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Cited by 19Reproductive Health and ContraceptionEstrogen and related hormone effectsEffects and risks of endocrine disrupting chemicals

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

Open access
Kangasniemi, M H, Arffman, R K, Joenväärä, S, Haverinen, A, Luiro, K, Tohmola, T, Renkonen, R, Heikinheimo, O +2 more·2023·Human Reproduction
DOI 10.1093/humrep/deac250PMC PMC9825269
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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

AI snapshot

Written from the paper’s full text.

TL;DR

In a randomized spin-off trial, an ethinylestradiol-based combined oral contraceptive altered many more serum proteins than an estradiol valerate-based combined oral contraceptive or dienogest alone. The findings suggest EE has broader systemic proteomic effects, while EV more closely resembles the progestin-only preparation.

Key findings

  • Among 446 quantified proteins/protein families, 121 changed significantly within the EE + DNG group versus 5 in EV + DNG and none in DNG only over 9 weeks.
  • Between-group differences were significant for 63 proteins/protein families: 58 for EE + DNG vs EV + DNG, 61 for EE + DNG vs DNG only, and 17 for EV + DNG vs DNG only.
  • The most affected functions during EE + DNG use were the complement system, acute phase response signaling, metabolism, and the coagulation system; validation showed EE + DNG increased fetuin-B, CBG, and SHBG more than the other preparations.

Methods

  • Spin-off from a randomized, controlled, two-center clinical trial; 59 healthy women were randomized to EE + DNG, EV + DNG, or DNG only continuously for 9 weeks, with serum samples available from 44 women (EE + DNG n = 14, EV + DNG n = 16, DNG only n = 14).
  • Serum proteins were analyzed by quantitative, discovery-type label-free proteomics using high- and low-abundance fractions, with peptide identification/quantitation and pathway analysis.
  • Within-group changes used Wilcoxon tests with Benjamini–Hochberg correction; between-group differences used Kruskal–Wallis with Benjamini–Hochberg and Mann–Whitney post hoc tests; fetuin-B ELISA, CBG ELISA, and SHBG immunoassay were used for validation.

Limitations

  • Stated by the paper: the trial’s power analysis was not based on the proteomic analysis of this spin-off, and future targeted proteomic analysis with samples from another trial should confirm the results.
  • Stated by the paper: the 9-week study period is relatively short for concluding long-term effects, and discovery-type quantitation is less accurate than targeted methods.
  • Evident from the text: the analyzed groups were small (n = 14–16), participants were healthy, young, white volunteer women, and the original trial excluded women over 35 years, BMI ≥25 kg/m², smokers, and those with COC contraindications, limiting generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/humrep/deac250

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 51 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In all, 17 proteins/protein families altered differently between the EV + DNG and DNG only groups.

    “In all, 58 proteins/protein families altered differently between the EE + DNG and EV + DNG groups, 61 between EE + DNG and DNG only and 17 between EV + DNG and DNG only.”
    Quote in the paperSubstantial claim
  • Findingown data

    During 9 weeks of use, 5 proteins/protein families changed significantly in the EV + DNG group.

    “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.”
    • Also stated in: § Proteomic analysis · plain
      “A total of 122 proteins/protein families changed significantly during the 9-week trial within at least one group: 121 in the EE + DNG and 5 in the EV + DNG group. No changes were observed in the DNG-only group.”
    Quote in the paperSubstantial claim
  • Findingown data

    Use of EE + DNG led to predicted inhibition of the complement system.

    “The use of EE + DNG led to predicted inhibition of the complement system”
    Quote in the paperSubstantial claim
  • Findingown data

    Use of EE + DNG led to predicted activation of acute phase response signaling.

    “activation of acute phase response signaling”
    Quote in the paperSubstantial claim
  • Findingown data

    The most affected functions during EE + DNG use were the complement system, acute phase response signaling, metabolism and the coagulation system.

    “The most affected functions during the use of EE + DNG were the complement system, acute phase response signaling, metabolism and the coagulation system.”
    Quote in the paperSubstantial claim
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 35

  • May combine two claims.

    Findingown data

    EV + DNG also increased these proteins, but the increase was significantly milder compared with EE + DNG.

    “EV + DNG also increased these proteins, but the increase was significantly milder compared with EE + DNG.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    Fetuin-B is part of the FXR/RXR activation pathway.

    “Fetuin-B is part of the FXR/RXR activation pathway (Fig. 4)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the pathway analysis, 19 proteins related to the complement system were altered during EE + DNG treatment, which predicts inhibition of this pathway.

    “In the pathway analysis, as many as 19 proteins related to the complement system were altered during EE + DNG treatment, which predicts inhibition of this pathway.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    New combinations containing E2, its ester estradiol valerate (EV), and estetrol (E4) have proven effective in combined contraceptives.

