NEUROENDOCRINOLOGY OF PUBERTY

这项拟议的研究是先前授予临床研究中心试点研究的成果，1354-P方案，GnRH的成熟作用-溴隐亭的影响。胎儿的下丘脑-垂体轴是非常活跃的，但在出生后的几个月到2 - 4年内，根据性别，轴是静止的，好像中枢神经系统（CNS）通路发展到抑制下丘脑促性腺激素释放激素（GnRH）的分泌。最近认识到GnRH神经元具有多巴胺受体，加上1354-P方案的先导数据，导致我们的假设，即多巴胺能通路在儿童中期抑制GnRH分泌，并在青春期变得越来越不活跃。我们的试验数据表明，溴隐肽，一种多巴胺激动剂，可以迅速抑制夜间黄体生成素（LH）的增加，由此推断，青春期男孩和女孩的GnRH分泌也会受到抑制。如果多巴胺能途径参与抑制青春期GnRH分泌，那么在正常情况下黄体生成素分泌被抑制的白天，给予多巴胺拮抗剂应该解除青春期儿童黄体生成素分泌的抑制。在本研究中，将通过检查儿童和成人多巴胺激动剂的急性和慢性作用以及确定儿童多巴胺拮抗剂的急性作用，系统地探索多巴胺能中枢神经系统通路在控制青春期GnRH分泌中的作用。溴芥子碱抑制夜间GnRH分泌的能力将通过分析在口服溴芥子碱前、一次给药后和7天口服溴芥子碱前2000至1200小时间隔10至20分钟的血液样本中LH脉冲频率和振幅来确定。在每项研究结束时，将通过给药外源性GnRH来评估垂体储备。一剂量口服甲氧氯普胺的急性效应将在0800 - 1200h之间测定LH分泌，随后测定垂体对外源性GnRH的反应。

This proposed research is an outgrowth of a previously awarded Clinical Research Center pilot study, Protocol 1354-P, Maturational roles of GnRH--Effects of Bromocriptine. The hypothalamic-pituitary axis is remarkably active in the fetus, but within months to 2 - 4 years after birth, depending on sex, the axis is quiescent, as if central nervous system (CNS) pathways develop to restrain hypothalamic gonadotropin- releasing hormone (GnRH) secretion. The recent recognition that GnRH neurons have receptors for dopamine, coupled with the pilot data from Protocol 1354-P, have led to our hypothesis that dopaminergic pathways restrain GnRH secretion in mid-childhood and become increasingly less active at puberty. Our pilot data indicate that bromocriptine, a dopamine agonist, produces prompt suppression of the nocturnal increase in luteinizing hormone (LH) and, by inference, GnRH secretion in pubertal boys and girls. If dopaminergic pathways are involved in restraint of pubertal GnRH secretion, then administration of dopamine antogonists should disinhibit LH secretion in pubertal children during the daytime when LH secretion is normally suppressed. In this research, a systematic exploration of the role of dopaminergic CNS pathways in the control of pubertal GnRH secretion will be undertaken by examining acute and chronic effectos of dopamine agonists in children and adults and by determining the acute affects of dopamine antagonists in children. The ability of bromocriptine to suppress nocturnal GnRH secretion will be determined by analysis of LH pulse frequency and amplitude from LH measurements in blood samples obtained at 10 to 20 minute intervals from 2000 to 1200h before, after one dose, and after 7 days of oral bromocruptine administration. Pituitary reserve will be assessed by administraton of exogenous GnRH at the completion of each study. The acute effects of one dose of oral metoclopramide will be determined on LH secretion between 0800 and 1200h followed by determination of pituitary responsiveness to exogenous GnRH.