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Carcinogenicity and hormone studies with the tissue-selective estrogen receptor modulator bazadoxifene
- Source :
- Journal of Cellular Physiology. 228:724-733
- Publication Year :
- 2012
- Publisher :
- Wiley, 2012.
-
Abstract
- 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.
- Subjects :
- Male
Selective Estrogen Receptor Modulators
medicine.medical_specialty
Indoles
Carcinogenicity Tests
Physiology
medicine.drug_class
Clinical Biochemistry
Mammary gland
Estrogen receptor
Food Contamination
Biology
Rats, Sprague-Dawley
Internal medicine
medicine
Animals
Pituitary Neoplasms
Receptor
Ovarian Neoplasms
Estradiol
Cysts
Body Weight
Pituitary tumors
Estrogens
Haplorhini
Cell Biology
Luteinizing Hormone
medicine.disease
Rats
Endocrinology
medicine.anatomical_structure
Receptors, Estrogen
Selective estrogen receptor modulator
Estrogen
Pituitary Gland
Carcinogens
Female
Luteinizing hormone
Hormone
Subjects
Details
- ISSN :
- 00219541
- Volume :
- 228
- Database :
- OpenAIRE
- Journal :
- Journal of Cellular Physiology
- Accession number :
- edsair.doi.dedup.....1931ebeec185c1f9291cf07ff908a4b1