The present study compares the effects of
tamoxifen and
EM-800, both administered at the oral daily dose of 100 microg for 6 months, on the uterus, vagina, and mammary gland in the mouse at histopathological examination. Treatment of intact animals with
EM-800 resulted in uterine and vaginal
atrophy even greater than that achieved after
ovariectomy, while the developmental growth of the mammary gland was completely blocked and serum LH was increased. In ovariectomized animals, treatment with
EM-800 decreased uterine and vaginal wt below the values observed in control ovariectomized mice while no significant change was observed on serum LH, thus indicating the lack of estrogenic activity of
EM-800.
Tamoxifen, on the other hand, showed a stimulatory estrogenic-like action on the mouse uterus in both intact and ovariectomized animals, thus resulting in moderate to severe
endometrial hyperplasia. These morphological changes were accompanied by a marked stimulation of both the estrogenic and androgenic
17beta-hydroxysteroid dehydrogenase as well as 5alpha-reductase uterine activities. The histological atrophic changes observed in the vagina after
tamoxifen treatment were less pronounced than those seen
after treatment with
EM-800. The agonistic
estrogen-like action of
tamoxifen was also illustrated by the suppression of serum LH levels in ovariectomized animals. A marked stimulation of the ovarian stroma, accompanied by a significant reduction in folliculogenic activity, was observed after
EM-800 or
tamoxifen administration, although the interstitial ovarian
hyperplasia was more pronounced after
EM-800 treatment. While both
antiestrogens blocked the developmental growth of the mammary gland,
EM-800 showed more potent antiestrogenic activity than
tamoxifen. The highly potent and specific antiestrogenic activity of
EM-800 suggests that this compound could improve the
therapy of
breast cancer while avoiding the undesirable stimulation of the endometrium.