Insights on estetrol, the native estrogen: from contraception to hormone replacement therapy

Estetrol (E4) is a natural estrogen that has recently emerged as new option for contraception and hormone replacement therapy (HRT). Unlike other estrogens, E4 primarily stimulates nuclear estrogen receptor alpha (ERα) and does not activate membrane ERα. For this reason, this novel estrogen has tissue-specific effects across various organs such as liver, vascular endothelium, mammary glands, brain, vagina, and uterus. The selective activation of the nuclear ERα results in distinct pharmacological properties that contribute to its unique therapeutic profile. Moreover, E4 shows minimal interaction with the hepatic cytochrome P450 enzyme system, leading to a favorable pharmacokinetic profile and a reduced potential for drug-drug interactions. Currently, E4 is commercially available in combination with drospirenone as a combined oral contraceptive and its application in HRT is undergoing late-stage clinical development. Many studies have demonstrated that E4 has a lower impact on hemostatic and metabolic parameters compared to other estrogens, potentially reducing the risk of adverse effects commonly associated with hormonal therapies such as thromboembolic events or dyslipidemia. Beyond its role in contraception and HRT, E4 shows promising therapeutic potential in other medical fields, including neuroprotection in neonatal hypoxic-ischemic encephalopathy, enhancement of hematopoietic stem cell transplantation outcomes and prostate cancer management. This review synthesizes the latest evidence on E4 primarily focusing on its pharmacological characteristics and clinical applications. The findings suggest that E4 versatility and peculiar mechanism of action may represent an important therapeutic option for a broad spectrum of medical conditions.