University of Oulu

Haverinen, AH, Luiro, KM, Szanto, T, et al. Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation: A randomized clinical trial. Acta Obstet Gynecol Scand. 2022; 101: 1102- 1111. doi: 10.1111/aogs.14428

Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation : a randomized clinical trial

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Author: Haverinen, Annina H.1; Luiro, Kaisu M.1; Szanto, Timea2,3;
Organizations: 1Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
2Department of Hematology and Comprehensive Cancer Center, Unit of Coagulation Disorders, Helsinki University Hospital, Helsinki, Finland
3Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
4Department of Obstetrics and Gynecology, University of Oulu, Oulu University Hospital and Medical Research Center PEDEGO Research Unit, Oulu, Finland
5Department of Hemostasis, Finnish Red Cross Blood Service, Helsinki, Finland
6Hemostasis and Platelet Laboratory, Fimlab Laboratoriot Oy Ltd, Vantaa, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
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Language: English
Published: John Wiley & Sons, 2022
Publish Date: 2022-10-03


Introduction: Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E₂] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin.

Material and methods: We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2–3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). Clinical trial registration: NCT02352090.

Results: Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change −24%, 95% confidence interval [CI] −32% to −15%; p < 0.01) and time to thrombin peak (−26%, 95% CI −37% to −16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%–67% vs +147%,95% CI 96%–198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%–38% vs +64%, 95% CI 51%–76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127–206] pmol/L to 194 pmol/L, 95% CI 149–250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers.

Conclusions: Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.

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Series: Acta obstetricia et gynecologica Scandinavica
ISSN: 0001-6349
ISSN-E: 1600-0412
ISSN-L: 0001-6349
Volume: 101
Issue: 10
Pages: 1102 - 1111
DOI: 10.1111/aogs.14428
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Funding: This work was supported by The Swedish Cultural Foundation in Finland (AH); Helsinki University Hospital Research Funds (JST, OH, AH, KL, TS, RL); The Sigrid Juselius Foundation (JST, TP); The Finnish Medical Association (TP, MHK); The Academy of Finland (JST, TP); University of Oulu Graduate School (MHK), Emil Aaltonen Foundation (MHK), Finska läkaresällskapet (AH), The Paolo Foundation (AH), Orion Research Foundation (AH), and University of Helsinki Graduate School (AH).
Copyright information: © 2022 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.