Metabolism of Estradiol Fatty Acid Esters in Man*

Abstract

Fatty acid esters of estradiol coupled at the C-17 position are naturally occurring metabolites of estradiol (E₂). They have been recovered after incubation of E₂ with human tissue and identified in human plasma. We investigated the primary metabolic transformation of E₂, namely C-17 oxidation, of two representative fatty acid esters, in five normal subjects (four men and one woman), aged 25-55 yr, using a radiometric method. The transfer of tritium from the C-l7α position to tritium water after iv injection of free E₂ was compared to that of E₂-17β-stearate and E₂-17β-arachidonate. Both esters were oxidized at the C-17 position to a greater extent than was free E₂. In addition, the oxidation of the E₂ fatty acid esters proceeded more slowly. Thus, the time necessary to reach half the maximal extent of reaction ranged from 30-45 min for the three E₂-17/3- arachidonate studies and from 2.5-4 h for the five E₂-17β- stearate studies, while that for free E₂ was less than 15 min in each instance. The disappearance of intact E₂-17β-stearate from plasma after bolus injection was studied in two subjects (one of the five above and one additional subject). The t values calculated for the 0−60 min period were 24 and 16 min. The rate of disappearance of E₂-17β-stearate was slower than that of E₂. The biological activity of E₂ esters is thought to reside in their ability to be converted, by hydrolysis, to free E₂. The E₂ esters must undergo hydrolysis before the oxidation of free E₂ to estrone can proceed. Since the oxidation reaction is extremely rapid, studying the rate of oxidation after injection of the E₂ fatty acid esters provides an index of their in vivo hydrolysis and, thus, a measure of their subsequent biological activity as the free hormone. The unsaturated arachidonate ester of E₂ was oxidized at a faster rate than the saturated stearate ester; this implies that the hydrolysis of the arachidonate ester was faster. Evidence of continuing oxidation of E₂-17β-stearate at times well after its level in plasma markedly decreased indicates that the ester is removed from the circulation before its subsequent hydrolysis and oxidation. We conclude that in man, the C-17 oxidation of both E₂-17β- arachidonate and E₂-17β-stearate proceeds more slowly but to a greater extent than that of the free steroid. The expected biological consequences of these differences would be delayed onset, increased intensity, and prolonged duration of the estrogenic activity of the fatty acid esters of E₂ relative to the unesterified steroid.