In vitro fertilization has resulted in an estimated 4000-5000 births in the world. The procedure has been accepted in Europe, America and Australia and several hundred IVF clinics are operating successfully. The newer procedures of GIFf, embryo freezing and donor oocyte IVF have become established and are dealt with in several chapters. GIFf has become the procedure of choice for patients with infertility of unknown origin. Oocyte freezing represents an important new technology which is being developed. The routine IVF procedure has improved slightly; variation in results can be reduced by quality control of laboratory and clinical techniques. Male factor infertility has been dealt with by IVF in mild and moderate cases, but newer techniques will be required to deal with severe problems in the male. Most countries have accepted that the straightforward IVF pro cedure is ethical. Limitations concerning the use of donor oocytes and embryo experimentation exist in some religions and countries; legal control of the new reproductive technologies ranges from the passage of statutes to no control at all. Many countries are still considering the need for legislative control. The text endeavours to indicate new areas of importance and to guide those organizing services as to how to introduce newer technolo gies.

It is well established that progesterone plays a role in the brain and hypophysis as a facilitator and inhibitor of sexual behavior and gonadotropin release in the female rat (Everett 1961; Caligaris et al. 1971; Brown-Grant and Naftolin 1972; Dorner 1972; Meyerson 1972; Barraclough 1973; Goldman and Zarrow 1973; Mann and Barraclough 1973; Freeman et al. 1976; Feder and Marrone 1977; Goodman 1978; Attardi 1981), guinea pig (Morin and Feder 1974), and primates (Odell and Swerdloff 1968; Spies and Niswender 1972; Yamaji et al. 1972; Karsch et al. 1973; Dierschke et al. 1973; Knobi11974; Clifton et al. 1975). In an attempt to learn whether a specific progesterone uptake mechanism exists in the brain and the hypophysis, the distribution and retention pattern of radioactivity after in vivo injection of labeled progesterone was studied. Early work of Kato (1963) did not show a selective uptake of radioactivity in the hypo- thalamus of immature and estrogen-primed immature rats after injection oflow- specific-activity [14C]progesterone, but some tendency of the reticular formation to take up radiation was observed. Laumas and Farooq (1966) reported that after intravenous administration of labeled progesterone to ovariectomized estrogen- treated rats, radioactivity in the brain and pituitary appeared to show a very slight, insignificant increase 1-2 min after injection, but the uptake pattern was not definite, as had been seen with estradiol. Seiki et al.

Different genetic diagnostic and treatment options are used worldwide to improve routine IVF procedures for the benefit of patients. This handbook updates the new genetic diagnostic technologies that have been translated to the clinic, aiming to improve outcomes in the clinic and result in a healthy baby in the home. Chapters cover the use of genetic technologies in a personalized manner to unravel the possible genetic risks for the couple wishing to conceive, in terms of sperm, the embryo, the endometrium, miscarriage, and finally the fetus. This expanded new edition covers the range of the latest genetic diagnostic technologies being translated into practice internationally to improve routine IVF procedures for the benefit of patients. Bringing together international experts to discuss their work, this text gives a context for the developments in this very fast-moving area of research and offers a comprehensive and rounded appraisal of hot topics.

Calcium in Human Biology provides an authoritative review of current knowledge and points the way to further progress in the understanding of this essential nutrient. In addition to considering the established importance of an adequate dietary source of available calcium for the formation of sound bones and teeth, there is detailed discussion of the part calcium plays in a variety of aspects of human metabolism. The book is written primarily for those working in the nutritional sciences and related fields. It will also be of interest to clinicians, nutritionists, and to those interested more generally in the biological sciences, as well as to those in the important sectors of the food industry which utilise or produce dairy products and other foods significant to the supply of dietary calcium.

