Chronic cimetidine use in men is associated with hyperestrogenic side effects such as gynecomastia, which may be linked to inhibition of estradiol 2-hydroxylation. As this property of the drug might be helpful in hypoestrogenic states such as osteoporosis, we investigated the effect of cimetidine on estradiol metabolism in premenopausal and postmenopausal women. Using an in vivo radiometric assay, we found that the extent of estradiol 2-hydroxylation in premenopausal women (n = 9) was decreased by a 1-month course of cimetidine, 800 mg twice daily (44.0% +/- 3.5% v 31.2% +/- 4.1%, P less than .001). Among premenopausal smokers (n = 3), the response to cimetidine was approximately the same as nonsmokers. Serum estradiol levels (follicular phase) in these women were unaltered by cimetidine after 1 month, while concentrations of sex hormone-binding globulin (SHBG) were decreased by 30% (P = .018). Postmenopausal women (n = 5) initially received a lower dose of cimetidine (600 mg twice daily) for 2 weeks, followed by a higher dose (1200 mg twice daily) for another 2 weeks. The extent of estradiol 2-hydroxylation was significantly reduced by the low dose (44.4% +/- 4.5% v 24.3% +/- 3.0%, P less than .005), with minimal further reduction after the high dose (21.7% +/- 1.6%). After 4 weeks of cimetidine treatment, serum estradiol levels increased significantly from 30.0 +/- 6.4 to 59.8 +/- 13.1 pg/mL (P = .033), while SHBG was unaffected. Cimetidine was found to have little effect on selected biochemical indices of bone and calcium metabolism in both groups of women.(ABSTRACT TRUNCATED AT 250 WORDS)