Evidence suggests that amelioration of hyperinsulinemic insulin resistance in men with calcium channel blockers of the dihydropyridine class is associated with a fall in serum insulin and a rise in serum dehydroepiandrosterone sulfate (DHEA-S) concentrations. The present study was conducted to determine whether 1) the nondihydropyridine calcium channel blocker diltiazem also reduces circulating insulin levels in humans, and 2) a reduction in circulating insulin with a calcium channel blocker is associated with a rise in serum DHEA-S concentrations in women as well as men. Ten obese hypertensive men and 13 obese hypertensive postmenopausal women were studied. Subjects were assessed at baseline and after the oral administration of diltiazem (60 mg, three times daily) for 18 days. Diltiazem treatment was associated with reductions in fasting serum insulin levels in both the men (from 91 +/- 14 to 56 +/- 12 pmol/L; P < 0.03) and women (from 92 +/- 20 to 48 +/- 9 pmol/L; P = 0.05). Serum glucose levels did not change in either group. In men, concurrent with the fall in serum insulin levels, serum DHEA-S levels rose from 4.05 +/- 1.06 to 6.91 +/- 1.32 mumol/L (P < 0.04), and serum DHEA levels rose from 14.4 +/- 3.0 to 24.3 +/- 4.6 nmol/L (P = 0.05) with diltiazem treatment, whereas serum cortisol did not change. In contrast, diltiazem administration in the women was not associated with any change in serum DHEA-S, DHEA, or cortisol levels. These observations suggest that the action of calcium channel blockers to lower fasting serum insulin levels is not specific for the dihydropyridine class and applies to both men and women. Furthermore, the finding of a sex-based disparity in DHEA-S and DHEA responses to insulin reduction suggests that the metabolism of these steroids may be regulated differently in men than in women.