In few areas of medicine is progress more spectacular than in the field of prenatal diagnosis. New clinical techniques such as chorion villus sampling, detailed ultrasound scanning and cordocentesis are being evaluated by obstetricians, and refinement of biochemical testing is widening the scope of maternal serum screening. In the laboratory, dramatic advances in molecular biology are occurring: families at risk of genetic disease can be investigated with gene probes, and preimplantation diagnosis of the embryo is now becom ing a reality. These technical advances have important ethical and practical implications, among which will be a further increase in public expectations of the standards required of antenatal services. Clini cians will need a high degree of skill to inform healthy women about the options for screening normal pregnancies, and to counsel high-risk women about the benefits and limitations of prenatal diagnosis. Obstetricians, scientists and health service managers will face the difficult task of deciding how prenatal diagnosis can be made available to women in a caring and cost-effective way. Recognising the rapid progress in this field, the Royal College of Obstetricians and Gynaecologists made prenatal diagnosis the subject of its 23rd Study Group. An international panel of leading researchers, whose expertise ranged from molecular biology to philosophy, was invited to participate in a three day workshop, with time for in-depth discussion as well as the presentation of papers.

In the past decade fetal heart rate monitoring has become a generally ac cepted method for fetal surveillance during pregnancy and labor. Although its importance has been doubted recently, I personally feel that this method has become an important obstetric tool. It has not only improved our knowledge about fetal behavior and fetal condition throughout gesta tion, but it has especially improved fetal surveillance during labor; the most dangerous period of human life has never been as safe as nowadays. The only people who can question the advantage of fetal heart rate moni toring are those who did not experience the period before fetal heart rate monitoring was generally introduced. The first paper on the history of fetal heart rate monitoring takes us back to the beginning of fetal surveillance and provides an introduction to the different aspects of fetal observation which are covered later in this volume. Common practices of fetal surveillance in different countries are discussed, and the paths that future developments will take are suggested. An outline of the physiological aspects of fetal heart rate regulation is fol lowed by discussion of the pathophysiology with which the obstetrician is very often confronted."

HRT and Osteoporosis is a response to the increasing awareness among both the medical profession and the general public that ovarian failure is an important cause of osteoporosis and that much of the bone loss after the menopause can be prevented by oestrogen treatment. There is now an urgent need on the part of women, their doctors and those responsible for public health policy for practical guidance on such questions as the safety and acceptability of long-term treatment with sex hormones, the economic costs and benefits of such treatment, and the role of specialists and GPs in promoting and monitoring hormone replacement therapy. All these issues and more are considered here. The book comprehensively reviews current knowledge of the subject and gives recommendations for clinical practice and future research.

It will be a long time before the quality of this profusely illustrated book is overtaken and the present spate of books on the subject of obstetric ultrasound may, as a result, suffer a numerical set-back - especially with translation into English which will "deliver the milk on everyone's doorstep". Two of the authors studied in our department in Glasgow and worked like If there are any rewards for teaching, then we humble Scots who demons. have had the privilege have had more than our share as a result of the pride with which we regard our pupils. In my own old age and looking back over the last thirty years, the innumer able difficulties, set-backs and disappointments have been more than compen sated for by those who have turned the subject from a laughable eccentricity (as I have at one time experienced) into a science of increasing exactitude. This transformation has come about, not by any efforts of mine, but by the enthusiasm and ingenuity of those who would probably have achieved as much on their own if given the encouragement which I ultimately received in Glasgow University life. Limbo must be the expected lot of most of us ordinary mortals but the work lives on. And so, in this reminiscent and philosophical mood I beg leave to quote a little poem which I wrote at an age when young men do that sort of thing.