    “New combinations containing E2, its ester estradiol valerate (EV), and estetrol (E4) have proven effective in combined contraceptives.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Junge et al., 2011 source

      Not checked in the free run.

    • cites Sitruk-Ware and Nath, 2013

      Not checked in the free run.

    • cites Stanczyk et al., 2013 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisereasoning

    Serum proteomic analysis provides an option to investigate the broad pharmacodynamic effects during medication use.

    “Serum proteomic analysis provides an option to investigate the broad pharmacodynamic effects during medication use.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Natural estrogen-containing combined oral contraceptives induce good cycle control and provoke less marked changes in metabolic and endocrine parameters compared with ethinylestradiol.

    “They induce good cycle control and provoke less marked changes in metabolic and endocrine parameters compared with EE”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Junge et al., 2011 source

      Not checked in the free run.

    • cites Sitruk-Ware and Nath, 2013

      Not checked in the free run.

    • cites Stanczyk et al., 2013 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Original packages were modified by removing placebo pills and pills containing only estrogen to minimize the differences in hormonal contents.

    “Original packages were modified by removing placebo pills and pills containing only estrogen to minimize the differences in hormonal contents.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In the liver, combined oral contraceptives stimulate the synthesis of steroid-binding globulins, such as sex hormone-binding globulin (SHBG), thereby affecting circulating free steroid levels.

    “In the liver, COCs stimulate the synthesis of steroid-binding globulins, such as sex hormone-binding globulin (SHBG), thereby affecting circulating, free steroid levels”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Mashchak et al., 1982 source

      Not checked in the free run.

    • cites Wiegratz et al., 2003 source

      Not checked in the free run.

    • cites Sitruk-Ware et al., 2007a,b

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The sample size calculation of the study was based on glucose metabolism, which was the trial's primary outcome.

    “The sample size calculation of the study was based on glucose metabolism, which was the trial’s primary outcome (Haverinen et al., 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Haverinen et al., 2021 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Ethinylestradiol is a potent estrogen having up to 600 times greater effect on hepatic protein synthesis than natural estradiol (E2).

    “It is a potent estrogen having up to 600 times greater effect on hepatic protein synthesis than natural estradiol (E2)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mashchak et al., 1982 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study protocol was approved by the independent Ethics Committee of Helsinki University Central Hospital and the Finnish Medicines Agency.

    “The study protocol has been described previously (Haverinen et al., 2021), and it was approved by the independent Ethics Committee of Helsinki University Central Hospital and the Finnish Medicines Agency.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The maximal false discovery rate was set to 1%.

    “The maximal false discovery rate was set to 1%, and fragment and peptide errors were set as automatic.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Statistically significant results were further compared with the Mann-Whitney post hoc test, in which a value of P < 0.05 was considered significant.

    “Statistically significant results were further compared with the Mann–Whitney post hoc test, in which a value of P < 0.05 was considered significant.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To investigate differences between study groups, differential variables were analyzed with the Kruskal-Wallis test and the Benjamini-Hochberg procedure.

    “These differential variables were then analyzed with the Kruskal–Wallis test and the Benjamini–Hochberg procedure.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    In all, 10% of the samples were acquired as triplicates: the percentage coefficient of variation for the high-abundance proteins was 1.82, and for the low-abundance proteins 8.11.

    “In all, 10% of the samples were acquired as triplicates: the percentage coefficient of variation for the high-abundance proteins was 1.82, and for the low-abundance proteins 8.11.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Samples from 44 women were available for analysis (EE + DNG n = 14, EV + DNG n = 16 and DNG only n = 14).

    “Samples from 44 women were available for analysis (EE + DNG n = 14, EV + DNG n = 16 and DNG only n = 14).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The power analysis of the trial was not based on the proteomic analysis of this spin-off study.

    “The power analysis of the trial was not based on the proteomic analysis of this spin-off study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study was registered with ClinicalTrials.gov (NCT02352090) and the EU Clinical Trials Register (EudraCT Number 2014-001243-20).

    “The study was registered with ClinicalTrials.gov (NCT02352090; https://clinicaltrials.gov/) and the EU Clinical Trials Register (EudraCT Number 2014-001243-20; https://www.clinicaltrialsregister.eu).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Women (n = 59) were randomized to use either EE + DNG, EV + DNG or DNG only continuously for 9 weeks.

    “Women (n = 59) were randomized to use either EE + DNG, estradiol valerate (EV) + DNG or DNG only continuously for 9 weeks.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The net effect of combined oral contraceptives results from both estrogen and progestin action and their interplay.

