Reproductive Biology – serie

Reproductive tract infections (RTis) have become a silent epidemic that is devastating women's lives. Each year, thousands of women die needlessly from the consequences of these infections, including cervical cancer, ectopic pregnancy, acute and chronic infections of the uterus and the fallopian tubes, and puerperal infections. For many women, this happens because they receive medical attention too late, if at all. The terrible irony of this tragedy is that early diagnosis of and treatment for many RTis do not require high-technology health care. For the hundreds of millions of women with chronic RTis acquired from their sexual partners, life can become a living hell. Infection is a major cause of infertility, and it leads to scorn and rejection in many countries. These women may experience constant pain, have festering lesions of the genital tract, be at enhanced risk of second­ ary diseases, and endure social ostracism. The problems associated with RT!s have grown even greater in the past decade with the emergence of human immunodeficiency virus (HIV) and AIDS. Preexisting sexually transmitted disease, particularly when associated with genital tract ulcers, raises women's vulnerability to the transmission of HIV 3-5 fold.

The cause of many of the adverse reproductive outcomes and developmental diseases among offspring is not well understood. Most of the epidemiologic and experimental animal research has focused on the relationship between maternal exposures including medications, tobacco smoke, alcohol, infections, and occupation and the occurrence of spontaneous abortion, low birth weight, and birth defects. The potential role of paternal exposures has not been investigated as extensively despite long-standing animal research that demonstrates the induction of mutations in the male germ cell after exposure to certain agents and subsequent reproductive failure or early pregnancy loss. Given this relative lack of interest, acquisition of epidemiologic data and the development of a definitive model or mechanism for potential male-mediated effects has been hindered. However, recent laboratory and epidemiologic investigations have suggested that paternal exposures may be more important than previously suspected. This topic has been termed by some as "male-mediated developmental toxicity. " This is meant to refer to the effects of exposures and other factors relating to the male parent that result in toxicity to the conceptus and abnormal development. The developmental endpoints of interest can include fetal loss, congenital abnormalities, growth retardation, cancer, and neurobehavioral effects. These effects may operate through a variety of mechanisms including gene mutation, chromosomal aberrations, seminal fluid transfer of toxicants and epigenetic events.

The search for a reversible male contraceptive has centered upon the suppression of sperm production or sperm motility. Gossypol, a natural substance extracted from the cotton plant, appears to cause both of these effects. Its ability to reduce spermatogenesis in men is undeniable and has been demonstrated in both large studies in China and a smaller confirmatory study in Brazil. These investiga­ tions have revealed the remarkable fact that with gossypol, it is possible to separate an effect on the testis' gamete-producing function from an effect on its hormone-producing function. Thus, it is possible to maintain normal testosterone levels and libido while sperm counts (and motility) fall. Because of this unique and important action, gossypol warrants the fullest possible evaluation as a potential male contraceptive. Sheldon J. Segal vii ACKNOWLEDGMENT Lynn C. Landman played a major role in this publication by skillfully editing the manuscripts which were submitted for inclusion in this volume. Janet O'Connell added her efforts in editing, assembling texts and figures and handling final details required for publication. I thank these talented colleagues for their invaluable contributions.

The cause of many of the adverse reproductive outcomes and developmental diseases among offspring is not well understood. Most of the epidemiologic and experimental animal research has focused on the relationship between maternal exposures including medications, tobacco smoke, alcohol, infections, and occupation and the occurrence of spontaneous abortion, low birth weight, and birth defects. The potential role of paternal exposures has not been investigated as extensively despite long-standing animal research that demonstrates the induction of mutations in the male germ cell after exposure to certain agents and subsequent reproductive failure or early pregnancy loss. Given this relative lack of interest, acquisition of epidemiologic data and the development of a definitive model or mechanism for potential male-mediated effects has been hindered. However, recent laboratory and epidemiologic investigations have suggested that paternal exposures may be more important than previously suspected. This topic has been termed by some as "male-mediated developmental toxicity. " This is meant to refer to the effects of exposures and other factors relating to the male parent that result in toxicity to the conceptus and abnormal development. The developmental endpoints of interest can include fetal loss, congenital abnormalities, growth retardation, cancer, and neurobehavioral effects. These effects may operate through a variety of mechanisms including gene mutation, chromosomal aberrations, seminal fluid transfer of toxicants and epigenetic events.

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.

