Ethinylestradiol
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Ethinylestradiol: From Acne and Menopausal Conditions to Zinc, Elevated Plasma
One-Sentence Summary
Ethinylestradiol is a synthetic estrogen, originally used for acne, postmenopausal osteoporosis and osteoporosis, and postmenopausal atrophic vaginitis (and, in contraceptive products, for hormonal contraception). The TxGNN model's top-ranked prediction is elevated plasma zinc, but it has 0 clinical trials and 0 publications behind it. This prediction rests on model output alone. The most evidence-backed candidate in the list is amenorrhea (11 publications, no registered trials), which is discussed below as a research question.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acne, postmenopausal osteoporosis, osteoporosis, postmenopausal atrophic vaginitis (from the knowledge graph; licence records in Singapore carry no indication text) |
| Predicted New Indication | Zinc, elevated plasma |
| TxGNN Prediction Score | 99.63% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 7 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available. Based on known information, ethinylestradiol is a synthetic estrogen widely used in combined hormonal contraceptives. It is established for acne and for estrogen-deficiency conditions, and in principle estrogen signalling could be relevant to other hormone-sensitive conditions.
For the top-ranked prediction, elevated plasma zinc, no mechanistic link has been identified. The high score (0.996) is a graph-based prediction only. Estrogen-containing contraceptives are generally reported to alter circulating trace metals rather than treat a disorder of them, so this prediction is not credible without further evidence.
Other predictions fall into three groups:
- Acne-adjacent skin and gland conditions (PAPA syndrome, demodicidosis, sebaceous gland anomaly, familial acanthosis nigricans): these likely come from the acne link in the graph. Estrogen-containing pills reduce sebum by suppressing ovarian androgens and raising SHBG, which gives some plausibility for non-specific sebaceous gland anomalies. The other conditions are driven by autoinflammation, parasites or genetics, and hormonal modulation does not address them.
- Amenorrhea (rank 5): this is the only prediction with a plausible physiological rationale. Estrogen/progestin therapy supports the endometrium and induces withdrawal bleeding, and hormone therapy for hypoestrogenic amenorrhea is established practice in some settings. The supplied literature is mostly about cycle control in contraceptive users, not treatment of amenorrhea, so it is plausible but not rigorously evidenced here.
- No credible link (duodenal ulcer, duodenogastric reflux, isolated congenital adermatoglyphia): no supporting mechanism. Hypoalphalipoproteinemia has only a weak directional rationale, since oral estrogens raise HDL but also raise triglycerides and thrombotic risk.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
The top-ranked prediction (elevated plasma zinc) has no related literature. The table below shows the literature for the best-supported candidate, amenorrhea (rank 5). Most items concern ethinylestradiol-containing contraceptives rather than treatment of amenorrhea.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 15025547 | 2004 | Review | Drugs | Ethinylestradiol/chlormadinone acetate (0.03/2 mg) is an effective contraceptive with antiandrogenic properties, and was more effective than EE/levonorgestrel for mild-to-moderate facial acne |
| 17656175 | 2007 | Observational study | Contraception | Women switching to a chlormadinone acetate/EE pill were assessed for cycle control, dysmenorrhea, androgen-related skin conditions and tolerability |
| 9115000 | 1997 | Comparative clinical study | Contraception | 12-month comparison of 20 µg vs 30 µg EE with gestodene; the 20 µg pill had more intermenstrual bleeding |
| 3161265 | 1985 | Pharmacodynamic study | Acta Obstet Gynecol Scand Suppl | Assessed androgenicity of progestogens, including desogestrel alone and with EE |
| 20551602 | 2010 | Observational study | Horm Res Paediatr | NT-proCNP and bone development in females with anorexia nervosa; indirectly relevant |
| 29854486 | 2018 | Case report | Case Rep Endocrinol | 46,XY disorder of sex development from 17α-hydroxylase/17,20-lyase deficiency, with consequences of late diagnosis |
| 12280230 | 1985 | Review | IPPF Med Bull | Clinical use of biphasic and triphasic pills |
| 5282948 | 1971 | Comparative study | Acta Cytologica | Compared the estrogenic potential of mestranol and ethinylestradiol |
| 12281247 | 1977 | Clinical evaluation | The Antiseptic | Evaluation of a low-dose oral contraceptive (Lyndiol 1 mg) |
| 4778356 | 1973 | Clinical study | Bruxelles Medical | Clinical study of a normophasic oral contraceptive |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN14870P | BELARA film-coated tablet 0.03mg/2mg | Film-coated tablet | Not stated in the registry data |
| SIN04784P | DIANE-35 TABLET | Sugar-coated tablet | Not stated in the registry data |
| SIN12334P | YASMIN TABLET | Film-coated tablet | Not stated in the registry data |
| SIN04834P | MICROGYNON 30 TABLET | Sugar-coated tablet | Not stated in the registry data |
| SIN06136P | MERCILON TABLET | Tablet | Not stated in the registry data |
Two further registrations exist (SIN12423P, EVRA transdermal patch; SIN14894P, LIZA film-coated tablets), giving 7 valid single-ingredient licences in total.
Safety Considerations
- Contraindications suggested by the knowledge graph (these are graph associations, not label text): hypertension, epilepsy, anxiety and neurotic disorders, porphyria, kidney disease, liver disease, gallbladder disease, hyperglycemia and diabetes mellitus (including diabetic ketoacidosis), congestive heart failure, adrenocortical insufficiency/Addison disease, hypothyroidism, systemic lupus erythematosus, asthma, benign prostatic hyperplasia, and hypercalcemia.
- Drug Interactions: 100 interactions were found. Most of those listed are Moderate, including antidiabetic agents (acarbose, acetohexamide, alogliptin, chlorpropamide, empagliflozin, glimepiride, glipizide, glyburide, albiglutide, dulaglutide), corticosteroids (betamethasone, budesonide, dexamethasone), antibiotics (doxycycline, amoxicillin, clarithromycin), chenodeoxycholic acid and eliglustat. Minor interactions include ascorbic acid and cimetidine.
Please refer to the package insert for label warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The top-ranked prediction (elevated plasma zinc) has no trials, no literature and no plausible mechanism, so it is a model artefact. Of the other nine candidates, only amenorrhea has a plausible rationale and some literature, and that literature mostly addresses contraceptive cycle effects (evidence level L4, research question only). The drug is widely marketed in Singapore, but label warnings and contraindications have not been reviewed.
To proceed, the following is needed:
- HSA package insert warnings and contraindications (a blocking gap for safety screening)
- Detailed mechanism of action data
- For amenorrhea: targeted literature review or trials of ethinylestradiol-based therapy in hypoestrogenic amenorrhea, and confirmation that the approved Singapore indications cover it
- Review of the knowledge-graph contraindications (e.g., hypertension, liver disease, diabetes) against the label
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.