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Relative Carcinogenic Activity of Various Synthetic and Natural Estrogens in the Syrian Hamster Kidney¹

Medical Research Laboratories, Veterans Administration Medical Center [J. J. L.], and Departments of Urological Surgery [J. J. L., S. A. L., J. K. K.], Anatomy [J. A. P.], and Laboratory Medicine and Pathology [L. K. T. L.], University of Minnesota Medical School, Minneapolis, Minnesota 55455

Both synthetic and natural estrogens have been studied for their ability to induce renal carcinomas in castrated male hamsters after 9.0 months of treatment. Tumor foci were detected in frozen serial sections stained histochemically for esterase activity. Both diethylstilbestrol (DES) and 17ß-estradiol had equal ability (100%) to induce renal tumors [20.5 ± 3 (S.E.) tumor foci] in these animals. Hexestrol induced the same incidence and number of renal carcinoma foci as DES or 17ß-estradiol. However, -dienestrol and DES 3,4-oxide showed an 86 to 88% incidence of renal tumors in hamsters (10.8 ± 3). When equilin and d-equilenin, components of therapeutic conjugated estrogens, were tested, only equilin had a 76% incidence of renal tumor foci (5.5 ± 0.9). The ability of these stilbene and steroidal estrogens to compete for renal tumor estrogen receptor generally correlated well with their ability to cause renal tumorigenesis in the hamster with one notable exception. Although ethinyl estradiol competed as well as did DES or 17ß-estradiol for estrogen receptor, had similar ability to induce renal progesterone receptor, and led to similar high serum prolactin levels as either DES or 17ß-estradiol, it had only weak carcinogenic activity (21%) in the hamster kidney (0.6 ± 0.5 foci). These data represent the first detailed analysis of the relative carcinogenic activity of different estrogens within a given tumor-inducing system, and based on the carcinogenicity data of hexestrol and -dienestrol presented herein, they suggest that epoxidation of the olefinic double bond and the p-quinone metabolite of DES probably are not involved significantly in its carcinogenic activity. Moreover, the poor carcinogenic activity of ethinyl estradiol in this system, despite strong estrogenicity, suggests that estronic activity alone may not be sufficient to effect renal tumorigenesis in the hamster.

¹ This investigation was supported by Grant CA 22008 from the National Cancer Institute, NIH, Department of Health and Human Services, and the General Medical Research Fund of the Veterans Administration. Presented in part at the 24th Congress of the European Society of Toxicology, Satellite Symposium on the Mechanisms of Estrogen Carcinogenicity: Role of Metabolites, Rome, Italy, March 31, 1983.

² To whom requests for reprints should be addressed, at the Medical Research Laboratories, Veterans Administration Medical Center, 54th Street and 48th Avenue South, Minneapolis, Minn. 55417.

³ Recipient of Grant AM 26962 of the NIH, Department of Health and Human Services.

Received 5/ 6/83. Accepted 8/ 2/83.

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