Estetrol/drospirenone for combined oral contraception: a systematic review of efficacy, cycle control, and safety
In brief
Estetrol-drospirenone oral contraceptive matches efficacy and cuts clot-related lab markers versus ethinyl estradiol
A systematic review of 25 trials found that the 15 mg estetrol/3 mg drospirenone pill provides contraceptive efficacy and cycle control comparable to traditional combined pills, while producing smaller changes in laboratory measures of clotting and metabolism. It also relieves dysmenorrhea, but real-world data on actual thromboembolic risk are still lacking.
- Journal
- Frontiers in endocrinology (Q1)
- Published
- 24 July 2026
- Study design
- Systematic review / meta-analysis of RCTs
- Evidence level
- Level 1, High (CEBM 1a)
- Authors
- Manuel Sánchez-Prieto, Sandra Coll, Marina Romero-Domínguez, Marta Avella-Marcos, Mireia Castilla, Margarita Gómez Del Valle, et al.
- PMID
- 42568434
- DOI
- 10.3389/fendo.2026.1867343
Why clinicians should know about it
- Picked for Pediatrics and Child Health (top studies of the week, 9 August 2026): High-quality evidence in a top journal
- Picked for Obstetrics and Gynecology (top studies of the week, 9 August 2026).
Abstract
OBJECTIVE: 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. METHODS: 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-metabolic effects, ovarian suppression, and noncontraceptive clinical outcomes. Risk of bias was assessed using design-specific tools, and certainty of evidence was graded by outcome. RESULTS: 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-metabolic effects than ethinyl estradiol-containing 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. CONCLUSIONS: 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-containing formulations. However, current evidence does not establish comparative thromboembolic safety, which requires dedicated postauthorization and real-world comparative studies.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.