The purpose of this study was to evaluate the effects on hormonal milieu of 1-year therapy with 10 mg/day oral dehydroepiandrosterone (DHEA) or 50 microg transdermal estradiol plus 100 mg/day oral micronized progesterone in a group of 20 healthy postmenopausal women (age=50-58 and years since menopause (ysm)=1-6) and also the effects observed by combining these two therapies in a group of 12 postmenopausal women (age=54-61 and ysm=6-10) characterized by lower baseline DHEA and DHEAS levels (<2.40 and <0.55 microg/ml, respectively). DHEA produced a significant rise in androgens levels, whereas HRT did not. Moreover, DHEA alone induced a significantly lower increase in estrogens and beta-endorphin levels and a higher decrease in cortisol levels than HRT. DHEA and HRT also produced a significant similar increase in allopregnanolone levels. DHEA plus HRT induced a significantly higher increase in testosterone and estradiol and a lower increase in allopregnanolone and beta-endorphin levels and a significantly lower decrease in cortisol levels than HRT alone treated group. A similar increase was observed in progesterone and SHBG levels in all groups. These results suggest that 10-mg DHEA seems to be the proper dose to replace androgen deficiency in subjects with reduced Delta-5 androgens plasma levels. However, the aging process and the number of years since menopause may further modulate the effects of hormone therapy on hormonal milieu.