University of Oulu

Kangasniemi, M. H., Arffman, R. K., Haverinen, A., Luiro, K., Hustad, S., Heikinheimo, O., Tapanainen, J. S., & Piltonen, T. T. (2022). Effects of estradiol- and ethinylestradiol-based contraceptives on adrenal steroids: A randomized trial. Contraception, S0010782422002463.

Effects of estradiol- and ethinylestradiol-based contraceptives on adrenal steroids : a randomized trial

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Author: Kangasniemi, Marika H1; Arffman, Riikka K1; Haverinen, Annina2;
Organizations: 1Department of Obstetrics and Gynecology, University of Oulu, Oulu University Hospital and Medical Research Centre PEDEGO Research Unit, Oulu, Finland
2Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
3Department of Clinical Science and Core Facility for Metabolomics, University of Bergen, Norway
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.8 MB)
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Language: English
Published: Elsevier, 2022
Publish Date: 2022-10-03


Objectives: Ethinylestradiol (EE)-based combined oral contraceptives (COC) affect adrenal function by altering steroid and corticosteroid-binding globulin (CBG) synthesis that may contribute to adverse effects related to these drugs. The effects of COCs containing natural estrogens remain unclear. We compared the effects of COCs containing estradiol valerate (EV) and EE on cortisol and other adrenal steroid hormones.

Study design: A spin-off study of a randomized, open-label trial. Fifty-nine healthy women were allocated to groups that engaged in the continuous use of EV+dienogest (DNG), EE+DNG, or DNG only for 9 weeks. We measured changes in adrenal steroids, CBG, and the free cortisol index (FCI).

Results: Treatment with EE+DNG increased total cortisol (mean increment 668 nmol/L, p < 0.001) and cortisone (10 nmol/L, p= 0.001) levels, whereas the change from the baseline was insignificant for the EV+DNG and DNG-only groups. Dehydroepiandrosterone sulfate decreased by 24% in the EE+DNG group but remained unchanged in the EV+DNG and DNG-only groups. Aldosterone and 17-hydroxyprogesterone levels did not differ between the groups. All preparations increased CBG, but the increase in the EE+DNG group (median increment 42 µg/mL, p < 0.001) was 9- and 49-fold higher than that in the EV+DNG and DNG-only groups, respectively. The FCI remained unchanged in all study groups, indicating that cortisol and CBG mainly increased in parallel, although some individuals demonstrated larger alterations in the cortisol–CBG balance.

Conclusions: In COCs, EV had a milder effect on circulating CBG and adrenal steroid levels than EE; however, further research is necessary to determine the long-term effects.

Trial Registration: NCT02352090

Implications: EV-based COC had reduced effects on circulating CBG and adrenal steroids compared to EE, probably due to a lower hepatic impact. Whether the sensitization of the adrenals to ACTH varies according to COC contents and whether it relates to experienced side effects needs to be investigated. These results encourage further research and development of contraceptives containing natural estrogens.

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Series: Contraception
ISSN: 0010-7824
ISSN-E: 1879-0518
ISSN-L: 0010-7824
Volume: In press
DOI: 10.1016/j.contraception.2022.08.009
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Funding: Funding was obtained from Helsinki University Hospital research funds (JST, OH, AH, KL), the Sigrid Juselius Foundation (JST, TTP), the Academy of Finland (JST, TTP 315921 & 321763), the Finnish Medical Association (MHK, AH, TTP), the University of Oulu Graduate School (MHK), the Emil Aaltonen Foundation (MHK), the Swedish Cultural Foundation in Finland (AH), the Novo Nordisk Foundation (RKA), Orion Research Foundation (AH), and the Northern Ostrobothnia Regional Fund (RKA). The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.
Academy of Finland Grant Number: 321763
Detailed Information: 321763 (Academy of Finland Funding decision)
Copyright information: © 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (