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

Patrick Neven, Tore Lunde, Pierluigi Benedetti-Panici, Aila Tiitinen, Bogdan Marinescu, Tobie De Villiers, Tim Hillard, Antonio Cano, Eitan Peer, Deborah Quail, Thomas Nickelsen, Mireille Smets, Rudy Gevers, Guido Vanderick, Frederic Van Den Brul, Herman Depypere, Sven Skouby, Anette Peen, Lars Andersen, Torben PhilipsenBirger Moller, Erik Poulsen, Lars Olof Abrahamsson, Anne Jessen, Bent Ottesen, Jens Lyndrup, Tuula Salmi, Risto Tuimala, Ulla Puistola, Jukka Puolakka, Tarja Jarvi, Pentti Kilkku, Marjo Tuppurainen, Marc Levrier, Monique Commenges, Veronique Kerlo, Lucien Chaby, Michèle Scheffler, Veronique Pascal, Patrick Madelenat, Charles Nahmanovici, Francoise Mousteou, Dominique Crestinu, Dominique Wiel-Masson, Alain Audebert, Gerard Mage, Aliette Siboni-Frisch, Marie Hélène Cayrol, Isabelle Zordan-Ducasse, Martine Gelas, Pascale Mirakian, Bruno Mazenod, Colette Ferrand-Desneiges, Martine Pollack, Nicole Douay, Katty Ardaens, Francis Sailly, Martine Perdrix, George Creatsas, Maire Milner, John Bonnar, Zion Ben-Rafael, Yair Frenkel, Nahman Eckstein, Carlo Campagnoli, Carmine Nappi, Annibale Volpe, Alberto Bacchi, Domenico De Aloysio, Vincenzo Giambanco, Costante Donati Sarti, Sergio Schonauer, Secondo Guaschino, J. Schram, W. Stroobants, H. The, A. Broekman, T. M. Hameeteman, Beth Morrel, Tjeerd D. Ypma, Leen Pijpers, Lodewijk J.Bosch Van Drakenstein, B. Eriksen, Hans Ejner Ipsen, Terje Soerdal, Gunnar Nordland, Randi Simes Dugal, Oeyvin Skarra, Tor Loevset, Unn Baerug, Romuald Debski, Alina Warenik-Szymankiewicz, Violetta Skrzypulec-Ciszek, Tomasz Rechberger, Tomasz Pertynski, Jerzy Mielnik, Stanislaw Rozewicki, Fernanda Aguas, Ana Fatela

Research output: Contribution to journalArticlepeer-review

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 (E2) 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 < 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 < 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 < 0.001], and the difference in the effect of both compounds on change in uterine volume at endpoint reached statistical significance (P < 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 < 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.

Original languageEnglish
Pages (from-to)157-167
Number of pages11
JournalBJOG: An International Journal of Obstetrics and Gynaecology
Volume110
Issue number2
DOIs
StatePublished - 1 Feb 2003
Externally publishedYes

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