Endometrial secretion aspiration prior to embryo transfer does not reduce implantation rates

Analysis of protein patterns in endometrial secretion fluid may offer a relatively non-invasive means of assessing endometrial receptivity during fertility treatment cycles. In order to study the impact of the removal of endometrial secretions on embryo implantation, a prospective matched controlled study was performed. In 66 women undergoing IVF, endometrial fluid was obtained transcervically by aspiration just prior to embryo transfer (study group). Biochemical and ongoing pregnancy rates were compared with 66 control patients matched for stimulation treatment protocol, age, number of collected oocytes and number of high quality embryos. The protein content and uterine fluid protein profile in each sample was determined. Respective biochemical and ongoing pregnancy rates per embryo transfer were 36 and 33% in patients who underwent aspiration of endometrial secretion, compared with 33 and 30% respectively in matched control patients (P = 0.84 and P = 0.85). The protein content in endometrial fluid was sufficient for protein pattern analysis. Uterine fluid aspiration prior to IVF embryo transfer is a safe method for obtaining sufficient material for uterine secretion electrophoresis, thus allowing analysis of protein patterns serving as receptivity markers during treatment cycles. This technique may offer a novel tool for assessing endometrial receptivity during treatment cycles without affecting implantation rates.     

Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis

Mechanical endometrial injury (biopsy/scratch or hysteroscopy) in the cycle preceding ovarian stimulation for IVF has been proposed to improve implantation in women with unexplained recurrent implantation failure (RIF). This is a systematic review and meta-analysis of studies comparing the efficacy of endometrial injury versus no intervention in women with RIF undergoing IVF. All controlled studies of endometrial biopsy/scratch or hysteroscopy performed in the cycle preceding ovarian stimulation were included and the primary outcome measure was clinical pregnancy rate. Pooling of seven controlled studies (four randomized and three non-randomized), with 2062 participants, showed that local endometrial injury induced in the cycle preceding ovarian stimulation is 70% more likely to result in a clinical pregnancy as opposed to no intervention. There was no statistically significant heterogeneity in the methods used, clinical pregnancy rates being twice as high with biopsy/scratch (RR 2.32, 95% CI 1.72–3.13) as opposed to hysteroscopy (RR 1.51, 95% CI 1.30–1.75). The evidence is strongly in favour of inducing local endometrial injury in the preceding cycle of ovarian stimulation to improve pregnancy outcomes in women with unexplained RIF. However, large randomized studies are required before iatrogenic induction of local endometrial injury can be warranted in routine clinical practice.Some women undergoing IVF treatment fail to conceive despite several attempts with good-quality embryos and no identifiable reason. We call this ‘recurrent implantation failure’ (RIF) where the embryo fails to embed or implant within the lining of the womb. Studies have shown that inducing injury to the lining of the womb in the cycle before starting ovarian stimulation for IVF can help improve the chances of achieving pregnancy. Injury can be induced by either scratching the lining of the womb using a biopsy tube or by telescopic investigation of the womb using a camera. We performed a collective review of the available good-quality studies that used the above two methods in the cycle prior to starting ovarian stimulation for IVF. We pooled results from seven studies, which included 2062 women with RIF and assessed the difference in clinical pregnancy rates for those undergoing injury to the womb lining compared with no injury prior to IVF. The results suggest that inducing injury is 70% more likely to result in a clinical pregnancy as opposed to no treatment. Furthermore, scratching of the lining was 2-times more likely to result in a clinical pregnancy compared with telescopic evaluation of the lining of the womb. This study suggests that in women with RIF, inducing local injury to the womb lining in the cycle prior to starting ovarian stimulation for IVF can improve pregnancy outcomes. However, large studies are required before this can be warranted in routine clinical practice.     

Cytokines and chemokines during human embryo implantation: roles in implantation and early placentation

The complex processes of embryo implantation and early placentation require a plethora of locally acting molecules, which are themselves tightly regulated. Among these are cytokines (including chemotactic chemokines), which are synthesized by several cell types at the maternal-fetal interface. Those produced by endometrial epithelium may be secreted apically into the uterine lumen, where they affect blastocyst development, migration, and attachment, or basally with effects on the transformation of the underlying stroma. Decidualized stromal cells, which subsequently form a major component of the decidua of pregnancy, also produce cytokines that act to drive the decidualization process and chemokines that are chemoattractants both for leukocytes such as uterine natural killer cells and macrophages, and for trophoblast migration. Activated leukocytes within the developing decidua also contribute regulatory cytokines to the local microenvironment. Disturbances in the production of individual cytokines have been demonstrated in the endometrium of some infertile women and in those with recurrent miscarriage. It is important to establish whether a signature of endometrial cytokines may provide a clinically useful indication of women who will experience difficulty in establishing a viable pregnancy.     

