Treating Inflammation in PCOS to Ameliorate Ovarian Dysfunction

 描述（由申请人提供）：多囊卵巢综合征（PCOS）的特征是高雄激素血症、排卵功能障碍和多囊卵巢。胰岛素抵抗是多囊卵巢综合征的一个共同特征，由此产生的高胰岛素血症被认为是促进高雄激素血症的理论依据。然而，30-50%患有PCOS的瘦女性没有胰岛素抵抗。患有PCOS的女性也表现出慢性低度炎症。我们已经证明，在PCOS中，葡萄糖摄入激活核因子κB（NFκB），炎症的主要信号最终导致单核细胞（MNC）内炎症通路的上调。这种现象与过度肥胖无关，与循环雄激素高度相关。此外，在体外暴露于促炎刺激物， 能够直接刺激卵巢卵泡膜细胞雄激素的产生。水杨酸盐给药已显示抑制NFκB活化，并且水杨酸盐的非乙酰化形式在人体中耐受良好。这项研究是一项随机、双盲、安慰剂对照的研究，共有90名PCOS患者参加。45名PCOS患者（15名无胰岛素抵抗（IR）的瘦型患者，15名IR瘦型患者和15名肥胖患者）接受双水杨酯（一种非乙酰化水杨酸盐）治疗，口服剂量为每日3-4 gm，持续12周，将与45名年龄和身体组成匹配的PCOS对照妇女接受安慰剂进行比较。总体假设是炎症导致卵巢功能障碍，独立于过度肥胖或IR。具体目的是，I：检查双水杨酸给药对PCOS患者卵巢分泌雄激素和胰岛素敏感性的影响。二：探讨双水杨酯对多囊卵巢综合征（PCOS）患者脂质摄入和葡萄糖输注诱导的单核细胞炎症反应的影响。该方法包括评价卵巢雄激素分泌对人绒毛膜促性腺激素管理和胰岛素敏感性的两步胰腺钳沿着与排卵监测之前和之后salsalate管理的血糖正常期。在治疗期间，还将通过测量活性氧、炎症标志物的RNA和蛋白质含量、核因子κB活化和培养物中的细胞因子释放来评价MNC对脂质摄入的炎症反应和两步钳夹的高血糖期。我们预期接受双水杨酯治疗的PCOS妇女，无论肥胖程度或IR状态如何，卵巢雄激素分泌减少，炎症减轻。这些结果将是重要的，因为它们将表明在PCOS中，用非甾体抗炎药治疗直接减弱卵巢雄激素分泌和由饮食成分引发的炎症。这将导致PCOS治疗的重要进展，这将改善雄激素过多和减少炎症。

 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.