Treating Inflammation in PCOS to Ameliorate Ovarian Dysfunction

 描述(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共同特征，由此产生的高胰岛素血症被理论上认为会促进这种疾病的高雄激素血症。然而，30%-50%的患有多囊卵巢综合征的瘦女性没有胰岛素抵抗。患有多囊卵巢综合征的女性也表现出慢性低度炎症。我们已经证明，在多囊卵巢综合征中，葡萄糖摄取激活了核因子κB(NFκB)，这是炎症的主要信号，最终导致单核细胞内炎症途径的上调。这种现象与过度肥胖无关，与循环中的雄激素高度相关。此外，在体外暴露于促炎刺激是 能够直接刺激卵泡膜细胞雄激素的产生。水杨酸盐给药已被证明可以抑制NFκB的激活，非乙酰化形式的水杨酸盐在人类中具有很好的耐受性。这项拟议的研究是一项随机、双盲、安慰剂对照的研究，对象为90名患有多囊卵巢综合征的女性。45名PCOS患者(15名瘦身无胰岛素抵抗(IR)，15名瘦身伴IR，15名肥胖)服用水杨酸盐，一种非乙酰化水杨酸盐，每天口服3-4克，持续12周，将与45名年龄和身体成分匹配的接受安慰剂的PCOS对照组妇女进行比较。最重要的假设是，炎症导致卵巢功能障碍，与过度肥胖或IR无关。本研究的具体目的是：1.观察水杨酸盐对多囊卵巢综合征患者卵巢雄激素分泌能力和胰岛素敏感性的影响。II：观察水杨酸盐对多囊卵巢综合征大鼠脂肪摄入和葡萄糖输注诱导的单核细胞炎症反应的影响。该方法包括评估卵巢雄激素分泌对人绒毛膜促性腺激素注射的响应，以及在两步胰钳的正常血糖阶段期间的胰岛素敏感性，以及在给药前和后的排卵监测。在治疗过程中，还将通过测定培养中的活性氧、炎症标志物的核糖核酸和蛋白质含量、核因子κB的激活和细胞因子的释放来评估单核细胞对脂质摄入的炎症反应和两步夹的高血糖阶段。我们的预期是，无论肥胖程度或IR状态如何，接受沙柳酸盐治疗的多囊卵巢综合征患者都会表现出卵巢雄激素分泌减少和炎症减轻。这些结果将具有重要意义，因为它们将表明，在多囊卵巢综合征患者中，使用非类固醇抗炎剂治疗直接减轻卵巢雄激素分泌和由饮食成分引发的炎症。这将导致多囊卵巢综合征的治疗取得重要进展，从而缓解雄激素过剩并减少炎症。

 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.