Norethisterone
| Evidence Level: L4 | Predicted Indications: 10 |
Table of Contents
Norethisterone: From Endometriosis and Ovarian Failure to Amenorrhea
One-Sentence Summary
Norethisterone is a synthetic progestin originally used for conditions such as endometriosis, primary ovarian failure, and postmenopausal symptoms. The TxGNN model predicts it may be effective for amenorrhea, but there are currently no registered clinical trials and the 20 publications retrieved are mostly older contraceptive reviews in which amenorrhea appears as a side effect, not a treated condition.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acne, primary ovarian failure, endometriosis, postmenopausal osteoporosis, atrophic vulvovaginitis (from the knowledge graph; no approved-indication text is available from Singapore labels) |
| Predicted New Indication | Amenorrhea |
| TxGNN Prediction Score | 99.60% |
| Evidence Level | L4 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 4 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known pharmacology, norethisterone is a synthetic progestin with progesterone receptor agonist activity. Cyclic progestin administration induces withdrawal bleeding and is used in the workup and management of secondary amenorrhea when estrogen levels are adequate. It also suppresses the hypothalamic-pituitary-gonadal axis, which is the basis of its contraceptive effect.
Its original indications (endometriosis, primary ovarian failure) are hormone-driven gynaecological conditions, so a link to menstrual disorders is mechanistically sensible.
However, the direction of the relationship is ambiguous. In most of the retrieved publications, amenorrhea is something norethisterone and related contraceptives cause, not something they treat. The prediction may therefore reflect a side-effect association rather than a therapeutic one.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
The 20 retrieved publications are mostly older contraceptive reviews. The most relevant are listed below (systematic reviews and clinical studies prioritised).
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 23641480 | 2013 | Systematic Review | Cochrane Database Syst Rev | Combination injectable contraceptives are effective and reversible; acceptability may be limited by bleeding pattern changes |
| 18843662 | 2008 | Systematic Review | Cochrane Database Syst Rev | Earlier version of the same review on combination injectable contraceptives |
| 38530848 | 2024 | Randomised trial | PLoS One | WHICH trial: effects of DMPA-IM vs norethisterone enanthate on estradiol levels and menstrual effects |
| 41489365 | 2026 | Observational/Mechanistic | Biology of Reproduction | In 521 women, DMPA-IM and NET-EN similarly lowered estradiol, but DMPA-IM caused more amenorrhea |
| 8336583 | 1993 | Randomised trial | Med J Aust | Continuous low-dose oestrogen plus progestogen hormone replacement therapy: efficacy and acceptability |
| 6786825 | 1981 | Phase I clinical trial | Contraception | In 20 women, norethisterone enanthate/acetate abolished LH/FSH peaks; menstrual disorders including amenorrhea occurred |
| 6230212 | 1983 | Survey | Contraception | Management approaches for menstrual disturbances in injectable progestogen users |
| 3695501 | 1987 | Formulation study | J Steroid Biochem | Norethisterone microspheres; amenorrhea among the main side effects |
| 12279634 | 1983 | Review | Contraception, Fertilité, Sexualité | Amenorrhea during and after pill use |
| 31056890 | 2019 | Case report | JBRA Assist Reprod | Autoimmune hypothyroidism with intermittent ovarian failure and secondary amenorrhea |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN06679P | NORCOLUT TABLET 5 mg | Tablet | Not available |
| SIN04755P | SUNOLUT TABLET 5 mg | Tablet | Not available |
| SIN03934P | NORCUTIN TABLETS 5 mg | Tablet | Not available |
| SIN10960P | ACTIVELLE TABLET | Film-coated tablet | Not available |
Safety Considerations
- Contraindications (knowledge graph, not label text): Associated conditions include hypertension, epilepsy, liver disease, gallbladder disease, kidney disease, diabetes mellitus and hyperglycaemia, hypertriglyceridaemia, hypercalcaemia, porphyria, hypothyroidism, systemic lupus erythematosus, asthma, anxiety and dysthymic disorders, and female breast carcinoma.
- Drug Interactions: 100 interactions were identified; the 20 reviewed are all Moderate. Most involve antidiabetic agents (acarbose, metformin, alogliptin, linagliptin, dapagliflozin, nateglinide, exenatide, dulaglutide, albiglutide, lixisenatide, pramlintide and several insulins), because progestins can affect glucose control. Others include aprepitant, clotrimazole, metreleptin, and prucalopride.
Please also refer to the package insert for full safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The prediction score is high, but there are no registered trials and the literature is mostly old contraceptive reviews where amenorrhea is an adverse effect. Whether norethisterone treats or causes amenorrhea is unresolved, so the evidence is only at the mechanistic level (L4).
To proceed, the following is needed:
- Singapore package insert warnings and contraindications (not yet obtained, and required before safety screening)
- Detailed mechanism of action data
- A focused review of progestin challenge or cyclic progestin therapy for secondary amenorrhea, separating treatment effects from side effects
- Approved-indication text for the Singapore registrations, to confirm whether menstrual disorders are already covered
- Prospective or registered trial evidence for amenorrhea as a treated condition
Other predicted indications: Anovulation (rank 4) has some indirect literature support, mainly on managing abnormal uterine bleeding with oral progestogens, and is at L4 as a research question. The remaining predictions (ranks 2, 3, and 5–10, including fragile X carrier symptoms, ovarian remnant syndrome, luteoma of pregnancy, and several chromosomal disorders) have no literature or trials, are at L5, and are on Hold.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.