PROJECT 2 - GnRH-Gonadotrophe Responses - Steroid-Metabolic Interactions

项目 2 - GnRH 促性腺激素反应 - 类固醇代谢相互作用

• 批准号: 7683451
• 负责人: MARGARET A SHUPNIK
• 金额: $ 27.23万
• 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/7683451
• 关键词: Affect; Age; Androgen Antagonists; Androgen Receptor; Androgenization; CAG repeat; Cells; Clinical; Data; Enzymes; Estrogens; Event; Feedback; Female; Fertility; Flutamide; Follicle Stimulating Hormone; Frequencies; Genes; Genetic Transcription; Glucose Intolerance; Gonadotrope Cell; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Hormones; Hyperandrogenism; Hyperinsulinism; Hypothalamic structure; In Vitro; Infertility; Insulin; Insulin Resistance; Length; Link; Luteinizing Hormone; Measures; Menstrual cycle; Metabolic; Metformin; Modeling; Modification; Molecular; Mus; Obesity; Ovarian; Pathway interactions; Patients; Pattern; Periodicity; Pharmaceutical Preparations; Physiologic pulse; Physiological; Pituitary Gland; Pituitary Gonadotropins; Process; Progesterone; Proteasome Inhibitor; Proteins; Receptor Signaling; Regulation; Resistance; Role; Signal Transduction; Signaling Molecule; Site; Small Interfering RNA; Steroid biosynthesis; Steroids; Symptoms; Syndrome; Testing; Testosterone; Transgenic Mice; Ubiquitination; Woman; enzyme pathway; hormone regulation; human GNRH2 protein; insulin sensitizing drugs; mouse model; multicatalytic endopeptidase complex; prenatal; prevent; promoter; reproductive; reproductive axis; response; restoration; transcription factor

Temporally regulated secretion of the pituitary gonadotropins luteinizing hormone (LH) and folliclestimulating hormone (FSH) is critical for steroidogenesis and fertility. LH and FSH are tightly controlled by hypothalamic gonadotropin-releasing hormone (GnRH) pulses, and directly and indirectly by ovarian steroids. GnRH pulse amplitude and frequency are regulated physiologically by estrogen (E), progesterone (P) and testosterone (T). High-frequency GnRH pulses occur with E stimulation and favor LH secretion and LH subunit gene transcription, whereas low-frequency pulses occur with P plus E and preferentially stimulate FSH secretion and the FSHbeta gene. Polycystic ovarian syndrome (PCOS) conservatively affects between 6-8% of women of reproductive age, and is characterized by hyper-androgenism, erratic menstrual cycles, and infertility. Many women also have insulin resistance and hyper-insulinemia, with or without obesity. Between 30-90% of PCOS patients have increased LH/FSH ratios, and P is less effective in reducing GnRH pulse frequency and altering gonadotropin secretion in these women. P sensitivity can be partially restored by antiandrogens in some women. Treatment with the insulin sensitizing drug, metformin, can also restore fertility in some subjects, but sites and mechanism of action of insulin or this drug on the reproductive axis are unclear. Understanding mechanisms underlying GnRH gonadotrope regulation is critical to develop treatments for PCOS. Proposed studies will use the prenatal androgenized (PNA) mouse model that mimics many symptoms of PCOS, including elevated LH and T, erratic reproductive cycles and glucose intolerance. We will examine regulated gonadotropin expression, and responses to GnRH and P feedback in PNA and control gonadotropes. Treatment of mice with antiandrogen and metformin will test potential contributions of elevated T or insulin insensitivity to PNA responses. The role of androgen receptor CAG repeat length in influencing T responses will be evaluated in vitro and in transgenic mice. We will also examine the pulsatile GnRH stimulation of gonadotropin gene transcription requirement for proteasome activity, and if insulin or T modulate this process and may thus contribute to dysregulated LH/FSH ratios seen in PCOS.

垂体促性腺激素促黄体生成素（LH）和卵泡刺激素的时间调节分泌 激素（FSH）对类固醇生成和生育力至关重要。LH和FSH受以下因素的严格控制： 下丘脑促性腺激素释放激素（GnRH）脉冲，并直接和间接通过卵巢 类固醇. GnRH脉冲的幅度和频率在生理上受雌激素（E）、孕激素 (P)睾酮（T）。高频GnRH脉冲伴随E刺激发生，有利于LH分泌， LH亚单位基因转录，而低频脉冲发生与P加E和优先刺激 FSH分泌和FSH β基因。多囊卵巢综合征（PCOS）是一种多囊卵巢综合征。 6-8%的育龄妇女，其特征是雄激素过多，月经周期不稳定， 和不孕症。许多妇女也有胰岛素抵抗和高胰岛素血症，有或没有肥胖。 30-90%的PCOS患者LH/FSH比值升高，P降低GnRH的效果较差 脉冲频率和改变促性腺激素分泌在这些妇女。P敏感性可部分恢复 抗雄激素的作用用胰岛素增敏药物二甲双胍治疗，也可以恢复 某些受试者的生育能力，但胰岛素或该药物对生殖轴的作用部位和机制 不清楚。了解GnRH促性腺激素调节的机制对于开发 治疗PCOS。拟议的研究将使用产前雄激素化（PNA）小鼠模型，模拟 PCOS的许多症状，包括LH和T升高，不稳定的生殖周期和葡萄糖耐受不良。 我们将研究调节促性腺激素的表达，以及对PNA中GnRH和P反馈的反应， 控制促性腺激素用抗雄激素和二甲双胍治疗小鼠将测试以下因素的潜在贡献： 升高的T或胰岛素对PNA反应的不敏感性。雄激素受体CAG重复序列长度在卵巢癌中的作用 将在体外和转基因小鼠中评估影响T应答的因素。我们还将检查 促性腺激素释放激素刺激促性腺激素基因转录需要蛋白酶体活性，如果胰岛素或T 调节这一过程，因此可能导致PCOS中LH/FSH比值失调。