ObjectivesThe primary objective was to compare the vaginal bleeding pattern during administration of tibolone and low-dose continuous combined estradiol plus norethisterone acetate (E 2 / NETA). The secondary objectives were efficacy on vasomotor symptoms and vaginal atrophy.Design A randomised, double-blind, double-dummy, group comparative intervention trial.Setting Multicentre study executed in 32 centres in 7 European countries.Sample Five hundred and seventy-two healthy symptomatic postmenopausal women, aged 45-65 years.Methods Participants were randomised to receive 2.5 mg tibolone or 1 mg 17b estradiol plus 0.5 mg norethisterone acetate (E 2 / NETA) daily for 48 weeks.Main outcome measures Prevalence of vaginal bleeding, hot flushes and adverse events.Results The incidence of bleeding was significantly lower in the tibolone group during the first 3 months of treatment (18.3 versus 33.1%; P < 0.001) when compared with the E 2 /NETA group. This effect on the bleeding pattern was sustained throughout the study, although reaching statistical significance again only in 7-9 months of treatment (11 versus 19%; P < 0.05). In both treatment groups, vasomotor symptoms and vaginal atrophy were significantly reduced to a similar extent when compared with baseline. The prevalence of breast pain/tenderness was significantly lower with tibolone compared with E 2 /NETA (3.2 versus 9.8%; P < 0.001).Conclusion Tibolone reduces menopausal symptoms to a similar extent as conventional low-dose continuous combined hormone therapy but causes significant less vaginal bleeding in the first 3 months of treatment. This constitutes an important argument for woman adherence to therapy.

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As no case of hyperplasia was diagnosed among the 301 interpretable biopsies at 1 year and there was only one case of simple hyperplasia in the 197 post-baseline biopsies at 3 years, the endometrial safety of this extract has been demonstrated. Furthermore, as demonstrated by the lack of change in endometrial thickness associated with the histologic results, we suggest that this extract does not exert a mitogenic effect on the endometrium. These results suggest that daily administration of 70 mg of a specific, standardized isoflavone extract for 3 years could be a safe treatment for both endometrium and breast.

These results of endometrial biopsy and endometrial thickness suggest that daily administration of 70 mg of a specific and standardized isoflavone extract for 12 months does not stimulate the endometrium.