Developmental Origins of Polycystic Ovary Syndrome: Very Early Phenotypes During the Mini Puberty of Infancy and Beyond

项目摘要 多囊卵巢综合征（PCOS）是育龄妇女最常见的内分泌疾病之一， 年龄，并与显着的负面生殖和代谢结果。由于PCOS的严重性， 受影响妇女的女儿的患病风险增加，据报告患病率高达约70%。 一些研究已经确定，不同的生殖和代谢表型，可以观察到PCOS 青春期前的女儿，表明PCOS的发病机制开始于早期发育阶段， 这些有危险的女孩此外，对PCOS动物模型的研究表明，暴露于雄激素 或抗苗勒管激素（AMH）在关键发育期，如胎儿生命，新生儿期，或 青春期可使后代在青春期发育期间形成PCOS的生殖和/或代谢表型。 生殖成熟在青春期之前，下丘脑-垂体-性腺（HPG）轴是静止的，除非在 “婴儿期的迷你青春期”，即生命最初几个月的短暂发育阶段。关于HPG 轴在这段时间是活跃的，促性腺激素和性类固醇达到青春期水平。我们的总体 有一种假说认为，青春期过短将揭示多囊卵巢综合征妇女女儿的早期生殖表型， 以促性腺激素和AMH分泌的改变为特征。早期的研究 由于在这个年龄组进行侵入性测试的挑战，我们将采用微创手术 这些方法将使我们能够检查PCOS女儿的早期代谢和生殖表型， 伤害这些年轻女孩的危险。三个目的将测试以下假设：1）PCOS女儿有一个独特的 以促性腺激素和AMH增加为特征的婴儿期青春期小发育期的生殖表型 水平和降低性激素结合球蛋白（SHBG）; 2）PCOS的女儿将发展代谢 表型的特征是增加体脂肪积累和降低胰岛素敏感性，在头两年， 3）PCOS女儿在婴儿期青春期的LH和AMH水平将呈正相关 与母体睾酮和AMH水平呈负相关，与母体胰岛素敏感性呈负相关， 妊娠中期脂联素水平。我们将招募120名PCOS女性和120名对照女性 女性在怀孕的第二个三个月。我们将测量生殖激素和 胰岛素敏感性和分泌。我们会收集定时尿液 用于评估婴儿C肽、促性腺激素分泌和类固醇激素代谢的样本 1个月、2个月和3个月大的女儿。我们将获得肥胖和毛细血管血液样本的措施， 在3、6、12、18和24个月大的女婴中测量SHBG、AMH和脂联素。如果 目标的实现，这项研究的影响将导致我们对早期的理解范式的转变， PCOS的机制。通过拟议的研究，我们还将建立一个队列， 在PCOS风险增加的女孩中进行的研究。

PROJECT SUMMARY Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in women of reproductive age and is associated with significant negative reproductive and metabolic outcomes. As PCOS is highly heritable, daughters of affected women have increased risk, with reported prevalence rates as high as ~70%. Several studies have established that distinct reproductive and metabolic phenotypes can be observed in PCOS daughters prior to puberty, suggesting the pathogenesis of PCOS begins at an early developmental stage in these at-risk girls. Further, studies in animal models of PCOS have demonstrated that exposure to androgens or anti-Mullerian hormone (AMH) during critical developmental periods such as fetal life, the neonatal period, or puberty can program the offspring to develop the reproductive and/or metabolic phenotypes of PCOS during reproductive maturity. Prior to puberty, the hypothalamic-pituitary-gonadal (HPG) axis is quiescent, except during the “mini puberty of infancy”, a transient developmental stage during the first several months of life. The HPG axis is active during this time and gonadotropin and sex steroids reach pubertal levels. Our overarching hypothesis is that mini puberty will unmask an early reproductive phenotype in daughters of women with PCOS, characterized by alterations in gonadotropin and AMH secretion. Studies during this very early age have been limited due to the challenges of pursuing invasive testing in this age group. We will employ minimally invasive methods which will allow us to examine early metabolic and reproductive phenotypes in PCOS daughters without risk of harm to these young girls. Three Aims will test the hypotheses that: 1) PCOS daughters have a distinct reproductive phenotype during the mini puberty of infancy characterized by increased gonadotropin and AMH levels and decreased sex hormone binding globulin (SHBG); 2) PCOS daughters will develop a metabolic phenotype characterized by increased body fat accrual and decreased insulin sensitivity in the first two years of life; 3) LH and AMH levels in PCOS daughters during the mini puberty of infancy will be positively associated with maternal testosterone and AMH levels and negatively associated with maternal insulin sensitivity and adiponectin levels during the second trimester of gestation. We will enroll 120 women with PCOS and 120 control women early in their second trimester of pregnancy. We will measure reproductive hormones and markers of insulin sensitivity and secretion in these women between 24 and 28 weeks gestation. We will collect timed urine samples for assessment of C-peptide, gonadotropin secretion, and steroid hormone metabolism in their infant daughters at 1, 2, and 3 months of age. We will obtain measures of adiposity and capillary blood samples for measurement of SHBG, AMH, and adiponectin at 3, 6, 12, 18, and 24 months of age in the infant daughters. If the Aims are achieved, the impact of this research will result in a paradigm shift in our understanding of the early mechanisms of PCOS. Through the proposed study, we will also establish a cohort for continued longitudinal studies in girls at increased risk for PCOS.