Compartmentalized uterotrophic effects of tamoxifen, toremifene, and estradiol in the ovariectomized Wistar (Han) rat

The comparative uterotrophic responses of ovariectomized Wistar (Han) rats to tamoxifen, toremifene, and 17 beta-estradiol have been determined over a period of 72 h. Uterine wet weight; luminal epithelial cell hypertrophy; a nd BrdU labeling index in the different tissue compartments of the uterus, and the immunohistochemical expression of nuclear estrogen receptor alpha ( nER alpha), and nuclear progesterone receptor (nPR) were examined. Luminal epithelial cell hypertrophy was produced by all three compounds to a simila r degree. 17 beta-Estradiol produced an increase in uterine wet weight due to fluid imbibition over the 3-day period, and an increase in DNA synthesis in the endometrial stromal and myometrial compartments of the uterus, as m easured by increased BrdU incorporation. Estradiol increased the expression of nER alpha and nPR in the myometrium with time and decreased nER alpha l evels from the overexpressed levels in control ovariectomized rat luminal e pithelial cells. Tamoxifen and toremifene caused a smaller increase in uter ine weight and the BrdU labeling index in the endometrial stroma and myomet rium than did estradiol, and they increased the expression of nER alpha and nPR in the myometrium. Tamoxifen and toremifene differed from estradiol in that they did not decrease the expression of nER alpha in the luminal epit helial cells of the uterus. The response of PR expression was the same for tamoxifen, toremifene, and estradiol, and was therefore considered to be th e most reliable indication of an estrogen-agonist effect in this study. The ability to distinguish differential, compartmentalized effects for agonist s of estrogen action in the uterus will allow a better risk assessment for new pharmaceuticals that are used as breast cancer chemotherapeutic agents, especially where their use may also be associated with an increased risk o f uterine cancers, in particular.