{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T16:51:20Z","timestamp":1793206280487,"version":"4.5.0"},"reference-count":118,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T00:00:00Z","timestamp":1639008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009595","name":"Service Public de Wallonie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Many factors must be considered and discussed with women when initiating a contraceptive method and the risk of venous thromboembolism (VTE) is one of them. In this review, we discuss the numerous strategies that have been implemented to reduce the thrombotic risk associated with combined oral contraceptives (COCs) from their arrival on the market until today. Evidences suggesting that COCs were associated with an increased risk of VTE appeared rapidly after their marketing. Identified as the main contributor of this risk, the dosage of the estrogen, i.e., ethinylestradiol (EE), was significantly reduced. New progestins were also synthetized (e.g., desogestrel or gestodene) but their weak androgenic activity did not permit to counterbalance the effect of EE as did the initial progestins such as levonorgestrel. Numerous studies assessed the impact of estroprogestative combinations on hemostasis and demonstrated that women under COC suffered from resistance towards activated protein C (APC). Subsequently, the European Medicines Agency updated its guidelines on clinical investigation of steroid contraceptives in which they recommended to assess this biological marker. In 2009, estradiol-containing COCs were marketed and the use of this natural form of estrogen was found to exert a weaker effect on the synthesis of hepatic proteins compared to EE. In this year 2021, a novel COC based on a native estrogen, i.e., estetrol, will be introduced on the market. Associated with drospirenone, this preparation demonstrated minor effects on coagulation proteins as compared with other drospirenone-containing COCs. At the present time, the standard of care when starting a contraception, consists of identifying the presence of hereditary thrombophilia solely on the basis of familial history of VTE. This strategy has however been reported as poorly predictive of hereditary thrombophilia. One rationale and affordable perspective which has already been considered in the past could be the implementation of a baseline screening of the prothrombotic state to provide health care professionals with objective data to support the prescription of the more appropriate contraceptive method. While this strategy was judged too expensive due to limited laboratory solutions, the endogenous thrombin potential-based APC resistance assay could now represent an interesting alternative.<\/jats:p>","DOI":"10.3389\/fendo.2021.769187","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T11:35:29Z","timestamp":1639049729000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":159,"title":["Combined Oral Contraceptives and Venous Thromboembolism: Review and Perspective to Mitigate the Risk"],"prefix":"10.3389","volume":"12","author":[{"given":"Laure","family":"Morimont","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Haguet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Dogn\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulysse","family":"Gaspard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Douxfils","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,9]]},"reference":[{"key":"B1","volume-title":"Contraceptive Use by Method 2019: Data Booklet (ST\/ESA\/SER.A\/435)","year":"2019"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(61)91061-3","article-title":"Pulmonary Embolism","volume":"278","author":"Jordan","year":"1961","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198109103051104","article-title":"Oral Contraceptives and Cardiovascular Disease (First of Two Parts)","volume":"305","author":"Stadel","year":"1981","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.5703.203","article-title":"Thromboembolic Disease and the Steroidal Content of Oral Contraceptives: A Report to the Committee on Safety of Drugs","volume":"2","author":"Inman","year":"1970","journal-title":"Br Med J"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-0528.1973.tb15981.x","article-title":"Speculation About Mortality Trends From Venous Thromboembolism Disease in England and Wales and Their Relation to the Pattern of Oral Contraceptive Usage","volume":"80","author":"Vessey","year":"1973","journal-title":"J Obstetrics Gynaecology Br Commonwealth"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(77)90888-1","article-title":"Haemostatic, Lipid, and Blood-Pressure Profiles of Women on Oral Contraceptives Containing 50 \u00b5g or 30 \u00b5g Oestrogen","author":"Meade","year":"1977","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1976.03270200017021","article-title":"Estrogen-Containing