Pharmacokinetic variability of contraceptive steroids is a relatively under-explored area of contraceptive research, and hardly a common point of discussion among those who plan and deliver family planning services. Nevertheless, numerous independent studies over the last 15 years have indicated that women in different regions of the world vary in their pharmacokinetic response to contraceptive steroids. The causes of such variability are not known, but it has important consequences for contraceptive effectiveness. It may also offer insight to the basis of contraceptive side-effects. The impetus for this volume was to collect documentation of pharmacokinetic variability of contraceptive steroids, and to explore both the possible causes and implications of these data. Factors known to affect steroid pharmacokinetics, such as concurrent use of specific medications, are reviewed by Back and Orme. Other factors known to affect endogenous steroid dynamics are presented in chapters by Bradlow, Longcope, Goldin and Snow, because of their possible role in contraceptive steroid pharmacokinetics.

Over the past decade, the AIDS pandemic has propagated so widely and exerted such a dev­ astating impact that one may properly ask the question, Why not concentrate all AIDS efforts on disease control alone? Why link AIDS with women's reproductive health? What is the scientific basis for this linkage? And how might AID~ control and women's health objectives be promot­ ed simultaneously? These questions constitute the principal themes addressed in this monograph. The 15 chapters in this volume are intended to provide state-of-the-art reviews of key interac­ tions between AIDS and women's reproductive health for an audience of scientists and policy makers in the AIDS and population fields. Impetus for this monograph comes in pan from what we perceive to be an inadequate global response, thus far, to AIDS and women's health ;>roblems. A common platform has failed to emerge among the disparate professional communities working in the areas of AIDS, STDs, and family planning. As a result, endeavors in these fields have been isolated, and opportunities for joint action have been missed. An enormous and, as yet, unharnessed potential exists for power­ ful interdisciplinary collaborations that could strengthen policies and programs against these pressing health problems of humankind.

Human reproduction is the most dynamic of processes. The events which lead to the birth of a normal healthy infant have their origin long before actual fertilization. Indeed, the whole process can be looked upon as a continuum. Human fertilization and early development, once sequestered in the protective environment of the fallopian tubes and uterus, have now been exposed in the laboratory. These events have, over time, been extensively observed and catalogued in animal models. The tools of modem morphology and molecular biology have reopened issues long since considered settled as facets of early reproduction are reexplored. This volume, consisting of the proceedings of a workshop on uterine and embryonic factors in early pregnancy, has been designed to enhance that effort. Attention is focused largely on early embryonal development with special attention to the interrelationship between the embryo and the uterus in early pregnancy. Each of the contributing scientists brings with him or her the perspective of one specific discipline or another. The common denominator is the application of emerging techniques in modem molecular biology to problems pertaining to embryonal-uterine interaction. The goal is to consider specific areas of concern in a multidisciplinary way and to reexplore the factors behind early development and implantation. Uterine complement, the function of uterine macrophages immunoregulatory loops in the peri-implantation period, colony stimulating factors and interferon-like factors are reviewed and their interrelationship explored. Uterine angiogenesis factors as well as embryonic growth factors are also considered.

The annual meeting of the Perinatal Biochemical Group of the Spanish Biochemical Society held in Madrid on December 15-16, 1989, provided an excellent opportunity to bring together a group of distinguished investigators both from Spain and from abroad with a common interest in developmental endocrinology and biochemistry. The aim of the symposium was to present and discuss the most recent developments in the areas of endocrine and biochemical processes critical to normal growth and maturation of the newborn. To achieve a high degree of interaction among the participants, subject reviews as well as short communications were include in the program. The reviews provided in-depth information on selected important topics. The purpose of short communications was two fold: (i) to provide a forum to discuss on-going investigations on related areas; and (ii) to present opportunities for active participation by young investigators. This format proved very successful in generating fruitful discussions among the participants. Taken together the review chapters and the short communications have resulted in a coherent and unified subject presentation. Advances in biochemistry, molecular biology and cell biology have provided not only new and exciting experimental approaches but also have opened up new directions in the investigation of differentiation and developmental processes at cellular, molecular and biochemical levels during the early stages of growth and maturation. In recent years a wealth of information in these areas of development has emerged at a rapid rate.

Advances in basic biological research have proceeded rapidly in recent years. The fields of molecular genetics and immunology have experienced dramatic breakthroughs, capturing the imagination of both the scientific community and the general public. With less public notice, receptor biology has brought a cascade of new discoveries and insights. The entire science of pharmacology has been virtually rewritten in terms of receptor phenomenology. In particular, the discovery of specific receptors for steroid and protein hormones has been of seminal importance. With this new information, we have advanced our understanding of the mechanism and specifity of hormone action. We can now explain how hormones interact selectively with specific target cells and how hormones alter biochemical events within the target cells. These facts have already impacted on applied problems of clinical medicine, particularly in diagnosis and treatment of cancer and some metabolic diseases. Now, a new and important application of basic receptor biology and chemistry looms ahead. Within a few short years since the discovery of the progesterone receptor, chemists have synthesized molecules with a greater affinity for the receptor than progesterone itself and which, while occupying the receptor, fail to trigger the events which transform a target cell from the unstimulated to the stimulated state. This is the basis of the competitive inhibitory action of the anti-progestational agent, synthesized by the chemists at Roussel Uc1af, Paris, and designated RU 486.

