The aim of this study was to investigate the possible role of prostaglandins (PG) in the control of the hypohtalamic-pituitary-adrenocortical axis in normal volunteers. Acute oral administration of 100 mg indomethacin (ID) or 1.5 g acetylsalicylic acid (ASA) did not alter ACTH and cortisol plasma levels. Administration of 300 mg daily ID for 4 days delayed the onset, but increased the magnitude, of the response of ACTH to insulin hypoglycaemia, while it blunted the cortisol response. Administration of 3.2 g ASA daily depressed ACTH response to hypoglycaemia leaving the cortisol response unchanged, except for a 15 min delay in onset. These results are interpreted assuming that ID and ASA chiefly acted at the pituitary and hypothalamic level, respectively, and that ID, but not ASA, interfered with adrenocortical cortisol production. Our findings support the concept, based on animal studies, that PG enhance hypothalamic CRF release and adrenocortical steroidogenesis and may restrain ACTH secretion in the pituitary.