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Cited by 19Adrenal Hormones and DisordersReproductive Health and ContraceptionEstrogen and related hormone effects

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

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Kangasniemi, Marika H, Arffman, Riikka K, Haverinen, Annina, Luiro, Kaisu, Hustad, Steinar, Heikinheimo, Oskari, Tapanainen, Juha S, Piltonen, Terhi T·2022·Contraception
DOI 10.1016/j.contraception.2022.08.009
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Abstract

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. CONCLUSION: 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: ClinicalTrials.gov 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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Crossref · 10.1016/j.contraception.2022.08.009

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Authors
Kangasniemi, M. H., Arffman, R. K., Haverinen, A., Luiro, K., Hustad, S., Heikinheimo, O., Tapanainen, J. S., & Piltonen, T. T.
Affiliations
  • Oulu University Hospital (FI)
  • University of Helsinki (FI)
  • University of Bergen (NO)
Corresponding author
Kangasniemi, Marika H
ORCID
Venue
Contraception
Publisher
Elsevier BV
Published
2022-12
Volume
116
Pages
59-65
ISSN
0010-7824 (ISSN-L)
DOI
10.1016/j.contraception.2022.08.009
OpenAlex
W4294838678
Cited by
19
References
27
Citations by year
2026: 6 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 1
FWCI
2.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Contraception (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
  • Pohjois-pohjanmaan Rahasto
  • Academy of Finland (TTP 315921, 321763)
  • Novo Nordisk Foundation
  • Swedish Cultural Foundation
  • Sigrid Jusélius Foundation
  • HUS Helsinki University Hospital
  • Oulun Yliopiston Tutkijakoulu
  • Japan Science and Technology Agency
  • Emil Aaltosen Säätiö
  • Orionin Tutkimussäätiö
  • Finnish Medical Association
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • 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
Keywords
ethinyl estradiol, estradiol valerate, combined oral contraceptives, dienogest, adrenal steroids, cortisol, corticosteroid-binding globulin, cortisone, dehydroepiandrosterone sulfate, natural estrogens, ACTH sensitivity
MeSH terms
Contraceptives, Oral, Combined, Estradiol, Estrogens, Ethinyl Estradiol, Female, Humans, Hydrocortisone, Nandrolone, Levonorgestrel

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