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

Two studies (Studies A and B) were conducted to measure efficacy and safety of constant 17beta-estradiol (E2), 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.

In two 360-day, multicenter, double-blind, parallel-group studies, 1,253 subjects were randomized to receive daily, unopposed E2 1 mg or one of three constant estrogen, pulsed progestin regimens: E2 1 mg/NGM 30 microg, E2 1 mg/NGM 90 microg, or E2 1 mg/NGM 180 microg.

Bleeding control improved over time in women treated with E2 1 mg/NGM 90 microg: 69% of women were free of bleeding (irrespective of spotting) during month 1, 71% during month 6, and 80% during month 12. E2 1 mg/NGM 30 microg 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 E2 1-mg group and 76% in the E2 1-mg/NGM 90-microg group. E2 1 mg/NGM 90 microg was at least as effective as E2 1 mg alone in causing maturation of vaginal epithelial cells. All regimens were well tolerated.

Pulsed dosing of NGM 90 microg for 3 days off and 3 days on along with continuous administration of E2 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.