The steroid-regulated Epidermal Growth Factor (EGF) family and their receptors (HERs) are expressed in the endometrium during implantation in specific spatiotemporal patterns. While there is a well-developed body of knowledge regarding the altered expression of these proteins and adverse effects on implantation in rodents, their expression patterns have not been comprehensively studied in humans during the endometrial cycle and implantation, nor is it known how the hormonal manipulations used during in vitro fertilization (IVF) alter their expression patterns. Our central hypothesis is that the synchronous development of endometrium and invasive trophoblast during early pregnancy is coordinated through the activities of EGF family growth factors, which are expressed in a steroid-dependent, spatiotemporal pattern. Interruption of these signaling pathways by an altered steroid state found during IVF procedures will impact significantly on implantation rates. We will compare the spatiotemporal expression patterns of EGF family growth factors and HER receptor subtypes in endometrial biopsy specimens obtained from women undergoing controlled ovarian hyperstimulation with gonadotropins for the purpose of oocyte donation. We will determine how estrogen and/or progesterone regulate EGF family growth factors and HER gene expression in isolated and co-cultured human uterine epithelial and stromal cells to identify how the Hyperestrogenic State alters this expression. With this information in hand we will determine the effect of candidate EGF family growth factors determined above on specific HER-mediated signaling on trophoblast cell proliferation and invasiveness using in vitro cultured cytotrophoblast cells. Our hypothesis predicts that trophoblast proliferation and differentiation are promoted in a ligand and receptor-specific manner. At the conclusion of this proposed research we will know the effect of hormonal changes found during IVF on EGF family growth factors and their receptors. Further, we will know the effect of this altered expression on trophoblast function. This information will provide mechanistic based strategies to correct the altered endometrial changes associated with IVF treatment. This information in turn can be used in the future to test IVF ovulation induction protocols to improve implantation rates.
