Evidence suggests that hyperinsulinemic insulin resistance may reduce serum levels of the adrenal steroid dehydroepiandrosterone (DHEA) sulfate in humans. This study was conducted to assess the influence of physiological concentrations of insulin on serum adrenal steroid levels by lowering circulating insulin in nondiabetic men through the administration of the biguanide metformin. A total of 28 nondiabetic men were studied. The study group consisted of 16 obese and hypertensive men, and the control group of 12 nonobese and normotensive men. The men were studied at baseline and after the oral administration of 500 mg metformin, 3 times daily, for 21 days. Metformin administration resulted in significant reductions in serum insulin levels and concurrent increases in serum DHEA sulfate levels in both groups of men. The mean fasting serum DHEA sulfate concentration rose by 48% in the obese hypertensive men (from 5.9 +/- 0.8 to 8.7 +/- 0.7 mumol/L; P < 0.02) and by 80% in the nonobese normotensive men (from 3.5 +/- 0.5 to 6.3 +/- 0.9 mumol/L; P < 0.05). When the results from both groups were combined, changes in serum DHEA sulfate levels (i.e. day 21 value minus day 0 value) correlated positively with baseline fasting serum insulin levels (r = 0.44; P = 0.02; n = 28). Moreover, changes in fasting serum DHEA sulfate levels correlated inversely with changes in fasting serum insulin levels (r = -0.38; P < 0.05; n = 28). These findings lend further credence to the idea that insulin acts as a physiological regulator of DHEA sulfate metabolism and lowers circulating DHEA sulfate concentrations in men.