Stimulatory effect of adrenocorticotropin on cortisol, aldosterone, and dehydroepiandrosterone secretion in normal humans: Dose-response study

The short ACTH test is widely used in clinical practice for the diagnosis of adrenal insufficiency. It is classically performed administering 250.0 μg ACTH(1-24) although 1.0 μg ACTH dose has been reported having maximal stimulatory effect on cortisol levels in normal subjects. We aimed to define the maximal and the minimal stimulatory ACTH dose on cortisol, aldosterone, and dehydroepiandrosterone (DHEA) in humans. To this goal, in 12 normal volunteers (6 males and 6 females; age, 22-34 yr; body mass index 20-25 kg/m²; body surface 1.6-1.9 m²), we studied the dose-response effect of eight ACTH doses (0.01, 0.03, 0.06, 0.125, 0.5, 1.0, 25.0, and 250.0 μg) on cortisol, aldosterone, and DHEA levels. Each ACTH dose administered at 0 min was followed by a second ACTH dose of 250.0 μg at +60 min. The cortisol Δ areas under response curve (ΔAUCs) after all ACTH doses, apart from 0.01 μg, were significantly higher (P < 0.02) than that after placebo, showing a clear dose-response relationship (P < 0.001). The doses of 0.03 and 1.0 μg ACTH were the minimal and maximal effective doses, respectively. The cortisol response to 250.0 μg ACTH was not modified by pretreatment with 0.01, 0.03, and 0.06 μg ACTH doses, whereas it was progressively reduced by increasing the dose of ACTH pretreatment (P < 0.001). The aldosterone ΔAUCs to all but 0.01 μg ACTH doses were significantly higher (P < 0.02) than that after placebo, showing a clear dose-response relationship (P < 0.001). The dose of 0.03 μg was the minimal effective stimulating dose, whereas 25.0 μg showed the same aldosterone-releasing effect of 250.0 μg. The aldosterone response to 250.0 μg ACTH, preceeded by placebo, was not modified by pretreatment with 0.01 and 0.03 μg ACTH doses, whereas it was reduced by increasing the dose of ACTH pretreatment (P < 0.05-0.02). The DHEA ΔAUCs to all ACTH doses were significantly higher (P < 0.01) than that after placebo, showing a clear dose-response relationship (P < 0.001). The doses of 0.01 and 1.0 μg ACTH were the minimal and maximal effective dose, respectively. The DHEA response to 250.0 μg ACTH was not modified by pretreatment with 0.01, 0.03, 0.06, and 0.125 μg ACTH doses, whereas it was progressively reduced by pretreatment with 0.5, 1.0, and 25.0 μg ACTH doses (P < 0.01). In conclusion, these results show that an extremely low ACTH dose is needed to stimulate adrenal steroids and, among them, DHEA seems the most sensitive to corticotropin stimulation.