The study of implantation in the human has yielded convincing evidence for a defined period of uterine receptivity that is characterized by developmental changes on the surface epithelium of the endometrium. Using the integrin alpha-v beta-3 and its ligand osteopontin (OPN), we have described a pattern of expression for each that corresponds well with the time of implantation. We have studied he regulation of these proteins and found that each protein is independently regulated by two separate pathways, yet both pathways involve he coordinated action of estrogen and progesterone. Polycystic ovarian syndrome (PCOS) is a common endocrine problem in reproductive-aged women, resulting in infertility and frequent miscarriage. Our studies suggest that androgen receptors (ARs) and two p160 coactivators, AIB-1 and TIF2, are over- expressed in the endometrium of women with PCOS. These changes are associated with aberrant patterns of integrin expression and retarded endometrial development in ovulatory patients with this disorder. We hypothesize that the elevated AR and co-activator expression sensitizes the endometrium to weaker androgens and promotes androgen action in response to lower concentrations of strong androgens. Furthermore, other steroid hormones, such as estrogen or progesterone may activate AR or ER in response to elevated coactivator expression in these women. If this occurs, estrogen, which is a potent inhibitor of uterine receptivity, could interfere with the expression of critical genes during the time of maximal uterine receptivity. To investigate this important biologic question we propose 3 Aims: 1) To investigate the expression of alpha-5 beta-3 and its ligand OPN in normal and PCOS endometrium and to use these biomarkers to study the pathways that may render the endometrium of PCOS women infertile. Methods will include characterization of ERalpha and ERbeta, PR-A and PR-B and AR throughout the menstrual cycle, assessment of steroid regulation of alpha-5 beta-3 and OPN using their respective promoters, and in vitro techniques to study paracrine mechanisms of steroid action in the endometrium. 2) Prospectively study the expression of three p160 co- activators in the endometrial epithelial and stromal cells throughout the menstrual cycle in normal and PCOS endometrium. Using in vivo models we will investigate the consequences of coactivator over expression in these cells. 3) Using DNA microarray analysis, we plan to further characterize the altered pattern of gene expression in women with PCOS compared to normal cycling women. Knowing what changes occur in the endometrium of androgenized endometrium we hope to begin to better understand the mechanism of dysfunction that occurs. Validation of these changes will provide new avenues for research into the effects of androgens on the endometrium. The complex relationships between steroid receptors and their ligands and co-activators provide a framework to investigate the mechanisms by which uterine receptivity is regulated and dysregulated in certain infertility states.
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