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

描述(申请人提供)：多囊卵巢综合征(PCOS)是一种常见的疾病，影响7%的育龄妇女，其特征是雄激素水平升高、少无排卵和多囊卵巢形态。多囊卵巢综合征与多毛症、粉刺、月经周期不规律和不孕不育有关，并会增加肥胖、代谢综合征和2型糖尿病的风险。尽管多囊卵巢综合征很常见，并与显著的发病率有关，但其病因仍不清楚。神经内分泌异常--即促黄体生成素(LH)和促性腺激素释放激素(GnRH)搏动性增加并相对缺乏卵泡刺激素(FSH)--通常出现在该疾病中，并与其病理有关。孕酮(P)是促性腺激素释放激素(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对P负反馈的下丘脑敏感性受损，这与雄激素升高有关，并被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先兆。与PCOS的成年女性一样，HA的女孩表现出高的黄体生成素脉冲频率，一些透明质酸青少年还存在P对黄体生成素脉冲抑制的损害，提示这些女孩的黄体生成素(GnRH)脉动性异常可能与下丘脑负反馈受损有关。本研究旨在通过研究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青春期女孩神经内分泌异常是如何发生的，以提高我们对正常青春期和异常青春期的理解。通过这样做，这项研究可能有助于指导未来对多囊卵巢综合征的治疗--也许还有预防--在其在青春期后期和成年期完全表现出来之前。这项研究的目的是评估(A)P在正常青春期成熟期间引导GnRH分泌的作用；(B)这一过程在HA环境中可能会如何改变；以及(C)如何根据睡眠状况对GnRH频率进行不同的控制，以解释有和没有HA的女孩GnRH分泌的观察模式。因此，本研究的目标是：特定目标1：确定生理上相关的磷浓度是否抑制青春期早期女孩的黄体生成素脉冲频率。具体目标2：确定患有和不患有HA的青春期晚期女孩的GnRH脉冲频率对P负反馈的反应是否取决于睡眠和清醒状态。 公共卫生相关性：多囊卵巢综合征(PCOS)是一种常见的荷尔蒙疾病，以男性激素水平升高、排卵障碍和卵巢囊肿为特征，会导致成年女性的显著发病率，包括毛发生长异常、粉刺、月经不调、不育，以及糖尿病、肥胖症和代谢综合征风险的增加。多囊卵巢综合征可能在青春期开始，当时女孩出现类似于患有多囊卵巢综合征的成年女性的病理和激素异常。这项研究将通过确定孕酮在正常和高雄激素血症少女青春期成熟过程中的作用来研究PCOS的发展，希望对青春期激素异常的更好理解将有助于该疾病的预防和治疗。

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.