NEUROENDOCRINOLOGY OF PUBERTY

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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.