"Theoretically, one should obtain essentially the same clinical picture from failure of an end-organ to respond to a hormone as from a decreased production or absence of said hormone. " With these words, Fuller Albright began his now classic paper describing a novel disease, pseudo hypoparathyroidism (PHP), and a novel concept, hormone resis- tance as a cause of disease. Soon, other hormone resistance disorders such as nephrogenic diabetes insipidus (NDI) were recognized, and the concept was extended to resistance to other substances such as calcium ions in familial hypocalciuric hypercalcemia (FHH). Later, diseases characterized by excess rather than deficient hormone action such as McCune-Albright syndrome (MAS) and familial male precocious puberty (FMPP) were recognized to be caused by autonomous endocrine hyperfunction. Although many i!!vestigators provided careful and detailed descriptions of the clinical features of these and other related endocrine disorders, an understanding of pathogenesis proved elusive for many years. In just the past few years, we have gone from clinical description to a molecular understanding of these interesting disorders. This remarkable progress reflects a synthe- sis of three distinct, but now overlapping, areas of biomedical research: the aforemen- tioned recognition and careful clinical description of specific diseases, the elucidation of the basic mechanisms of signal transduction, and the application of the powerful tools of molecular biology and genetics. Fundamental studies on the mechanisms of hormone action by Rodbell and colleagues at NIH culminated in the discovery of a major signal transduction pathway involving heterotrimeric G proteins.

Cheryl S. Watson University o/Texas Medical Branch Cellular steroid action has been thoroughly studied in the nuclear compartment. However, nuclear steroid receptor mechanisms have been unable to explain some of the rapid activities of steroids, partiCUlarly those which occur in a time frame of seconds to minutes [reviewed in (1;2)]. Based on these and other considerations, an alternative membrane-associated receptor form was long ago proposed to exist (3). Others interpret the location of the steroid receptors mediating these rapid effects as peri membrane or cytoplasmic. New experimental tools have been brought to bear on the topic of receptors for steroids which mediate non-genomic actions, and thus investigative activity and focus regarding this type of steroid receptor has recently increased significantly. However, there may be multiple answers to the question "how do steroids mediate rapid nongenomic effects?" Steroid actions initiated at the cell membrane can impinge on important phases in the lifespan of a cell: proliferation, migration, differentiation, and release of hormones or neurotransmitters functioning as signals to other cells.

In September of 1977 scientists from many countries met at the Asticou Inn in Maine to present and discuss papers written especially for this monograph. The presentations were informal and directed to the special interests of the audience in order to generate discussions. The authors, many of whom are pioneers and leaders in their field, then had the oppor tunity to revise their contributions, which were brought together with the edited discussions to form this volume. The basic research studies presented here are important because of the essential role of gonadotropins in regulating the ovary and testis. This monograph will therefore be of interest to those concerned with fertility regulation, population control, possible new methods for contraception, and to those concerned with reproduction in domestic animals. Re searchers in other fields may find this monograph useful, as it has been de termined that gonadotropins are secreted by many tumors and are im plicated in many cancers. Human choriogonadotropin also seems to be found in most, if not all, cells of the human body. The significance of this, however, is unknown."

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.

Calcium-Sensing Receptor provides an overview of various aspects of the calcium receptor's biochemistry, physiology and pathophysiology that is suitable both for those who have been working in the field of Ca2+0-sensing as well as those who are new to this discipline. Calcium-Sensing Receptor is the nineteenth volume published in the Endocrine Updates book series under the Series Editorship of Shlomo Melmed, MD.