Oral Contraceptives Agents: A Basis for Their Thrombogenicity","volume":"236","author":"Wessler","year":"1976","journal-title":"JAMA"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(87)80129-1","article-title":"Coagulation Effects of Oral Contraception","volume":"157","author":"Bonnar","year":"1987","journal-title":"Am J Obstet Gynecol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1080\/13625180600772741","article-title":"Metabolic and Clinical Effects of Progestogens","volume":"11","author":"Wiegratz","year":"2006","journal-title":"Eur J Contracept Reprod Health Care"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2012.02.042","article-title":"Progestin-Only Contraception and Venous Thromboembolism","volume":"129","author":"Blanco-Molina","year":"2012","journal-title":"Thromb Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.26015","article-title":"The Clinical Relevance of Progestogens in Hormonal Contraception: Present Status and Future Developments","volume":"9","author":"Regidor","year":"2018","journal-title":"Oncotarget"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmi046","article-title":"New Progestagens for Contraceptive Use","volume":"12","author":"Sitruk-Ware","year":"2006","journal-title":"Hum Reprod Update"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.maturitas.2008.11.011","article-title":"Pharmacological Profile of Progestins","volume":"61","author":"Sitruk-Ware","year":"2008","journal-title":"Maturitas"},{"key":"B14","doi-asserted-by":"publisher","first-page":"CD004861","DOI":"10.1002\/14651858.CD004861.pub2","article-title":"Types of Progestogens in Combined Oral Contraception: Effectiveness and Side-Effects","author":"Lawrie","year":"2011","journal-title":"Cochrane Database Syst Rev"},{"key":"B15","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1080\/13697130500148875","article-title":"Pharmacology of Estrogens and Progestogens: Influence of Different Routes of Administration","volume":"8","author":"Kuhl","year":"2005","journal-title":"Climacteric"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2020.05.017","article-title":"Oral Contraceptive Generations - Time to Stop Using a Marketing Myth to Define Nomenclature","volume":"102","author":"Creinin","year":"2020","journal-title":"Contraception"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/0010-7824(94)90045-0","article-title":"Comparative Progestational and Androgenic Activity of Norgestimate and Levonorgestrel in the Rat","volume":"49","author":"Kuhnz","year":"1994","journal-title":"Contraception"},{"key":"B18","article-title":"Pharmacology of Progestogens","volume":"8","author":"Kuhl","year":"2011","journal-title":"J Reproduktionsmed Endokrinol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1046\/j.1525-1497.1999.08108.x","article-title":"Benefits and Risks of Third-Generaiton Oral Contraceptives","volume":"14","author":"LeBlanc","year":"1999","journal-title":"J Gen Internal Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)91927-9","article-title":"Effect of Different Progestagens in Low Oestrogen Oral Contraceptives on Venous Thromboembolic Disease","volume":"346","year":"1995","journal-title":"Lancet"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)91928-7","article-title":"Risk of Idiopathic Cardiovascular Death and Nonfatal Venous Thromboembolism in Women Using Oral Contraceptives With Differing Progestagen Components","volume":"346","author":"Jick","year":"1995","journal-title":"Lancet"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.312.7023.83","article-title":"Third Generation Oral Contraceptives and Risk of Venous Thromboembolic Disorders: An International Case-Control Study","volume":"312","author":"Spitzer","year":"1996","journal-title":"BMJ"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)91929-5","article-title":"Enhancement by Factor V Leiden Mutation of Risk of Deep-Vein Thrombosis Associated With Oral Contraceptives Containing a Thirg-Generation Progestogen","volume":"346","author":"Bloemenkamp","year":"1995","journal-title":"Lancet"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(96)07496-X","article-title":"Population-Based Study of Risk of Venous Thromboembolism Associated With Various Oral Contraceptives","volume":"349","author":"Farmer","year":"1997","journal-title":"Lancet"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/S0010-7824(97)00119-4","article-title":"First-Time Use of Newer Oral Contraceptives and the Risk of Venous Thromboembolism","volume":"56","author":"Suissa","year":"1997","journal-title":"Contraception"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/5.6.746","article-title":"The Changing Scene - an Unnecessary Pill Crisis","volume":"5","author":"Heinemann","year":"1999","journal-title":"Hum Reprod Update"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/5.6.736","article-title":"The Aftermath of a Pill