MECHANISM OF ANTIPROGESTATIONAL ACTION OF SYNTHETIC STEROIDS

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Abstract
This study was designed to investigate the mechanism of antiprogestational action of synthetic steroids, danazol (17.alpha.-hydroxy-pregn-4-en-20-yno [2,3-d] isoxazol-17-ol) and R2323 (13.beta.-ethyl-17.alpha.-hydroxy-18,19-dinor-17.alpha.-pregna-4,9,11-trien-20-yn-3-one). Estrogen primed rabbit uteri were used for this study. The sucrose gradient analysis in the supernatant of 248 000 .times. g (maximum) of the uterine homogenate showed that progesterone-8S binding was inhibited by each synthetic steroid, and the kinetic study revealed that each steroid was a competitive inhibitor, where Kd of progesterone-protein binding was 8.1 .times. 10-10 M, Ki of danazol-protein binding was 2.7 .times. 10-8 M and Ki of R2323-protein binding was 6.6 .times. 10-9 M. Apparently these synthetic steroids bind to progresterone receptor with moderate binding affinities. The modified Anderson''s exchange assay of nuclear receptor demonstrated that danazol- or R2323-receptor complex can enter into the uterine nuclei in a lesser degree than does progesterone-receptor complex. RNA synthesis by the uterine chromatin was stimulated if the progesterone-receptor complex was added, but this stimulation was inhibited by addition of danazol or R2323. The chromatin RNA transcription was not induced by danazol- or R2323-receptor complex. Apparently such a synthetic steroid binds to a progesterone receptor, and the steroid-receptor complex enters into the nucleus but does not activate the chromatin template, thus resulting in the antiprogestational effect.