Introduction
ADVERSE EVENTS
In addition to the contraceptive effect, combined oral contraceptives (COCs) have vast effects on female physiology. In the liver, COCs stimulate the synthesis of steroid-binding globulins, such as sex hormone-binding globulin (SHBG), thereby affecting circulating, free steroid levels (The net effect of COCs results from both estrogen and progestin action and their interplay (Recently, natural estrogens have been included in COCs to reduce EE-related adverse events. New combinations containing E2, its ester estradiol valerate (EV), and estetrol (E4) have proven effective in combined contraceptives. They induce good cycle control and provoke less marked changes in metabolic and endocrine parameters compared with EE (Serum proteomic analysis provides an option to investigate the broad pharmacodynamic effects during medication use. Instead of specific, planned targets, this shotgun method analyzes all proteins and enables a broad overview and novel findings. To our knowledge, this is the first study to utilize such discovery-type proteomic analysis on hormonal contraceptives.This study compared changes induced in the serum proteome during the use of COCs containing different estrogen components. A progestin-only preparation (containing the same progestin) was included as an active control. This study is a spin-off of a larger randomized controlled trial comparing the metabolic effects of EE + dienogest (DNG), EV + DNG and DNG only. We hypothesized that the EV + DNG preparation would have a milder impact on the serum proteome than that of EE + DNG and that the effect of DNG only would be neutral.