Related Experiment Video
Updated: Aug 28, 2026

An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Natural estrogens: the new reference in contraception. An Italian expert opinion paper
Angelo Cagnacci1, Stefano Lello2, Anna Capozzi2
1Academic Unit of Obstetrics and Gynecology, IRCCS-San Martino Hospital, Department of Neuroscience, Obstetrics and Gynecology Unit, Rehabilitation, Ophthalmology, Genetics and Maternal and Pediatric Sciences, University of Genova, Genova, Italy.
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.
Related Concept Videos
Birth Control Methods
Intrauterine Drug Delivery Systems
Hormonal Regulation
Hormonal Regulation
Pharmaceutical Alternatives: Stability-Related Therapeutic Nonequivalence
Adrenergic Antagonists: ɑ and β-Receptor Blockers

