Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial

Abstract

STUDY QUESTION Does an estradiol-based combined oral contraceptive (COC) have a milder effect on the serum proteome than an ethinylestradiol (EE)-based COC or dienogest (DNG) only? SUMMARY ANSWER The changes in serum proteome were multifold after the use of a synthetic EE-based COC compared to natural estrogen COC or progestin-only preparation. WHAT IS KNOWN ALREADY EE-based COCs widely affect metabolism, inflammation, hepatic protein synthesis and blood coagulation. Studies comparing serum proteomes after the use of COCs containing EE and natural estrogens are lacking. STUDY DESIGN, SIZE, DURATION This was a spin-off from a randomized, controlled, two-center clinical trial. Women (n = 59) were randomized to use either EE + DNG, estradiol valerate (EV) + DNG or DNG only continuously for 9 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were healthy, young, white volunteer women. Serum samples were collected before and after 9 weeks of hormonal exposure. Samples from 44 women were available for analysis (EE + DNG n = 14, EV + DNG n = 16 and DNG only n = 14). Serum proteins were analyzed by quantitative, discovery-type label-free proteomics. MAIN RESULTS AND THE ROLE OF CHANCE Altogether, 446 proteins/protein families with two or more unique peptides were detected and quantified. The number of proteins/families that altered over the 9-week period within the study groups was 121 for EE + DNG and 5 for EV + DNG, while no changes were detected for DNG only. When alterations were compared between the groups, significant differences were detected for 63 proteins/protein families, of which 58 were between the EE + DNG and EV + DNG groups. The most affected functions during the use of EE + DNG were the complement system, acute phase response signaling, metabolism and the coagulation system. The results were validated by fetuin-B and cortisol-binding globulin ELISA and sex hormone-binding globulin immunoassay. LARGE SCALE DATA Data are available via ProteomeXchange with identifiers PXD033617 (low abundance fraction) and PXD033618 (high abundance fraction). LIMITATIONS, REASONS FOR CAUTION The power analysis of the trial was not based on the proteomic analysis of this spin-off study. In the future, targeted proteomic analysis with samples from another trial should be carried out in order to confirm the results. WIDER IMPLICATIONS OF THE FINDINGS The EE-based COC exerted a broader effect on the serum proteome than the EV-based COC or the DNG-only preparation. These results demonstrate that the effects of EE in COCs go far beyond the established endpoint markers of estrogen action, while the EV combination is closer to the progestin-only preparation. The study indicates that EV could provide a preferable option to EE in COCs in the future and signals a need for further studies comparing the clinical health outcomes of COCs containing EE and natural estrogens. STUDY FUNDING/COMPETING INTEREST(S) Funding for this researcher-initiated study was obtained from the Helsinki University Hospital research funds, the Hospital District of Helsinki and Uusimaa, the Sigrid Juselius Foundation, the Academy of Finland, the Finnish Medical Association, the University of Oulu Graduate School, the Emil Aaltonen Foundation, the Swedish Cultural Foundation in Finland, the Novo Nordisk Foundation, Orion Research Foundation and the Northern Ostrobothnia Regional Fund. The funders had no role in study design, data collection and analysis, publishing decisions or manuscript preparation. T.P. has received honoraria for lectures, consultations and research grants from Exeltis, Gedeon Richter, MSD, Merck, Pfizer, Roche, Stragen and Mithra Pharmaceuticals. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. TRIAL REGISTRATION NUMBER ClinicalTrials.gov NCT02352090 TRIAL REGISTRATION DATE 27 January 2015 DATE OF FIRST PATIENT’S ENROLMENT 1 April 2015

Menopause Hormone Replacement Therapy and Lifestyle Factors affect Metabolism and Immune System in the Serum Proteome of Aging Individuals

“…None of the proteins investigated were associated with an underweight BMI, however, 19 proteins were linked to overweight and obesity, respectively, with APOC2 and fibulin 1 (FBLN1) showing novel associations with elevated BMI 21,[43][44][45][46][47] . We found new associations with HCU in 15 out of 55 proteins that had not been reported in the related studies before 21,[48][49][50] , such as the phospholipid transfer protein (PLTP), monocyte differentiation antigen (CD14), alpha-1-antichymotrypsin (SERPINA3) and the coagulation factor V (F5) (see Figure 2). Among all covariates, highest effect sizes and significance were reported for HCU (see Figure 1D) with the top 5 candidates being angiotensinogen (AGT), peptidoglycan recognition protein 2 (PGLYRP2), serpin family A member 6 (SERPINA6), fetuin B (FETUB) and ceruloplasmin (CP).…”

Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis

“…Metformin has previously been shown to decrease CRP, both in obese and nonobese women, compared with placebo ( 83 ). COCP appears to increase CRP ( 79 , 84 , 85 ), yet the significance of these effects remains unknown.…”

Pervasive Influence of Hormonal Contraceptives on the Human Plasma Proteome in a Broad Population Study

“…Indeed, an impact of oral contraceptives, and to a lower extend also of the menstrual cycle, on plasma protein and metabolite abundances has also been reported previously (Klipping et al, 2021; Ramsey et al, 2016), yet, the use of hormonal contraceptives is not yet systematically accounted for in the typical epidemiological studies. In the liver, oral contraceptives stimulate the synthesis of steroid-binding globulins, such as sex hormone-binding globulin (SHBG), thereby affecting circulating, free steroid levels and they further increase low-grade inflammation, alter lipid metabolism and affect the coagulation system, resulting in an increased risk for thromboembolic events (Kangasniemi et al, 2023). We were able to independently validate these findings using our extensive dataset, which identifies a substantial number of plasma proteins that are significantly impacted by the use of oral hormonal contraceptives.…”