Norethisterone
| Evidence Level: L3 | Predicted Indications: 1 |
Table of Contents
Norethisterone: From Hormonal Contraception to Amenorrhea
One-Sentence Summary
Norethisterone is a first-generation 19-nortestosterone progestin whose formal “original indication” is not recorded in this evidence pack, but the supporting literature consistently frames it as a component of hormonal contraception and menstrual-cycle regulation. The TxGNN model predicts it may be effective for Amenorrhea, with 8 clinical trials and 20 publications currently identified, though most trials study norethisterone only as an “add-back” component in heavy-menstrual-bleeding/fibroid trials rather than as a primary amenorrhea therapy. Overall evidence strength is currently assessed as L3 (observational/systematic-review level), insufficient on its own to support an unguarded “Go” decision.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not documented in evidence pack (no license/indication records available); literature context suggests hormonal contraception |
| Predicted New Indication | Amenorrhea |
| TxGNN Prediction Score | 99.60% |
| Evidence Level | L3 |
| India Market Status | Not marketed |
| Number of Registrations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data for norethisterone is not available in this evidence pack (flagged as a High-severity data gap, DG002). Based on general pharmacological knowledge of the drug class, norethisterone is a synthetic progestin (19-nortestosterone derivative) known to suppress ovulation via negative feedback on the hypothalamic-pituitary-ovarian axis, and to induce secretory transformation and withdrawal bleeding of the endometrium. This is the pharmacological basis on which progestins including norethisterone are already used clinically to induce or regulate menstrual bleeding, including in patients with amenorrhea — note this is general pharmacology reasoning, not a mechanism sourced from a specific field in this dataset, and should be independently verified.
Consistent with this, several of the identified clinical trials use norethindrone acetate as an “add-back therapy” component (alongside GnRH antagonists such as relugolix and estradiol) specifically to manage menstrual bleeding patterns in women with uterine fibroids — a related but distinct indication from amenorrhea itself. The literature further includes a Phase I trial and a secondary RCT analysis that directly measured amenorrhea incidence associated with norethisterone-based injectable contraceptives, providing more direct (though still indirect) support for the TxGNN association. The very high TxGNN score (99.6%) likely reflects that this is largely a “known pharmacological use” pattern rather than a novel repurposing hypothesis, which should temper enthusiasm despite the high score.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT06953076 | N/A | Recruiting | 111 | Ultrasound imaging study of uterine fibroid changes during relugolix/estradiol/norethisterone treatment; not an amenorrhea efficacy trial |
| NCT01441635 | Phase 2 | Completed | 271 | Elagolix (not norethisterone) proof-of-concept for heavy uterine bleeding with fibroids |
| NCT05620355 | Phase 3 | Unknown | 312 | BG2109 ± add-back therapy for heavy menstrual bleeding from fibroids; status unresolved |
| NCT01817530 | Phase 2 | Completed | 571 | Elagolix ± add-back therapy vs placebo for heavy menstrual bleeding with fibroids |
| NCT03751124 | Phase 3 | Completed | 229 | Randomized withdrawal study of relugolix + estradiol/norethindrone acetate, long-term (104-week) safety/efficacy in fibroid-related heavy bleeding |
| NCT03049735 | Phase 3 | Completed | 388 | LIBERTY 1: relugolix + low-dose estradiol/norethindrone acetate vs placebo for fibroid-related heavy menstrual bleeding |
| NCT03103087 | Phase 3 | Completed | 382 | LIBERTY 2: same design as LIBERTY 1, confirmatory trial |
| NCT03412890 | Phase 3 | Completed | 477 | LIBERTY Extension: open-label, single-arm long-term safety/efficacy extension |
