Treating Inflammation in PCOS to Ameliorate Ovarian Dysfunction

治疗 PCOS 炎症以改善卵巢功能障碍

• 批准号: 9567552
• 负责人: FRANK GONZALEZ
• 金额: $ 73.71万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9567552
• 关键词: Acne; Affect; Age; Androgens; Anovulation; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Body Composition; CYP17A1 gene; Cells; Chronic; Closure by clamp; Compensatory Hyperinsulinemia; Data; Development; Dietary Component; Disease; Dose; Double-Blind Method; Endocrine; Endometrial Carcinoma; Enzymes; Ethnic Origin; Evaluation; Exhibits; Exposure to; Functional disorder; Gel; Glucose; Hirsutism; Human; Human Chorionic Gonadotropin; Hyperandrogenism; Hyperglycemia; Hyperinsulinism; In Vitro; Infertility; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Ingestion; Insulin; Insulin Resistance; Link; Lipids; Measurement; Measures; Modeling; Molecular; Monitor; Mononuclear; Morphology; Non-Steroidal Anti-Inflammatory Agents; Nuclear; Obesity; Oral; Ovarian; Ovarian Ablation; Ovary; Ovulation; Pancreas; Pathogenesis; Pathway interactions; Phase; Physiological; Placebos; Polycystic Ovary Syndrome; Premenopause; Production; Proteins; RNA; Randomized; Reactive Oxygen Species; Reporting; Research; Role; Salicylic Acids; Signal Transduction; Skin Manifestations; Stimulus; Testing; Testosterone; Thinness; Up-Regulation; Wit; Woman; Women' s Group; abdominal fat; base; cytokine; expectation; in vivo; inflammatory marker; insulin sensitivity; molecular marker; novel therapeutics; ovarian dysfunction; placebo controlled study; public health relevance; randomized placebo controlled trial; response; salicylsalicylic acid; theca cell

 DESCRIPTION (provided by applicant): Polycystic Ovary Syndrome (PCOS) is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovaries. Insulin resistance is a common feature of PCOS, and the resultant hyperinsulinemia has been theorized to promote hyperandrogenism in the disorder. However, 30-50% of women with PCOS who are lean do not have insulin resistance. Women with PCOS also exhibit chronic low-grade inflammation. We have shown that in PCOS, glucose ingestion activates nuclear factor κB (NFκB), the cardinal signal of inflammation culminating in upregulation of the inflammation pathway within mononuclear cells (MNC). This phenomenon is independent of excess adiposity and is highly correlated with circulating androgens. In addition, in vitro exposure to proinflammatory stimuli is capable of directly stimulating ovarian theca cell androgen production. Salicylate administration has been shown to suppress NFκB activation, and the nonacetylated form of salicylate is well tolerated in humans. The proposed research is a randomized double-blind placebo-controlled study of 90 women with PCOS. Forty-five subjects with PCOS (15 lean without insulin resistance (IR), 15 lean with IR and 15 obese) receiving salsalate, a nonacetylated salicylate, at an oral dose of 3-4 gm daily for 12 weeks will be compared with 45 age- and body-composition-matched control women with PCOS receiving placebo. The overarching hypothesis is that inflammation contributes to ovarian dysfunction, independent of excess adiposity or IR. The specific aims are, I: To examine the effect of salsalate administration on the ovarian capacity to secrete androgen on and insulin sensitivity in PCOS. II: To examine the effect of salsalate administration on the inflammatory response of mononuclear cells induced by lipid ingestion and glucose infusion in PCOS. The approach involves evaluation of ovarian androgen secretion in response to human chorionic gonadotropin administration and insulin sensitivity during the euglycemic phase of a two-step pancreatic clamp along with ovulation monitoring before and after salsalate administration. The inflammatory response of MNC to lipid ingestion and the hyperglycemic phase of the two-step clamp will also be evaluated during treatment by measuring reactive oxygen species, the RNA and protein content of inflammation markers, nuclear factor κB activation and cytokine release in culture. It is our expectation that women wit PCOS receiving salsalate will exhibit decreased ovarian androgen secretion and reduced inflammation regardless of degree of adiposity or IR status. These results will be significant because they will show that in PCOS, treatment with a non-steroidal anti-inflammatory agent directly attenuates ovarian androgen secretion and inflammation triggered by dietary components. This will lead to important advances in the therapy of PCOS that will ameliorate androgen excess and by reducing inflammation.

 描述（由应用程序提供）：多囊卵巢综合征（PCOS）的特征是高狂力，排卵功能障碍和多囊卵巢。胰岛素抵抗是PCOS的一个共同特征，所得的高胰岛素血症已被理论上促进该疾病中的高狂力主义。但是，有30％至50％的瘦肉女性没有胰岛素抵抗。患有PCOS的女性还暴露了慢性低度炎症。我们已经表明，在PCOS中，葡萄糖摄取激活了核因子κB（NFκB），炎症的主要信号在单核细胞（MNC）内炎症途径上调时最终导致。该现象与过量肥胖无关，并且与循环雄激素高度相关。另外，体外暴露于促炎性刺激是 能够直接刺激卵巢硫代细胞雄激素产生。水杨酸酯的给药已显示可抑制NFκB的激活，并且在人类中，非乙酰化形式的水杨酸酯形式良好。拟议的研究是对90名PCOS女性的随机双盲安慰剂对照研究。患有PCOS的45名受试者（15个无胰岛素抵抗（IR），15瘦的IR和15个肥胖的受试者，接受salsalate，非乙酰化水杨酸盐，每天的口服剂量为3-4 gm，为期12周，将与45岁和身体组成的对照女性接受PCOS接受PCOS的45 gm。总体假设是，炎症导致卵巢功能障碍，独立于过度肥胖或IR。 i的具体目的是：检查salsalate给药对PCOS中雄激素对雄激素和胰岛素敏感性的卵巢能力的影响。 II：检验盐盐给药对PCOS中脂质摄入和葡萄糖输注诱导的单核细胞炎症反应的影响。该方法涉及评估卵巢雄激素分泌，以响应人类绒毛膜促性腺激素的给药和胰岛素敏感性，在两步胰腺夹具的葡萄糖阶段，以及在给药之前和之后进行排卵监测。在治疗期间，也将通过测量活性氧，感染标志物的RNA和蛋白质含量，核因子κB激活和细胞因子释放，在治疗期间还可以评估MNC对脂质摄入和两步夹的高血糖期的炎症反应。我们的期望是，无论肥胖程度或IR状态程度如何，都会杀死患有salsalate的PCOS的女性将杀死删除的卵巢雄激素分泌并减少感染。这些结果将很重要，因为它们将表明，在PCOS中，用非甾体类抗炎剂治疗直接减弱卵巢雄激素的分泌和饮食成分触发的感染。这将导致PCOS治疗的重要进展，这些PCO将改善雄激素超过并通过减少注射。