The effects of A-ring and D-ring metabolites of estradiol on the proliferation of vascular endothelial cells

The effects of 14 estradiol metabolites on the proliferation of cultured en dothelial cells of human umbilical cord veins were examined and compared wi th that of their parent substance estradiol. The relationship between dosag e and effect was tested over the pharmacological concentration range of 10( -8) to 10(-5) M. Estradiol showed a biphasic behaviour, in the form of stim ulation at low concentrations and inhibition at the highest concentration. All 10 A-ring metabolites tested stimulated the growth of the endothelial c ells at the lower concentrations. At the highest concentration, the 5 A-rin g metabolites: 2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestriol, 4-hy droxyestrone and 4-hydroxyestradiol caused significant inhibitions. Except for the 2-hydroxyestradiol, methylation of these metabolites resulted in th e loss of the proliferation inhibiting effect. The D-ring metabolites showe d no marked effects compared to the A-ring metabolites except for 16 alpha- hydroxyestrone which had an inhibiting effect from 10(-7) to 10(-5) M. Our results show that estradiol metabolites can influence the growth of vascula r endothelial cells in the concentration range tested. While the antiprolif erative action of 2-methoxyestradiol has been known for some time this stud y is the first to show the potential capacity of non-methylated metabolites of the A-ring metabolism in inhibiting endothelial proliferation. This may open up new clinical pharmacological aspects in the anti-angiogenetic trea tment of tumors. (C) 2000 Elsevier Science Inc. All rights reserved.