EE, following oxidative formation of a very reactive metabolite, irreversibly inhibits cytochrome P450 enzymes involved in its metabolism, and this may also play a role in the increased potency of EE relative to estradiol. Indeed, EE is said to have a marked effect on hepatic metabolism, and this is one of the reasons, among others, that natural estrogens like estradiol may be preferable. A 2-fold accumulation in EE levels with an EE-containing COC has been observed following 1 year of therapy.