It is a truism that as we age there are a number of underlying physiological changes conspiring to alter our level of behavioral and cognitive function ing. Despite the inherent interrelatedness of these behavioral and cognitive changes, all too often the papers we read confine themselves to specific, isolated components of the developing process. Although exceptions nat urally exist, we believe that these exceptions should become rule. Although an integrated approach is important in all areas of adult devel opment, it is perhaps particularly germane in the study of atypical aging. Here, changes in overall functioning can occur in rapid succession, with the synchrony of decline between different subprocesses making it difficult to factor changes in one process from changes in another. For example, because changes in cognitive functioning co-occur with other dramatic changes in (motoric) response capacities, it is unclear how one can effec tively study changes in the ability to cognize independent of changes in the very mechanisms (ability to execute motor sequences) so often used to index cognitive performance."

It has been my privilege and pleasure during the past half century to participate in the unfolding of present-day concepts of the mammalian female reproductive cycles. When the studies recorded here began in the late 1930s it was already established that cyclic ovarian function is governed by gonadotropic secretions from the anterior pituitary gland, the "conductor of the endrocrine orchestra," and that in turn this activity is importantly dependent in some way upon secretion of estro gens and progesterone by the ovaries. Although a role of the nervous system was recognized for the reflex-like induction of ovulation in rabbits and cats and the in duction of pseudopregnancy in rats and mice, and although there was even some evidence of neural participation in ovulation in rats, a major central neural role in the female cycle of most species was not apparent. Gonadotropic fractions of pitui tary extracts having distinct follicle-stimulating and luteinizing activities in test ani mals had been obtained, and these respective effects had been fairly well charac terized. Prolactin was well known for its lactogenic activity, but its luteotropic role in rats and mice had yet to be revealed. The molecular structure of the several estro gens and progesterone was known, and they were readily available as synthetic pro ducts. The broad concept of ovarian-pituitary reciprocity appeared to be an accept able explanation of the female cycle, with the ovary in control through the rhythmic rise and fall in secretion of follicular estrogen.

Research in diabetes has accelerated in two areas, both of which are being reviewed in CTMI. The first is the use of a variety of animal models; the second is basic research in human investigation, islet cell antigens, and mapping of genes as sociated with susceptibility to disease. Dr. Thomas Dyrberg accepted editorial responsibility for this volume, which covers the first area. A second book, to be published later in the year, is edited by Drs. Brekkeskov and Hansen (CTMI 164, see page VI for contents). Although the contributors to both volumes represent the international scientific community, the editors are from the Hagedorn Research Laboratory in Denmark. Work at this institute and the Steno Memorial Hospital has been dedicated to research in diabetes for decades, and the insti tutions were appointed WHO Collaborating Centres for Re search and Training on the Pathogenesis of Diabetes Mellitus in 1983. It is worth noting that while addressing the hypothesis of the role of class II major histocompatibility glycoproteins in autoimmune diabetes (insulin-dependent diabetes, IDDM) a number of investigators established animal models in which class II molecules were expressed under the control of the rat insulin promoter. While generating interesting information on 100M, the finding of immunologic tolerance in such transgenic mice has attracted the attention of several basic immunologic laboratories for quite different reasons. Thus, we are reminded again of the Pasteur dictum that "chance favors the prepared mind. " Michael B. A. Oldstone, M. D."

The account of "neonatal sterilization" is the story of the advocates of direct effect of steroids on the gonads and those who believed in the indirect influence, mediated through the hypothalamus and/or the pituitary gland. As often happens in biology, both convictions represent the same image seen from different perspectives. Prof DC Johnson (Kansas City, KS) reminisced the beginning of the story in a letter to me. I am paraphrasing parts of the letter with his permission. "As a starting point we could pick the life-long research of Emil Steinach ... " Steinach recognized the influence of testes on the develop ment of accessory sex organs in 1894, described virilization of females and feminization of males in 1913, and identified the controlling influence of the hypophysis on the gonads in 1928. He reviewed his work in a book Sex and Life, Forty Years of Biological and Medical Experience (E Steinach and L Loebe!; Faber and Faber, London, 1940). He got on the wrong road in later years and that is the reason everybody seems to have forgotten him. He presented his hypothesis that estrogen has a direct effect upon the testes, i. e. hormone antagonism, at the 1st International Congress on Sex Research in 1926.