Scare: Regression to Reassurance","volume":"5","author":"Spitzer","year":"1999","journal-title":"Hum Reprod Update"},{"key":"B28","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/0010-7824(96)00112-6","article-title":"The Increased Risk of Venous Thromboembolism and the Use of Third Generation Progestagens: Role of Bias in Observational Research","volume":"54","author":"Lewis","year":"1996","journal-title":"Contraception"},{"key":"B29","doi-asserted-by":"publisher","first-page":"CD010813","DOI":"10.1002\/14651858.CD010813.pub2","article-title":"Combined Oral Contraceptives: Venous Thrombosis","author":"de Bastos","year":"2014","journal-title":"Cochrane Database Syst Rev"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.323.7305.131","article-title":"Third Generation Oral Contraceptives and Risk of Venous Thrombosis: Meta-Analysis","volume":"323","author":"Kemmeren","year":"2001","journal-title":"BMJ"},{"key":"B31","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1080\/13697130500330382","article-title":"Pharmacology of Different Progestogens: The Special Case of Drospirenone","author":"Sitruk-Ware","year":"2005","journal-title":"Climacteric"},{"key":"B32","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1080\/13697130500330309","article-title":"Added Benefits of Drospirenone for Compliance","author":"Foidart","year":"2005","journal-title":"Climacteric"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1046\/j.1538-7836.2003.00264.x","article-title":"Estrogens, Progestogens and Thrombosis","volume":"1","author":"Rosendaal","year":"2003","journal-title":"J Thromb Haemost"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2004.00983.x","article-title":"Prothrombotic Changes in Users of Combined Oral Contraceptives Containing Drospirenone and Cyproterone Acetate","volume":"2","author":"van Vliet","year":"2004","journal-title":"J Thromb Haemost"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.2147\/OAJC.S179673","article-title":"Venous Thrombosis and Hormonal Contraception: What\u2019s New With Estradiol-Based Hormonal Contraceptives","volume":"9","author":"Fruzzetti","year":"2018","journal-title":"Open Access J Contracept"},{"key":"B36","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1016\/j.contraception.2016.04.014","article-title":"Progestin-Only Contraception and Thromboembolism: A Systematic Review","volume":"94","author":"Tepper","year":"2016","journal-title":"Contraception"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0378-5122(96)00994-2","article-title":"Effects of Progestogens on Haemostasis","volume":"24","author":"Kuhl","year":"1996","journal-title":"Maturitas"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-0452","article-title":"Androgen Receptor Inhibits Estrogen Receptor-Alpha Activity and Is Prognostic in Breast Cancer","volume":"69","author":"Peters","year":"2009","journal-title":"Cancer Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1080\/j.1600-0412.2002.810603.x","article-title":"Can Changes in Sex Hormone Binding Globulin Predict the Risk of Venous Thromboembolism With Combined Oral Contraceptive Pills","volume":"81","author":"Odlind","year":"2002","journal-title":"Acta Obstet Gynecol Scand"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(03)00950-5","article-title":"Sex Hormone\u2013Binding Globulin\u2014A Surrogate Marker for the Prothrombotic Effects of Combined Oral Contraceptives","volume":"190","author":"van Rooijen","year":"2004","journal-title":"Am J Obstetrics Gynecol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deh612","article-title":"Association Between Sex Hormone-Binding Globulin Levels and Activated Protein C Resistance in Explaining the Risk of Thrombosis in Users of Oral Contraceptives Containing Different Progestogens","volume":"20","author":"van Vliet","year":"2005","journal-title":"Hum Reprod"},{"key":"B42","volume-title":"Guideline on Clinical Investigation of Steroid Contraceptives in Women - EMEA\/CPMP\/EWP\/519\/98 Rev","year":"2005"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2012.04720.x","article-title":"Sex Hormone-Binding Globulin as a Marker for the Thrombotic Risk of Hormonal Contraceptives","volume":"10","author":"Raps","year":"2012","journal-title":"J Thromb Haemost"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2012.04878.x","article-title":"Sex Hormone-Binding Globulin Levels Are Not Causally Related to Venous Thrombosis Risk in Women Not Using Hormonal Contraceptives","volume":"10","author":"Stegeman","year":"2012","journal-title":"J\u00a0Thromb Haemost"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117458","article-title":"Physiological Anticoagulation: Resistance to Activated Protein C and Venous Thromboembolism","volume":"94","author":"Dahlb\u00e4ck","year":"1994","journal-title":"J Clin Invest 94"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.3.1004","article-title":"Familial