COMPARATIVE EFFECTS OF 28-DAY TREATMENT WITH THE NEW ANTIESTROGEN EM-800 AND TAMOXIFEN ON ESTROGEN-SENSITIVE PARAMETERS IN INTACT MICE

Following 28 days of oral administration, in intact mice, the novel no n-steroidal anti-estrogen EM-800 was at least 30-fold more potent than tamoxifen in inhibiting uterine weight. Moreover, the maximal inhibit ory effect achieved with tamoxifen on uterine weight was only 40% that with EM-800. The pure anti-estrogenic activity of EM-800 on the hypot halamopituitary-gonadal axis is illustrated by the increase in ovarian weight, while tamoxifen, due to its estrogenic activity, decreased ov arian weight. EM-800 is 10- to 30-fold more potent than tamoxifen in i nhibiting uterine and vaginal estrogen receptors. Since 17 beta-hydrox ysteroid dehydrogenase (17 beta-HSD) is the key enzyme in estradiol fo rmation, the potent inhibitory effect of EM-800 on uterine 17 beta-HSD could play an additional role by decreasing the availability of estra diol in the uterine tissue, while tamoxifen, on the contrary, stimulat es activity of the enzyme, The atrophic changes in both the endometria l and myometrial layers achieved with EM-800 almost reached those obse rved 28 days after ovariectomy. EM-800 also resulted in a marked decre ase in the number of ovarian developing follicles and corpora lutea, w hile the number of atretic follicles was increased. Tamoxifen treatmen t, on the other hand, produced an increase in both the number and crow ding of the endometrial glands and a mild atrophy of the myometrial la yer. Tamoxifen caused atrophic changes of the vaginal epithelium, espe cially at the highest doses, though the atrophy was much less pronounc ed than that following EM-800 treatment or ovariectomy. In addition to being at least 30-fold more potent than tamoxifen in inhibiting uteri ne weight, the novel anti-estrogen causes atrophy of the endometrium, stimulates the hypothalamopituitary-gonadal axis and inhibits uterine 17 beta-HSD activity, while tamoxifen exerts opposite and estrogen-lik e effects on these parameters. (C) 1997 Wiley-Liss, Inc.