CENTRAL GLUCOCORTICOID CONTROL OF PITUITARY LH RELEASE

尽管糖皮质激素过量的生理和药理状态， 包括压力，一直与减少 生殖内分泌功能在大鼠和其他物种， 糖皮质激素抑制下丘脑- 垂体促黄体生成激素（LH）轴尚未明确。 而 很少有研究调查糖皮质激素可能 通过神经内分泌机制抑制LH释放， 这些激素已经在大鼠的离散神经部位中被确定 脑，并已定位于最近在特定的下丘脑核团 已经参与了垂体LH释放的控制。 结果 初步数据研究表明，脑室内（icv） 施用有效的糖皮质激素受体激动剂可以促进 完整成年男性循环LH水平呈剂量比例下降 大鼠 这些数据表明，中枢糖皮质激素受体介导了 对LH释放的抑制作用，并表明这些受体可能 存在于影响神经内分泌调节的神经通路中， 垂体LH 以下提案中概述的研究将力求 确定中枢糖皮质激素受体的类型， 抑制LH释放。 将开展研究，调查 ICV给药的分级剂量的高选择性激动剂 高亲和力I型和低亲和力II型糖皮质激素受体 雄性大鼠外周血浆LH水平。 平行研究将 评估这些受体亚型对生理学的意义， 调节激素释放通过调查的影响， 对基础和应激刺激的LH释放的特异性受体阻断。 根据观察到的全球药理学操作结果， 糖皮质激素受体群体，我们将利用已发表的信息 关于糖皮质激素受体亚型的微分布， 将选择性受体激动剂施用到离散脑的大鼠脑 部位，以表征神经解剖分布， 介导垂体LH释放下降的糖皮质激素受体。 最后，将进行免疫细胞化学分析以确定 视前区和下丘脑内的糖皮质激素受体 与免疫可证实的促黄体激素内存在的受体结合， 释放激素（LHRH）的神经元成分。

Although physiologic and pharmacologic states of glucocorticoid excess, including stress, have been consistently correlated with diminished reproductive endocrine function in the rat and other species, the mechanism(s) and site(s) of glucocorticoid inhibition of the hypothalamic- pituitary luteinizing hormone (LH) axis are not clearly understood. While few studies have investigated the possibility that glucocorticoids may suppress LH release via a neuroendocrine mechanism, specific receptors for these hormones have been identified in discrete neural sites within the rat brain, and have been localized recently within specific hypothalamic nuclei already implicated in the control of pituitary LH release. Results from preliminary data studies indicate that intracerebroventricular (icv) administration of a potent glucocorticoid receptor agonist can promote a dose-proportionate decline in circulating LH levels in intact adult male rats. These data indicate that central glucocorticoid receptors mediate a suppressive effect upon LH release, and suggest that such receptors may exist within neural pathways that influence neuroendocrine regulation of pituitary LH. The studies outlined in the following proposal will seek to identify the type(s) of central glucocorticoid receptor that serves to inhibit LH release. Studies will be undertaken to investigate the effects of icv administration of graded doses of highly selective agonists of the high affinity type I and the low affinity type II glucocorticoid receptor on peripheral plasma LH levels in the male rat. Parallel studies will evaluate the significance of these receptor subtypes to the physiological regulation of hormone release through investigation of the effects of specific receptor blockade on basal and stress-stimulated LH release. Based upon observed results of global pharmacologic manipulation of glucocorticoid receptor populations, we will utilize published information concerning the microdistribution of glucocorticoid receptor subtypes in the rat brain to administer selective receptor agonists to discrete brain sites, in an effort to characterize the neuroanatomical distribution of glucocorticoid receptors that mediate a decline in pituitary LH release. Lastly, immunocytochemical analyses will be carried out to determine whether glucocorticoid receptors within the preoptic area and hypothalamus bind to receptors present within immunodemonstrable luteinizing hormone- releasing hormone (LHRH)-containing neuronal elements.