Extensive modulation of the circulating blood proteome by hormonal contraceptive use across two population studies

BACKGROUND: The study of circulating blood proteins in population cohorts offers new avenues to explore lifestyle-related and genetic influences describing and shaping human health. METHODS: Utilizing high-throughput mass spectrometry, we quantified 148 highly abundant proteins, functioning in the innate and adaptive immune system, coagulation and nutrient transport in 3632 blood plasma, and 500 serum samples from the CHRIS and BASE-II cross-sectional population studies, respectively. Through multiple regression analyses, we aimed to identify the main factors influencing the circulating proteome at population level. RESULTS: Many demographic covariates and common medications affect the concentration of high-abundant plasma proteins, but the most significant changes are linked to the use of hormonal contraceptives (HCU). HCU particularly alters amongst others the levels of Angiotensinogen and Transcortin. We robustly replicated these findings in the BASE-II cohort. Furthermore, our results indicate that combined hormonal contraceptives with ethinylestradiol have a stronger effect compared to bioidentical estrogens. Our analysis detects no lasting impact of hormonal contraceptives on the plasma proteome. CONCLUSIONS: HCU is the dominant factor reshaping the high-abundant circulating blood proteome in two population studies. Given the high prevalence of HCU among young women, it is essential to account for this treatment in human proteome studies to avoid misinterpreting its impact as sex- or age-related effects. Although we did not investigate the influence of HCU-induced proteomic changes on human health, our data suggest that future studies on this topic are warranted. Millions of women use hormonal contraceptives which can cause side effects, such as skin issues, stomach problems, mood changes, and high blood pressure. In two population studies, we studied the effects of age, sex, body mass index and hormonal contraceptives on the abundance of proteins that are necessary for all aspects of normal body function. We found that hormonal contraceptives had by far the biggest impact on over one-third of the examined proteins, many of which are related to health status and lifestyle. Contraceptives with synthetic estrogen had a stronger effect than those made to be chemically identical to the ones naturally occurring. However, we found no lasting changes in blood proteins after stopping contraceptive use. These results highlight the importance of considering contraceptive use in future research to distinguish the role of contraceptives from age and sex effects, and to better understand their impact on health. eng

• Dordevic, N.
• Dierks, C.
• Hantikainen, E.
• Farztdinov, V.
• Amari, F.
• Verri Hernandes, V.
• De Grandi, A.
• Domingues, F. S.
• Shomroni, O.
• Textoris-Taube, K.
• Bahr, V.
• Schmid, H.
• Demuth, I.
• Kurth, F.
• Mülleder, M.
• Pramstaller, P. P.
• Rainer, J.
• Ralser, M.