Effects of estrogens and metabolites on endometrial carcinogenesis in young adult mice initiated with N-ethyl-N'-nitro-N-nitrosoguanidine

Cancer Lett. 2004 Jul 28;211(1):1-9. doi: 10.1016/j.canlet.2004.01.029.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / chemically induced
  • Adenocarcinoma / pathology
  • Animals
  • Carcinogenicity Tests
  • Carcinogens
  • Endometrial Hyperplasia / chemically induced
  • Endometrial Hyperplasia / pathology
  • Endometrial Neoplasms / chemically induced*
  • Endometrial Neoplasms / pathology
  • Estrogens / metabolism
  • Estrogens / toxicity*
  • Female
  • Methylnitronitrosoguanidine / analogs & derivatives*
  • Mice
  • Mice, Inbred ICR


  • Carcinogens
  • Estrogens
  • Methylnitronitrosoguanidine
  • ENNG