This monograph represents the first comprehensive review of hormones in human amniotic fluid and includes data published up to and including 1980. Recently, more extensive use of amniocentesis for prenatal diagnosis and evaluation of fetal lung maturation has shown that amniotic fluid hormone measurements can aid in the diagnosis of fetal and placental abnormalities. The material is presented in two main sections dealing with steroid and protein hormones. The methods of identification and quantitation are delineated, and the findings are discussed in relation to the clinical conditions. In addition, particular attention has been directed towards up-to-date review of the sources, metabolism and transfer of human amniotic fluid hormones. The review is intended to serve the needs of clinicians, basic scientists and students, providing detailed information on human amniotic fluid hormones in order to improve patient care and indicate possibilities for further investigations. Ttibingen, January 1982 A.E. Schindler Contents Introduction A. 1 Origin of Human Amniotic Fluid . 2 B. C. Origin and Regulation of Steroids in Human Amniotic Fluid . 5 D. Methods of Isolation and Identification of Steroids in Human Amniotic Fluid 6 I. C , C , and C Steroids . 6 30 29 28 II. C Steroids 6 27 1. Cholesterol 6 2. Cholestanol . 6 3. ,::l7 -Cholestenol and ,::l8 -Cholestenol. 6 4. 7-Dehydrocholesterol and Desmosterol . 6 ,::l5_C Steroids. III. 7 21 1. Pregnenolone 7 2. 16cx-H ydroxypregnenolone. 7 3. 17cx-Hydroxypregnenolone.

Endocrinology and Metabolism: Progress in Research and Clinical Prac tice is a new series that has been designed to present timely, critical reviews of constantly evolving fields; to provide practical and up-to-date guidance in the solution of pertinent clinical problems; to offer an alterna tive to the laborious search of the literature (and the often frustrating reading of highly technical articles); and to translate the language of the laboratory into that of the practice of medicine. We think that this volume and those to come will prove useful to physi cians (and to physicians in training), as well as to investigators in a wide variety of specialties; in short, to anyone who seeks answers to questions in endocrinology and metabolism. The first chapter of this volume could well serve as a general introduc tion to the entire series. It points out how our growing understanding of the molecular basis of biologic communication has led to the discovery of a growing number of clinical syndromes, as well as to the realization that phenotypically similar diseases may have radically different pathogenetic mechanisms and thus may require radically different therapeutic strata gems."

Dr. Raymond Pederson, Dr. Jill Dryburgh and I commenced work on GIP in 1968, when, with the generous help of Professor Viktor Mutt and Professor Erik Jorpes of the Karolinska Inst, itute, Stockholm, we were able to establish that there existed an inhibitory material for acid secretion in cholecystokinin-pancreozymin prepara tions. Once the physiological evidence for the inhibitor was established it seemed appropriate to seek help in its isolation. Dr. J. Dryburgh and Dr. R. Pederson were left to bioassay fractions in Vancouver whilst I enjoyed the company of Professor Mutt at the Karolinska for one year, as a Medical Research Council of Canada Visiting Scientist. Purification of the inhibitory factor proceeded rapidly due, in no small measure, to Professor Mutt's untirmg efforts on my behalf. Later that year, Dr. Dryburgh joined us in Stockholm to begin the sequence work on GIP. This was completed late in 1970 in Vancouver. In Stockholm in June 1970, I met a fellow Canadian Dr. John Dupre (McGill University) at a cocktail party who kept commenting about the possibility of GIP being an insulinotropic hormone, the "incretin" of earlier days. At that time, gastrointestinal physiologist as I was, I did not recognize the importance of his comment. This became apparent two or three years later when Dr. Dupre demonstrated that GIP was insulinotropic in man. In 1972, Maryanne Kuzio and Dr."

