Metabolic Syndrome in PCOS: Precursors and Interventions

描述(申请人提供)：多囊卵巢综合征(PCOS)是年轻女性最常见的疾病之一，它经常与胰岛素抵抗、葡萄糖耐量异常和其他胰岛素抵抗或代谢综合征(MBS)的特征有关。此外，与肥胖无关，受影响的妇女的平均低密度脂蛋白水平显著升高，高危低密度脂蛋白水平的患病率增加。PCOS存在遗传易感性，我们利用高雄激素血症的生殖表型，在染色体19p3.2靠近胰岛素受体基因的位置发现了一个主要易感基因。我们现在已经将这个变异(等位基因8[A8]D19S884)的位置映射到纤维蛋白3基因内含子55的一个二核苷酸重复的等位基因。我们的家族研究表明：1)生殖和代谢异常都是可遗传的，2)男性和女性一级亲属(FDR)都受到影响，3)高雄激素血症是MBS和LDL升高的独立预测因子，4)A8与先证者及其FDR中更严重的代谢表型有关。我们有非常令人兴奋的新数据，A8与肝脏胰岛素抵抗有关。这一建议的主要假设是：1)高雄激素血症在PCOS代谢异常的发病机制中起着独立的作用，2)高雄激素血症是由A8 PCOS易感变异引起的，3)高雄激素血症在生命的早期就开始产生代谢异常，在青春期之前就会产生。有两个具体目标。目的1：验证存在多囊卵巢综合征经前标志物的假设，该标志物可识别有代谢异常风险的女孩。将对FDRs进行研究，以确定是否存在月经前期表型，以及A8是否识别有风险的女孩。具体目标2：验证高雄激素血症单独或与胰岛素抵抗协同作用导致PCOS年轻女性代谢异常的假设。我们将确定雄激素受体拮抗剂氟他胺、胰岛素增敏剂二甲双胍或这些药物的组合是否能降低内脏脂肪、改善胰岛素敏感性或改善多囊卵巢综合征女性的血脂异常。此外，我们将确定A8基因型是否可以预测对这些干预措施的反应。这项拟议的研究具有重大的科学和公共卫生意义，因为它承诺确定多囊卵巢综合征代谢异常的先兆和新的治疗靶点。

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is one of the most common conditions of young women, and it is frequently associated with insulin resistance, glucose intolerance and other features of the insulin resistance or metabolic syndrome (MBS). In addition, affected women have significantly elevated mean LDL levels and an increased prevalence of at risk LDL levels, independent of obesity. There is a genetic susceptibility to PCOS and we have identified a major susceptibility gene on chromosome 19p3.2 near the insulin receptor gene using the reproductive phenotype of hyperandrogenemia. We have now mapped the location of this variant (allele 8 [A8] D19S884) to an allele of a dinucleotide repeat in intron 55 of the fibrillin 3 gene. Our family studies indicate that: 1) both reproductive and metabolic abnormalities are heritable, 2) male as well as female first-degree relatives (FDRs) are affected, 3) hyperandrogenemia is an independent predictor of MBS and LDL elevations and 4) A8 is associated with a more severe metabolic phenotype in both probands and their FDRs. We have extremely exciting new data that A8 is associated with hepatic insulin resistance. The overarching hypothesis of this proposal is that 1) hyperandrogenemia plays an independent role in the pathogenesis of the metabolic abnormalities in PCOS, 2) hyperandrogenemia results from A8 PCOS susceptibility variant and 3) hyperandrogenemia begins early in life producing metabolic abnormalities prior to puberty. There are two specific aims. Aim 1: To test the hypothesis that there are premenarchal markers of PCOS that identifies girls at risk for metabolic abnormalities. FDRs will be studied to determine whether there is a premenarchal phenotype and whether A8 identifies at risk girls. Specific Aim 2: To test the hypothesis that hyperandrogenemia, alone or in synergy with insulin resistance, contributes to metabolic abnormalities in young women with PCOS. We will determine whether the androgen receptor antagonist flutamide, the insulin sensitizing agent metformin or a combination of these medications reduces visceral adiposity, improves insulin sensitivity, or ameliorates dyslipidemia in women with PCOS. Further, we will determine whether A8 genotype predicts response to these interventions. The proposed research has substantial scientific as well as public health implications because it promises to identify precursors of and novel therapeutic targets for metabolic abnormalities in PCOS.