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（由申请方提供）：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。GnRH从下丘脑释放，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）调节GnRH释放的理解。近年来，脑内合成和释放的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，从卵巢循环E2调节下丘脑-垂体功能，通过负反馈和正反馈机制，我们的初步数据与微透析方法表明，E2合成和释放在下丘脑似乎发挥作用的GnRH释放的调节。也就是说，1）在切除卵巢（OVX）的雌性猴体内，将苯甲酸雌二醇（EB）短暂输注到茎正中隆起（S-ME）中，刺激GnRH释放，潜伏期短（<10 min），2）这种快速GnRH释放伴随着E2释放，3）电刺激（ES）内侧基底下丘脑也刺激GnRH和E2释放，4）芳香酶抑制剂，来曲唑，抑制自发和EB-诱导的GnRH和E2的释放。值得注意的是，在微透析液中发现的E2的来源必须是下丘脑来源，因为猴子是OVX，并且用液相色谱-质谱（LC/MS/MS）方法进行分析可以区分E2和EB。因此，在本R21提案中，我们将检验神经雌激素对控制GnRH释放，从而控制生殖功能很重要的假设。目的1将检验E2对GnRH释放的快速作用代表下丘脑中的神经雌二醇作用和S-ME中的神经雌二醇释放有助于调节GnRH/LH释放的假设。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将检验EB暴露时间区分快速刺激作用和负反馈抑制E2对GnRH/LH释放的作用的假设。将使用体内微透析方法和连续采血在OVX成年雌性猴中进行实验。将通过RIA评估透析液中的GnRH和血浆样本中的LH，并通过LC/MS/MS评估透析液中的E2水平。非人灵长类动物中拟议项目的结果将为开发R 01项目提供基础，从而导致神经雌激素参与控制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。