Epidermal Growth Factor and Insulin Induce the Proliferation of Guinea Pig Endometrial Stromal Cells in Serum-Free Culture, Whereas Estradiol and Progesterone Do Not1

Abstract

Guinea pig endometrial stromal cells were cultured in serum-free medium to assess the effects of growth factors and ovarian steroids on cell proliferation. When the cells were made quiescent by serum depletion, [3H]thymidine incorporation was increased by the addition of insulin plus epidermal growth factor (EGF), reaching a peak after 24 h of stimulation. This effect was dose-dependent. Both factors acted synergistically. Estradiol-17 beta (E2), either alone or with various concentrations of growth factors, had no mitogenic effect. Thus, cell proliferation appeared to be estrogen-insensitive, despite a high level of estrogen receptors (19,000 sites per cell). The integrity of these receptors was checked by transfecting cells with a plasmid containing an estrogen-responsive element linked to a CAT gene: E2-induced CAT activity was reduced by the antiestrogen ICI 164,384. Despite the presence of progesterone receptors, the cells, either primed with E2 or not, were not growth-stimulated by progesterone. E2 had no effect on cells cultured in the presence of dextran-coated charcoal-stripped serum. Thus, whatever the culture conditions, stromal cells with functional estrogen receptors were insensitive to the putative mitogenic effects of E2 and progesterone. However, they were highly responsive to the mitogenic effects of insulin and EGF.

Long-term Alcohol Consumption and Risk of Endometrial Cancer Incidence: A Prospective Cohort Study

“…Hyperinsulinemia may increase the levels of free estrogens through decreasing concentrations of circulating sex hormone binding globulin (30,31). Finally, hyperinsulinemia through decreasing levels of IGFBP-1 increases circulating free IGF-1, which by binding and activating IGF-1 receptors in the endometrium, stimulates cell proliferation (32)(33)(34)(35)(36)(37). These two counteracting mechanisms by which alcohol might be associated with endometrial cancer risk probably cancel each other.…”

Diabetes mellitus and risk of endometrial cancer: a meta-analysis

“…Finally, hyperinsulinaemia leads to decreased levels of insulin-like growth factor binding protein 1. This in turn increases circulating free IGF-1, which stimulates endometrial cell proliferation [54][55][56][57][58][59]. Finally, the adipocyte-secreted hormone, adiponectin, is an endogenous insulin sensitiser lying upstream of all the above-mentioned hormonal factors and capable of affecting their circulatory levels [60].…”

Diabetes and Risk of Endometrial Cancer: A Population-Based Prospective Cohort Study

“…35,36). Finally, hyperinsulinemia through decreasing levels of insulin-like growth factor (IGF)-binding protein-1 and IGF-binding protein-3 increases circulating free IGF-I, which by binding and activating IGF-I receptors in the endometrium stimulates cell proliferation (37)(38)(39)(40)(41)(42). Decreased circulating IGF-binding protein-3 levels may also have a direct regulatory role in cell growth control and cancer (43,44).…”