title: Endometrial profile of bazedoxifene acetate alone and in combination with conjugated equine estrogens in a primate model.
abstract: 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.
authors.affiliation: Wake Forest University Primate Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Kelly.Ethun@gmail.com
authors.forename: Kelly F
authors.initials: KF
authors.lastname: Ethun
authors.forename: Charles E
authors.initials: CE
authors.lastname: Wood
authors.forename: J Mark
authors.initials: JM
authors.lastname: Cline
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Register
authors.forename: Susan E
authors.initials: SE
authors.lastname: Appt
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Clarkson
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004714:Endometrial Hyperplasia / Q000139:chemically induced; D004717:Endometrium / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D008252:Macaca fascicularis; D023421:Models, Animal; D010052:Ovariectomy; D011897:Random Allocation; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage*
chemical_list: D047628:Estrogen Receptor alpha; D004966:Estrogens, Conjugated (USP); D007211:Indoles; D020845:Selective Estrogen Receptor Modulators; C447119:bazedoxifene