EE has, albeit rarely (at the low dosages that are now used in COCs), been associated with cholestatic hepatotoxicity similarly to 17α-alkylated anabolic-androgenic steroids and 17α-ethynylated 19-nortestosterone progestins [REF].
The high doses of EE that were used in early COCs were associated with a significantly increased risk of endometrial cancer in certain preparations, for instance those containing the progestogen dimethisterone [REF].