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（由申请人提供）：多囊卵巢综合征 (PCOS) 的特点是雄激素过多症、排卵功能障碍，多囊卵巢是 PCOS 的一个共同特征，理论上认为，由此产生的高胰岛素血症会促进该疾病的高雄激素症。 -50% 的瘦身 PCOS 女性没有胰岛素抵抗，患有 PCOS 的女性也表现出慢性胰岛素抵抗。我们已经证明，在 PCOS 中，葡萄糖摄入会激活核因子 κB (NFκB)，这是炎症的主要信号，最终导致单核细胞 (MNC) 内炎症途径的上调。这种现象与过度肥胖无关。此外，体外暴露于促炎刺激物与循环雄激素高度相关。 水杨酸盐能够直接刺激卵巢卵泡膜细胞产生雄激素，已被证明可以抑制 NFκB 激活，并且非乙酰化形式的水杨酸盐在人类中具有良好的耐受性。这项研究是一项针对 90 名 PCOS 女性的随机双盲安慰剂对照研究。 45 名 PCOS 受试者（15 名瘦身且无胰岛素抵抗 (IR)，15 名瘦身患有 IR，15 名肥胖）接受双水杨酸（一种非乙酰化药物）每天口服 3-4 克水杨酸，持续 12 周，将与 45 名年龄和身体成分匹配的 PCOS 女性接受安慰剂进行比较。总体假设是，炎症会导致卵巢功能障碍，与过度肥胖无关。具体目标是： I：检查双水杨酸给药对 PCOS 卵巢分泌雄激素的能力和胰岛素敏感性的影响。水杨酸给药对 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包括评估两步胰钳夹的正常血糖阶段对人绒毛膜促性腺激素给药的卵巢雄激素分泌和胰岛素敏感性。服用双水杨酸前后的排卵监测也会监测MNC对脂质摄入的炎症反应和两步钳夹的高血糖阶段。在治疗过程中，通过测量培养物中的活性氧、炎症标记物的 RNA 和蛋白质含量、核因子 κB 激活和细胞因子释放来进行评估。我们预计，接受双水杨酯治疗的 PCOS 女性，无论炎症程度如何，都会表现出卵巢雄激素分泌和炎症减轻。这些结果将具有重要意义，因为它们将表明，在多囊卵巢综合征中，使用非类固醇抗炎药治疗会直接减弱卵巢雄激素分泌和饮食成分引发的炎症。多囊卵巢综合症治疗的重要进展将改善雄激素过多并减少炎症。