A little picture is worth a million words. Chinese proverb Prenatal human development is an extremely complicated process related to genetics, biochemistry, anatomy, and physiology. There are no developmental changes, either chemical or morphologic, without simultaneous changes in molecular organization. The astonishing buildup ofbiostructures always precedes their proper function. The development of an embryo is genetically coded and is based on interactions related to the selective switching on and off of genes. Interactions are cell-to-cell mediated, mediated by extracellular fluids, or mediated by special pathways. Every substance involved in developmental is to be recognized by its target. interactions, before triggering a metabolic or a morphogenic event, Complex physical and immunologic recognitions are involved in the process of differentiation. Small pieces of evidence are collected to create a mosaic picture elucidating the development. This picture is fascinating and represents the biggest biological puzzle: the puzzle of development. There is no doubt that analysis of human prenatal development is a basis for understanding normal and pathologic relationships between structure and function. Today, there are approximately 2000 different inborn congenital anomalies and syndromes. This book attempts to present a complete realistic account of human morphogenesis, the differentiation of structures, using direct photographs of normal specimens obtained from legal medical abortions of unwanted pregnancies. Emphasis has been placed on contemporary techniques: histochemistry and scanning electron microscopy. The text is as simple as possible; meticulous detailed anatomic descriptions have been omitted.

These four volumes comprising "GnRH Analogues in Cancer and Human Reproduction" are a distillation of the presentations of the invited speakers at a landmark International Symposium bearing the same name, organized by one of us (B. L. ) and held in Geneva, Switzerland in February 1988. The Symposium was truly interdisciplinary spanning gonadal hormone dependent disease including various forms of cancer and ranging to control of fertility, both pro- and conception. The international flavor can be caught from the 480 participants and 259 contributors drawn from 14 countries. The Symposium, and therefore this book, would not have been possible without the backing of The International Committee for Research in Reproduction and the sponsorship of the International Society of Gynecologic Endocrinology, The Swiss Society of Fertility and Sterility, The University of Geneva School of Medicine, The Swiss Society of Endocrinology and The US Foundation for Studies in Reproduction Inc., and help from the World Health Organization. B. H. Vickery B. Lunenfeld June 1989 LIST OF CONTRIBUTORS TO THE SERIES H. Bartermann A. Abbondante First Institute of Obstetrics and Urologische Universitatsklinik Kiel Gynecology Arnold-Heller Strasse 7 University "La Sapienza" D-2300 Kiel 1, FRG Rome, ltaly M. Bartholomew P. Abel Department of Medicine/Endocrinology Department of Urology Milton S. Hershey Medical Center Hammersmith Hospital Pennsylvania State University DuCane Road PO Box 850, Hershey, PA 17033, USA London W12 OHS, UK D. Beck H.

The critical role of growth factors in normal as well as abnormal cellular growth and function has become overwhelmingly apparent in recent years. The significant advances in reproductive biology within this rapidly expanding field were highlighted at the Serono Symposia, USA, symposium entitled Growth Factors in Reproduc tion. The conference focused on growth factors as polyfunctional regulators of growth and development in the reproductive system. The program was organized into five areas: (1) growth factors as polyfunctional regulators of growth and development, (2) growth factors and gonadal function, (3) regulation of normal and neoplastic mammary growth, (4) regulatory peptides in reproductive tract development and function, and (5) embryo-maternal signaling. This volume constitutes the contributions ofthe invited symposium speakers and is organized into sections representing the five topic areas of the sessions. Drs. Eli Y. Adashi, Robert B. Dickson, David C. Lee, James Hammond, John A. McLachlan, and R. Michael Roberts, who served as chairmen ofthese sessions, not only provided invaluable advice and assistance in organizing the symposium, but contributed significantly to its content. The enthusiasm and esprit de corps of the poster presenters and discussion participants also helped make this symposium succeed as the first of its kind. Finally, special thanks are due Drs. James Posillico and Lisa Kern ofSerono Symposia, USA, for their guidance and support in the conception and planning of the symposium and in the publication of this volume."

