A multicentre randomised trial to compare uterine safety of raloxifene with a continuous combined hormone replacement therapy containing oestradiol and norethisterone acetate

Neven, Patrick;Lunde, Tore;Benedetti-Panici, Pierluigi;Tiitinen, Aila;Fatela, Ana;et.al.
(2003) BJOG : an international journal of obstetrics and gynaecology — Vol. 110, n° 2, p. 157-167 (2003)

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  • Neven, Patrick
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  • Lunde, Tore
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  • Benedetti-Panici, Pierluigi
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  • Tiitinen, Aila
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  • Fatela, Ana
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Abstract
Objective: To compare the uterine effects of 60 mg of raloxifene with a continuous combined hormone replacement therapy, a preparation of 2 mg 17β-oestradiol (E<inf>2</inf>) and 1 mg norethisterone acetate for a duration of 12 months. Design: A randomised, double-blind trial. Setting: Multicentre: Europe, Israel, South Africa. Population: Asymptomatic postmenopausal women with risk factors for osteoporosis or cardiovascular disease who had an endometrial thickness of less than 5 mm. One thousand and eight women were randomised for the six month core; of these 420 were invited to continue into a six month extension period. Methods: Randomisation to either raloxifene or continuous combined hormone replacement therapy. Patients, recruiters and assessors were blinded to the treatment used. Main outcome measures: The frequency of vaginal spotting/bleeding as recorded in a diary, endometrial thickness and uterine volume as measured by transvaginal ultrasonography at baseline and after 6 and 12 months. Results: After six months of therapy with raloxifene, the rate of women on raloxifene reporting vaginal bleeding and spotting (6.8%) was similar to the rate in the lead-in phase (8.3%) but increased from 7.0% to 55.1% in the continuous combined hormone replacement therapy group. Raloxifene treatment was not associated with a significant change from baseline to endpoint in mean endometrial thickness (P = 0.11), whereas continuous combined hormone replacement therapy treatment was associated with an increase in this value of mean (SD) of 1.2 (2.2) mm (P &lt; 0.001). Compared with raloxifene, mean endometrial thickness for women on continuous combined hormone replacement therapy was significantly increased at endpoint [4.6 (2.1) mm vs 3.5 (1.7) mm; change from baseline P &lt; 0.001]. In the raloxifene group, there was a trend towards a decrease from baseline in uterine volume [from 31.4 (20.3) to 30.3 (16.2) mm; P = 0.37]; in the continuous combined hormone replacement therapy group, there was a significant increase in uterine volume [from 31.3 (16.3) to 54.0 (36.1) mm; P &lt; 0.001], and the difference in the effect of both compounds on change in uterine volume at endpoint reached statistical significance (P &lt; 0.001). Statistically significant differences between the treatment groups were sustained for all parameters during the extension period. Early discontinuation rates, both overall and due to adverse events, were significantly lower (P &lt; 0.001) in the raloxifene group after 6 and 12 months. Conclusion: Compared with continuous combined hormone replacement therapy, 6 and 12 months of raloxifene treatment do not lead to vaginal bleeding/spotting, are not associated with increased endometrial thickness or uterine volume and result in a significantly lower rate of early treatment discontinuations in asymptomatic women receiving treatment to prevent long term postmenopausal health risks.

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Neven, P., Lunde, T., Benedetti-Panici, P., Tiitinen, A., Marinescu, B., De Villiers, T., Hillard, T., Cano, A., Peer, E., Quail, D., Nickelsen, T., Smets, M., Gevers, R., Vanderick, G., Van Den Brul, F., Depypere, H., Skouby, S., Peen, A., Andersen, L., et al. (2003). A multicentre randomised trial to compare uterine safety of raloxifene with a continuous combined hormone replacement therapy containing oestradiol and norethisterone acetate. BJOG : an international journal of obstetrics and gynaecology, 110(2), 157-167. https://doi.org/10.1046/j.1471-0528.2003.02252.x (Original work published 2003)