Steroid hormone production within the gonads and adrenals requires a continuous supply of cholesterol derived from de novo synthesis within the gland and from uptake of circulating plasma lipoproteins. Steroid hormone secretion was prospectively studied over 24 months in 64 hypercholesterolemic subjects (group I, aged 52 +/- 1 years [mean +/- SEM], 61% male) participating in a randomized double-blind clinical trial of pravastatin (20 to 80 mg daily), a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, compared with patients taking cholestyramine or other lipid-lowering drugs (group II). Attempts were made in both groups to maintain serum low-density lipoprotein cholesterol (LDL-C) levels between the 25th and 50th percentile for age and gender. At 24 months, serum LDL-C level decreased by 42% +/- 3% in group I and 44% +/- 1% in group II (P < .001 v baseline, NS between groups). Basal secretion of cortisol, aldosterone, and dehydroepiandrostenedione sulfate (DHEA-S) was maintained throughout the study. However, the serum DHEA-S secretory response to Cortrosyn (Organon, West Orange, NJ) diminished in both treatment groups at 6 and 12 months (P < .05). In men, basal serum testosterone levels and the testosterone response to human chorionic gonadotropin (HCG) did not change. There was some diminution of sperm motility noted in both treatment groups at 6 and 12 months in the subset of men undergoing semen analysis (n = 14, P < .05). In conclusion, pravastatin had no significant effect on steroid metabolism. Changes noted in DHEA-S were not specific for pravastatin, suggesting that this impairment is related to lipid-lowering effects.