Seminars in reproductive endocrinology最新文献

Since the advent of insulin therapy for diabetes mellitus, the survival of mothers with diabetes prior to pregnancy and their offspring has greatly improved. Nevertheless, the observation that the earliest stages of organogenesis can be impaired in the offspring of women with diabetes raises the question of how abnormal fuel metabolism disturbs embryogenesis. Research into this process has been made possible in recent years by advances in molecular biology which makes it possible to study gene expression in early embryos, and by the availability of genetically engineered mutant mouse strains. Using these approaches, a model is emerging in which elevated glucose, by disturbing expression of genes which regulate embryonic development and cell cycle progression, causes premature cell death of emerging organ structures, thereby causing defective morphogenesis. Investigation into the signaling mechanisms by which excess glucose metabolism exhibits toxic effects on embryo gene expression will explain how diabetic embryopathy occurs on a molecular and cellular level, as well as increase our understanding of the role of metabolic homeostasis in proper embryonic development.

Glucocorticoid hormone action in target tissues is modulated by 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which interconverts active cortisol and corticosterone and their inert 11-keto metabolites, cortisone and 11-dehydrocorticosterone. Two different 11 beta-HSD isoforms exist: a low-affinity NADP-dependent dehydrogenase/oxoreductase (11 beta-HSD1) and a high-affinity NAD-dependent dehydrogenase (11 beta-HSD2). This brief review describes the expression and distribution of 11 beta-HSD isoforms in human placenta. In particular, it discusses the results of studies dealing with the expression of 11 beta-HSD activity in experimental models representative of the fetomaternal interface in the early gestation. The findings have implications in terms of protection of the fetus against corticosteroid toxicity and modulation of active glucocorticoid levels and their biological effects in early pregnancy.

A variety of models have been developed to study endometrial receptivity which involves normal, appropriately timed endometrial development and remodeling for blastocyst attachment and trophoblast invasion during the luteal phase of the menstrual cycle. Due to species differences, the human is by far the best model per se by which to study human endometrial receptivity. Techniques have evolved to obtain in vivo data on endometrial receptivity using hysteroscopy, ultrasonography or magnetic resonance imaging. Despite species differences, comparative studies of mammalian models and tissue- and cell culture models using endometrial tissue or cells harvested at particular phases of the reproductive cycle, or following experimental manipulation, have been used productively to study endometrial function. Differences as well as similarities have proven to be instructive. Such models have been used to study a variety of entities, such as homotypic and heterotypic cell-cell interaction, the role of steroids, cytokines, growth factors, immunomodulatory agents and pharmacological substances. These models have also been used to study cellular, biochemical and molecular mechanisms involved with uterine receptivity. This chapter was designed to provide a critical review of contemporary literature relating to in vivo models and laboratory strategies and paradigms for the study of uterine receptivity for blastocyst implantation.

Implantation of the blastocyst in endometrium requires establishment of a coordinated molecular dialogue between the embryo and the endometrium. Factors instrumental in the preparation of a receptive endometrium are derived from the hypothalamic-pituitary-gonadal axis. These factors modulate the expression of genes that drive the endometrium throughout the characteristic menstrual cycles. During each menstrual cycle, a series of coordinated, architectural, morphological, cytochemical, and molecular changes ultimately lead to the preparation of a receptive endometrium during the putative "receptive period" or "implantation window." It is during this critical period that a proper dialogue can be established between an intrusive blastocyst and a receptive endometrium. If, for any reason, this dialogue is not established or is perturbed, the embryo is aborted. The natural fate of the receptive endometrium, in the absence of implantation, is development of a second set of changes that ultimately lead to menstruation. The identity of the molecular repertoire that makes endometrium receptive to implantation and/or lead to menstruation is being revealed and broadly includes cytokines, heat shock factors, adhesion molecules and matrix metalloproteases. We identified a novel gene of the transforming growth factor-beta, superfamily of molecules, the so-called endometrial bleeding--associated factor or ebaf, whose expression is confined to the late secretory and menstrual phases. Various forms of female infertility were associated with dysregulated expression of ebaf during the implantation window. The findings show an occult molecular defect of endometrial receptivity that seems to be due to dysregulated and premature expression of a member of the premenstrual molecular repertoire. The dysregulated expression of ebaf may assist in the identification, prognostication, and monitoring of treatment of infertile women.

