Seminars in reproductive endocrinology最新文献

Members of the Transforming Growth Factor-beta (TGF-beta) family are one of the few endogenous inhibitors of cell growth. As uncontrolled cellular proliferation is a hallmark of cancer, an important question to address is how cancer cells escape normal growth regulatory mechanisms to become malignant. In this context, components of the TGF-beta growth response pathway are considered to be tumor suppressor genes, as absence of one or more of TGF-beta receptor and signaling proteins cause loss of cell growth regulation through an inability to regulate proteins that directly block cells in G1 phase of the cell cycle. Endometrial carcinoma (ECA) provides an excellent paradigm to study the changes that accompany loss of TGF-beta-mediated growth, control as a function of neoplastic development, since it is generally preceded by complex hyperplasia. Type 1 ECA is characterized as an estrogen-induced cancer, which responds well to progestin therapy. Since it has become increasingly evident that steroids can regulate growth through growth factors, ECA is also an ideal model for investigating the role for gonadal steroids in the loss of TGF-beta growth regulation in the etiopathogenesis of ECA. Thus, hormonal carcinogenesis adds another level of complexity in studying loss of growth regulation in human cancers. The purpose of this review is to 1) provide the most current background information on how TGF-beta functions including its activation, receptors, signal transduction mechanisms, and control of the cell cycle. 2) present recent information that shows how malignant cells subvert the growth inhibitory effects of TGF-beta by incurring defects in every aspect of the pathway that mediates the TGF-beta growth inhibitory response, and 3) describe the putative role for TGF-beta in the oncogenesis of ECA, provided primarily by the results from our laboratory. Understanding the molecular events involved in TGF-beta function in normal cells and its lack of function in tumor cells should identify novel therapeutic targets in human cancers.

This article reviews carbohydrate and fat metabolism in both healthy pregnant women and women with gestational diabetes. Emphasis is placed on more recent investigations that have utilized stable, nonradioactive isotopes with insulin clamps to study gestational fuel metabolism. In early pregnancy, glucose-stimulated insulin secretion is increased, insulin sensitivity is unchanged or enhanced, and glucose tolerance is normal or slightly improved. Late gestation is characterized by accelerated fetal growth, rising concentrations of several diabetogenic hormones, and increased insulin resistance. The increased resistance reduces maternal glucose utilization, sparing carbohydrates for the rapidly growing fetus. The inhibitory effect of insulin on the rate of lipolysis is also significantly reduced during the third trimester of pregnancy. An earlier than normal switch from carbohydrate to fat utilization serves to promote the use of lipids as a maternal energy source. Women with gestational diabetes have been reported to have either comparable or increased insulin resistance during late gestation with several studies also demonstrating reduced insulin secretory capacity.

The endometrium acquires the ability to implant the developing embryo within a specific time window, termed the "receptive phase." During this period the endometrium undergoes pronounced structural and functional changes induced by the ovarian steroids estrogen and progesterone, which prepare it to be receptive to invasion by the embryo. These steroid-induced molecules, when identified, may serve as useful markers of uterine receptivity. In the present article, we provide a brief description of the molecules that have emerged as candidate markers of steroid hormone action in rodents and humans during implantation.