Diabetes and Wellbeing presents a range of effective psychological principles proven to positively impact the emotional wellbeing of individuals with type 1 and 2 diabetes. The guide takes an explicitly CBT approach to motivate sufferers in essential self-care tasks. * Written in a practical style, for those newly diagnosed with diabetes, individuals managing its challenges for many years, and healthcare professionals * Reveals how the stress of daily diabetes management can affect an individual s ability to stay motivated and engaged in essential self-care tasks that are vital for good health * Presents proven techniques for improving emotional wellbeing * First book to take an explicitly CBT approach to diabetes, simultaneously drawing on solution-focused behavioural therapy and mindfulness approaches * Fills the gap information of this kind among healthcare professionals and individuals with diabetes

An enormous amount of research effort has been directed toward elucidating the mechanism by which substances are extruded from cells; and reviews have been written and symposia held in order to systematize the plethora of evidence made available. However, the approaches employed to study the secretory process have been so diverse that it is difficult, if not impossible, for one individual or even a group of individuals to keep abreast of all aspects of the field and to analyze them critically. Thus I undertook the writing of this volume with a great deal of trepidation. In searching for some starting point, I naturally considered as my primary focus the role of calcium in the secretory process, which has occupied my research interests for the past 13 years. But since so much experimentation has been carried out on this and related topics during the last decade or two, I felt it was still necessary to visualize this venture from two alternative ap proaches: (1) a more general one, which would cover the subject of calcium and the secretory process from a broad perspective, but of course not in great detail, and (2) a more specific one, restricting coverage to carefully defined limits but with comprehensive analysis of limited topics. The final course undertaken appears to lie somewhere between these two extremes."

Macromolecular (specifically peptide-based) drugs could potentially be highly effective medicines. However they have a relatively short duration of action and variable therapeutic index. An example of such a peptide is Glucagon-like Peptide I which could potentially be used as a revolutionary drug for diabetes. This is because it stimulates insulin only when the blood glucose level is high thereby reducing the risk of hypoglycemia (a significant disadvantage of using insulin is that an insulin overdose is the single most potent cause of life-threatening hypoglycemia). However it's short duration of action (half-life of 2 minutes in plasma) precludes its therapeutic use. In this volume, the use of novel therapeutics like GLP1 as an alternative to tradition insulin-based drugs in diabetes is described. Application of Peptide-Based Prodrug Chemistry in Drug Development elucidates the traditional concept of prodrugs as "specialized non-toxic protective groups used in a transient manner to alter or to eliminate certain limiting properties in the parent small molecule" (IUPAC definition). It goes on to provide insight into how prodrugs of peptides (with GLP1 as an example) could be appropriately used to extend the biological half life, broaden the therapeutic index of macromolecules and improve the pharmacodynamics of such drugs. Author explains the logic behind designing peptide prodrugs, synthetic procedures and bioassays to examine the conversion of the prodrug to the drug under therapeutic conditions. The prodrugs described slowly convert to the parent drug at physiological conditions of 37C and pH 7.2 driven by their inherent chemical instability without the need of any enzymatic cleavage. The diketopiperazine and diketomorpholine (DKP and DMP) strategies for prodrug conversion are demonstrated in detail with special emphasis on the chemical flexibility that it offers to develop prodrugs with variable time actions. This book will be of useful to chemists, biochemists, medicinal chemists, biologists and people in the medical profession (doctors). It may be used in undergraduate classes but will certainly help post-graduate students and advanced professionals. The author is grateful to Prof. Richard DiMarchi (Standiford H. Cox Professor of Chemistry and the Linda & Jack Gill Chair in Biomolecular Sciences at Indiana University) for valuable suggestions. The foreword for the book has been written by Prof. Jean Martinez, (Legion d'Honneur awarded by the French Republic; Professor of Chemistry and Medicinal Chemistry of the University of Montpellier, France; and Chairman of European Peptide Society, 2002-2010).

Calcium metabolism is regulated by three specific hormones: parathor- mone, calciferol metabolites, and calcitonin. Cyclic AMP also plays an important part in calcium regulation, and its concentration in urine can be taken as a measure of parathyroid function. Methods for quantitative measurement of, e.g. calcium-regulating hormones and vitamin D metabolites as well as of cAMP are absolutely necessary for safe differential diagnosis of diseases of the parathyroid like hypo- and hyperparathyroidism. In this monograph all presently available methods are summarized as to whether they can already be obtained as test kits or are still being tested. Radioimmunoassays for the various peptide fragments such as 53-84, 44-68, 28-48, and 1-34 are described, as are immunochemiluminescence methods and adenylate cyclase bioassays. The same is true for the vitamin D metabolites, where the various assays for calcidiol and calcitriol such as HPLC, protein-binding assay with second antibody separation, and double antibody RIA are dex scribed. Finally, determination of calcitonin and cAMP is discussed in detail. This is a practically and clinically oriented monograph for working in the fields of internal medicine, endocrinology, and laboratory medicine.

