CARCINOGENIC ACTIVITIES OF VARIOUS STEROIDAL AND NONSTEROIDAL ESTROGENS IN THE HAMSTER-KIDNEY - RELATION TO HORMONAL ACTIVITY AND CELL-PROLIFERATION

The therapeutic use of estrogens has been associated with an increased risk of same of the most predominant, as well as less prevalent, canc ers in women, The estrogen-induced renal tumor is one of the primary a nimal models to evaluate the carcinogenic properties of estrogens. Cor relations were made with various estrogens by using parameters of estr ogenicity end points such as competitive binding, progesterone recepto r induction, and alterations in prolactin levels; in vitro renal proxi mal cell proliferation; and in vivo estrogen-induced carcinogenicity. The most potent estrogens were Moxestrol (MOX), diethylstilbestrol (DE S), and 17 beta-estradiol, followed by indenestrol B, 16 alpha-hydroxy estrone, and 11 beta-methoxyestradiol with moderate estrogenic activit ies, whereas 11 beta-methytestradiol, 17 alpha-estradiol, indanestrol, and deoxoestrone were all relatively weaker. As expected, hydrolyzed Premarin (unconjugated estrogens) was strongly estrogenic Of the estro gens tested, MOX was the most potent carcinogenic estrogen in the hams ter kidney. Both 16 alpha-hydroxyestrone and 11 beta-methoxyestradiol induced intermediate tumor incidences with distinctly lower frequencie s of renal tumor foci compared to the most potent carcinogenic estroge ns. However, hamsters treated for 9.0 months with 11 beta-methylestrad iol, 17 alpha-estradiol, deoxoestrone, and indanestrol exhibited no tu mors. In contrast, treatment with estrone, equilin plus d-equilenin, a nd hydrolyzed Premarin for the same time period resulted in 100% renal tumor incidences and numerous tumor foci. Cell proliferation studies of cultured hamster kidney proximal tubule cells were carried out at v arying estrogen concentrations (0.01-100 nM). Exposure to MOX resulted in consistently high renal cell proliferative response over a concent ration range of 0.1-10 nM. Strongly carcinogenic estrogens such as est rone had a maximal renal cell proliferation response (2.4-fold above u ntreated control levels) between 0.1 and 10 nM, DES and 17 beta-estrad iol responded at 1.0 nM, and 4-hydroxyestradiol responded at 10 nM. In terestingly, exposure to ethinylestradiol, a potent estrogen, at simil ar or higher doses as those used for DES and 17 beta-estradiol, yielde d only a 10% renal tumor incidence and induced only a 1.7-fold increas e in proximal tubule cell proliferation. In contrast, 17 alpha-estradi ol, deoxoestrone, indanestrol, and 11 beta-methylestradiol, all weakly estrogenic and noncarcinogenic agents, had relatively little effect o n tubule cell proliferation. The hydrolyzed Premarin exhibited a maxim al 2.0-fold cell proliferative response at 10 nM. The present results provide clear evidence that, in the hamster kidney, the degree of carc inogenicity of a given estrogen correlates with its ability to induce proximal tubule cell proliferation in vitro. Therefore, the ability of estrogen to enhance tubule cell proliferation is a more accurate indi cator of its carcinogenicity in this system than either the estrogen-r esponsive end points used or the amount of catechol metabolites genera ted in this tissue as reported earlier.