Blastocyst implantation in the baboon usually occurs between 8 and 10 days post ovulation. Changes that occur within this window of receptivity and immediately following implantation can be divided into three distinct phases. The first phase, regulated by estrogen and progesterone, is characterized primarily by changes in both the luminal and glandular epithelial cells in preparation for blastocyst apposition and attachment. The second phase is the further modulation of these steroid induced changes in both epithelial and stromal cells by embryonic signals. The final phase is associated with trophoblast invasion and the remodeling of the endometrial stromal compartment. During the initial phase, the actions of estrogen and progesterone are dependent on the presence of specific receptors. Estrogen up-regulates both its own receptor (ER) and the progesterone receptor (PR), while progesterone down-regulates this expression pattern. However, the pattern of progesterone-induced down-regulation of ER and PR is confined to the epithelial cells and demonstrates a gradient effect from the functionalis to the basalis. What is most intriguing is that the loss of epithelial PR is closely correlated with the establishment of uterine receptivity. Coincident with the changes in ER and PR expression, epithelial cells undergo alterations in their cytoskeletal architecture and secretory profile. These changes can be counteracted by PR antagonist treatment during the luteal phase. Although estrogen and progesterone play a critical role in establishing the initial phase of uterine receptivity, it is becoming increasingly evident that the embryo induces functional receptivity in ruminants and rodents. In our studies in the primate, we demonstrate that chorionic gonadotrophin when infused in a manner that mimics blastocyst transit, has physiological effects on the three major cell types in the uterine endometrium. The luminal epithelium undergoes endoreplication and distinct epithelial plaques are evident. The glandular epithelium responds by inducing transcriptional and post-translational modifications in the major secretory product, glycodelin. The stromal fibroblasts initiate their differentiation process into a decidual phenotype and are characterized by the expression of actin filaments. In phase three, blastocyst attachment to the surface epithelium and subsequent implantation is associated with local remodeling of the maternal stroma, smooth muscle, and endothelium of the blood vessels by the trophoblast. In addition, there is a gradual diminution of the epithelial plaques on the luminal surface although the glandular epithelium remains highly secretory. The most dramatic effect is on the stromal fibroblasts, which in response to embryonic stimuli, differentiate into decidual cells, the major cell type of the gestational endometrium. This differentiation is characterized by the expression of insulin-like growth factor binding protein-1 (IGFBP-1) in these

Maternal steroid hormones play a critical role in establishing the receptive phase of implantation. In addition to that, the embryo is able to modulate endometrial molecules during the apposition phase (chemokines) and the adhesion phase (adhesion and anti-adhesion molecules). Moreover, the human embryo also exerts a coordinated regulation of endometrial epithelial apoptosis during these implantation phases. In this work, we analyze the embryonic regulation of implantation in humans using an in vitro model.

Partial reduction of molecular oxygen can generate reactive oxygen species (ROS), including the hydrogen peroxide, and the free radicals superoxide and hydroxyl. The formation of ROS is a feature of many degenerative diseases, such as atherosclerosis and neurodegeneration, Organisms contain a battery of defense mechanisms to prevent the formation of ROS, to scavenge them, and to repair the damage they cause. Free radicals are also involved in signal transduction pathways. For example, the free radical nitric oxide is involved in signal transduction in both the cardiovascular and central nervous systems. The interplay between nitric oxide and ROS has been a major focus of recent studies, as nitric oxide is an efficient radical scavenger. However, in some cases, such as in the formation of peroxynitrite from nitric oxide and superoxide, the product is potentially more deleterious that the parent radicals. This review describes the major chemical species involved in oxidative stress and free radical biochemistry, and gives a brief overview of their role in pathological conditions.

Our central hypothesis proposes that oxidatively damaged red blood cells (RBCs), apoptotic endometrial cells or undigested endometrial tissue may signal the recruitment and activation of mononuclear phagocytes. Women with endometriosis are prone to respond to this stimulus with an inadequate macrophage scavenger receptor response although the secretory response is not impaired. Activated macrophages in the peritoneal cavity generate an oxidative stress, which consists of lipid peroxides, their degradation products, and products formed from their interaction with low-density lipoprotein (LDL) apoprotein and other proteins. The lipoproteins of the peritoneal fluid (interstitial fluid) have been shown to have lower vitamin E levels and to be more readily oxidized than plasma, so peritoneal fluid may actually contribute to the disease process actively rather than as a passive carrier of mediators of inflammation and growth. As a result of such a stress, a sterile, inflammatory reaction with secretion of growth factors, cytokines, and chemokines is generated, which is deleterious especially to successful reproduction. We propose that such a pro-oxidant environment (peritoneal fluid as well as activated macrophages) promotes growth of ectopic endometrium. The data presented in this review are just the beginning of exploring the role of oxidative stress in mediating the pathophysiology of endometriosis. Only by understanding the mechanisms involved in the pathogenesis of endometriosis can we develop the basis for new diagnostic and therapeutic approaches.