The effects of medroxyprogesterone acetate (MPA) (I) and related compounds (II-VI) upon angiogenesis induced by basic fibroblast growth factor (bFGF) or transforming growth factor-alpha (TGF-alpha) were investigated using a rabbit corneal system for assay of angiogenesis. Dexamethasone (Dex) was used as a positive control. The MPA analogues tested were 6,6'-dehydro-MPA (II), megestrol acetate (III), 1-dehydromegestrol acetate (IV), melengestrol acetate (V), and 1-dehydromelengestrol acetate (VI). The inhibitory activities of these steroids using bFGF were in the order: Dex = MPA = (VI) = (V) > (IV) > (III). Steroid (II) was inactive. 5 alpha-dihydrotestosterone was weakly active, while estradiol-17 beta and progesterone were inactive. The angiostatic activity of MPA was completely abolished by mefipristone (RU 486) which showed no anti-angiogenic activity in this assay. With TGF-alpha, the order of angiostatic activities was Dex = (VI) > (IV) > (III) > (V). Steroid (II) was again inactive. Dex, MPA, and all the MPA analogues except steroid (II) markedly inhibited the activity of plasminogen activator secreted by cultured calf pulmonary artery endothelial cells, but did not inhibit growth of these cells. The binding affinities of MPA and its analogues to glucocorticoid, progesterone and androgen receptors were determined, but were found not to be correlated with their angiostatic activities.