The aim of this study was to examine the role of heparin in the realization of oestradiol (OE2) effects in the uterus. Ovariectomized rats were treated with a single injection of OE2 dipropionate (10 micrograms/rat, i.m.) along with injections of heparin (in doses of 0.4 mg/rat, i.m.). OE2 effects in the uterus were determined by measuring mitotic indices, proliferating cell nuclear antigen (PCNA)-labelling indices, DNA content, and volumes of cells, nuclei and nucleoli in luminal and glandular epithelia and stromal cells of the endometrium 24, 36 and 48 h after the injection of OE2. Heparin treatment inhibited the OE2-stimulated increase in mitotic activity and DNA content of the uterine structures, whereas OE2-induced increases in cell, nucleus and nucleolus volumes in all uterine structures tested at all the times were greatly augmented by heparin. The OE2-induced increase in PCNA-labelling index in all the cell types had a tendency to increase as the result of heparin action. In the absence of OE2, heparin had no effect on any of the uterine parameters. The effect of heparin is probably realized via changes in the mechanism of oestrogen action in the uterus. Heparin probably prevents passage of the cells from the G1- to the S-phase of the cell cycle and prolongation of the G1-phase with consequent accumulation of the cells in this phase of the cell cycle. This probably leads to reduction of mitotic activity. Furthermore, cells in G1-phase probably prolong their biosynthetic processes causing enlargement of the cell, nucleus and nucleolus volumes.

The aim of this study was to examine the effect of long-term treatment with glucocorticoids on the uterine response to oestradiol. Ovariectomized rats were treated with crystal triamcinolone acetonide (0.1 mg/100 g, i.m.) or saline (0.1 ml/100 g i.m.) for 29 days. Over this period five injections were administered, one per week. On the second day after the last triamcinolone injection, rats were treated with a single injection of oestradiol dipropionate (5 micrograms/100 g, s.c.) or vehicle (olive oil, 0.1 ml/100 g, s.c.). The effects of oestradiol in the uterus were determined by measuring mitotic index, bromodeoxyuridine (BrdU)-labelling index (BrdU was injected 2 h before the rats were killed; 2 mg/100 g, i.p.), and proliferating cell nuclear antigen (PCNA)-labelling index 24, 36 and 48 h after the injection of oestradiol or vehicle. Long-term treatment with glucocorticoids resulted in dissimilar changes in oestradiol-induced proliferation in epithelial and connective-tissue (stroma) components of the uterus. In luminal and glandular epithelia, there was an initial reduction in proliferation at 24 h, followed by an increase at 36 h and a further reduction at 48 h after the oestradiol injection. In stromal cells of the endometrium, triamcinolone treatment caused a large constant increase in oestradiol-induced proliferation throughout the experiment. The glucocorticoid treatment had no effect on the parameters without oestradiol administration.

Glucocorticoids have been known to be involved in the regulation of some aspects of estrogen action on the uterus. However, the effect of glucocorticoids on changes in uterine morphogens produced by chronic estrogen exposure is not known. Therefore, the aim of this work was to examine the role of glucocorticoids on proliferative and morphogenetic uterine reactions induced by continuous estrogen treatment. Ovariectomized mice received subcutaneous injections of estradiol dipropionate in olive oil (2 microg per 100 g body weight once a week) or vehicle and drank water with or without dexamethasone (2 mg/l) for 30, 60 and 90 days. Treatment with dexamethasone caused a marked reduction in estradiol-induced changes in uterine weight, in proliferation (estimated from the proportion of mitotic and BrdU-labeled cells in all uterine tissues), and in changes in estradiol-dependent morphogenesis, which was redirected from the formation of atypical hyperplasia in animals receiving only estradiol to the appearance of simple or cystic endometrial hyperplasia in animals receiving both estradiol and dexamethasone. Estradiol alone increased dramatically the number of perpendicular oriented mitoses in luminal and glandular epithelia, and administration of dexamethasone inhibited this effect. In the absence of estradiol, chronic treatment with dexamethasone has no effect on all uterine parameters tested. Thus, chronic glucocorticoid treatment produces a complex antiestrogenic effect in the uterus of mice. Estradiol-induced changes in mitosis orientation are probably responsible for changes in the shape of glands and development of endometrial hyperplasia.

The aim of this work was to examine the role of prolactin and dopaminergic drugs, which affect prolactin secretion, on proliferative and morphogenetic reactions in the uterus under continuous estrogen treatment. Ovariectomized mice received injections of estradiol dipropionate (2 microg per 100 g, weekly) or vehicle and daily injections of prolactin (0.25 mg/100 g) or saline (0.05 ml) for 30 days. Other groups of mice received injections of estradiol or vehicle and injections of saline, and were allowed to drink bromocriptine (25 mg/l), metoclopramide (25 mg/l), or only tap water for 30 days. Prolactin administration results in a decrease in the incidence of abnormal glands with abnormal epithelium, the incidence of atypical hyperplasia, uterine weight, proliferation (the number of mitotic and bromodeoxyuridine-labeled cells) and the levels of estrogen receptor-alpha, but causes an increase in the level of beta-catenin in uterine tissues of estrogen-treated mice. The effect of metoclopramide, which increases prolactin secretion, is principally similar to prolactin, but much less expressed. Bromocriptine, which reduces prolactin levels, increases uterine weight, proliferation, the levels of estrogen receptor-alpha, the incidence of abnormal glands with abnormal epithelium, the incidence of complex and atypical hyperplasia, and decreases the level of beta-catenin in uterine structures of estrogen-treated mice. In the absence of estradiol, none of the treatments used had any effect on the parameters tested. Thus, prolactin or metoclopramide produce antiestrogenic effects in the uterus of mice and prevent the formation of atypical hyperplasia which has an unfavorable prognosis, but bromocriptine has the opposite effect. Estrogen receptor-alpha and beta-catenin were associated with the actions of prolactin, metoclopramide and bromocriptine on estrogen-dependent processes in the uterus.

It is suggested that the action of peroxisome proliferator-activated receptors (PPARs) cross-talks with estrogen signaling in the uterus. However, it is not known how PPAR agonists affect estrogen-dependent processes in the uterus, especially proliferation and morphogenetic changes. The effects of agonists of PPAR-alpha and -gamma on proliferative and morphogenetic reactions in the uterus under short- and long-term estrogen treatments were therefore examined. Ovariectomized mice were treated with estradiol dipropionate (4 micro g/100 g, s.c., once a week) or vehicle and rosiglitazone (PPAR-gamma agonist) or fenofibrate (PPAR-alpha agonist) or with no additional treatment for 2 days or for 30 days. Treatment with estradiol and PPAR agonists for 2 days did not affect uterine mass. In mice treated with estradiol and rosiglitazone for 2 days, proliferation was enhanced and levels of estrogen receptors-alpha and beta-catenin were decreased in all uterine tissues. Treatment with estradiol and fenofibrate for 2 days had the opposite effects on the parameters tested. In animals treated with estradiol and rosiglitazone for 30 days, uterine mass was increased, abnormal uterine glands and atypical endometrial hyperplasia were found more often and levels of estrogen receptors-alpha and beta-catenin were decreased. In animals treated with estradiol and fenofibrate for 30 days, uterine mass was decreased, most of the uterine glands had a normal structure, no cases of atypical hyperplasia were diagnosed, proliferative activity was declined and the levels of estrogen receptors-alpha and beta-catenin were markedly higher. Treatment with rosiglitazone or fenofibrate did not affect the serum estradiol level in the mice which received estradiol together with PPAR agonists for 30 days. Thus, rosiglitazone exerted the proliferative and morphogenetic effects of estradiol, but fenofibrate had the opposite effect. The actions of rosiglitazone and fenofibrate are associated with changes in the expression of estrogen receptors-alpha and beta-catenin in the uterus.