Cardiovascular pharmacology of estradiol metabolites

A discussion of the role of endogenous estradiol metabolites in mediating important biological actions of estradiol is essentially nonexistent in standard textbooks of pharmacology and endocrinology. Indeed, the prevailing view is that all biological effects of estradiol are initiated by binding of estradiol per se to estrogen receptors and that estradiol metabolites are more or less irrelevant. This orthodox view, which is most likely incorrect, is the fundamental premise (an estrogen is an estrogen is an estrogen) underlying the design of important clinical trials such as the Heart and Estrogen/Progestin Replacement Study and the Women's Health Initiative Study. Accumulating data provide convincing evidence that some metabolites of estradiol, the major estrogen secreted by human ovaries, are biologically active and mediate multiple effects on the cardiovascular and renal systems that are largely independent of estrogen receptors. More specifically, metabolites of estradiol, particularly catecholestradiols and methoxyestradiols, induce multiple estrogen receptor-independent actions that protect the heart, blood vessels, and kidneys from disease. These protective effects are mediated in part by the inhibition of the ability of vascular smooth muscle cells, cardiac fibroblasts, and glomerular mesangial cells to migrate, proliferate, and secrete extracellular matrix proteins, as well as by an improvement in vascular endothelial cell function. The purpose of this review is to highlight the cardiovascular and renal pharmacology of catecholestradiols and methoxyestradiols. The take home message is simple: that when it comes to cardiovascular and renal protection, the concept that all estrogenic compounds are created equal may not be true.