Sequential Observation of Spontaneous Endometrial Adenocarcinoma Development in Donryu Rats

Abstract

Sequential observation of spontaneous endometrial adenocarcinoma development revealed a clear, hormone-dependent, histogenetic pathway in Donryu rats. The first histological changes of the uterine endometrium appeared in both the lining epithelium and uterine gland of the endometrium at 6 mo of age, along with the beginning of persistent estrus. These changes included areas of tall columnar epithelium and gland formation in the lining epithelium as well as metaplastic change in the uterine gland. At 8 mo of age, endometrial hyperplasias were found, with subsequent increase in both incidence and degree. At 8–10 mo of age, hyperplasias were all within the limit of grade ++. After 12 mo of age, however, severe hyperplasias (grade + + +) began to increase markedly, and adenocarcinomas developed at 15 mo of age. The findings thus suggest that uterine endometrial adenocarcinomas arise from hyperplastic lesions, which should therefore be regarded as preneoplastic, as in the human case. Sequential analysis of plasma gonad steroids also ascertained a link between the appearance of these lesions and an increased estrogen: progesterone ratio, suggesting that estrogen may play an important role in development of both hyperplastic and neoplastic lesions. In Fischer-344 rats used for comparative assessment of strain differences, neither advanced histological changes nor hormonal changes were evident.