The title "Stem Cells from Cord Blood, In Utero Stem Cell Develop ment, and Transplantation-Inclusive Gene Therapy" suggests that more than one topic is combined in one workshop. Indeed, at first glance the recovery of stem cells from cord blood has to be seen as separate from the attempts to achieve effective in utero therapy by stem cell trans plantation, because the first issue deals with an innovative stem cell source as an alternative to bone marrow, which is already spreading rapidly in medical practice, whereas the second topic is still strictly ex perimental and only investigated in medical centers with the appropri ate background. It is, however, not only justified, but helpful to com bine the two topics in one workshop and consequently to cover them in the same volume of the Ernst Schering Research Foundation Work shop series, because they are intimately related and both based on the new insights into the biology of stem cells. Professor Werner Arber, the Nobel Laureate from the University of Basel, pointed out in his In- Professor Dr. W. Holzgreve VI Preface The participants of the workshop troductory Lecture that our understanding of hematopoietic stem cells as descendents of totipotent cells and our current approaches to using them in post-and prenatal therapy have been furthered significantly by genetic engineering technologies which are "artificial contributions to the process of biologic evolution.""

Polycystic ovary syndrome (PCOS) is the most common endocrine disturbance, affecting 10 15% of women in the UK. The definition of PCOS has been much debated, while its pathophysiology appears to be multifactorial and is still being actively researched. There is no doubt that PCOS has a significant effect on quality of life and psychological morbidity and, as many specialists are involved in its management, a multidisciplinary approach is required. The 59th RCOG Study Group brought together a range of experts who treat women with PCOS. This book presents the findings of the Study Group, including: a definition of PCOS the accuracy of diagnostic interventions the particular challenges of adolescent diagnosis and management the correlation to ethnicity current approaches to therapy the potential individualisation of therapy the role of the alternative therapies used to manage some aspects of PCOS."

The 15th International Symposium of the Japan Human Cell Society on Cell and Molecular Biology of Endometrial Carcinoma brought together leading researchers from Japan and around the world. The papers collected here are the work of twenty-two leaders in their field and are organized in ten major categories. The first section, in vitro experimental systems, takes up the pioneering work by Kuramoto in 1968 and Nishida in 1980 in establishing, respectively, the HEC-1 and hormone-responsive endometrial carcinoma cell lines. Other topics include apoptosis, proliferation, and growth factors; cell cycle regulators; signaling pathways; angiogenesis; carcinogenesis; hormones and hormone receptors; genes and gene expression; endometrial receptivity; and chemo-resistance and -sensitivity. Presenting the latest work in the cell and molecular biology of endometrial carcinoma, this volume is a valuable resource for gynecologists, pathologists, and molecular biologists.

Millennium Development Goals (MDGs) 4 and 5, created under the auspices of the United Nations, challenged political, financial, medical and civil society leaders to improve both child and maternal health. The 58th RCOG Study Group brought together a range of experts - including midwives, obstetricians and gynaecologists, anaesthetists and paediatricians - to provide an up-to-date review of progress to date and the challenges around meeting these MDGs. This book presents the findings of the Study Group, with sections covering: the size of the problem clinical problems and solutions - maternal clinical problems and solutions - neonatal training and development specific challenges in specific countries (Afghanistan, Zimbabwe, Egypt and Sri Lanka)."

Care for Children Born Small for Gestational Age is a comprehensive handbook that serves to synthesize the extensive recent literature in the area to provide a practical resource aimed at a wide range of healthcare professionals, including obstetricians, midwives, neonatologists, and primary care physicians. This comprehensive handbook includes an in-depth survey of the prevention, diagnosis, treatment and long-term monitoring of children born small for gestational age, as well as related conditions such as intrauterine growth restriction, metabolic syndrome and type 2 diabetes. Additionally, the short and long-term psychiatric and social consequences of this condition are addressed.