The first edition of "Testosterone: Action, Deficiency, Substitu tion" was published in 1990. Since then our understanding of the hormone that turns males into men has tremendously increased. Therefore, the editors felt that a second extended edition of the book is warranted in order to summarize established and recent findings in the field and to present the reader with an up-to-date is reflected by the textbook. The increased mass of knowledge growth of the volume from 14 to 20 chapters. In the updated edition the biochemistry and metabolism of androgens have been complemented by extensive information on the molecular biology of the androgen receptor and its disorders. The key role of testosterone in spermatogenesis is now better de fined. We have a more complete understanding of the psychotro pic effects of testosterone and know so much about the different target organs and functions that individual chapters deal with testosterone and the prostate, lipids and the cardiovascular sys tem, hair, bones and muscles. The general chapter on pharmacol ogy and clinical uses of testosterone, in particular in male hypo gonadism, is extended by pharmacokinetic studies on testoster one preparations and individual substitution modalities using testosterone esters as well as implants and advanced trans dermal applications. The physiologic basis and possible clinical applica tions of testosterone in non-gonadal diseases, in male senes cence, in hormonal male contraception and in transsexuals are discussed. The last chapter describes the role of "investigative" steroid biochemistry applied to tracking anabolic steroid abuse."

Starting in 1986, the European School of Oncology has expanded its activities in postgraduate teaching, which consisted mainly of traditional disease-orientated courses, by promoting new educational initiatives. One of these is the cloister seminars, short meetings intended for highly qualified oncologists and dealing with specific, controversial aspects of clinical practice and research. Another is the institution of permanent study groups, also called task forces, where a limited number of leading experts are invited to meet once a year with the aim of defining the state of the art and possibly reaching a consensus on developments and treatment in specific fields of oncology. This series of ESO Monographs was designed with the specific purpose of disseminating the results of the most interesting of the seminars and study groups, and providing concise and updated reviews of the subjects discussed. It was decided to keep the layout very simple in order to keep costs to a minimum and make the monographs available in the shortest possible time, thus overcoming a common problem in medical literature: that of the material being outdated even before publication. Umberto Veronesi Chairman, Scientific Committee European School of Oncology Table of Contents How to Read this Monograph F.CAvALLI ......... . 1 Experimental Strategies for Studying the Development of Breast Cancer with Special Reference to Steroid Hormones, Growth Factors and Oncogenes R.J.B. KING . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 5 . . .

Reproductive ageing affects both individuals and wider society, and obstetricians and gynaecologists are witness to the impact of reproductive ageing and to some of the fears and misapprehensions of the general public. This book raises awareness of societal trends and their implications. The wider importance of the subject to the whole of society is emphasized by contributions from outside the world of obstetrics and gynaecology, both within and outside medicine. The 56th RCOG Study Group brought together a range of experts to examine reproductive ageing. This book presents the findings of the Study Group, with sections covering: background to ageing and demographics basic science of reproductive ageing pregnancy: the ageing mother and medical needs the outcomes: children and mothers future fertility insurance: screening, cryopreservation or egg donors? sex beyond and after fertility fertility treatment: science and reality - the NHS and the market the future: dreams and waking up."

This book helps to improve the quality of the care in gynaecological practice. Improvement is driven by clinical effectiveness and increasing patient demands, and for each area of practice described this book outlines the service organization needed to achieve this improvement. The goal is to help clinicians take responsibility for developing services that meet the needs of their patients as well as managing their individual medical conditions. The book demonstrates that much can be achieved within current resources and without the need for major additional expense. Different approaches are demonstrated but the key issue is the patient pathway, with the underlying philosophy of continuous improvement in quality. Trainees, clinicians, managers and commissioners of services in obstetrics and gynaecology will find this book of immense practical value.

