Role of progesterone in nonhuman primate implantation

Herein we review the morphological and physiological effects of estradiol and progesterone (P) on the nonhuman primate uterus. Progesterone action acts to prepare the endometrium for embryo implantation, which normally occurs only during a brief period in the mid-luteal phase of the menstrual cycle. During this window of implantation, P stimulates secretory morphological differentiation and suppresses estrogen receptor alpha (ERalpha), in the endometrial functionalis zone. Reduced endometrial ERalpha is a definitive physiological marker for the onset of endometrial receptivity in primates. These actions of P are specific for the functionalis zones, and P does not fully inhibit ERalpha in the glands of basalis zone of nonhuman primates. Paradoxically, during the secretory phase of the cycle, progesterone receptor (PR) is also reduced in the glandular epithelium of the progestin-responsive functionalis zone. Therefore, P action on the epithelium in the functionalis zone may be mediated by paracrine factors arising from the PR-positive cells in the stroma. Genomic analysis of the endometrium of women and nonhuman primates has revealed numerous secretory phase genes that may contribute to differentiation of the endometrium. However, the exact nature and function of these putative factors have been elusive. We propose that nonhuman primates, especially macaques, can provide a valuable animal model for experimentally testing the functional role of P-regulated genes on endometrial receptivity.     

Role of aneuploidy on embryo implantation

Approximately 30% of oocytes in the human species carry a chromosomal imbalance. This condition has severe clinical consequences as approximately one-third of spontaneous abortions are aneuploid. The most obvious link to the increase of aneuploidy in oocytes is maternal age. This has been directly confirmed by the analysis of polar bodies. Their analysis permits to give confirmation of the high predisposition of oocytes to meiotic errors. Also, the study of chromosomes on sperm has revealed a frequency of 6-7% aneuploidy in normal sperm samples, and is significantly increased in cases of severe oligoasthenoteratospermia or azoospermia due to testicular failure. During the preimplantation period there is a progressive loss of abnormal embryos at specific stages in early development, through growth arrest and degeneration of abnormal embryos. The frequency of chromosomal abnormalities is strictly related to the category of patients (advanced maternal age, repeated cycles, altered karyotype, repeated miscarriages, TESE). Based on these considerations, preimplantation genetic diagnosis for aneuploidy is proposed in reproductive medicine with the finality of improving the clinical outcome after IVF. Substantial evidence has been accumulated on the positive impact of the technique, reporting increased implantation rates and a concomitant decrease of spontaneous abortions and trisomic pregnancies.     

Role of chemokines in the endometrium and in embryo implantation

PURPOSE OF REVIEW: Chemokines are well known for their roles in the immune system; convincing evidence has emerged demonstrating a broader role for chemokines in the endometrium, particularly during embryo implantation. This review highlights the evidence on newly defined roles for chemokines in the endometrium during embryo implantation, with particular focus on those chemokines expressed by the endometrium. RECENT FINDINGS: The highly regulated temporal and spatial expression of chemokines in the endometrium leads not only to specific recruitment and activation of appropriate leucocytes but also coordinates the precisely orchestrated invasion of trophoblasts through the decidua and maternal vasculature. Results to date implicate chemokine signalling at the maternal-foetal interface in important processes during implantation and placentation, such as leucocyte recruitment and controlled trophoblast invasion. Unravelling such actions of chemokines in the endometrium has provided new insights into these complex processes. SUMMARY: Disturbances of chemokine production, processing, or actions are likely to contribute to dysfunction of implantation and placentation, with implications for early pregnancy loss and disturbed placental and foetal development. More research into altered chemokine function in such conditions may provide leads for new clinical interventions.     

Molecules in blastocyst implantation. Role of matrix metalloproteinases,cytokines and growth factors

Initiation of implantation is due not to passive growth pressure but to an active biochemical process that requires a blastocyst to interact with a carefully prepared endometrium. This versatile and dynamic process requires a variety of different molecules secreted by human trophoblast as well as endometrial cells that play a unique role. Several molecules have been shown to regulate, by an autocrine and paracrine manner, the cross-talk between the implanting blastocyst and the endometrial epithelium. Particularly, the molecular dialogue involves either cell-to-cell or cell-to-extracellular matrix interactions, mediated by matrix metalloproteinases, cytokines and growth factors. The present overview of the literature reports on the most significant molecules involved in the implantation process and describes the mechanisms of interaction and control. Since impaired blastocyst implantation is a significant cause of natural and in vitro fertilization pregnancy failure, a better understanding of the aforementioned molecular dynamics would be useful in improving the chance of viable pregnancy.     