Contraceptives have always provided ground for controversy. This book describes and discusses latest findings concerning the advantages as well as hazard and risk factors of contraception. The clinical impact of oral contraceptives on metabolism is particularly highlighted. In addition, behavioral methods, intrauterine devices, implants and modern approaches in animal and clinical research in the field of immunization against pregnancy are considered. Last, but not least, the book summarizes the complex ethical, religious and political aspects of family planning and contraception.

It is about 15 years since the first presentation on uteroglobin was given to a group of developmental biologists, reproductive physiologists, and geneticists who had gathered in November 1966 at Konstanz (Germany). In the following decade so much knowledge was accumulated that a special symposium seemed appropriate. This was organized as a satellite symposium to the International Congress of Endocrinology at Hamburg and brought together 50 scientists at Aachen. These scientists, working in the field of pro teins and steroids, in early pregnancy, recognized the impact of what had been reported, and many of them later agreed to contribute to this booN. and thus to present their research d, ta available until December 1980. The present volume covers a relatively broad spectrum of data and observations which shed some light on preimplantational embryonic life and on the supports and obstacles provided by the maternal organism with respect to final accomplishment of normal im plantation and establishment of pregnancy. The book will serve both as a textbook and as a scientific dictionary for Ph.D. students, postdoctoral fellows and advanced scientists working in this area. The course of early pregnancy depends very much on a proper balance of steroid hor mones, and the induction of protein synthesis by steroid hormones is one of the well known fundamental processes in cellular differentiation and embryonic development."

The epididymis has great significance in the reproductive biology of the male and it is gaining recognition as an organ worthy of study in its own right - where the secretory and absorptive activities of one tissue (the epithelium) profoundly modify the function of another (the spermatozoon). Apart from cases of epididymal agenesis or physical blockage, however, it is not yet known to what extent mal functions of the epididymis contribute to "unexplained" male infer tility, but its importance as a target for antifertility agents in the male is now widely appreciated. This monograph evolved from two lectures on epididymal func tion given at the National Research Institute for Family Planning, Beijing and the Sichuan Provincial Family Planning Research Insti tute, Chengdu, China in 1983. In order to stress for this audience the central importance of the epididymis in fertilisation, and so highlight its potential for attack by antifertility agents, the talks attempted to put the epididymis in reproductive perspective by stressing the func tional development of the sperm cells during their sojourn in the epididymis, rather than merely listing the changes observed in them."

Sixteen years is a long time, not only in human life but also in the rapid history of contemporary endocrinology. Since the publication of the first edition of this monograph, numerous new lines of research and discoveries have greatly contrib- uted to our knowledge of the physiological and pathological regulation of aldos- terone biosynthesis in man and animals. The first reports about a sensitive ra- dioimmunoassay for plasma aldosterone and about a preparation of dispersed zona glomerulosa cells were published in 1970 (Mayes et al. 1970; Haning et al. 1970). These two developments alone turned out to have a tremendous impact on research in aldosterone physiology (for reviews see Coghlan et al. 1979b; J. F. Tait et al. 1980b). In 1971, atrial natriuretic peptides, somatostatin, and the precursor molecule of ACTH had not yet been discovered. Angiotensin antagonists and con- verting-enzyme inhibitors were not yet available. The clinical syndrome of hypo- reninemic hypo aldosteronism was unknown. The possible roles of prostaglandins and dopamine in the control of aldosterone pwduction had not been considered. Cyclic AMP was then the only substance with a clearly established second-mes- senger function.

A cutting-edge review of how derangements in the hormonal and growth factor mechanisms controlling normal mammary development lead to breast cancer. Drawing on the multidisciplinary expertise of leading authorities, the book highlights the roles of oncogenes and tumor suppressor genes, spelling out the importance of autocrine/paracrine loops (e.g., stromal epithelial interactions) in supporting breast cancer cell proliferation and the progression to hormone independence. The book's many prominent contributors also illuminate significant recent advances in the biochemistry and physiology of hormone receptors and review the state-of -the-art in the endocrine therapy of breast cancer. Endocrinology of Breast Cancer provides a unique integrated overview of the most significant basic and clinical developments concerning the hormonal aspects of breast cancer.

