NEUROENDOCRINOLOGY OF PUBERTY

这项拟议的研究是先前获奖的临床研究中心先导研究的结果，协议1354-P，促性腺激素释放激素的成熟作用--溴隐亭的影响。下丘脑-垂体轴在胎儿中非常活跃，但在出生后几个月至2-4年内，该轴处于静止状态，这取决于性别，似乎中枢神经系统(CNS)途径的发展抑制了下丘脑促性腺激素释放激素(GnRH)的分泌。最近对GnRH神经元具有多巴胺受体的认识，再加上1354-P协议的试点数据，导致我们假设多巴胺能途径在童年中期抑制GnRH的分泌，并在青春期变得越来越不活跃。我们的试验数据表明，多巴胺激动剂溴隐亭能迅速抑制青春期男孩和女孩夜间黄体生成素(LH)的增加，并由此推断，GnRH的分泌。如果多巴胺能途径参与抑制青春期促性腺激素释放激素的分泌，那么在青春期儿童的黄体生成素分泌通常被抑制的白天，给药应解除对青春期儿童黄体生成素分泌的抑制。在这项研究中，将通过检测多巴胺激动剂对儿童和成人的急性和慢性影响以及通过确定多巴胺拮抗剂对儿童的急性影响来系统地探索多巴胺能中枢神经系统在青春期GnRH分泌控制中的作用。溴隐亭抑制夜间促性腺激素释放激素分泌的能力将通过分析口服溴隐亭前、服药后一次和服药7天后每隔10~20分钟采集的血液标本中的促黄体生成素脉冲频率和幅度来确定。在每项研究结束时，将通过给予外源性GnRH来评估垂体储备。口服一剂甲氧氯普胺的急性效应将在0800-1200h之间测定，然后测定垂体对外源性GnRH的反应性。

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.