The practice of clinical reproductive medicine has practice in the era of managed care and coordinat gradually moved from its initial 1980-90 hospital ing ancillary offsite medical personnel. base to its present (circa 2001) office site of oper The objective of this text is to assist in this ongo ation. With this transition have been improvements ing endeavor by presenting in a clear, concise man in efficiency of practice often in response to ner many of the topics relevant to contemporary increased pressure to provide the most patient sat office-based infertility practice. The initial half of isfaction. An added challenge of office-based prac this text addresses topics which focus upon general tice has been taking on many of the responsibili concepts of infertility evaluation and practice. The ties of what had been traditionally the hospital's latter half is a practical approach to the execution domain. Some of these new responsibilities have of specific office-based infertility procedures. We included the ordering of operative supplies and hope this book will assist all medical personnel who equipment, the establishment of quality control dedicate their clinical effort in achieving what is programs, construction and maintenance of special most coveted by our patients, the birth of a healthy laboratory spaces, redesigning efficient methods of newborn. DAVID B. SEIFER, M. D. UMDNJ-Robert Wood Johnson Medical School ROBERT L. COLLINS, M. D. The Reproductive Center, Youngstown, Ohio October 2001 vii Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi . . . . . . . . . . . . . . . . . 1 Evaluation of the Female for Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Bryan D."

THE DISCOVERY OF INSULIN, C-PEPTIDE AND PROINSULlN, SPECIES DIFFERENCES Crude insulin was extracted and isolated from dog pancreases removed 7-1 Degrees weeks after ligation of the pancreatic duct for the first time in 1921 by Banting and Best. Its lifesaving properties were subsequently documented in pancreatectomized dogs in 1922. Only about six months elapsed from its discovery until systematic collection of calf and ox pancreases and, later, porcine pancreases was established and the blood glucose lowering effect in diabetics using the crude extract from these glands proven. It was not until 1960, however, that the primary structure of all three species of insulin, lO7 human, porcine and bovine, was elucidated . It then became evident that the differences between bovine, porcine and human insulin amounted to at mosl 3 amino acids. These apparently small differences have a significant impact on the physico-chemical characteristics of the three insulins which again affect, e.g., the rate of absorption of insulin lO9 preparations from the subcutaneous tissue and their immunogenicity, i.e.

Painful Diabetic Neuropathy in Clinical Practice provides a concise, didactic and essential resource for clinicians in the management of neuropathic pain in diabetic patients. This volume opens with overviews of epidemiology, classification and clinical features, including a discussion of the negative effect of painful neuropathic symptoms on quality of life. These are followed by a chapter on diagnosis and staging, which includes approaches to history taking, clinical examination, pain assessment scales, testing and staging. The book concludes with a chapter on the various approaches in the management of neuropathic pain, including the most up-to-date guidelines on the pharmacological treatment of this condition. This concise handbook is an invaluable reference for primary care practitioners and diabetologists who wish to keep up to date with the diagnosis and management of neuropathic pain. Content Level Professional/practitioner

For many years, patients who complained of prostatism had only a few treatment choices. The patient was either a candidate for an elective prostatectomy, or the operation was deferred until the patient became more symptomatic. The present text summarizes the multiple options which have become available to the practicing urologist. Minimally invasive techniques such as transurethral incision of the prostate, balloon dilatation, hyperthermia, laser therapy, and prostatic stents are described. Medical treatment with alpha-blockers, 5 alpha-reductase inhibitors, and flutamide are addressed by authors who have had extensive clinical experience with the use of these agents.

The actions of honnones upon systems outside of the usual target sites for such molecules represents an area of increasing interest and growing clinical significance. This volume represents a cross-section of such actions of honnones upon several relevant sites. In the first chapter of this volume Dr. Malick discusses the current status of endorphins as analgesic agents. It is now known that a more primary level of control exists for iJ-endorphin in that a 41-amino acid pep- tide has been isolated from ovine hypothalamus; this peptide stimulates iJ-endorphin release as well as the secretion of corticotropin (Vale et al. , 1981). The analgesic properties of corticotropin and its immunoactive-like analogs are well known. so it does not come as a surprise that these two classes of analgesic peptides are regulated by a common hypothalamic con- trol peptide. It may also be of interest to observe that an increase in iJ-en- dorphin concentration in the pituitary occurs in genetically obese mice and rats, and that such obesity can be attenuated through the administration of nalaxone (Margules et al. , 1978). It has also been determined that genet- ically obese mice have a probable cholecystokinin deficiency in the cerebral cortex in that this peptide is a satiety-inducing agent (Saito, et al. , 1981). The analgesic properties of the latter have also been observed. The extra-pituitary actions of another pituitary peptide, as examined in the second chapter of this volume by Dr.