Since the first description of Philadelphia chromosome-negative chronic myeloproliferative disorders more than 100 years ago, the diagnosis and therapy of these conditions have been based primarily on clinical experience and judgement. Until recently very little was known about the molecular basis of these diseases. In order to spark research in this area basic scientists and clinicians from various parts of the world have contributed to this volume, the first of its kind to put together the current knowledge. The book deals with the new WHO classification of these disorders, novel aspects of diagnostic pathology, the search for disease-relevant genes utilizing molecular biology and proteomic techniques, the description of the roles of PVR-1 and VHL genes for polycythemias and the discovery of the gene mutation responsible for the idiopathic hypereosinophilic syndrome. A chapter on anagrelide, an important novel drug for the treatment of primary thrombocythemia, is included.

Describes the ability of a series of endocrine-derived compounds, i.e. CHRH, LHRH, somatostatin, anti-androgens, and aromatase inhibitors to exert a direct anti-neoplastic activity or to potentiate the activity of traditional chemotherapeutic agents on neuroendocrine and solid tumors. In addition, a new class of potent GH-releasers, GSHs/Ghrelin, endowed with important endocrine and extra-endcocrine action, is presented. Therefore, in addition to traditional chemotherapy, characterized by high toxicity and non-selective action on tumoral cells, the reader can find a new approach with more selective, less cytotoxic endocrine derived compounds.

In 2001 we wrote the book Graves' Disease: A Practical Guide (McFarland), which described the causes, diagnosis, treatment and disease course of Graves' disease and other hyperthyroid disorders, such as toxic multinodular goiter, thyroiditis, resistance to thyroid hormone, and hyperthyroidism caused by medications and genetic mutations. The present work continues the above but focuses on subsequent advances in disease pathology, including discoveries regarding the genetic, immune system, and environmental factors that lead to hyperthyroid disorders; new guidelines for conventional treatment; and alternative and complementary medical therapies are included. Additional sections describe special circumstances such as hyperthyroidism in pregnancy and in children, and transient hyperthyroidism in the newborn.

This book was written at the invitation of Dr. H. GOTZE of Springer-Verlag for the series "Monographs in Endocrinology." It is not a comprehensive account of the prostaglandins but has been writ ten with a deliberate emphasis upon those aspects of the field in which I am particularly interested and to which, in some cases, I have made a contribution. I am grateful to Miss E. PFISTERER and her colleagues of Springer Verlag for their excellent work. I should also like to thank my wife without whose patience, encouragement and help this book would never have been completed. Finally this is an appropriate time to express my sincere gratitude to those scientists who over the years have given me samples of prostaglandins-namely Professors S.BERGSTROM and B.SAMUELSSON of the Karolinska Institute, Stockholm, Professor D. A. VAN DORP of the Unilever Research Laboratories, Vlaardingen and Dr. J. E. PIlm of the Upjohn Company, Kalamazoo. Without their help work in this field would have been extremely difficult."

The building of conceptual models is an inherent part of our interaction with the world, and the foundation of scientific investigation. Scientists often perform the processes of modelling subconsciously, unaware of the scope and significance of this activity, and the techniques available to assist in the description and testing of their ideas. Mathematics has three important contributions to make in biological modelling: (1) it provides unambiguous languages for expressing relationships at both qualitative and quantitative levels of observation; (2) it allows effective analysis and prediction of model behaviour, and can thereby organize experimental effort productively; (3) it offers rigorous methods of testing hypotheses by comparing models with experimental data; by providing a means of objectively excluding unsuitable concepts, the development of ideas is given a sound experimental basis. Many modern mathematical techniques can be exploited only with the aid of computers. These machines not only provide increased speed and accuracy in determining the consequences of model assumptions, but also greatly extend the range of problems which can be explored. The impact of computers in the biological sciences has been widespread and revolutionary, and will continue to be so.

