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: 8702755
• 负责人: Ei Terasawa-Grilley
• 金额: $ 22.58万
• 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/8702755
• 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; 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; public health relevance; 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研究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激素控制生殖功能。拟议的研究旨在增加我们对雌二醇 (E2) 对 GnRH 释放调节的了解。最近，大脑中合成和释放的E2在学习/记忆以及性行为中发挥重要作用的概念已经出现。尽管众所周知，来自卵巢的循环 E2 通过负反馈和正反馈机制调节下丘脑-垂体功能，但我们使用微透析方法的初步数据表明，下丘脑合成和释放的 E2 似乎在 GnRH 释放的调节中发挥作用。也就是说，1) 将苯甲酸雌二醇 (EB) 短暂输注到去卵巢 (OVX) 雌性猴体内的柄正中隆起 (S-ME) 中，可在短潜伏期（<10 分钟）内刺激 GnRH 释放，2) GnRH 的快速释放伴随着 E2 的释放，3) 下丘脑内侧基底的电刺激 (ES) 也刺激了 GnRH 和 E2 的释放，并且4) 芳香酶抑制剂来曲唑抑制 GnRH 和 E2 的自发释放和 EB 诱导的释放。值得注意的是，微透析液中发现的 E2 来源必定是下丘脑来源，因为猴子是 OVX，并且使用液相色谱-质谱 (LC/MS/MS) 方法进行分析可区分 E2 和 EB。因此，在这个 R21 提案中，我们将检验神经雌激素对于控制 GnRH 释放以及生殖功能非常重要的假设。目标 1 将检验以下假设：E2 对 GnRH 释放的快速作用代表下丘脑中神经雌二醇的作用，而 S-ME 中神经雌二醇的释放有助于调节 GnRH/LH 释放。这将通过检查 EB、ES 和来曲唑对 GnRH/LH 释放的影响来实现。目标 2 将检验以下假设：EB 暴露期可区分 E2 对 GnRH/LH 释放的快速刺激作用和负反馈抑制作用。实验将使用体内微透析方法和连续血液采样在 OVX 成年雌性猴子中进行。透析液中的 GnRH 和血浆样品中的 LH 将通过 LC/MS/MS 通过 RIA 和透析液中的 E2 水平进行评估。拟议的非人类灵长类项目的结果将为开发 R01 项目提供基础，从而导致神经雌激素参与控制 GnRH 释放的突破性研究。 PI相信，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。