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(申请人提供)：本提案的总体目标是研究非人灵长类动物中促性腺激素释放激素(GnRH)神经元的调节。促性腺激素释放激素从下丘脑释放出来，通过垂体促性腺激素控制生殖功能。建议的研究旨在增加我们对雌二醇(E2)对GnRH释放的调节的了解。近年来，在大脑中合成和释放E2在学习记忆和性行为中起着重要作用的概念已经出现。虽然众所周知，卵巢循环中的E2通过负反馈和正反馈机制调节下丘脑-垂体功能，但我们的微透析方法的初步数据表明，在下丘脑合成和释放的E2似乎在调节GnRH的释放中发挥作用。也就是说，1)在去卵巢(OVX)雌性猕猴的茎正中隆起(OVX)内短暂注入苯甲酸雌二醇(EB-ME)可刺激GnRH的释放，但潜伏期短(10分钟)，2)GnRH的快速释放伴随着E_2的释放，3)电刺激下丘脑内侧基底核(ES)同时刺激GnRH和E_2的释放，4)芳香化酶抑制剂来曲唑抑制自发的和EB诱导的GnRH和E_2的释放。值得注意的是，在微透析液中发现的E2的来源肯定来自下丘脑，因为猴子是OVX，用LC/MS/MS(LC/MS/MS)方法分析区分E2和EB。因此，在这个R21提案中，我们将检验神经雌激素对控制GnRH释放从而实现生殖功能的重要假设。目的1验证E_2对促性腺激素释放激素的快速作用代表下丘脑的神经雌二醇作用，而S-ME的神经雌二醇释放参与促性腺激素释放激素/黄体生成素的调节。这将通过检查EB、ES和来曲唑对GnRH/LH释放的影响来实现。目的2验证EB暴露期对促性腺激素释放激素/黄体生成素释放的快速刺激作用和负反馈抑制作用的假设。实验将在OVX成年雌性猴子身上进行，使用体内微透析方法和连续采血。透析液中的GnRH和血浆样本中的黄体生成素将通过RIA和LC/MS/MS来评估，透析液中的E2水平将通过非人类灵长类动物的拟议项目提供基础，该项目将为开发R01项目提供基础，该项目将导致对神经雌激素参与控制GnRH释放的开创性研究。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。