more intuitive study to greater empiricism. Frequently, chapters are di vided into discrete sections to discuss each rather distinct era of inquiry. This approach, when used, can provide a valuable historical overview of the early clinical formulations about each disease. Even though many of the earlier research philosophies and techniques may seem so simplistic as to mitigate against their inclusion, early research hypotheses were often generated from astute observation of clinical findings and relationships. In addition to shaping later empirical questions, a review of historical ante cedents provides a yardstick by which to measure the progress of more current studies, even though much is yet to be learned. As is true of any refinement of knowledge, the juxtaposition of the two approaches of study reveals that some of the early postulations about patient attributes and disease consequences have been confirmed, while other suppositions have been discarded. Although the generally subjective assessment methods used in the early studies may not have provided an optimal data base, it is interesting to note which clinical impressions were able to withstand greater empirical rigor and which were not. The book at its inception was intended to provide a succinct introduc tion to psychoneuroendocrinology research for practitioners and scientists who might be relatively unfamiliar with the area. However, it quickly became apparent that the sophistication of the information could not be readily reduced without vast oversimplification and loss of substance."

Thyroid carcinoma is an uncommon malignan ing the available non-human lines, as models cy. In the vast majority of patients, if treated for cell cycle studies and oncogene/anti appropriately, it is associated with a benign oncogene regulation, because they are unaware clinical course. Why then does it hold a con of the often fundamental dichotomy between tinuing fascination for so many physicians? thyroid malignancy and prognosis. Third, the The answer is probably directly dependent very nature of the benign clinical course has suggested to the major health research fund on the very benign nature of most thyroid ing agencies that thyroid cancer is not worthy maligllancies. While there are terrible excep of study in a time of scarce resources. tions, the follicular and papillary thyroid can Nothing could be further from the truth. cers behave in a way quite alien to "common" This gratifying clinical course is the very reason neoplasia, since they grow and metastasize why the study of human thyroid cancer has the slowly. We believe that if only we could under potential for contributing further to our fun stand such a transformed state, we would be able to learn a great deal about the normal and damental understanding of malignancy and, abnormal regulation of the cell cycle and im perhaps more importantly, the mechanisms by prove our understanding of cancer. which the human body can resist neoplastic However, recent advances in the biology of cells."

The ability to measure accurately the hormones regulating calcium homeosta sis is the fundamental first step toward understanding the roles these hormones play in health and disease. Techniques for such measurements have only been available for the past 10 years or so and remain in a state of rapid development. Sensitive parathyroid hormone (PTH) radioimmunoassays appeared in the early 1970s, and with them came a whole new appreciation for the prevalence and implications of hyperparathyroidism, primary or secondary, in the popu lation. The calcitonin (CT) radioimmunoassay came later and achieved rapid success in the. diagnosis of a previously poorly understood cancer, medullary carcinoma of the thyroid, frequently associated with the familial multiple endo crine neoplasia type 2 syndromes (a and b). As the sensitivity of the calcitonin radioimmunoassay has improved, our understanding of the role of calcitonin in normal physiological processes has increased. The knowledge that vitamin D must be metabolized to produce its biologic effects is only 15 years old. This has had profound implications in our understanding of a variety of metabolic bone, kidney, and gastrointestinal diseases. Assays to measure the major cir culating form of vitamin D, 25-hydroxyvitamin D, were described 10 years ago. Assays for the other metabolites, in particular, 1,25-dihydroxyvitamin D, were described even more recently. As of today, we know of many vitamin D metabolites and have developed the techniques to measure most of them; how ever, many questions remain concerning their physiological role."

