Lithium treatment enhances estradiol-induced proliferation and hyperplasia formation in the uterus of mice

Abstract

Objectives: It is suggested that the Wnt/β-catenin pathway plays a role in the regulation of estrogen action in the uterus. However, this suggestion has not been proved. Lithium can mimic increased activity of the Wnt/β-catenin pathway by blocking the activity of glycogen synthase kinase-3β. There are no data on the effects of lithium on estrogen-dependent processes in the uterus. This work was therefore aimed to examine the action of lithium on proliferative and morphogenetic reactions in the uterus under short- and long-term estrogen treatments. Study design: Ovariectomized mice received estradiol dipropionate (2 μg per 100 g; s.c.) once a week or vehicle and drank tap water with 0.05% lithium chloride or plain tap water for 2 or 30 days. Results: In animals treated with estradiol and lithium for a month, the incidence of atypical endometrial hyperplasia was significantly higher. In animals treated with estradiol and lithium for 2 days or for a month, uterine mass, the number of mitotic cells and BrdU-labelled cells in luminal epithelium, glandular epithelium, stromal and myometrial cells was markedly greater, whereas the levels of estrogen receptors-α, β-catenin and glycogen synthase kinase-3β were markedly lower in all uterine compartments, than in those in mice received estradiol with no lithium to drink. Conclusions: Lithium treatment results in an increase in estradiol-induced proliferative and morphogenetic changes in the uterus. This action of lithium is associated with decreased expression of estrogen receptors-α, β-catenin and glycogen synthase kinase-3β in the uterus.