Association of estrogens with human plasma lipoproteins: Studies using estradiol-17β and its hydrophobic derivative

Abstract

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-17β (E 2) was compared with its hydrophobic derivative (estradiol-3,17-diacetate, E 2AA) 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 E 2 was predominantly bound to HDL and lipoprotein-free fractions, E 2AA 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 E 2 with lipoproteins were also confirmed by polyacrylamide gel electrophoretic separation of E 2-labeled plasma. In normal plasma, however, < 10% of E 2 was associated with lipoproteins when measured by radioimmunoassay. Incubation of E 2AA and E 2 with human dermal capillary endothelial cells showed similar uptake by 24 hours. A significant portion of E 2AA was hydrolyzed to estradiol-17-onoacetate both in plasma and in cells. The addition of HDL and LDL to medium containing lipoprotein-deficient serum significantly reduced labeled E 2 and E 2AA uptake, respectively, by endothelial cells. These studies suggest that (1) although the association of E 2 with HDL under normal conditions may be small, it increases significantly with higher estrogen concentrations of E 2; (2) the hydrophobic ester of E 2 shows increased binding to VLDL and LDL; and (3) this approach may be useful in manipulating the delivery of selected E 2 derivatives to cells.