Pathophysiology and therapeutic strategy for late reproductive aged women with PCOS

项目摘要 多囊卵巢综合征(PCOS)是一种高度流行的生殖疾病，其特征是 高雄激素血症(HA)与少/无排卵多囊卵巢综合征也与代谢综合征有关， 肥胖和胰岛素抵抗。在患有多囊卵巢综合征的年轻女性中，几个因素导致HA：a) 黄体生成素分泌过多，b)卵巢类固醇合成异常，c)肾上腺异常 类固醇激素生成，以及d)高胰岛素血症/胰岛素抵抗。感兴趣的HA(和月经功能) 多囊卵巢综合征患者随年龄增长而改善。然而，上述医管局的相对贡献与 患有多囊卵巢综合征的青壮年妇女和晚育年龄妇女的因素尚不清楚。识别 多囊卵巢综合征老年妇女HA的最重要预测因子(S)将对设计至关重要 对患有多囊卵巢综合征的老年妇女最相关的治疗策略。而口服避孕药 (OCS)在解决HA和月经功能障碍方面有效，它们还与 心血管不良风险可能会随着年龄的增长而进一步增加。因此，对于年长的女性来说 对于多囊卵巢综合征，替代疗法(如二甲双胍)可能更可取。在患有多囊卵巢综合征的年轻女性中， 二甲双胍已被证明对治疗月经失调和生化HA有效。 然而，在老年多囊卵巢综合征患者中，OC与二甲双胍的相对可取性尚不清楚。我们 建议确定四个已建立的HA(促黄体生成素分泌， 卵巢对重组人绒毛膜促性腺激素的反应，肾上腺对 肾上腺皮质激素治疗和高胰岛素血症)对老年女性和年轻女性的影响 生理研究中的多囊卵巢综合征(目标1)。我们还将确定相对可取性(如所确定的 生活质量评估：二甲双胍与OCS治疗晚期育龄妇女多囊卵巢综合征的比较 随机交叉研究中的年龄(目标2)。成功完成这些研究将提供1) 更全面、更有凝聚力地了解HA的决定因素如何随年龄增长而变化 多囊卵巢综合征；以及2)对老年生殖年龄相关治疗策略的关键洞察 患有多囊卵巢综合征的女性。这项K23拨款中的拟议研究将在以下指导下进行 克里斯托弗·R·麦卡特尼，医学博士，他为理解 近18年多囊卵巢综合征的病理生理学研究我所在机构的研究环境 (弗吉尼亚大学)非常合作和支持。有了巨大的研究支持和 我的导师和我的机构的奉献，我将继续完善我的研究技能所需的 成为一名独立的临床研究人员。

Project Summary Polycystic ovary syndrome (PCOS) is a highly prevalent reproductive disorder characterized by hyperandrogenism (HA) and oligo/anovulation. PCOS is also associated with metabolic syndrome, obesity and insulin resistance. In young women with PCOS, several factors contribute to HA: a) excess luteinizing hormone (LH) secretion, b) abnormal ovarian steroidogenesis, c) abnormal adrenal steroidogenesis, and d) hyperinsulinemia/ insulin resistance. Of interest, HA (and menstrual function) improves with age in PCOS. However, the relative contributions of the aforementioned HA-related factors in young adult vs. late reproductive-aged women with PCOS are not known. Identifying the most important predictor(s) of HA in older women with PCOS will be critically important for devising the most relevant therapeutic strategies for older women with PCOS. While oral contraceptives (OCs) that are effective in addressing HA and menstrual dysfunction, they are also associated with adverse cardiovascular risks that may be further increased with age. Therefore, for older women with PCOS, alternative therapies (e.g., metformin) could be preferable. In young women with PCOS, metformin has been shown to be effective for treating menstrual dysfunction and biochemical HA. However, the relative desirability of OC vs. metformin is not known in older PCOS women. We propose to determine the relative contributions of four established predictors of HA (LH secretion, ovarian response to recombinant human chorionic gonadotropin administration, adrenal response to adrenocorticotropic hormone administration, and hyperinsulinemia) in older vs. young women with PCOS in a physiological study (Aim 1). We will also determine the relative desirability (as determined by quality of life assessments) of metformin vs. OCs in treating PCOS in women of late reproductive age in a randomized cross-over study (Aim 2). Successful completion of these studies will provide 1) a more complete and cohesive understanding of how the determinants of HA change with aging in PCOS; and 2) critical insight into age-relevant therapeutic strategies for older reproductive aged women with PCOS. The proposed studies in this K23 grant will be performed under the mentorship of Christopher R. McCartney, M.D., who has made significant contributions to understanding the pathophysiology of PCOS for the past 18 years. The research environment at my institution (University of Virginia) is very collaborative and supportive. With a tremendous research support and dedication from my mentor and my institution, I will continue to refine my research skills needed to become an independent clinical investigator.