Interaction of progestins with steroid receptors in human uterus

Abstract

Norethindron (17.beta.-hydroxy-19-nor-17.alpha.-pregn-4-en-20-yn-3-one) and norethindron acetate (17.beta.-acetoxy-19-nor-17.alpha.-pregn-4-en-20-yn-3-one) interfered to a varying degree, by competitive inhibition, with the binding of progesterone and estradiol to respective cytoplasmic receptors in the human uterus. Progesterone binding to 4S macromolecule was saturable and co-specific for progestins. Competitors like norgestrel (17.beta.-hydroxy-18-methyl-19-nor-17.alpha.-pregn-4-en-20-yn-3-one), 19-norprogesterone, medroxyprogesterone acetate (17.alpha.-acetoxy-6.alpha.-methylpregn-4-ene-3,20-dione) and compound R5020 (17,21-dimethyl-19-norpregna-4,9-diene-3,20-dione) possessed higher binding affinities for the progestin receptor. The Kd for the progesterone-receptor interaction was 0.6-1.6 nM and the receptor concentration ranged between 6600 and 8200 sites/cell. Norethindrone and norethindrone acetate competed for the progesterone receptor with inhibition constants (Ki) of 6.8 and 72 nM respectively. Gradient displacement and competitive-receptor assays indicated that norethindrone acetate-binding affinity for progestin receptor was approximately 1/10 that of norethindrone and progesterone. The progestins also inhibited estradiol binding to 4.6S estrogenic receptor by 8-12%, involving interaction at the estradiol-binding site with a calculated Ki value of 0.5-0.8 .mu.M. The competitive interaction of progestins with steroid receptors may be of putative importance in explaining the progestin action at the target site.