Estrogen Induces a Systemic Growth Factor Through an Estrogen Receptor-Alpha-Dependent Mechanism

Estrogen induces proliferation of uterine epithelium through a paracrine action of estrogen receptor (ER (alpha)) in the underlying stroma. In ovariectomized mice primed with progesterone, estrogen stimulates proliferation in both the epithelium and the stroma. We set out to test whether a paracrine mode of action is involved in estrogeninduced proliferation of the uterine stroma. Epithelial and mesenchymal tissues derived from uteri of neonatal ER (alpha) null mice (ER(alpha)KO) or wild-type mice were separated and recombined in all four possible configurations (ER(alpha)+ or ER(alpha)- epithelium with ER(alpha)+ or ER(alpha)- mesenchyme) and grafted into female athymic mice. After 5 wk, hosts were ovariectomized and challenged with hormone treatment, and cellular proliferation was monitored by thymidine autoradiography. Results showed that, although the full response of the epithelium was dependent on an ER(alpha)-positive mesenchyme, stromal cell proliferation was independent of tissue ER(alpha). This latter observation suggests that the response of the stroma was due to a systemic factor induced in the ER(alpha)positive hosts. To test this possibility, pieces of whole uterus from neonatal wild-type or ER(alpha)KO mice were grafted into syngeneic wild-type or ER(alpha)KO hosts. In these whole-uterus grafts, estradiol stimulated ER(alpha) KO uterine stroma when they were grown in wild-type hosts but not when grown in ER(alpha)KO hosts. The epithelium of whole-uterus ER(alpha)KO grafts did not respond to estrogen, regardless of the host phenotype. These observations suggest that treatment of progesterone-primed mice with estradiol stimulates production of a systemic factor that is capable of inducing uterine stromal cell proliferation and that this systemic factor is produced by an ER(alpha)-dependent mechanism.