"When a thing ceases to be a subject of controversy, it ceases to be a subject of interest. " WILLIAM HAZLITT (1778-1830) This is the fourth volume in a series which we started in 1997. In 1976, Varco and Delaney edited a "surgical bestseller" entitled Controversy in Surgery. This was fol lowed by a second volume in 1985. The immense success of these books among both surgical trainees and experienced surgeons, and their wide international ap peal, supported the editors' notion that a view of controversy is integral to teach ing. However, despite major advances in surgical science and practice, no other similar publication has since been put together with the objective of addressing major controversies in surgery. The aim of this series is to address such deficiency by covering the most crucial current controversies in general, vascular and trauma surgery. Since almost everything is controversial in surgery, we will be able to tackle different issues almost each year. The editors have selected a nationally/internationally recognized authority for each topic. Most books available today are either "North American: ' "British-Com monwealth" or "British-European: ' contributing to the constant transatlantic rival ry. Our series specifically aims to bridge this "culture gap" and includes North American, British, European, and other authors while maintaining a cohesive structure. This will hopefully also broaden the appeal of such a book across both sides of the Atlantic and beyond."

This book is divided into two main sections, and covers a broad range of issues important for health practitioners to be aware of when caring for people with co-morbid diabetes and depression. Section One of the book contains the overall ideas and the more recent developments in measuring psychological morbidity in people with diabetes. When attempting to identify people with depression or other psychological problems, it is important for practitioners to recognize the limitations of screening as well as its utility. Issues such as the basic principles regarding when and when not to screen, the cultural applicability of tools, different questionnaire formats and key concepts such as sensitivity and specificity of tools, and their positive and negative predictive value, will be considered. In particular there has been increased interest in the concept of diabetes-related distress and several tools have been developed to measure this. There are broad-based measures of distress such as the Problem Areas in Diabetes (PAID) scale, the Diabetes Adjustment Scale (DAS), The Diabetes Health Profile, The Fear of Hypoglycemia Scale, etc. There are also a range of generic quality of life tools which have been used effectively in people with diabetes; for example the Medical Outcomes Survey Short-Forms (SF36, SF12), the World Health Organisation Well-being questionnaire (WHO-5) and the EQ5-D. These tools are important because they measure aspects of psychological well-being that are specifically associated with the experience of having a long-term conditions and so have important implications for both self-care and health care practice. The potential overlap of symptoms of depression and symptoms of diabetes-related distress are considered in this section and the implications for practice discussed. Section Two covers the most commonly used tools that have been used to screen for depression. For each tool considered some information which is easily referred to by the readeris set out in a table which includes details of the authors, time of first use, country where it was first developed, some examples of the questions used, the languages it is available in, data on sensitivity/specificity. Each instrument will then be discussed in terms of its use in research as well as practice, and its applicability in different patient groups, different cultural settings and so on. Guidance on the practical use of each tool is included, and the most popular depression screening tools are focussed on.

This book represents the proceedings from a conference that took place in Dallas in the spring of 1999 which was entitled "Pediatric Gender Assignment - A Critical Reappraisal". Some participants rightfully argued that the conference really focused on the issue of pediatric gender assignment, and that reassignment was not applied in most cases. Their comments were reflected in the title of this monograph. This multidisciplinary meeting was sponsored by a conference grant from the National Institutes of Health, and a broad inquiry into this complex topic took place from many points of view. Basic scientists offered insight into mechanisms of sexual differentiation of the gonads, physical phenotype and imprinting of the central nervous system. Endocrinologists reviewed their experience in diagnosis and management, surgeons described traditional as well as innovative approaches, and there was strong representation from the ethical and behavioral sciences. In putting together such a panel, it was essential that we identify a cast of speakers who could address their viewpoints with strong convictions, and yet not let their passions render the meeting counter productive. We were not disappointed. While many differing points of view were firmly expressed by the panelists and audience, all viewpoints were accorded the respect they deserved. The concept behind the meeting and this book really originated in 1997 shortly after Diamond and Sigmundson published their long term follow up study of the John/Joan case.

