapy while reminding the reader as to why evaluating quality of life is an important part of management. Finally, the section on GH pharmacology takes the reader through innovative developments of long-acting GH formulations with some products on the threshold of clinical use. This section provides a balanced evidence based review of the effects of GH supplementation in aging and in sports where recent data indicates an enhancing effect on a selective aspect of performance. Growth Hormone Related Diseases and Therapy: A Molecular and Physiological Perspective for the Clinician integrates a wealth of information and will prove an invaluable reference for pediatric endocrinologists, adult endocrinologists, endocrine scientists and internists interested in the human biology of GH."

A panel of outstanding investigators surveys and explains the major cutting-edge methods used in thryroid receptor (TR) research and explains their practical experimental details. Described in step-by-step detail to ensure robust experimental results, the techniques presented cover a wide variety of key areas, including TR in development and knockout (mouse and Xenopus), transcriptional regulation by TRs in both cell-free systems and in living cells, and TR mutant analysis of patients. Additional methods provide powerful tools for the isolation of TR-regulated protein complexes, for studying the oncogene v-Erba in blood cell differentiation, and for target gene analysis in the brain. Microarray chip methods are also presented for analyzing the organs of transgenic mice to identify target genes in the liver.

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.

to the Endothelin System David M. Pollock ascular endothelial cells form a monolayer lining in all of the blood vessels of V the circulation. Initially, they were thought to function as a crude filter allow- ing nutrients from the blood stream to diffuse through to the underlying tissues without letting proteins or blood cells escape. We now know that endothelial cells are important regulators of circulatory function, due in large measure to their rec- ognized ability to synthesize and release many factors that regulate vascular smooth muscle tone. Endothelial-derived factors, including relaxing and contracting sub- stances such as prostacyclin, nitric oxide (NO), and endothelin (ET), have been identified as important contributors in the regulation of vascular tone. Endothe- lial cells have a highly active metabolic function and are involved in clearing a number of agents from circulating blood. In addition, they have the enzyme that inactivates bradykinin and converts angiotensin I into the very potent pressor agent, angiotensin II (Ang II). Endothelial cells also generate various proteins like von Willebrand's factor, tissue plasminogen activator, growth promoting factors and lipids such as platelet activating factor. It is now clear that in addition to the regu- lation of vascular tone and hemodynamics, endothelial cells playa critical role in regulating growth and proliferative processes, inflammation and hemostasis.

Stuart Handwerger, MD and a distinguished panel of clinicians and experts review the most significant recent developments in molecular and cellular biology, powerful advances that have produced new diagnostic methods and improved treatments for many pediatric endocrine diseases. Topics range from the growth hormone/prolactin/placental lactogen gene family and their regulation of growth, to steroid hormones, sexual development, and mineral corticoid action. Additional chapters examine the pathophysiology of insulin-dependent diabetes mellitus, the molecular genetics of thyroid cancer, the molecular basis of hypophosphatemic rickets, and inherited diabetes insipidus. Molecular and Cellular Pediatric Endocrinology offers today's clinicians and researchers not only the latest findings on endocrine diseases in their pediatric manifestations, but also highly practical insights into today's cutting-edge diagnostics, treatment strategies, and powerful new therapeutics.

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.

Most of the following chapters were presented as plenary lectures or symposium talks at the 1986 XXXth Congress of the International Union of Physiological Sciences in Vancouver, B.C. A distinguished international group of endocrinologists and physiologists have contributed up-to-date reviews of their particular fields. The early chapters are largely concerned with the brain and neuroendocrine mechanisms controlling the secretion of gonadotropin releasing hormone (GnRH) and its action on the anterior pitui- tary gland. Later chapters focus on the gonads themselves and the systemic and intrinsic hormones influencing the functional cytology of ovarian and testicular cells. Such comprehensive subjects as sex differentiation, puberty, placentation and parturition are also discussed authoritatively. According to Pfaff and Cohen and Arai et al., gonadal steroids, especially estrogen, exert multiple effects on certain hypothalamic and preoptic neurons, including growth, protein synthesis and electrical changes, which promote plasticity and facilitate synaptogenesis. The electrophysio- logy of the hypothalamic GnRH pulse generator in the rhesus monkey is reviewed more specifically by Knobil. In ovariectomized ewes, Clarke finds both positive and negative effects of estrogen on hypothalamic release of GnRH as well as on pituitary responsiveness to the peptide. Flerk6 et al.

In Cushing's Disease, leading authorities in the field offer a thorough review of the pathogenesis, diagnostic algorithm and treatment options for this complex disease. Beginning with a fascinating history of Cushing's disease that outlines its historical significance to both endocrinology and neurosurgery, the book goes onto to cover the full range of important issues, including the molecular pathogenesis of Cushing's, anatomic pathology, the diagnosis of Cushing's syndrome, the differential of pseudo-Cushing's syndromes, hypercortisolemia, surgical removal of the corticotroph adenoma, post-operative management and assessment of remission, radiotherapeutic options, and the exciting developments in medical therapy. In addition, the book also addresses Cushing's disease in the pediatric population, given that its clinical manifestations and impact on growth can be severe; silent corticotroph adenomas as a distinct clinical entity; diagnosis and management of Cushing's disease during pregnancy, bilateral adrenalectomy, and, finally, the long-term psychological manifestations of hypercortisolemia. Comprehensive and an invaluable addition the literature, Cushing's Disease is an essential reference for enhancing diagnosis and treatment of this debilitating disorder.

Ghrelin is a 28-amino acid acylated peptide predominantly produced by the stomach. It displays strong GH-releasing activity mediated by the hypothalamus-pituitary GH secretagogue (GHS)-receptors specific for synthetic GHS. Ghrelin also acts on other central and peripheral receptors and enables other actions including: stimulation of lactotroph and corticotroph secretion; food-intake; gastro-entero-pancreatic functions; metabolic; cardiovascular activity; and anti-proliferative effects. This volume aims to highlight the impact and function of the hormone ghrelin and provide insight to neuroendocrinologies and researchers interested in its molecular and clinical relevance.