Estetrol‐based combined oral contraceptives: A systematic review of clinical outcomes

INTRODUCTION: Combined oral contraceptive pills (COCs) are a common contraceptive method among women of reproductive age. Ethinylestradiol (EE) is a frequently used estrogen component in COCs. However, EE may increase the risk of cardiovascular complications by affecting coagulation, fibrinolysis, and blood pressure. Lowering the dose of EE to minimize the risk has been linked to disadvantageous bleeding patterns. The natural estrogen estetrol (E4) has been introduced as an alternative component to EE. E4 has been suggested to have beneficial effects on targeted tissue with a limited impact on the liver and coagulation, compared to EE-containing COCs, and thus, offers a potential for improving the safety of future COCs. This systematic review examines the safety and efficacy of COCs containing E4 compared to traditional COCs. MATERIAL AND METHODS: A systematic search was conducted in Embase and PubMed databases. Studies investigating the effects of COCs containing E4 in a study population of healthy women of reproductive age were included. All clinical outcomes related to contraceptive efficacy, bleeding patterns, mood and sexual health, endocrine and liver metabolism parameters, and markers for cardiovascular health were evaluated. Literature reviews, meta-analyses, and in vivo and animal studies were excluded. Retrieval and assessment of articles were performed in Covidence software following PRISMA guidelines and Cochrane risk of bias assessment tools. RESULTS: Fourteen studies were included in the review. Results indicate that E4-containing COCs offer a high contraceptive reliability, predictable menstrual cycles, and favorable bleeding patterns. E4-containing COCs effectively suppressed ovulation while allowing for rapid return of ovulation after discontinuation. Furthermore, E4-containing COCs present milder effects on coagulation factors and a more neutral impact on thrombin generation, suggesting a reduced risk for venous thromboembolisms. CONCLUSIONS: E4-containing COCs could potentially be a safer and more effective alternative to contraceptive use. The findings should be interpreted with caution, as study limitations such as design and confounder bias, small study populations, and short follow-up times characterize the studies included in this review. Further, industry sponsorship bias cannot be ruled out. Further independent research is needed to confirm long-term safety and applicability of E4-containing COCs across diverse populations.