Role of neuroestrogens in control of GnRH release

神经雌激素在控制 GnRH 释放中的作用

• 批准号: 8837042
• 负责人: Ei Terasawa-Grilley
• 金额: $ 18.34万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837042
• 关键词: Address; Adult; Aging; Aromatase; Aromatase Inhibitors; Auditory area; Behavioral; Benzoates; Birds; Blood specimen; Brain; Clinical Management; Contraceptive methods; Data; Development; Disease; Electric Stimulation; Embryo; Employee Strikes; Enzymes; Estradiol; Estradiol Benzoate; Estrogen Receptors; Exposure to; Feedback; Female; Goals; Gonadotropin Hormone Releasing Hormone; Health; Hippocampus (Brain); Human; Hypothalamic structure; In Vitro; Infertility; Infusion procedures; Learning; Letrozole; Life; Macaca mulatta; Mammals; Measurement; Measures; Medial; Mediating; Memory; Menopause; Methodology; Methods; Microdialysis; Monkeys; Neurons; Neurosecretory Systems; Neurotransmitters; Ovary; Ovulation; Perfusion; Physiological; Physiology; Pituitary Gland; Pituitary Gonadotropins; Plasma; Play; Primates; Puberty; Rattus; Recording of previous events; Regulation; Reporting; Reproduction; Research; Research Design; Role; Sampling; Sex Behavior; Songbirds; Source; System; Testing; Textbooks; Therapeutic; Traction; base; direct application; gonad function; in vivo; insight; liquid chromatography mass spectrometry; median eminence; nonhuman primate; novel; pituitary gonadal axis; reproductive; reproductive function; research study; tool

DESCRIPTION (provided by applicant): The overall objective of this proposal is to investigate the regulation of gonadotropin-releasing hormone (GnRH) neurons in the non-human primate. GnRH is released from the hypothalamus and controls reproductive function through pituitary gonadotrophins. The proposed studies are designed to increase our understanding of estradiol (E2) regulation of GnRH release. Recently, the concept that E2 synthesized and released in the brain plays an important role in learning/memory as well as sexual behaviors has emerged. Although it is well known that circulating E2 from the ovary regulates hypothalamo-pituitray function via negative and positive feedback mechanisms, our preliminary data with a microdialysis method indicate that E2 synthesized and released in the hypothalamus appears to play a role in the regulation of GnRH release. That is, 1) a brief infusion of estradiol benzoate (EB) into the stalk-median eminence (S-ME) in vivo in ovariectomized (OVX) female monkeys stimulated GnRH release with a short latency (<10 min), 2) this rapid GnRH release is accompanied by E2 release, 3) electrical stimulation (ES) of the medial basal hypothalamus also stimulated both GnRH and E2 release, and 4) the aromatase inhibitor, letrozole, suppressed spontaneous and the EB-induced release of GnRH and E2. Remarkably, the source of E2 found in microdialysates must be of hypothalamic origin, as monkeys were OVX and analysis with a liquid chromatography-mass spectrometry (LC/MS/MS) method distinguishes E2 from EB. Therefore, in this R21 proposal we will test the hypothesis that neuroestrogens are important for control of GnRH release, hence reproductive function. Aim 1 will test the hypothesis that the rapid action of E2 on GnRH release represents neuroestradiol action in the hypothalamus and neuroestradiol release in the S-ME contributes to regulation of GnRH/LH release. This will be accomplished by examining the effects of EB, ES, and letrozole on GnRH/LH release. Aim 2 will test the hypothesis that the EB exposure period distingushes rapid stimulatory action from negative feedback inhibitory E2 action on GnRH/LH release. Experiments will be conducted in OVX adult female monkeys using an in vivo microdialysis method and serial blood sampling. GnRH in dialysates and LH in plasma samples will be assessed by RIA and E2 levels in dialysates by LC/MS/MS. Results from the proposed project in non-human primates will provide a basis for developing R01 projects leading to groundbreaking studies of the involvement of neuroestrogens in control of GnRH release. The PI believes that this will ultimately bring new insights into the neuroendocrine mechanism of reproductive function in humans.

描述（由申请人提供）：该提案的总体目标是调查非人类灵长类动物中促性腺激素释放激素（GNRH）神经元的调节。 GNRH从下丘脑释放，并通过垂体促性腺营养蛋白控制生殖功能。拟议的研究旨在增加我们对雌二醇（E2）对GNRH释放的调节的理解。最近，出现了E2在大脑中合成并释放的概念在学习/记忆以及性行为中起着重要作用。尽管众所周知，从卵巢循环E2通过负和正反馈机制调节下丘脑 - 上al-pituitray功能，但我们使用微透析方法的初步数据表明，在下丘脑中合成并释放的E2似乎在GNRH发行的调节中起作用。也就是说，1）短暂输注苯二醇苯甲酸酯（EB）在卵巢切除术（OVX）雌性猴子中的体内stalk-Median Eminence（S-Me）刺激了GNRH的GNRH释放（<10分钟），并伴随着E2的Elect opent impulation（Es2），Es Electal sereled（Es）均伴随着Es Electer（Es）的稳定性。 GnRH和E2释放，以及4）芳香酶抑制剂，letrozole，自发抑制和EB诱导的GnRH和E2的释放。值得注意的是，在微观鉴定物中发现的E2来源必须是下丘脑的起源，因为猴子是OVX，并且具有液相色谱 - 质谱法（LC/MS/MS）方法的分析将E2与EB区分开。因此，在此R21提案中，我们将检验以下假设：神经雌激素对于控制GNRH释放很重要，因此是生殖功能。 AIM 1将检验以下假设：E2对GnRH释放的快速作用代表下丘脑中的神经雌激素作用，而S-ME中的神经雌激素释放则有助于调节GnRH/LH释放。这将通过检查EB，ES和LeTrozole对GNRH/LH释放的影响来实现。 AIM 2将检验以下假设：EB暴露周期避免了对GNRH/LH释放的负反馈抑制E2作用的快速刺激作用。实验将在OVX成年雌猴中使用体内微透析方法和连续抽水进行。透析液和血浆样品中LH的GnRH将通过LC/MS/MS在透析液中的RIA和E2水平评估。拟议项目在非人类灵长类动物中的结果将为开发R01项目提供基础，从而导致对神经雌激素参与GNRH释放的开创性研究。 PI认为，这最终将为人类生殖功能的神经内分泌机制带来新的见解。