Synergistic effects of androgen and estrogen on the mouse uterus and mammary gland

Many studies have suggested that elevated estrogens and androgens may be etiologically related to the development of breast cancer, endometrial cancer and uterine leiomyomas. We and other investigators have previously shown that estrogen and androgen are synergistic in the induction of mammary carcinogenesis in the Noble rat. However, the mechanisms behind the synergy is unknown, and it is unclear whether such synergy is unique for the Noble rat and for the mammary gland. In this study we treated female FVB mice with 17beta-estradiol (E2) and 5alpha-dihydrotestosterone-bezonate (DHT-B), alone and in combination, using silastic tubing for 2-7 months. The results showed that DHT-B alone induced proliferation of uterine endometrial epithelium and myometrial smooth muscle cells, whereas E2 alone induced much more pronounced growth of endometrial epithelium without affecting smooth muscle cells. Combined treatment with E2+DHT-B caused an even more severe hyperplasia of endometrial epithelium and myometrial muscle cells, compared with the treatment with each hormone alone. Uterine leiomyomas were observed in 2 of 6 mice at 7 months of combined treatment but not in any of 6 or 7 mice receiving each single hormone. DHT-B alone induced growth and secretion of mammary ductal cells, as well as growth of mammary stroma. E2 alone stimulated much more pronounced growth of both ductal cells and alveolar cells and secretion of alveolar cells, but had no effect on mammary stroma. Treatment with both E2 and DHT-B caused more severe hyperplasia of mammary ducts and alveoli, compared to the treatment with each hormone alone. Intraductal hyperplasia occurred early and frequently in the E2+DHT-B- treated mice, but no mammary tumors were observed. These results suggest that E2 and DHT-B have synergistic effects on the growth of uterine endometrial epithelium and myometrial muscle cells, as well as mammary epithelial ducts and alveoli.