Natural estrogens: the new reference in contraception. An Italian expert opinion paper.

INTRODUCTION: Combined oral contraceptives (COCs) have undergone continuous pharmacological evolution since their introduction in the 1960s. The replacement of synthetic ethinyl estradiol (EE) with natural estrogens - estradiol (E2), estradiol valerate (E2V), and estetrol (E4) - represents a significant advancement in improving the tolerability, safety, and acceptability of hormonal contraception. AREAS COVERED: This paper surveys the extensive literature existing on the historical and pharmacological evolution of COCs, with particular focus on the role of the estrogenic component in balancing efficacy and tolerability. The pharmacokinetic and pharmacodynamic profiles of available estrogens are discussed, highlighting the distinctive properties of estradiol, estradiol valerate and estetrol. Evidence from clinical trials and observational studies supporting a favorable metabolic, hemostatic, and cardiovascular profile of natural estrogen-based COCs is reviewed, alongside emerging data supporting their designation as a first-line contraceptive option. EXPERT OPINION: Natural estrogens represent the culmination of approximately 70 years of COC development. Their incorporation into clinical guidelines as first-line options requires comprehensive awareness among healthcare providers and broader access for users. Further lines of research may focus on pharmacological optimization and long-term safety across diverse populations as in women with comorbidities to fully realizing their clinical wide potential.