This book brings together some of the results and ideas produced by a large number of people-colleagues and students with whom I am privileged to work in the laboratory at Rockefeller University. In terms of my personal history I see it as a confluence of creative forces persons from whom I have learned. I was instructed in neuroanatomy by Walle J. H. Nauta at M. I. T., and later in a course at Harvard Medical School under the direction of Richard Sidman. At Harvard Medical School, where M. I. T. graduate students were allowed to cross register, the superb neurophysiology course was under the guiding spirit of Stephen Kuffler. Later, I benefited greatly from participating in his summer course in electrophysiological techniques at Woods Hole. Eric Kandel and his colleagues have provided us with the most exciting contemporary approach to the conceptualization and study of cellular mechanisms for behavior. Here at Rockefeller, Carl Pfaffmann and Neal Miller have been leaders in every sense of the word. Not only did they provide me with opportunities to grow to scientific maturity; they also set an example of clear thinking about mechanisms for mammalian behavior patterns. I wrote this book to show how the systematic use of increasingly detailed electrophysiological, neuroanatomical, and neuroendocrine tech niques can explain the mechanism for a mammalian behavioral response. The behavior in question happens to be sensitive to steroid hormones and plays a central role in reproduction."

Diabetes mellitus represents one of the most frequent and serious clinical syn dromes in contemporary medicine. Since the end of the nineteenth century, the endocrine pancreas has been implicated in the pathogenesis of this disease. Several pathologists of the twentieth century detected various lesions and mor phologic alterations in the pancreatic islets of diabetic patients, but the patho physiologic basis of their findings remained long obscure. The systematic mi croscopic work of WILLY GEPTS clarified the views and related the variety in histopathology to differences in origin, duration and clinical expression of the disease. Over the past two decades, the concept of a multifactorial origin of diabetes has become widely accepted. Various agents and mechanisms have been identified which can lead to a quantitative or qualitative deficit in pancre atic B-cells. The purpose of this book is to bring an update on the many path ways which may induce an absolute or relative insufficiency in insulin release and hence a diabetic state. Rather than bringing a complete account on all re search relevant to the understanding of the pathology of the diabetic pancreas, the authors of the various chapters of this volume have focussed on selected processes which can impair B-cell function, survival or regeneration.

Recent years have seen tremendous progress in the field of hormone action and consequent signal transduction. The 40th Colloquium Mosbach was devoted to the discussion of results concerning the molecular process of hormone action, especially the processes following hormone binding to the corresponding receptors. Structural and functional aspects of steroid hormone receptors as well as ion-channel-coupled and enzyme-linked receptors were treated in detail. Particular interest focussed on the latest results concerning transcriptional control, protein phosphorylation, the role of G-Proteins, oncogene proteins, involvement of phospholipases and the regulation of ion channels.

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.

As I reflect on the evolution of this book, I am struck by the differences be tween my early conceptions and the final product. When I was first ap proached by Springer-Verlag regarding a monograph on my interests in the area of fetal lung development, I imagined that it would be relatively easy to summarize my contributions, plus the work of other investigators as needed for proper perspective. This rather naive idea was abandoned as I prepared my initial outlines for the monograph. I quickly realized that con tributions from my laboratory are not sufficient for telling the story of "hormones and lung maturation." The result of this decision is a longer and more heavily-referenced book than I originally envisioned. Although I have attempted to discuss in considerable detail most aspects of hormones and the fetal lung, I know with certainty that I have not in cluded all relevant references in each area. In most of these instances this reflects my impatience or lack of diligence, and I offer my apologies to those investigators whose work has been so omitted. In some situations published work has not been cited in a deliberate decision to limit the breadth of discussion or, rarely, due to my judgment of major shortcom ings in experimental design or execution."

The term polycystic ovary syndrome (peOS) is meant to describe a clinical endocrinopathy characterized by menstrual irregularity and evidence of hyperandrogenism. While recognized since the 1800s, a clinical composite was not constructed until 1935 when Stein and Leventhal reported their findings of seven women with infertility, menstrual dysfunction, hirsutism, and enlarged ovaries. Notably, the ovaries contained numerous multiple cysts and the ovarian capsule was thickened. At the time, this preciseness of definition was sufficient to entitle the entity Stein-Leventhal syndrome. Subsequently, over the intervening years as investigators attempted to un ravel the pathophysiology and genesis of this disorder and the number of reported studies increased, there ensued a gradual and distinct terminologic conversion to polycystic ovary syndrome, which, whether intentional or not, connoted a less well-defined condition. Perhaps this is appropriately so, given the seemingly broadening spectrum of clinical presentations and the continuing debate over what constitutes peos. The expansive new knowledge about peos was discussed to a significant degree at an international symposium organized by Serono Symposia USA and held in Boston in the late spring of 1995. Ovarian physiology, including the fate of the follicular unit, was a central focus with several presentations on the genesis, growth, and death of ovarian cellular components. A discus sion of the regulation of ovarian cell function was also highlighted and comprised a major portion of the program."

