Aspects on the Mode of Action of Antiestrogens and Antiprogestogens

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Abstract
Most so-called antiestrogens are ‘estrogenic’ in the mouse uterine growth test and in the Allen-Doisy test (in mice or rats). With regard to their uterotrophic effects, they were classified as giving normal (cis- and trans-clomiphene, ICI-46,474 and U-11,555A); impeded (estriol, DMS and ent-estradiol); partial (U-11100A and CN- 55,945) or practically no response (MER-25). A similar classification was obtained in a modified Allen-Doisy test in mice. As antiestrogens, the impeded estrogens are fairly inactive, while compounds such as U-11100A, CN-55,945 and MER-25 are more effective. This difference could be traced back to differences in interaction with estradiol-17Β at the uterine level: the impeded estrogens have rather high affinities for estrogen receptors but are easily lost to the circulation while the other compounds have lower affinities but still remain on the receptors for a longer period of time. Compounds U-11,555A, U-11100A, MER-25, ICI-46,474 and 66/179 produced an estrogen-like ultrastructural picture of the luminal epithelium of the rat uterus. However, when given before a standard dose of estradiol-17Β to a progesterone-treated rat, all except U-11,555A, which was inactive, were antiestrogenic, i. e., inhibited the so-called attachment reaction which is believed to be a prerequisite for implantation of the ovum. Two compounds, R2323 and 66/179 which have been described as antiprogestational, could not selectively counteract the effects of progesterone on rat uterine epithelial ultrastructure. Closer analysis of the ultrastructural effects of MER-25 revealed that at doses which are negative in conventional tests for estrogenicity the whole uterus looked atrophic except the uterine luminal epithelium which showed marked estrogen-like stimulation.

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