Neuroestrogen restraint of GnRH in juvenile female primates

神经雌激素对幼年雌性灵长类动物 GnRH 的抑制作用

• 批准号: 9225244
• 负责人: Jon E Levine
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9225244
• 关键词: Acceleration; Adolescent; Adult; Animals; Area; Aromatase; Aromatase Inhibition; Aromatase Inhibitors; Autopsy; Blood specimen; Brain; CYP19A1 gene; Cardiovascular Diseases; Data; Development; Effectiveness; Ensure; Environmental Risk Factor; Enzymes; Estradiol; Estrogen Antagonists; Estrogens; Excision; Feedback; Female; Fertility; Foundations; Gene Silencing; Gonadal Hormones; Gonadal Steroid Hormones; Gonadal structure; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Hypothalamic structure; Injectable; Injection of therapeutic agent; Letrozole; Lifting; Macaca; Macaca mulatta; Measures; Mediating; Mediator of activation protein; Mental disorders; Messenger RNA; Modeling; Monitor; Monkeys; Neurons; Neurosecretion; Normal Range; Oral; Ovarian; Ovariectomy; Ovary; Pathogenesis; Peripheral; Physiologic pulse; Physiological Processes; Pituitary Gonadotropins; Precocious Puberty; Preoptic Areas; Prevalence; Primates; Puberty; Public Health; RNA Sequences; Radioimmunoassay; Regulation; Reproduction; Risk; Role; Sampling; Serum; Signal Transduction; Source; System; Testing; Tissues; Validation; Variant; Viral Vector; design; girls; gonad function; hypothalamic pituitary gonadal axis; infancy; liquid chromatography mass spectrometry; malignant breast neoplasm; neuronal circuitry; neuroregulation; neurotransmission; novel; premature; prepuberty; public health relevance; relating to nervous system; reproductive; reproductive axis; reproductive development; reproductive hormone; restraint; sex; small hairpin RNA; vector

 DESCRIPTION (provided by applicant): Juvenile development is characterized by pronounced suppression of reproductive hormone release, a mechanism that maintains gonadal quiescence until the onset of reproductive maturation. In primates, this juvenile "brake" is believed to be mediated by signals that arise within the brain and actively suppress hypothalamic neurosecretion of the major neural effector of reproductive hormone release, gonadotropin- releasing hormone (GnRH). Diminishment of this central restraint is believed to contribute to the acceleration of pulsatile GnRH release that, in turn, initiates pubertal maturation. Premature lifting of this restraint may underlie the pathogenesis of true precocious puberty, as well as earl pubertal onset within the range of normal variation. The neural signals that impose the juvenile brake remain unclear. In adulthood, the "GnRH pulse generator" is homeostatically suppressed by negative feedback actions of gonadal steroids, principally estradiol in females. Recent studies have demonstrated that estrogens produced in the brain itself may modulate GnRH release, and we have obtained preliminary evidence to suggest that extra-gonadal estrogens may contribute to the suppression of the GnRH pulse generator. The proposed studies are therefore designed to test the novel hypothesis that neuroestrogens mediate the prepubertal restraint of GnRH release during the juvenile period of development in female primates. In Aim 1, prepubertal female rhesus macaques will be ovariectomized and treated with a vehicle or letrazole, an inhibitor of the estrogen synthesizing enzyme, aromatase (CYP19A1). We will monitor secretion of pituitary gonadotropins, LH and FSH, to determine if systemic inhibition of aromatase in non-gonadal tissues results in a premature activation of GnRH release. In Aim 2, a viral vector expressing shRNA corresponding to aromatase, or a vector expressing a scrambled RNA sequence, will be injected into the hypothalamic areas critical for negative feedback regulation of GnRH release. Gonadotropin levels will be monitored to determine if localized hypothalamic inhibition of aromatase expression likewise results in premature activation of GnRH release. We predict that the results obtained in Aim 1 will demonstrate that non-gonadal estrogens exert some or all of the juvenile restraint on the GnRH pulse generator, and that Aim 2 will confirm neuroestrogens as specific mediators of this important physiological process.

 描述（由申请方提供）：幼年发育的特征是生殖激素释放受到明显抑制，这是一种维持性腺静止直至生殖成熟开始的机制。在灵长类动物中，这种幼年“制动”被认为是由脑内产生的信号介导的，并且主动抑制生殖激素释放的主要神经效应物促性腺激素释放激素（GnRH）的下丘脑神经分泌。这种中枢抑制的减少被认为有助于加速脉动性GnRH释放，进而启动青春期成熟。过早解除这种束缚可能是真性性早熟的发病机制，也可能是正常变异范围内青春期提前发作的发病机制。施加青少年制动的神经信号仍然不清楚。在成年期，“GnRH脉冲发生器”受到性腺类固醇（主要是雌性雌二醇）负反馈作用的稳态抑制。最近的研究表明，在大脑本身产生的雌激素可能会调节GnRH的释放，我们已经获得了初步的证据表明，性腺外的雌激素可能有助于抑制GnRH脉冲发生器。因此，拟定的研究旨在检验新的假设，即神经雌激素介导雌性灵长类动物青春期发育期间GnRH释放的青春期前抑制。在目的1中，将青春期前雌性恒河猴切除卵巢，并用载体或来曲唑（雌激素合成酶芳香酶（CYP 19 A1）的抑制剂）治疗。我们将监测垂体促性腺激素、LH和FSH的分泌，以确定非性腺组织中芳香化酶的全身抑制是否导致GnRH释放的过早激活。在目标2中，将表达对应于芳香酶的shRNA的病毒载体或表达乱序RNA序列的载体注射到对GnRH释放的负反馈调节至关重要的下丘脑区域中。将监测促性腺激素水平，以确定芳香酶表达的局部下丘脑抑制是否同样导致GnRH释放的过早激活。我们预测，在目标1中获得的结果将证明，非性腺雌激素对GnRH脉冲发生器产生部分或全部的青少年抑制作用，目标2将确认神经雌激素作为这一重要生理过程的特异性介质。