Changing levels of cystic fibrosis transmembrane regulator (CFTR) expression in the rat uterus during the estrous cycle have been reported by our laboratory. To understand the regulation of CFTR in the female reproductive tract, we investigated the modulation of CFTR expression by sexual hormones in reproductive tissues. Administration of PMSG to immature females, which showed no uterine CFTR messenger RNA by in situ hybridization, stimulated CFTR expression in the uterine epithelium 48 h post injection, coincident with the PMSG-induced peak in follicular estradiol. Twelve hours after administration of 17 beta-estradiol to immature and ovariectomized mature females, but not after progesterone injection, uterine CFTR expression was detected. CFTR messenger RNA was also found in the normal adult oviduct, being undetectable after ovariectomy and reappearing after estrogen treatment. On Western blots, a band of the predicted mol wt of CFTR was found in uterine and oviductal membrane preparations from estrogen-treated animals. Using an immunoperoxidase assay, apical labeling was observed in uterine and oviductal epithelial cells of estrogen-treated rats, similar to that reported for CFTR in Cl(-)-secreting epithelia. These results describe for the first time the hormonal up-regulation of CFTR in vivo, implying estrogen as a physiological regulator of CFTR in the female reproductive tract.