Don't just survive - thrive! That's the message of this state-of-the-art guide to diabetes management. From causes, symptoms and side effects to treatments and diet, this book will help British diabetics understand all types of diabetes and delivers sound advice on staying fit and feeling great. The best-selling second edition has been updated to cover key information on managing pre-diabetes, plus new content on screening tests, medications and lifestyle advice. With additional information on the latest advances in therapy for diabetes and its complications, this new edition will make sure you're covered from every aspect.

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."

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.

In the last decade, it has become increasingly evident that the clini- cal and morphologic changes underlying many of the complications of diabetes, including cataract formation, retinopathy, nephropathy, neuropathy, and macrovascular disease, are preceded by a variety of disturbances of biochemical and physiologic origin. Dr. Cohen has recently written a superb monograph, entitled Diabetes and Protein Glycosylation: Measurement and Biologic Relevance, in which she thoroughly explores how enhanced nonenzymatic glycosylation in uncontrolled diabetes underscores the pressing need for main- tenance of long-term euglycemia. In the present volume, The Polyol Paradigm and Complications of Diabetes, she reviews, in a most succinct and thorough manner, how another biochemical mechan- ism, involving the polyol pathway, is involved in the pathogenesis of such diabetes complications as retinopathy, neuropathy, nephropa- thy, and cataract formation. Dr. Cohen gives us a clearly written and comprehensive mono- graph, reviewing the chemistry of the polyol pathway and of the aldose reductase inhibitors, and the pathophysiologic significance of increased polyol pathway activity in a variety of tissues affected by Vlll Foreword diabetes mellitus. She insightfully describes the relationship of increased polyol pathway activity to altered metabolism of inositol- containing phospholipids and to changes in various tissue concentra- tions of myo-inositol. Finally, she provides us with a careful review of the existing experimental and clinical studies with a variety of different aldose reductase inhibitors that have been and are being performed in the hope of preventing or reversing long-term compli- cations of diabetes.

Neuroendocrine Perspectives, Volume 7, is part of an international book series designed to keep clinicians and researchers appraised of important trends and new data in basic and clinical neuroendocrinology. It focuses on four very rapidly evolving major topics: - the role of dopaminergic regulation of the intermediate pituitary lobe in elucidating intracellular signal transaction pathways and other regulatory mechanisms involved in transsynaptic regulation of peptide biosynthesis, post-translational processing, and hormone secretion; - the physiological and clinical implications of corticotropin releasing factor for such areas as diagnosing Cushing's syndrome, defining the hypothalamic and pituitary origins of secondary adrenal insufficiency, and distinguishing Cushing's syndrome from psychiatric states associated with hypercortisolism; - the large number of neurotrophic factors that affect CNS neurons and of neurite promoting factors that modulate neuronal performance, with emphasis on their mechanisms of action and their possible therapeutic applications to peripheral neuropathies and central diseases; - and the many factors that regulate changes in female reproductive cycles during middle age, with careful distinction between neuroendocrine and ovarian components and special attention to the possible cause-and-effect relationship within the cascade of events resulting in acyclicity and infertility.

This book is an edited collection of the literature on leptin beginning with the discovery of leptin and a study of its affect on animals and in humans. Chapters will focus on the discovery, history, roles and regulation of leptin in all the major areas of physiology, as well as on assay methods, phylogeny and genetics. The timing of this volume is long overdue and is the first comprehensive coverage of leptin physiology in the field.

- This series is indexed in index Medicus

- The turn around time for this series is fast, making the research as accurate as a journal

Biomedical devices that contact with blood or tissue represent a wide range of products. Depending on their potential harm to a body, medical devices are categorized according to the degree, so their safety can be assured. All biomaterials are by definition designed to contact with a body for a certain period of time. The nature of the body contact, as well as the duration a material contacts with the body may initiate unwanted biological In comparison with invasive devices Oike catheters and medical responses. implants contact directly with tissue or with the circulating blood) non invasive devices (like wound-dressings and contact lenses contact with the skin, the sclera, and the mucosa or with open wounds) have a lesser risk of hurting a patient. When blood contacts with a foreign material, plasma proteins become absorpted to the surface within a few seconds. The reactions that follow, the so-called intrinsic pathway lead to the formation of fibrin and activation of platelets and white blood cells, result in blood clot formation."

