Estetrol

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Cat Number

API0232176

CAS Number

15183-37-6

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CAS Number

15183-37-6

EINECS

840-340-4

Storage

Store at room temperature

Synonyms

Estetrol anhydrous; 15alpha-hydroxyestriol; estetrolum; oestetrol; ENB39R14VF; Estetrol (anhydrous)

Molecular Formula

C18H24O4

Molecular Weight

304.4

Smiles

C[C@]12CC[C@H]3[C@H]([C@@H]1[C@H]([C@H]([C@@H]2O)O)O)CCC4=C3C=CC(=C4)O

Appearance

Off-white solid

Melting Point

233-236°C

Boiling Point

491.9±45.0°C (Predicted)

Relative Density

1.343±0.06 (Predicted)

General Description

Estetrol (E4) is a natural estrogenic steroid hormone produced exclusively by the human fetal liver during pregnancy, characterized by the presence of four hydroxyl groups (-OH) at positions 2, 4, 15, and 16α. Its structure is a 1,3,5(10)-estratriene derivative with a molecular weight of 304.4 Da. Estetrol is a white crystalline powder with a relatively low binding affinity for the estrogen receptor.

Mechanism of Action

Estetrol acts as a selective estrogen receptor modulator (SERM) with tissue-selective agonist and antagonist properties. It binds to estrogen receptors (ERα and ERβ) but with a lower affinity and different conformational change than estradiol, leading to distinct transcriptional activity. It has tissue-selective actions, acting as an estrogen agonist in bone and the cardiovascular system, but with minimal stimulation of breast and endometrial tissues.

Application

Estetrol is indicated as a component of combined oral contraceptives (with drospirenone) for the prevention of pregnancy. It is also being investigated for the treatment of menopausal symptoms and as a potential therapy for breast cancer due to its minimal proliferative effects on the breast. The drug offers a favorable hemostatic and metabolic profile compared to ethinylestradiol.

In a randomized non-inferiority trial, 36 healthy women started combined oral contraceptives containing estetrol/drospirenone (E4/DRSP) or ethinyl estradiol/gestodene (EE/GS) on cycle days 7–9. Ovulation was inhibited in 61.1% of participants in both groups (adjusted RR 0.95, 95% CI 0.56–1.59). Cervical mucus and adverse events did not differ. High ovulation rates limited confirmation of non-inferiority, though delayed-start E4/DRSP appears comparable to EE/GS.

Fig. 1 Absolute risk difference (ARD) for ovulation inhibition. (Ittipuripat S, et al., 2025)

References

Ittipuripat S, et al. Delayed start of estetrol drospirenone versus ethinyl estradiol gestodene for ovulation inhibition in a noninferiority randomized controlled trial. Sci Rep. 2025;15(1):43682.

In a 12‑week double‑blind study (257 postmenopausal women), estetrol (E4) 15 mg demonstrated estrogenic effects on vaginal cytology, increasing superficial cells and decreasing parabasal/intermediate cells (P<0.01). It significantly reduced vaginal dryness (‑0.40, P=0.03) and dyspareunia (‑0.47, P=0.0006), with symptom reporting decreasing by 41‑50%. Menopause Rating Scale scores improved (‑3.1, P=0.069). E4 15 mg is a promising treatment for genitourinary syndrome of menopause beyond vasomotor symptoms.

Fig. 2 Vaginal MV at baseline and at W12 (LOCF). (Gaspard U, et al., 2023)

References

Gaspard U, et al. A multicenter, randomized, placebo-controlled study to select the minimum effective dose of estetrol in postmenopausal participants (E4Relief): part 2-vaginal cytology, genitourinary syndrome of menopause, and health-related quality of life. Menopause. 2023;30(5):480-489.

Does Estetrol require protection from light during storage?

Yes, it is photosensitive. Light exposure can cause photodegradation and isomerization of the steroid ring. Store in light-resistant containers, preferably amber glass.

What is the recommended storage temperature for Estetrol?

Store at controlled room temperature (15-25°C). Avoid excessive heat above 30°C, which can accelerate oxidation of the phenolic A-ring.

Is Estetrol stable in tablet formulations with standard excipients?

Yes, when formulated with moisture-protective packaging.

How is the impurity estetrol-3-sulfate (a process-related impurity) monitored?

This impurity is quantified using a stability-indicating HPLC method with mass spectrometric detection, ensuring it remains within ICH limits.