title: Effects of tibolone and hormone replacement therapy on the breast of cynomolgus monkeys.
abstract: OBJECTIVE
  To measure the effects of 2 years of treatment with tibolone on the breasts of cynomolgus macaques (Macaca fascicularis) in comparison with conventional hormone replacement therapy.
  
  
  METHODS
  Ovariectomized cynomolgus macaques were randomized into five groups and treated for 2 years. Groups included controls (n = 31) and four drug treatments, including tibolone at 0.05 mg/kg (LoTIB, n = 30) or 0.2 mg/kg (HiTIB, n = 31), conjugated equine estrogens at 0.042 mg/kg (CEE, n = 28), or CEE + medroxyprogesterone acetate (MPA) at 0.167 mg/kg (CEE + MPA, n = 29). Endpoints included histologic, histomorphometric, and immunohistochemical assessment of the mammary gland.
  
  
  RESULTS
  Tibolone did not cause stimulation of the breast in contrast to distinct proliferative responses of the breast to CEE and CEE + MPA, as measured by increases in breast epithelial tissue area and expression of the proliferation marker Ki67 in breast epithelial cells. Tibolone at the higher dose increased progesterone receptor expression in the breast relative to controls, indicating partial estrogen-agonist activity, but without induction of proliferation. Progesterone receptor expression was also induced by CEE.
  
  
  CONCLUSIONS
  Tibolone may have an advantage over conventional hormone replacement therapy because it does not stimulate proliferation in the breast. This lack of mammotrophic effect may reflect a lower risk for promotion of breast cancer.
authors.affiliation: Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. jmcline@wfubmc.edu
authors.forename: J Mark
authors.initials: JM
authors.lastname: Cline
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Register
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Clarkson
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects* / Q000473:pathology; D004359:Drug Therapy, Combination; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced; D008252:Macaca fascicularis; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D009652:Norpregnenes / Q000494:pharmacology*; D010052:Ovariectomy; D045167:Progesterone Congeners / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004966:Estrogens, Conjugated (USP); D009652:Norpregnenes; D045167:Progesterone Congeners; D017258:Medroxyprogesterone Acetate; C027385:tibolone