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: 10626723
• 负责人: Su H. Kim
• 金额: $ 4.62万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626723
• 关键词: Accounting; Address; Adrenal Glands; Age; Aging; Alternative Therapies; Amenorrhea; Androgens; Anovulation; 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; design; diminished ovarian reserve; high risk; improved; inhibin B; insight; insulin sensitizing drugs; interest; mullerian-inhibiting hormone; older women; 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.

项目摘要 多囊卵巢综合征（PCOS）是一种高度普遍的生殖障碍，其特征是 超雄激素（HA）和寡素/动脉。 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，有几个因素导致HA：A） 过多的黄体生成激素（LH）分泌，b）异常卵巢类固醇生成，c）异常肾上腺 类固醇生成和D）高胰岛素/胰岛素抵抗。感兴趣的HA（和月经功能） 随着PCOS的年龄增长。但是，上述HA相关的相对贡献 未知的年轻成人与晚期生殖老年妇女的因素尚不清楚。识别 患有PCOS的老年妇女的HA最重要的预测因子对于设计至关重要 PCOS的老年妇女最相关的治疗策略。而口服避孕药 （OC）有效解决HA和月经功能障碍，它们也与 不良心血管风险可能会随着年龄的增长而进一步增加。因此，对于有 PCOS，替代疗法（例如，二甲双胍）可能是可取的。在PCOS的年轻女性中 二甲双胍已被证明可有效治疗月经功能障碍和生化HA。 但是，在老年PCOS女性中，OC与二甲双胍的相对可取性是不知道的。我们 建议确定四个既定的HA预测因子的相对贡献（LH分泌，， 卵巢对重组人绒毛膜促性腺激素给药的反应，肾上腺对 在年龄较大的年轻女性中 PCOS在一项生理研究中（AIM 1）。我们还将确定相对的可取性（如确定 通过生活质量评估）二甲双胍与OCS治疗PCOS的生殖妇女 在一项随机交叉研究中的年龄（AIM 2）。这些研究的成功完成将提供1） 对HA的决定因素如何随着衰老而变化的更完整和凝聚力的理解 pcos; 2）对年龄相关的老年生殖老化治疗策略的批判性见解 PCOS的女性。这项K23赠款中提出的研究将根据 克里斯托弗·R·麦卡特尼（Christopher R. McCartney），医学博士，为理解 在过去的18年中，PCOS的病理生理学。我机构的研究环境 （弗吉尼亚大学）非常协作和支持。得到巨大的研究支持和 我的导师和机构的奉献精神，我将继续完善我的研究技能 成为独立的临床研究者。