To assess the effect of weight reduction on serum dehydroepiandrosterone (DHEA)-sulfate, insulin, and glucose, these parameters were assessed in 18 men and 29 women before and after weight loss achieved by a 2-month 1000-1400 kcal diet. Men and women did not differ at baseline with respect to age, body mass index (BMI), or serum insulin and glucose, but serum DHEA-sulfate was almost 2-fold higher in women than men (5.4 +/- 0.5 vs. 2.8 +/- 0.2 mumol/L; P < 0.001). During the diet, men and women experienced similar reductions in BMI of 3.5 kg/m2 and 3.2 kg/m2, respectively. Fasting serum insulin fell by 38% in men and 33% in women, and did not differ between sexes at the diet's end (135 +/- 7 vs. 156 +/- 8 pmol/L; P = NS). Serum glucose fell slightly in both men and women, but did not differ between sexes. Weight loss in men was associated with a 125% rise in serum DHEA-sulfate from 2.8 +/- 0.2 to 6.3 +/- 0.3 mumol/L (P < 0.0001). In contrast, serum DHEA-sulfate did not change with weight loss in women (P = 0.35). Serum DHEA-sulfate at the end of the diet did not differ between men and women (6.3 +/- 0.3 vs. 5.2 +/- 0.5 mumol/L; P = 0.10). Hence, dietary weight loss accompanied by equivalent reductions in body mass index and serum insulin between sexes was associated with a marked rise in serum DHEA-sulfate in men, whereas in women serum DHEA-sulfate did not change. Although speculative, these findings are consistent with the idea that insulin acts in a sex-specific fashion to reduce circulating DHEA-sulfate in men only.