Effects of Tibolone and Continuous Combined Conjugated Equine Estrogen/Medroxyprogesterone Acetate on the Endometrium and Vaginal Bleeding: Results of the OPAL Study

Abstract

The primary objective of the Osteoporosis Prevention and Arterial effects of tiboLone study was to compare the effect of tibolone and placebo on the progression of the common carotid artery intima-medial thickness; the common carotid artery intima-medial thickness and bone data will be presented elsewhere. A secondary objective was to assess the effects of tibolone (2.5 mg), continuous combined conjugated equine estrogen/medroxyprogesterone acetate [0.625/2.5 mg], and placebo on the endometrium and vaginal bleeding; these results are the subject of this report. This 3-year, three-arm, international, randomized, double-blind, parallel group, placebo-controlled clinical trial enrolled 866 postmenopausal women (aged 45-79 years). The endometrium was assessed by annual transvaginal ultrasound scans and end-of-study biopsies (United States/United Kingdom centers only). Vaginal bleeding was recorded in daily diaries. Endometrial thickness measured by transvaginal ultrasound scan increased slightly during the first year with tibolone and conjugated equine estrogen/medroxyprogesterone acetate, without any further progression. After 3 years, there were no significant differences between the tibolone, conjugated equine estrogen/medroxyprogesterone acetate, and placebo groups in the incidence of proliferation (1.4%, 4.8%, and 0%, respectively), endometrial hyperplasia (0% in all groups), or cancer (1, 0, and 1 case, respectively). During the first 3 months, bleeding/spotting rates were greater with conjugated equine estrogen/medroxyprogesterone acetate (48%) than with tibolone (18%; P < .001) or placebo (3%; P < .001). During 3 years of treatment, the incidence of bleeding/spotting was 66%, 48%, and 23% for conjugated equine estrogen/medroxyprogesterone acetate, tibolone, and placebo, respectively. The mean number of bleeding/spotting days was greater in the conjugated equine estrogen/medroxyprogesterone acetate than the tibolone or placebo groups (61, 28, and 7 days, respectively; P = .023 vs tibolone; P < .0001 vs placebo). The mean number of bleeding/spotting episodes was also greater in the conjugated equine estrogen/medroxyprogesterone acetate group (13 episodes) compared with the tibolone group (six episodes; P < .001) and placebo group (four episodes; P < .001). Vaginal bleeding was more commonly reported as an adverse event with conjugated equine estrogen/medroxyprogesterone acetate than tibolone (26.4% vs 10.8%, P < .0001) and as the reason for premature discontinuation (9% vs 2%, P = .001). Compared with conjugated equine estrogen/medroxyprogesterone acetate, tibolone has a better tolerability profile with respect to vaginal bleeding but with a similar endometrial safety. These results reinforce the endometrial safety profile of tibolone.