Progesterone and dexamethasone inhibition of uterine epithelial proliferation in two models of estrogen-independent growth

Abstract

It is believed that progestins and glucocorticoids block estrogen-induced growth of the uterus by perturbing the mechanism of estrogen stimulation. We have examined the effect of progesterone or dexamethasone on two rodent models of estrogen-independent proliferation of uterine epithelium. Tissues of the neonatal mouse uterus exhibit high rates of deoxyribonucleic acid synthesis in the absence of endogenous steroids. Progesterone and dexamethasone inhibit deoxyribonucleic acid synthesis in the uterine epithelium of 4-day-old mice. When grafted beneath the kidney capsule of an ovariectomized adult, the tissues of the neonatal uterus continue to grow without the addition of estrogen. Both progesterone and dexamethasone blocked uterine epithelial mitotic activity in these allografts. A true growth response can be stimulated in the uterus of an ovariectomized rat by intraluminal instillation of cholera toxin. In the present study, autoradiographic analysis showed that cholera toxin stimulation of deoxyribonucleic acid synthesis was confined to the epithelial compartment in ovariectomized, vehicle-treated rats. When ovariectomized rats were pretreated with progesterone, cholera toxin induced deoxyribonucleic acid synthesis in the stroma but not in the epithelium. Thus progesterone and dexamethasone inhibit uterine epithelial proliferation that is not driven by estrogen stimulation. Therefore in these estrogen-independent model systems, the inhibitory effects of these steroids cannot be due to antagonism of estrogen receptor—mediated events. These observations suggest that inhibition in estrogen-induced uterine epithelial proliferation may also work through a mechanism unrelated to antagonism of estrogen receptor action.