University of Oulu

M H Kangasniemi, R K Arffman, S Joenväärä, A Haverinen, K Luiro, T Tohmola, R Renkonen, O Heikinheimo, J S Tapanainen, T T Piltonen, Ethinylestradiol in combined hormonal contraceptive has a broader effect on serum proteome compared with estradiol valerate: a randomized controlled trial, Human Reproduction, Volume 38, Issue 1, January 2023, Pages 89–102,

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

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Author: Kangasniemi, M. H.1; Arffman, R. K.1; Joenväärä, S.2,3;
Organizations: 1Department of Obstetrics and Gynecology, Clinical Research Unit, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
2Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
3HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
4Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
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Language: English
Published: Oxford University Press, 2022
Publish Date: 2022-11-28


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, reason 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.

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Series: Human reproduction
ISSN: 0268-1161
ISSN-E: 1460-2350
ISSN-L: 0268-1161
Volume: 38
Issue: 1
Pages: 89 - 102
DOI: 10.1093/humrep/deac250
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Funding: Funding was obtained from Helsinki University Hospital research funds (J.S.T. and A.H.), the Hospital District of Helsinki and Uusimaa (K.L., T.T. and O.H.), the Sigrid Juselius Foundation (J.S.T. and T.T.P.), the Academy of Finland (J.S.T. and T.T.P. 315921 and 321763), the Finnish Medical Association (M.H.K., A.H. and T.T.P.), the University of Oulu Graduate School (M.H.K.), the Emil Aaltonen Foundation (M.H.K.), the Swedish Cultural Foundation in Finland (A.H.), the Novo Nordisk Foundation (R.K.A.), Orion Research Foundation (A.H.) and the Northern Ostrobothnia Regional Fund (R.K.A.). The funders had no role in study design, data collection and analysis, publishing decisions or manuscript preparation.
Academy of Finland Grant Number: 321763
Detailed Information: 321763 (Academy of Finland Funding decision)
Copyright information: © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.