Effect of twenty-four-week treatment with the antiestrogen EM-800 on estrogen-sensitive parameters in intact and ovariectomized mice.
Treatment with the antiestrogen EM-800, at the daily oral dose of 3 microg, 10 microg, 30 microg, or 100 microg for 24 weeks, caused a marked inhibition of uterine and vaginal weight in both intact and ovariectomized mice. Maximal 64% and 41% inhibitions of uterine weight were achieved in intact and ovariectomized animals, respectively. Similar inhibitory effects of EM-800 were observed on vaginal weight with maximal inhibitions of 71% and 35%, in intact and ovariectomized animals, respectively. The pure antiestrogenic activity of EM-800 on the hypothalamo-pituitary-ovarian axis is illustrated by the 76-91% increases in ovarian weight observed in intact animals treated with the 10-100 microg doses of the antiestrogen. Serum 17beta-estradiol was 93% increased at the 100 microg daily dose of EM-800, whereas serum androstenedione, testosterone, and dihydrotestosterone were 141-713% increased over control at the same dose of the antiestrogen. Serum LH was increased by treatment with EM-800 in intact animals, whereas no effect was observed on the elevated gonadotropin levels in ovariectomized animals. At all doses used in intact animals, the antiestrogen caused a complete disappearance of the glandular elements of the mammary gland, the atrophy being comparable with that observed in ovariectomized mice. The mammary gland of EM-800-treated animals was exclusively composed of an atrophied ductal system lined by atrophied epithelial cells with an absence of lobulo-glandular elements. No effect of the compound was observed on the histology of the mammary gland in ovariectomized animals, thus showing the pure antiestrogenic effect of EM-800 on the mammary gland, as shown also for the uterus, vagina, and hypothalamo-pituitary axis. At histopathology, all doses of EM-800 in intact animals led to a moderate to severe uterine and vaginal atrophy. The uterine atrophy affected both the myometrium and the endometrium. Interestingly, the uterine atrophy achieved in intact animals treated with EM-800 was greater than that observed after ovariectomy alone, thus clearly demonstrating the pure antiestrogenic activity of EM-800. The present data show the highly potent and pure antiestrogenic activity of EM-800 on all parameters measured after 6 months of treatment in both intact and ovariectomized mice, a maximal effect being reached at the daily 10 microg dose of the antiestrogen in intact animals.
Luo
S
S
Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center, Québec, Canada.
Sourla
A
A
Labrie
C
C
Gauthier
S
S
Merand
Y
Y
Belanger
A
A
Labrie
F
F
D000735:Androstenedione / Q000097:blood; D000818:Animals; D001284:Atrophy; D001578:Benzopyrans / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000097:blood; D004958:Estradiol / Q000097:blood; D004965:Estrogen Antagonists / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D007986:Luteinizing Hormone / Q000097:blood; D008321:Mammary Glands, Animal / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D011422:Propionates / Q000494:pharmacology*; D013739:Testosterone / Q000097:blood; D013997:Time Factors; D014599:Uterus / Q000473:pathology; D014621:Vagina / Q000473:pathology
D001578:Benzopyrans; D004965:Estrogen Antagonists; D004967:Estrogens; D011422:Propionates; D013196:Dihydrotestosterone; D013739:Testosterone; D000735:Androstenedione; D004958:Estradiol; D007986:Luteinizing Hormone; C106945:EM 800