Association of estrogens with human plasma lipoproteins: studies using estradiol-17beta and its hydrophobic...

Estrogen replacement therapy is widely used to combat symptoms of menopause, but factors influencing the transport of estrogen in plasma and its cellular uptake have been explored only to a limited extent. In this study, labeled estradiol-17beta (E2) was compared with its hydrophobic derivative (estradiol-3,17-diacetate, E2AA) in terms of (1) distribution within various lipoproteins and lipoprotein-free fractions of human plasma by ultracentrifugation and (2) uptake by human endothelial cells. Although added E2 was predominantly bound to HDL and lipoprotein-free fractions, E2AA was associated to some degree with VLDL and LDL but was still present in significant amounts in HDL and lipoprotein-free fractions. Significant associations of E2 with lipoproteins were also confirmed by polyacrylamide gel electrophoretic separation of E2-labeled plasma. In normal plasma, however, <10% of E2 was associated with lipoproteins when measured by radioimmunoassay. Incubation of E2AA and E2 with human dermal capillary endothelial cells showed similar uptake by 24 hours. A significant portion of E2AA was hydrolyzed to estradiol-17-monoacetate both in plasma and in cells. The addition of HDL and LDL to medium containing lipoprotein-deficient serum significantly reduced labeled E2 and E2AA uptake, respectively, by endothelial cells. These studies suggest that (1) although the association of E2 with HDL under normal conditions may be small, it increases significantly with higher estrogen concentrations of E2; (2) the hydrophobic ester of E2 shows increased binding to VLDL and LDL; and (3) this approach may be useful in manipulating the delivery of selected E2 derivatives to cells.