Estriol
| Evidence Level: L3 | Predicted Indications: 1 |
Table of Contents
Estriol: From Topical Estrogen Cream to Amenorrhea
One-Sentence Summary
Estriol is an estrogen. In the US market records it appears only in topical cream products, and none of those records lists an approved indication. The TxGNN model predicts it may be effective for amenorrhea, especially functional hypothalamic amenorrhea. The support is thin: 3 clinical trials (none directly relevant) and 13 publications, of which only one small interventional study looks at estriol in this condition.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not stated in the license records (all listed products are topical creams) |
| Predicted New Indication | Amenorrhea |
| TxGNN Prediction Score | 99.18% |
| Evidence Level | L3 |
| US Market Status | ✓ Marketed |
| Number of NDAs | 11 license records (ANDA and other listings, not all NDAs) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available. Estriol is a weak natural estrogen, and estrogen replacement is a standard concept in conditions of low estrogen. Amenorrhea is often accompanied by low estrogen, so the prediction is biologically plausible.
The best-supported link is functional hypothalamic amenorrhea (FHA). In FHA, stress or metabolic factors suppress GnRH pulses from the hypothalamus. This lowers LH and FSH, reduces ovarian function, and produces a low-estrogen state. A small human study (PMID 22137494) reports that estriol administration modulated LH secretion in women with FHA. A 2023 review (PMID 37371858) proposes that low-dose estrogens act as neuroendocrine modulators that may help restore the positive feedback mechanism. Estrogen replacement in premature ovarian failure, another cause of amenorrhea, is also plausible.
There are important limits. The link rests on small studies and a hypothesis-generating review. The 0.99 TxGNN score is a computational prediction, not clinical confirmation. Amenorrhea is heterogeneous (hypothalamic, ovarian, anatomical), so estriol is unlikely to help across all subtypes.
Clinical Trial Evidence
None of these trials tests estriol for amenorrhea, so none counts as direct evidence.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT04487392 | Phase 2 | Withdrawn | 0 | Photobiomodulation for vulvovaginal atrophy in postmenopausal women. Withdrawn before enrollment, and the condition differs from amenorrhea. |
| NCT04090957 | Phase 3 | Completed | 1015 | Placebo-controlled trial of estetrol (E4Comfort II) for vasomotor symptoms in postmenopausal women. Estetrol is a different molecule from estriol. |
| NCT04209543 | Phase 3 | Completed | 1570 | Placebo-controlled trial of estetrol (E4Comfort I) for vasomotor symptoms in postmenopausal women. Estetrol is a different molecule from estriol. |
Literature Evidence
No randomized controlled trials were found. Several abstracts are not available, so some summaries are based on titles only.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 22137494 | 2012 | Small interventional study | Fertility and Sterility | Evaluated estriol’s effect on hypothalamic-pituitary function and gonadotropin secretion in women with FHA. Reports that estriol modulates LH secretion. |
| 37371858 | 2023 | Review | Biomedicines | Proposes low-dose estrogens as neuroendocrine modulators in FHA, possibly triggering positive feedback. Hypothesis-generating. |
| 16526238 | 2005 | Clinical study | Medicinski Pregled | Effects of estrogen-progestagen therapy on lipid and hormonal profiles in premature primary ovarian failure (hypergonadotropic amenorrhea). Not estriol-specific. |
| 14194444 | 1964 | Clinical trial (per title) | J Obstet Gynaecol Br Commonw | Gonadotrophin treatment in idiopathic secondary amenorrhea. Historical, and does not test estriol. |
| 4102186 | 1971 | Case report | Lancet | Endocrine findings in two patients with premature ovarian failure. |
| 2949864 | 1986 | Observational study | Zhong Xi Yi Jie He Za Zhi | Relationship between “kidney deficiency” (a traditional Chinese medicine concept) and gonadal function changes in amenorrhea and oligomenorrhea. |
| 7026111 | 1981 | Review | Clin Obstet Gynecol | Neoplasia and hormonal contraception. Only indirectly relevant. |
| 4254759 | 1971 | Review | Br J Psychiatry | Review of anorexia nervosa. Abstract not available, so its relevance is unclear. |
US Market Information
These records come from the market data. Several entries have no license number or approved indication in the source data.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| Not provided | LMNOOP Feminine Cream | Cream | Not stated |
| M016 | JARDIENT | Cream | Not stated |
| Not provided | Beilloso Women Estriol | Cream | Not stated |
| ANDA075357 | Arthcal ESTROGEN | Cream | Not stated |
| Not provided | Flocean INTIMATE COMFORT | Cream | Not stated |
Showing 5 of 11 license records. All are topical creams. Because the predicted indication would likely need systemic estrogen exposure, route compatibility remains unassessed.
Safety Considerations
Please refer to the package insert for safety information. Drug interaction queries returned no results.
Conclusion and Next Steps
Decision: Hold
Rationale: The prediction score is high and the FHA mechanism is plausible. However, the only direct human evidence is one small study, and none of the registered trials tests estriol for amenorrhea. Safety screening is also blocked because package insert data is missing.
To proceed, the following is needed:
- Package insert warnings and contraindications (blocking for safety screening)
- Detailed mechanism of action data (MOA)
- Confirmation of the drug identity in the two estetrol trials (NCT04090957, NCT04209543)
- Controlled trials of estriol in a defined amenorrhea subtype, such as FHA
- Route and formulation assessment, since all marketed products are topical creams
- Clarification of the original approved indication and the license status of the entries with no license number
This report is for research reference only and does not constitute medical advice. Repurposing candidates require clinical validation before any clinical use.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.