RETINOIC ACID INHIBITS ESTROGEN-INDUCED UTERINE STROMAL AND MYOMETRIAL CELL PROLIFERATIONS

Retinoic acid, a potent natural derivative of vitamin A, influences pr oliferation in many cell types. However, little is known about the rol e of retinoic acid in estrogen-induced proliferation in normal physiol ogical systems. In this study we sought to determine if in vivo admini stration of retinoic acid influences the proliferation of a normal est rogen target tissue, the immature rat uterus. The results indicate tha t treatment of animals with 30 mg/kg all-trans-retinoic acid for 3 day s before 17 beta-estradiol (E(2)) administration diminishes DNA synthe sis and cell division by approximately 50% in uterine stromal and myom etrial cells. Luminal epithelial cell proliferation is not inhibited, indicating that the antiproliferative effects of all-trans-retinoic ac id treatment are cell type-specific. The inhibition is retinoid-specif ic and fully reversible 1 week after discontinuing all-trans-retinoic acid treatment. The inhibitory effect of all-trans-retinoic acid is no t due to a change in E(2) receptor levels assessed by Ligand binding. E(2) induction of c-jun, a gene expressed primarily in myometrial cell s, is unaffected in retinoid-treated animals. This is the first demons tration that retinoic acid inhibits estrogen-induced proliferation of uterine stromal and myometrial cells in a physiological setting.