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Endometrial profile of bazedoxifene acetate alone and in combination with conjugated equine estrogens in a primate model

Ethun, Kelly F. DVM, PhD; Wood, Charles E. DVM, PhD; Cline, J. Mark DVM, PhD; Register, Thomas C. PhD; Appt, Susan E. DVM; Clarkson, Thomas B. DVM

doi: 10.1097/GME.0b013e31827ce57a
Original Articles

Objective: Concerns of breast cancer risk in postmenopausal women taking combined estrogen + progestin therapy have generated interest in the use of selective estrogen receptor modulators (SERMs) as potential progestin alternatives. Endometrial proliferation and cancer risk are major concerns, however, for estrogens and certain types of SERMs when given alone. The primary aim of this study was to evaluate the endometrial profile of bazedoxifene acetate (BZA), a third-generation SERM, alone and in combination with conjugated equine estrogens (CEE) in a postmenopausal primate model.

Methods: Ninety-eight ovariectomized cynomolgus monkeys (Macaca fascicularis) were randomized to receive no hormone treatment (controls), BZA 20 mg, CEE 0.45 mg, or the combination of BZA 20 mg + CEE 0.45 mg once daily for 20 months in a parallel-arm study design. The primary outcome measure was endometrial epithelial proliferation.

Results: BZA + CEE and BZA treatment resulted in significantly less endometrial epithelial area and Ki67 expression compared with CEE (P < 0.001 for all). The prevalence of endometrial hyperplasia and other estrogen-induced morphologic changes in the BZA + CEE and BZA groups was not significantly different from controls. The addition of BZA to CEE completely inhibited the expression of estrogen receptor-α–regulated genes (TFF1 and PGR), whereas BZA alone had no effect. BZA + CEE and BZA treatment also resulted in lower estrogen receptor-α protein expression in the endometrium compared with the control and CEE groups (P < 0.05 for all).

Conclusions: BZA given at a clinically relevant dose inhibits estrogen effects on the endometrium and lacks uterotropic effects when given alone.

From the Wake Forest University Primate Center and the Department of Pathology/Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC.

Received September 3, 2012; revised and accepted November 6, 2012.

Funding/support: This work was supported by grants from Pfizer Inc. (an investigator-initiated grant to Wake Forest School of Medicine; principal investigator, T.B.C.) and the National Center of Research Resources (grant 5T32 RR07009-32 to K.F.E. and grant K01 RR 021322-05 to C.E.W.).

Financial disclosure/conflicts of interest: Wake Forest School of Medicine has received an investigator (T.B.C.)–initiated grant (bazedoxifene acetate) from Pfizer. T.B.C., C.E.W., and S.E.A. were paid coinvestigators, and K.F.E. was a paid research fellow on this grant. J.M.C. and T.C.R. were unpaid coinvestigators. T.B.C. and J.M.C. have served as paid consultants to Pfizer, and J.M.C. is the principal investigator on a pending investigator-initiated proposal to Pfizer related to bazedoxifene acetate.

The contents are solely the responsibility of the authors and do not necessarily represent the views of the National Institutes of Health, National Center of Research Resources, or Pfizer.

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Address correspondence to: Kelly F. Ethun, DVM, PhD, Wake Forest University Primate Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040. E-mail: Kelly.Ethun@gmail.com

© 2013 by The North American Menopause Society.