In depression and aging an increase in nocturnal cortisol secretion and a blunted nocturnal growth hormone (GH) surge have been described. In normal young men, growth hormone-releasing hormone (GHRH) promotes GH release and reduces plasma cortisol. Here, we examined whether GHRH could help to restore sleep-endocrine regulation in patients with depression and aging. GHRH (4x50 microgram, at 2200, 2300, 2400 and 0100 h) or saline (placebo) was injected intravenously to 42 patients with depression (19 females, 23 males) and matched controls (age range 19-76 years). Blood samples were withdrawn at 20 min intervals between 2200-0700 h and analysed using Manova (D.F. 1, 72). Patients compared to controls had significantly higher levels of ACTH and cortisol, particularly during the first half of the night (F=9 and F=11.8, each p<0.05). GHRH reduced ACTH during the first and cortisol secretion during the second half of the night in males, regardless of diagnosis, but enhanced it in females (F=5.1 and F=4.0, each p<0.05). ACTH and cortisol secretion were inversely related to NREM and stage 2 sleep in patients (r= -0.42, -0.42 and r= -0.36, -0.39, respectively, each p<0.05) but not in controls. Our data suggest that: 1) female gender, depression and aging add-on to enhance HPA activity, and 2) hyperactivity of the HPA system and the decrease in NREM and in particular stage 2 sleep in depression are interrelated. In men, GHRH can restore some of the sleep-endocrine alterations associated with depression and aging.