Developmental mechanism of estrogen-induced irreversible changes in the mouse cervicovaginal epithelium.

Neonatal female mice of the NMRI strain, given injections of 17 beta-estradiol or DES, were studied with respect to immediate effects and those that appeared in the animal's adult stage. With the estrogen dose used (5 micrograms daily), proliferation of the pseudostratified columnar epithelium in the upper part of the müllerian vagina was inhibited. This resulted in the occurrence of regions containing an RCE in the uterine cervix and upper vagina of adult animals instead of the normal squamous epithelium. Later, the RCE developed into adenosis; subsequently, suspected malignant changes were seen. Besides the morphologic differences compared with control animals, neonatal estrogen treatment resulted in changes in the amount of CVA. Compared with controls, the amount of CVA was high in the superficial mucified vaginal cells of neonatally DES-treated mice, subsequently castrated and given estrogen as adults. The RCE had a low level of CVA. An interaction of estradiol and prolactin was important for the CVA level. Neonatal estrogen treatment may result in persistent changes in the regulation of plasma prolactin. A comparison is made between the estrogen-induced changes in mice and the DES effects in the female offspring of women exposed to DES during pregnancy. The importance of the mouse model for the study of the relevance of estrogen-induced, irreversible changes and other factors in the development of human clear cell adenocarcinomas in the vagina and cervix is stressed.