Pituitary-adrenal reserve was evaluated in control and idiopathic-hypopituitary (IH) subjects using the plasma 11-deoxycortisol response to a 4-hr infusion of metyrapone, the urinary 17-hydroxycorticosteroid (17-OHCS) response to oral metyrapone and the plasma corticoid response during a combined arginine-insulin tolerance test (AITT). In the iv metyrapone test, mean (±sd) 11-deoxycortisol values in μg/lOO ml for control subjects (N = 16) are: 0 hr = 0.8 ± 0.5; 4 hr = 5.4 ± 1.8; 5 hr = 5.9 ± 1.5. For IH patients untreated with corticosteroids (N = 9) the corresponding values were: 1.5 ± 1.3; 7.9 ± 4.1; and 8.5 ± 4.3, respectively. All of the control and 8 of 9 IH subjects showed significant positive responses. Six of the IH subjects had abnormal oral metyrapone tests on at least 1 occasion. During the AITT, mean values (±sd) in ng/100 ml for control subjects (N = 10) were: baseline = 9.3 ± 4.8; 45 min after insulin = 20.3 ±x 4.5; 60 min after insulin = 23.9 ± 4.7. Corresponding values in untreated IH subjects (N = 9) were 11.0 ± 3.3; 23.7 ± 4.7; and 27.0 d= 6.7. All control and IH subjects had significant positive responses to the AITT. Two patients with organic hypopituitarism and 1 IH patient treated with cortisone failed to respond to any of these stimuli. These data suggest that IH patients with abnormal oral metyrapone tests may have a mild defect in control of ACTH secretion which is overcome by more potent stimuli such as iv metyrapone or insulin induced hypoglycemia. The latter 2 may be more useful in assessing the need for corticoid replacement.