Vaginal bleeding in postmenopausal women taking low-dose norethindrone acetate and ethinyl estradiol combinations

Objective: To determine the effect of continuous combined treatment with no rethindrone acetate and ethinyl estradiol (E2) on vaginal bleeding, spottin g, or bleeding and/or spotting in postmenopausal women. Methods: Two randomized clinical trials were conducted in which participant s recorded information on the daily occurrence of vaginal bleeding or spott ing. In study 1, 219 postmenopausal women reporting at least ten hot hushes per week were randomized to placebo or one of four treatment groups (0.2 m g norethindrone acetate/1 mu g ethinyl E2, 0.5 mg norethindrone acetate/2.5 mu g ethinyl E2, 1 mg norethindrone acetate/5 mu g ethinyl E2, or 1 mg nor ethindrone acetate/10 mu g ethinyl E2). In study 2, 266 postmenopausal wome n reporting at least 56 moderate to severe hot flushes were randomized to p lacebo or one of three treatment groups (0.5 mg norethindrone acetate/2.5 m u g ethinyl E2, 1 mg norethindrone acetate/5 mu g ethinyl E2, or 1 mg noret hindrone acetate/10 mu g ethinyl E2). The total duration of treatment was 1 6 weeks in study 1 and 12 weeks in study 2. In both studies, subjects repor ted in daily diaries whether they had either bleeding or spotting. Results: In study 1, there was a significantly greater relative risk (RR) f or bleeding in the group receiving 1 mg norethindrone acetate/10 mu g ethin yl E2 at study weeks 4 and 8 (RR = 1.36 and 95% confidence interval [CI] 1. 01, 1.83; RR = 1.37 and 95% CI 1.1, 1.72; respectively) compared with place bo, but not at study weeks 12 or 16. The group receiving 1 mg norethindrone acetate/5 mu g ethinyl E2 also had a significantly greater risk at weeks 4 and 8 (RR = 1.5 and 95% CI 1.15, 1.96; RR = 1.33 and 95% CI 1.00, 1.77; re spectively), whereas the other dose combinations did not differ from placeb o. Results from study 2 were similar to those of study 1. Conclusion: Although there was a greater risk for bleeding and/or spotting at the higher doses of norethindrone acetate and ethinyl E2, this risk decl ined over time. If compliance with hormone replacement therapy regimens is influenced at least in part by vaginal bleeding, the combined norethindrone acetate/ethinyl E2 regimen investigated in these studies may provide a tre atment option. (Obstet Gynecol 2000; 96:366-72. (C) 2000 by The American Co llege of Obstetricians and Gynecologists).