{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T05:02:00Z","timestamp":1784869320553,"version":"3.55.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To systematically evaluate the evidence on the contraceptive efficacy, cycle control, safety, and selected noncontraceptive effects of estetrol 15 mg\/drospirenone 3 mg (E4\/DRSP) and to assess certainty of evidence by outcome using the GRADE approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A systematic review was conducted in accordance with PRISMA 2020. PubMed\/MEDLINE, Scopus, and Google Scholar were searched for eligible studies published through February 2026. Clinical trials and comparative studies evaluating E4\/DRSP in women of reproductive age were included. Outcomes were grouped into contraceptive efficacy, bleeding\/cycle control, safety and tolerability, hemostatic and endocrine\u2013metabolic effects, ovarian suppression, and noncontraceptive clinical outcomes. Risk of bias was assessed using design-specific tools, and certainty of evidence was graded by outcome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 25 eligible publications\/study reports were included, comprising phase 2 dose-finding studies, pivotal phase 3 contraceptive trials, pooled analyses, mechanistic comparator studies, adolescent data, and indication-specific studies. E4\/DRSP demonstrated robust contraceptive efficacy, predictable bleeding patterns, and an acceptable tolerability profile. Across mechanistic studies, E4\/DRSP showed less pronounced hemostatic and endocrine\u2013metabolic effects than ethinyl estradiol\u2013containing comparators. The most consistent biological differentiation of E4\/DRSP was observed for APC resistance and thrombin-generation endpoints, which were less affected than with EE-containing comparators. The strongest noncontraceptive evidence was observed for dysmenorrhea, supported by a randomized, double-blind, placebo-controlled trial. Certainty of evidence was moderate for contraceptive efficacy, cycle control, common adverse events, and surrogate hemostatic\/metabolic outcomes; high for dysmenorrhea versus placebo; low for endometriosis-related and menstrual symptom outcomes; and very low for clinical thromboembolic risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>E4\/DRSP is an effective combined oral contraceptive with favorable cycle control and a consistent biologic profile suggesting lower hepatic\/hemostatic impact than ethinyl estradiol\u2013containing formulations. However, current evidence does not establish comparative thromboembolic safety, which requires dedicated postauthorization and real-world comparative studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1867343","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T04:23:25Z","timestamp":1784867005000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Estetrol\/drospirenone for combined oral contraception: a systematic review of efficacy, cycle control, and safety"],"prefix":"10.3389","volume":"17","author":[{"given":"Manuel","family":"S\u00e1nchez-Prieto","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Dexeus Mujer, Hospital Universitario General de Catalunya","place":["Sant Cugat del Vall\u00e9s, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Coll","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Dexeus Mujer, Hospital Universitario General de Catalunya","place":["Sant Cugat del Vall\u00e9s, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Romero-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Hospital QuironSalud M\u00e1laga","place":["M\u00e1laga, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Avella-Marcos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Dexeus Mujer, Hospital Universitario General de Catalunya","place":["Sant Cugat del Vall\u00e9s, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireia","family":"Castilla","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Dexeus Mujer, Hospital Universitario General de Catalunya","place":["Sant Cugat del Vall\u00e9s, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarita","family":"G\u00f3mez del Valle","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Dexeus Mujer, Hospital Universitario General de Catalunya","place":["Sant Cugat del Vall\u00e9s, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Franco-Camps","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Dexeus Mujer, Hospital Universitario General de Catalunya","place":["Sant Cugat del Vall\u00e9s, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1136\/bmjsrh-2018-CHC","article-title":"Combined hormonal contraception (revision due by January 2024)","volume":"45","year":"2019","journal-title":"BMJ Sex Reprod Health"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2026.2636570","article-title":"Combined oral contraceptives and pharmacokinetic drug interactions: impact on efficacy and safety","volume":"22","author":"Geriesh","year":"2026","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1080\/13625187.2024.2317295","article-title":"Health benefits of combined oral contraceptives - 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