These four volumes comprlslng "GnRH Analogues in Cancer and Human Reproduction" are a distillation of the presentations of the invited speakers at a landmark International Symposium bearing the same name, organized by one of us (B. L. ) and held in Geneva, Switzerland in February 19B8. The Symposium was truly interdisciplinary spanning gonadal hormone dependent disease including various forms of cancer and ranging to control of fertility, both pro- and conception. The international flavor can be caught from the 480 participants and 259 contributors drawn from 14 countries. The Symposium, and therefore this book, would not have been possible without the backing of The International Committee for Research in Reproduction and the sponsorship of the International Society of Gynecologic Endocrinology, The Swiss Society of Fertility and Sterility, The University of Geneva School of Medicine, The Swiss Society of Endocrinology and The US Foundation for Studies in Reproduction Inc., and help from the World Health Organization. B. H. Vickery B. Lunenfeld June 1989 xiii LIST OF CONTRIBUTORS TO THE SERIES A. Abbondante H. Bartermann First Institute of Obstetrics and Urologische Universitatsklinik Kiel Gynecology Arnold-Heller Strasse 7 University "La Sapienza" 0-2300 Kiel 1, FRG Rome, ltaly M. Bartholomew P. Abel Department of Medicine/Endocrinology Department of Urology Milton S. Hershey Medical Center Pennsylvania State University Hammersmith Hospital DuCane Road PO Box 850, Hershey, PA 17033, USA London W12 OHS, UK D. Beck H.

Due to the introduction of molecular and cellular biology approaches, our understanding of ovarian physiology has reached a new level during the last few years. The present volume provides a new perspective on the ovary from molecular and cellular to whole organ levels, from non-mammalian and rodent to human levels and from paracrine, neuroendocrine and endocrine levels as well. These papers represent the proceedings of the Ninth Ovarian Workshop sponsored by Serono Symposia, USA, July 9-11, 1992 in Chapel Hill, North Carolina.

Physical illness cannot be effectively treated other than in the context of the psychological factors with which it is associated. The body may have the disease, but it is the patient who is ill. Research psychologists from a number of different backgrounds have, in the past few decades, turned increasingly to the study of physical illness, and there is now an extensive literature on preventive behaviors, the role of stress in the etiology of illness, the patient's reactions to illness and its treatment, and the physician-patient relationship. At the same time practicing clinical psychologists have extended their concern beyond the treatment of speci fically psychiatric disorders, to include also the psychological care of people experiencing distress through illness or injury. Traditionally, these patients have tended to fall through the net, unless their distress is so great that it assumes the proportion of a psychiatric disorder that can then be treated in its own right. Because the physical disorder is the primary one, its existence has detracted from the salience of the very real emotional disturbance to which it can give rise. Moreover, emotional reactions in this setting, being the norm, seems to have been regarded as not meriting special attention and care. This situation is chang ing, and it is not just psychologists or psychiatrists who are responsible for the shift in attitudes. Within general medicine itself, there is now a renewed empha sis on the care of the whole patient and not just the disease."

Various scientific evaluations taken from these chapters were presented during the international symposium, 'Carcinoma of the Cervix, ' which was held from September 4-7, 1980 in Kiawah Island, Charleston, South Carolina, U.S.A. An international selection of research investigators have contributed reviews designed to be informative to medical, graduate and post-graduate students, as well as clinicians, oncologists and investigators working in the area of female carcinoma. An attempt has been made to provide a total coverage of current progress in carcinoma of the cervix. In particular, the following major areas are included: Epidemiology, Histology & Histochemistry, Ultra structure, Physiology & Biochemistry, Genetics & Cytogenetics, Immunology, Diagnosis, and Patho physiology & Complications. Major changes have occurred in incidence and mortality rates for carcinoma of the cervix in the past decade. Mass screening programs and their ability to detect earlier stage diseases have attributed to a reduction in invasive diseases. Most cervical cancers could be prevented by an extension of cytologic screening programs in high risk areas. Greater resources must be provided to reach high risk areas in order to prevent the occurrence of cervical cancer."

