It is still discussed controversially to what extent the nocturnal activity of the hypothalamus-pituitary-adrenocortical system depends on sleep and awakening in the morning. Therefore, we investigated the association of plasma ACTH and cortisol levels with undisturbed nocturnal sleep and spontaneous awakening in 14 healthy male subjects (between 2300 h and 1100 h). Between sleep onset and 476.9 min after sleep onset mean plasma cortisol level was significantly (P < 0.01) higher (210 +/- 15 vs. 155 +/- 9 nmol/L) in the group with a shorter (476.9 +/- 15.0 min; n = 7; mean +/- SEM) than in the group with a longer total sleep time (596.9 +/- 14.4 min; n = 7). Spontaneous awakening in the morning was not linked to the presence of any specific sleep stage or to rising plasma ACTH and cortisol levels. However, spontaneous awakening was followed by a brief rise in plasma ACTH and cortisol in both groups. Thereafter, during wakefulness plasma ACTH and cortisol abruptly declined in all subjects irrespective of the time of awakening. The slope of the plasma ACTH and cortisol curves differed significantly (ACTH: P < 0.001; cortisol: P < 0.002, for all subjects) comparing the time after awakening (until 1100 h) with a time interval of identical length before awakening. We conclude that the duration of sleep and nocturnal ACTH and cortisol secretion are interrelated. Furthermore, the data suggest that the endogenous early morning activation of the hypothalamus-pituitary-adrenocortical system is terminated by mechanisms closely associated with awakening.