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

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:36416543", "kind": "science-record", "revision": 3, "content_hash": "sha256:d93535276b2b052f46737b43f9423b610777128fa46327d764d8bdf6b3925d83", "created_at": "2026-11-01T19:00:53Z", "updated_at": "2026-11-01T22:08:08Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial.", "doi": "10.1093/humrep/deac250", "pmid": "36416543", "authors": ["M H Kangasniemi", "R K Arffman", "S Joenväärä", "A Haverinen", "K Luiro", "T Tohmola", "R Renkonen", "O Heikinheimo", "J S Tapanainen", "T T Piltonen"], "journal": "Human reproduction (Oxford, England)", "year": 2023, "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?\nSUMMARY 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.\nWHAT 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.\nSTUDY 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.\nPARTICIPANTS/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.\nMAIN 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.\nLARGE SCALE DATA: Data are available via ProteomeXchange with identifiers PXD033617 (low abundance fraction) and PXD033618 (high abundance fraction).\nLIMITATIONS, 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.\nWIDER 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.\nSTUDY 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.\nTRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02352090.\nTRIAL REGISTRATION DATE: 27 January 2015.\nDATE OF FIRST PATIENT’S ENROLMENT: 1 April 2015.", "claims": [{"id": "claim-method", "statement": "The changes within the study groups were analyzed with the Wilcoxon test using the Benjamini–Hochberg procedure to control false discovery rates. To investigate the differences between the study groups, we calculated the difference between the baseline and 9 weeks for all proteins. These differential variables were then analyzed with the Kruskal–Wallis test and the Benjamini–Hochberg procedure. 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The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (Perez-Riverol et al., 2022) partner repository with the dataset identifiers PXD033617 and 10.6019/PXD033617 for the low-abundance proteins and PXD033618 and 10.6019/PXD033618 for the high fraction."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The EE-based COC exerted a broader effect on the serum proteome than the EV-based COC or the DNG-only preparation.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:36416543", "locator": "sections[0] \"Abstract\" paragraph 9", "quote": "The EE-based COC exerted a broader effect on the serum proteome than the EV-based COC or the DNG-only preparation."}, {"asset": "source:pmid:36416543", "locator": "sections[0] \"Abstract\" paragraph 6", "quote": "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."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "The EE-based COC exerted a broader effect on the serum proteome than the EV-based COC or the DNG-only preparation.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:36416543"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "blocked", "blocked_on": "data:accession_absent", "description": "The GEO series accession resolves and its sample accessions are listed. 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