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.

In addition to spontaneous uterine endometrial adenocarcinomas at a high incidence (35.1%), development of endometrial hyperplasia/adenoma was also frequently detected in rats of the Donryu strain. The total yield of all observed proliferative endometrial lesions was very high (60.6%). The tumors arose commonly in the uterine horn of aged rats. Histologically, most demonstrated glandular structures, consisting of cuboidal or columnar cells with weak eosinophilic or basophilic cytoplasm and large nuclei. In about half of the animals with adenocarcinomas, metastasis to remote organs such as the lung was observed. Histological examination of the ovary and vaginal epithelium revealed ovarian cysts, atrophy of the ovary and cornification of the vaginal epithelium more frequently in rats with endometrial carcinomas than in animals without tumors. These findings indicate that adenocarcinoma development in Donryu rats is associated with endocrine imbalance [increased serum estrogen: progesterone (E2:P)ratios]. By comparative investigation of strain differences, it was confirmed that irregular estrous cycles began earlier with higher incidence in Donryu rats than in F344 rats, a low-incidence strain. Histological findings of the ovary and vaginal epithelium also suggested relatively increased estrogen levels in Donryu rats compared to F344 rats. Estimated plasma values of gonad steroids showed that the E2:P ratio in Donryu rats at 12 months of age was about five times that in F344 rats. These results therefore indicate that hormone imbalance, particularly an increased E2:P ratio, may play an important role in the spontaneous occurrence of endometrial adenocarcinoma in Donryu rats.

BackgroundNot only joint destruction but also muscle wasting due to rheumatoid cachexia has been problem in terms of quality of life of patients with rheumatoid arthritis (RA). In the present study, we performed histopathological examination and assessed relationships between characteristic parameters relating to muscle and joint swelling in a collagen-induced arthritis (CIA) model using cynomolgus monkeys (CMs).MethodsFemale CMs were used and CIA was induced by twice immunizations using bovine type II collagen with Freund’s complete adjuvant. Arthritis level was evaluated from the degree of swelling at the peripheral joints of the fore and hind limbs. Food consumption, body weight, and serum biochemical parameters were measured sequentially. Five or 6 animals per time point were sacrificed at 2, 3, 5 and 9 weeks after the first immunization to obtain quadriceps femoris specimens for histopathology. Pimonidazole hydrochloride was intravenously administered to determine tissue hypoxia in skeletal muscle.ResultsGradual joint swelling was observed and the maximum arthritis score was noted at Week 5. In histopathology, necrosis of muscle fiber in the quadriceps femoris was observed only at Week 2 and the most significant findings such as degeneration, atrophy, and regeneration of muscle fiber were mainly observed at Week 5. Food consumption was decreased up to Week 4 but recovered thereafter. Body weight decreased up to Week 5 and did not completely recover thereafter. A biphasic increase in serum cortisol was also observed at Weeks 2 and 5. Histopathology showed that muscle lesions were mainly composed of degeneration and atrophy of the muscle fibers, and ATPase staining revealed that the changes were more pronounced in type II muscle fiber than type I muscle fiber. In the pimonidazole experiment, mosaic pattern in skeletal muscle was demonstrated in the intact animal, but not the CIA animal. Increased arthritis score was accompanied by a decrease in serum creatinine, a marker that reflects muscle mass.ConclusionsMuscle wasting might exacerbate joint swelling in a collagen-induced arthritis model of cynomolgus monkeys.

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