COMT and hyperhomocysteinemia: This mechanistic hypothesis suggests that hyperhomocysteinemia exerts its pathogenic effects largely through metabolic accumulation of intracellular SAH, a strong non-competitive inhibitor of the catechol-O-methyltransferase (COMT)-mediated methylation metabolism of endogenous and exogenous catechols (including 2-OH-E2 and 4-OH-E2) [19,20].