Throughout life, the adrenal cortex exhibits dramatic morphogenic and steroidogenic changes. While there is subtle senescent decline in aldosterone, and a similarly subtle increase in cortisol, the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) decline with age in a situation similar to menopause, and this decline is considered by some to aggravate some age-related diseases. This decline is associated with an almost complete loss of the inner zone of the adrenal cortex, known as the zona reticularis. This review addresses these adrenal cortical changes, and explores their clinical significance. In particular, the clinical data on DHEA replacement in aging is addressed.

Cancer and its link to reproductive hormones is an area of intense concern for our patients and has been the subject of much speculation. But if estrogen causes breast cancer, for example, most women would eventually develop the disease. We know this is not the case! Actually, estrogen and progesterone have been linked to a decrease as well as an increase in cancer, depending upon the type of tumor under investigation. The purpose of this manuscript is to review the data supporting those relationships.

It is now recognized that immunosuppressive factors synthesized by placenta may play a critical role in the maintenance of pregnancy. Over the last several years our group and others have formulated a hypothesis that trophoblast Fas ligand (FasL) plays an important role in maintaining fetal immune privilege in human pregnancy by actively promoting apoptosis (programmed cell death) of activated maternal lymphocytes bearing Fas (i.e., the FasL receptor). This review initially provides background information and updates aspects of the Fas/FasL signaling system, including the role of caspases and molecules recruited to the Fasl/Fas signaling complex and the revised functions ascribed to membrane and soluble forms of FasL. Information is then presented concerning the role of FasL at immune-privileged sites including the eye and testis. Pathways through which the placenta and tumors avoid may avoid immune clearance vis-à-vis the FasL/Fas signaling cascade are described. A model is then presented through which FasL production by human syncytiotrophoblasts and extravillous trophoblasts may protect the fetus against the cytolytic actions of activated Fas-bearing maternal lymphocytes in the intervillous space and in the placental bed, respectively. We conclude with a review of studies in support this model that specifically demonstrate trophoblast expression of FasL and identify potential lymphocyte targets (i.e., Fas-expressing maternal immune cells) of trophoblast FasL.

Embryo implantation is a complex process consisting of multiple cross-talks between maternal and embryonic cells. Defining the mechanisms underlying implantation at molecular level is challenging task in reproductive biology. In order to identify molecules involved in cellular interactions between trophoblastic and endometrial epithelial cells, we have established two human cell lines, trophoblastic HT-H and endometrial epithelial SNGM. These two cell types exhibit cell adhesion at their respective apical cell membranes. Molecules involved in this unique cell adhesion were identified by expression complementary DNA cloning and were named trophinin, tastin, and bystin. Trophinin is a membrane protein thought to have self-binding activity and thus mediates homophilic cell adhesion. Tastin and bystin are cytoplasmic proteins required for trophinin to exhibit cell adhesion activity. Trophinin is strongly expressed in trophectoderm of monkey blastocysts. In human endometrium, trophinin is expressed for a limited period in the luminal epithelium at the time expected for implantation. In human placenta, trophinin, tastin, and bystin are strongly expressed in trophoblast and endometrium at the uteroplacental interface at an early stage in pregnancy. All these molecules disappear from the human placenta in the second trimester. The unique expression pattern and cell adhesion activity exhibited by trophinin, tastin, and bystin suggest strongly the involvement of these molecules in the initial attachment of blastocyst to uterus.

From animal and human studies is it clear that mammalian embryos are vulnerable to injury during the earliest preimplantation stages of development. Exposure to some agents during this brief period has resulted not only in fetal loss but also in malformations. Thus, the potential for maternal induced embryotoxicity exists earlier than previously expected. This period is marked by a drastic change in metabolic needs at the late morula stage. Glucose becomes the predominant exogenous energy substrate and enters the blastocyst via one of three facilitative glucose transporters, GLUT1, GLUT2, and GLUT3. It has been shown that maternal diabetes adversely affects the preimplantation embryo. Recent work has revealed that hyperglycemia leads to a downregulation of the GLUTs at the blastocyst stage in the mouse. This downregulation results in decreased glucose transport into the blastocyst of diabetic mice and thus lower intraembryonic free glucose levels. The embryos are starving themselves of the key substrate necessary for survival. Maternal diabetes also causes a decrease in the number of cells in rat blastocyst and recently hyperglycemia has been shown to induce apoptosis in the mouse blastocyst via cell death effector pathways involving BAX and caspases. Significant loss of key progenitor cells from the blastocyst may predispose these diabetic embryos to later developmental deficiencies manifesting as dysmorphogenesis, fetal loss or early growth delay. The hypothesis that the hyperglycemia-induced decrease in glucose transport triggers apoptosis is presented and discussed as a novel mechanism to explain preimplantation diabetic embryopathy.