Toxicological Sciences, Vol 48, 197-205, Copyright © 1999 by Society of Toxicology
P Carthew, RE Edwards, BM Nolan, MJ Tucker and LL Smith
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.
ARTICLES
Compartmentalized uterotrophic effects of tamoxifen, toremifene, and estradiol in the ovariectomized Wistar (Han) rat
MRC Toxicology Unit, University of Leicester, United Kingdom. PC13@le.ac.uk
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