The pregnant host is at risk for any of the viral diseases her nonpregnant counterpart acquires. Additionally, pregnancy heightens our concerns regarding specific viral diseases be cause of their potential for enhanced adverse effects on both maternal and fetal well-being. All too often the obstetrician relinquishes responsibility for the management of the gravida infected by a viral pathogen, and those expert in infectious diseases are confounded by the influence of pregnancy on these conditions. A major goal of this textbook is to narrow the gap between the two aforementioned management dichotomies in the virally infected pregnant woman. Weare at the infancy of our understanding of viral infections in pregnancy. The current and anticipated advancements are due in large part to a burgeoning oftechnological achievements in the areas of immunodiagnostics, molecular biology, and pharmacotherapeutics. Our in utero diagnostic capabilities, both invasive and noninvasive, have also allowed us new opportunities to study the effects of various maternal infectious disease processes on the developing fetus. New insights have been recognized pertaining to the maternal-fetal interface, the placenta, in that this structure is now acknowledged to function as both a mechanical and an immunological barrier to vertical transmission of infection. These observations suggest that there will be an outpouring of new data in the next several years that clinicians will need to master to maintain an appropriate level of expertise in the care of their patients.

It is in the surgical aspect of their specialty that the gynecologists' work may be most frequently judged by their peers or by the litigious society that currently exists. Great and commendable progress has been made over the past 30 years in the basic scientific, endocrinologic and obstetric aspects of the specialty, but this has occurred with a commen surate de-emphasis of surgical procedures and surgical training, a decline in devotion to technical detail and perfection, and a tendency to take surgery for granted. Obstetric and gynecologic residency programs provide increasing numbers of specialists with average competence in the performance of the common, rather standardized gynecologic operations. In general, technical skill in the extirpative operations can be acquired far more readily than proficiency in the art of reconstructive surgery. At present, for a number of reasons, gynecologic surgical training is most deficient in regard to the surgical correction of severe forms of obstetrically damaged genital tract supports. The operations for pro lapse defy standardization and require great technical individualization; this must be based on the surgeon's judgment developed through expe rience, a thorough understanding of normal pelvic anatomy, and recog nition of the deficiency responsible for the prolapse in individual cases.

The mechanisms that initiate labour (i. e., the conversion of the quies cent uterus to an active and reactive organ at term) are poorly under stood. Of considerable importance are the factors that control preterm labour and preterm birth, with their devastating effects on society. This problem is the leading obstetrical issue. Preterm labour affects ap proximately 10% of all pregnant women (even higher numbers are re- Abb. I. The participants of the workshop VI Preface ported for less developed countries or where prenatal healthcare is a low priority) and it is the leading cause of morbidity and mortality of babies. Current practices to arrest preterm labour, once initiated, are in effective. In addition, procedures to stimulate labour and dilate the cer vix at term may not be used effectively. On October 19th - 21 st, 1992, a Schering Foundation Workshop took place in Berlin to discuss the "Basic Mechanisms Controlling Term and Preterm Labour." Leading scientists from Europe and North America were assembled to consider the fundamental systems which regulate the uterus and cervix during pregnancy. The topics in the sym posium ranged from key cellular events governing uterine contractility and cervical dilatation during labour to clinical advances and applica tions. This book contains the proceedings of the workshop. We were pleased to have been part of the workshop and to have been responsible for its organization."

The advent in the 1960s of the unique and exciting new form of energy called laser brought to medicine a marvelous tool that could accomplish new treatments of previously untreatable disorders as well as improved treat ment of mundane problems. This brilliant form of light energy is many times more powerful than the energy of the sun yet can be focused microscopically to spot sizes as small as 30 microns. Lasers can be directed into seemingly inaccessible areas by mirrors or fiberoptic cables or can be directly applied into sensitive areas such as the retina without damage to intervening structures. There has been a rapid proliferation in the use of lasers in all surgical specialties. Starting with bold ideas and experiments of "thought leaders" in each specialty, the application of lasers has evolved into commonplace usage. Beginning with the era when laser presentations and publications were an oddity, now nearly all specialty areas have whole sections of meetings or journals devoted exclusively to laser usage. Laser specialty societies within a specialty have developed and residency training programs routinely instruct trainees in laser techniques. Basic science and clinical experimentation has supported laser knowledge. Laser usage has also become international. Newer wavelengths and accessories have added to the armamentarium of laser usage. Despite the rapid growth in laser interest, no single source exists to instruct the many new laser users in proper, safe, and effective use of this new modality."