Stephen P. Ethier and a panel of leading investigators comprehensively analyze the cellular, molecular, and endocrine factors in the development of cancers of the breast, prostate, endometrium, and ovary. Concentrating on defining the most important unresolved issues in the field, the authors review how steroid hormones function to regulate normal mammary gland homeostasis in humans, with particular emphasis on the roles of estrogen, progesterone, and growth factors. Comprehensive and up-to-date, Endocrine Oncology offers both basic and clinical researchers not only the latest molecular and cellular findings on endocrine cancers, but also a powerful critical analysis that will prove invaluable to all endocrinologists and oncologists working in the area today.

Carole Mendelson has assembled a panel of leading investigators to critically review the various classes of endocrine, paracrine, and neuroendocrine factors that play a role in the regulation of lung development and surfactant production. Special attention is accorded the actions of glucocorticoids in lung development and the synthesis of surfactant glycerophospholipids and proteins. Also extensively treated are the roles of cell-cell interactions and the elaboration of various growth factors and bioactive peptides in pulmonary cell differentiation, gene expression, and pathophysiology. State-of-the-art and comprehensive, Endocrinology of the Lung constitutes a powerful new standard guide that illuminates the complex endocrinology of the lung for all those actively investigating hormone action in pulmonary biology and medicine today.

The 6th triennial meeting of the International Study Group for Tryp- tophan Research (ISTRY) was held May 9-12, 1989 in Baltimore, Maryland (USA). From the wide variety of topics and disciplines represented, as documented in this volume, it is clear that tryptophan research and ISTRY are alive and well. ISTRY traces its or1g1ns to at a tryptophan symposium organized in 1971 by H. Schievelbein at Hohenried near Munich (Germany). Up to that time there had been occasional international tryptophan conferences at irregular inter- vals. A number of participants at the Hohenried meeting felt that an inter- national tryptophan organization should be formed to organize regular meet- ings and to foster collaboration and information exchange on tryptophan-re- lated topics. Thanks mainly to the founding work of H. Schievelbein and W. Kochen, an executive committee was elected and ISTRY was born. The inaugural meeting in 1974 was held in Padova (Italy) to honor L. Musajo, one of the foremost pioneers in tryptophan studies. This first ISTRY meeting was suc- cessfully organized by L. Musajo, G. Allegri, A. De Antoni, and C. Costa, and was critical in assuring the viability of the new organization. Subsequent meetings were held in 1977 in Madison, Wisconsin (USA), organized by R.R. Brown, D.P. Rose, and W.E. Knox, honoring C.P. Berg; 1980 in Kyoto (Japan), organized by O. Hayaishi, R. Kido, Y. Ishimura, T. Deguchi, T. Hino, T.

This book includes the most significant contributions of the First International Symposium on "Multiple risk factors in cardiovascular disease", chaired by Professors A. V. Chobanian (Boston), A. M. Gotto Jr. (Houston), c. Lenfant (Bethesda), R. Paoletti and A. Zanchetti (Milan), held in Washington DC, 10-12 December 1990, which focused on the risk factors for cardiovascular disease and their interactions. The need for this symposium is based on the epidemiological evidence that individuals from industrialized countries often possess two or more risk factors which synergically increase the global risk profile. The evidence that isolated vascular risk factors are not commonly found in high risk patients but more often a combination of risk factors are detected, is highlighted. Many recent epidemiological data identifying the intrinsic and environ mental factors contributing to the development of atherosclerosis are discussed. These results, in parallel to basic and clinical research, underline how atherosclerosis is a complex and multifac torial process involving the influences of lipid deposition, blood pressure, rheologic forces, carbohydrate tolerance, and thrombogenic factors (fibrinogen and platelets). Atherosclerosis is markedly accelerated by other risk factors, more so in the presence of concomitant hypercholes terolemia, hypertension, diabetes, upper body obesity. Furthermore, the risk associated with anyone of these risk factors varies widely depending on level of the associated atherogenic risk factors.

