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 ............ ."

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.

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."

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.

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.

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.

Although physiological and anatomical evidence had clearly indicated for many years that the secretion of anterior pituitary hormones is under control by the central nervous system, it is only recently that the isolation and determination of structure of three hypo- thalamic hypophysiotropic hormones have been accomplished. This has brought the concept of neurohormonal control of adenohypophyseal function into precise biochemical and chemical terms. The relative ease of synthesis of TRH (thyrotropin-releasing hormone), LH-RH (luteinizing hormone-releasing hormone), somatostatin and their analogues has opened a new era in the field of endocri- nology and has led to a rapid expansion of our knowl- ge of the control of anterior pituitary function. The rapid evolution of fundamental and clinical research on hypothalamic hormones and the many potential clinical applications indicate the importance of inte- grating the knowledge gained in recent years. This is well illustrated in the Proceedings of the International Symposium on Hypothalamus and Endocrine Functions held in Quebec City on September 21-24th, 1975, which indi- cates that impressive progress has been made in large variety of aspects of hypothalamic hormone research.

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."

To obey the precepts of therapeutic rationality, we should avoid treating the "effect" when there is a way to attack the cause. But what is the cause of diabetes? Diabetes is a molecular disease, that is, a disease in which important cellular components are seriously impaired. Eventually, the activities or the products arising from the impairment find expression in various ways, finally culminating in the abnormalities of diabetes. How early is early enough to attempt to delay this sequence of events? What will provide us with the basis to explore ways and means of halting the progression of the pathological process? What are the new approaches for the treatment of early diabetes? The Fourth International Symposium on Early Diabetes, sponsored by the Diabetes Center of the New York Medical College, held in Algarve, Portugal in November 1978, from which this book evolved, attempted to answer some of these questions. A list of the participants, including their affiliations, will be found preceding the index. Rafael A. Camerini-Davalos v Acknowledgments To our sponsors, U.S.V. Pharmaceutical Corp., Pfizer Pharmaceuticals, Ames Company, Hoechst, Frankfurt; supporters, Boehringer, Manheim, Laboratoires Servier, Nordisk Laboratory, The Upjohn Company, Eli Lilly and Company, F. Hoffman La Roche; and contributors, Bayer A. G. Leverkusen, McNeil, Novo Research Institute, ICI Belgium, Hope for Diabetics Foundation, New York, we express our appreciation for the financial support which made possible the Fourth International Symposium on Early Diabetes. THE ORGANIZING COMMITTEE Rafael A. Camerini-Davalos, M.D.

During the last two decades, progress in steroid hormone research has resulted in the development of new approaches to contraception as well as diagnosis and treatment of endocrine disorders and cancers. Although significant advances have been made in the purification, characterization, immunochemistry and molecular biology of steroid receptors, the precise molecular mechanism of steroid hormone action has remained obscure. This book captures the detailed presentations made at the first conference on Steroid Receptors in Health and Disease held at Meadow Brook Hall, Oakland University in the fall of 1987. The purpose of this international con ference was to facilitate scientific exchange toward a better understand ing of the mode of action of steroid hormones. The scientific sessions consisted of poster presentations and state-of-the-art lectures, the latter of which make up this volume. The first chapter is meant to provide the reader with a more general background of the topics covered in the book, as well as to discuss certain theme-related issues that are either not yet well-established or accepted or are in the stage of infancy. It is hoped that this volume will serve as a useful treatise for students and investigators interested in basic and clinical aspects of biological regulation by steroid hormones. A task of this magnitude could not have been undertaken without the encouragement, advice and continued generous assistance of the members of the scientific committee. I am gratefully indebted to Drs."

Diabetes is a serious illness that can be managed If you're one of the 17 million Americans stricken with diabetes, it's time to strike back. The pH Miracle for Diabetes offers an easy-to-follow program that will help you take control of Type 1 or Type 2 diabetes. Showing you how you can maintain the proper alkaline environment your body needs, this all-natural plan can help you slow, stop, or even reverse the disease and the damage it causes-without the high doses of medication most diabetics use. In just twelve weeks, this groundbreaking program will revitalize your health and renew your spirit. Discover: * Which foods you should eat, which to avoid, and which are best for normalizing blood sugar levels * Dozens of delicious recipes to balance your body's pH * How to replace low-blood sugar quick fixes with healthy, effective alternatives * Guidelines for managing stress and exercising safely * How the "no pain, no gain" approach to fitness leads to overacidity and a rise in blood sugar * Why a cleanse-or "liquid feast"-is the most effective start to the pH eating plan and renewing your energy ...and much more.

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."

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."

