Role of neuroestradiol in regulation of the GnRH surge

神经雌二醇在 GnRH 激增调节中的作用

基本信息

批准号：
10417073
负责人：
Ei Terasawa-Grilley
金额：
$ 37.66万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/10417073
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

项目摘要

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/总结该提案的总体目标是研究促性腺激素释放激素的调节非人类灵长类动物中的 (GnRH) 神经元。 GnRH 由下丘脑释放并控制通过垂体促性腺激素发挥生殖功能。拟议的研究旨在揭示其作用神经雌二醇在排卵前 GnRH 激增中的作用。多年来的研究表明，卵巢释放的循环 E2 有助于学习和记忆，保护神经元免于神经细胞死亡，并调节生殖功能。然而，最近，一个新的关于 E2 的作用的概念，E2 在大脑中局部合成和释放，作为神经元的神经调节剂功能，已经出现。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）似乎对于促性腺激素的完全激增是必要的。那也就是说，雌二醇苯甲酸酯 (EB) 引起的卵巢切除 (OVX) 雌性猴中的 LH 激增大大减弱在芳香酶阻滞剂来曲唑存在的情况下。芳香酶是 E2 合成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断剂。在提议的项目中，我们将测试中心假设，即神经雌二醇在下丘脑中合成和释放在排卵前 GnRH 释放的调节中起着至关重要的作用。提出了三个具体目标。目标1将检验神经雌二醇是雌激素正反馈影响的一个组成部分的假设 GnRH 释放。在目标 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间使用来曲唑注射液作为工具并测量 LH 释放的变化。目标 2 将检验以下假设： EB 诱导的 GnRH 激增期间神经雌二醇的增加是持续性的基本机制 GnRH 释放升高。在目标 2 中，我们将测量雌二醇和 GnRH 的释放以及循环 LH EB 处理的 OVX 猴中使用微透析方法和连续血液采样，然后进行 E2 和 E2 采用液相色谱-质谱 (LC/MS/MS) 和 RIA 进行分析。目标 3 将检验假设体内排卵前 GnRH 激增期间下丘脑的芳香酶活性增加。可视化对于芳香酶，我们将使用正电子发射断层扫描 (PET) 扫描，并以 11C 标记的塞曲唑作为标记。拟议的研究有很大潜力证明下丘脑合成的 E2 增加在体内排卵前促性腺激素激增期间。反过来，这一发现将修改目前公认的认为卵巢来源的 E2 仅控制下丘脑-垂体-性腺轴的教条。