The clinical relevance of having more than one estrogen in combined hormonal contraception to address the needs of women.

UNLABELLED: This chapter examines the potential of natural estrogens, particularly estradiol and estetrol, in combined hormonal contraceptive pills as alternatives to the widely used synthetic ethinyl estradiol. Current evidence highlights the promise of these natural estrogens in providing effective contraception with improved safety profiles and maintained tolerability.

WHAT WE KNOW: Estradiol and estetrol exhibit favorable safety and efficacy profiles compared to ethinyl estradiol.

WHAT WE THINK WE KNOW: Initial studies suggest that estetrol combined with drosperinone provide effective contraception with a predictable bleeding patternand reduced risk for venous thromboembolism compared to ethinyl estradiol containing pills. Such risk may also be further mitigated by non-oral administration of estradiol.

WHAT WE DO NOT KNOW: Long-term efficacy and safety data are needed to confirm the benefits of natural estrogens and their impact on diverse populations and comorbid conditions. By addressing these gaps, future research can enhance our understanding of natural estrogens in hormonal contraception, ultimately refining their use in clinical practice.