Proliferation, mitosis orientation and morphogenetic changes in the uterus of mice following chronic treatment with both estrogen and glucocorticoid hormones

Abstract

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 morphogenes 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 µg 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.

Effects of histone deacetylase inhibitors on estradiol-induced proliferation and hyperplasia formation in the mouse uterus

“…In our previous experiments, treatments sometimes had an effect on proliferation but had no action on morphogenetic changes in the uterus, and vice versa (Gunin et al 2001(Gunin et al , 2004a. The present results show that histone deacetylase blockers affect both proliferation and morphogenetic alterations.…”

“…Our previous observations clearly showed that treatment with estradiol for 30 days was quite enough to produce expressed estrogen-dependent changes in uterine morphology and to induce hyperplastic changes in the uterus (Gunin et al 2001(Gunin et al , 2002(Gunin et al , 2004a. This estradiol dose and treatment regime produced estradiol levels in the blood that were close to the normal physiologic values (Gunin et al 2004a).…”

“…To estimate the extent of any hyperplastic or neoplastic changes in the endometrium, uterine glands were subdivided into four morphological types: (1) normal glands (simple tubular glands which can appear in section as round, oval, or elongated with a narrow lumen; this type has no branches or daughter glands); (2) cystic glands (round-shaped glands of more than average or large size); (3) glands with daughter glands (these glands have various shapes (round, elongate, tortuous) and sizes and have forming or formed daughter gland or glands inside the epithelium or inside the mother gland lumen, or on the outer surface of the mother gland); (4) conglomerate of glands (this type has a very complex architecture in which individual glands are closely disposed to each other almost without intervening stroma and have multiple interconnecting lumens -this type may develop from glands with daughter glands), as described in Gunin et al 2001). The numbers of each type of gland were calculated in randomly selected sections.…”

“…Proliferative processes were assessed from the number of mitotic and BrdU-labelled cells as described previously (Gunin et al 2001). Mitoses were counted in sections stained with iron haematoxylin.…”

“…It is known that the action of estrogen is regulated by a variety of extracellular factors -such as hormones, growth factors and others (Couse & Korach 1999, Gunin et al 2001. Recent data showed that estrogen also recruits intracellular regulatory systems to bring about its action (Couse & Korach 1999, Deroo et al 2004, Gunin et al 2004b.…”