Retinoic acid inhibits estrogen-induced uterine stromal and myometrial cell proliferation

Retinoic acid, a potent natural derivative of vitamin A, influences proliferation in many cell types. However, little is known about the role of retinoic acid in estrogen-induced proliferation in normal physiological systems. In this study we sought to determine if in vivo administration of retinoic acid influences the proliferation of a normal estrogen target tissue, the immature rat uterus. The results indicate that treatment of animals with 30 mg/kg all-trans-retinoic acid for 3 days before 17 beta-estradiol (E2) administration diminishes DNA synthesis and cell division by approximately 50% in uterine stromal and myometrial cells. Luminal epithelial cell proliferation is not inhibited, indicating that the antiproliferative effects of all-trans-retinoic acid treatment are cell type-specific. The inhibition is retinoid-specific and fully reversible 1 week after discontinuing all-trans-retinoic acid treatment. The inhibitory effect of all-trans-retinoic acid is not due to a change in E2 receptor levels assessed by ligand binding. E2 induction of c-jun, a gene expressed primarily in myometrial cells, is unaffected in retinoid-treated animals. This is the first demonstration that retinoic acid inhibits estrogen-induced proliferation of uterine stromal and myometrial cells in a physiological setting.