ABSTRACT
OBJECTIVES: It is suggested that the Wnt/beta-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/beta-catenin pathway by blocking the activity of glycogen synthase kinase-3beta. 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 microg per 100g; 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-alpha, beta-catenin and glycogen synthase kinase-3beta 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-alpha, beta-catenin and glycogen synthase kinase-3beta in the uterus.
Subject(s)
Endometrial Hyperplasia/pathology , Estradiol/pharmacology , Lithium Chloride/pharmacology , Uterus/drug effects , Administration, Oral , Animals , Cytoskeletal Proteins/metabolism , Disease Models, Animal , Estradiol/administration & dosage , Female , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Injections, Subcutaneous , Lithium Chloride/administration & dosage , Mice , Ovariectomy , Random Allocation , Receptors, Estrogen/metabolism , Trans-Activators/metabolism , Uterus/pathology , beta CateninABSTRACT
BACKGROUND: It has been shown that long-term glucocporticoid administration to chronically estradiol-treated mice decreases uterine weight, proliferation in all uterine tissues, the number of perpendicularly oriented mitoses in uterine epithelia and the incidence of atypical endometrial hyperplasia. However, mechanisms of chronic glucocorticoid action on estrogen-dependent processes in the uterus are unclear. METHODS AND RESULTS: Results of present research showed that adding of glucocorticoid dexamethasone (in drinking water, 2mg/l) to estradiol-treated mice led to a decrease in the level of glucocorticoid receptor, to an increase in levels of estrogen receptor-alpha, beta-catenin and glycogen synthase kinase-3beta in uterine tissues of ovariectomized mice at 30, 60 and 90 days of the treatment. When vehicle was used instead estradiol, dexamethasone did not produce detectable changes in all parameters tested at all periods of observation. CONCLUSION: Results allow to conclude that estrogen and glucocorticoid receptors, beta-catenin and glycogen synthase kinase-3beta are involved in estrogen-dependent changes in uterine morphology and hyperplasia formation.
