Name: China Supplier High Quality ESTETROL for estrogen CAS 15183-37-6
Brand: Wuhan Fortuna Chemical Co., Ltd.

Estetrol (E4) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. It is classified as a native estrogen with selective tissue action (NEST). Recently synthesized for medicinal use, it is the active ingredient in the new birth control pill Nextstellis® and is being developed for menopausal hormone therapy. Its key advantage is a proposed improved safety profile compared to older estrogens, particularly regarding blood clot (thrombotic) risk.

1. Origin and Chemical Definition

Source: A natural steroid hormone, one of the four major estrogens (along with E1, E2, E3) found in humans. It is produced by the fetal liver and reaches detectable levels in the mother's blood during pregnancy.
Chemical Class: Estrogen (steroid).
Key Feature: It has a unique molecular structure with four hydroxyl groups (making it a "tetrol"), which influences how it is metabolized and how it interacts with estrogen receptors in the body.

2. Mechanism of Action: Selective Tissue Action

Estetrol's promise lies in its selective effects, which are different from those of the most commonly used estrogen, estradiol (E2).

Estrogen Receptor Agonist: It activates the nuclear estrogen receptors (ERα and ERβ) in most tissues, providing the desired estrogenic effects (e.g., controlling ovulation, relieving menopausal symptoms).
Antagonistic Effects in the Liver: This is its most critical property. In the liver, Estetrol acts differently. It does not significantly stimulate the production of clotting factors (like sex hormone-binding globulin, angiotensinogen, and others), which are associated with the increased risk of venous thromboembolism (VTE) seen with traditional estrogens like ethinylestradiol. This selective action is why it is believed to have a lower risk of causing blood clots.

3. Key Properties and Uses

Therapeutic Uses:
Contraception: Combined oral contraceptive (Nextstellis®), where it is paired with the progestin drospirenone. It is effective at preventing pregnancy with good cycle control.
Menopausal Hormone Therapy (MHT): Currently in clinical trials for relieving vasomotor symptoms (hot flashes) and vulvovaginal atrophy in postmenopausal women. Its tissue-selective profile could make it a safer option for MHT, especially for women at risk for cardiovascular issues.
Benefits (Theoretical and Observed):
Lower Thrombotic Risk: The primary proposed benefit over ethinylestradiol.
Good Efficacy: Effective at controlling ovulation and menopausal symptoms.
Favorable Metabolic Profile: Appears to have a neutral or positive effect on lipid profiles and blood pressure.

4. Comparison with Other Estrogens

Estrogen	Type	Key Feature / Use	Main Risk Concern
Estetrol (E4)	Natural, Native	Selective tissue action (NEST)	Potentially lower thrombotic risk
Estradiol (E2)	Natural, Bio-identical	Menopausal Hormone Therapy, Patches	Standard thrombotic risk for oral forms
Ethinylestradiol (EE)	Synthetic	Classic "pill" estrogen in most COCs	Significantly higher thrombotic risk
Conjugated Equine Estrogens (CEE)	Mixed (from horses)	Menopausal Hormone Therapy (e.g., Premarin)	Standard thrombotic risk

Conclusion

Estetrol is a groundbreaking natural estrogen that represents a significant innovation in hormonal medicine. Its development capitalizes on decades of research into creating a "safer" estrogen that provides the therapeutic benefits where they are needed (brain, bone, vagina) while minimizing unwanted stimulation in other tissues (liver). While long-term data is still being gathered, its introduction marks a potential new era for safer oral contraception and menopausal hormone therapy.