{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T21:17:34Z","timestamp":1787865454246,"version":"build-2784847793"},"reference-count":38,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T00:00:00Z","timestamp":1659225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007083","name":"Orionin Tutkimuss\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007083","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010135","name":"Finska L\u00e4kares\u00e4llskapet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010135","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004756","name":"Emil Aaltosen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004756","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006432","name":"Tutkijakoulu, Oulun Yliopiston","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006432","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["obgyn.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Obstet Gynecol Scand"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>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\u2010potency estrogens (ie, estradiol [E<jats:sub>2<\/jats:sub>] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV\u2009+\u2009dienogest (DNG), EE\u2009+\u2009DNG, 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and methods<\/jats:title><jats:p>We enrolled 59 healthy, 18\u2010 to 35\u2010year\u2010old, non\u2010smoking women, of whom three discontinued. The participants were randomly allocated to 9\u2009weeks of continuous treatment with EV 2\u00a0mg\u2009+\u2009DNG 2\u20133\u00a0mg (<jats:italic>n<\/jats:italic>\u00a0=\u200920), EE 0.03\u2009mg\u2009+\u2009DNG 2\u00a0mg (<jats:italic>n<\/jats:italic>\u00a0=\u200920), or DNG 2\u00a0mg (<jats:italic>n<\/jats:italic>\u00a0=\u200919). Blood samples were collected at baseline and after 9\u2009weeks. 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\u00a0p<jats:sc>m<\/jats:sc>). In vivo coagulation assessment was based on levels of prothrombin fragment 1\u00a0+\u00a02 (F1\u2009+\u00a02) (thrombin generation) and D\u2010dimer (fibrin turnover). Clinical trial registration: NCT02352090.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Lag time and time to thrombin peak remained unaltered after exposure to EV\u2009+\u2009DNG, whereas EE\u2009+\u2009DNG shortened both lag time (mean percentage change \u221224%, 95% confidence interval [CI] \u221232% to \u221215%; <jats:italic>p<\/jats:italic>\u00a0&lt;\u20090.01) and time to thrombin peak (\u221226%, 95% CI \u221237% to \u221216%; <jats:italic>p<\/jats:italic>\u00a0&lt;\u20090.01). EV\u2009+\u2009DNG induced lower thrombin peak and endogenous thrombin potential than EE\u2009+\u2009DNG (peak; +45%, 95% CI 22%\u201367% vs +147%,95% CI 96%\u2013198%; <jats:italic>p<\/jats:italic>\u00a0&lt;\u20090.01, and endogenous thrombin potential; +26%, 95% CI 15%\u201338% vs +64%, 95% CI 51%\u201376%; <jats:italic>p<\/jats:italic>\u00a0&lt;\u20090.01). Median F1\u2009+\u00a02 levels remained unchanged with EV\u2009+\u2009DNG (<jats:italic>p<\/jats:italic>\u00a0=\u20090.22) but increased within normal ranges with EE\u2009+\u2009DNG (from 152\u2009pmol\/L, 95% CI 127\u2013206]\u00a0pmol\/L to 194\u2009pmol\/L, 95% CI 149\u2013250\u2009pmol\/L, <jats:italic>p<\/jats:italic>\u00a0=\u20090.04). The within\u2010group change in D\u2010dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Both in vitro and in vivo thrombin generation was lower after exposure to EV\u2009+\u2009DNG compared with EE\u2009+\u2009DNG. The lower thrombin generation measures after treatment with EV\u2009+\u2009DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aogs.14428","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T06:38:55Z","timestamp":1659335935000},"page":"1102-1111","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation: A randomized clinical trial"],"prefix":"10.1111","volume":"101","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5213-9747","authenticated-orcid":false,"given":"Annina H.","family":"Haverinen","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Helsinki and Helsinki University Hospital  Helsinki 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Unit  Oulu Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leena","family":"Hiltunen","sequence":"additional","affiliation":[{"name":"Department of Hemostasis Finnish Red Cross Blood Service  Helsinki Finland"},{"name":"Hemostasis and Platelet Laboratory Fimlab Laboratoriot Oy Ltd  Vantaa Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8908-8605","authenticated-orcid":false,"given":"Susanna","family":"Sainio","sequence":"additional","affiliation":[{"name":"Department of Hemostasis Finnish Red Cross Blood Service  Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terhi T.","family":"Piltonen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Oulu, Oulu University Hospital and Medical Research Center PEDEGO Research Unit  Oulu 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