CRC ENDMETRM PDF

Preface

The ENDOMETRIUM is a research-oriented text devoted to a comprehensive multidisciplinary account of the uterine endometrium. This book is the first to focus on the endometrium in terms of defining the regulatory biological interrelationships between epithelial and stromal cell phenotypes, endothelial cells, extracellular matrix and immunobiological elements. The aim is to provide a parent language and the principles to translate our diverse understandings of reproductive cyclicity and embryo-endometrial interrelationships into a vocabulary common to all investigators and students. This base will also serve to establish the endometrium, intellectually and technically, as a singular, productive, fundamental biological model system for investigators from a broad spectrum of disciplines interested in the regulatory biology of cell-cell, cell-substratum and reciprocal paracrine communication. This cardinal information will be complemented by emerging studies of oncology, aging and gene expression.

To accomplish these goals authoritative authors were enlisted. All are active in studies of the structure-function principles that govern endometrial biology. They were encouraged to go beyond cataloging basic information and build on emerging conceptual and technical motifs to critically reexamine the established database. This approach would support new directions and concepts and discourage insularity of ideas and practice thereby fostering an open forum that would promote a new inter-disciplinary interrogation of benefit to all members of the diverse community of reproductive sciences. Avenues would then emerge for the exchange of ideas, materials and technology, which is central to integration of fundamentals and the basis for continued discussion.

Until late in the 19th century our knowledge of the female reproductive system was fragmentary, limited to observations of gross morphology and physiology. These relatively uncompounded methods of study persisted until the 1920s when microscopically discernable changes replaced other forms of observation. The discovery of sex steroid hormones served to motivate and expand the scope of study of reproductive biology beyond the directly observable. Steroid biochemistry was later augmented by the discovery of the trophic hormones of pituitary and placenta. Post World War II access to pure steroid and polypeptide hormones allowed the production of specific antibodies and the application of immunobiologic strategies. From studies, focused predominantly on hypothalamic regulation of the pituitary, evolved the concept of negative feedback and the clarification of the basic principles of homeostasis. Electron microscopy revealed fascinating new vistas of cellular structure.

The application of the intellectual and technical assets of molecular biology then created a new atmosphere in reproductive sciences. The beginnings of an understanding of gene expression emerged. Advances in gene targeting technology crystallized the linkage between hormone receptor complexes and the cell specific nuclear genetic apparatus. It is sobering, however, that of the more than 50 gene knockout models in which the implantation process in the mouse is compromised, none has yet yielded a satisfactory molecular mechanistic explanation of embryo-endometrial interaction. Thus we are learning that the challenge for today's science is to pass beyond reductionist biology and embrace a diversity of analytical procedures and tactics even greater than available to investigators in other times. The application of both in vivo and in vitro methods, across disciplines extending from molecular biology to systems physiology, is an opportunity not previously available. It is in this context that lessons learned from the elucidation of endocrine/paracrine signaling pathways in species of varying cellular complexity will enlarge the prospect of altering reproductive processes. We may, in the future, be able to modulate physiological responses in different living organisms through the understanding of a series of common mechanisms.

There is no organ other than the uterus that, in the exercise of its normal functions, displays so great a range of cyclic complexities in growth and adaptation. Mammals in general, their reproductive systems more generally, testify to the adaptations, the diversion of strategies that have evolved to serve a common goal, i.e. a successful outcome of the sum of the processes, species and adaptations, which regulate gestation. Historically the uterus has not occupied the centre of reproductive biol-ogy research. Rather, it has played a role secondary to the analysis of ovarian and testicular function and gametogenesis. Yet these studies contributed to the recognition of the unique cyclicity of the endometrium in different mammalian species, particularly as it applied to the stringently regulated transient period during which the embryo is permitted to attach and implant. The fundamentals of this unusual program of regulatory cell endocrinology were utilized effectively to develop the technologies that allowed embryo transfer into the uterus to yield live off-spring. Yet in almost five decades of investigation we have not been able to resolve the most critical problems of infertility, pregnancy wastage and fetal growth restriction. Many of the contributions to this book relate the development and exercise of ideas and research programs that seek to enlarge our understanding of endometrial interactions with embryos and the outcome of pregnancy in a range of different mammalian species.

