Novel effects of hormonal contraceptive use on the plasma proteome
Open accessAbstract
BACKGROUND: Hormonal contraceptive (HC) use may increase cardiometabolic risk; however, the effect of HC on emerging cardiometabolic and other disease risk factors is not clear. OBJECTIVES: To determine the association between HC use and plasma proteins involved in established and emerging disease risk pathways. METHOD: Concentrations of 54 high-abundance plasma proteins were measured simultaneously by LC-MRM/MS in 783 women from the Toronto Nutrigenomics and Health Study. C-reactive protein (CRP) was measured separately. ANCOVA was used to test differences in protein concentrations between users and non-users, and among HC users depending on total hormone dose. Linear regression was used to test the association between duration (years) of HC use and plasma protein concentrations. Principal components analysis (PCA) was used to identify plasma proteomic profiles in users and non-users. RESULTS: After Bonferroni correction, 19 proteins involved in inflammation, innate immunity, coagulation and blood pressure regulation were significantly different between users and non-users (P<0.0009). These differences were replicated across three distinct ethnocultural groups. Traditional markers of glucose and lipid metabolism were also significantly higher among HC users. Neither hormone dose nor duration of use affected protein concentrations. PCA identified 4 distinct proteomic profiles in users and 3 in non-users. CONCLUSION: HC use was associated with different concentrations of plasma proteins along various disease-related pathways, and these differences were present across different ethnicities. Aside from the known effect of HC on traditional biomarkers of cardiometabolic risk, HC use also affects numerous proteins that may be biomarkers of dysregulation in inflammation, coagulation and blood pressure.
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Previously, only one study has utilized a proteomic analysis method during contraceptive use.
“Previously, only one study has utilized a proteomic analysis method during contraceptive use (Josse et al., 2012).”
From Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial (2023) · cites this paper as Josse et al., 2012
Similar to our data, differences were observed in proteins related to inflammation, innate immunity, coagulation, and blood pressure regulation.
“Similar to our data, differences were observed in proteins related to inflammation, innate immunity, coagulation, and blood pressure regulation (Josse et al., 2012).”
From Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial (2023) · cites this paper as Josse et al., 2012
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“15,16 For example, a cross-sectional study on dietary patterns and the plasma proteome reported that different dietary habits 1 Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.”
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Rosati, D., Ricaño-Ponce, I., Omosa-Manyonyi, G., Bruno, M., Kamau, N. W., Jaeger, M., Kumar, V., Netea, M. G., van der Ven, A. J. A. M., & ten Oever, J. (2024) · Journal of Fungi · doi:10.3390/jof10090638 · Cited by 2 · see citing works
“Studies on healthy women also show the systemic effects of oestrogens, as hormonal contraceptives affect the plasma concentrations of proteins involved in inflammatory and immune-related pathways [5,6].”
BackgroundDierks, C., Mizrak, R. S., Shomroni, O., Farztdinov, V. M., Textoris‐Taube, K., Ludwig, D., Rainer, J., Mülleder, M., Demuth, I., & Ralser, M. (2024) · medRxiv · doi:10.1101/2024.06.22.24309293 · Cited by 2 · see citing works
“Statistical significant associations with MHT were found for peptidoglycan recognition protein 2 (PGLYRP2), angiotensinogen (AGT) and plasminogen (PLG), which have been described before to be influenced by estradiol-based hormone therapy or medication, such as hormonal contraceptives 21,71,154,155 .”
BackgroundCaffeine intake and the plasma proteome
Tian, O., Josse, A. R., & El‐Sohemy, A. (2013) · The FASEB Journal · doi:10.1096/fasebj.27.1_supplement.1080.3 · Cited by 1 · see citing works
“hormonal contraceptive use and the plasma proteome [191].”
BackgroundInfluentialMahdavi, S. M., Rosychuk, K., Jenkins, D. J. A., Percy, A. J., Borchers, C. H., & El‐Sohemy, A. (2025) · Nutrients · doi:10.3390/nu17081398 · Cited by 1 · see citing works
“Those using hormonal contraceptives were excluded due to their known effects on the plasma proteome [37], as were those missing genetic, dietary, and proteomic data.”
Martini, M., & Fairus, M. (2017) · Jurnal Kesehatan Metro Sai Wawai · doi:10.26630/jkm.v10i2.1730 · Cited by 1 · see citing works
Plasma Carotenoids and Premenstrual Symptoms in a Multi-Ethnic Population of Young Women
Kerzner, S., Zeitoun, T., Jarosz, A. C., García‐Bailo, B., & El‐Sohemy, A. (2021) · Nutrients · doi:10.3390/nu13113870 · Cited by 1 · see citing works
Sanna, S., Zhernakova, D. V., Grosso, F., Chillotti, F., Busonero, F., Camarda, S., Viscito, M., Lenarduzzi, S., Incollu, S., Vriz, G. B., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-9148671/v1 · Cited by 1 · see citing works
Mahdavi, S. S. (2018) · TSpace (University of Toronto)
Alharbi, O. (2018) · TSpace (University of Toronto)
Saghazadeh, A., Mahmoudi, M., & Rezaei, N. (2019) · Springer eBooks · doi:10.1007/978-3-030-16073-9_24
Ghosh, N., Garg, I., & Srivastava, S. (2025) · Life Sciences in Space Research · doi:10.1016/j.lssr.2025.02.008
- Authors
- Josse, A. R., Garcia-Bailo, B., Fischer, K., & El-Sohemy, A.
- Affiliations
- University of Toronto (CA)
- ORCID
- Josse, Andrea R.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-09-12
- Volume
- 7
- Issue
- 9
- Pages
- e45162
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3440362
- OpenAlex
- W1979631415
- Cited by
- 35
- References
- 43
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 4 · 2022: 3 · 2021: 1 · 2019: 2 · 2018: 4 · 2017: 4 · 2015: 3 · 2014: 1 · 2013: 6
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
- ETH Zürich Research Collection (cc-by)
- Funders
- Advanced Foods and Materials Network
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Keywords
- hormonal contraception, plasma proteome, cardiometabolic risk, inflammation, innate immunity, coagulation, blood pressure regulation, C-reactive protein, glycolipid metabolism, proteomic profile, ethnic differences, women's health
- MeSH terms
- Adult, Analysis of Variance, Blood Glucose, Blood Pressure, Blood Proteins, C-Reactive Protein, Cardiovascular Diseases, Contraceptives, Oral, Hormonal, Cross-Sectional Studies, Dose-Response Relationship, Drug, Female, Humans, Male, Risk Factors, Time Factors, Biomarkers, Linear Models, Proteome, Principal Component Analysis, Proteomics, Lipid Metabolism, Young Adult
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