The state of health care is reflected by perinatal and neonatal morbidity and mortality as well as by the frequencies of long-term neurologic and developmental disorders. Many factors, some"without immediately recognizable significance to childbearing and many still unknown, undoubtedly contribute beneficially or adversely to the outcome of pregnancy. Knowledge concerning the impact of such factors on the fetus and surviving infant is critical. Confounding analyses of pregnancy outcome, especially these past two or three decades, are the effects of newly undertaken invasive or inactive therapeutic approaches coupled with the advent of high technology. Many innovations have been intro duced without serious efforts to evaluate their impact prospectively and objectively. The consequences of therapeutic misadventures character ized the past; it seems they have been replaced to a degree by some of the complications of applied technology. Examples abound: after ov eruse of oxygen was recognized to cause retrolental fibroplasia, its restriction led to an increase in both neonatal death rates and neurologic damage in surviving infants. Administration of vitamin K to prevent neonatal hemorrhagic disease, particularly when given in what we now know as excessive dosage, occasionally resulted in kernicterus. Prophy lactic sulfonamide use had a similar end result. More recent is the observation of bronchopulmonary dysplasia as a complication of re spirator therapy for hyaline membrane disease. The decade of the eighties opened with the all-time highest rate of cesarean section in the United States."

Professor Philip Bromage From the earliest stirrings of modern surgical anesthesia, novice surgeons struggling to learn from the living what there was a strong intuitive feeling that anesthesia of part they were denied an opportunity to learn from the dead_ of the body would be better for the patient than complete But that is largely nostalgia for a past era_ Today, the visual anesthesia of the whole organism. In 1848, James Young arts and the plastics industry have united to give us superb Simpson spent some time and effort seeking this elusive teaching models and techniques that did not exist a few goal, but after a few ingenious though unsuccessful experi decades ago, and they have developed two- and three ments, he gave up the search and turned back to general dimensional surrogate cadavers that are imbued with a anesthesia as the only practical solution to surgical pain more vivid artistry than ever existed on the marble slabs relief at that time_ amid the formalin reek of our old dissecting rooms_ earl Koller's simple but brilliant application of cocaine to This book is a fresh and highly successful attempt to repair some of the bridges that were burnt with the passing of the the eye in 1884 opened the door to a whole new universe of neural anatomy and pharmacology_ Within a decade or old anatomy days_ Together, the authors have contributed"

T HE prediction of the probability of the safe passage of the fetus through the birth canal is the primary function of the attendant at the start of labor. The means of determining the relative size of the fetal head and the internal diameters of the pelvis have therefore been the objects of deep concern down through the centuries. Manual techniques of clinical evaluation of cephalo-pelvic relations reached their peak a generation or two ago. A massive nomenclature existed with respect to pelvic planes and diam eters. To these were related various positions, attitudes, stations, and synclitisms of the fetal head. Measurements depended on digital efforts to explore the interior and on dubious implications drawn from external pelvimetry. The mechanisms of labor, as it might occur under the innumerable possible pelvic measure ments and fetal orientations, were the subject of hours of stu dent drilling and remained a lifelong preoccupation of the most seasoned specialist. The increasing safety of cesarean section somewhat miti gated the consequences of error. When a borderline internal conjugate was digitally determined, a trial labor might be per mitted with the assurance that an ultimate solution was in reserve. Mistakes of two kinds persisted, however. On the one hand, trial labor might be permitted to continue too long and, with penicillin not yet discovered, a delayed cesarean section v vi Foreword could be perilous. Alternately, to be on the safe side, many un necessary elective sections might be carried out.