Thrombophilia Due to a Previously Unrecognized Mechanism Characterized by Poor Anticoagulant Response to Activated Protein C: Prediction of a Cofactor to Activated Protein C","volume":"90","author":"Dahlb\u00e4ck","year":"1993","journal-title":"Proc Natl Acad Sci"},{"key":"B47","doi-asserted-by":"crossref","DOI":"10.1016\/B978-0-12-813726-0.00129-X","article-title":"Activated Partial Thromboplastin Time","volume-title":"Transfusion Medicine and Hemostasis","author":"Roshal","year":"2019"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V82.7.1989.1989","article-title":"Anticoagulant Proteinc C Pathway in Majority of Thrombophilic Patients","volume":"82","author":"Griffin","year":"1993","journal-title":"Blood"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)80081-9","article-title":"Venous Thrombosis Due to Poor Anticoagulant Response to Activated Protein C-Leiden Thrombophilia Study","volume":"342","author":"Koster","year":"1993","journal-title":"Lancet"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199402243300801","article-title":"Resistance to Activated Protein C as a Basis for Venous Thrombosis","volume":"330","author":"Svensson","year":"1994","journal-title":"N Engl J Med"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/369064a0","article-title":"Mutation in Blood Coagulation Factor V Associated With Resistance to Activated Protein C","volume":"364","author":"Bertina","year":"1994","journal-title":"Nature"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2423(09)49006-1","article-title":"Chapter 6 Factor V Leiden and Activated Protein C Resistance","volume":"49","author":"Segers","year":"2009","journal-title":"Adv Clin Chem"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1653788","article-title":"Sensitivity to Activated Protein C; Influence of Oral Contraceptives and Sex","volume":"73","author":"Henkens","year":"1995","journal-title":"Thromb Haemost"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1995.tb05323.x","article-title":"Resistance to Activated Protein C in Healthy Women Taking Oral Contraceptives","volume":"91","author":"Olivieri","year":"1995","journal-title":"Br J Haematol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1097\/00001721-199701000-00006","article-title":"Effect of Activated Protein C on Thrombin Generation and on the Thrombin Potential in Plasma of Normal and APC-Resistant Individuals","volume":"8","author":"Nicolaes","year":"1997","journal-title":"Blood Coagul Fibrinolysis"},{"key":"B56","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1111\/j.1365-2141.1999.01302.x","article-title":"Acquired APC Resistance and Oral Contraceptives: Differences Between Two Functional Tests","volume":"105","author":"Curvers","year":"1999","journal-title":"Br J Haematol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/0010-7824(82)90078-6","article-title":"Serum Levels and Pharmacokinetics of Norethisterone After Ingestion of Lynestrenol: Its Relation to Dose and Stage of the Menstrual Cycle","volume":"26","author":"Kuhl","year":"1982","journal-title":"Contraception"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2005.01430.x","article-title":"Determinants of the APTT- and ETP-Based APC Sensitivity Tests","volume":"3","author":"de Visser","year":"2005","journal-title":"J Thromb Haemost"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.2217\/17455057.2.5.761","article-title":"Venous Thrombosis and Oral Contraceptives: Current Status","volume":"2","author":"Tchaikovski","year":"2006","journal-title":"Womens Health (Lond)"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2009.03711.x","article-title":"APC Resistance: Biological Basis and Acquired Influences","volume":"8","author":"Castoldi","year":"2010","journal-title":"J Thromb Haemost"},{"key":"B61","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1515\/cclm-2019-0471","article-title":"Validation and Standardization of the ETP-Based Activated Protein C Resistance Test for the Clinical Investigation of Steroid Contraceptives in Women: An Unmet Clinical and Regulatory Need","volume":"58","author":"Douxfils","year":"2020","journal-title":"Clin Chem Lab Med"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2010.03773.x","article-title":"Prothrombin G20210A Carriers the Genetic Mutation and a History of Venous Thrombosis Contributes to Thrombin Generation Independently of Factor II Plasma Levels","volume":"8","author":"Lavigne-Lissalde","year":"2010","journal-title":"J Thromb Haemost"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2012.03.009","article-title":"Clinical and Biological Factors That Contribute to Thrombin Generation in Prothrombin G20210A Carriers: A Case-Control Study in a Single Thrombophilia Center","volume":"129","author":"Marco","year":"2012","journal-title":"Thromb Res"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2010.10.017","article-title":"Elevated Factor