Technical improvements over the past twenty years have made endos copy the procedure of choice for examination of the hollow organs of the genitourinary and gastrointestinal tracts. The development of electro surgical techniques, laser technology, injection therapy, and a wide variety of other modalities now allow the endoscopist to treat many problems that in the past required open surgery. The simultaneous development of transcutaneous abdominal sonography has had an equally dramatic impact on the practice of gastrointestinal and geni tourinary surgery. The marriage of these proven technologies, known as endoscopic sonography, provides an exciting new modality that promises to further revolutionize the diagnosis and management of many intraabdominal diseases. Endoscopic sonography opens new frontiers by overcoming the primary limitations of its parent technologies. Fiberoptic endoscopy is limited by the inability to see beyond the luminal surface, this is particularly important when considering neoplastic disease because depth of wall invasion is a key factor in determining treatment. The limiting factor in transcutaneous sonography is the distance between the transducer and the target organ. With endoscopic sonography, the transducer is placed in close proximity to the target organ. This allows the use of high frequency waves (greater than 5 MHz), which provide better tissue resolution and eliminates the image distortion caused by overlying structures.

The majority of scientists interested in fertilization and early developmental processes will undoubtably have encountered the works of Alberto Monroy at some time in their careers. Alberto's contribution to this field spans oogenesis to embryogenesis, where he used physiological, biochemical and morphological tools to answer a number of basic problems in cell biology. This multi-disciplinary approach, together with his remarkable intellectual flexibility and humour has had an enormous impact on this field and all those fortunate enough to have worked with him. The chapters in this book have been divided into four sections. The initial presentations revolve around late events of gameteogenesis, that lead to a physiologically mature gamete. Probably the most exciting area for research at the moment is the identification of the cytoplasmic mechanisms responsible for the meiotic arrest of oocytes and the factors responsible for initiating their maturation (Chapters 3 and 4). Less is known about the physiological changes in the male gamete in preparation for fertilization and this may be identified as a major area for future research. Although comparable data for the plant kingdom is presently restricted to studies on marine algae, new techniques for isolating angiosperm gametes (Chapters 1 and 17) promise rapid advances in this field. The second section looks at the events and molecules involved in gamete recognition, binding and fusion. One of the most controversial topics is when does sperm-egg fusion actually occur (Chapter 14).

ENTERING ON A CREATIVE AND ENTERPRISING PROJECT, DRS. DIZEREGA and Rodgers have taken an innovative look at the peritoneum. They have provided an interesting, informative, and stimulating text about an organ that is rarely considered independently-usually being thought of only as a part of other organs or organ systems. The peritoneum is an active membrane that serves as both a secretory organ and a structure that modulates diffusion and osmosis. Both of these important functions are described in great detail. The text is divided in classic fashion. The authors first examine the peritoneal anatomy from both macro and cellular viewpoints, during which exploration it becomes clear that what appears simply to be a lacy covering over abdominal organs actually is a complex structure. Fur thermore, during the discussion on its embryologic development the au thors make comprehensible the complexity confronting the student of the peritoneum. The authors then proceed to the practicalities associated with this im portant organ. To surgeons, for example, the key to the peritoneum is understanding the organ's repair mechanism, as it is adhesions formed on the peritoneal surfaces that interfere with the surgeon's hope of success."

Many of the studies discussed in this book were addition to discussions of a variety of hormonal, presented at the First Pan American Congress of biochemical, immunological, physical, and me Andrology, which was held in Caracas, Venezuela, chanical approaches. It is our hope that the efforts in March 1979. An international group of in of the contributors will help to intensify research vestigators have contributed reviews designed to and development of improved methods for safely be informative to medical, graduate, and post regulating male fertility. graduate students, as well as clinicians and in vestigators working in the area of male reproduc G. R. CUNNINGHAM tion. Current physiological concepts that may W. B. SCHILL provide insight for new initiatives are examined in E. S. E. HAFEZ TABLE OF CONTENTS Preface v Contributors IX Foreword by C. SCHIRREN XI 1. PHYSIOLOGY OF MALE REPRODUCTION 1. Hormonal regulation of testicular function 5 P. FRANCHIMONT 2. Inhibin: new gonadal hormone 15 P. FRANCHIMONT, A. DEMOULIN, J. VERSTRAELEN-PROYARD, M. T. HAZEE-HAGELSTEIN, and J. P. BOURGUIGNON 3. Morphological features of the epididymis: possible significance in male contraception 25 T. D. GLOVER 4. Regulatory physiology of male accessory organs 35 E. S. E. HAFEZ and G. R. CUNNINGHAM 5. Methods for evaluating contraceptive techniques 41 T. Z. HOMONNAI and F. G. PAZ II. HORMONAL CONTRACEPTION 6. Inhibition of male reproductive processes with an LH-RH agonist 55 A. CORBIN and F. J. BEX 7."

