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: 9761548
• 负责人: Ei Terasawa-Grilley
• 金额: $ 38.84万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761548
• 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 该提案的总体目的是调查促性腺激素释放激素的调节 （GnRH）非人类灵长类动物中的神经元。 GNRH从下丘脑和对照中释放 通过垂体促性腺激素生殖功能。拟议的研究旨在发现角色 神经雌激素的神经雌二醇。 多年来，已经表明，从卵巢中释放的E2循环促进了学习和记忆， 保护神经元免受神经元细胞死亡的影响，并调节生殖功能。但是，最近，一个新的 关于E2的作用，合成并在大脑中局部释放的概念，作为神经调节剂 功能已经出现。实际上，我们的初步数据表明E2在茎中合成并释放 下丘脑的中位数（S-ME）对于全促性腺激素激增似乎是必要的。那 是，雌二醇苯甲酸酯（EB）诱导的Ovariectomized（OVX）雌猴的LH激增大大减弱 在芳香酶阻滞剂letrozole的情况下。芳香酶是E2合成所需的酶 雄激素和letrozole是用于芳香化酶合成的常用竞争阻滞剂。在提议中 项目，我们将测试中心假设，即在下丘脑中合成并释放的神经雌二醇 在调节排卵前GNRH释放中起着至关重要的作用。提出了三个具体目标。目标1意志 检验神经雌二醇是雌激素积极反馈对影响的一部分的假设 GnRH发布。在AIM 1中，我们将评估EB诱导的LH激增期间神经雌二醇增加的时机 使用Letrozole注入作为工具，并测量LH释放的变化。 AIM 2将检验以下假设 在EB引起的GNRH激增期间，神经雌二醇增加是持续的基础机制 GNRH释放的高程。在AIM 2中，我们将测量雌二醇和GNRH的释放以及循环LH 和E2在EB处理的OVX猴子中使用微透析法和串行血液采样，然后是 用液相色谱 - 质谱法（LC/MS/MS）和RIA分析。 AIM 3将检验假设 下丘脑中的芳香化酶活性在体内刺激前GNRH潮中增加。可视化 芳香化酶我们将使用11C标记的切唑作为标记的正电子发射断层扫描（PET）扫描。 拟议的研究具有很大的潜力，可以证明下丘脑中合成的E2增加 在体内的促性促性腺激素激增过程中。反过来，这一发现将修改当前接受的 卵巢起源E2的教条仅控制下丘脑 - 垂体 - 基达轴。