Agonistic and antagonistic effects of clomiphene citrate and its isomers.

Abstract

The agonistic and antagonistic properties of clomiphene citrate (CL) and its isomers were examined in the rat uterus. Immature rats (21 days old) were injected with various doses of estradiol benzoate (EB), CL, zuclomiphene (ZUC, cia isomer), and enclomiphene (ENC, trans isomer), and uterine weight or epithelial cell height was measured. EB treatment produced a typical doseresponse curve for uterine weight with a steep slope, while the curves resulting from treatment with CL, ZUC, or ENC were attenuated with a very shallow slope. These differences in shapes of the dose-response curves render the determination of relative potency estimates inaccurate and misleading. In contrast, the shapes of the dose-response curves for epithelial cell hypertrophy were similarforallfour compounds. EB was more potent than any form of clomiphene;however,the maximum extent of cellular hypertrophy was not as great. The half maximal dose for each compound was EB, 0.35 ± 0.04 Mg; ENC, 25.0 ± 2.0 Mg; CL, 35.0 ± 3.1 Mg; and ZUC, 65.0 ± 7.1 ug. The ability of these drugs to antagonize the action of EB was examined by injecting EB plus CL, ZUC, or ENC and measuring the uterine weight or epithelial cell hypertrophy 72 h later. All three forms of the drug were antagonistic to EB-induced uterine weight gain over the same dose ranges in which they were agonistic by themselves. No antagonistic effects were observed on estradiol stimulation of epithelial cell hypertrophy. These data show that CL and its isomers are fully capable of stimulating epithelial cell hypertrophy in the rat uterus, and thus, valid relative potency estimates can be obtained with this response. This is not true when uterine weight gain is used because differential cell stimulation is not taken into account. In addition, CL and its isomers are agonistic and antagonistic over the same dose ranges when uterine weight gain is used; however, no antagonism of estrogen-stimulated cellular hypertrophy is measured. Therefore, broad generalizations concerning the estrogenicity or antiestrogenicity of these compounds are not warranted and can be made only when specific endpoints are evaluated.