During the first half of nocturnal sleep, the secretory response of the pituitary-adrenal axis to either CRH or vasopressin (VP) administration is reduced. Two experiments were performed aiming (i) to investigate the impact of sleep on the response to a combined CRH/VP administration and (ii) to specify the onset of sleep associated pituitary-adrenal suppression and its relation to specific sleep stages. In experiment I, we compared the effect of simultaneous administration of VP (0.5 IU i.v., within 6 min) and CRH (50 micrograms bolus i.v., in the third min of VP infusion) on the secretion of ACTH, cortisol and GH in healthy men during the first nocturnal epoch of slow wave sleep (SWS) and during nocturnal wakefulness. The increase of ACTH and cortisol concentrations after combined VP/CRH administration was distinctly higher during wakefulness than sleep (P < 0.01). In experiment II, CRH (30 micrograms/h, after an initial bolus of 30 micrograms) was continuously infused in 7 healthy men on 2 nights. On one of the nights, the men were allowed to sleep (between 23.00 h and 05.00 h) after a 3-h period of wakefulness, on the other night they stayed awake throughout the experiment. In both conditions, CRH enhanced ACTH/cortisol plasma levels. Compared with concentrations during continuous wakefulness, sleep and in particular SWS was associated with a suppression of ACTH/cortisol levels (P < 0.05). The findings further support an inhibitory influence of early nocturnal sleep on pituitary-adrenal activity. The effect appears to be strongest during SWS and is probably mediated via hypothalamic secretion of a release inhibiting factor of ACTH.