Suppression of uterine insulin-like growth factor binding protein 5 by estrogen is mediated in part by insulin-like...

Insulin-like growth factor I (IGF-I) is an important mediator of estradiol-induced uterine growth in vivo. Insulin-like growth factor binding proteins (IGFBPs) are known to regulate access of insulin-like growth factors to IGF receptors. In this report we demonstrate that the positive uterotrophic agent estradiol, suppresses expression of the IGFBP-5 gene in the uterus to less than 15% of control values, while oophorectomy results in uterine involution and is associated with a greater than 3-fold stimulation of uterine IGFBP-5 gene expression. Immunohistochemical studies show that in intact rat uterus, the luminal epithelial cells are weakly stained with IGFBP-5 antibodies. Following ovariectomy, IGFBP-5 is confined in the luminal epithelial layer and longidinal smooth muscle cells. Administration of estradiol to ovariectomized rats increases uterine weight and uterine IGF-I gene expression, while immunostaining of IGFBP-5 in the luminal epithelial cells and longidinal smooth muscle cells is almost extinguished. In vitro studies using primary uterine cells reveal that IGF-I increases thymidine incorporation and inhibits IGFBP-5 gene expression, whereas estradiol has no effect suggesting that in vivo estradiol-induced IGFBP-5 suppression is mediated through increased IGF-I production. Our results suggest that in vivo, the uterotrophic effects of estradiol are mediated at least in part by estradiol-stimulated uterine IGF-I expression which in turn inhibits IGFBP-5 expression, an action which would be expected to increase IGF bioactivity.