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Interactive Effects of Bazedoxifene acetate and Conjugated Equine Estrogens on the Breast and Reproductive Tract of Postmenopausal Monkeys

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abstract
Concerns of breast cancer risk with conjugated equine estrogens (CEE) and medroxyprogestrone acetate have generated interest in alternatives for the progestin component in postmenopausal estrogen co-therapy. Bazedoxifene acetate (BZA) is a third-generation selective estrogen receptor modulator (SERM) currently under investigation as a possible choice for this role. The primary objective of this project was to determine if BZA given at the clinical target dose of 20 mg/day would inhibit the proliferative effects of CEE (0.45 mg/day) on the breast and endometrium without attenuating the maturation effects of CEE on the vaginal mucosa. As part of a nonhuman primate translational trial evaluating the global benefit to risk profile of BZA+CEE and BZA alone, we found that the addition of BZA to CEE significantly antagonized the stimulatory actions of CEE on breast and endometrial Ki67 immunolabeling, epithelial area, and specific markers of ER alpha activation, while BZA alone had no effect. Global gene expression profiles in the breast showed that BZA+CEE more closely resembled BZA than CEE alone. BZA+CEE and BZA did not significantly upregulate pathways or genes related to cell cycle progression or proliferation in the breast. The addition of BZA to CEE also inhibited CEE-induced changes in breast and endometrial morphology. For instance, BZA+CEE treatment resulted in less lobular enlargement in the breast and reduced the prevalence of simple endometrial hyperplasia, stromal fibrosis, and cystic dilation compared to CEE. BZA alone had no effect on these measures, indicating that BZA lacks an estrogen agonist profile in the breast and endometrium. In the vagina, BZA completely inhibited CEE effects on vaginal proliferation, maturation, and keratinization, while having no estrogenic activity when given alone. A comparable pattern was seen in the endocervical glands, but BZA only partially antagonized CEE effects on epithelial cell height. Interestingly, BZA with and without CEE resulted in lower ER alpha immunolabeling in the breast, endometrium, vagina, and endocervical glands compared to control and CEE. Collectively, these findings demonstrate that the target dose of BZA given alone and with CEE (0.45 mg/day) lacks an estrogenic profile in the breast, endometrium, and vaginal epithelium of the postmenopausal macaque model.
subject
Bazedoxifene acetate
Estrogen
Estrogen receptor alpha
Hormone therapy
Menopause
Selective estrogen receptor modulators
contributor
Ethun, Kelly (author)
Appt, Susan E. (committee chair)
Kaplan, Jay R. (committee member)
Cline, J. Mark (committee member)
Register, Thomas C. (committee member)
Chen, Haiying (committee member)
date
2012-06-12T08:36:04Z (accessioned)
2012-12-12T09:30:07Z (available)
2012 (issued)
degree
Molecular Pathology (discipline)
embargo
2012-12-12 (terms)
identifier
http://hdl.handle.net/10339/37303 (uri)
language
en (iso)
publisher
Wake Forest University
title
Interactive Effects of Bazedoxifene acetate and Conjugated Equine Estrogens on the Breast and Reproductive Tract of Postmenopausal Monkeys
type
Dissertation

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