Comparison of estrogenic components used for hormonal contraception

Attempts have been made over the years to replace ethinyl estradiol (EE) in combined oral contraceptives (COCs) with the less potent natural estrogen estradiol (E₂), or its prodrug, E₂ valerate (E₂V), to improve their safety and tolerability. Recently, a COC incorporating a novel weak natural estrogen, estetrol (E₄), combined with drospirenone, has become available. We present a comparative analysis of the three prevailing estrogens used in COCs, focusing on their structure-function relationships, receptor-binding affinity, potency, metabolism, pharmacokinetic parameters, and pharmacodynamics. The binding affinity of EE to estrogen receptor (ER)α is twice that of E₂, whereas its affinity for ERβ is about one-half that of E₂. E₄ has a lower binding affinity for the ERs than E₂. The high potency of EE is notable in its dramatic increase in estrogen-sensitive hepatic globulins and coagulation factors. EE and E₂ undergo extensive and comparable metabolism, while E₄ produces only a very limited number of metabolites. E₄ has the highest bioavailability among the three estrogens, with E₂ having <5%. Studies demonstrate consistent ovulation inhibition, although a higher dose of E₄ (15 mg) in COCs is required to achieve follicular suppression compared to E₂ (1-3 mg) and EE (0.01-0.035 mg). E₂ and E₄ in COCs may be less stimulatory of coagulant proteins than EE. Studies with E₂/dienogest suggest a comparable risk of venous thromboembolism to EE/levonorgestrel, while data assessing risk with an E₄-based COC are insufficient. Nevertheless, the E₄-based formulation shows promise as a potential alternative to EE and E₂ due to its lower potency and possibly fewer side effects.