The present study assessed effects of
estrogens and their
steroid metabolites on the endometrial
carcinogenesis in young adult mice initiated with N-
ethyl-N'-nitro-N-nitrosoguanidine (
ENNG). A total of 272 female CD-1 (ICR) mice were used and equally divided into 17 groups. Mice were implanted
cholesterol pellets to the back subcutis at 9 weeks of age. Pellets contained nothing (control) or one of the experimental agents, three different
estrogens and their 13 different
steroid metabolites, at a concentration of 0.5% (w/w).
At 10 weeks of age, mice were given a single intra-uterine administration of
ENNG at a dose of 25 mg/kg
body weight. When reaching the 30 weeks of age (20 weeks after the
ENNG treatment), mice were sacrificed to assess the development of endometrial proliferative lesions. While endometrial proliferative lesions, including
hyperplasias and
adenocarcinomas, were observed in all groups, the incidences of
hyperplasias in the groups treated with
2-hydroxyestriol,
2-methoxyestradiol,
2-methoxyestriol and 16-epiestriol were significantly higher than that in the control group. On the other hand,
adenocarcinomas were significantly developed in the groups treated with
estrone,
estradiol,
estriol, 16beta-hydroxyestrone, 16alpha-hydroxyestrone and 17-epiestriol. These results indicate that, on the endometrial
carcinogenesis in mice initiated with
ENNG,
estrogens and their metabolites belonging to the 16alpha-hydroxylation pathway and the upstream of the 16beta-hydroxylation pathway exert both promoting and progressing effects, whereas, the
estrogen metabolites belonging to the 2- and 4-hydroxylation pathways (
catechol estrogens) and the downstream of the 16beta-hydroxylation pathway exert only promoting or no effects. It is thus suggested that a metabolic profile of
estrogens may be crucial for the endometrial
carcinogenesis and that the rate of the 16alpha-hydroxylation may be associated with the increased carcinogenic risks of
estrogens on the endometrium.