Immunosuppressive activity of proteases in cervical carcinoma

OBJECTIVE: The host immune response is essential for restraining both HPV infections and HPV-related cervical cancer. We previously reported a direct correlation between proteolytic activity and malignant progression from precursor lesions to invasive cervical carcinoma. The present study was undertaken to investigate whether proteinases from cervical carcinoma extracts and representative purified proteinases involved in tumor progression could regulate lymphocyte proliferation to phytohemagglutinin (PHA) mitogen. METHODS: Extracts were prepared from tissue samples obtained from patients with invasive cervical squamous carcinoma, squamous intra-epithelial lesions or women with normal cervix. Lymphocytes obtained from a single healthy donor were pre-incubated with one of these extracts in the presence or absence of proteinase inhibitors, and stimulated with PHA during 72 h. The proliferative response was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) method (re-validated with thymidine uptake). RESULTS: Lymphocyte proliferation was significantly decreased by cervical carcinoma extracts, while only slightly decreased by squamous intra-epithelial lesions or normal extracts. Inhibitor assays indicated that proteinases from cervical carcinoma were responsible for 53.30% of total suppressive activity. We found that purified enzymes such as trypsin, cathepsin B, uPA and type IV collagenase suppressed the proliferative response in a dose-dependent fashion. CONCLUSIONS: Our data suggest that in addition to the classic role in tumor invasion, proteases could represent an immune evasion mechanism in cervical carcinoma.     

Cytokines in implantation

The endometrium of most species is now recognized as an important site of production of cytokines and their receptors. The cellular origin of the cytokines varies but many predominate in the uterine glandular or luminal epithelium or in the decidualized stromal cells. From studies in genetically modified mice it is clear that implantation of the blastocyst can proceed in the absence of most individual cytokines, although leukemia inhibitory factor and interleukin-11 have indisputable roles in this process. In other cases, such as CSF-1, GM-CSF, IL-1, and IL-6, the numbers of implantation sites or litter sizes are reduced when the cytokine is absent. The same cytokines that are implicated in implantation in mice are generally maximally expressed in human endometrium with maximal production in the secretory phase, particularly during the "window of implantation," but functional studies of their role in implantation in women and other primates are still required.     

Angiogenesis in implantation

Problem Implantation failure and early pregnancy loss are common following natural conceptions and they are particularly important clinical hurdles to overcome following assisted reproduction attempts. The importance of adequate vascular development and maintenance during implantation has recently become a major focus of investigation. Materials and methods Review of current published literature was undertaken to summerize the cells and cell products that regulate tissue vascularity during implantation. Results Vascular development at the maternal fetal interface can be regulated by a number of different cell types; two principal candidates are trophoblast and natural killer cells. A wide range of soluble factors, some with well established angiogenic functions as well as other more novel factors, can contribute to vascular development and maintenance at the maternal–fetal interface. Conclusions Robust vascular development occurs during implantation and early placentation of normal pregnancies. Studies to define the extent and mechanisms by which defects in vascularity contribute to human implantation failure and early miscarriage need to be undertaken. Vascular development during implantation is mediated by numerous cell types and cell products and aberrant vascularity likely contributes to implantation failure and early pregnancy loss.     

SDF-1/CXCR4在女性生殖系统肿瘤及胚胎着床中的作用

基质细胞衍生因子-1(stromalcell-derived factor 1,SDF-1)是CXC趋化因子家族的成员,CXCR4是目前已知SDF-1的唯一受体。SDF-1/CXCR4在调控胚胎着床,诱导胎盘血管生成,肿瘤细胞趋向性侵袭、转移等方面发挥作用。本文综述SDF-1/CXCR4在女性生殖系统肿瘤中的研究现状,及其在胚胎着床过程中的作用。     

Embryonic regulation in implantation

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.     