As I read this unique volume on diabetes and pregnancy edited by Lois Jovanovic, I was struck by two themes that run throughout these collected chapters. First, this volume provides an excellent assessment of past problems, present management, and future challenges presented by dia betes in pregnancy. Orury's unique, longitudinal experience with diabetes iIi pregnancy provides the reader with an important overview, as does Coetzee's discussion of gestational diabetes. Current problems-deter mining the etiology and prevention of congenital malformations in infants of diabetic mothers (10M), assessment of antepartum fetal condition, management of pregnant patients with diabetic retinopathy, recognition of thyroid dysfunction in the pregnant diabetic woman, and understanding the multitude of metabolic sequelae observed in the 10M-are thoroughly reviewed. Finally, important considerations for future treatment and ther apy such as the adaptation of the fetal pancreas to the disordered intra uterine environment often seen in maternal diabetes, the use of fetal pan creatic tissue for transplantation, the application of exercise in the management of the pregnant woman with diabetes, and the long-term con sequences for the 10M provide an exciting glimpse into the future. The second important theme that emerges is the critical role the problem of diabetes in pregnancy has played in our understanding of maternal and fetal physiology. Clinical observations supported by basic research have emphasized the role of fetal fuels in teratogenesis.

Obesity is a serious medical problem that affects millions of people, especially in Western societies. Although long considered a complicating factor in a variety of diseases, there is now widespread agreement that obesity itself should be classified and treated as a disease and that it has important conse quences for personal health, quality of life and cost to society. Understanding obesity and the means of treating it have been hampered in the past. There have been misperceptions that obesity is a behavioral disorder and that its treatments provides only cosmetic benefits. Pharmacologic approaches to treatment have suffered from problems of limited efficacy, reduced activity upon chronic use, and serious side effects, including abuse liability, cardiac disease, hypertension, and respiratory complications. Finally, there has been a proliferation of consumer and natural products with unproven benefits. This book attempts to address both the problems associated with obesity and the approaches to treating it. In the first section devoted to pathology, Drs. DIGIROLAMO, HARP, and STEVENS elaborate in Chap. 1 on how obesity and its medical complications develop. As described by Dr. PI-SUNYER in Chap. 2, obesity is a disease seen most often in affluent Western societies and is associated with the aforemen tioned medical problems, as well as Type II diabetes mellitus and gallbladder disease. Drs. CHAGNON, PERUSSE, and BOUCHARD review the human genetics of obesity in Chap. 3, and Drs."

In the years since the initial discovery that blood from diabetic patients contains increased amounts of a posttranslationally gluco sylated form of hemoglobin (hemoglobin Ale)' an impressive number of studies have clarified and expanded the use of glycohemoglobin levels to assess disease status. Many other structural proteins have been shown to undergo similar changes, including proteins from tissues most commonly affected in diabetes (e.g., lens, aorta, peripheral nerve, basement membrane). Thus, the nonenzymatic glycosylation of hemoglobin emerges as an invaluable model for the pathogenesis of certain chronic diabetes complications. In addition to reviewing a wealth of investigative possibilities in the area of these chronic complications-including eye, kidney, nerve, and vascular disease-Dr. Cohen indicates how enhanced nonenzymatic glycosylation in uncontrolled diabetes underscores the pressing need for maintenance of long-term euglycemia. Dr. Cohen is an endocrinologist and diabetes specialist whose research activities have largely focused on the chemistry and metabo lism of the basement membrane in diabetes. This superb monograph on nonenzymatic glycosylation clearly shows the major trends of her past and present research and clinical activities. This book is beautifully written and a pleasure to read. It provides great insight into the mechanisms of the pathogenesis of the oom- vii viii Foreword cations of diabetes and should be of immense value not only to basic and clinical investigators, but also to internists, diabetologists, and endocrinologists in clinical practice."

It has been a challenge for us to edit this volume of Endocrinology and Metabo lism: Progress in Research and Clinical Practice. The topic of the pathogenesis of insulin-dependent, type I diabetes mellitus is particularly appropriate for this series, since advances in this area have been made, to a large extent, by applying state-of-the-art laboratory techniques to clinical samples. Over the last several years, a number of lines of evidence have been gathered, suggesting that classic type I diabetes mellitus results from the autoimmune des truction of pancreatic beta-cells in genetically susceptible individuals. This hypothesis is particularly appealing because it offers a rational approach to the prevention of diabetes by immunosuppression. We have tried to present a balanced, authoritative summary of the information currently available to support the autoimmune hypothesis for the pathogenesis of human type I diabetes, to place this information in historical perspective, to include relevant information from animal models of type I diabetes in which more invasive experimentation is ethical, and, finally, to update the reader on the current status of attempts to intervene in the progression of diabetes with immunosuppressive drugs. New York, New York Fredda Ginsberg-Fellner Robert C. McEvoy Contents Preface.. . . .. .. .. . . . . . . . . . . . . ... . . . . . . . . . . . .. . . . . . . .. . . . . v Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Xl . . . . . . . . . . . . . 1. The Autoimmune Hypothesis of Insulin-Dependent Diabetes: 1965 to the Present . . . . . . . . . . . . ..................... . . . . . .