Note: none of these trials use amenorrhea as the primary endpoint — norethindrone acetate appears as a low-dose “add-back” component within GnRH-antagonist regimens for heavy menstrual bleeding/uterine fibroids. Only NCT03751124, NCT03049735, and NCT03103087 are completed Phase 3 RCTs with norethisterone as a study-drug component; none is a completed Phase 3 RCT with amenorrhea as the studied endpoint.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 41489365 | 2026 | RCT (secondary analysis) | Biology of Reproduction | Secondary analysis of the Women’s Health Injectable Contraception and HIV trial; compares NET-EN vs DMPA-IM effects on the HPG axis and amenorrhea incidence, finding NET-EN produces less amenorrhea than DMPA-IM |
| 38530848 | 2024 | RCT | PLoS One | WHICH randomized trial comparing DMPA-IM vs norethisterone enanthate (NET-EN) on estradiol levels and menstrual/behavioral outcomes |
| 6786825 | 1981 | Phase I clinical trial | Contraception | Phase I trial of norethisterone enanthate and norethisterone acetate in 20 women; abolished LH/FSH peaks and reported amenorrhea/spotting as menstrual disorder outcomes |
| 37863160 | 2024 | RCT (subgroup analysis) | American Journal of Obstetrics and Gynecology | LIBERTY Long-Term Extension subgroup in Black/African American women: relugolix + estradiol/norethindrone acetate improved fibroid-associated heavy menstrual bleeding over 52 weeks |
| 23641480 | 2013 | Systematic review (Cochrane) | Cochrane Database of Systematic Reviews | Review of combination injectable contraceptives, including bleeding-pattern change outcomes |
| 18843662 | 2008 | Systematic review (Cochrane) | Cochrane Database of Systematic Reviews | Earlier Cochrane review of combination injectable contraceptives, same topic area |
| 37103532 | 2023 | Review | Obstetrics and Gynecology | Review of oral GnRH antagonists for uterine leiomyomas, including add-back regimens containing norethindrone acetate |
| 2660092 | 1989 | Review | Pediatric Clinics of North America | General review of hormonal contraception principles for adolescent care |
| 12317413 | 1987 | Review | Current Therapeutics | General review of oral contraceptives |
| 3659794 | 1987 | Review | La Revue du Praticien | Review of progestational contraception |
India Market Information
Norethisterone is currently not marketed in this jurisdiction — 0 registrations are on record, so no license/authorization table is available.
Safety Considerations
- Drug Interactions: 159 interactions are on record (DDInter source), all classified as Moderate severity. The listed interactions are overwhelmingly with antidiabetic agents (e.g., Metformin, Acarbose, Alogliptin, Linagliptin, Dapagliflozin, Dulaglutide, Exenatide, Lixisenatide, Nateglinide, Pramlintide, Metreleptin, and multiple insulin formulations), plus Aprepitant, Clotrimazole, and Prucalopride. This pattern is consistent with the known tendency of progestins to reduce glucose tolerance/insulin sensitivity, and warrants glucose monitoring in diabetic patients if this drug is used.
Detailed package-insert warnings and contraindications are not available in this evidence pack (flagged as a Blocking data gap, DG001) and must be obtained from the official product label before any safety evaluation can be completed.
Conclusion and Next Steps
Decision: Hold
Rationale:
- A Blocking data gap (missing official label warnings/contraindications, DG001) currently prevents completion of even the initial S1 safety review, which the evidence pack itself flags as blocking.
- Evidence directly supporting amenorrhea specifically is L3 — the completed Phase 3 RCTs involve norethindrone acetate only as an add-back component in fibroid/heavy-menstrual-bleeding regimens, not as a therapy studied for amenorrhea as the primary endpoint.
- The drug has zero registrations and is not currently marketed in this jurisdiction, adding a regulatory-pathway gap on top of the evidence gap.
To proceed, the following is needed:
- Official product label / package insert (warnings, contraindications) to resolve DG001 and enable the S1 safety review
- Detailed mechanism-of-action documentation to resolve DG002 and validate the mechanistic rationale
- Clarification of the drug’s documented original indication(s), which are currently absent from regulatory records
- Trials or studies with amenorrhea (rather than heavy menstrual bleeding/fibroids) as the primary endpoint, to strengthen evidence beyond L3
- A regulatory pathway assessment given the drug’s current unmarketed status
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.