The fetal period of human growth and development has become an area of intense study in recent years, due in large part to the development of diagnostic ultrasound. More than 2,000 articles have been published in the last five years describing anatomy and pathology in utero, as reflected in sonographic images. Yet, no stan dard reference exists to correlate these images with fetal gross anatomy and at tempts to draw parallels from adult structure have often led to false assumptions. The dictum "the newborn is not a miniature adult" is all the more valid for the fetus. This text aims to provide a comprehensive reference for normal sectional anat omy correlated with in utero ultrasound images. In addition, magnetic resonance images of therapeutically aborted or stillborn fetuses are paired with similar gross sections to serve as a foundation upon which current in vivo studies may build. Lastly, a miscellaneous section illustrates several anatomic points useful in the understanding of fetal anatomy. These points include the changing anatomy of the fetal brain during gestation and the anatomy of the meninges, the fetal heart, and ductus venosus. It is our hope that this atlas will provide a clear picture of fetal anatomy, rectify some of the confusion which exists in antenatal diagnosis, and stimulate further interest in fetal development."

The state of health care is reflected by perinatal and neonatal morbidity and mortality as well as by the frequencies of long-term neurological and developmental disorders. Many factors, some without immediately recognizable significance to childbearing and many still unknown, undoubtedly contribute beneficially or adversely to the outcome of pregnancy. Knowledge concerning the impact of such factors on the fetus and surviving infant is critical. Confounding analyses of pregnancy outcome, especially these past 2 or 3 decades, are the effects of newly undertaken invasive or inactive therapeutic approaches coupled with the advent of high technology. Many innovations have been introduced without serious efforts to evaluate their impact prospectively and objectively. The consequences of therapeutic misadventures character ized the past; it seems they have been replaced to a degree by some of the complications of applied technology. Examples abound: after overuse of oxygen was recognized to cause retrolental fibroplasia, its restriction led to an increase in both neonatal death rates and neurologic damage in surviving infants. Administration of vitamin K to prevent neonatal hemorrhagic disease, particularly when given in what we now know as excessive dosage, occasionally resulted in kernicterus. Prophy lactic sulfonamide use had a similar end result. More recent is the observation of bronchopulmonary dysplasia as a complication of re spirator therapy for hyaline membrane disease. The decade of the eighties opened with the all-time highest rate of cesarean section in the United States."

The chapters in this book represent presentations at the first meeting ever held on the regulation and actions of follicle stimulating hormone. The meeting took place on the campus of Northwestern University, Evanston, Illinois, from October 25 to 28, 1990. The idea for this meeting was conceived by Neena B. Schwartz, and the valuable advice of the organizing committee contributed greatly to its scientific success. We gratefully acknowledge the funding and coordination of this meeting by Serono Symposia, USA. We also wish to acknowledge the financial contributions made by Northwestern University. We especially thank the invited speakers, poster presenters, and discussion participants who pro vided the science, interest, and enthusiasm that made this meeting on FSH a success. MARY HUNZICKER-DUNN NEENA B. SCHWARTZ vii Contents Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv 1. An Overview of FSH Regulation and Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ULRIKE LUDERER AND NEENA B. SCHWARTZ Part I. Neuroendocrinology of FSH Secretion 2. Modulation of Gonadotropin Secretion by Proteins of the Inhibin Family: Studies in the Female Rat. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 CATHERINE RIVIER AND WYLIE V ALE 3. Control of Follicle Stimulating Hormone Secretion in the Male Rhesus Monkey (Macaca mulatta) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 TONY M. PLANT 4. The Physiology of Puberty in Seasonally Breeding Birds . . . . . . . . . . . 54 BRIAN K. FOLLETT 5. Hypothalamic Regulation of FSH Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 JON E. LEVINE, LISA A. CONAGHAN, ULRIKE LUDERER, AND FRANK J. STROBL 6. Photoperiodic Control of Reproduction in Male Hamsters: Role of FSH in Early Stages of Photo stimulation . . . . . . . . . . . . . . . . . . . . . . . 83 FRED W. TUREK AND NEENA B."

The Helene Harris Memorial Trust has become recognized as providing one of the most important international fora for the presentation of research in ovarian cancer. Four biennial meetings have taken place, the most recent of which was held between May 11-14, 1993, in Toronto, Canada. This forum has grown in stature from its inception in 1987 and has brought together interdisciplinary clinical and scientific researchers from around the world who are endeavouring to perform 'cutting edge' studies in the field. The assembled group of presti gious investigators met on this occasion to present their data, to exchange ideas, and to arrange collaborations with the goal of developing new means of detection, treatment and cure of ovarian cancer. The incentive for the establishment of the Trust and its international forum was the prema ture loss through ovarian cancer of Helene Harris, the wife of Mr John Harris. Mr Harris and the Trustees looked for a meaningful way to honour the memory of Helene and to advance the noble cause of gaining an increase in the scientific knowledge of the subject. For those of us who spend most of our waking hours assisting patients and their families who are devastated by this disease, the Trust's generosity provides inspiration, hope and the opportunity for their practical application in a unique professional forum.

