PROJECT 1 - TESTOSTERONE - GnRH PULSE FREQUENCY AND THE EVOLUTION OF PCOS IN ADOL

项目 1 - 睾酮 - GnRH 脉冲频率和 ADOL 中 PCOS 的演变

• 批准号: 7683449
• 负责人: John C Marshall
• 金额: $ 31.84万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683449
• 关键词: Adolescence; Adolescent; Adrenal Glands; Adult; Affect; Aftercare; Age; Androgen Receptor; Androgens; Anovulation; CAG repeat; Clinical; Corticotropin; Dexamethasone; Disease; Dyslipidemias; Early identification; Estradiol; Etiology; Evolution; Exons; Exposure to; Feedback; Female; Female Adolescents; Flutamide; Frequencies; Genetic Polymorphism; Goals; Hyperinsulinism; Hypothalamic structure; Incidence; Insulin; Metabolic syndrome; Metformin; Modification; Obesity; Ovarian; Ovary; Physiologic pulse; Physiological; Plasma; Prevalence; Production; Progesterone; Puberty; Regulation; Role; Sleep; Staging; Steroids; Syndrome; Testosterone; Weight; Woman; girls; prepuberty; prospective; reproductive; response

Polycystic Ovarian Syndrome (PCOS) is a common clinical disorder affecting 6-8% of women of reproductive age. Features include anovulation and hyperandrogenemia, commonly associated with hyperinsulinemia, obesity, dyslipidemia and other manifestations of the metabolic syndrome. Plasma LH levels are elevated in up to 90% of subjects, which reflects a persistent rapid frequency of GnRH secretion. This impairs the ability to differentially secrete FSH and LH resulting in anovulatory cycles and hyperandrogenemia (HA). The etiology of the disorder is unknown, but adolescent girls with HA also demonstrate rapid GnRH pulse secretion and elevated LH, which evolves before or during pubertal maturation. In both adolescents and adults, abnormal regulation of GnRH in part reflects impaired sensitivity to progesterone (P) inhibition, a consequence of elevated androgen levels. We propose that elevated androgens prior to and during pubertal maturation, impair the normal evolution of ovarian regulation of GnRH secretion. Obesity is common in girls (approx. 1 in 5 of 6-19yo) and is associated with marked HA in 60- 90%. Thus, the recent increase in obesity may predispose to PCOS via elevated androgens impairing steroid feedback on the hypothalamus and resulting in abnormal GnRH secretion. In SA1 we aim to assess the role of plasma androgens in modifying GnRH sensitivity to negative feedback of estradiol (E2) and P in both normal and HA girls. We will assess if the normal rise in testosterone (T) is part of the normal modification of hypothalamic feedback set points during adolescence and also establish if excess androgen impairs feedback and whether this can be corrected by androgen receptor (AR) blockade or by reduction of insulin and T after treatment with metformin for 3 months. We will also examine potential mechanisms of varied hypothalamic sensitivity to HA by examining polymorphisms of the AR CAG repeat. We identified that nocturnal P secretion occurs in pre and early pubertal girls, which may represent the initiation of normal ovarian control of GnRH pulse secretion. In SA2 we assess the role of P in suppressing GnRH frequency during the day and during sleep in both normal and HA girls, and if impaired, whether this can be corrected by AR blockade. Prepubertal obesity is associated with marked elevations in T and in SA3 we explore the contribution of the adrenal gland to the production of P and excess T in early puberty, a stage when the ovary is relatively immature.

多囊卵巢综合征（PCOS）是一种常见的临床疾病，影响6-8%的女性， 生育年龄特征包括无排卵和高雄激素血症，通常与 高胰岛素血症、肥胖、血脂异常和代谢综合征的其他表现。血浆LH 水平在高达90%的受试者中升高，这反映了GnRH分泌的持续快速频率。 这损害了差异分泌FSH和LH的能力，导致无排卵周期， 高雄激素血症（HA）。这种疾病的病因尚不清楚，但患有HA的青春期女孩也 表现出快速的GnRH脉冲分泌和LH升高，在青春期之前或期间发展 成熟在青少年和成人中，GnRH的异常调节部分反映了敏感性受损 孕酮（P）抑制，雄激素水平升高的结果。我们建议， 青春期成熟前和青春期成熟期间的雄激素损害卵巢对GnRH调节的正常进展 分泌物肥胖症在女孩中很常见（大约。6- 19岁儿童中的5例中有1例），60- 19岁儿童中与显著HA相关。 百分之九十因此，最近肥胖症的增加可能通过升高的雄激素损伤而易患PCOS。 类固醇反馈作用于下丘脑，导致GnRH分泌异常。 在SA 1中，我们的目的是评估血浆雄激素在调节GnRH对负反馈的敏感性中的作用。 正常和HA女孩雌二醇（E2）和P。我们将评估睾丸激素（T）的正常升高是否 下丘脑反馈设定点在青春期的正常修改的一部分，也建立，如果 雄激素过多会损害反馈，这是否可以通过雄激素受体（AR）阻断来纠正 或二甲双胍治疗3个月后减少胰岛素和T。我们还将研究潜在的 通过检测AR CAG重复序列多态性来研究不同下丘脑对HA敏感性的机制。 我们发现，夜间P分泌发生在青春期前和早期的女孩，这可能代表了 启动正常卵巢对GnRH脉冲分泌的控制。在SA 2中，我们评估了P在抑制 正常和HA女孩白天和睡眠时的GnRH频率，如果受损， 可以通过AR阻断来纠正。青春期前肥胖与T和SA 3显著升高相关 我们探讨了肾上腺在青春期早期产生P和过量T的作用， 当卵巢相对不成熟时。