Human embryonic implantation is a relatively unreliable process, failing in approximately 30% of conception cycles. One common condition associated with implantation failure is polycystic ovary syndrome (PCOS), which is the clinical focus of this application. Implantation is a complex and highly regulated process dependent upon precise endocrine and paracrine coordination of endometrial receptivity. Several proteins with diverse functions have been identified in the endometrial surface epithelium. The expression of these proteins coincides with the timing of blastocyst attachment and trophoblast invasion. Ovarian hormones, and progesterone in particular, are believed to be the primary regulators of endometrial proteins expressed in the narrow window of implantation. Prior studies have established that glycodelin-A (GdA) is expressed in secretory phase and early pregnancy endometrial epithelium. GdA concentrations are decreased in cases with PCOS as well as in other causes of failed implantation and recurrent pregnancy loss. We discovered that GdA transcription is directly regulated by progestin-receptor complexes and that one of its biological activities is the inhibition of monocyte chemotaxis. Experiments proposed in this application are designed to evaluate the molecular mechanisms resulting in lower GdA production in PCOS. Laboratory experiments will establish the roles of androgens, luteinizing hormone (LH) and insulin on GdA biosynthesis in vitro models. GdA signaling and action in monocytes and other potential target cells will be evaluated. The GdA receptor will be purified and characterized. A case-control study of normal fertile women and women with PCOS will be conducted to dissect the potential pathways involved in GdA dysregulation in the latter group. Mock cycles will be induced and monitored by endometrial biopsies to determine the correlation of elevated androgens, LH and insulin to impaired GdA expression. Finally, a noninvasive quantitative evaluation of cervical fluid GdA will be developed as a potential marker for an """"""""open"""""""" implantation window. Characterization of an optimal state for endometrial receptivity will have broad public health implications. Women suffering PCOS, infertility, recurrent pregnancy loss, and even later pregnancy complications such as preeclampsia and intrauterine growth restriction, will benefit from a better understanding of the cellular physiology of implantation and placentation. ? ?
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