VIII Enhances Thrombin Generation in the Presence of Factor VIII-Deficiency, Factor XI-Deficiency or Fondaparinux","volume":"127","author":"Szlam","year":"2011","journal-title":"Thromb Res"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1160\/TH07-09-0581","article-title":"Influence of Coagulation Factors and Tissue Factor Concentration on the Thrombin Generation Test in Plasma","volume":"99","author":"Duchemin","year":"2008","journal-title":"Thromb Haemost"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1080\/13625180902850039","article-title":"Pharmacokinetics of an Oral Contraceptive Containing Oestradiol Valerate and Dienogest","volume":"14","author":"Zeun","year":"2009","journal-title":"Eur J Contracept Reprod Health Care"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2009.03.018","article-title":"Bleeding Pattern and Cycle Control With an Estradiol-Based Oral Contraceptive: A Seven-Cycle, Randomized Comparative Trial of Estradiol Valerate\/Dienogest and Ethinyl Estradiol\/Levonorgestrel","volume":"80","author":"Ahrendt","year":"2009","journal-title":"Contraception"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(94)05011-8","article-title":"New Knowledge in the Physiology of Hormonal Contraceptives","volume":"170","author":"Lobo","year":"1994","journal-title":"Am J Obstet Gynecol"},{"key":"B69","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.contraception.2009.08.010","article-title":"Review of Clinical Experience With Estradiol in Combined Oral Contraceptives","volume":"81","author":"Fruzzetti","year":"2010","journal-title":"Contraception"},{"key":"B70","first-page":"256","article-title":"A Comparison Between Effects of Estradiol Valerate and Low Dose Ethinyl Estradiol on Haemostasis Parameters","volume":"61","author":"Lindberg","year":"1989","journal-title":"Thromb Haemostasis"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(82)90218-6","article-title":"Comparison of Pharmacodynamic Properties of Various Estrogen Formulations","volume":"144","author":"Mashchak","year":"1982","journal-title":"Am J Obstetrics Gynecol"},{"key":"B72","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.contraception.2004.03.004","article-title":"Effect of Four Oral Contraceptives on Hemostatic Parameters","volume":"70","author":"Wiegratz","year":"2004","journal-title":"Contraception"},{"key":"B73","volume-title":"Qlaira: Summary of Product Characteristics (SmPC)","year":"2018"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.3109\/09513590.2012.662547","article-title":"An Overview of the Development of Combined Oral Contraceptives Containing Estradiol: Focus on Estradiol Valerate\/Dienogest","volume":"28","author":"Fruzzetti","year":"2012","journal-title":"Gynecol Endocrinol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.2165\/11591200-000000000-00000","article-title":"Hemostatic Effects of a Novel Estradiol-Based Oral Contraceptive: An Open-Label, Randomized, Crossover Study of Estradiol Valerate\/Dienogest Versus Ethinylestradiol\/Levonorgestrel","volume":"11","author":"Klipping","year":"2011","journal-title":"Drugs R D"},{"key":"B76","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.clinthera.2011.11.006","article-title":"Estradiol Valerate\/Dienogest: A Novel Combined Oral Contraceptive","volume":"34","author":"Borgelt","year":"2012","journal-title":"Clin Ther"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/j.maturitas.2012.01.007","article-title":"The Pharmacology of Nomegestrol Acetate","volume":"71","author":"Ruan","year":"2012","journal-title":"Maturitas"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.2165\/11590220-000000000-00000","article-title":"Metabolic and Haemostatic Effects of Estradiol Valerate\/Dienogest, a Novel Oral Contraceptive: A Randomized, Open-Label, Single-Centre Study","volume":"31","author":"Junge","year":"2011","journal-title":"Clin Drug Investig"},{"key":"B79","doi-asserted-by":"publisher","first-page":"13","DOI":"10.2217\/whe.12.70","article-title":"A New Contraceptive Pill Containing 17b-Estradiol and Nomegestrol Acetate","volume":"9","author":"Christin-Maitre","year":"2013","journal-title":"Womens Health"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.3109\/13625187.2011.604450","article-title":"Effects of a Monophasic Combined Oral Contraceptive Containing Nomegestrol Acetate and 17beta-Oestradiol Compared With One Containing Levonorgestrel and Ethinylestradiol on Haemostasis, Lipids and Carbohydrate Metabolism","volume":"16","author":"Agren","year":"2011","journal-title":"Eur J Contracept Reprod Health Care"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1160\/TH10-05-0327","article-title":"Haemostatic Effects of a New Combined Oral Contraceptive, Nomegestrol Acetate\/17beta-Estradiol, Compared With Those of Levonorgestrel\/Ethinyl Estradiol. A Double-Blind, Randomised Study","volume":"105","author":"Gaussem","year":"2011","journal-title":"Thromb