This volume contains the Proceedings of the Serono Symposium on Pre implantation Embryo Development, held in Newton, Massachusetts, in 1991. The idea for the symposium grew out of the 1989 Serono Symposium on Fertilization in Mammals* at which preimplantation development was the predominant suggestion for a follow-up topic. This was indeed a timely subject in view of the recent resurgence of interest in this funda mental phase of embryogenesis and its relevance to basic research and applied fertility studies in humans, food-producing animals, and endangered species. The symposium brought together speakers from a broad range of disciplines in order to focus on key regulatory mechanisms in embryo development, using a wide variety of animal models, and on representative topics in human preimplantation embryogenesis. The culmination of preimplantation development is a blastocyst con taining the first differentiated embryonic tissues and capable of initiating and sustaining pregnancy. The central objective of the symposium was to throw light on the regulation of cellular and molecular events underlying blastocyst formation. It was particularly appropriate that the date of the symposium marked the 20th anniversary of the publication of the classic volume Biology of the Blastocyst, the proceedings of an international workshop held in 1970. This book, which summarized most of the information then available on this topic in mammals, was edited by the pioneer in blastocyst research, Dr. Richard B1andau, who was the guest speaker at the symposium."

A Woman With Cancer Deborah came to University Hospital when she was 25. She was the mainstay of a young farming family. Her husband, Merle, was now farming his family land, working hard to keep financially solvent during these difficult f;lrming days. They had four children: Carolyn, 4 months; Michael, 17 months; John, 4 years; and Susie, 5 years. There was nothing special about this woman or her circumstances; she was like every woman who had ordinary daily chores and responsibilities, people in her life about whom she cared and who cared for her, worries, goals, dreams, and her life before her. Deborah's 4-week postpartum checkup and Pap smear were normal; however, six weeks later she had heavy, irregular bleeding. To Deborah this symptom picture did not seem to fit the pattern of her other preg nancies, and so she returned to her doctor. A large lesion was found on the posterior cervix and biopsies of the tissue revealed moderately dif ferentiated adenocarcinoma of the cervix. Referral to the University Hospital 60 miles away confirmed the diagnosis. Further tumor workup, which included a pelvic ultrasound, bladder cystoscopy, sigmoidoscopy, and chest x-ray, was normal, although the IVP was notable for nonvi sualization of the right ureter, thought to be secondary to an enlarged lymph node."

Third edition of the atlas discussing pathophysiology, epidemiology, diagnosis, prevention and treatment of postmenopausal osteoporosis, as well as the importance of bone quality and strength in fracture risk.

Fully illustrated with over 120 full colour images
Thoroughly revised and updated new edition
Written by a team of world-leading experts in bone health

Recent advances in molecular biology have provided new dimensions in the study of the reproductive system. There has been major progress in our understanding of the molecular mechanisms of hormone action in the past few' years. The symposium on "Molecular Basis of Reproductive Endocrinology" was organized to highlight new research findings on the regulation of the hypothalamic-pituitary-gonadal axis. The emphasis of the symposium was on physiological questions answered by the molecular biology approach. Studies on the functional relevance of gonadotropin releasing hormone and LH and FSH gene expression were presented, together with research on the molecular biology of ovarian and testicular steroidogenic enzymes and protein hormones. Also, several novel aspects of hormone gene expression in placental tissues were reviewed. The symposium was held July 25 to 26, 1991, immediately prior to the 24th Annual Meeting of the Society for the Study of Reproduction, on the campus of the University of British Columbia in Vancouver. Serono Symposia, USA generously financed and coordinated the meeting. We are indebted to Dr. Bruce K. Burnett and Dr. L. Lisa Kern for their professional assistance in the organization of the symposium. We would also like to thank Drs. Victor Gomel, Basil Ho Yuen, and John Challis, who served as session moderators. Most of all, we truly appreciate the efforts of all the invited speakers, poster presenters, and discussants in making this a memorable event as the largest one-day meeting of the Serono Symposia USA, series.

