Implantation Defects in Infertile Women with Endometriosis

Abstract

The endometrium undergoes characteristic histologic changes during the menstrual cycle as it prepares for embryo implantation. Historic and current data suggest the presence of a defined period of maximal uterine receptivity during the mid-secretory phase occurring between days 7 and 10 postovulation. In recent years, we and others have sought to define biochemical markers of receptivity that might be used to better understand this time of endometrial differentiation. Based on the work with cell adhesion molecules, we have discovered three different integrins that are only coexpressed during this time in the cycle when embryos will successfully implant. By studying the regulation of one of these, the alpha(v)beta3 integrin, and its extracellular matrix ligand, osteopontin (OPN), we have defined two separate regulatory pathways that may regulate endometrial receptivity. While alpha(v)beta3 expression appears to be stimulated by EGF or heparin-binding EGF, osteopontin is stimulated by progesterone. We now believe the former pathway is a paracrine-mediated signal, while the latter is a direct effect of progesterone on the estrogen-primed endometrial epithelium. In women with endometriosis, it appears that alpha(v)beta3 expression is reduced, while OPN expression is unaffected. Interestingly, binding of OPN to the surface epithelium appears quite limited when alpha(v)beta3 expression is lacking. Such evidence continues to reinforce the notion that endometrium from some women with endometriosis is dysfunctional and may account for the reduction in cycle fecundity noted in this group of patients.

Effect of bisphenol A on human endometrial stromal fibroblasts in vitro

“…regulated EGR1, MMP10, stanniocalcin 1 (STC1), ALDH1A1, cadherin 18 and IGFBP3 genes, which are known to be expressed in endometrial stromal cells and involved in endometrial physiology (Aghajanova et al, 2010;Talbi et al, 2006). Moreover, up-regulation in Ishikawa epithelial cells of HOXA10 and osteopontin (Naciff et al, 2010;Smith and Taylor, 2007), which are important for endometrial receptivity in vivo (Daftary and Taylor, 2001;Lessey, 2002), is in line with the current finding of IGFBP1 up-regulation by BPA in human endometrial stromal cells at the same concentration. These data support potential effects of high-dose BPA exposure on endometrial maturation and function, with possible consequences on endometrium-embryo communication.…”

Endometrial Pinopode and αv 3 Integrin Expression Is Not Impaired in Infertile Patients with Endometriosis

“…Integrins have been proposed to be sensitive indicators of endometrial receptive status and specifically αvβ3 integrin expression has been reported to be reduced in women with endometriosis; thus, that integrin has been proposed as a useful marker of the disease (14,15). However, other authors did not confirm these findings (16)(17)(18).…”

Molecular mechanisms of membrane interaction at implantation

“…In the human endometrium, integrin avb3 exhibits a mid-secretory phase increase of expression influenced by ovarian hormone signaling (Daftary et al, 2002;Lessey, 2002). Indeed, avb3 is up-regulated in immature ovariectomized rats in response to exogenous progesterone, or a combination of estrogen and progesterone, indicating that the epithelial expression of avb3 is regulated, at least in part, by maternal hormones, and progesterone in particular (Srinivasan et al, 2009).…”

“…A number of studies have reported that the expression of epithelial avb3 is associated with the window of implantation and that the endometrium is devoid of this particular integrin in certain cases of infertility (Lessey et al, 1992;Castelbaum et al, 1994), endometriosis (Lessey et al, 1994;Lessey, 2002;Wei et al, 2009;Casals et al, 2012), and idiopathic infertility (Lessey et al, 1995). The level of integrin b3 mRNA on day 21 has been suggested as a possible indicator with which to predict success rates following ART, while avb3 has been considered as a clinical biomarker for human implantation (Elnashar and Aboul-Enein, 2004).…”

“…Levels of both proteins are increased in the epithelium of the human endometrium during the mid-to late-secretory phase, and have thus been proposed as clinical markers for discriminating receptive from nonreceptive endometrium (Apparao et al, 2001;Lessey, 2002;Lessey and Castelbaum, 2002;Quenby et al, 2007;Erikson et al, 2009). Binding of OPN to integrins activates integrin receptors and cytoskeletal proteins and subsequently promotes focal adhesions in the trophectoderm of embryos.…”