To determine whether a reduction in insulinemia would be associated with a rise in serum dehydroepiandrosterone (DHEA) sulfate in insulin-resistant men, 29 middle-aged (30-59 yr old) and 28 elderly (60-80 yr old) hypertensive men were enrolled into a single blind, placebo-controlled study, in which benfluorex was administered to improve insulin sensitivity and reduce circulating insulin. Men in each age group received either benfluorex (150 mg) or placebo three times daily for 6 weeks, and fasting serum insulin, glucose, DHEA, DHEA sulfate, and cortisol were determined before and after treatment. Glucose tolerance was also assessed by an oral glucose tolerance test. Benfluorex treatment lowered diastolic and systolic blood pressures and improved glucose tolerance in both age groups. In middle-aged men, benfluorex (n = 12) reduced both the area under the curve for glucose (AUCGLUCOSE; from 977 +/- 27 to 814 +/- 27 mmol/L.min; P = 0.0001) and the AUCINSULIN (from 78.1 +/- 7.9 to 44.5 +/- 5.7 nmol/L.min; P < 0.0001) during the oral glucose tolerance test. In elderly men, benfluorex (n = 15) also reduced both the AUCGLUCOSE (from 1100 +/- 60 to 864 +/- 26 mmol/L.min; P < 0.0001) and the AUCINSULIN (from 88.9 +/- 5.6 to 44.8 +/- 5.8 nmol/L.min; P < 0.0001). Concurrent with the reduction in insulinemia, benfluorex treatment was associated with rises in both serum DHEA sulfate and unconjugated DHEA. In middle-aged men, serum DHEA sulfate and DHEA rose from 6.80 +/- 0.75 to 10.52 +/- 1.02 mumol/L (P < 0.015) and from 13.69 +/- 1.95 to 22.78 +/- 2.90 nmol/L (P < 0.03), respectively. In elderly men, serum DHEA sulfate and DHEA rose from 5.16 +/- 0.67 to 8.36 +/- 1.21 mumol/L (P < 0.015) and from 8.47 +/- 0.99 to 22.61 +/- 3.24 nmol/L (P < 0.0005), respectively. In neither middle-aged nor elderly men did serum cortisol change with benfluorex treatment. Neither glucose tolerance nor serum DHEA, DHEA sulfate, or cortisol levels changed in either middle-aged (n = 17) or elderly (n = 13) men treated with placebo. We conclude that benfluorex treatment lowers blood pressure, improves glucose tolerance, reduces the glucose-stimulated insulin response, and increases serum DHEA and DHEA sulfate in both middle-aged and elderly men.(ABSTRACT TRUNCATED AT 400 WORDS)