The purpose of this series of volumes is to present a comprehensive view of the complications that result from the use of acceptable diagnostic and thera peutic procedures. Individual volumes will deal with iatrogenic complications involving (1) the alimentary system, (2) the urinary system, (3) the respiratory and cardiac systems, (4) the skeletal system and (5) the pediatric patient. The term iatrogenic, derived from two Greek words, means physician-in duced. Originally, it applied only to psychiatric disorders generated in the patient by autosuggestion, based on misinterpretation of the doctor's attitude and comments. As clinically used, it now pertains to the inadvertent side effects and complications created in the course of diagnosis and treatment. The classic categories of disease have included: (1) congenital and developmen tal, (2) traumatic, (3) infectious and inflammatory, (4) metabolic, (5) neoplastic, and (6) degenerative. To these must be added, however, iatrogenic disorders a major, although generally unacknowledged, source of illness. While great advances in medical care in both diagnosis and therapy have been accomplished in the past few decades, many are at times associated with certain side-effects and risks which may result in distress equal to or greater than the basic condi tion. Iatrogenic complications, which may be referred to as "diseases of medical progress," have become a new dimension in the causation of human disease."

This volume represents the Proceedings of the World Conference on Embryo Transfer, In Vitro Fertilization and Instrumental Insemination held on September 24-27, 1980 in Kiel, West Germany. Professor Dr. L. Mettler and Dr. H. H. Riedel of Frauenklinik der UniversiUit in Kiel were the local co chairpersons, who contributed very richly to the program. Basic research, clinical trials, preparation of manuscripts, editorial assistance and presentation of results were generously supported by the following institutions and organizations: Kulturministerium des Landes Schleswig-Holstein Medizinische FakuItat der Christian-Albrechts-UniversiUit, Kiel Wayne State University School of Medicine; Detroit, Michigan, USA C. S. Mott Center for Human Growth and Development; Detroit, Michigan, USA Universitats-Frauenklinik und Hebammenlehranstalt; Kiel, West Germany Serono GmbH; Freiburg, West Germany Hutzel Hospital; Detroit Medical Center; Detroit, Michigan, USA Deutsche Gesellschaft fUr Gynaekologie und Geburtshilfe; West Germany Deutsche Gessellschaft zum Studium der Fertilitat und Sterilitat; Sektion Andrologie Thanks are also due to Aponti GmbH (5000 Koln 21), Bayropharm GmbH (5000 Koln 80), Deutsche Lufthansa (5000 Koln), Organon GmbH (8024 Oberschleissheim), Winthrop GmbH (6080 New Isenburg), and Wisap GmbH (8029 Sauerlach), for financial assistance. Sincere appreciation and gratitude are due to the contributors who meticulously prepared their chapters; to Ms Jackie Mucci for editorial skills and assistance, and Ms. Jackie Smieska for editorial help. Thanks are also due to Dr. H. D. Brackebusch for his assistance during the conference; to Ms. E. Seiss for her secretarial assistance; and to Mr."

The concept of the foeto-placental unit as an integrated endocrine organ has been defined recently by many in vivo studies at the 17th- 20th week of gestation. A functioning foeto-placental unit is necessary for most of the increased oestrogen production of pregnancy and for the provision of glucocorticoids and aldosterone to the foetus. Neither the foetus nor the placenta alone have the necessary enzyme systems for the synthesis of these groups of steroids. However, when the foetus and placenta function as a unit, all of the enzyme systems are present for the synthesis of these steroids from circulating cholesterol. The placenta, but not the mid-gestation foetal adrenal, can synthesize physiologically significant amounts of pregnenolone from circulating cholesterol. Part of the pregnenolone is converted to progesterone in the placenta by the 3 -HSD system (absent in the foetus). The progesterone is transferred to the foetus where it is transformed by C-II, C-17, C-18 and C-21 hydroxylases (all absent in the placenta) to cortisol, corticosterone and aldosterone. Pregnenolone transferred from the placenta to the foetus undergoes 171X-hydroxylation, side chain splitting and sulfurylation (absent in the placenta) and is converted to DHAS. The DHAS may undergo 161X-hydroxylation (absent in the placenta) in the foetal liver and be transported to the placenta as 161X-OH-DHAS. There it is subjected to a neutral steroid sulfatase (absent in the foetus) and is converted to oestriol by action of the 3 -HSD system and the aromatizing enzyme system."

