Role of neuroestradiol in regulation of the GnRH surge

神经雌二醇在 GnRH 激增调节中的作用

• 批准号: 10025846
• 负责人: Ei Terasawa-Grilley
• 金额: $ 15.5万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025846
• 关键词: Adolescent; Adult; Aging; Androgens; Animals; Applications Grants; Aromatase; Aromatase Inhibitors; Attention; Attenuated; Blood specimen; Brain; Brain imaging; Clinical Management; Contraceptive Agents; Contraceptive methods; Data; Development; Enzymes; Estradiol; Estradiol Benzoate; Estrogens; Event; Feedback; Female; Fertility; Goals; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Grant; Hour; Hypothalamic structure; Infertility; Infusion procedures; Injections; Label; Lead; Learning; Letrozole; Life; Liquid Chromatography; Measures; Memory; Menopause; Methodology; Methods; Microdialysis; Monkeys; Neuromodulator; Neurons; Neurophysiology - biologic function; Neurosecretory Systems; Ovarian; Ovary; Ovulation; Perfusion; Periodicity; Pharmaceutical Preparations; Physiology; Pituitary Gland; Pituitary Gonadotropins; Play; Positron-Emission Tomography; Primates; Puberty; Public Health; Recording of previous events; Regulation; Reporting; Research; Role; Serum; Steroids; Supplementation; Testing; design; experimental study; gonad function; in vivo; liquid chromatography mass spectrometry; median eminence; neuron loss; nonhuman primate; novel strategies; pituitary gonadal axis; prepuberty; proliferative phase Menstrual cycle; reproductive function; tandem mass spectrometry; tool

Abstract/Summary 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 gonadotropins. The proposed studies are designed to uncover the role of neuroestradiol in the preovulatory GnRH surge. It has been shown for many years that circulating E2 released from the ovaries facilitates learning and memory, protects neurons from neuronal cell death, and regulates reproductive function. However, more recently, a new concept regarding the role of E2, synthesized and released locally in the brain, as a neuromodulator of neural functions, has emerged. In fact, our preliminary data indicate that E2 synthesized and released in the stalk- median eminence (S-ME) of the hypothalamus appears to be necessary for the full gonadotropin surge. That is, estradiol benzoate (EB)-induced LH surge in ovariectomized (OVX) female monkeys was greatly attenuated in the presence of the aromatase blocker letrozole. Aromatase is the enzyme necessary for E2 synthesis from androgens and letrozole is a commonly used competitive blocker for aromatase synthesis. In the proposed project, we will test the central hypothesis that neuroestradiol, synthesized and released in the hypothalamus plays a critical role in regulation of preovulatory GnRH release. Three Specific Aims are proposed. Aim 1 will test the hypothesis that neuroestradiol is an integral part of the estrogen's positive feedback influence on GnRH release. In Aim 1, we will assess the timing of neuroestradiol increases during the EB-induced LH surge using letrozole injection as a tool and measuring the changes in LH release. Aim 2 will test the hypothesis that neuroestradiol increases during the EB-induced GnRH surge are an underling mechanism of the sustained elevation of GnRH release. In Aim 2 we will measure release of estradiol and GnRH as well as circulating LH and E2 in EB treated OVX monkeys using a microdialysis method and serial blood sampling followed by analysis with liquid chromatography-mass spectrometry (LC/MS/MS) and RIA. Aim 3 will test the hypothesis that aromatase activity in the hypothalamus increases during the preovulatory GnRH surge in vivo. To visualize aromatase we will use positron emission tomography (PET) scan with 11C-labeled cetrozole as a marker. The proposed study has great potential to demonstrate that E2 synthesized in the hypothalamus increases during the preovulatory gonadotropin surge in vivo. In turn, this finding will modify the presently accepted dogma that E2 of ovarian origin solely controls the hypothalamo-pituitary-gonadal axis.

摘要/摘要 这项建议的总体目标是研究促性腺激素释放激素的调节。 非人灵长类(GnRH)神经元。GnRH从下丘脑和对照组释放 通过脑下垂体促性腺激素发挥生殖功能。拟议的研究旨在揭示这一角色 神经雌二醇在排卵前促性腺激素释放激素激增中的作用。 多年来已有研究表明，卵巢分泌的雌二醇会促进学习和记忆， 保护神经元免受神经细胞死亡，并调节生殖功能。然而，最近，一种新的 关于在大脑中局部合成和释放的E2作为神经调节剂的作用的概念 功能，已经出现了。事实上，我们的初步数据表明，E2在茎中合成和释放- 下丘脑的正中隆起(S-ME)似乎对促性腺激素的全面激增是必要的。那 雌二醇苯甲酸酯(EB)对去卵巢(OVX)雌性猕猴的促黄体生成素(LH)峰明显减弱 在芳香酶阻滞剂来曲唑的存在下。芳香酶是合成雌二醇所必需的酶。 雄激素和来曲唑是芳香酶合成常用的竞争性阻滞剂。在建议的 项目中，我们将测试中枢假说，即神经雌二醇在下丘脑合成和释放 在排卵前GnRH释放的调节中起关键作用。提出了三个具体目标。目标1将 测试神经雌二醇是雌激素正反馈对 GnRH释放。在目标1中，我们将评估EB诱导的黄体生成素高峰期间神经雌二醇升高的时间。 以来曲唑注射液为工具，测定促黄体生成素释放的变化。目标2将检验这一假设 EB诱导的GnRH峰期间神经雌二醇的升高是持续的 GnRH释放的升高。在目标2中，我们将测量雌二醇和促性腺激素释放激素以及循环中的黄体生成素 用微透析法和连续采血方法对EB处理的去势猴子进行雌二醇和雌二醇的检测 采用液-质联用(LC/MS/MS)和放射免疫分析。目标3将检验这一假设 在体内排卵前促性腺激素释放激素高峰期间，下丘脑的芳香酶活性增加。形象化 芳香酶我们将使用正电子发射断层扫描(PET)以11C标记的西曲唑为标记。 这项拟议的研究具有很大的潜力来证明在下丘脑中合成的E2增加 排卵前促性腺激素在体内激增。反过来，这一发现将修改目前被接受的 认为起源于卵巢的雌二醇只控制下丘脑-垂体-性腺轴的教条。