Botanists and zoologists have recognized for centuries the specificity of various insects for plants, and entomolo- gists have long been aware that insects defend themselves from predators by emitting repulsive odors. Only recently have chemists and biologists established a joint endeavor for studying the chemical relationships between plants and insects. The present symposium volume of the Phytochemical Society of North America's RECENT ADVANCES IN PHYTOCHEMISTRY consists of eight papers dealing with phytochemical relation- ships between plants and their insect herbivores. The fifteenth P.S.N.A. annual symposium and meeting was held in August, 1975, on the campus of The University of South Florida, Tampa. The chemical defenses of apparent and unapparent plants were contrasted by Feeny. Rodreguiz and Levin illustrated parallel defense mechanisms of plants and insects and then Hendry, Kostelc, Hindenlang, Wichmann, Fix and Koreniowski discussed chemical messengers for both plants and insects. Subsequently Beck and Reese reviewed plant contributions to insect nutrition and metabolism.Indepth studies for the monarch butterfly-milkweed interaction were presented by Roeske, Seiber, Brower, and Moffitt and for the cotton boll weevil-cotton plant relationship by Hedin, Thompson, and Gueldner. In the latter portion of the symposium Rhoades and Cates presented a general theory concerning the coevolu- tion of insects and plant antiherbivore chemistry.

Contraceptive research has entered the new age of vaccines. Realistic prospects exist for the development of an entirely new battery of vaccines for use in human and veterinary medicine. Among them may be anti-fertility vaccines, based on physiological mechanisms applicable to either the female or male. This volume is a comprehensive review - a status report - of the subjects including fundamental work on the search for useful epitopes and ranging to applied vaccinology. One vaccine to prevent pregnancy, for use by women, has already been studied extensively. G.P. Talwar, the volume's editor and his colleagues in New Oelhi, India, published in 1976 a landmark series of papers describing the immunological properties of a preparation consisting of the alum-precipitated beta-subunit of human chorionic gonadotropin (hCG) chemically linked to tetanus toxoid. The principle of enhancing antigenicity of a self-protein by linkage of the epitope to a carrier protein was employed and tested clinically. These trials, carried out under the auspices of the Indian Council for Medical Research, were the first application of the carrier protein concept for a vaccine for human use. The encouraging results stimulated a wave of research not only on the use of hCG-based vaccines, but on other antigens as well.

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.

There is a prov1s10n in the charter of each Study Section of the Division of Research Grants at the National Institutes of Health that stipulates that "workshops" are to be held periodically to aid Study Section members in their appraisals of recent developments in their fields and to identify future challenges worthy of investigation. The Reproductive Endocrinology Study Section was established on December 13, 1985 to review research grants and research training activities relating to reproductive endocrinology, including aspects of management of reproductive endocrine disorders and hormonal imbalances as related to infertility and during pregnancy and puberty, breast cancer and prostate cancer. It held its first workshop, entitled, "Autocrine and Paracrine Mechanisms in Reproductive Endocrinology," in October, 1988 in Shrewsbury, MA at The Worcester Foundation for Experimental Biology. The proceedings of this workshop, which are detailed herein, reflect the fact that autocrine and paracrine interactions are rapidly being accepted as an exciting area of research by scientists investigating the physiological and biochemical mechanisms of hormone action in the male and female reproductive systems. The material covered is novel and wide-ranging, extending from theoretical considerations of mechanisms of growth factor action and the role of cell cycle stage in determining hormone action to investigations of autocrine and paracrine interactions during development to discussions of the potential clinical ramifications of the basic research findings. Such an extensive inventory is necessary for two reasons.

Reproductive tract infections (RTis) have become a silent epidemic that is devastating women's lives. Each year, thousands of women die needlessly from the consequences of these infections, including cervical cancer, ectopic pregnancy, acute and chronic infections of the uterus and the fallopian tubes, and puerperal infections. For many women, this happens because they receive medical attention too late, if at all. The terrible irony of this tragedy is that early diagnosis of and treatment for many RTis do not require high-technology health care. For the hundreds of millions of women with chronic RTis acquired from their sexual partners, life can become a living hell. Infection is a major cause of infertility, and it leads to scorn and rejection in many countries. These women may experience constant pain, have festering lesions of the genital tract, be at enhanced risk of second­ ary diseases, and endure social ostracism. The problems associated with RT!s have grown even greater in the past decade with the emergence of human immunodeficiency virus (HIV) and AIDS. Preexisting sexually transmitted disease, particularly when associated with genital tract ulcers, raises women's vulnerability to the transmission of HIV 3-5 fold.