title: Effect of toremifene and ospemifene, compared to acolbifene, on estrogen-sensitive parameters in rat and human uterine tissues.
abstract: BACKGROUND
  Although the first generation selective estrogen receptor modulator (SERM) tamoxifen (TAM) is well known for its uterotrophic activity, this study compares the stimulatory effect of the TAM derivatives toremifene (TORE) and ospemifene (OSPE) on estrogen-sensitive parameters in rat and human uterine tissues.
  
  
  METHODS
  Ovariectomized female rats were treated daily orally for 10 days with 0.75 mg/rat of TORE, OSPE or acolbifene (ACOL, a pure estrogen antagonist in the uterus and mammary gland), which was used for comparison. Human endometrial carcinoma Ishikawa cells were incubated for 5 days with increasing doses of compounds, in the absence or presence of 1 nM estradiol (E2).
  
  
  RESULTS
  TORE and OSPE revealed 52% and 56% increases, respectively, in uterine weight, whereas ACOL had no effect. Similar effects were observed on vaginal weight. Endometrial epithelial height increased from 15.82±0.20 to 48.94± 2.12 and 42.14±1.95 μm with TORE and OSPE, respectively, whereas ACOL had no effect. Alkaline phosphatase activity, an estrogen-sensitive parameter in Ishikawa cells, was increased by 144% and 135% with OH-TORE and OH-OSPE, respectively. Owing to their intrinsic estrogenic activity, at maximal concentrations, OH-TORE and OH-OSPE blocked the stimulatory effect of E2 by only 89% compared to 100% with ACOL.
  
  
  CONCLUSIONS
  The present in vitro and in vivo data show similar stimulatory effects of 4-hydroxytoremifene (OH-TORE) and OH-OSPE on estrogen-sensitive parameters. ACOL, a third generation SERM, has no effect on any of these parameters. Such data add to the potential uterine safety limitations of triphenylethylene-derived SERMs for long-term use in humans.
authors.forename: Fernand
authors.initials: F
authors.lastname: Labrie
authors.forename: Céline
authors.initials: C
authors.lastname: Martel
authors.forename: Sylvain
authors.initials: S
authors.lastname: Gauthier
authors.forename: Georges
authors.initials: G
authors.lastname: Pelletier
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Sancéau