In the first section of this volume, we have attempted to bring together some of the papers that reflect exciting new areas of development in relation to neuroendocrine investigation. Very recently, specific nucleotide recognition sequences for thyroid hormones, steroid hormones and the fundamental intracellular regulator, cyclic AMP, have been determined. In this section, the preliminary characterization and investigation of the nuclear binding proteins that mediate the actions of cAMP are described. Not only does this represent an important advance in cell biology, but it may represent a further level of alteration in control in normal and disease states. Intercellular pituitary "cross talk" is well described in the in vitro setting. The active molecules are clearly It is now important able to exert significant actions at the subnanomolar level. to design experiments in order to define the precise physiological relevance of these novel and potentially important observations. Paracrine and autocrine cellular interactions are of established importance in growth control in a variety of body tissues. But it is only very recently that the investigation of normal and abnormal anterior pituitary growth has reached the forefront of neuroendocrine research. This is perhaps surprising, beause the inhibitory effects of doapmine agonism on lactotroph growth and differentiation have been appreciated for some time. The anterior pituitary gland produces numerous growth factors that exert a variety of functional effects on pituitary hormone synthesis and release.

In the middle of the 17th century, the great French philosopher Rene Descartes wrote (L'Homme, J. Le Gras, Paris, 1669) that a suitable stimulation of the brain results in two types of "movements": exterior movements, designed to seek desirable ends and to avoid undesirable or harmful ones and interior movements or "passions" which through the release of "animal spirits" regulate the heart, the liver, and other organs. When it appears appropriate to meet a threat with force, the passion of rage causes the release of strong spirits, whereas when avoidance appears to be the better choice, the passion of fear causes the brain to release weak spirits. We do not know what influence, if any, Descartes had on the thinking of Walter B. Cannon (Bodily Changes in Pain, Hunger, Fear and Rage, Appleton and Co. , New York, 1920), of Hans Selye (The Story of the Adaptation Syndrome, Acta, Inc. , Montreal, 1952), ofG. W. Harris or of R. Guillemin (Hypothalamic-Hypophysial Interrelationships. A Sym posium. c. c. Thomas, Springfield, 1956), but it is interesting to reflect upon the durable value of great ideas which constantly resurface even if modified by other ideas and by new techniques, as if propelled by a preordained intellectual imperative.

Conceptual advances in the biological sciences are marked by the applica tion of new techniques and experimental strategies. Nowhere has this ge neric principle been more apparent than in the study of testicular cells, as judged by the evolution of themes presented at the Testis Workshop over the past 23 years. Like its predecessors, the 1995 Testis Workshop was structured to offer fresh insights and approaches for understanding the mechanisms of spermatogenesis and steroidogenesis. The chapters pre sented in this book emphasize three aspects of testicular cell function: first, the molecular analysis of the cell cycle; second, examination of the cell cycle, including the function and identification of specific macromolecules that direct the proliferation and differentiation of germ cells; and third, the development of Leydig cells and the role of specific macromolecules in the formation of testicular steroids. Each chapter is based on a lecture presented at the XIIIth Testis Work shop held on March 30 to April 1, 1995, at the Radisson Plaza Hotel in Raleigh, North Carolina. The selection of topics reflects the recommenda tions of the workshop'S organizing committee. Sincere thanks are due to the speakers who agreed to lecture and prepare chapters."