Immunohistochemical evaluation of human placental implantation: an initial study

Immunohistochemical staining for human chorionic gonadotropin and factor VIII-related antigen with the avidin-biotin complex immunoperoxidase technique was used as a marker for syncytiotrophoblast and endothelial cells, respectively, in the human placental bed. Material from placental implantation sites at varying stages of gestation (8 weeks to term) was studied. Trophoblastic invasion of the uterine stroma and blood vessels were evaluated. Syncytiotrophoblasts lining placental villi and anchoring villi were positive for human chorionic gonadotropin at all stages of gestation studied. Endothelial cells lining maternal uterine blood vessels were positive for factor VIII-related antigen. At early stages of intrauterine placentation (8 and 11 weeks) trophoblastic invasion of uterine blood vessels and trophoblastic incorporation in the walls of dilated vessels were present. An unexpected finding, however, was the large number of giant cells in the superficial placental bed which had morphology suggestive of syncytiotrophoblast but which were negative for human chorionic gonadotropin. In addition, many enlarged, rather pleomorphic cells lining superficial blood vessels were found to be positive for factor VIII-related antigen, which identified them as endothelial cells and not migrating trophoblastic elements. This study demonstrates that human chorionic gonadotropin and factor VIII-related antigen immunoperoxidase staining is a helpful adjunct in evaluating human placentation and suggests extension of the technique with use of other antibodies to evaluate components of the placental bed.     

The role of integrins in human embryo implantation.

Integrins are adhesion molecules present in endometrial, decidual, and extravillous cytotrophoblast (EVCT) cells. They participate in cell-cell adhesion as well as in adhesion between cells and components of the extracellular matrix, and they play an important role in the endometrial phenotype change that occurs during the secretory phase, the first stage of implantation. At the beginning of pregnancy, the change in integrin expression is synchronized with the trophoblast attachment (embryo-endometrium interactions with integrins alpha(v)beta3, alpha4beta1, alpha6beta1, and alpha7beta1) and the embryo's invasion of the decidua (integrins alpha6beta4-->alpha5beta1-->alpha1beta1-->alpha4beta1 switch from proliferative to endovascular EVCT). Several diseases, including preeclampsia, intrauterine growth retardation caused by vascular problems and defective luteal phases, may be explained by anomalies in integrin patterns.     

Paracrine regulators of implantation.

Classical and contemporary studies have shown that endocrine regulation exerted by ovarian hormones priming the endometrium is essential for embryo implantation. Increasing evidence indicates that steroid-induced molecules acting as paracrine modulators are necessary for embryo-uterine interactions. That is the case for calcitonin, heparin-binding epidermal growth factor (EGF)-like growth factor, leukaemia inhibitory factor and other molecules. Furthermore, when the blastocyst enters the uterine cavity, it starts the complex signals that will drive embryo adhesion. The paracrinology of this process is based on the local interplay of molecules, such as the secretion of cytokines that may facilitate the acquisition of endometrial receptivity by controlling the expression of adhesion and anti-adhesion proteins. Finally, during the embryonic invasive phase, uterine stromal-trophoblast dialogue may modulate this self-controlled proteolytic and immunological process to avoid damage to both the embryo and maternal environment.     

Materno-foetal dialogue and human embryo implantation: some evolving concepts

Multiple immunogical mechanisms allow fetal allograft tolerance. In this review, we first describe the maternal and embryological side in order to expose the dangers for the embryo enabling the development of materno-fetal strategies that will allow fetal survival and growth.     

Endometrial LGR7 expression and implantation failure

Implantation failure is considered as a major cause of infertility in women with recurrent pregnancy loss (RPL) and in otherwise healthy women with unexplained infertility. Preliminary data in primates suggested that relaxin (RLX) is involved in endometrial preparation for implantation. In a prospective observational study, the endometrial RLX receptor (LGR7) expression was assessed in three groups of patients with regular ovulatory cycle and normal uterine cavity: 23 with RPL (Group A), 23 with unexplained infertility undergone at least three cycles of failed in vitro fertilization (IVF) reporting good oocyte and embryo quality (Group B), 23 with proven fertility (Group C). Assessment of LGR7 expression was performed with both polymerase chain reaction (PCR) analysis and immunohistochemistry on endometrial samples obtained with hysteroscopic biopsy performed in the secretory phase of the menstrual cycle. Endometrial LGR7 was less expressed in group A and B versus C, both by PCR analysis (p?=?0.024) and immunohistochemistry. The decreased expression of the endometrial RLX receptor in women with implantation failures, both in vitro fertilization failure and recurrent pregnancy loss, suggests that RLX may play a crucial role in the structural and functional changes of the endometrium during the window of implantation.     

Uterine contractility and embryo implantation

PURPOSE OF REVIEW: The aim of this article is to assess the importance of uterine contractility in the implantation of human embryos. RECENT FINDINGS: Recent findings show that the receptive phase of the endometrium seems to occur in close association with the appearance of pinopodes and endometrial integrins that may be activated by the IL-1 system. Throughout the menstrual cycle wavelike activity patterns of the uterus were identified with adequate wave patterns appearing to be related to successful reproduction in spontaneous cycles and in assisted reproduction. Such patterns are controlled by steroid hormones. Embryo attachment to the predecidualized endometrium and its invasion may be determined by the expression of proteolytic enzymes that require uterine quiescence for implantation. The uterine activity was detected both in vitro and in vivo by using invasive intrauterine pressure and noninvasive ultrasound approaches. Progesterone promotes local vasodilatation and uterine musculature quiescence by inducing nitric oxide synthesis in the decidua. At present, until new evidence emerges to demonstrate otherwise, the effects of progesterone are, directly or indirectly, the only determinant of endometrial preparation for embryo nidation, with the induction of uterine quiescence being one of these effects. SUMMARY: Adequate uterine contractility may provide for gamete/embryo transportation through the utero-tubal cavities and successful embryo implantation in spontaneous or assisted reproduction. Inadequate uterine contractility may lead to ectopic pregnancies, miscarriages, retrograde bleeding with dysmenorrhea and endometriosis.     