Recent advances in molecular biology have provided new dimensions in the study of the reproductive system. There has been major progress in our understanding of the molecular mechanisms of hormone action in the past few' years. The symposium on "Molecular Basis of Reproductive Endocrinology" was organized to highlight new research findings on the regulation of the hypothalamic-pituitary-gonadal axis. The emphasis of the symposium was on physiological questions answered by the molecular biology approach. Studies on the functional relevance of gonadotropin releasing hormone and LH and FSH gene expression were presented, together with research on the molecular biology of ovarian and testicular steroidogenic enzymes and protein hormones. Also, several novel aspects of hormone gene expression in placental tissues were reviewed. The symposium was held July 25 to 26, 1991, immediately prior to the 24th Annual Meeting of the Society for the Study of Reproduction, on the campus of the University of British Columbia in Vancouver. Serono Symposia, USA generously financed and coordinated the meeting. We are indebted to Dr. Bruce K. Burnett and Dr. L. Lisa Kern for their professional assistance in the organization of the symposium. We would also like to thank Drs. Victor Gomel, Basil Ho Yuen, and John Challis, who served as session moderators. Most of all, we truly appreciate the efforts of all the invited speakers, poster presenters, and discussants in making this a memorable event as the largest one-day meeting of the Serono Symposia USA, series.

The findings of immunogenetic linkages, autoantibodies including autoislet cell and autoinsulin antibodies-and viruses in diabetes has attracted increasing interest among immunologists, virologists, geneticists and clinicians. To gather together the recent avalanche ef new and exciting information emerging in this area, Current Topics in Microbiology and Immunology has put together two volumes on this subject. The first volume, CTMI 156, (see page VI for contents) provided data on the animal models and experimental approaches currently employed to evaluate both the autoimmune and virologic factors contributing to the causation and patho genesis of diabetes. The second is this current volume. It is edited by Drs. BAEKKESKOV and HANSEN and focuses on current knowledge in human diabetes. This volume on human diabetes contains ten chapters from leading researchers. The book is arranged in two components. The first part critically analyzes the genes in man that playa role in susceptibility to insulin dependent diabetes mellitus (IDDM). The second segment analyzes the role(s) that various environ mental factors play in IDDM and provides data on the autoantigens, aberrant immune responses, and the role of cytokines and free radicals in the pathogenesis of diabetes. La Jolla, California MICHAEL B. A. OLDSTONE, M.D. This collection of studies was conceived as part of a two-volume review of the immunology of diabetes. The contents of Volume 156, which forms part 1, are listed below."

For many years now I have devoted much of my time to lecturing and writing on the subject of cardiovascular disease (CVD). In this book I have outlined the development of my approach to this problem. I must admit that the details of my theories have undergone continuous modification as a result of the lessons learned in treating a large number of patients, but the basic message has remained the same. I believe that the delay in the utilization oftestosterone treatment for CVD has arisen from a failure by specialists in endocrinology, biochemistry, physi ology, and cardiology to understand each other's point of view and therefore to effectively coordinate their clinical efforts. This is like four people starting to climb the various faces of a pyramid, unaware of each other's presence until they reach the apex. It is hoped that bringing specialists in these different disciplines together at "summit meetings" will help them discover the true nature of this disease, the cardiovascular specialist understanding the underlying lack of anabolic steroids, and the other three grasping the way in which treatment with these compounds can effectively counteract the metabolic disturbance which is the cause of CVD. Even apart of the language barrier, writing this book has by no means been an easy task. Please consider my situation; one cannot be a cardiologist, endocrinologist, biologist, biochemist, and physiologist all in one person. This fact may open me to criticism.

