Estetrol

Estetrol, also known as E4, is a natural estrogen, a steroid hormone produced during pregnancy. It is synthesized mainly by the fetal liver and released into the maternal circulation. In humans, estetrol is one of four estrogens detected in fetal and maternal blood during pregnancy, alongside estradiol, estrone, and estriol.

Estetrol production occurs exclusively during pregnancy; its levels rise during mid- to late pregnancy and fall after birth. It is formed in the fetus and transferred to the maternal circulation.

In terms of pharmacology, estetrol binds estrogen receptors ERα and ERβ with lower affinity than estradiol and exhibits tissue-selective activity. It has a relatively weak effect on hepatic protein synthesis in experimental models, which has led to speculation that estetrol-based therapies might have a different safety profile, particularly with regard to liver-related factors. Data from humans are limited, and the cardiovascular and thrombotic implications remain uncertain.

Estetrol has been studied as a potential component of combined hormonal therapies, including contraception and menopausal hormone therapy. Several pharmaceutical programs have developed estetrol-containing products; regulatory approvals and availability vary by country, and as of the early 2020s many products were in development or subject to clinical trials rather than widely marketed.

Safety considerations remain the subject of ongoing research. While preliminary data suggest possible differences from conventional estrogens in hepatic effects, robust evidence on cardiovascular risk, venous thromboembolism, and other adverse events is not yet established.