Physiological Mechanisms of Diethylstilbestrol Organotropic Carcinogenesis

Abstract

Treatment of pregnant women with diethylstilbestrol (DES) during pregnancy has been demonstrated to be associated with an increased risk in the female offspring for development of an otherwise very rare type of malignancy: clear-cell adenocarcinoma of the vagina and cervix. The present knowledge about this association is reviewed. In experimental animals, many different types of malignancy can be induced by DES administered in large doses and during long periods. For the human situation there are as yet no indications that exposure to DES during fetal life has resulted in any generally increased incidence of malignant tumors. By injecting neonatal mice with DES for the first five days after birth, histologically malignant changes develope in the uterine cervix of the animals when more than one year old. A comparison is made between this animal model and development of tumors in the human female offspring of DES treated mothers. In the female mice, neonatal DES treatment results in a disturbed epithelial differentiation process in the upper part of the vagina and the uterine cervix, a disturbed development of the hypothalamic-pituitary gland control system as well as a disturbance in the normal development of the lymphoid system. The abnormal epithelial differentiation process results in development of adenosis and within these areas the malignant changes later appear. We do not know whether adenosis is a pre-cancerous condition or not, in the meaning that it contains dormant malignant cells. Other factors could act upon adenosis to result in cancer. The reasons for DES being called a “carcinogen” are reviewed. The possibility for factors in the environment acting as potential transplacental carcinogens in the human fetus should not be excluded.