Hyperactivity of the HPA-system in major depression is reflected by an increased secretion of adrenal hormones especially cortisol and dehydroepiandrosterone (DHEA). In women for whom androgenicity is associated with cardiovascular disorders the dominant source of androstenedione and testosterone secretion are the adrenal glands. To date, there is only sparse information about the regulation of androstenedione, testosterone and dihydrotestosterone (DHT) concentrations in women with severe major depression.Therefore, 11 pre- and postmenopausal, severely depressed, hypercortisolemic women (Hamilton Depression Scale, 31.3+/-5.9; age, 28-77 yrs; mean, 48. 1+/-18.1 yrs) and 11 age-matched healthy female controls (age, 24-81 yrs; mean, 47.9+/-21.5 yrs) underwent a 24 hour (h) blood sampling starting at 0800 h with 30-minute sampling intervals. By applying multivariate analysis of covariance with age as covariate, androstenedione, testosterone and DHT plasma levels at 0900 h show a trend for elevated concentrations in depressed women compared to controls (F(1,19)=2.7; P=0.057). Univariate F tests reveal a significant difference between the groups for androstenedione (4. 19+/-1.571 vs 2.584+/-1.257 nmol/l; P<0.05) testosterone (1.110+/-0. 278 vs 0.833+/-0.347 nmol/l; P<0.05) and DHT (0.656+/-0.207 vs 0. 483+/-0.242 nmol/l; P<0.05). Mean ACTH (16.4+/-10.4 vs 10.4+/-2.4 pmol/l; P=0.89), LH (13.5+/-11.8 vs 8.9+/-9.2 IU/l; P=0.12), FSH (35. 2+/-33.1 vs 31.3+/-35.7 IU/l; P=0.67) and estradiol (135.4+/-157.4 vs 82.2+/-85.1 pmol/l; P=0.20) plasma levels did not differ between patients and controls. Further, there was a trend towards an age related decline in testosterone secretion in healthy controls (r=-0. 24; P=0.08) which did not occur in depressed patients (r=0.17; P=0. 96), while the calculated ratio of DHEA to testosterone was similar in both groups (0.2+/-0.14 vs 0.13+/-0.7; P=0.21, unpaired t-test). In conclusion, androstenedione, testosterone and DHT concentrations all were increased in hypercortisolemic women with severe major depression. These findings are best explained as a consequence of an overstimulation of the adrenal glands through pituitary and hypothalamic sites of the HPA-system.