ETIOLOGICAL FACTORS OF OBESITY-ASSOC HYPERANDROGENEMIA IN PERIPUBERTAL GIRLS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 多囊卵巢综合征（PCOS）是一种以高雄激素血症和排卵功能障碍为特征的常见疾病。此外，PCOS与肥胖和许多代谢异常相关，包括胰岛素抵抗、葡萄糖耐受不良、血脂异常和高血压。多囊卵巢综合征的病理生理机制很多。神经内分泌异常在大多数PCOS患者中起重要作用，PCOS与促性腺激素释放激素（GnRH）脉冲发生器对孕酮和雌二醇负反馈的相对抵抗有关。这种下丘脑对负反馈的抵抗似乎是高雄激素血症（HA）的结果，也可能发生在患有HA的青少年中。我们假设青春期周围的HA可以代表成年PCOS的先驱，可以通过诱导下丘脑对负反馈的抵抗来促进PCOS的发展。然而，青春期周围HA的原因在很大程度上仍然未知。肥胖是一个公认的病理生理因素，在HA的成年PCOS，最近的数据表明，青春期周围的肥胖与HA。然而，青春期肥胖和HA之间的关系以及在肥胖女孩中观察到的雄激素水平的显著变化之间的潜在机制尚不清楚。我们收集的初步数据表明，与雄激素水平较低的肥胖女孩相比，雄激素水平较高的青春期前和青春期早期肥胖女孩也表现出更大程度的胰岛素抵抗。这个试验项目的主要目标是开始建立胰岛素抵抗之间的关系，如胰岛素钳夹研究所确定的，在肥胖的青春期女孩中引起HA。其次，研究者的目的是评估黄体生成素升高的作用--通过在青春期频繁采集LH血样来确定肥胖相关HA的作用。对青春期周围HA的潜在因素进行表征，可以预测哪些青春期前和青春期早期的女孩随后会发展为PCOS症状。该项目产生的数据将促进未来的新研究，以调查导致PCOS的代谢和经典内分泌途径之间的复杂相互作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polycystic ovary syndrome (PCOS) is a common disorder of women marked by hyperandrogenemia and ovulatory dysfunction. Additionally, PCOS is associated with obesity and a number of metabolic abnormalities including insulin resistance, glucose intolerance, dyslipidemia, and hypertension. A number of pathophysiological mechanisms underlie PCOS. Neuroendocrine abnormalities play a significant role in most women with PCOS, and PCOS is associated with relative resistance of the gonadotropin releasing hormone (GnRH) pulse generator to negative feedback by progesterone and estradiol. This hypothalamic resistance to negative feedback appears to be a result of hyperandrogenemia (HA), and can also occur in adolescents with HA. We have hypothesized that peripubertal HA-which can represent a forerunner of adult PCOS-can promote the development of PCOS in part via induction of hypothalamic resistance to negative feedback. However, the cause of peripubertal HA remains largely unknown. Obesity is a well-recognized pathophysiological factor in the HA of adult PCOS; and recent data demonstrate that peripubertal obesity is associated with HA. However, the mechanisms underlying the relationship between peripubertal obesity and HA-and the marked variability of androgen levels observed among obese girls-are unknown. We have gathered preliminary data that suggests that obese pre- and early pubertal girls with high androgen levels also exhibit greater degrees of insulin resistance compared to obese girls with lower androgens. The primary goal of this pilot project is to begin to establish the relationship between insulin resistance-as determined by insulin clamp studies-in causing HA in obese peripubertal girls. Secondarily, the investigators aim to assess the contributions of elevated luteinizing hormone-determined by frequent blood sampling for LH in obesity-associated HA across puberty. Characterization of the factors underlying peripubertal HA may permit prediction of which pre- and early pubertal girls will subsequently go on to develop symptoms of PCOS. Data generated by this project will prompt novel future studies to investigate the complex interactions among metabolic and classical endocrine pathways that lead to PCOS.