The importance of osteoporosis in the United Kingdom as a cause of death and disability is now well recognised. There are in excess of 200,000 osteoporotic-related fractures in the UK per annum asso ciated with an estimated cost of GBP942,000,000. Following hip fracture it is known that about 50% of patients are unable to live indepen dently and about 20% of such patients die within the first 6 months. These figures, compelling as they are, reflect poorly on current medical practices which manifestly have failed to identify patients with low bone density at risk of fracture. The hope is that the techni cal advances which have enabled bone mineral density, and other allied indices, to be measured with high precision and accuracy offers the chance of identifying patients at risk of fracture and guiding the clinician to make treatment decisions which may reduce the patients' risk of fracture. In the UK, services for identifying patients at risk of fracture are still in their infancy and are not uniformly available throughout the country. This situation is, however, likely to improve particularly fol lowing the publication of the Royal College of Physicians report "Osteoporosis -clinical guidelines for prevention and treatment" and the recognition in "Our Healthier Nation" that osteoporosis pre vention should be included as a target to achieve a reduction of 20% in accidents by 2010.

Nineteen cutting-edge review articles by leading authorities provide a comprehensive overview of the normal function of the pituitary and of the diagnosis and treatment of pituitary disorders. Topics range from normal hypothalamic-pituitary interactions and the processes that disrupt them to new advances in pituitary imaging and appropriate surgical intervention in various pituitary disorders. Among the diseases discussed are congenital hypopituitarism, deficiency states, strategies for evaluating patients with hyperprolactinemia, Cushing's syndrome, acromegaly, and glycoprotein pituitary tumors.

When the kidney fails its intended mission to manage the body 's waste products, physicians must perform multi-level and simultaneous adjustments to replicate kidney function. The management of the body 's absorption, reabsorption, utilization and excretion of calcium and phosphate requires constant fine tuning. This book provides an overview of the state-of-the-art clinical and basic science aspects of abnormal calcium and phosphate metabolism and its management.

Diagnosis and Management of Polycystic Ovary Syndrome is a comprehensive clinical reference work for primary care physicians, internists, general endocrinologists, obstetricians, gynecologists and students. PCOS is a common but frequently misdiagnosed disease. Many symptoms can be alleviated by early intervention and effective management.

Prominent endocrinologists are gathered to detail current research and treatment in this metabolic disorder, affecting a growing population. The chapters are comprehensive, providing cutting edge knowledge on pathogenesis, manifestations, diagnosis and treatment of PCOS. Each chapter will be concise concluding with cogent practice points.

The variety of medical issues presenting in PCOS patients result in late referrals or in- appropriate advice. This title will be a tool in a further understanding of the metabolic and genetic basis of PCOS, while providing management strategies.

Disorders of Emotion in Neurologic Disease, Volume 183 in the Handbook of Clinical Neurology Series, informs clinicians on which neurologic diseases are likely to have a secondary effect on emotion, what to look for in diagnosis, and best practices for treatment. The book begins with an understanding of the neurological basis for emotions in order to better understand what goes awry in neurological disease. It then discusses specific neurologic diseases and disorders affecting emotion.

Andrology for the Clinician consists of two parts: In Part One, the busy clinician can easily find the problem-orientated information he or she needs on such issues as male factor fertility problems, male contraception, and male genital tract infection and tumours. Part Two contains in-depth subject-orientated information and adds important scientific background information to the recommendations received in Part One. Several leading experts have contributed to this work, which has been extensively subedited by world-renowned editors to ensure a well-structured didactic design and homogeneous content. This outstanding book is of great value for all Urologists, Andrologists, Dermatologists, Endocrinologists, Gynaecologists, Reproductive Biologists, GPs, Gerontologists, Psychologists, Psychiatrists, Paediatricians and anyone else interested in the problems of male sex and constitution.

