The interaction of C-17 esters of estradiol with the estrogen receptor.

Various C-17 alkyl esters of estradiol (E2) were tested as ligands for the estrogen receptor. The naturally occurring fatty acid esters, represented by E2-17-stearate, E2-17-palmitate, and E2-17-arachidonate, did not compete with [3H]E2 for receptor-binding sites. [3H]E2-17-stearate did not bind in a specific or saturable manner to uterine cytosol. On the other hand, the long-acting pharmacological esters of E2, E2-17-acetate, -propionate, -valerate, etc., were highly effective in competing for the binding of [3H]E2 to the uterine receptor. However, it was found that these short chain esters were hydrolyzed to E2 when incubated with uterine cytosol under the conditions used for the binding assay. Consequently, [3H]E2-17-acetate and [3H] E2-17-valerate were tested as ligands in an assay in which the hydrolytic activity was minimized by partially purifying the receptor with (NH4)2SO4 precipitation and by limiting the duration of the incubation. In this assay there was no specific binding of the C-17-valerate ester. There was a relatively small amount of specifically bound radioactivity in the incubation of the acetate ester, but upon high performance liquid chromatographic analysis, the specifically bound steroid was found to be E2 and not the ester. These results indicate that the C-17 esters of E2, from C2 to the long chain fatty acids, all of which are potent long-acting estrogens, exert their estrogenic effects only after hydrolysis to the free C18 steroid.