Combination metformin and oral contraceptive for PCOS

多囊卵巢综合征（PCOS）是导致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重要作用。胰岛素抵抗增加了2型糖尿病、高血压、血脂异常、高凝状态和心血管疾病的长期风险，心血管疾病是美国妇女死亡的主要原因。几十年来，口服避孕药（OCRs）一直是不寻求怀孕的PCOS女性的标准治疗。OCP产生一种高雌激素状态，有利地抑制卵巢和雄激素的产生。虽然OCP对PCOS有几个好处，但有限的证据表明OCP可能会恶化PCOS的胰岛素抵抗。因此，PCOS慢性管理的最佳药物治疗仍不清楚。 本研究的目的是确定在口服避孕药中加入胰岛素增敏剂是否会改善高雌激素血症对PCOS高胰岛素抵抗的不良影响。具体而言，我们将进行一项双盲、随机研究，以确定二甲双胍和炔雌醇35 mcg诺孕酯，0.25 mg（Ortho-Cyclen，Ortho-McNeil Pharmaceuticals）与OCP单一疗法相比，将：1）改善胰岛素敏感性，如通过频繁取样的静脉内葡萄糖耐量试验（FSIVGTT）直接测量的; 2）有利地影响代谢综合征的组分; 3）降低与心血管风险相关的炎症标志物（hsCRP、派-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用性的非侵入性测量。我们假设胰岛素增敏药物和OCP联合治疗是PCOS的最佳维持治疗，可改善临床、激素和代谢参数，降低胰岛素抵抗相关的长期风险。 本研究的结果将：1）为更大规模的随机对照试验提供基础，评价OCP-胰岛素增敏剂和其他联合治疗对肥胖和瘦型PCOS女性的影响; 2）提供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PCOS中胰岛素抵抗的机制;和3）导致管理PCOS的慢性治疗的新方法。

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.