In the past, determination of bone maturity relied on visual evaluation of skeletal development in the hand and wrist, most commonly using the Greulich and Pyle atlas. The Gilsanz and Ratib digital atlas takes advantage of digital imaging and provides a more effective and objective approach to assessment of skeletal maturity. The atlas integrates the key morphological features of ossification in the bones of the hand and wrist and provides idealized, sex- and age-specific images of skeletal development New to this revised second edition is a description and user manual for Bone Age for iPad(r), iPhone(r) and iPod touch(r), which can be purchased and used separately from this book. The App can be easily employed to calculate the deviation of the patient's age from the normal range and to predict a possible growth delay. This easy-to-use atlas and the related App will be invaluable for radiologists, endocrinologists, and pediatricians and also relevant to forensic physicians.

Recent advances in cellular and molecular biology have markedly increased our understanding of normal and abnormal hypothalamic-pituitary-testicular function. Like other volumes in the Contemporary Endocrinology series, the goal of Male Hy- gonadism: Basic, Clinical, and Therapeutic Principles is to link current knowledge of basic biology to the practice of medicine. The development of new methods for testost- one replacement has substantially increased the number of men who are seeking to determine whether they are hypogonadal, and who are using testosterone replacement therapy, thus mandating a broader understanding of testosterone deficiency. The chapters of this book were contributed by authors from around the world, and from various scientific and clinical disciplines, who have devoted their careers to the study of the physiology and pathophysiology of the male. Thus, this comprehensive and focused volume is intended for a wide audience encompassing both basic scientists and practicing clinicians. Its scope will provide a wealth of information for students and fellows as well.

Until recently, endocrinology and critical care medicine were two specialties in medicine that were rather uncomfortable with each other and hence quite i- lated. Fortunately, these two 'alien' disciplines have joined forces in successful attempts to perform high quality research in order to clarify the unknown. By integrating endocrinology in critical care medicine, or vice-versa depending on the specialty of the observer, new experimental and clinical data on the complex endocrine and metabolic derangements accompanying non-endocrine severe i- nesses came available which generated important novel insights with relevant clinical implications. In addition, the state of the art diagnosis and management of primary endocrine diseases that represent life-threatening situations leading to ICU admission has been updated. This issue of Contemporary Endocrinology aims at compiling the new ?ndings. The book indeed covers both areas of 'Acute Endocrinology' that are often taking care of at very distant sites within hospitals. The ?rst part deals with the classical life-threatening illnesses caused by primary endocrine diseases such as thyrotoxicosis, hypothyroidism, acute adrenal crisis, acute calcium disorders, pheochromocytoma, severe hyper- and hypoglycemia . The second part looks at endocrinology from the ICU side, starting with a g- eral overview of the dynamic neuroendocrine and metabolic stress responses in the condition of intensive care-dependent, non-endocrine critical illness.

Expert clinicians comprehensively review the endocrine and metabolic responses to critical illness, explore the mechanisms and outcomes (positive and negative) of those responses to severe stress, and consider possible endocrine interactions that are not yet fully defined. The contributors explain in detail the endocrine response to a multitude of critical illnesses, including cancer, liver failure, renal failure, trauma, burns, AIDS and other infections, starvation, cardiac disease, pulmonary disease, and organ transplants. The book offers significant basic knowledge of high clinical relevance by collating and defining the numerous interactions of the endocrine system and critical disease states, by discussing the basic pathophysiological processes involved, and by reviewing the clinical relevance of such responses.

A critical review by prominent experts of both the cutting-edge of stem cell biology and the application of stem cells to endocrine diseases, including diabetes, infertility, and liver-associated metabolic disorders. The authors discuss current research to modify stem cells, develop an endocrine-like cell, and use adult bone marrow stem cells to treat autoimmune diseases, including endocrine-based autoimmune diseases. Topics of interest include a review of all stem cell subtypes and their characteristics, approaches to promoting endocrine development from stem cells, and evidence for endocrine cell function from stem cells. The authors also outline how best to develop preclinical studies that will determine the safety and efficacy of stem cell therapies for endocrine disorders.