Haemost"},{"key":"B82","doi-asserted-by":"publisher","first-page":"39","DOI":"10.2147\/OAJC.S50693","article-title":"Comparison of the Pharmacologic and Clinical Profiles of New Combined Oral Contraceptives Containing Estradiol","volume":"4","author":"Jensen","year":"2013","journal-title":"Open Access J Contraception"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1080\/13625187.2021.1987410","article-title":"Prospective Controlled Cohort Study on the Safety of a Monophasic Oral Contraceptive Containing Nomegestrol Acetate (2.5mg) and 17\u03b2-Estradiol (1.5mg) (PRO-E2)","volume":"26","author":"Reed","year":"2021","journal-title":"Eur J Contracept Reprod Health Care"},{"key":"B84","volume-title":"Assessment Report for Combined Hormonal Contraceptives Containing Medicinal Products-EMA\/739865\/2013","year":"2014"},{"key":"B85","doi-asserted-by":"publisher","first-page":"697","DOI":"10.7326\/0003-4819-143-10-200511150-00006","article-title":"Trends in the Incidence of Venous Thromboembolism During Pregnancy or Postpartum: A 30-Years-Based Study","volume":"143","author":"Heit","year":"2005","journal-title":"Ann Internal Med"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2016.06.010","article-title":"Impact of Estrogen Type on Cardiovascular Safety of Combined Oral Contraceptives","volume":"94","author":"Dinger","year":"2016","journal-title":"Contraception"},{"key":"B87","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1080\/13697130802073425","article-title":"Estetrol Review: Profile and Potential Clinical Applications","author":"Coelingh Bennink","year":"2008","journal-title":"Climacteric"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2008.03.027","article-title":"Estetrol: A Unique Steroid in Human Pregnancy","volume":"110","author":"Holinka","year":"2008","journal-title":"J Steroid Biochem Mol Biol"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201404112","article-title":"The Uterine and Vascular Actions of Estetrol Delineate a Distinctive Profile of Estrogen Receptor Alpha Modulation, Uncoupling Nuclear and Membrane Activation","volume":"6","author":"Abot","year":"2014","journal-title":"EMBO Mol Med"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00024.2016","article-title":"Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications","volume":"97","author":"Arnal","year":"2017","journal-title":"Physiol Rev"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2006.01.025","article-title":"Integration of Membrane and Nuclear Estrogen Receptor Signaling","volume":"144","author":"Zhang","year":"2006","journal-title":"Comp Biochem Physiol A Mol Integr Physiol"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.4184","article-title":"Combined Estrogenic and Anti-Estrogenic Properties of Estetrol on Breast Cancer May Provide a Safe Therapeutic Window for the Treatment of Menopausal Symptoms","volume":"6","author":"G\u00e9rard","year":"2015","journal-title":"Oncotarget"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2018.06.010","article-title":"Effect of Estetrol, a Selective Nuclear Estrogen Receptor Modulator, in Mouse Models of Arterial and Venous Thrombosis","volume":"477","author":"Valera","year":"2018","journal-title":"Mol Cell Endocrinol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-11355-1_12","article-title":"Unique Vascular Benefits of Estetrol, a Native Fetal Estrogen With Specific Actions in Tissues (NEST)","author":"Foidart","year":"2019","journal-title":"Sex Steroids\u2019 Effects Brain Heart Vessels"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.3109\/13625187.2015.1068934","article-title":"Unique Effects on Hepatic Function, Lipid Metabolism, Bone and Growth Endocrine Parameters of Estetrol in Combined Oral Contraceptives","volume":"20","author":"Mawet","year":"2015","journal-title":"Eur J Contracept Reprod Health Care"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2016.04.015","article-title":"Bleeding Pattern and Cycle Control With Estetrol-Containing Combined Oral Contraceptives: Results From a Phase II, Randomised, Dose-Finding Study (FIESTA)","volume":"94","author":"Apter","year":"2016","journal-title":"Contraception"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1080\/13625187.2017.1336532","article-title":"Estetrol Combined With Drospirenone: An Oral Contraceptive With High Acceptability, User Satisfaction, Well-Being and Favourable Body Weight Control","volume":"22","author":"Apter","year":"2017","journal-title":"Eur J Contracept Reprod Health Care"},{"key":"B98","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/j.contraception.2020.08.015","article-title":"Evaluation of the Effect of a New Oral Contraceptive Containing Estetrol and Drospirenone on Hemostasis Parameters","volume":"102","author":"Douxfils","year":"2020","journal-title":"Contraception"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2020.1750365","article-title":"Estetrol (E4): The New Estrogenic Component of Combined Oral Contraceptives","volume":"13","author":"Grandi","year":"2020","journal-title":"Expert Rev Clin Pharmacol"},{"key":"B100","volume-title":"CHMP Summary of Positive Opinion for Lydisilka","year":"2021"},{"key":"B101","volume-title":"CHMP Summary of Positive Opinion for Drovelis","year":"2021"},{"key":"B102","article-title":"U.S. Medical Eligibility Criteria for Contraceptive Use","volume-title":"MMWR Recomm Rep","year":"2016"},{"key":"B103","volume-title":"Medical Eligibility Criteria for Contraceptive Use","year":"2015"},{"key":"B104","volume-title":"UK Medical Eligibility Criteria for Contreceptive Use (UKMEC)","year":"2016"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.163.9.1105","article-title":"Role of Family History in Identifying Women With Thrombophilia and Higher Risk of Venous Thromboembolism During Oral Contraception","volume":"163","author":"Cosmi","year":"2003","journal-title":"Arch Intern Med"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1160\/TH15-01-0045","article-title":"Risk Factors for Venous Thromboembolism in Women Under Combined Oral Contraceptive. The Pill Genetic Risk Monitoring (PILGRIM) Study","volume":"115","author":"Suchon","year":"2016","journal-title":"Thromb Haemost"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1016\/S0049-3848(11)70009-3","article-title":"Epidemiology of the Contraceptive Pill and Venous Thromboembolism","volume":"127","author":"Hannaford","year":"2011","journal-title":"Thromb Res"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1007\/5584_2016_120","article-title":"Genetic Risk Factors in Venous Thromboembolism","volume":"906","author":"Hotoleanu","year":"2017","journal-title":"Adv Exp Med Biol"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1160\/TH15-02-0141","article-title":"Classic Thrombophilic Gene Variants","volume":"114","author":"Mannucci","year":"2015","journal-title":"Thromb Haemost"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.16666","article-title":"The Joint Effect of Genetic Risk Factors and Different Types of Combined Oral Contraceptives on Venous Thrombosis Risk","volume":"191","author":"Khialani","year":"2020","journal-title":"Br J Haematol"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1641152","article-title":"Type of Combined Contraceptives, Factor V Leiden Mutation and Risk of Venous Thromboembolism","volume":"118","author":"Hugon-Rodin","year":"2018","journal-title":"Thromb Haemost"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2020.08.006","article-title":"Letter to the Editors-in-Chief in Response to the Article of Abou-Ismail, Et Al. Entitled \u201cEstrogen and Thrombosis: A Bench to Bedside Review\u201d (Thrombosis Research 192 (2020) 40\u201351)","volume":"193","author":"Morimont","year":"2020","journal-title":"Thromb Res"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.4414\/smw.2016.14392","article-title":"About Pill Protect\u00ae","volume":"146","author":"Michaud","year":"2016","journal-title":"Swiss Med Weekly"},{"key":"B114","doi-asserted-by":"publisher","first-page":"e0182041","DOI":"10.1371\/journal.pone.0182041","article-title":"Risk Prediction of Developing Venous Thrombosis in Combined Oral Contraceptive Users","volume":"12","author":"McDaid","year":"2017","journal-title":"PloS One"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12233","article-title":"Current Knowledge on the Genetics of Incident Venous Thrombosis","author":"Morange","year":"2013","journal-title":"J Thromb Haemost"},{"key":"B116","doi-asserted-by":"publisher","first-page":"134482","DOI":"10.1016\/j.neulet.2019.134482","article-title":"Could Rs4379368 be a Genetic Marker for North Indian Migraine Patients With Aura?: Preliminary Evidence by a Replication Study","volume":"712","author":"Kaur","year":"2019","journal-title":"Neurosci Lett"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-11-319053","article-title":"KNG1 Ile581Thr and Susceptibility to Venous Thrombosis","volume":"117","author":"Morange","year":"2011","journal-title":"Blood"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1055\/s-0040-1714140","article-title":"Oral Contraceptives and Venous Thromboembolism: Focus on Testing That May Enable Prediction and Assessment of the Risk","volume":"46","author":"Douxfils","year":"2020","journal-title":"Semin Thromb Hemost"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.769187\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T11:35:38Z","timestamp":1639049738000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.769187\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,9]]},"references-count":118,"alternative-id":["10.3389\/fendo.2021.769187"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.769187","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,9]]},"article-number":"769187"}}