Progesterone's Role in Pubertal Maturation in Normal and Hyperandrogenemic Adoles

描述（由申请人提供）：多囊卵巢综合征（PCOS）是一种常见病，影响7%的育龄妇女，其特征是雄激素水平升高、少排卵和多囊卵巢形态。多囊卵巢综合征与多毛、痤疮、月经周期不规律和不孕症有关，并导致肥胖、代谢综合征和2型糖尿病的风险增加。虽然多囊卵巢综合征是常见的，并与显著发病率相关，病因尚不清楚。神经内分泌异常——即黄体生成素（LH）和促性腺激素释放激素（GnRH）搏动增加与相对促卵泡激素（FSH）缺乏——通常存在于该疾病中，并导致其病理。孕酮(P)被认为是GnRH合成和分泌的主要调节因子。事实上，患有多囊卵巢综合征的女性表现出下丘脑对P负反馈的敏感性受损，这与雄激素升高有关，并通过雄激素受体拮抗剂逆转。青春期女孩的高雄激素血症（HA）被认为是多囊卵巢综合征的前兆。与患有PCOS的成年女性一样，HA女孩表现出LH脉冲频率升高，一些HA青少年也有P抑制LH脉冲的损伤，这表明这些女孩的LH （GnRH）脉冲异常可能与下丘脑负反馈受损有关。本课题旨在通过研究P在正常和HA青春期女孩青春期成熟中的作用，更好地了解HA青春期周围女孩神经内分泌异常的发生机制，以提高我们对正常和异常青春期的认识。这样做，这项研究可能有助于指导未来的治疗——也许是预防——多囊卵巢综合征在青春期晚期和成年期完全表达之前。本研究的目的是评估(a)在正常青春期成熟过程中P在指导GnRH分泌中的作用；（二）在医管局的情况下，这个过程会如何改变；(c) GnRH频率的差异控制取决于睡眠状态，如何解释在有和没有HA的女孩中观察到的GnRH分泌模式。因此，本研究计划的目的是：具体目的1：确定生理相关的P浓度是否会抑制青春期早期女孩的LH脉冲频率。具体目的2：确定GnRH脉冲频率对P负反馈的反应是否取决于有和没有HA的青春期晚期女孩的睡眠和清醒状态。

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is a common disorder affecting 7% of reproductive age women marked by elevated androgen levels, oligo-anovulation, and polycystic ovarian morphology. PCOS is associated with hirsutism, acne, irregular menstrual cycles and infertility and causes an increased risk for obesity, the metabolic syndrome, and type 2 diabetes mellitus. Although PCOS is common and associated with significant morbidity, the etiology remains unknown. Neuroendocrine abnormalities-namely, increased luteinizing hormone (LH) and gonadotropin-releasing hormone (GnRH) pulsatility with relative follicle-stimulating hormone (FSH) deficiency-are commonly present in the disorder and contribute to its pathology. Progesterone (P) is thought to be the major regulator of GnRH synthesis and secretion. Indeed, women with PCOS demonstrate impaired hypothalamic sensitivity to P negative feedback, which is related to elevated androgens and is reversed by androgen-receptor antagonism. Hyperandrogenemia (HA) in adolescent girls is thought to be a precursor to PCOS. As with adult women with PCOS, girls with HA demonstrate elevated LH pulse frequency, and some HA adolescents also have impairment of LH pulse suppression by P, suggesting that abnormal LH (GnRH) pulsatility in these girls may be related to impaired negative feedback at the hypothalamus. This research proposal aims to better understand how neuroendocrine abnormalities arise in peripubertal girls with HA by studying the role of P in pubertal maturation in normal and HA adolescent girls in order to improve our understanding of normal and aberrant puberty. In doing so, this research may help guide future treatment-and perhaps prevention-of PCOS before its full expression in late adolescence and adulthood. The goal of this research is to assess (a) the role of P in directing GnRH secretion during normal pubertal maturation; (b) how this process may be altered in the setting of HA; and (c) how differential control of GnRH frequency depending on sleep status may explain observed patterns of GnRH secretion in girls with and without HA. Hence, this research proposal aims: Specific Aim 1: To determine whether physiologically-relevant P concentrations suppress LH pulse frequency in early pubertal girls. Specific Aim 2: To determine whether GnRH pulse frequency responsiveness to P negative feedback depends on sleep vs. wake status in late pubertal girls with and without HA. PUBLIC HEALTH RELEVANCE: Polycystic ovary syndrome (PCOS) is a common hormonal disorder marked by elevated male hormone levels, impaired ovulation and cysts on the ovaries that causes significant morbidity in adult women, including abnormal hair growth, acne, irregular menses, infertility, and an increased risk for diabetes, obesity and the metabolic syndrome. Likely, PCOS begins in puberty when girls develop pathologic and hormonal abnormalities similar to adult women with PCOS. This research will study the development of PCOS by determining the role of progesterone during pubertal maturation in normal and hyperandrogenemic adolescent girls with the hope that an improved understanding of hormonal abnormalities during puberty will aid in the prevention and treatment of the disorder.