The endometrium undergoes a period of receptivity towards the embryo, defined by both morphological and biochemical changes. We hypothesize that both endocrine and paracrine regulatory components maintain a """"""""receptive"""""""" endometrium. Acquisition of uterine receptivity appears to be associated with disappearance of the progesterone receptor on cycle day 19 to 20. Inadequate progesterone leading to persistent PR results in histological and biochemical immaturity of the endometrium. EGF and EGF-like molecules are important to implantation in both human and rodent species. One endometrial integrin, the alpha v beta vitronectin receptor, appears in the glandular and luminal epithelium at or near the time of embryo attachment, and later in the decidua, when invasion occurs. This integrin is inhibited by estrogen and progesterone and stimulated by EGF. Further, certain conditions associated with infertility exhibit aberrant alpha v beta 3 expression. The purpose os this proposal is to 1)document the use of the alpha v beta 3 integrin marker of uterine receptivity for diagnosis of defects in uterine receptivity in women with infertility, 2) discover shared attributes of women with these defects, 3) identify other proteins or endometrial products aberrantly expressed in the setting of defective uterine receptivity, and 4) clarify the molecular mechanisms regulating endometrial cycle-specific integrin expression. We hypothesize that inflammatory cytokines and androgens contribute to these deficits. To accomplish this we plan to prospectively examine alpha v beta 3 in women with infertility during their initial evaluation and to randomize those with endometriosis to two treatment regimens. Secondly, we will investigate the expression of the alpha v beta 3 integrin in women with polycystic ovarian disease associated with hyperandrogenism and anovulation. RIA will be used to compare concentrations of sex steroids, peptide hormones and selected cytokines between groups, in serum and in peritoneal fluid. The expression of androgen receptors in endometrium of normal and hyperandrogenic women will be examined. Regulation of the beta 3 integrin subunit gene will be investigated using an in vitro model of endometrial epithelium, the well characterized Ishikawa cell line, we will determine the effects of hormones, paracrines factors, and peritoneal fluid on the regulation of the alpha v beta integrin. With the beta 3 promoter in a CAT reporter gene construct, the regulatory sequences involved in control of this integrin subunit will be defined. It is expected that a better understanding of the mediators of normal cycle fecundity will improve our ability to diagnosis and treat couples with infertility as well as to aid in developing new methods of contraception.
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