    “The net effect of COCs results from both estrogen and progestin action and their interplay”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sitruk-Ware and Nath, 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    At least two unique peptides per protein were required.

    “The proteins were assembled from the peptides by using the parsimony principle, and at least two unique peptides per protein were required.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    As the progestin component of combined oral contraceptives modulates the estrogen effects, the net effect of a combined oral contraceptive depends on both the type of estrogen and the properties of the progestin.

    “As the progestin component of COCs modulates the estrogen effects, the net effect of a COC depends on both the type of estrogen and the properties of the progestin”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Sitruk-Ware and Nath, 2013

      Not checked in the free run.

    • cites Abou-Ismail et al., 2020 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The changes within the study groups were analyzed with the Wilcoxon test using the Benjamini-Hochberg procedure to control false discovery rates.

    “The changes within the study groups were analyzed with the Wilcoxon test using the Benjamini–Hochberg procedure to control false discovery rates.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Combined oral contraceptives increase low-grade inflammation, alter lipid metabolism and affect the coagulation system, resulting in an increased risk for thromboembolic events.

    “COCs also increase low-grade inflammation, alter lipid metabolism and affect the coagulation system, resulting in an increased risk for thromboembolic events”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites van Rooijen et al., 2006 source

      Not checked in the free run.

    • cites Morin-Papunen et al., 2008 source

      Not checked in the free run.

    • cites Lidegaard et al., 2009 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study was a randomized, controlled, investigator-initiated clinical trial conducted at Helsinki and Oulu University Hospitals, Finland, between April 2015 and January 2018.

    “This randomized, controlled, investigator-initiated clinical trial was conducted at Helsinki and Oulu University Hospitals, Finland, between April 2015 and January 2018.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    EE-containing contraceptives alter lipid metabolism, increasing especially high-density lipoprotein and triglycerides, but also affect glucose metabolism.

    “EE-containing contraceptives alter lipid metabolism, increasing especially high-density lipoprotein and triglycerides, but also affect glucose metabolism (Morin-Papunen et al., 2008; Piltonen et al., 2012; Wang et al., 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Morin-Papunen et al., 2008 source

      Not checked in the free run.

    • cites Piltonen et al., 2012 source

      Not checked in the free run.

    • cites Wang et al., 2016 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    That previous cross-sectional study had selected targets for analysis and compared hormonal contraceptive use to non-use but did not specify the treatments.

    “However, that cross-sectional study had selected targets for analysis and compared hormonal contraceptive use to non-use but did not specify the treatments.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The FXR/RXR activation pathway is closely related to the LXR/RXR activation pathway.

    “which is closely related to the LXR/RXR activation pathway (Redinger, 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Redinger, 2003 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Many of the effects seen in this study have been previously observed with other targeted methods, which supports the reliability of the results.

    “However, many of the effects seen in this study have been previously observed with other targeted methods, which supports the reliability of the results.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the same study, EE + DRSP also increased CRP, although the difference compared to E4 + DRSP did not reach statistical significance.

    “In the same study, EE + DRSP also increased CRP, although the difference compared to E4 + DRSP did not reach statistical significance (Klipping et al., 2021).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Klipping et al., 2021 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    The main strength of the present study is that this randomized trial is the first comparison of EE- and EV-containing contraceptives combined with the same progestin.

    “The main strength of the present study is that this randomized trial is the first comparison of EE- and EV-containing contraceptives combined with the same progestin.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Study design and conductnone given

    As no previous data exist, estimating power for a discovery-type setup is extremely challenging.

    “On the other hand, as no previous data exist, estimating power for a discovery-type setup is extremely challenging.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    COCs increase the risk of thromboembolic events.

    “It is also well known that COCs increase the risk of thromboembolic events (Sitruk-Ware et al., 2007a; Lidegaard et al., 2009, 2012; de Bastos et al., 2014).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Sitruk-Ware et al., 2007a

      Not checked in the free run.

    • cites Lidegaard et al., 2009 source

      Not checked in the free run.

    • cites de Bastos et al., 2014

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Previous studies have demonstrated increases in angiotensinogen and binding globulins during the use of EE-based combined contraceptives, regardless of the administration route.

    “Previous studies have demonstrated increases in angiotensinogen and binding globulins during the use of EE-based combined contraceptives, regardless of the administration route (Sitruk-Ware et al., 2007b; Piltonen et al., 2012; Westhoff et al., 2013; Klipping et al., 2021).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Sitruk-Ware et al., 2007b

      Not checked in the free run.

    • cites Piltonen et al., 2012 source

      Not checked in the free run.

    • cites Westhoff et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Proteomic analysis was not considered in the original sample size calculation, given that the analysis was not the primary outcome.