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 is a unique book in that it brings together the two key investigative techniques in Gynaecology and Obstetrics, namely ultrasound and endoscopy. So often in the past they were regarded by their exponents as rival techniques but it is now recognised that they are complementary to each other. Consequently future trainees in endoscopy should become efficient in transvaginal sonography and vice versa. Ultrasound can be used to study the morphology of the pelvic organs such as the endometrium, myometrium and ovaries, and being non-invasive, safe and convenient can be repeated as often as is deemed necessary to monitor changes over time; for example in the investigation of the infertile woman the development of the dominant follicle, the maturation of the endometrium and the formation of the corpus luteum can be documented throughout the menstrual cycle while growth of ovarian cysts can be precisely measured to determine the need for surgery. A seldom-mentioned strength of the ultrasound examination is its interactive quality, for example by performing abdominal palpation during the scan, the mobility of the uterus and ovaries can be assessed. Also the images as they appear can be shown to the patient to aid understanding. Ultrasound can also determine function and the use of Doppler has been used for example to access endometrial receptivity, follicular maturity and the likelihood of malignancy in the endometrium or ovary.

The birth of a baby is the culmination of months of anticipation and plan ning. Most often, mother and infant are healthy and readily able to estab lish close contact-a bond. However, in some situations either mother or baby or both present complications. The more prompt and rational the treatment, the sooner the normal parent-infant relationship will commence. This book is devoted exclusively to the first days following birth. In its 15 chapters, postpartum and postnatal physiology and pathophy i: .;logy are reviewed by 18 specialists. Normal and abnormal development of mother and child is correlated with proven means of clinical management. Chapters 1 through 3 cover maternal postpartum developments and complications. Chapter 4 stresses the importance of a normal parent newborn relationship, a concept of increasing concern in modern society. The following ten chapters discuss neonatal physiology and pathophysi ology; the effects of obstetric anesthesia on infant behavior, pulmonary function measurements in the postnatal period and treatment of the sick newborn are discussed in detail. The final chapter reviews maternal and perinatal mortality; the data, based on extensive surveys in New York City, indicate that current management is effecting an overall decline in mortality."

by Dr. Donald L. King The past decade has seen the ascent of ultrasonography to a preeminent position as a diagnostic imaging modality for obstetrics and gynecology. It can be stated without qualification that modern obstetrics and gynecology cannot be practiced without the use of diagnostic ultrasound, and in particular, the use of ultrasonogra phy. Ultrasonography quickly and safely provides detailed, high resolution images of the pelvic organs and gravid uterus. The quality and quantity of diagnostic information obtained by ultra sonography far exceeds anything previously available and has had a revolutionary impact on the management of patients. High resolution static images permit the intrauterine diagnosis of fetal growth retardation and fetal abnormalities. In addition to tradi tional images, newer dynamic imaging techniques allow observa tion of fetal motion, cardiac pulsation, and respiratory efforts. The use of ultrasonography for guidance has greatly augmented the safety and utility of amniocentesis. One of the great virtues of diagnostic ultrasound has been its apparent safety. At present energy levels, diagnostic ultrasound appears to be without any injurious effect. Although all the availa ble evidence suggests that it is a very safe modality and that the benefit to risk ratio is very high, the actual safety margin for its use Vll as yet remains unknown. As a consequence, practitioners are urged to limit its use only to those situations in which genuine clinical indica tions exist and real benefit to the patient is likely to result."