The International Women's Health Coalition was pleased to be the convenor and host of the first Christopher Tietze International Symposium, held in Berlin in September 1985. The papers in this volume represent a wide range of international views and experience with the prevention and treatment of contraceptive failure. We believe the issues discussed at the Tietze Symposium to be of interest and concern to women throughout the world and to those who would serve them. The Coalition intends to l1'ive broad distribution to this volume and encourages those interested in these issues to be in touch with the Coalition in New York City (see address below). We would like to thank The Ford Foundation, Stewart Mott, The David and Lucile Packard Foundation, the Population Crisis Committee, and The Uockefeller Foundation for their support of this Symposium. In particular we would like to express our appreciation to Sarah Lewit Tietze and Uta Landy for the devotion ann dedication which made this Symposium possible and a worthy memorial to Christopher Tietze.

Endometriosis provides a unique clinical and scientific challenge. It is being diagnosed with increasing frequency and yet we are unsure of the significance of this in many patients. Its appearance varies from a tiny focus of disease to a potently destructive phenomenon. Weare still unsure of the relative value of medical or surgical treatment. The pathogenesis and control of the cellular function of the disease proVide many scientific problems. The presence of a comparative normal epithelium, namely endometrium, provides a unique research opportunity. It is probable that only through basic science research will we be able to solve the clinical dilemmas that endometriosis presents. We felt that it was important to create a book that explored the important scientific and clinical problems. We therefore invited acknowledged experts from both Europe and the United States of America to review their fields. The purpose of these reviews is not only to provide a resource for clinicians and scientists but also to stimulate thought and new ideas for research and treatment. To fulfil that aim we have asked that the authors be more speculative than normal for a volume such as this. We thank them for responding to their task so well and hope that you will feel as stimulated by their efforts as we have been.

Interest in sexuality and reproductive function does not cease when people begin to age. Instead, a new set of questions arises. Women want to know if it is safe to have babies in their late thirties and early forties. They want to know more about hot flashes and other symptoms of menopause-which ones are dangerous and which are merely uncomfortable. They are eager to learn about the relative risks and benefits of estrogen replacement therapy. Men, too, are concerned about age-related changes in their sexual function. Experts in reproductive physiology, gerontology, and genetics met at the National Institutes of Health in June of 1984 to discuss these and other concerns about aging and the reproductive system. The conference on Aging, Reproduc tion, and the Climacteric was sponsored by the American Fertility Society, The National Institute on Aging, and the National Institute of Child Health and Human Development. This volume is based on the proceedings of that confer ence."

This volume contains papers presented at the Conference on the Demographic and Programmatic Consequences of Contraceptive In novations, which was sponsored by the Committee on Population and held at the National Academy of Sciences, October 6-7, 1988. The papers consider how new contraceptive methods currently being developed and changes in the use of already available contraceptives could affect contraceptive practice, levels and patterns of abortion use, and the health of women. In addition, several of the papers re view the probable consequences of introducing new technology into family planning programs in developing countries. The Committee on Population sponsored this conference in order to stimulate think ing and to provide a forum for scientists, family planning program managers, and donor agency personnel to exchange information and ideas about these important issues. The committee is publishing these papers to expand the discussion of consequences of contracep tive innovations and to give scientists, policy makers, and members of the public who could not attend the conference an opportunity to learn about new developments in fertility control and their likely consequences for individuals and the societies in which they live. NEED FOR NEW METHODS While a strong case can be made that the pill and the intrauterine device (IUD) have contributed to declines in the level of unintended pregnancies around the world, it is also clear that for many couples existing methods present problems.

