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Endometrial Effects of Tibolone

Department of Obstetrics and Gynecology (D.F.A.), Contraceptive Research and Development (CONRAD) Clinical Research Center, Eastern Virginia Medical School, Norfolk, Virginia 23507; Wayne State University/Hutzel Women’s Hospital (S.H.), Detroit, Michigan 48201; Bone Metabolism Section (J.C.G.), Creighton University Medical Center, Omaha, Nebraska 68131; Division of Obstetrics and Gynaecology (J.R.), King’s College School of Medicine at Guy’s and St. Thomas’ Hospitals, London SE5 9RT, United Kingdom; Department of Obstetrics and Gynecology (S.S.), Frederiksberg University Hospital, 2000 Copenhagen, Denmark; McGill and Sir Mortimer B. Davis Jewish General Hospital (A.F.), Montréal, Québec, Canada H3T IE2; NV Organon (W.d.H.), 5340 BH Oss, The Netherlands; and Organon International (V.S., F.A.H.), Roseland, New Jersey 07068

Address all correspondence and requests for reprints to: David F. Archer, M.D., Director, CONRAD Clinical Research Center, 601 Colley Avenue, Norfolk, Virginia 23507. E-mail: archerdf{at}evms.edu.

Background and Objectives: The Tibolone Histology of the Endometrium and Breast Endpoints Study is a multicenter, randomized, double-blind study designed to address the conflicting reports in the literature about the endometrial safety of tibolone (1.25 or 2.5 mg/d). Tibolone was compared with continuous combined conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) (0.625 + 2.5 mg/d).

Methods: Subjects were randomized in a 1:1:2 ratio to tibolone 1.25 mg/d, 2.5 mg/d, and CEE/MPA, respectively. The one-sided 95% confidence interval (CI) has been evaluated for the incidence of abnormal endometrial histology (hyperplasia or carcinoma) and hyperplasia and carcinoma separately for each of the two treatment groups and the treatment groups combined after 1 and 2 yr of treatment with tibolone, compared with CEE/MPA.

Results: A total of 3240 women were randomized, with 3224 receiving at least one dose of study medication. The incidence and upper one-sided 95% CI for the incidence of abnormal endometrium (hyperplasia or carcinoma), and hyperplasia and carcinoma separately, were calculated at end point, yr 1, and yr 2. The incidence (upper one-sided 95% CI) of abnormal endometrium at end point was 0.0 (0.5), 0.0 (0.4), and 0.2 (0.5) in the tibolone 1.25 mg, 2.5 mg, and CEE/MPA groups, respectively. During the entire treatment period, amenorrhea was reported more frequently with tibolone 1.25 mg (78.7%) and 2.5 mg (71.4%) than CEE/MPA (44.9%).

Conclusion: The Tibolone Histology of the Endometrium and Breast Endpoints Study results confirm previous findings that tibolone does not induce endometrial hyperplasia or carcinoma in postmenopausal women, and it is associated with a better vaginal bleeding profile than CEE/MPA.

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