Abstract
Endometriosis is a disorder that affects 5% of the normal population but is present in up to 40% of women with pelvic pain and/or infertility. Recent evidence suggests that the endometrium of women with endometriosis exhibits progesterone insensitivity. One endometrial protein that fluctuates in response to progesterone is the estrogen receptor-alpha (ER alpha), being down-regulated at the time of peak progesterone secretion during the window of implantation. Here we demonstrate that the biomarker of uterine receptivity, beta 3 integrin subunit, is reduced or absent in some women with endometriosis and that such defects are accompanied by inappropriate over-expression of ER alpha during the mid-secretory phase. Using a well-differentiated endometrial cell line we showed that the beta 3 integrin protein is negatively regulated by estrogen and positively regulated by epidermal growth factor (EGF). By competing against estrogen with various selective estrogen receptor modulators (SERMs) and estrogen receptor agonists and antagonists, inhibition of expression of the beta 3 integrin by estrogen can be mitigated. In conclusion, we hypothesize that certain types of uterine receptivity defects may be caused by the loss of appropriate ER alpha down-regulation in the mid-secretory phase, leading to defects in uterine receptivity. Such changes might be effectively treated by timely administration of the appropriate anti-estrogens to artificially block ER alpha and restore normal patterns of gene expression. Such treatments will require further clinical studies.
Highlights
Uterine receptivity is regulated by the cyclic secretion of ovarian steroids as a consequence of follicular development and subsequent ovulation
We recently demonstrated that the reduction in endometrial beta 3 integrin expression in polycystic ovarian syndrome (PCOS) was associated with elevated expression of ER-alpha and an over-expression of steroid receptor coactivators [20]
Based on histologic score (HSCORE) determinations, the expression of ER-alpha in all three cell types was significantly lower in the secretory than the proliferative phase
Summary
Uterine receptivity is regulated by the cyclic secretion of ovarian steroids as a consequence of follicular development and subsequent ovulation. While progesterone is an effective anti-estrogen, its role is to reduce ER-alpha concentration rather than to act as a competetive inhibitor of E2 binding, thereby rendering the endometrium resistant to estrogen during the window of implantation. This phenomenon has been observed in several mammalian species [6,7,8]. The highly specialized and specific mid-secretory repertoire of endometrial gene expression coincides with a reduction in the expression of ER-alpha [10] Based on such studies, we suggest that the combination of progesterone action and coincident estrogen withdrawal is required to stimulate key implantation-specific events in the mid-secretory phase of the menstrual cycle
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