    “Proteomic analysis was not considered in the original sample size calculation, given that the analysis was not the primary outcome.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Study design and conductnone given

    In the field of discovery-type proteomics, the groups of 14 are quite extensive, especially considering the trial with repeated measurements.

    “However, in the field of discovery-type proteomics, the groups of 14 are quite extensive, especially considering the trial with repeated measurements.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    One major fetuin-B outlier was removed from the EE + DNG group, which did not affect the statistical analysis.

    “One major fetuin-B outlier was removed from the EE + DNG group, which did not affect the statistical analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Josse et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Both FXR/RXR and LXR/RXR pathways, also affected by EE + DNG in the present study, play critical roles in regulating lipid and glucose metabolism.

    “Both of these pathways, also affected by EE + DNG in the present study, play critical roles in regulating lipid and glucose metabolism (Edwards et al., 2002; Redinger, 2003; Wang et al., 2008).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Edwards et al., 2002 source

      Not checked in the free run.

    • cites Redinger, 2003 source

      Not checked in the free run.

    • cites Wang et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Randomization was successful regarding clinical characteristics but also at the proteome level, as reflected in the mixed clustering of baseline samples.

    “Randomization was successful regarding the clinical characteristics but also at the proteome level, as reflected in the mixed clustering of baseline samples.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The 9-week study period is relatively short for concluding long-term effects.

    “However, we acknowledge that the 9-week study period is relatively short for concluding long-term effects.”
    Quote in the paperNot a substantial claim
41 of 41

  • The paper relies on this without support.

    Most trials comparing combined oral contraceptives with different estrogens have included preparations that also differ in the progestin component, so knowledge of the specific estrogen effects in combined oral contraceptives is lacking.

    “However, most trials comparing COCs with different estrogens have included preparations that also differ in the progestin component; hence, knowledge of the specific estrogen effects in COCs is lacking.”

  • The paper relies on this without support.

    This is the first study to utilize discovery-type proteomic analysis on hormonal contraceptives.

    “To our knowledge, this is the first study to utilize such discovery-type proteomic analysis on hormonal contraceptives.”

  • The paper relies on this without support.

    Studies comparing serum proteomes after use of combined oral contraceptives containing ethinylestradiol and natural estrogens are lacking.

    “Studies comparing serum proteomes after the use of COCs containing EE and natural estrogens are lacking.”

  • The paper relies on this without support.

    Some effects and health outcomes of combined oral contraceptives, as well as their mode of action, remain poorly understood.

    “Even though millions of women worldwide use COCs, some of the effects and health outcomes, as well as their mode of action, remain poorly understood.”

  • The paper relies on this without support.

    A broader effect on the serum proteome is clinically less desirable than a narrower effect.

    “Therefore, EV could provide a preferable option to EE in COCs in the future.”
5 of 5

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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • 120-fold comparison uses a group with no detected changes

    Minor

    The discussion says EE + DNG affected 120 times as many proteins as DNG only, but the paper reports no detected changes in the DNG-only group. A fold ratio relative to zero detected changes is undefined.

1 of 1

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Authors
Kangasniemi, M. H., Arffman, R. K., Joenväärä, S., Haverinen, A., Luiro, K., Tohmola, T., Renkonen, R., Heikinheimo, O., Tapanainen, J. S., & Piltonen, T. T.
Affiliations
  • Oulu University Hospital (FI)
  • University of Helsinki (FI)
Corresponding author
Kangasniemi, M H
ORCID
Venue
Human Reproduction
Publisher
Oxford University Press (OUP)
Published
2022-11-23
Volume
38
Issue
1
Pages
89-102
ISSN
  • 0268-1161 (ISSN-L)
  • 1460-2350
DOI
10.1093/humrep/deac250
PMC
PMC9825269
OpenAlex
W4309832109
Semantic Scholar
f61c250a30a8478df05118c3c48244c05b18f6c1
Cited by
19
References
52
Citations by year
2026: 6 · 2025: 7 · 2024: 4 · 2023: 2
FWCI
2.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Human Reproduction (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
  • Helsinki University Hospital
  • Hospital District of Helsinki and Uusimaa
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
Keywords
ethinyl estradiol, estradiol valerate, combined oral contraceptives, dienogest, serum proteome, natural estrogens, progestin-only contraception, complement system, acute phase response, coagulation, fetuin-B, corticosteroid-binding globulin, sex hormone-binding globulin, label-free quantitative proteomics, young women, hormonal contraception side effects, metabolism
MeSH terms
Contraceptives, Oral, Combined, Estradiol, Estrogens, Ethinyl Estradiol, Female, Humans, Progestins, Levonorgestrel, Proteome, Proteomics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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