Efficacy and safety of a constant-estrogen, pulsed-progestin regimen in hormone replacement therapy.

Objective-Two studies (Studies A and B) were conducted to measure efficacy and safety of constant 17β-estradiol (E 2 ), pulsed norgestimate (NGM) hormone replacement therapy on bleeding and vasomotor symptoms in postmenopausal women. NGM was pulsed in a 3-days-off/3-days-on fashion. Study A also assessed effects of treatment on vaginal cytology. Study Design-In two 360-day, multicenter, double-blind, parallel-group studies, 1,253 subjects were randomized to receive daily, unopposed E 2 1 mg or one of three constant estrogen, pulsed progestin regimens: E 2 1 mg/NGM 30 μg, E 2 1 mg/NGM 90 μg, or E 2 1 mg/NGM 180 μg. Results-Bleeding control improved over time in women treated with E 2 1 mg/NGM 90 μg: 69% of women were free of bleeding (irrespective of spotting) during month 1, 71% during month 6, and 80% during month 12. E 2 1 mg/NGM 30 μg had a lower incidence of bleeding but provided inadequate endometrial protection. Among subjects with vasomotor symptoms at baseline, the percentage of asymptomatic subjects at the end of 3 months was 70% in the E 2 1-mg group and 76% in the E 2 1-mg/NGM 90-μg group. E 2 1 mg/NGM 90 μg was at least as effective as E 2 1 mg alone in causing maturation of vaginal epithelial cells. All regimens were well tolerated. Conclusion-Pulsed dosing of NGM 90 μg for 3 days off and 3 days on along with continuous administration of E 2 is effective in treating vasomotor symptoms and vulvovaginal atrophy, provides endometrial protection (i.e., no cases of endometrial hyperplasia or cancer), and has a bleeding profile acceptable to the majority of women studied.