Norethisterone
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Norethisterone: From Hormonal Contraception to Amenorrhea Management
One-Sentence Summary
Norethisterone (DB00717) is a synthetic progestin whose original approved indication is not documented in this Evidence Pack, though the literature evidence base shows it is long established as a component of hormonal contraceptives and menstrual-disorder therapies. The TxGNN model predicts it may be effective for Amenorrhea (disease), with 8 clinical trials and 20 publications currently associated with this direction — though most of the trial evidence concerns norethindrone acetate used as add-back therapy alongside a GnRH antagonist (relugolix), not as monotherapy.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available — no approved indication text on file (0 EU licenses recorded) |
| Predicted New Indication | Amenorrhea (disease) |
| TxGNN Prediction Score | 99.60% |
| Evidence Level | L1 (≥2 completed Phase 3 RCTs, but as part of a combination regimen) |
| EU Market Status | ✗ Not marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data for norethisterone is currently unavailable (Data Gap DG002). Based on the literature retrieved in this Evidence Pack, norethisterone (norethindrone) is a synthetic progestin widely used across hormonal contraceptive formulations (oral, injectable, and combination regimens) and in menstrual-cycle management. As a progestin, it acts on the progesterone receptor to suppress gonadotropin release, inhibit ovulation, and induce endometrial atrophy — the same pharmacological actions that underlie its long-documented ability to produce amenorrhea and reduce menstrual bleeding (see PMID 6786825, PMID 2150587, PMID 7159393).
The strongest trial evidence in this pack, however, comes from the LIBERTY program (NCT03049735, NCT03103087, NCT03751124, NCT03412890) and related studies, in which norethindrone acetate is co-administered with the GnRH antagonist relugolix and low-dose estradiol as “add-back therapy” for heavy menstrual bleeding associated with uterine fibroids. In this context, amenorrhea is a desired treatment endpoint of the overall regimen, and norethisterone’s progestin activity contributes mechanistically to endometrial suppression while estradiol mitigates hypoestrogenic side effects. This makes the amenorrhea signal mechanistically plausible, but it is important to note the evidence largely reflects combination-product use rather than norethisterone monotherapy for amenorrhea.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03049735 | Phase 3 | Completed | 388 | LIBERTY 1: relugolix + estradiol + norethindrone acetate vs placebo for heavy menstrual bleeding in uterine fibroids |
| NCT03103087 | Phase 3 | Completed | 382 | LIBERTY 2: replication study of relugolix + E2/NETA combination therapy in fibroid-associated bleeding |
| NCT03751124 | Phase 3 | Completed | 229 | Randomized withdrawal study evaluating long-term (up to 104 weeks) efficacy/safety of relugolix + E2 + NETA |
| NCT03412890 | Phase 3 | Completed | 477 | LIBERTY Extension: long-term (28-week) safety/efficacy of relugolix + E2/NETA in participants completing pivotal studies |
| NCT01817530 | Phase 2 | Completed | 571 | Elagolix ± add-back therapy vs placebo on heavy menstrual bleeding in fibroids |
| NCT01441635 | Phase 2 | Completed | 271 | Proof-of-concept study of elagolix for uterine bleeding/fibroid volume reduction |
| NCT05620355 | Phase 3 | Unknown | 312 | BG2109 ± add-back therapy for heavy menstrual bleeding in uterine fibroids |
| NCT06953076 | N/A | Recruiting | 111 | Ultrasound-based assessment of fibroid transformation during relugolix/estradiol/norethisterone treatment |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 38530848 | 2024 | RCT | PLoS One | WHICH trial: compared DMPA vs NET-EN injectable contraceptives on estradiol levels and menstrual/behavioral outcomes |
| 37863160 | 2024 | RCT (extension) | Am J Obstet Gynecol | LIBERTY Long-Term Extension: relugolix + E2/NETA sustained improvement in fibroid-associated heavy bleeding over 52 weeks |
| 6786825 | 1981 | Clinical Trial | Contraception | Phase I trial of norethisterone enanthate/acetate: abolished LH/FSH peaks; amenorrhea and spotting were common menstrual effects |
| 23641480 | 2013 | Systematic Review | Cochrane Database Syst Rev | Review of combination injectable contraceptives, including bleeding-pattern effects |
| 18843662 | 2008 | Systematic Review | Cochrane Database Syst Rev | Earlier Cochrane review of combination injectable contraceptives |
| 37103532 | 2023 | Review | Obstet Gynecol | Oral GnRH antagonists (with steroid add-back, incl. NETA) for uterine leiomyoma management |
| 8313486 | 1993 | Report/Review | Bull World Health Organ | WHO memorandum on once-a-month injectable contraceptives (incl. norethisterone-containing formulations) |
| 2660092 | 1989 | Review | Pediatr Clin North Am | General review of hormonal contraception principles |
| 12222332 | 1991 | Review | Entre nous | Review of once-a-month estrogen/progestogen injectables |
| 3322079 | 1987 | Review | Akusherstvo i ginekologiia | Review of prolonged-action contraceptives |
EU Market Information
Norethisterone is not currently marketed under this evidence pack’s regulatory dataset (market_status: Not marketed), with 0 marketing authorizations on file. No license records, product names, or approved indication texts are available.
Safety Considerations
Please refer to the SmPC for safety information. Key warnings, contraindications, and drug-interaction data are all marked as Data Gaps in this Evidence Pack (DG001, Blocking severity — TFDA label warnings/contraindications not yet retrieved; DDI query returned no results).
Conclusion and Next Steps
Decision: Hold
Rationale:
- The drug is not currently marketed in this jurisdiction (0 authorizations), and a Blocking data gap (DG001) prevents initial safety screening (S1). Additionally, the strongest clinical evidence supports norethisterone as an add-back component of a combination regimen (relugolix + estradiol + NETA) rather than as monotherapy for amenorrhea, so the mechanistic link to the standalone predicted indication needs further clarification before advancing.
To proceed, the following is needed:
- Retrieve TFDA/EMA label warnings and contraindications (resolve DG001)
- Retrieve detailed mechanism of action data from DrugBank (resolve DG002)
- Confirm whether the predicted indication applies to norethisterone monotherapy or only within the relugolix/estradiol/NETA combination product
- Determine EU regulatory pathway options given current “not marketed” status
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.