The treatment of menopausal and postmenopausal symptoms is a focus of considerable debate, on account of both the medical and social factors involved. And perhaps the cause of the greatest current interest and concern is not so much the effectiveness of present-day treatment but its safety. Opinions on the subject vary; and to resolve the arguments we must turn to the results of scientific experiment, both the clinical and biological. It is only by comparing experimental results that it is possible to move forward, albeit slowly, towards a generally agreed consensus based upon objective scientific data. It is for this reason that we are particularly grateful to Ayerst Laboratories whose support and help have enabled us to turn our original proposal for an International Symposium into a reality. We are also grateful to the publishers for the efficiency with which they have organized the publication of the Proceedings. It is our hope and that of all the distinguished participants that all readers of this volume will be able to find something in it which will stimulate further thought and discussion - even though they may not necessarily agree with all the conclusions expressed - for the success of a Symposium turns not only on the subject under examination but also on the quality of debate and discussion it encourages.

About 21 years ago prenatal diagnosis became part of the physician's diagnostic armamentarium against genetic defects. My first monograph in 1973 (The Prenatal Diagnosis of Hereditary Disorders) critically assessed early progress and enunciated basic principles in the systematic approach to prenatal genetic diagnosis. Six years later and under the current title, a subsequent volume provided the first major reference source on this subject. The present second (effectively third) edition, which was urged in view of the excellent reception of the two earlier volumes, reflects the remarkable growth of this new discipline and points to significant and exciting future developments. Notwithstanding these advances, the use of the new tools and techniques for the benefit of at-risk parents has taken many more years than most anticipated. Key factors have been the lack of teaching of human genetics in medical schools in the preceding decades and the difficulty of educating practicing physicians in a new scientific disci pline. Even today the teaching of genetics in medical schools leaves much to be desired and this will further delay the introduction of newer genetic advances to the bedside."

The no-man's-land between reproductive physiology and immunology is becoming crowded. The last 10 years have seen a revolution in our under standing of many reproductive processes, brought about by the application of ever more sophisticated immunological methods. The increasing precision of these techniques has given us specific ways of assaying, enhancing or blocking hormonal mechanisms to yield more critical and interpretable information. In this volume eleven authors have presented the current status and future prospects of some immunological aspects of reproduction and fertility con trol. These include the relationships between mother and fetus, the diagnosis of pregnancy, the immunological complications seen in clinical management of human reproduction and some novel approaches for immunological control of fertility. We hope that in these chapters we have achieved an up-to-date account of a fast-moving field that calls on several disciplines. We intend the book to provide an adequate background and a current review for research workers and clinicians who wish both to understand the complex mechanisms involved and to develop improved scientific and clinical methods. We hope too that the student and newcomer will find this a useful reference book."

Discrimination of self from nonself is the major function of the immune system and understanding the mechanism(s) involved a main employer of immunologists. Hence, the age-old puzzle of why a fetus that contains a panel of major histocompatibility (MHC) antigens derived from its mother and its father is not rejected (spontaneously aborted) by lymphocytes from its mother who should theoretically recognize foreign MHC molecules from the father has remained of great interest. This dilemma has enticed immunologists and developmental biologists for many years. This volume was created to present the information currently on hand in this subject to the scientific public. The guest editor, Professor Lars Olding, has a long and distinguished history of contributions in this field, having been one of the main propo nents of the argument that lymphocytes from the fetus play an active role in this process by suppressing lymphocytes from the mother from proliferating and thereby acting as killer cells. His work has defined the phenomenon and identified suppressor molecules (factors) involved in the process. In a different but related chapter, Margareta Unander extends such observations to the clinical study of women with repeated "habitual" mIS carriages."

Surgical Diseases in Pregnancy explores the special problems confronted by the gynecologic surgeon treating pregnant patients. These problems include acute appendicitis, inflammatory bowel disease, breast cancer, carcinoma of the cervix, ovarian tumors, renal stones, and incompetent cervical os. Other topics discussed are induced abortion; septic abortion and septic thrombophlebitis; ectopic pregnancy; surgical disease of the endocrine glands during pregnancy; gastroduodenal, hepato-biliary and pancreatic emergencies during pregnancy; pregnancy in the kidney transplant recipient; and pregnancy and cardiac prosthetic valves.