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

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

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

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

Evidence accumulated over the past decade show that gonadal steroid hormones participate in an important way in the physiological and pa thophysiological regulation of the cardiovascular system. The hor monal profile appears to put males at a disadvantage biologically in terms of cardiovascular diseases. The incidence of hypertension is higher in men than in pre-monopausal women indicating an influence of gender on the hypertensive disease process. Males and females have equivalent cholesterol levels until puberty but males suffer an ex ponential increase in heart disease in their forties, while the female rise does not start until a decade later, after menopause. Animal and human studies provided ample evidence, that estrogens lower the levels of low density lipoproteins and keep high density lipoproteins elevated. These changes may be advantageous in the prevention of heart diesease. Co ronary artery atherosclerosis has been shown to be more pronounced in ovarectomized female monkeys as in intact females. Androgen, con versely, lowers the high density lipoproteins and elevates low density lipoproteins. Regarding blood pressure, it is well established that hypertension is more severe or develops more rapidly in male than fe male rats in several genetic forms of hypertension, and that gonadal steroid hormones are probably playing an important role in explaining this observation. Risk factors of human hypertension and coronary heart dies ease include menopause and ovarectomy."

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

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

Amenorrhea: A Case-Based Clinical Guide is a comprehensive review of the current knowledge regarding normal female reproductive physiology. Replete with interesting case vignettes and providing diagnostic algorithms and therapeutic strategies for amenorrhea, Amenorrhea: A Case-Based Clinical Guide is divided into three sections. The first section is composed of two chapters that provide a thorough review of basic science and clinical knowledge about the organ systems responsible for normal physiology of the menstrual cycle. The second section includes discussion about menstrual cycle disruption as it relates to hypothalamic-pituitary dysfunction, surgical and natural menopause, genetic defects, premature ovarian failure/insufficiency and the effects of caloric excess and restriction. The third section offers an update on the physiological effects of prolonged amenorrhea induced surgically or by hypothalamic dysfunction and also includes an original chapter that focuses solely on the impact of race and ethnicity on the prevalence and diagnosis of amenorrhea. Amenorrhea: A Case-Based Clinical Guide brings together chapters from renowned experts who offer state-of-the-art, clinically useful information in a case-based, reader-friendly fashion. This title will be a welcome addition to the bookshelves of all clinicians who practice in women's health settings.

Endocrinology, as a discipline, was a late arrival in the corpus of established subjects. Its growth in recent years has been prodigious, extending from mor phology to molecular levels. Most of the major endocrine glands were noted by the early anatomists, although the adrenal glands were not described until 1563 by Bartholomaeus Eustachius (1520-1574). On the other hand, elucidation of the function of these glands was extremely slow. Key work by A. A. Berthold (1849), although overlooked at the time, showed that comb atrophy in castrated fowl was prevented by testis transplantation. The idea that glands produced substances reach ing the bloodstream directly and not via excretory ducts stemmed from Claude Bernard, who first used the term internal secretion in 1855. The clinical observa tions of Thomas Addison at Guy's Hospital-published as a monograph in 1855 entitled The Constitutional and Local Effects of Disease of the Suprarenal Capsules -were seminal. However, the stimulus of this early research did not bring imme diate widespread further investigations. Upon the discovery of secretin in 1902, Bayliss and Starling considered the term "internal secretion" to be clumsy, and the term "hormone" was coined (from OQ UW-1 excite or arouse) and it was first used by Starling in his Croonian of 1905."

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

The discovery of mammalian nitric oxide (NO-) synthesis from I-ar- ginine has led to profound increases in our understanding of basic physiological and pathophysiological processes. This understanding has been achieved by major advances in several areas. Three major ni- tric oxide synthase (NOS) isoforms have been identified at the protein and gene level and their specific tissue localization has been linked to processes subject to regulation by NO-. The molecular basis for the di- verse effects of NO- on cell function has been shown to derive from its chemical reactivity with oxygen-containing species and both heme and non-heme iron-dependent enzymes. The potential regulation of heme- dependent enzymes such as cytochromes P450, guanylate cyclase, cy- clooxygenase, and mitochondrial cytochrome oxidase continues to emerge as a key area in NO- research. In addition, it has become clear that the expression of NOS isoforms and NO- release from cells is subject to regulation by sexual steroids and that, in tum, NO- has the potential to regulate steroid biosynthesis via inhibition of cytochromes P450 involved in steroidogenesis. These recent observations on interactions between the NO-/NOS and cytochrome P450/sexual steroid pathways have important implica- tions for understanding fundamental mechanisms involved in endocri- nological processes. They are also likely to lead to novel insights and novel therapeutic approaches for the management of pathophysiologi- cal conditions associated with alterations in sexual steroid hormones.