Is the nephrology community facilitating excess cardiovascular deaths in patients with kidney failure and anemia by treating to a subnormal hematocrit? Why have clinicians and nephrologists permitted health insurance companies and the government to decide when anemia therapy should begin in persons with progressive kidney failure? Is iron the only variable that can be manipulated to maximize response to recombinant erythropoietin? Are we using too much intravenous iron in kidney failure patients, and is oral iron supplementation worthless in sustaining iron stores during long-term erythropoietin treatment? When does left ventricular hypertrophy begin to emerge in patients with progressive renal disease and is there convincing evidence that anemia is a significant cause of LVH in this setting? Is darbepoetin alfa, a new novel, long-acting erythropoietin, really superior to recombinant erythropoietin? This book is a compilation of proceedings from a conference in Brooklyn convened to address these and other controversial and unresolved issues in renal anemia management.

A little over 12 years ago I wrote a small volume entitled Infertility. It seemed to me at that time that significant advances in the field called for the publication of such a volume. The following is from the preface to that volume: During the past 15 years considerable progress has been made in the field of infertility diagnosis and management. It is perhaps a paradox that much of this increased knowledge has come about because of Western medicine's preoccupation with the search for a means to control reproduction. As a result, we have achieved new insights into the physiologic mechanisms involved in reproduction, and we have found better methods for measuring physiologic changes in reproductive health and disease. To these advances can be added improvements in the utilization of endoscopic and surgical techniques, in the diagnosis and treatment of infections and endometriosis, and in the treatment of hormonal disorders. During this period, too, through workshops and conferences and in journals and texts, these latest advances have been made available to physi cians, an outstanding example being the two volumes of Progress in Infer tility, edited by Drs. Jan Behrman and Robert Kistner. As necessary as these publications are, they do not offer an overall view of infertility diag nosis and management."

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.

THE STATE oF HoRMONE AcTioN levels were induced in concert with ligand occupa tion of certain membrane receptors and this second AND MoLECULAR REGULATION messenger (cAMP) was postulated to initiate intra cellular phosphorylation of unknown targets. At Molecular Endocrinology and Regulation is a this point, the field ofPeptide Hormone Action also burgeoning field, having experienced a remarkable came into being. period of growth since the late 1960s. At that time, These fields developed together for much ofthe there was no field of Hormone Action. The prevail next decade. Hormone Action Conferences invari ing view of how hormones worked ranged from ably contained talks on both types of receptors and effects on membrane transport of nutrients and progress was rapid and in concert with the explo precursors for RNA and protein synthesis, to effects sion molecular biology. In the steroid field, on the translation of mRN A at the level of ribo progress was more rapid initially, but by the mid somes. Therewas, however, asmallcadreofvoices 1980s, the peptide field attained equal mechanistic that predicted a possible nuclear action on mRN A status and the source of specialized conferences of synthesis. The first such paper was presented at the national endocrine meetings in 1967 and dealt with its own. Steroid hormone action investigators concen hormonal stimulation of oviductal protein synthe tratedonfirst understanding the "pathway" of action sis. It was about this time that a small group of for their hormones."

Physiological, pharmacological and molecular biological data generated over the past three decades have demonstrated the existence of two major families of extracellular receptors, the P1, a family of four G-protein coupled receptors and the P2, a family of at least 12 receptors responsive to purine (ATP, ADP) and pyrimidine (UTP) nucleotides through which adenosine and ATP can function as extracellular messengers. The present two-part volume represents an integrated compendium of invited chapters by leading researchers in the area focusing on advances in the understanding of purinergic and pyrimidinergic signaling systems, their role(s) in tissue function and pathophysiology and advances in developing potential new medications based on the modulation of P1 and P2 receptor signaling processes. The volumes will thus provide the reader with a topical, comprehensive and integrated overview of this important area.

Every year there are new and exciting developments in assisted human reproduction, but how much do we really know about the underlying causes of infertility? This volume explores recent progress in the understanding of the genetics of spermatogenesis and male infertility. Topics include fundamental advances and current problems in the development and function of the testis, an outline of clinical findings in male infertility and an overview of the role of the Y chromosome in male fertility. Comprehensive critiques of posttranscriptional control during spermatogenesis, mammalian meiotic sterility, and comparative genetics of human spermatogenesis from the perspective of yeast, Drosophila and mice provide a global overview of the field.