Neonatal Stimulation of the Uterus by Clomiphene, Tamoxifen and Nafoxidine: Relationship to the Development of Reproductive Tract Abnormalities

Abstract

Triphenylethylene derivatives, such as Clomid and Tamoxifen, are drugs that are in common use for the induction of ovulation and treatment of breast cancer, respectively. They are generally considered to be estrogen antagonists; however, it is well known that they may also act as agonists (15). While most investigators have been primarily interested in their antagonistic properties, we have concentrated on their estrogenic capacities. Triphenylethylene drugs cause long-term retention of the estrogen receptor in the nuclei of uterine cells and this is accompanied by a sustained stimulation of uterotropic activity (6–8, 10, 12, 17, 20, 29). This stimulation is primarily due to the ability of these drugs to stimulate the epithelium of the uterine lumen, whereas estradiol, a physiological estrogen, causes all tissues of the uterus to grow (9, 10, 17, 34). Therefore, even though these drugs are decidedly anti-estrogenic in some tissues, they are long acting estrogens in others. Since chronic exposure to estrogens is known to result in preneoplastic and neoplastic changes in the reproductive tract (22), we considered the possibility that triphenylethylene derivatives might cause such changes in the fetal and neonatal rat (5,30).