EE has rarely (at the low dosages that are now used in COCs) been associated with cholestatic hepatotoxicity similarly to 17α-alkylated androgens/anabolic steroids and 17α-ethynylated 19-nortestosterone progestins. Glucuronide metabolites of EE, via effects on the ABCB11 (BSEP) and MRP2 (ABCC2) proteins and consequent changes in bile flow and bile salt excretion, appear to be responsible for the cholestasis. High concentrations of estradiol, via its metabolite estradiol glucuronide, are also implicated in cholestasis, for instance in cholestasis of pregnancy. However, the incidence and severity of cholestatic hepatotoxicity appear to be much greater with EE than with estradiol, which is due to its 17α-ethynyl substitution and consequent reduced metabolism.