The European School of Oncology came into existence to respond to a need for information, education and training in the field of the diagnosis and treatment of cancer. There are two main reasons why such an initiative was considered necessary. Firstly, the teaching of oncology requires a rigorously multidiscipli nary approach which is difficult for the Universities to put into practice since their system is mainly disciplinary orientated. Secondly, the rate of technological development that impinges on the diagnosis and treatment of cancer has been so rapid that it is not an easy task for medical faculties to adapt their curricula flexibly. With its residential courses for organ pathologies and the seminars on new techniques (laser, monoclonal antibodies, imaging techniques etc.) or on the principal therapeutic controversies (conservative or mutilating surgery, primary or adjuvant chemotherapy, radiotherapy alone or integrated), it is the ambition of the European School of Oncology to fill a cultural and scientific gap and, thereby, create a bridge between the University and Industry and between these two and daily medical practice. One of the more recent initiatives of ESO has been the institution of permanent study groups, also called task forces, where a limited number of leading experts are invited to meet once a year with the aim of defining the state of the art and possibly reaching a consensus on future developments in specific fields of on cology."

This monograph brings together our work concerning the relationships be tween the hypothalamus, pituitary and testis. The studies span approximate ly a decade of collaborative work. Over this period our contributions and those of many others have advanced greatly our understanding of many aspects of male reproductive biology. This monograph attempts to survey these developments and to highlight many unresolved issues. It also provides an opportunity to demonstrate the value of investigations which relate bio chemical to structural parameters and to illustrate the importance of animal studies in elucidating biological principles with clinical applications. The reverse is also important since the pathophysiology of human disorders of ten provides insight into hitherto unsuspected basic mechanisms. In any rapidly expanding field it is difficult to stop revising and extending a manuscript. It is equally difficult to quote every reference in the field but we trust that those of significance have not been omitted. Some of our former students have collaborated with us as co-authors in producing this monograph. It is equally important to recognise the contributions of our other former students and colleagues who have physically participated in the studies and without whose intellectual contributions a number of concepts would not have been elucidated. Their work is acknowledged in the text of the monograph and the extensive list of references."

The role of electrical signalling in the control of endocrine secretions by the brain has been clear for many years. Recently, the influences of hormones on synthetic events in neuroendocrine cells have raised new questions concerning the peptides released from such neurons. This volume concentrates on the relation between these two fields and asks how electrical action potentials facilitate secretion of substances from nerve cells which control endocrine events. While stimulus-secretion coupling has been studied extensively in other physiological contexts, this is the first treatment of the phenomenon in an exclusively neuroendocrine setting.

The field of steroid hormone action has continued to expand into the realm of molecular biology at a pace even faster than most of us ever imagined. techniques of molecular biology have made it possible to clone The hormone-regulated genes and to examine steroid-receptor interactions with these genes. Nucleotide sequences of these genes, which show preferential binding of steroid receptors, have been identified. These results are complemented by the identification of chromatin acceptor proteins, which also show preferential binding for steroid-receptor complexes. Thus, one can envision the day when cloned genes, purified acceptor proteins, and receptor-steroid complexes will be recombined in vitro to form a functional unit. Cellular localization of steroid receptors has undergone recent revision, and it now appears that receptors are localized primarily in the nuclear compartment. These findings, although controversial, will lead to a reassessment of many of the previous concepts of steroid-receptor interactions and regulation. The way in which these observations at the of physiology, molecular and cellular levels fit into the overall scheme development, and evolution are continuing to progress, and the future promises some very exciting syntheses of understanding at all levels of biological organization. The third Meadow Brook Conference on hormones was held in order to bring together investigators who will undoubtedly contribute heavily to this future synthesis and to permit a free exchange of ideas and concepts as they relate to the current state-of-the-art in molecular endocrinology. Spring 1986 ARUN K. Roy JAMES H. CLARK Contents Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Experts in the field of endocrinology as well as ophthalmologists, oncologists, orthopedists and oral surgeons discuss the nature and mechanism of action of growth-stimulating substances whose biological and clinical activities in humans have been demonstrated or are being investigated. The monograph represents a good sampler of current basic and applied knowledge in the field.