Role of hyperandrogenemia in abnormal pubertal gonadotropin-releasing hormone (GnRH) secretion and development of PCOS

高雄激素血症在青春期促性腺激素释放激素（GnRH）分泌异常和多囊卵巢综合征（PCOS）发展中的作用

• 批准号: 9122655
• 负责人: Su H. Kim
• 金额: $ 6.91万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9122655
• 关键词: Acute; Adolescent; Adult; Androgen Receptor; Androgens; Anovulation; Back; Data; Data Reporting; Development; Disease; Feedback; Follicle Stimulating Hormone; Frequencies; Functional disorder; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Health; Hour; Hyperandrogenism; Insulin Resistance; Luteal Phase; Luteinizing Hormone; Mediating; Metabolic; Metabolic syndrome; Modeling; Morbidity - disease rate; Neurosecretory Systems; Obesity; Oligonucleotides; Ovarian; Ovulation; Pattern; Physiologic pulse; Physiological; Play; Polycystic Ovary Syndrome; Prevention strategy; Preventive; Production; Progesterone; Puberty; Regulation; Role; Sleep; Spironolactone; Study models; Testing; Woman; Work; base; design; girls; hormone deficiency; insight; public health relevance; reproductive; treatment strategy; Acute; Adolescent; Adult; Androgen Receptor; Androgens; Anovulation; Back; Data; Data Reporting; Development; Disease; Feedback; Follicle Stimulating Hormone; Frequencies; Functional disorder; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Health; Hour; Hyperandrogenism; Insulin Resistance; Luteal Phase; Luteinizing Hormone; Mediating; Metabolic; Metabolic syndrome; Modeling; Morbidity - disease rate; Neurosecretory Systems; Obesity; Oligonucleotides; Ovarian; Ovulation; Pattern; Physiologic pulse; Physiological; Play; Polycystic Ovary Syndrome; Prevention strategy; Preventive; Production; Progesterone; Puberty; Regulation; Role; Sleep; Spironolactone; Study models; Testing; Woman; Work; base; design; girls; hormone deficiency; insight; public health relevance; reproductive; treatment strategy

 DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is a prevalent reproductive disorder characterized by hyperandrogenism (HA) and oligo/anovulation with subfertility. It is also associated with obesity, insulin resistance and metabolic syndrome. PCOS is marked by excessive ovarian androgen production; ovarian HA is in part related to persistently elevated gonadotropin releasing hormone (GnRH) pulse frequency, which promotes high luteinizing hormone (LH) levels and relative follicle stimulating hormone (FSH) deficiency. The mechanisms underlying the neuroendocrine abnormalities of PCOS remain unclear. The emergence of PCOS is often traced back to puberty. Peripubertal HA is believed to represent a precursor to adult PCOS. The beginning of puberty is marked by sleep-related increases of LH pulse amplitude and frequency (mirroring GnRH pulses). Across normal pubertal maturation, there are day-night changes in LH (GnRH) pulse frequency. Although the underlying mechanisms for the diurnal changes are not known, these changes are thought to be important for appropriate gonadotropin secretion. Progesterone is the primary modulator of day-to-day GnRH pulse frequency in adult women, most notably by slowing GnRH pulse frequency (negative feedback) during the luteal phase of menstrual cycle. Our group has reported data suggesting a differential sensitivity of the GnRH pulse generator to progesterone negative feedback depending on sleep status during puberty. These data are consistent with the notion that sex steroids (e.g., progesterone) may be important regulators of daytime LH pulse frequency across puberty, while nighttime LH pulse frequency is heavily influenced by higher sleep centers (and less responsive to sex steroid feedback). The sensitivity of GnRH pulse generator to inhibition by progesterone is impaired in adults with PCOS, and this appears to be related to HA (it is reversed by androgen receptor blockade). Our preliminary data in pubertal girls suggested altered regulation of day-to-night change of LH pulse frequency that is specific to those with HA. Thus, we propose that pubertal HA may play an important role in aberrant pattern of GnRH secretion, causing LH excess and relative FSH deficiency, both of which contribute to worsening HA and disturbances of follicular development (and ovulation) as seen in PCOS. We propose the following aims to test our hypotheses. In Aim 1, we will assess the acute effect of progesterone on wake vs. sleep-related LH pulse frequency in mid- to late pubertal girls with and without HA. In Aim 2, we will assess effect of androgen receptor-blockade (spironolactone) on progesterone-associated suppression of LH pulse frequency in mid- to late pubertal girls with HA. A better understanding a potentially causal role of peripubertal HA will support the development of a rational preventive and/or treatment strategies to decrease morbidity associated with PCOS.

 描述（由适用提供）：多囊卵巢综合征（PCOS）是一种普遍的生殖障碍，其特征是高雄激素（HA）和具有差异性的寡源性/无卵形。它也与肥胖，胰岛素抵抗和代谢综合征有关。 PCOS的特征是卵巢雄激素过量产生。卵巢HA部分与持续升高的促性腺激素释放的马酮（GnRH）脉冲频率有关，该脉冲频率促进了高黄叶型马酮（LH）水平和相对叶片刺激的马酮（FSH）缺陷。 PCOS神经内分泌异常的基础机制尚不清楚。 PCOS的出现通常被追溯到青春期。据信，Peripubertal HA代表了成年PCOS的前体。青春期的开始是与睡眠相关的LH脉冲放大器和频率（镜像）GnRH脉冲的增加。在正常的青春期成熟度中，LH（GNRH）脉冲频率发生了昼夜变化。尽管尚不清楚差异变化的基本机制，但这些变化对于适当的促性腺激素分泌很重要。孕酮是成年女性日常GNRH脉冲频率的主要调节剂，最著名的是在月经周期的黄体阶段减缓GnRH脉冲频率（负反馈）。我们的小组报告了数据表明，根据青春期的睡眠状态，GNRH脉冲发生器对孕酮负反馈的差异敏感性。这些数据与性类固醇（例如，孕酮）可能是青春期LH脉冲频率的重要调节剂的观点一致，而夜间LH脉冲频率受到较高睡眠中心的影响很大（对性类固醇反馈的反应较小）。在患有PCOS的成年人中，GnRH脉冲发生器对孕酮抑制的敏感性受损，这似乎与HA有关（它被雄激素受体阻滞逆转）。我们在青春期女孩中的初步数据表明，调节对HA患者的LH脉冲频率的日夜变化改变了调节。这是我们建议，青春期HA可能在GnRH分泌的异常模式中起重要作用，从而导致LH超过和相对FSH缺乏，这两种缺乏症有助于HA和PCOS所见的卵泡发育（和排卵）的令人担忧的灾难。我们提出以下目的旨在检验我们的假设。在AIM 1中，我们将评估孕酮对尾流与睡眠相关的LH脉冲频率的急性作用，其中有或没有HA。在AIM 2中，我们将评估雄激素受体阻滞（螺内酯）对孕激素相关的抑制HA中半天到晚期的LH脉冲频率的抑制作用。更好地理解围叶伯伯纳群岛HA的潜在因果关系将支持发展理性的预防和/或治疗策略，以降低与PCOS相关的发病率。