Mechanisms of implantation

Successful embryo implantation in mammals requires the co-ordinated development of a blastocyst competent to implant and an adhesive endometrium. Given the indispensable role of implantation for the furtherance of the species, a number of molecular mechanisms have evolved to regulate the process. A variety of molecules, produced by embryo as well as maternal tissue participates in the cross-talk between the implanting blastocyst and the endometrium. The interplay between the various molecules and the routes in which they are involved is beginning to be elucidated. Because impaired implantation represents the most important limiting factor in the establishment of pregnancy, it is believed that research in the field will allow clinicians to improve the respective rates. This paper reviews certain groups of molecules that are considered to have key roles in the mechanisms of implantation.     

Physiology of implantation

This article explains why we have had to come to a central role for innate immunity rather than the threat of maternal rejection of the foetal allograft. We encompass briefly the role of inflammation in implantation, not only for invasion adhesion, but also to prepare future "tolerance". In this context, we envisage the role of TWEAK and complement.     

Atosiban improves implantation and pregnancy rates in patients with repeated implantation failure

This prospective cohort study examined the effects of atosiban on uterine contraction, implantation rate (IR) and clinical pregnancy rate (CPR) in women undergoing IVF/embryo transfer. The study enrolled 71 women with repeated implantation failure (RIF; no pregnancies from an average of 4.8 previous embryo transfers with a mean of 12 top-quality embryos) undergoing IVF/embryo transfer using cryopreserved embryos. The total atosiban dose was 36.75 mg. The IR per transfer and CPR per cycle were 13.9% and 43.7%, respectively. Before atosiban, 14% of subjects had a high frequency of uterine contractions (?16 in 4 min). The frequency of uterine contractions was reduced after atosiban. This reduction of uterine contractions in all cycles was significant overall (from 6.0 to 2.6/4 min; P < 0.01), in cycles with ?16 uterine contractions/4 min at baseline (from 18.8 to 5.1; P < 0.01) and in cycles with <16 uterine contractions/4 min (from 3.9 to 2.2; P < 0.01). IR and CPR improved in all subjects, irrespective of baseline uterine contraction frequency. This is the first prospective study showing that atosiban may benefit subjects with RIF undergoing IVF/embryo transfer with cryopreserved embryos. One potential mechanism is the reduction in uterine contractility, but others may also contribute.Many women undergoing IVF/embryo transfer do not achieve the outcome that they wish for. In fact, IVF/embryo transfer repeatedly fails for a subgroup of patients. There are limited options available to help these patients with repeat implantation failure (RIF) to become pregnant. This study looks at one potential new treatment option for women who experience RIF. A drug called atosiban is already being used to delay premature labour by inhibiting contractions of the uterus. In this study, atosiban was given at the time of embryo transfer to women undergoing IVF/embryo transfer. Atosiban reduced the number of uterine contractions in these patients and also increased the implantation and pregnancy rates. The pregnancy rate went from zero to 43.7%. The beneficial effects of atosiban were observed not only in patients who had a high frequency of uterine contractions at baseline but also in those who had a low frequency. These findings suggest that atosiban may have other benefits in addition to its effect on contractions of the uterus. More studies are required to find out exactly how atosiban works and to increase the knowledge of its use in patients with RIF undergoing IVF/embryo transfer.     

Acceptability of norplant implantation in China

The results of Norplant subdermal implants in 10,718 women receiving Norplant-6 and 1,208 women accepted Norplant-2 were analyzed. Up to May 31, 1988, the 3-year cumulative pregnancy rate was 0.2 per 100 acceptor for Norplant-6 and 0.1 per 100 acceptor for Norplant-2 and the continuation rate was 78.6 and 73.1 per 100 acceptor respectively. Menstrual disturbance constituted the majority (70%) of terminations. Cumulative termination rate for medical reasons was only 4.2 and 6.3 per 100 acceptor for Norplant-6 and Norplant-2 respectively. It is concluded preliminarily that the Norplant subdermal implantable contraceptive system is a safe and acceptable to the Chinese women.