Although neonatal screening was begun only 20 years ago, and is consequently still in its early stages, it is already a classic example of efficient preventive pediatrics. At present, routine neonatal screening covering a satisfactory percentage of newborn babies is carried out in only a small part ofthe world. For some five diseases enough infants have been screened to give reasonably reliable information about the frequency of these diseases in various populations. Interesting differences are beginning to appear in popula tions of different ethnic and racial background. The medical importance of neonatal screening is especially obvious in metabolic diseases that are not too rare and for which effective treatment depends upon an early diagnosis, such as phenylketonuria, galactosemia, and - a more recent screening pro gram - hypothyroidism. About 1 of 4000 newborns is affected with hypothyroidism and can receive timely substitution with thyroid hormone. Of 34.5 million babies tested for phenylketonuria, 3000 cases have been diagnosed in time to prevent mental retardation by means of dietary therapy."

Over a mere 5 years, neonatal cranial sonography has evolved from an obscure and largely experimental imaging possibility to the modality of preference in the examination of the young brain. The almost immediate acceptance of the ultrasound examination of the neonatal brain was based on a number of coinci dent factors, the most important of which was the emergence of a burgeoning population of premature neonates who were, for the first time, surviving be yond infancy. These delicate patients were beginning to withstand the rigors of extrauterine life when not fully prepared for it; pulmonary, cardiac, and infec tious diseases no longer claimed most of them. With survival, a new specter reared its head: Would the eventual mental and neurologic status of these same children be worth the expense and time needed to bring them through their first months? This issue became increasingly pressing as evidence mounted through the 1970s that very premature neonates were at a high risk for intracranial hemor rhage and posthemorrhagic complications. An imaging modality that could evaluate the premature brain was sorely needed. The CT scanner with its proven ability to diagnose intracranial hemorrhage was of little value in this regard. So too were static gray-scale or waterpath ultrasound units. These modalities all had the same limitation, lack of portability. As neonatal intensive care units proliferated, so did the technology that would soon allow cribside neonatal neuroimaging, the real-time sector scanner."

Very thorough knowledge of breast pathology is a sine qua non for interpretation of breast films ... progress in X-ray diagnosis could only be made by careful comparison of the film with the actual specimen. H.INGLEBY Multiplication of the same e"oneous diagnosis does not make that diagnosis co"ect. J.G.AzZOPARDI Paradoxically enough, our specialty considers the radiologist who mis takes a skin fibroma or the calcifications in a sponge kidney for a kid ney stone to lack basic knowledge, while the radiologist who imme diately calls for the surgeon because of a few white spots on a mammogram is thought to be acting according to the rules of medical practice. Misunderstandings and confusion with regard to breast pathology as well as the comfortable philosophy that superfluous biopsies are the price we have to pay for the early detection of carcinomas have in many places led to a loss of confidence in mammography. Yet this is a meth od with which carcinomas can be detected earlier than with any other imaging technique.

