Hyperandrogenism and Insulin Resistance in the Ontogeny of PCOS

PCOS 个体发育中的高雄激素血症和胰岛素抵抗

• 批准号: 8249340
• 负责人: RICHARD LEGRO
• 金额: $ 31.39万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249340
• 关键词: Adrenal Glands; Adult; Affect; Alleles; Androgens; Brothers; Characteristics; Child; Chromosomes, Human, Pair 19; Clinical; Data; Daughter; Development; Diagnostic; Disease; Double-Blind Method; Early treatment; Etiology; Family; Family Study; Feasibility Studies; Female infertility; First Degree Relative; Functional disorder; Genetic; Genetic Markers; Genomics; Glucose; Goals; Gonadal structure; Growth; Hyperandrogenism; Hyperinsulinism; Incidence; Infertility; Insulin; Insulin Resistance; Link; Literature; Longitudinal Studies; Metabolic; Metformin; Mission; Mothers; Oral; Phenotype; Polycystic Ovary Syndrome; Prevention; Prevention strategy; Production; Puberty; Randomized Controlled Trials; Recruitment Activity; Relative (related person); Research Personnel; Risk; Risk Assessment; Sister; Source; Staging; Stigmata; Study Subject; Syndrome; Testing; Translational Research; Vulnerable Populations; Woman; Work; base; case control; girls; improved; insight; novel; placebo controlled study; premature; prepuberty; programs; reproductive; response; social stigma; trait; transmission process

Polycystic Ovary Syndrome (PCOS), which is the most common endocrinopathy in women, presents clinically with anovulatory infertility. In girls, premature pubarche may be the earliest sign of PCOS. Many women with PCOS and girls with premature pubarche are also insulin resistant, a phenotypic characteristic common to both conditions. Familial clustering appears to be a feature of PCOS and our previous work has demonstrated that hyperandrogenism and insulin resistance are transmissible traits, We hypothesize that daughters of women with PCOS are likely to develop hyperandrogenism in mid puberty, exacerbated by hyperinsulinemia, and that transmission of a candidate allele on Chromosome 19 predicts risk. We propose a case/control longitudinal study of girls of women with PCOS compared to girls of women without PCOS, carefully matched for pubertal stage. We will phenotype these girls for abnormalities associated with PCOS and follow them through later pubertal stages. We present compelling preliminary data supporting our hypotheses and the feasibility of these studies. Further, the ontogeny of these abnormalities in the pubertal transition provides insight into the contributions of insulin resistance and hyperandrogenemia to the etiology of the syndrome, that will be further tested by a double blind randomized controlled trial of metformin in girls with premature pubarche. These studies are intended to provide a basis for identifying girls likely to develop PCOS and anovulatory infertility and to enable development of preventive strategies. Our specific aims are: to examine androgen status in daughters of women with PCOS and its temporal relation to hyperinsulinemia, to document the effects of insulin sensitization on improvement in hyperandrogenism and hyperinsulinemia in girls with premature pubarche, and to examine the predictive ability of genetic markers on the development of PCOS and response to metformin. These studies are important to several key goals of the U54 Reproductive Center mission including: 1) the etiology, pathophysiology, and prevention of female infertility due to PCOS, with particular emphasis on those conditions that are genetically based, and 2) the use of genomics to develop novel, non-invasive diagnostics for reproductive diseases and disorder

多囊卵巢综合征（PCOS）是女性最常见的内分泌疾病， 临床上与无排卵性不孕症有关。在女孩中，过早的阴毛可能是PCOS的最早迹象。许多 多囊卵巢综合征妇女和阴毛早长的女孩也有胰岛素抵抗，这是一种表型特征， 这两种情况都有共同点。家族聚集似乎是PCOS的一个特征，我们以前的工作已经证明， 表明高雄激素血症和胰岛素抵抗是可传递的性状，我们假设， 多囊卵巢综合征妇女的女儿可能在青春期中期出现高雄激素血症， 高胰岛素血症以及19号染色体上候选等位基因传递可预测风险。我们提出 一项对多囊卵巢综合征患者的女孩与非多囊卵巢综合征患者的女孩进行比较的病例/对照纵向研究， 与青春期的年龄相匹配我们将对这些女孩进行与PCOS相关的异常表型分析 并跟踪他们到青春期后期。我们提出了令人信服的初步数据支持我们的 这些研究的假设和可行性。此外，青春期这些异常的个体发育 转变提供了深入了解胰岛素抵抗和高雄激素血症的病因学的贡献 这将通过一项在女孩中进行的二甲双胍双盲随机对照试验进行进一步测试 阴毛过早发育这些研究的目的是为确定有可能发育的女孩提供基础。 多囊卵巢综合征和无排卵性不孕症，并制定预防战略。我们的具体目标是： 检查PCOS妇女女儿的雄激素状态及其与高胰岛素血症的时间关系， 记录胰岛素增敏对改善高雄激素血症和高胰岛素血症的作用 在青春期过早的女孩，并检查遗传标记的预测能力， PCOS的发展和对二甲双胍的反应。这些研究对实现《公约》的几个关键目标很重要。 U 54生殖中心的使命包括：1）女性生殖系统疾病的病因、病理生理学和预防 不孕症由于多囊卵巢综合征，特别强调那些条件是遗传基础，和2） 利用基因组学开发新的、非侵入性的生殖疾病和紊乱诊断方法