Innovative contraceptive approaches with estetrol: a review of mammalogical safety data

Abstract

Malignant and benign mammary gland diseases (MG) are leading causes of female oncological and hormone-dependent pathology. The mammalogical safety of combined hormonal contraceptives (CHCs) remains under debate, underscoring the need for regimens that minimally affect MG tissue proliferation and breast cancer (BC) risk. Estetrol (E4), a fetal natural estrogen with selective tissue activity (NEST), combined with drospirenone (DRSP), a fourth-generation progestogen, is regarded as a potentially safer contraceptive option from an oncological standpoint. This review synthesizes current experimental, clinical, and epidemiological evidence to assess the mammalogical safety and potential oncoprophylactic effects of CHCs containing E4 and DRSP, focusing on their influence on proliferation, migration, and the breast’s structural and functional state. The literature review incorporates findings from large case-control cohort studies evaluating breast cancer risk during CHC use (including the Danish registry), meta-analyses, and multicenter randomized clinical trials examining the efficacy and safety of combined oral contraceptives (COCs) with E4/DRSP. Large population-based studies report a modest relative increase in BC risk associated with modern CHCs (hazard ratio approximately 1.2). DRSP does not show a statistically significant increase in risk compared to other progestogens (hazard ratio 1.04, 95% confidence interval 0.96–1.12). Preclinical studies indicate that DRSP induces less proliferation in BC cell lines than first-generation progestins, and the E4/DRSP combination demonstrates no effect on tumor growth in in vivo models. E4 exhibits dualistic properties: it stimulates proliferation of normal and tumor breast tissue to a much lesser extent; in the presence of estradiol, it demonstrates anti-estrogenic and anti-migration effects through the GPER/ERK/SERPINB2 pathway; and it exerts a pro-apoptotic effect in endocrine-resistant BC cells. Clinical studies of E4 in patients with early and advanced ER-positive BC confirm no stimulating effect on Ki-67, increased apoptosis, and an acceptable safety profile. COCs containing E4/DRSP are associated with a low incidence of mastalgia (approximately 4%, mostly mild), rare discontinuations for mammalogical reasons, and high patient satisfaction. Russian observational studies in women with benign breast dysplasia report statistically significant reductions in mastalgia severity, decreases in glandular layer thickness, and reductions in the severity of adenomatosis, duct ectasia, and cysts, as well as improvements in quality of life. Collectively, these findings indicate that the E4/DRSP combination has a favorable mammological profile: it does not increase BC risk compared to other low-dose COCs, and E4, due to its tissue selectivity and anti-estrogenic, pro-apoptotic effects, enhances the safety of the combination. For women with benign breast dysplasia and mastalgia, COCs based on E4/DRSP provide effective contraception and clinically significant improvements in breast structure and symptoms. This evidence supports consideration of this drug as a preferred option in populations with increased cancer risk, provided that current eligibility criteria for contraceptive methods and regular breast screening are maintained.