NEUROENDOCRINOLOGY OF PUBERTY

下丘脑-垂体轴在胎儿时期非常活跃，但在出生后的几个月内，该轴处于静止状态，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。到了青春期，这种克制开始消失，先是在晚上，然后是白天。最近认识到GnRH神经元具有多巴胺受体，这导致了我们的假设，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。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对青春期儿童黄体生成素分泌的抑制。相反，多巴胺激动剂应该能够减少黄体生成素在夜间的分泌，此时黄体生成素在青春期儿童中最为活跃。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。首先，将在8名男孩和8名女孩中确定多巴胺激动剂溴隐亭对GnRH分泌产生急性和持续抑制的能力。将对8名男性和8名女性进行平行研究，以确定成人多巴胺能系统的活跃程度。下丘脑释放GnRH导致外周血LH浓度升高。因此，溴隐亭抑制夜间GnRH分泌的能力将通过经常获得的血液样本中的LH测量来确定。在这项研究之后，8名男孩和8名女孩将接受多巴胺拮抗剂甲氧氯普胺，以确定其解除青春期儿童LH脉冲频率和振幅白天抑制的能力。这些研究将扩展我们对控制青春期时间和节奏的中枢神经系统通路的认识。

The hypothalamic-pituitary axis is remarkably active in the fetus, but within months after birth, the axis is quiescent, as if central nervous system (CNS) pathways develop to restrain hypothalamic gonadotropin-releasing hormone (GnRH) secretion. At puberty, this restraint begins to disappear, first at night, and then in the daytime. The recent recognition that GnRH neurons have receptors for dopamine have led to our hypothesis that dopaminergic pathways restrain GnRH secretion in mid-childhood and become increasingly less active at puberty. If dopaminergic pathways are involved in restraint of pubertal GnRH secretion, then administration of dopamine antagonists should disinhibit LH secretion in pubertal children during the daytime when LH secretion is normally suppressed. Conversely, dopamine agonists should be able to decrease LH secretion at night, when it is most active in pubertal children. 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 effects of dopamine agonists in children and adults and by determining the acute effects of dopamine antagonists in children. Initially, the ability of the dopamine agonist, bromocriptine, to produce acute and sustained suppression of GnRH secretion will be determined in 8 boys and 8 girls. Parallel studies will be carried out in 8 men and 8 women to determine to what degree the dopaminergic system remains active in adults. Release of GnRH from the hypothalamus results in an increase of LH concentration in peripheral blood. Thus, the ability of bromocriptine to suppress nocturnal GnRH secretion will be determined from LH measurements in blood samples obtained frequently. Following this study 8 boys and 8 girls will receive the dopamine antagonist, metoclopramide, to determine its ability to disinhibit the daytime suppression of LH pulse frequency and amplitude seen in pubertal children. These studies will expand our knowledge of the CNS pathways that control the timing and tempo of puberty.