Objective: The aim of this study was to report the gynecologic safety findings from the Generations trial, a phase 3 study of the selective estrogen receptor modulator (SERM), arzoxifene.
Methods: A predefined objective of the trial was to evaluate the effects of arzoxifene on the genital tract. Gynecologic examinations were performed yearly, and further gynecologic assessment, including endometrial biopsy, was performed in a predefined subset of women and in those who developed vaginal bleeding.
Results: Overall, 9,354 women were randomized (4,678 to placebo, 4,676 to arzoxifene 20 mg/d). There were 13 adjudicated cases of endometrial cancer (placebo, 4 cases; arzoxifene, 9 cases: P = 0.165) and 6 cases of endometrial hyperplasia (placebo, 2 cases; arzoxifene, 4 cases). Endometrial thickness, assessed at 24- and 36-month transvaginal ultrasounds in a subset of women, increased slightly in women assigned to arzoxifene compared with baseline and women in placebo. At the last measurement, 3 (1.7%) women assigned to placebo and 21 (10.2%) assigned to arzoxifene had an endometrial thickness greater than 5 mm (P < 0.001 for difference between treatment groups). Endometrial polyps were more common in women treated with arzoxifene (n = 37) than in women treated with placebo (n = 18; P < 0.05). Vulvular and vaginal inflammation, including mycotic infections, and vaginal discharge were reported more frequently in women treated with arzoxifene than in women treated with placebo, as were urinary tract infections.
Conclusions: Gynecologic events were generally more common in women treated with arzoxifene than in women treated with placebo. The gynecologic effects of arzoxifene seem to differ from those of raloxifene, although both SERMs have a benzothiophene structure. Although all SERMs influence cells through the estrogen receptor, they need to be evaluated independently in terms of their effects on various tissues, including the genital tract.
Arzoxifene is a newer-generation SERM developed for the prevention and treatment of osteoporosis as well as for the prevention of breast cancer. This article summarizes the gynecological effects of Arzoxifene on postmenopausal women.
From the 1New York University School of Medicine, New York, NY; 2Department of Clinical Biochemistry and Molecular Pathology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; 3Multidisciplinary Breast Center, University Hospitals Leuven, Leuven, Belgium; and 4Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN.
Received February 25, 2011; revised and accepted May 10, 2011.
Funding/support: This study was funded by Eli Lilly and Company.
Financial disclosure/conflicts of interest: Dr. Goldstein serves on the Gynecological Advisory Board for Bayer, Eli Lilly and Company, Pfizer, Novo Nordisk; is a consultant for Cook ObGyn, and Philips Ultrasound; is on the Speakers Bureau for Eli Lilly and Company, Pfizer, Amgen; and is a Director of Sonosite, Inc. Dr. Bhattoa served as a clinical investigator for this trial and received financial support from Eli Lilly and Company for conducting clinical trials. Dr. Neven served as a member of the Data Safety Monitoring Board for the Generations trial for Eli Lilly and Company. Drs. Cox, Dowsett, Sipos, and Muram and Mr. Alam are full-time employees and stockholders of Eli Lilly and Company.
Clinicaltrial.gov number NCT00088010
Address correspondence to: Steven R. Goldstein, MD, New York University School of Medicine, 530 First Avenue, Suite 10N, New York, NY 10016. E-mail: email@example.com