Uterotrophic effects of tamoxifen, toremifene, and raloxifene do not predict endometrial cell proliferation in the ovariectomized CD1 mouse.
The uterotrophic responses of ovariectomized CD1 mice to tamoxifen, toremifene, and raloxifene have been compared to 17beta-estradiol after a treatment period of 72 h. Uterine and vaginal weight, luminal epithelial thickening, and 5-bromodeoxyuridine (BrdU) labeling index in the endometrial stroma were examined. All three pharmaceuticals, as well as 17beta-estradiol, produced increases in the classic estrogen-dependent variables of uterine and vaginal weights after the 3-day treatment period. Tamoxifen, toremifene, raloxifene, and estradiol all increased luminal epithelial thickness, and increased the BrdU labeling index in the endometrial stroma of the uterus. Although the dose response for the uterotrophic effect and the vaginal weight increases for toremifene differed from tamoxifen and raloxifene, in that there was no dose at which these effects were maximal, the stimulation of BrdU labeling index in the endometrial stroma was dose dependent and very similar for all three, at the clinically relevant doses. Treatment-related hypertrophic effects were estimated by examination of the nuclear profile density in the endometrial stroma. Estradiol and tamoxifen caused a greater hypertrophic effect than toremifene and raloxifene, indicating that factors other than an increase in cell number contribute to the overall uterotrophic effect. This demonstrates that the use of uterine weight to estimate the relative estrogenicity of drugs could give a misleading impression of the response of the uterus to estrogen agonists. Variables, such as increased DNA replication, which may be more important to a subsequent potential carcinogenic process in the uterus, for a particular drug, requires separate evaluation.
Carthew
P
P
MRC Toxicology Unit, University of Leicester, Leicester, LE1 9HN, United Kingdom.
Edwards
R E
RE
Nolan
B M
BM
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004717:Endometrium / Q000187:drug effects* / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000819:agonists*; D005260:Female; D006984:Hypertrophy / Q000139:chemically induced; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D010880:Piperidines / Q000494:pharmacology; D020849:Raloxifene Hydrochloride; D013629:Tamoxifen / Q000494:pharmacology; D017312:Toremifene / Q000494:pharmacology; D014599:Uterus / Q000187:drug effects*; D014621:Vagina / Q000187:drug effects / Q000473:pathology
D016588:Anticarcinogenic Agents; D004967:Estrogens; D010880:Piperidines; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D017312:Toremifene; D001973:Bromodeoxyuridine