Estetrol and its implications for contraception, venous thromboembolism, and breast cancer: an integrative review.

Combined oral contraceptives (COCs) provide benefits beyond contraception but are associated with risks such as venous thromboembolism (VTE) and breast cancer. This integrative review aimed to evaluate the efficacy and safety of estetrol (E4)-containing COCs regarding their risk of VTE and breast cancer. The PubMed database was searched for preclinical and clinical studies published through 2025. Data extraction followed a structured protocol, resulting in the inclusion of 15 studies in the review. Available evidence suggests that E4 has limited effects on the liver and the coagulation cascade, in addition to being associated with less breast tissue proliferation compared to other estrogens. However, clinical evidence regarding hard outcomes, including the long-term incidence of VTE and breast cancer, remains limited. Current evidence suggests a promising efficacy and safety profile but remains insufficient to rule out the risks of VTE and breast cancer.