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 (E-2), or its prodrug, E-2 valerate (E2V), to improve their safety and tolerability. Recently, a COC incorporating a novel weak natural estrogen, estetrol (E-4), 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)alpha is twice that of E-2, whereas its affinity for ER beta is about one-half that of E-2. E-4 has a lower binding affinity for the ERs than E-2. The high potency of EE is notable in its dramatic increase in estrogen-sensitive hepatic globulins and coagulation factors. EE and E-2 undergo extensive and comparable metabolism, while E-4 produces only a very limited number of metabolites. E-4 has the highest bioavailability among the three estrogens, with E-2 having <5%. Studies demonstrate consistent ovulation inhibition, although a higher dose of E-4 (15 mg) in COCs is required to achieve follicular suppression compared to E-2 (1-3 mg) and EE (0.01-0.035 mg). E-2 and E-4 in COCs may be less stimulatory of coagulant proteins than EE. Studies with E-2/dienogest suggest a comparable risk of venous thromboembolism to EE/levonorgestrel, while data assessing risk with an E-4-based COC are insufficient. Nevertheless, the E-4-based formulation shows promise as a potential alternative to EE and E-2 due to its lower potency and possibly fewer side effects. (c) 2023 Elsevier Inc. All rights reserved.