In a randomized, double-blind, placebo-controlled, multicenter, parallel-group study postmenopausal women with at least 60 hot flushes per week applied 0.87 g/d (n=136), 1.7 g/d (n=142), or 2.6 g/d (n=69) estradiol (E2) gel or placebo gel (n=137) topically for 12 weeks. With increasing E2 doses, mean trough serum E2 increased from 17 to 29 pg/mL. By weeks 3-5, E2 gel reduced moderate-to-severe hot flush rate by at least 7 hot flushes per day (P<.001) and reduced the severity score (P<.01). The numbers needed to treat for benefit for an 80% and 100% decrease in hot flush number were 3.2 and 6.3 for the 0.87-g/d group and 1.3 and 2.3 for the 2.6-g/d group. At week 12, vaginal pH was more acidic and vaginal maturation index more mature compared with placebo (P<.001). The lowest dose improved most bothersome vulvovaginal atrophy symptoms (P<.05). Estradiol gel was well tolerated at the site of application and produced no unexpected adverse effects. The 0.87 g/d dose (delivering an estimated 0.0125 mg E2 daily) produced fewest adverse events.
In a randomized, double-blind, placebo-controlled, multi-centre trial , healthy postmenopausal women (mean age 53 years, mean time since menopause 9 years) with moderate or severe hot flushes (at least seven per day for at least 1 week, or at least 50 per week) applied transdermal patches with a nominal delivery of 0.014 mg/d 17β-estradiol (micro-dose; n=147), or placebo (n=133) for 12 weeks. A third group of women used transdermal patches delivering 0.023 mg/d 17β-estradiol and 0.0075 mg/d levonorgestrel (low-dose E2/levonorgestrel; n=145). Mean weekly frequencies of moderate and severe hot flushes were significantly reduced with low-dose E2/levonorgestrel (–51.80; P<0.001) but also with micro-dose E2 (–38.46; P<0.001) as compared to placebo. Severity scores were also significantly reduced with both treatments compared with placebo. At week 12 endpoint, 41% of women receiving micro-dose E2 were treatment responders (75% or more reduction from baseline in hot flush frequency; P=0.003 compared with 24% placebo). There were no differences between active treatments and placebo regarding adverse events.