Glycodelin Regulation in Polycystic Ovarian Syndrome

描述（由申请人提供）：人类胚胎植入是一个相对不可靠的过程，大约30%的受孕周期失败。与植入失败相关的一种常见情况是多囊卵巢综合征（PCOS），这是本应用的临床重点。着床是一个复杂而高度调控的过程，依赖于子宫内膜容受性的精确内分泌和旁分泌协调。在子宫内膜表面上皮中发现了几种具有不同功能的蛋白。这些蛋白的表达与囊胚附着和滋养细胞侵袭的时间一致。卵巢激素，尤其是黄体酮，被认为是子宫内膜蛋白在植入窄窗期表达的主要调节因子。先前的研究已经证实，糖苷- a （GdA）在分泌期和妊娠早期子宫内膜上皮中表达。GdA浓度降低的情况下，多囊卵巢综合征以及其他原因的着床失败和反复妊娠丢失。我们发现GdA转录是由孕激素受体复合物直接调节的，其生物活性之一是抑制单核细胞趋化。本应用中提出的实验旨在评估导致PCOS中GdA产量降低的分子机制。实验室实验将建立雄性激素、黄体生成素（LH）和胰岛素对GdA体外生物合成的作用。将评估GdA在单核细胞和其他潜在靶细胞中的信号传导和作用。将对GdA受体进行纯化和表征。将对正常生育妇女和多囊卵巢综合征妇女进行病例对照研究，以剖析后者中GdA失调的潜在途径。模拟周期将通过子宫内膜活检诱导和监测，以确定雄激素、LH和胰岛素升高与GdA表达受损的相关性。最后，宫颈液GdA的无创定量评估将作为“开放”植入窗口的潜在标志。表征子宫内膜容受性的最佳状态将具有广泛的公共卫生意义。患有多囊卵巢综合征（PCOS）、不孕症、反复流产、甚至后来的妊娠并发症（如先兆子痫和宫内生长受限）的女性，将从更好地了解植入和胎盘的细胞生理学中受益。

DESCRIPTION (provided by applicant): 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.