Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder of reproductive-agedwomen. Women with PCOS exhibit poor reproductive performance and are at increased risk forendometrial hyperplasia. During the last funding periods, we described specific derangements in theendometrium of women with PCOS, including high levels of androgen receptors (AR), estrogen receptors(ER), and the pi6o coactivators. In this proposal, we are focused mainly on the role of estrogen andepidermal growth factor (EGF) in normal and PCOS endometrium. Estrogen has both positive andnegative effects on implantation. Progesterone limits the action of estrogen through down-regulation ofER and up-regulation of enzymes that metabolize estrogen at the time of embryo attachment. Persistentestrogen actions inhibit expression of specific proteins thought to be essential for normal implantation.EGF family proteins, on the other hand, stimulate expression of implantation related proteins. Wehypothesize that estrogen, acting through membrane associated pathways, stimulates the action of EGFfamily ligands. We will study for the first time a novel membrane-bound estrogen receptor, GPRso, inhuman endometrial epithelium and define the EGF-mediated signaling pathways elicited by estrogenbinding to this G-protein coupled receptor.
In Aim i. we will identify factors that influence the estrogenresponse during the menstrual cycle in normal and PCOS endometrium.
In Aim 2. we will describe keyeffects of estrogen on normal and PCOS endometrium by determining the membrane and nuclearreceptor mechanisms through which estrogen regulates the expression of estrogen response factors andother target genes.
In Aim a. we will dissect the signaling pathways used by estrogen in regulating theearly response gene, Cyr6i. Finally, in Aim 4. we will use in vivo and in vitro models to characterize theresponsiveness to progesterone and estrogen and determine the functions of epithelial and stromal cellsfrom normal and PCOS endometrium to identify paracrine factors that may underlie the regulatorydysfunction in PCOS. The experiments will utilize molecular analysis of a combination of humanendometrial cell lines, primary cultures of human endometrial cells and human tissue explant models toachieve these aims. Understanding normal and abnormal mechanisms of sex steroid action in humanendometrium will provide important insights toward the development, of improved infertility treatmentsand contraceptive approaches.
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