Estetrol

Estetrol (E4) is a naturally occurring estrogen produced exclusively by the fetal liver during pregnancy in women. It is one of four major estrogens alongside estrone (E1), estradiol (E2), and estriol (E3). Unlike the other major estrogens, estetrol's production is highly dependent on the presence of a viable fetus. Its unique production pathway and pharmacological properties have led to its development as a potential therapeutic agent.

Properties:

• Estetrol is a steroid hormone with four hydroxyl groups (3α, 15α, 16α, 17β), which distinguishes it from the other major estrogens.
• It exhibits tissue-selective estrogenic activity, acting as an estrogen receptor agonist in some tissues and as an estrogen receptor antagonist or partial agonist in others. This tissue selectivity may offer advantages in terms of safety and efficacy compared to traditional estrogen therapies.
• Estetrol has a relatively short half-life.
• It binds to both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), but with varying affinities depending on the tissue and target gene.

Clinical Applications and Research:

Estetrol is being investigated and used for various applications related to hormonal health, including:

• Hormone Therapy: Estetrol is used as a component of hormone therapy for menopausal symptoms.
• Contraception: Estetrol is used in some combined oral contraceptive pills, often in combination with a progestogen.
• Other Potential Uses: Research is ongoing to explore the potential use of estetrol in treating other conditions, such as osteoporosis, breast cancer, and cardiovascular disease, due to its unique estrogenic profile.

Mechanism of Action:

The mechanism of action of estetrol is complex and involves interactions with estrogen receptors (ERα and ERβ) in different tissues. The specific effects of estetrol vary depending on the target tissue, receptor subtype, and presence of other co-factors. Its tissue-selective estrogenic activity is thought to be related to its ability to differentially modulate the expression of estrogen-responsive genes in different tissues.

Safety and Tolerability:

Clinical trials and post-marketing surveillance are ongoing to assess the safety and tolerability of estetrol-containing products. Common side effects are generally similar to those associated with other estrogen-containing medications.

Synthesis:

Estetrol is synthesized by the fetal liver from dehydroepiandrosterone sulfate (DHEAS) supplied by the fetal adrenal glands and the maternal circulation. The fetal liver possesses unique enzymes necessary for the 15α-hydroxylation step required for estetrol production. After birth, estetrol production ceases in the infant.