Growth hormone (GH) secretion in patients with Cushing's syndrome is diminished to all the stimuli tested so far but the precise mechanisms through which this occurs are unknown. In order to investigate whether increased somatostatinergic tone might be responsible for this alteration, we studied the effect of pyridostigmine (120 mg p.o. at -60 min), which activates cholinergic synapses and thus suppresses hypothalamic somatostatin release on GH responses to GHRH (100 micrograms, i.v. at 0 min), in six patients with Cushing's syndrome. We found that while pyridostigmine markedly potentiated GH responses to GHRH, in all the normal subjects tested (n = 12), neither GHRH alone nor GHRH plus pyridostigmine elicited any increase in GH secretion in any of the patients with Cushing's syndrome. This suggests that chronic glucocorticoid excess induces marked alterations in the hypothalamic control of GH secretion.