"Neuropeptides and Stress" presents a comprehensive survey by leading pioneers in the field of the knowledge and concepts implicating neuropeptides in the regulations of responses to stress. Topics covered include: recent advances on the regulation and modulation of the behavioral, endocrine, autonomic, gastrointestinal, immune and analgesic responses to stress by neuropeptides. Neuroanatomical and biological data are considered. Special emphasis is given to corticotropin-releasing factor (CRF) and opioid peptides.

A growing majority of women in the western hemisphere have been delaying initiation of childbearing to later in life. Consequently, more than ever before, women in their late 30s to early 40s are attempting their first pregnancy. Since the incidence of most cancers increases with age, delayed childbearing results in more female cancer survivors interested in fertility preservation." Fertility Preservation in Females: Emerging Technologies and Clinical Applications" contains a selection of the valuable chapters and protocols of Seli and Agarwal s previously published hardcover text "Fertility Preservation: Emerging Technologies and Clinical Applications." Newly available in this convenient and affordable softcover format, this unique and practical reference guide for reproductive endocrinologists, gynecologists, embryologists, reproductive scientists, and oncologists provides strategies for fertility preservation in women, using a format that combines concise scientific background with practical methodological information and easy-to-grasp algorithms."

In a state-of-the-art synthesis of basic science and clinical practice, Roy Smith and a distinguished panel of researchers and clinicians review GH regulation and its action at the molecular level, and describe the basis for GH deficiency and the use of GH as therapy in a variety of clinical situations. The clinical presentation moves beyond the treatment of GH-deficient children to include the genetics of GH-deficiency, GH-deficiency in adults, osteoporosis, Syndrome X, sleep quality, GH in AIDS patients, GHRH in clinical studies. Timely and innovative, Human Growth Hormone: Research and Clinical Practice will benefit both basic and clinical researchers, as well as those clinical endocrinologists who want to use growth hormone not only in treating children, but also in treating adult disorders, including those associated with metabolic disease.

The selection of prolactin as the subject of the Midwest Con ference on Endocrinology was not only dictated by the recent ad vances in prolactin research but also by the long tradition in that particular area of Endocrinology in the laboratory of C.W. Turner at the University of Missouri. Therefore, it seems only appropri ate that these proceedings of the Tenth Midwest Conference on En docrinology are dedicated to the memory of this scientist, deceased in August 1975 before completion of this volume, whose pioneer in vestigations have contributed substantially to the advancement of our knowledge in many areas of Endocrinology and who played a major role in the early phases of prolactin research. This volume contains a review of the early studies in Turner's laboratory and the latest results obtained by some of the leading research workers in this area and should be a fitting memory to C.W. Turner. Some of the manuscripts printed here were prepared after the conference was held and include material of more recent origin. Much of the delay in publication was due to the length of time de voted to preparation of these manuscripts. To the other authors and participants, and to Plenum Press, we express our appreciation for their patience and cooperation. We also with to thank Mrs."

The past two decades have seen steady progress in our understanding of the pathogenesis of atherosclerosis. The role of low density lipoprotein (LOL) increase and of LOL receptor deficiency or malfunctions in familial hypercholesterolemia has been largely enlightened by the works of Brown and Goldstein. These authors postulated also that modification of LOL to a form recognized by the scavenger or acetyl-LOL receptor may be required for lipid loading of macrophage-derived foam cells in the lesions. A growing body of evidence suggests that oxidative modification of LOL could enhance its atherogenicity by its implication as a factor in the generation of foam cells. Thus, if the role of LOL in the pathogenesis of hypercholesterolemia was well established a great deal of information appears currently on new approaches such as the mechanisms leading to the accumulation of foam cells, the impact of LOL structural alterations, notably oxidation and the role of gene mutations of apolipoprotein Band/or LOL receptor The opening topic is devoted to these new avenues outlined in the field of hypercholesterolemia. The first part concerns the genetic aspects of atherosclerosis: mainly the genetics of apo 1 ipoprote ins , their transcriptional regulation, the amino acid mutations of the apo B gene and of the LOL receptor gene, the structural domains and the acylation sites of apoprotein B.