The European School of Oncology came into existence to respond to a need for information, education and training in the field of the diagnosis and treatment of cancer. There are two main reasons why such an initiative was considered necessary. Firstly, the teaching of oncology requires a rigorously multidiscipli nary approach which is difficult for the Universities to put into practice since their system is mainly disciplinary orientated. Secondly, the rate of technological development that impinges on the diagnosis and treatment of cancer has been so rapid that it is not an easy task for medical faculties to adapt their curricula flexibly. With its residential courses for organ pathologies and the seminars on new techniques (laser, monoclonal antibodies, imaging techniques etc.) or on the principal therapeutic controversies (conservative or mutilating surgery, primary or adjuvant chemotherapy, radiotherapy alone or integrated), it is the ambition of the European School of Oncology to fill a cultural and scientific gap and, thereby, create a bridge between the University and Industry and between these two and daily medical practice. One of the more recent initiatives of ESO has been the institution of permanent study groups, also called task forces, where a limited number of leading experts are invited to meet once a year with the aim of defining the state of the art and possibly reaching a consensus on future developments in specific fields of on cology."

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."

Early embryonic loss is a continuing social and economic global problem. In human populations the estimates of interruptions early in pregnancy range from 35-60%. In animal husbandry (swine, ruminants) fully 30% of pregnancies fail to survive early events of gestation. The futility associated with this persistant high risk is even more unsettling because of advances made in assisted reproductive technology which, although this very selective methodology has added to our knowledge of embryo-endometrial interactions, has resulted in a birth rate of only 14%. These studies have instigated comparisons of the live relative contributions of the embryo and the uterus to the outcome of pregnancy. These analyses have shown that we have learned significantly less about the role of the uterus in deciding the outcome of either natural or assisted pregnancies. In 1979 a quotation by George Corner was used to set the tone of a meeting that was devoted to discussion of the cellular and molecular aspects of implantation. In spite of the proliferation in research activity which occurred in the following 15 years our real understanding of the embryo transfer process has fallen short of our expectations. We use the Corner quotation, once again, to preface this symposium so that we may recall that the fundamental nature of the process which regulates embryo-endometrial interactions still escapes us.

This series of volumes dealing with reproductive health care has as its primary objective the improvement of the quality of human reproduction. The of knowledge and new technology give us opportunities as never explosion before to accomplish this end. The Editor has brought together contributors who are outstanding scientists from around the world. A number of the authors have personally made significant contributions to our body of knowledge in reproductive medicine. Bringing all this information together in an easily readable format is a great service. This is essential reading for all concerned with the control and improvement of human reproduction and the correction of its many deficits. xv P'art I Physio-anatom-ical Parameters 1 Uterine microvasculature and spontaneous abortion M. TAKADA In the implantation and subsequent development of a fertilized ovum, its integrity is most significant. However, with maternal local factors, i.e., unsatisfactory uterine conditions, implantation may not succeed even if the integrity of the fertilized ovum is excellent; if implantation is made, the maturation of the fetoplacental unit following implantation is disturbed, which leads to abnormalities in fetal development or to miscarriage. Thus, the uteroplacental unit, as well as the fetoplacental unit, plays an important role in the establishment and maintenance of pregnancy. Among the mechanisms of the utero placental unit, most significant is the physiological mechanism of the uterine microvasculature and its correspon dence to gestation. In particular, homeostasis of simultaneous cooperative development of the uterine wall and the placenta is most important."

Decision making in modem obstetrics and perinatology is con trolled by a variety of different factors, but there is little doubt that in industrialized countries one of the most powerful single factors is the concern and fear of causing permanent brain damage in the unborn and newborn. The dramatic increase in the rates of abdom inal deliveries in many parts of the world is certainly rooted to a substantial part in the bstetrician's concern not so much about possible perinatal death, but more so about permanent brain dam age in surviving children. This trend has been accelerated by the increasing number of litigations in connection with brain damage observed in many societies. This problem itself has many aspects, but it seems evident that litigation - justified or unjustified - is one modem expression of the human and social tragedy inflicted on individuals and families by the birth of a brain-damaged child. The medical, social, and human importance of the problem is in sharp contrast to the relative lack of scientific knowledge avail able. This became very clear when the National Institutes of Health published the excellent review in 1985 on "Prenatal and Perinatal Factors Associated with Brain Disorders" and its editor, J. M."

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."