Female Reproductive Tract

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

Abstract
Estrogen induces proliferation of uterine epithelium through a paracrine action of estrogen receptor (ER) 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 estrogen-induced proliferation of the uterine stroma. Epithelial and mesenchymal tissues derived from uteri of neonatal ER null mice (ERKO) or wildtype mice were separated and recombined in all four possible configurations (ER⁺ or ER^- epithelium with ER⁺or ER^- mesenchyme) and grafted into female athymic mice. After five weeks, hosts were ovariectomized, challenged with hormone treatment, and cellular proliferation was monitored by thymidine autoradiography. Results showed that, although the full response of the epithelium was dependent upon an ER-positive mesenchyme, stromal cell proliferation was independent of tissue ER. This latter observation suggests that the response of the stroma was due to a systemic factor induced in the ER-positive hosts. To test this possibility, pieces of whole uterus from neonatal wildtype or ERKO mice were grafted into syngeneic wildtype or ERKO hosts. In these whole-uterus grafts, estradiol stimulated ERKO uterine stroma when they were grown in wildtype hosts but not when grown in ERKO hosts. The epithelium of ERKO 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-dependent mechanism.

Key words: Estradiol receptor • Growth factors • Progesterone • Uterus

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