Physiology of Hypothalamic Neurosteroidal Progesterone

下丘脑神经甾体黄体酮的生理学

• 批准号: 6869516
• 负责人: PAUL E MICEVYCH
• 金额: $ 39.99万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6869516
• 关键词: adrenalectomy; astrocytes; enzyme activity; estrogens; hormone regulation /control mechanism; hydroxysteroid dehydrogenases; hypothalamic hormones; in situ hybridization; laboratory rat; luteinizing hormone; neurohormones; northern blottings; oligodendroglia; ovariectomy; progesterone; radioimmunoassay; sex behavior; steroid 17alpha monooxygenase; steroid hormone biosynthesis; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Neurosteroids, steroids synthesized in the brain, have been implicated in functions ranging from stress, depression, anxiety, to cognition. One neurosteroid is progesterone, a classic sex hormone involved in the regulation of reproduction. Although the CNS has the capacity to synthesize progesterone, to date it has appeared that only peripheral progesterone, from the ovaries and adrenals, regulates reproduction. Our preliminary studies have demonstrated that estrogen-induced hypothalamic progesterone synthesis is sufficient to initiate reproductive events necessary for ovulation and copulation. Estrogen stimulation of ovariectomized and adrenalectomized (ovx/adx) rats increased hypothalamic progesterone levels. In such animals, estrogen induced lordosis behavior and progesterone dependent proceptive behavior. Similarly, estrogen stimulation of ovx/adx rats induced a luteinizing hormone (LH) surge. In these rats, blocking 3beta-hydroxysteroid dehydrogenase (3beta-HSD), the enzyme that converts pregnenolone to progesterone, prevented the LH surge. Estrogen stimulates astrocytes in culture to synthesize progesterone, suggesting that glial cells may mediate estrogen-positive feedback. These data indicate that, absent the peripheral steroidogenic tissues, estrogen can induce progesterone dependent events by stimulating the synthesis of neurosteroidal progesterone. We propose to test the hypothesis: estrogen stimulates synthesis of hypothalamic progesterone that activates circuits regulating the LH surge and sexual behavior. Three experiments are proposed: First, using intact and ovx/adx rat models we will directly test whether the estrogen-induced LH surge is dependent on increased hypothalamic neurosteroidal progesterone. Second, we propose to determine whether estrogen increases the expression and/or activity of steroidogenic enzymes (P450 side chain cleavage and 3beta-HSD) needed to synthesize progesterone, in vitro and in vivo. Third, using the same intact and ovx/adx rat models, we will determine whether estrogen-induced hypothalamic progesterone is sufficient to facilitate sexual behavior. These studies will demonstrate the physiology of neurosteroidal progesterone and provide important new information about the mechanism of estrogen-positive feedback in the CNS.

描述（由申请人提供）：神经类固醇，即在大脑中合成的类固醇，与压力、抑郁、焦虑和认知等功能有关。黄体酮是一种神经类固醇，是一种参与生殖调节的经典性激素。尽管中枢神经系统具有合成孕酮的能力，但迄今为止，似乎只有来自卵巢和肾上腺的外周孕酮调节生殖。我们的初步研究表明，雌激素诱导的下丘脑黄体酮合成足以启动排卵和交配所需的生殖事件。卵巢切除和肾上腺切除（ovx/adx）大鼠的雌激素刺激增加了下丘脑孕酮水平。在这些动物中，雌激素诱导脊柱前凸行为和黄体酮依赖性感知行为。同样，对 ovx/adx 大鼠进行雌激素刺激会导致黄体生成素 (LH) 激增。在这些大鼠中，阻断 3β-羟基类固醇脱氢酶 (3β-HSD)（一种将孕烯醇酮转化为黄体酮的酶）可防止 LH 激增。雌激素刺激培养物中的星形胶质细胞合成黄体酮，这表明神经胶质细胞可能介导雌激素正反馈。这些数据表明，在缺乏外周类固醇生成组织的情况下，雌激素可以通过刺激神经类固醇黄体酮的合成来诱导黄体酮依赖性事件。我们建议检验以下假设：雌激素刺激下丘脑黄体酮的合成，从而激活调节 LH 激增和性行为的回路。提出了三个实验：首先，使用完整的 ovx/adx 大鼠模型，我们将直接测试雌激素诱导的 LH 激增是否依赖于下丘脑神经甾体黄体酮的增加。其次，我们建议确定雌激素是否会增加体外和体内合成孕酮所需的类固醇生成酶（P450 侧链裂解和 3β-HSD）的表达和/或活性。第三，使用相同的完整和 ovx/adx 大鼠模型，我们将确定雌激素诱导的下丘脑黄体酮是否足以促进性行为。这些研究将证明神经甾体黄体酮的生理学，并提供有关中枢神经系统雌激素正反馈机制的重要新信息。