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: 8136561
• 负责人: Jessicah S.P. Collins
• 金额: $ 5.87万
• 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/8136561
• 关键词: Accounting; Acne; Adolescence; Adolescent; Adult; Affect; Age; Androgen Receptor; Androgens; Anovulation; Characteristics; Chronic; Circadian Rhythms; Complex; Cyst; Data; Defect; Development; Disease; Dyslipidemias; Etiology; Feedback; Female Adolescents; Follicle Stimulating Hormone; Frequencies; Functional disorder; Future; Glucose Intolerance; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropin Releasing Hormone Inhibitor; Growth; Hair; Hirsutism; Hormonal; Hormones; Hour; Hyperinsulinism; Hypothalamic structure; Impairment; Infertility; Insulin Resistance; Luteinizing Hormone; Menstrual cycle; Menstruation; Metabolic syndrome; Modeling; Morbidity - disease rate; Morphology; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oligonucleotides; Ovarian; Ovarian Cysts; Ovary; Ovulation; Pathologic; Pathology; Pattern; Physiologic pulse; Pituitary Gland; Play; Polycystic Ovary Syndrome; Prevention; Process; Progesterone; Puberty; Regulation; Relative (related person); Research; Research Proposals; Resistance; Role; Sleep; Testing; Testosterone; Time; Woman; Work; awake; diabetes risk; early childhood; girls; hormone deficiency; hypothalamic pituitary axis; hypothalamic pituitary gonadal axis; improved; interest; 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，影响了雄激素水平升高，寡卵形和多囊卵巢形态的繁殖年龄女性的7％。 PCOS与多毛，痤疮，不规则的月经周期和不育有关，并导致肥胖，代谢综合征和2型糖尿病的风险增加。尽管PCOS是常见的，并且与明显的发病率有关，但病因仍然未知。神经内分泌异常 - 称为葡萄糖激素（LH）和促性腺激素释放激素（GNRH）脉冲性，伴有相对卵泡刺激激素（FSH）缺乏症，通常存在于该疾病中，并有助于其病理学。孕酮（P）被认为是GNRH合成和分泌的主要调节剂。实际上，患有PCO的女性表现出对P负反馈的下丘脑敏感性受损，这与升高的雄激素有关，并被雄激素受体拮抗作用逆转。青春期女孩中的高雄激素血症（HA）被认为是PCOS的先兆。与患有PCOS的成年女性一样，患有HA的女孩表现出LH脉冲频率的升高，一些HA青少年也受到P抑制LH脉冲抑制，这表明这些女孩中的LH（GNRH）脉冲异常可能与在负面反馈受损有关下丘脑。这项研究建议旨在通过研究p在正常和HA青春期女孩中P中的作用，以提高我们对正常和异常的青春期的理解，以更好地了解HA的神经内分泌异常。在此过程中，这项研究可能有助于指导未来的治疗，并可能在PCOS的青春期和成年后的全部表达之前进行预防。这项研究的目的是评估（a）P在正常的青春期成熟期间指导GnRH分泌中的作用； （b）在HA的环境中如何改变此过程； （c）根据睡眠状态的不同，GNRH频率的差异控制如何解释患有和没有HA的女孩的GNRH分泌模式。因此，该研究建议的目的是：特定目的1：确定与生理相关的P浓度是否抑制早期青春期女孩的LH脉冲频率。具体目标2：确定GNRH脉冲频率对P负反馈的响应是​​否取决于有或没有HA的晚期青春期女孩的睡眠与唤醒状态。 公共卫生相关性：多囊卵巢综合征（PCOS）是一种常见的激素疾病，以雄性激素水平升高，排卵受损和卵巢上的囊肿，导致成年女性的大量发病率，包括异常的头发生长，痤疮，不规则的长期，不典型，不育和不差，不育和不差，不育，不育，不符合性，糖尿病，肥胖症和代谢综合征的风险增加。当女孩形成与PCOS成年女性类似的病理和激素异常时，PCOS可能开始在青春期开始。这项研究将通过确定孕激素在青春期成熟过程中的作用在正常和高狂体青少年女孩中的作用来研究PCOS的发展，并希望对青春期期间的激素异常有改善的了解将有助于预防和治疗该疾病。