The original series, Advances in Prostaglandin Research, edited by Sultan M. M. Karim, was published by MTP Press in three volumes in 1975 and 1976. A glance at those books illustrates the progress that has been made since then. The thromboxanes were mentioned twice (first publication 1975) and prostacyclin not once (first publication 1976); leukotrienes were only on the horizon. The amazing generation of research data in the last 10-15 years has given new, broad insights into many areas, including asthma, inflammation, renal, cardiovascular and gastrointestinal diseases and in reproduction, and has led in some instances to real clinical benefit. This series, Advances in Eicosanoid Research, reflects the current understanding of prostaglandins , thromboxanes and leukotrienes. The aim is to provide an introductory background to each topic and the most up-to-date information available. Although each book stands alone, the eicosanoids cut across many boundaries in their basic actions; selected chapters from each book in the series will provide illuminating and productive information for all readers which will advance their education and research. In the production of this series, I must acknowledge with pleasure my collaboration with editors and authors and the patient endeavours of Dr Michael Brewis and the staff at MTP Press. KEITH HlLUER University of Southampton England ix Preface This book is an appraisal of areas in human reproduction where eicosanoid studies (prostaglandins, leukotrienes and thromboxanes) are contributing to physiological and pathological awareness and clinical advances.

Ovulation Induction gives an integrated view of basic ovarian physiology, pathophysiology, and the clinical management of ovulatory disorders. It provides core information upon which specialists can base clinical decisions. The most important feature is the inclusion of newer agents now available for ovulation induction. Newer clinical applications for older medications as well as various treatment combinations (including GnRH analogs) are thoroughly discussed. There is a frank discussion of risks, side effects, and the expense related to ovulation inducing agents. Many of the results in this book have never before been published in book form. Topics examined include the neuroendocrine regulation of the menstrual cycle, ovarian physiology and in vitro fertilization, the diagnosis of ovulation and the role of ultrasound in monitoring the follicular response, the use of clomiphene citrate for ovulation induction, and the role of bromocriptine and related compounds for ovulation induction in hyperprolactinemia.

The aim of this book is to transmit the message that asphyxia is the major cause of infant mortality in the ne asphyxia-if severe, caus onatal period. The sequelae of ing cerebral palsy; if mild, leading to MBD to seizures are all potential risks. It is important to make young physicians and nurses aware of this complication of the birth period, how to avoid it, and how to treat it. Facilitating such awareness is the chief purpose of this book. Alberto Lacoius-Petruccelli New York 7 Contents 1. Asphyxia: Definitions, History, and Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2. Occurrence in Utero, at Birth, and after Delivery ................................. 17 3. Physiopathology of Asphyxia and Its Staging .................................. 21 4. Work-up and Treatment in the Newborn: Delivery Room, Nursery, and Perinatal leU 25 5. Mechanical Ventilators .................... 31 6. Prognosis ................................ 37 7. Brain Asphyxia and Hemorrhage ., ........ 51 8. Types and Stages of Fetal Anoxia: Anoxic, Anemic, Stagnant, and Histotoxic ......... 57 9. Embryonic and Fetal Periods .............. 65 10. The Placenta: Origin and Functions ........ 77 9 CONTENTS 10 11. Fetal Circulation 87 12. Placental Insufficiency or Dysfunction ..... ."

The motive to prepare this volume on antibiotics for the physician caring for women was based upon the editor's perception that the subject matter had never been fully developed for the obstetrician-gynecologist. Most textbooks of infectious disease have a small section devoted to antibiotics, which has little relevance for the physician caring for post-operative or post-partum infections. Basic antibiotic pharmacology is described and there is a reflex prohibition of antibiotics for the pregnant woman. Correctly, the reader assumes that the authors themselves do not care for women with bacterial infections of the pelvis. Recent texts in infectious disease in obstetrics gynecology have been little better. Although the focus has been more clini cally oriented, space requirements have too often kept the discussions at a superficial level. A total focus upon antibiotics in this volume eliminates the restraints of space in prior publications. The greatest reward in my task as editor of this volume is related to the quality of the individual authors. They range from former students, to con temporary colleagues, to respected peers in infectious disease. Since the quality of this volume is related to the sum total of the individual chapters, I wish to comment about each of the contributors. Philip Mead from the University of Vermont is an old friend, who brings to the question of prophylactic antibiotics, his wide clinical experience and encyclopedic knowledge."

