['ACTH secretion is under hypothalamic stimulatory (feedforward) and adrenal inhibitory (feedback) control.', 'Assessment of overnight ACTH secretion during a hypocortisolemic clamp will permit the estimation of changing feedforward and feedback.', 'Seven healthy men.', 'An oral dose of placebo (PLAC), metyrapone (METY, 3 g), or ketoconazole (KTCZ, 1.2 g) was given at midnight (MN) to block glucocorticoid synthesis. Plasma ACTH was sampled every 10 min (MN to 0800 h).', 'Variable-waveform deconvolution analysis of ACTH secretion and approximate entropy (ApEn) analysis of pattern regularity.', 'Compared with PLAC, administration of METY and KTCZ reduced morning cortisol concentrations by >or=77 and 54% respectively (P<0.001). Hypocortisolemia elevated pulsatile ACTH secretion by 8.2- (METY) and 5.3-fold (KTCZ; both P<0.001). Basal ACTH secretion rose by 3.4-fold under METY-induced cortisol depletion (P=0.020). ACTH secretory-burst shape and half-life were stable. ApEn of ACTH release declined overnight (P=0.021) and with the drug (P=0.001), denoting enhanced feedforward coordination.'] Does hypocortisolemic clamp unmask jointly feedforward- and feedback-dependent control of overnight ACTH secretion?