Estrogens, autoimmunity and the heart.

Systemic inflammatory/autoimmune rheumatic diseases are associated with a significantly increased rate of atherosclerosis and cardiovascular disease. Several mechanisms of accelerated atherosclerosis have been proposed, including abnormal lipid and lipoprotein profiles, oxidative stress, enhanced apoptosis, thrombophilia, immune complexes and increased mononuclear cell infiltration of atherosclerotic lesions, local generation of cytokines and female estrogen deficiency. However, the widely shared enthusiasm about the cardioprotective potential of hormone replacement therapy (HRT) with estrogens, has come to an abrupt halt since very recent randomized trials failed to show a cardiovascular risk reduction in postmenopausal women. Several factors might play a role in these discrepancies, in particular, parts of the striking discrepancy between observational and randomized data have been attributed to an estrogen-mediated adverse effect on inflammation (enhancement, possibly dose-related). In fact, estrogens potentially increase the inflammatory/immune response in autoimmune rheumatic diseases. New roles for estrogen peripheral metabolites (hydroxylated) and their increased formation in inflammatory sites, might partially introduce some explanations for several apparently contrasting evidences.