Metabolic impact of combined hormonal contraceptives containing estradiol

Introduction: Is the replacement of ethinyl-estradiol (EE) with estradiol (E2) in combined hormonal contraceptives (CHCs) associated with fewer metabolic effects, leading to a further improvement on safety of hormonal contraceptives?Areas covered: This is a narrative review paper including all available data on the metabolic impact of CHCs containing E2 published in English up to December 2015. Modification of a metabolic variable of interest during the first months of treatment was considered as an outcome.Expert opinion: E2 was extensively used in oral contraceptives associated to nomegestrol acetate (NOMAc) in a monophasic 24 + 4 or its ester E2 valerate to dienogest (DNG) in a quadriphasic 26 + 2 regimen. The impact on the lipid metabolism and the hemostatic system of these preparations seems milder than that caused by EE-based ones, associated with no change of blood pressure. The impact on bone metabolism was instead similar to EE. Data available in the literature are mainly derived from studies having secondary minor metabolic outcomes as the primary end-point, and so currently not completely applicable on the real variables of interest (arterial or venous cardiovascular events, bone fractures). The preliminar parenteral use of E2 seems promising, both transdermal and vaginal, in particular after the introduction of a specific progestin with a high anti-ovulatory activity, like nestorone.