Combination metformin and oral contraceptive for PCOS

描述(申请人提供)：多囊卵巢综合征(PCOS)是美国女性不孕的最常见原因。PCOS的典型特征是高雄激素血症和慢性无排卵，但胰岛素抵抗在其发病机制中起着核心作用。胰岛素抵抗增加了患2型糖尿病、高血压、血脂紊乱、易凝聚性和心血管疾病的长期风险，心血管疾病是美国女性的主要死亡原因。几十年来，口服避孕药(OCRs)一直是不寻求怀孕的多囊卵巢综合征妇女的标准治疗方法。OCP创造了一种高雌激素状态，有利于抑制卵巢和雄激素的产生。尽管OCPs在PCOS中有几个好处，但有限的证据表明OCPs可能会加重PCOS的胰岛素抵抗。因此，多囊卵巢综合征慢性治疗的最佳药物治疗仍不清楚。 本研究的目的是确定在OCP中加入胰岛素增敏剂是否会改善高雌激素血症对PCOS高胰岛素抵抗的不利影响。具体地说，我们将进行一项双盲随机研究，以确定二甲双胍和乙炔雌二醇联合治疗是否与OCP单一治疗相比：1)通过频繁采样的静脉葡萄糖耐量试验(FSIVGTT)直接测量，改善胰岛素敏感性；2)有利于影响代谢综合征的组成部分；3)降低与心血管风险相关的炎症标志物(hsCRP、PAI-1、MCP-1、IL-6、VCAM-1和ICAM-1)的浓度；以及4)影响血流介导的扩张，这是血管内皮细胞一氧化氮可获得性的非侵入性测量。我们推测，联合应用胰岛素增敏药物和口服避孕药是PCOS改善临床、激素和代谢参数并降低与胰岛素抵抗相关的长期风险的最佳维持疗法。 这项研究的结果将：1)为一项更大规模的随机对照试验奠定基础，评估OCP-胰岛素增敏剂和其他联合疗法对患有多囊卵巢综合征的肥胖和消瘦女性的疗效；2)提供有关高雌激素血症和胰岛素增敏对糖尿病和心血管疾病风险降低的影响的数据，从而更好地了解多囊卵巢综合征胰岛素抵抗的机制；以及3)探索管理多囊卵巢综合征慢性治疗的新方法。

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is the most common cause of female infertility in the United States. PCOS is classically characterized by hyperandrogenism and chronic anovulation, but it has become apparent that insulin resistance plays a central role in its pathogenesis. Insulin resistance increases long-term risks for development of type 2 diabetes, hypertension, dyslipidemia, hypercoaguability, and cardiovascular disease, the leading cause of death in American women. For decades, oral contraceptive pills (OCRs) have been standard therapy for women with PCOS not seeking pregnancy. OCPs create a hyperestrogenic state that favorably suppresses ovarian and androgen production. Although OCPs have several benefits in PCOS, limited evidence suggests that OCPs may worsen insulin resistance in PCOS. Therefore, the optimal pharmacotherapy for chronic management of PCOS remains unclear. The aim of this study is to determine whether the addition of an insulin-sensitizing agent to an OCP will ameliorate the adverse effects of hyperestrogenemia on the hyperinsulinemic insulin resistance of PCOS. Specifically, we will conduct a double-blind, randomized study that will determine if combination therapy of Metformin and ethinyl estradiol 35 mcg norgestimate, 0.25mg (Ortho-Cyclen, Ortho-McNeil Pharmaceuticals), compared to OCP monotherapy, will: 1) improve insulin sensitivity as measured directly by the frequently sampled intravenous glucose tolerance test (FSIVGTT); 2) favorably affect components of the metabolic syndrome; 3) reduce concentrations of inflammatory markers associated with cardiovascular risks (hsCRP, PAI-1, MCP-1, IL-6, VCAM-1, and ICAM-1); and 4) affect flow-mediated dilatation, a noninvasive measure of vascular endothelial cell nitric oxide availability. We hypothesize that combination therapy with an insulin-sensitizing drug and an OCP is the optimal maintenance therapy for PCOS to improve clinical, hormonal, and metabolic parameters and reduce long-term risks associated with insulin resistance. The results of this study will: 1) provide the groundwork for a larger randomized, controlled trial evaluating the effects of combination OCP-insulin sensitizer and other combination therapies on obese and lean women with PCOS; 2) provide data on the effects of hyperestrogenemia and insulin sensitization on diabetes and cardiovascular disease risk reduction, leading to a better understanding of mechanisms of insulin resistance in PCOS; and 3) lead to novel ways of managing chronic therapy of PCOS.