L-tryptophan (TP) availability is a major factor regulating CNS serotonin concentration. Consequently, this essential amino acid was administered to healthy men and its effect on the pituitary hormone secretion investigated. The oral administration of 10 g of L-TP significantly increased L-TP levels by 15 min (19.1 .+-. 2.0 to 55.2 .+-. 7.5 .mu.g/ml, P < 0.01) and caused drowsiness in all subjects. In 11 men plasma cortisol decreased from a baseline of 8.1 .+-. 0.9 .mu.g/dl to 5.6 .+-. 0.7 .mu.g/dl by 45 min. The maximal nadir of 4.7 .+-. 0.8 .mu.g/dl, a decrease of 43.2% (range 33-87%), occurred at 15-75 min and was followed by a rebound above baseline to 11.2 .+-. 1.5 .mu.g/dl. A significant inverse relationship existed during the first 45 min between TP and cortisol concentrations. TP treatment 15 min before the i.v. administration of regular insulin (0.1 U[units]/kg) significantly blunted the peak ACTH and cortisol response to hypoglycemia. The infusion of L-TP was followed by a significantly greater fall in ACTH and cortisol levels than during a control infusion. Plasma prolactin (PRL) levels increased only slightly after TP alone, but increased markedly when TP was followed by the oral administration of 20 ml/kg water. The PRL response to water alone was not significant. Although TP administration also increased plasma growth hormone (GH) levels significantly, an increase of 5 ng/ml occurred in only 6 of 11 subjects. There were no significant changes in plasma thyrotropin (TSH), luteinizing hormone (LH), and follicle stimulating hormone (FSH) concentrations. TP treatment did not alter the GH response to hypoglycemia; the PRL and TSH response to TSH releasing hormone (TRH, 500 .mu.g i.v.), or the LH and FSH response to LH releasing hormone (LHRH, 100 .mu.g i.v.). TP admministration causes a significant decrease in both basal and stimulated pituitary ACTH release. Basal secretion of PRL and GH is variably increased. These effects are presumably mediated by conversion of TP to serotonin within the CNS and suggest that serotonin is a potent inhibitor of hypothalamic CRF [corticotropin releasing factor] elaboration in man.