MELATONIN STIMULATES GROWTH-HORMONE SECRETION THROUGH PATHWAYS OTHER THAN THE GROWTH HORMONE-RELEASING HORMONE

OBJECTIVE There is evidence that melatonin plays a role in the regulation of GH secretion. The aim of this study was to investigate the neuroendocrine mechanisms by which melatonin modulates GH secretion. Thus we assessed the effect of oral melatonin on the GH responses to GHRH administration and compared the effects of melatonin with those of pyridostigmine, a cholinergic agonist drug which is likely to suppress hypothalamic somatostatin release. DESIGN The study consisted of four protocols carried out during the afternoon hours. Study 1: oral melatonin (10 mg) or placebo were administered 60 minutes prior to GHRH (100 mug i.v. bolus). Study 2: GHRH (100 mug i.v. bolus) or placebo were administered at 0 minutes; oral melatonin or placebo were given at 60 minutes and were followed by a second GHRH stimulus (100 mug i.v. bolus) at 120 minutes. Study 3: placebo; oral melatonin (10 mg); oral pyridostigmine (120 mg); melatonin (10 mg) plus pyridostigmine (120 mg) were administered on separate occasions. Study 4: placebo; oral melatonin (10 mg); oral pyridostigmine (120 mg); melatonin (10 mg) plus pyridostigmine (120 mg) were administered on separate occasions 60 minutes prior to a submaximal dose (3 mug i.v. bolus) of GHRH. SUBJECTS Four groups of eight normal male subjects, ages 22-35 years, were randomly assigned to each protocol. MEASUREMENTS Growth hormone was measured by RIA at 15-minute intervals. RESULTS Oral melatonin administration had a weak stimulatory effect on GH basal levels. Prior melatonin administration approximately doubled the GH release induced by supramaximal (100 mug) or submaximal (3 mug) doses of GHRH. Melatonin administration restored the GH response to a second GHRH challenge, given 120 minutes after a first GHRH i.v. bolus. The GH releasing effects of pyridostigmine, either alone or followed by GHRH, were greater than those of melatonin. However, the simultaneous administration of melatonin and pyridostigmine was not followed by any further enhancement of GH release, either in the absence or in the presence of exogenous GHRH. CONCLUSIONS Our data indicate that oral administration of melatonin to normal human males increases basal GH release and GH responsiveness to GHRH through the same pathways as pyridostigmine. Therefore it is likely that melatonin plays this facilitatory role at the hypothalamic level by inhibiting endogenous somatostatin release, although with a lower potency than pyridostigmine. The physiological role of melatonin in GH neuroregulation remains to be established.