It is unclear, and really no longer relevant, whether the information explosion that we now contend with has been fostered by the growth of specialization and subspecialization in medicine, or vice versa. What is clear is that the two are mutually supportive and constitute what would be in endocrine parlance a short-loop positive feedback system. As a result, for most areas of medicine, even the subspecialist in that area has a problem in maintaining currency, the more general specialist has substan tial difficulty in doing so, and the generalist is tempted to abandon the effort altogether. Nevertheless, for all, both the internal pressures of conscience and self-esteem and the external pressures generated by peer review, recertifi cation, and subspecialty boards create the need for continuous self-educa tion. We are, therefore, in an era in which the means of dissemination of new information deserves as much creative attention as does its acquisition.

The present volume is the results of 6 years' work by our team, during which time 2300 CT scans of the pituitary region were carried out. This was made possible by the close collaboration between physicians and technicians in our neuroradiological department, as well as by numerous corresponding physi cians. We wish to express our gratitude for their confidence and our sincere thanks to our colleagues at Besan90n, Dijon, Grenoble, Lyon, Montpellier, and Strasbourg. Furthermore, we especially wish to thank the patients who willingly accepted the difficult requirements of these studies. We are grateful to the technicians at the Neuroradiology Department of the Centre Hospitalier et U niversitaire de Besan90n, who have perfected the methodology so as to meet the ever increasing imperatives for precise anatomical mapping of the pituitary gland and the surrounding region; without their efforts, this book would never have been possible. Finally, we wish to express our thanks to the medical photographer of our group, as well as the secretarial staff for their contribution to the successful production of this work. We thank Labora toires Guerbet and General Electric for their excellent assistance, and Springer Verlag for their care and competence in the production of this book. In writing Computed Tomography of the Pituitary Gland, we have sought to develop morphological study of the pituitary gland to a degree of reliability comparable to that of laboratory findings in endocrine disorders.

The International Foundation for Biochemical Endocrinology is incorporated as a nonprofit research and educational organization. It is dedicated to the dissemination of knowledge, cooperative research programs, and cultural interaction on an international basis. The Foundation is concerned with both basic research and practical applications of biological knowledge to the betterment of humanity. Among our interests are global resource management, human reproduction, hormonal regulation of normal and cancer cells, study of aging and degenerative diseases, brain peptides, peptide neurotransmitter compounds, mechanism of action of hormones, peptide hormone synthesis, and recombinant DNA techniques. This monograph is the ninth sponsored by the Foundation in the Biochemical Endocrinology series. The previous four have been: Hormonally Active Brain Peptides: Structure and Function (1982), K. W. McKerns and V. Pantie, eds.; Reproductive Processes and Contraception (1981), K. W. McKerns, ed.; Synthesis and Release of Adenohypophyseal Hormones (1980), M. Jutisz and K. W. McKerns, eds.; and Structure and Function of the Gonadotropins (1978), K. W. McKerns, ed. These have all been published by Plenum Press.

During the last ten years, the diagnostic approach to disorders of bone and mineral metabolism has benefited considerably from the development of radioimmunoassay and competitive protein- binding techniques for measurements of circulating parathyroid hormone, calcitonin, and biologically active vitamin D me- tabolites. Accumulated experiences with radiogrametrical and densinometric methods of quantitating appendicular bone mass now facilitate the detection of changes in bone mineral content heretofore unrecognized by routine roentgenographic vertebral analysis. During this same decade, the diagnosis of metabolic bone disease and the skeletal response to remedial therapeutic ma- neuvers have also been facilitated by the routine application of the bone biopsy. Improvements in tinctorial techniques, stan- dardization in methodology essential for adequate preparation of thin undecalcified specimens, and the incorporation of tetracy- cline bone formation or mineralization "markers" should now herald the "routine" use of this diagnostic procedure. Moreover, the compilation and ready availability of reference morphometric data, spanning the prepubescent years charac- terized by skeletal growth and remodeling and the later senes- cent period during which bone loss normally proceeds in an un- 7 8 FOREWORD relenting fashion, allow adequate differentiation between normal age-sex-related changes in skeletal turnover attendant on skeletal maturation and aging and acquired or inherited de- rangements in bone metabolism.