Bernard (Barney) Berelson had a major influence in the application of social science concepts and methods to population policy during the period from 1962 to 1980. This was the period when concern with population problems spread from a relatively small group of scholars and population activists to a much larger, diverse, international group of political and intellectual leaders and to the general public as well. There was an exponential growth in the number of scholars and service personnel in vari ous population and family specialities in this period. Barney came into the field with his appointment as Director of the Com munication Research Program of The Population Council in 1962. He had no previous training or experience in demography. Frank Notestein, Presi dent of The Population Council at the time, had the wisdom to appreciate the value and relevance of Barney's itTIpressive background in communica tion research and other social science areas, as well as his creative mind and leadership qualities. His influence on the Council's rapidly expanding program was so immediate and impressive that within a year, he was named Vice President. When Frank Notestein retired in 1968, Barney became President, a post he held for 6 very productive years."

Extensive basic research and clinical trials have in some aspect of reproductive physiology, gyne been conducted on inert and medicated intrauterine cology, or family planning. There is in this volume devices. In the last decade, substantial progress has an attempt to provide a total coverage of current been made in understanding the modes of action progress in medicated intrauterine devices. The and the physiological mechanisms of IUDs - pro volume is intended for a broad readership, includ gress resulting from modern techniques and in ing physicians, medical workers, medical personnel, strumentation in microanatomy, immunology, pa and administrators in family planning. It is hoped thology, endocrinology, biochemistry and biophy that this volume will serve as a stimulus to basic sics. Such studies, however, are scattered in such a scientists and clinicians concerned with intrauterine wide spectrum of journals that the clinician and devices to intensify their research toward better family planner can hardly keep up to date with the contraceptive techniques. advances. An attempt is made in this volume to coordinate physiological and clinical parameters. Little is September 1980 known about the possible role of diet, diseases and environmental factors. E. S. E."

Contraception is the most comprehensive exploration of the newest technologies in the area of contraception. Edited by renowned authorities Dr. Donna Shoupe and Dr. Florence Haseltine, with chapters written by leaders in the field, this book comprises the most up-to-date, practical and clinical information available and presents a thorough examination of clinical efficacy, side effects, mechanisms of action, and benefits of all types of contraception, including: - chapters on the IUD, the new subdermal implant Norplant, injectables, the diaphragm, condoms, sponge, female sterilization, vasectomy, and more - discussions of cutting edge contraceptive technologies, including the new progestin oral contraceptive pills, contraceptive vaginal rings, and RU 486, - an important chapter on AIDS and contraception. This book will serve as an invaluable reference providing useful, instructive background information and pertinent clinical applications for the physician, resident, and researcher. At such an exciting time for contraceptive technology, no one in the field can afford to be without this text.

The course of history is never one of smooth progression. Periods of relative quietness are interrupted by periods of wars and revolution. This pattern resembles that of a river which, before flowing into the delta, has to pass countless rapids. The same holds for the development of the science of medicine. In obstetrics some of these 'revolutions' or 'rapids' consist of the introduction of conservative obstetrical treatment by Lucas Johann Boer at the beginning of the nineteenth century, the discovery of the cause of puerperal sepsis by Oliver Wendell Holmes and Semmelweiss between 1843 and 1847, the introduction of the principle of asepsis by Pasteur in 1874, the introduction of prenatal care at the end of the nine teenth and the beginning of the twentieth century (Mijnlieff, Treub, De Snoo), the improvement of surgical techniques, the possibility to treat shock by bloodtransfusion, and, finally, the acquisition of new means for the effective therapy of infection. All these developments have led to a sharp reduction of maternal and perinatal mortality. In this connection it must be pointed out that such a reduction could never have been accomplished without the favourable social changes as a result of which medical and prenatal care could be made universally available. In recent years there has been another revolutionary develop ment in obstetrics. Two factors have been responsible for this: the ap plication of basic sciences in obstetrics, and the dissolution of the isolation with respect to other clinical disciplines."