The hypothalamic pulse generator: the reproductive core

Significant advances in our understanding of neuroendocrinology of the human GnRH pulse generator have been accomplished in the last decade. In particular, inhibitory effects of endogenous and exogenous opiates, endogenous and exogenous androgens, and endogenous and exogenous estrogens on the hypothalamic GnRH pulse generator have been inferred in men and/or women. Conversely, no definitive effects of serotonin and/or adrenergic agents have been reported. The overall role of dopamine in regulating the GnRH pulse generator in humans is not known because both facilitative effects of central dopamine and inhibitory effects of peripheral (extra blood-brain barrier) dopamine have been described. Accordingly, studies with more refined neuropharmacologic probes will be needed: 1) to examine the interactions among the preceding control systems in postmenopausal women, girls, and women studied at various stages of the menstrual cycle; and 2) to elucidate the importance of other, less well understood neurochemical pathways, such as those subserved by gamma-aminobutyric acid (GABA), bombesin, neuropeptide Y, CRH catecholestrogens, etc., as well as putative metabolic signals associated with strenuous exercise, nutrient deprivation, and stress. The availability of increasingly specific neurotransmitter probes and more penetrating neuroendocrine analytic tools should aid in further significant progress in these arenas and, therefore, ultimately help to delineate additional specific pathophysiologic mechanisms that subserve reproductive dysfunction in women.