Uterine contractility and embryo implantation

PURPOSE OF REVIEW: The aim of this article is to assess the importance of uterine contractility in the implantation of human embryos. RECENT FINDINGS: Recent findings show that the receptive phase of the endometrium seems to occur in close association with the appearance of pinopodes and endometrial integrins that may be activated by the IL-1 system. Throughout the menstrual cycle wavelike activity patterns of the uterus were identified with adequate wave patterns appearing to be related to successful reproduction in spontaneous cycles and in assisted reproduction. Such patterns are controlled by steroid hormones. Embryo attachment to the predecidualized endometrium and its invasion may be determined by the expression of proteolytic enzymes that require uterine quiescence for implantation. The uterine activity was detected both in vitro and in vivo by using invasive intrauterine pressure and noninvasive ultrasound approaches. Progesterone promotes local vasodilatation and uterine musculature quiescence by inducing nitric oxide synthesis in the decidua. At present, until new evidence emerges to demonstrate otherwise, the effects of progesterone are, directly or indirectly, the only determinant of endometrial preparation for embryo nidation, with the induction of uterine quiescence being one of these effects. SUMMARY: Adequate uterine contractility may provide for gamete/embryo transportation through the utero-tubal cavities and successful embryo implantation in spontaneous or assisted reproduction. Inadequate uterine contractility may lead to ectopic pregnancies, miscarriages, retrograde bleeding with dysmenorrhea and endometriosis.     

环氧化酶在胚泡着床中的作用

环氧化酶(COX)是前列腺素合成起始的关键限速酶,分COX-1和COX-2两种亚型,它们在围着床期时特异性表达于胚泡和子宫内膜,发挥各自不同的作用。COX在胚胎着床时的血管生成、子宫内膜蜕膜化,以及启动着床中发挥着重要调节作用。     

An integrated view of L-selectin and trophinin function in human embryo implantation

Determining molecular mechanisms of human embryo implantation is an extremely challenging task due to the limitation of materials and significant differences underlying this process among mammalian species. Recently, L-selectin and its ligand carbohydrate have been proposed as a system that mediates initial adhesion of human blastocysts to the uterine epithelia. We have also identified trophinin as a unique apical cell adhesion molecule potentially involved in the initial adhesion of trophectoderm of the human blastocyst to endometrial surface epithelia. In the mouse, the binding between ErbB4 on the blastocyst and heparin-binding epidermal growth factor-like growth factor on the endometrial surface enables the initial step of the blastocyst implantation. The evidence suggests that L-selectin and trophinin are included in human embryo implantation. This review summarizes findings relevant to the functions of L-selectin and trophinin in human embryo implantation, and proposes a model that reconciles these cell adhesion mechanisms.     

Effects of oxygen on cell turnover and expression of regulators of apoptosis in human placental trophoblast

Pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are associated with aberrant cell turnover, including increased apoptosis, in placental villous trophoblast. The increased apoptosis is associated with exaggerated expression of p53, which promotes cell cycle arrest or apoptosis via downstream proteins such as p21 or Bax. These changes in apoptosis and p53 expression are purported to result from exposure to altered oxygen tension. Using a model of villous trophoblast turnover, we examined the effect of 20%, 6% and 1% ambient oxygen (O(2)) on apoptosis, necrosis, proliferation and expression of p53 and related regulators of cell turnover, compared to both fresh tissue. Altered O(2) tension exerted an effect on cell turnover in cultured term villous tissue: cytotrophoblast proliferation was increased by culture in 20% O(2) and reduced in 1% O(2) (median proliferative index: fresh tissue=0.32%, 20% O(2)=0.9%, 6% O(2)=0.28%, 1% O(2)=0.07%). Apoptosis was increased in all culture environments, but was significantly enhanced by culture in 1% O(2) (median apoptotic index: fresh tissue=0.64%, 20% O(2)=2.96%, 6% O(2)=3.81%, 1% O(2)=9.2%). Necrotic cell death was also increased by culture in 1% O(2) compared to 6% and 20% O(2). The expression of p53, p21 and Mdm2 in both cytotrophoblast and stromal cells was increased following culture in 1% O(2). There was no alteration in the expression of Bax or Bcl-2. This study provides evidence that p53 is elevated in trophoblast following exposure to hypoxia. The potential role of the p53-pathway in the control of cell turnover in villous trophoblast and the regulation of p53 by altered O(2) tension merits further investigation.