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

黄体酮在正常和高雄激素血症青少年青春期成熟中的作用

• 批准号: 7999018
• 负责人: Jessicah S.P. Collins
• 金额: $ 5.58万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-06 至 2012-08-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999018
• 关键词: Acne; Adolescence; Adolescent; Adult; Affect; Age; Androgen Receptor; Androgens; Anovulation; Cyst; Development; Disease; Etiology; Feedback; Female Adolescents; Follicle Stimulating Hormone; Frequencies; Future; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Growth; Hair; Hirsutism; Hormonal; Hormones; Hypothalamic structure; Impairment; Infertility; Luteinizing Hormone; Menstrual cycle; Menstruation; Metabolic syndrome; Morbidity - disease rate; Morphology; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oligonucleotides; Ovarian; Ovary; Ovulation; Pathologic; Pathology; Pattern; Physiologic pulse; Polycystic Ovary Syndrome; Prevention; Process; Progesterone; Puberty; Relative (related person); Research; Research Proposals; Role; Sleep; Woman; diabetes risk; girls; hormone deficiency; improved; male; obesity risk; public health relevance; reproductive

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.

描述（由申请人提供）：多囊卵巢综合征 (PCOS) 是一种常见疾病，影响 7% 的育龄妇女，其特点是雄激素水平升高、少排卵和多囊卵巢形态。 PCOS 与多毛症、痤疮、月经周期不规律和不孕有关，并导致肥胖、代谢综合征和 2 型糖尿病的风险增加。尽管 PCOS 很常见并且发病率较高，但其病因仍不清楚。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，同时相对促卵泡激素 (FSH) 缺乏，常见于该疾病，并导致其病理学变化。黄体酮 (P) 被认为是 GnRH 合成和分泌的主要调节因子。事实上，患有 PCOS 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，并且可以通过雄激素受体拮抗作用来逆转。青春期女孩的高雄激素血症（HA）被认为是多囊卵巢综合症的先兆。与患有 PCOS 的成年女性一样，患有 HA 的女孩表现出 LH 脉冲频率升高，并且一些 HA 青少年也存在 P 对 LH 脉冲抑制的损害，这表明这些女孩异常的 LH (GnRH) 搏动可能与 LH 负反馈受损有关。下丘脑。本研究计划旨在通过研究 P 在正常和 HA 青春期女孩青春期成熟中的作用，更好地了解患有 HA 的围青春期女孩神经内分泌异常是如何发生的，以提高我们对正常和异常青春期的认识。这样做，这项研究可能有助于指导多囊卵巢综合症在青春期末期和成年期充分表现之前的未来治疗，甚至可能是预防。本研究的目的是评估 (a) P 在正常青春期成熟过程中指导 GnRH 分泌的作用； (b) 在医管局的背景下如何改变这一程序； (c) 如何根据睡眠状态对 GnRH 频率进行差异化控制来解释观察到的具有和不具有 HA 的女孩中观察到的 GnRH 分泌模式。因此，本研究提案的目标是： 具体目标 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。具体目标 2：确定 GnRH 脉冲频率对 P 负反馈的反应是否取决于有或没有 HA 的青春期晚期女孩的睡眠与清醒状态。 公共健康相关性：多囊卵巢综合征 (PCOS) 是一种常见的激素紊乱，其特征是雄性激素水平升高、排卵受损和卵巢囊肿，导致成年女性显着发病，包括毛发生长异常、痤疮、月经不调、不孕和患糖尿病、肥胖症和代谢综合征的风险增加。多囊卵巢综合症很可能始于青春期，此时女孩会出现与患有多囊卵巢综合症的成年女性类似的病理和激素异常。这项研究将通过确定孕激素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多囊卵巢综合症的发展，希望更好地了解青春期荷尔蒙异常有助于预防和治疗该疾病。