NEUROENDOCRINOLOGY OF PUBERTY

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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.