Circulating dehydroepiandrosterone sulfate (DS) declines in old age, falling to almost undetectable levels after the seventh decade. Since an accelerated decrease occurs after the menopause, we sought to determine whether ovarian factors may influence adrenal DS secretion independent of chronological age. DS, cortisol, and estradiol levels were compared in subjects grouped according to age, ovarian function, and estrogen replacement. Our data show that premature ovarian failure and ovariectomy in young as well as in postmenopausal subjects precipitate an earlier decline in DS levels. There were no accompanying changes in cortisol levels and no correlations among levels of DS, cortisol, and estradiol. Long term estrogen replacement (over 10 yr) in postmenopausal women over age 65 had no beneficial effect on the age-related DS decline. We suggest that ovarian factors separate from estrogen-mediated effects significantly influence the reduction of DS levels independent of age.