Two major issues, one cultural, the other technological have impeded our understanding of endometrial biology. Anthropocentricity has driven interest and funding to focus on efforts to develop experimental models from human systems. The bias favoring hemochorial placentation has deflected attention from nonprimate systems that provided the intellectual driving force for many early studies of embryo-endometrial interactions. Using contemporary analytical and judgemental tools, past investigators identified the hierarchy of processes that includes embryo attachment, initiation of placentation and the maintenance of pregnancy.

These studies established a conceptual framework that proved valuable in human studies which are necessarily limited by ethical, financial and societal considerations, as well as the relative inaccessibility of the organ. This has led to the increasing use of cell culture systems. However much remains to be done, particularly in improving our ability to culture specific primary cells. For example, despite the massive proliferative activity in the trophoblast that follows implantation and without which the conceptus is not viable, it still is not possible to produce sustainable proliferation in primary human trophoblast cultures. Nor have we the art and technology to develop cultures of primary endometrial cell phenotypes that respond faithfully to specific regulatory factors.

A few, too few, investigators continue to direct their attention to animal models for both comparative biology and species conservation purposes. Judging these data we are learning how to maximize the assets of comparative biology. The remarkable diversity of reproductive strategies to be found amongst mammalian species obligates every investigator to analyze in vivo and in vitro models, but to do so with caution. The programs that coordinate endometrial cell proliferation, growth and differentiation in different species afford the thoughtful investigator models in which both similarities and differences can prove instructive. It is to be hoped that studies of primates and other species will continue in the future with renewed vigor.

Even as this book was being organized it was apparent that our understanding of endometrial biology was in active transition. In the last decade genomics has evolved into a real scientific discipline. The sequencing of the genome has introduced astonishing technical advances and an unbelievable mass of data. With the first draft in hand, we are indeed entering the second genetic revolution. How will biology, reproductive science specifically, evolve from being a data-deplete to a data-replete science? How will the intellectual and technical level of effort and imaging advances in cell biology reshape our understanding of the endometrium and its interactions with the developing embryo?

Perhaps our next step in this second revolution, the focus of the next book devoted to the endometrium, will be the practices of functional genomics and proteomics. These emerging disciplines and their spin-offs will provide the information, interpretable on many different levels of biology, from which will materialize new perceptions of endometrial biology. Synthesis of data acquired using different tools (protein-protein interactions, mutational loss of function, computer derived ontogenesis) will require coordinated efforts to develop the algorithms and database correlates to integrate the data acquired by different tools and disciplines. The potential use of functional genomics will be the ability to utilize the data presented in this book and formulate protocols that will allow the simultaneous monitoring of many events, regardless of their level of expression, in an organism whose genome is entirely known.

Analysis of the genome will presage a new era of drug discovery in which therapy will be tailored to aberrations in the DNA sequence. Even if a free market economy will not support analytical and treatment practices based on specific single nucleotide polymorphisms (SNPs), a new molecular biology will emerge. Reproductive science has proved profitable for the pharmaceutical industry and will be a target field for the new pharmacogenomics. In time we will realize the promise that sequencing the eukaryotic genome will facilitate the solution of problems related to fertility, pregnancy wastage, endometriosis, cancer, reproductive aging and nuclear transfer technology and advance the design of novel contraceptives. New insights into the regulatory mechanisms integral to genetically controlled pathways will add a new dimension to the investigative abilities of the reproductive scientist. Promise approaches reality and as T.S.Eliot wrote, "and the end of all our exploring will be to arrive where we started and know the place for the first time."