Estrol, also known as E4, is a naturally occurring estrogen hormone that has gained attention in scientific discussions. It is a distinct member of the estrogen family, offering unique characteristics. Estrol’s specific properties and origins make it a subject of increasing interest for potential medical applications.
Its Unique Origin and Role
Estrol (E4) is primarily produced by the fetal liver during pregnancy, reaching the maternal bloodstream via the placenta. Both maternal and fetal estrol concentrations increase throughout pregnancy, peaking at high levels by term, with fetal levels often 10 to 20 times higher than maternal levels.
The precise role of estrol in embryonic physiology or human pregnancy is not fully understood and remains an area of ongoing research. Its exclusive production by the fetal liver during pregnancy makes it distinct from other estrogens, which are primarily produced by the ovaries or through conversion in other tissues.
How Estrol Differs from Other Estrogens
Estrol (E4) stands apart from the three major estrogens: estradiol (E2), estrone (E1), and estriol (E3). Estradiol is the most potent estrogen during a woman’s reproductive years, primarily produced by the ovaries. Estrone is the main estrogen after menopause, while estriol is significantly elevated during pregnancy.
Structurally, estrol has four hydroxyl groups. This unique structure contributes to its distinct receptor binding profile. Estrol has a moderate affinity for both human estrogen receptor alpha (ERα) and ERβ, showing a preference for ERα. It primarily stimulates nuclear ERα and does not activate membrane ERα. This selective action on the nuclear estrogen receptor alpha results in tissue-specific effects across various organs.
Estrol’s metabolic profile also contributes to its unique properties. It shows minimal interaction with the hepatic cytochrome P450 enzyme system, which suggests a favorable pharmacokinetic profile and a reduced potential for drug-drug interactions compared to other estrogens.
Medical Applications of Estrol
Estrol is a promising candidate for various medical applications. It is currently available in combination with drospirenone as a combined oral contraceptive, registered worldwide since 2022. This combination has shown effectiveness in inhibiting ovulation and providing good cycle control with a neutral metabolic effect.
Beyond contraception, estrol is undergoing late-stage clinical development for menopausal hormone therapy (MHT) and is expected to become available in 2026. Studies suggest that estrol has a lower impact on hemostatic and metabolic parameters compared to other estrogens, potentially reducing the risk of adverse effects such as thromboembolic events. This makes it a potential option for women seeking relief from menopausal symptoms.
Estrol is also being investigated for other therapeutic uses. Clinical development is ongoing for its use in treating advanced breast cancer and advanced prostate cancer. Estrol has been proposed as a component of an oral male contraceptive and is being researched for applications in dysmenorrhea, endometriosis, female sexual function, and neuroprotection in neonatal hypoxic-ischemic encephalopathy.