Pathophysiology and therapeutic strategy for late reproductive aged women with PCOS

晚育龄女性 PCOS 的病理生理学和治疗策略

• 批准号: 10397427
• 负责人: Su H. Kim
• 金额: $ 16.55万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397427
• 关键词: Accounting; Address; Adrenal Glands; Age; Aging; Alternative Therapies; Amenorrhea; Androgens; Attenuated; Biochemical; Cardiovascular system; Cells; Client satisfaction; Clinical Investigator; Corticotropin; Cross-Over Studies; Dedications; Doctor of Medicine; Double-Blind Method; Effectiveness; Environment; Etiology; Event; Female infertility; Follicle Stimulating Hormone; Functional disorder; Grant; Health; Hirsutism; Hormone secretion; Hyperandrogenism; Hyperinsulinism; Hypertension; Hypertriglyceridemia; Institution; Insulin Resistance; Light; Longitudinal Studies; Luteinizing Hormone; Medical; Menstrual cycle; Mentors; Mentorship; Metabolic; Metabolic syndrome; Metformin; Obesity; Observational Study; Oligonucleotides; Oral Contraceptives; Ovarian; Ovulation; Periodicity; Physiological; Polycystic Ovary Syndrome; Quality-of-Life Assessment; Randomized; Recombinant Human Chorionic Gonadotropin; Research; Research Support; Resolution; Risk; Steroid biosynthesis; Stimulus; Therapeutic; Universities; Virginia; Woman; age related; aged; anovulatory infertility; cardiovascular risk factor; cohesion; design; diminished ovarian reserve; high risk; improved; improved functioning; inhibin B; insight; insulin sensitizing drugs; interest; mullerian-inhibiting hormone; older women; oligo anovulation; paracrine; pill; reproductive; reproductive system disorder; response; skills; theca cell; venous thromboembolism; young adult; young woman

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.

项目概要 多囊卵巢综合症（PCOS）是一种非常普遍的生殖系统疾病，其特征是 雄激素过多症 (HA) 和少排卵/无排卵。 PCOS 还与代谢综合征有关， 肥胖和胰岛素抵抗。在患有 PCOS 的年轻女性中，有几个因素会导致 HA：a) 黄体生成素 (LH) 分泌过多，b) 卵巢类固醇生成异常，c) 肾上腺异常 类固醇生成，以及 d) 高胰岛素血症/胰岛素抵抗。感兴趣的是HA（和月经功能） 多囊卵巢综合症随着年龄的增长而改善。然而，上述HA相关的相对贡献 影响年轻成年女性与晚期育龄女性患 PCOS 的因素尚不清楚。识别 对于患有 PCOS 的老年女性来说，HA 最重要的预测因子对于设计至关重要 对于患有 PCOS 的老年女性来说最相关的治疗策略。口服避孕药的同时 （OC）可有效解决 HA 和月经失调问题，它们还与 随着年龄的增长，不良心血管风险可能会进一步增加。因此，对于年龄较大的女性来说 对于 PCOS，替代疗法（例如二甲双胍）可能更可取。在患有多囊卵巢综合症的年轻女性中， 二甲双胍已被证明可有效治疗月经失调和生化HA。 然而，OC 与二甲双胍在老年 PCOS 女性中的相对需求性尚不清楚。我们 建议确定四个已确定的 HA 预测因子（LH 分泌、 卵巢对重组人绒毛膜促性腺激素的反应，肾上腺对重组人绒毛膜促性腺激素的反应 老年女性与年轻女性的促肾上腺皮质激素管理和高胰岛素血症） 生理学研究中的 PCOS（目标 1）。我们还将确定相对合意性（根据确定的 通过生活质量评估）二甲双胍与口服避孕药治疗晚期生育女性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) 对 HA 的决定因素如何随衰老而变化有更完整、更有凝聚力的理解 多囊卵巢综合症； 2）对老年育龄期年龄相关治疗策略的批判性见解 患有多囊卵巢综合症的女性。 K23 资助中拟议的研究将在以下人员的指导下进行： 克里斯托弗·R·麦卡特尼 (Christopher R. McCartney) 医学博士，为理解疾病做出了重大贡献 过去 18 年 PCOS 的病理生理学。我所在机构的研究环境 （弗吉尼亚大学）非常合作和支持。凭借巨大的研究支持和 在我的导师和我的机构的奉献下，我将继续完善我所需的研究技能 成为一名独立的临床研究者。