Effects of low-dose norethindrone acetate plus ethinyl estradiol (0.5 mg/2.5 μg) in women with postmenopausal symptoms:: Updated analysis of three randomized, controlled trials

Background: Based on the potential risks of postmenopausal hormone therapy (HT) found by the Women's Health Initiative, guidelines for HT now recommend use of the lowest effective dose and shortest treatment duration consistent with individual treatment goals. Current (2003) guidance established by the US Food and Drug Administration (FDA) recommends that clinical assessments of HT include women with more frequent and more intense vasomotor symptoms than previously studied. Therefore, this analysis was conducted to further assess the efficacy of a low-dose combination of norethindrone acetate and ethinyl estradiol (NA/EE) previously assessed in dose-ranging studies, while meeting conservative FDA trial design and analysis criteria. Objectives: The aim of this post hoc analysis and overview was to present data on the efficacy and tolerability of a low-dose combination-NA/EE 0.5 mg/ 2.5 mu g-in the treatment of postmenopausal symptoms, based on data from previously published studies of NA/EE. In addition, the effects of low-dose NA/EE on bone and endometrium are briefly reviewed. Methods: Data from 3 previously published randomized, placebo-controlled trials were analyzed using current FDA guidance for the assessment of HT in postmenopausal women. Studies 1 and 2 assessed the efficacy of NA/EE at various doses, including 0.5 mg/2.5 mu g, in vasomotor symptom (hot-flush [HF]) relief over 16 and 12 weeks, respectively, using self-reporting of symptom frequency and intensity (scores: 0 = none; 1 = mild; 2 = moderate; and 3 = severe) in daily diaries. Study 3 assessed the effects of NA/EE at various doses, including 0.5 mg/2.5 mu g, on bone and endometrium, using quantitative computed tomography of the lumbar spine at 12 and 24 months and endometrial biopsy at 6, 12, 18, and 24 months of treatment. In all 3 studies, women were asked to record vaginal bleeding and spotting in diaries. Any adverse events were recorded in diaries and/or at clinic visits. Physical and gynecologic examinations and standard clinical laboratory testing were conducted at baseline and at appropriate follow-up visits in all 3 studies. Results: Studies 1, 2, and 3 enrolled 219, 266, and 1265 women, respectively. Overall, in studies 1 and 2, 91 % of women were white, the mean age was similar to 52 years, and mean time since last menstrual period was similar to 24 months. In study 1, NA/EE 0.5 mg/2.5 mu g was associated with significant reductions from baseline in mean weekly total HF frequency from week 4 (63.6%) through week 16 (73.7%) (all, P < 0.05). In study 2, the frequency of moderate or severe HFs was decreased by 61.1% at week 4 (P < 0.05) and by 82.2% at week 12 (P < 0.001) with NA/EE 0.5 mg/ 2.5 ug, and the mean intensity score was significantly lower than that with placebo at weeks 8 and 12 (both, P = 0.001). In study 3, cumulative amenorrhea rates were similar to 90% in the NA/EE 0.5-mg/2.5-mu g and placebo groups at 12 months. Lumbar spine bone mineral density (BMD) was maintained at 24 months with NA/EE 0.5 mg/2.5 mu g but was significantly decreased from baseline, by 7.4%, in the placebo group (P < 0.001). Endometrial hyperplasia was not observed in the group receiving NA/EE 0.5 mg/2.5 mu g over 24 months. The tolerability of NA/EE was similar to that of placebo. The most common adverse events experienced with NA/EE were headache (15.2%), abdominal pain (10.2%), and breast pain (9.0%). Conclusions: The results from this post hoc analysis and overview of 3 previously published studies suggest that NA/EE 0.5 mg/2.5 mu g was associated with decreased frequency and intensity of vasomotor symptoms. This dose of NA/EE was also associated with maintenance of BMD over 24 months, a significant positive effect on BMD compared with placebo. Low-dose NA/EE was also associated with cumulative amenorrhea rates comparable to those of placebo and was not associated with endometrial hyperplasia. This dose was well tolerated, with rates of adverse events generally similar to those of placebo.