Involvement of Androgen Receptor in 17β-Estradiol-Induced Cell Proliferation in Rat Uterus1

Although it is known that, in the uterus, estrogen receptor alpha (ERalpha) is involved in proliferation and progesterone receptor in differentiation, the role of the two other gonadal-hormone receptors expressed in the uterus, androgen receptor (AR) and estrogen receptor beta (ERbeta), remains undefined. In this study, the involvement of AR in 17beta-estradiol (E(2))-induced cellular proliferation in the immature rat uterus was investigated. AR levels were low in the untreated immature uterus, but 24 h after treatment of rats with E(2), there was an increase in the levels of AR and of two androgen-regulated genes, IGF-I and Crisp (cysteine-rich secretory protein). As expected, E(2) induced proliferation of luminal epithelial cells. These actions of E(2) were all blocked by both the antiestrogen tamoxifen and the antiandrogen flutamide. The E(2)-induced AR was found by immunohistochemistry to be localized exclusively in the stroma, mainly in the myometrium, where it colocalized with ERalpha but not with ERbeta. ERbeta, detected with two different ERbeta-specific antibodies, was expressed in both stromal and epithelial cells either alone or together with ERalpha. Treatment with E(2) caused down-regulation of ERalpha and ERbeta in the epithelium. The data suggest that, in E(2)-induced epithelial cell proliferation, ERalpha induces stromal AR and AR amplifies the ERalpha signal by induction of IGF-I. Because AR is never expressed in cells with ERbeta, it is unlikely that ERbeta signaling is involved in this pathway. These results indicate an important role for AR in proliferation of the uterus, where estrogen and androgen do not represent separate pathways but are sequential steps in one pathway.