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

Abstract

The comparative uterotrophic responses of ovariectomized Wistar (Han) rats to tamoxifen, toremifene, and 17beta-estradiol have been determined over a period of 72 h. Uterine wet weight; luminal epithelial cell hypertrophy; and BrdU labeling index in the different tissue compartments of the uterus, and the immunohistochemical expression of nuclear estrogen receptor alpha (nERalpha), and nuclear progesterone receptor (nPR) were examined. Luminal epithelial cell hypertrophy was produced by all three compounds to a similar degree. 17beta-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 measured by increased BrdU incorporation. Estradiol increased the expression of nERalpha and nPR in the myometrium with time and decreased nERalpha levels from the overexpressed levels in control ovariectomized rat luminal epithelial cells. Tamoxifen and toremifene caused a smaller increase in uterine weight and the BrdU labeling index in the endometrial stroma and myometrium than did estradiol, and they increased the expression of nERalpha and nPR in the myometrium. Tamoxifen and toremifene differed from estradiol in that they did not decrease the expression of nERalpha in the luminal epithelial cells of the uterus. The response of PR expression was the same for tamoxifen, toremifene, and estradiol, and was therefore considered to be the most reliable indication of an estrogen-agonist effect in this study. The ability to distinguish differential, compartmentalized effects for agonists 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 of uterine cancers, in particular.

Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats

“…As monotherapy TOR has a significant and equivalent stimulatory effect on uterine epithelium as TAM. These monotherapy findings are consistent with published studies in this rat model [24][25][26][27][28][29][30].…”

Long-term ovariectomy modulates the antidepressant-like action of estrogens, but not of antidepressants

“…In the present study, a significant reduction in uterus weight was observed 3 weeks post-OVX, indicating a reduction in gonadal circulatiing hormones (Bekku and Yoshimura, 2005;Carthew et al, 1999;Skarda, 2002). Furthermore, Barker and Galea (2009) showed that at 3 weeks post-OVX there is a decline in b-estradiol levels in certain brain areas such as hippocampus, amygdala and prefrontal cortex (Barker and Galea, 2009).…”

Dioxin Induces an Estrogen-Like, Estrogen Receptor-Dependent Gene Expression Response in the Murine Uterus

“…Previous studies have demonstrated that estrogens induce dramatic increases in uterine wet weight, luminal epithelial cell height, stromal thickness, and BrdU labeling (Carthew et al, 1999;Moggs et al, 2004b;Kwekel et al, 2005). In contrast, TCDD did not induce alterations in any of these histological or morphological endpoints (data not shown).…”