All authors were employees of Wyeth Research during the conduct of these investigations.
Original Research Article
Carcinogenicity and hormone studies with the tissue-selective estrogen receptor modulator bazadoxifene†
Version of Record online: 20 DEC 2012
Copyright © 2012 Wiley Periodicals, Inc.
Journal of Cellular Physiology
Volume 228, Issue 4, pages 724–733, April 2013
How to Cite
Wright, D. J., Earnhardt, J. N., Perry, R., Bailey, S., Komm, B., Minck, D. R. and Cukierski, M. A. (2013), Carcinogenicity and hormone studies with the tissue-selective estrogen receptor modulator bazadoxifene. J. Cell. Physiol., 228: 724–733. doi: 10.1002/jcp.24219
- Issue online: 20 DEC 2012
- Version of Record online: 20 DEC 2012
- Accepted manuscript online: 4 SEP 2012 08:22AM EST
- Manuscript Accepted: 22 AUG 2012
- Manuscript Received: 10 AUG 2012
Vol. 229, Issue 1, 126, Version of Record online: 23 SEP 2013
Bazedoxifene Acetate (BZA) is a selective estrogen receptor modulator (SERM) that is approved for the prevention and/or treatment of osteoporosis in postmenopausal women. To assess for carcinogenic potential, BZA was administered ad libitum in the diet to rats for 2 years. BZA caused an increase in benign ovarian tumors in female rats and decreased incidences of mammary tumors (females) and pituitary tumors (males and females). In addition, BZA provided a significant survival benefit at all dosages tested, which correlated with a significant reduction in pituitary and mammary gland tumors and decreased body weight gain (both genders). Additional studies were subsequently conducted in rats and monkeys to further explore the mechanisms likely responsible for the observed effects. Results from studies in hypophysectomized and chemically castrated female rats indicated that BZA did not directly stimulate formation of ovarian cysts, but an intact pituitary was required for cyst formation. Further, BZA increased estradiol concentrations in rats and monkeys. In monkeys, BZA increased concentrations of luteinizing hormone (LH) after onset of treatment and prohibited the preovulatory surge of LH until after cessation of treatment. These hormonal changes suggest that BZA inhibited both the positive and negative feedback effects of estrogen on gonadotropins and the resulting increase in LH caused formation and persistence of ovarian cysts, which eventually transformed into benign ovarian granulosa cell tumors in the rat carcinogenicity study. These results also suggest that the reductions in pituitary and mammary gland tumors were attributed to BZA-related antagonism of endogenous estrogens at the estrogen receptors. J. Cell. Physiol. 228: 724–733, 2013. © 2012 Wiley Periodicals, Inc.