Norethisterone
| Evidence Level: L5 | Predicted Indications: 1 |
Table of Contents
Norethisterone: From Hormonal Products (Indication Not Listed) to Amenorrhea
One-Sentence Summary
Norethisterone is a synthetic progestin found in 9 South African registered products, but the data received does not state its approved indication. The TxGNN model predicts it may be useful for amenorrhea, with a score of 99.6%. There are 7 clinical trials and 20 publications linked to this prediction, but none tests norethisterone alone for amenorrhea. The trials mostly use it as an add-back component in combination regimens, so the evidence is indirect.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not stated in the registration data received |
| Predicted New Indication | Amenorrhea |
| TxGNN Prediction Score | 99.60% |
| Evidence Level | L4 (indirect evidence only; no study tests norethisterone for amenorrhea) |
| South Africa Market Status | Marketed |
| Number of SAHPRA Registrations | 9 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available. Based on general pharmacology, norethisterone is a progestin with strong progestogenic and endometrium-stabilising activity. It suppresses endometrial growth and can restore withdrawal bleeding in oestrogen-primed, low-oestrogen or anovulatory states. This is a plausible link to amenorrhea management and may explain the high TxGNN score. This reasoning comes from general knowledge and is not confirmed by the data received.
The direction of the link needs care. In most of the trials found, norethisterone acetate is the add-back component of GnRH antagonist combinations (relugolix or elagolix). There, amenorrhea is a treatment outcome, meaning bleeding is suppressed. It is not the condition being treated. Using norethisterone to treat amenorrhea is a different clinical question, and these trials do not address it.
Clinical Trial Evidence
No SANCTR or PACTR identifiers were found. All 7 trials are from ClinicalTrials.gov and are ordered by relevance.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03049735 | Phase 3 | Completed | 388 | LIBERTY 1: relugolix + oestradiol + norethisterone acetate vs placebo (24 weeks) for fibroid-related heavy menstrual bleeding. Norethisterone is only one component. |
| NCT03103087 | Phase 3 | Completed | 382 | LIBERTY 2: same combination and design as LIBERTY 1. Norethisterone effect cannot be separated from relugolix and oestradiol. |
| NCT03412890 | Phase 3 | Completed | 477 | Open-label, single-arm extension (28 weeks). Long-term safety and bleeding-suppression data for the combination. No control arm. |
| NCT03751124 | Phase 3 | Completed | 229 | Randomised withdrawal study of the relugolix combination for up to 104 weeks. Informs the safety and endometrial effects of the add-back regimen. |
| NCT05620355 | Phase 3 | Unknown | 312 | BG2109 alone or with add-back therapy vs placebo for fibroid-related heavy menstrual bleeding. Regimen composition is unconfirmed. |
| NCT01817530 | Phase 2 | Completed | 571 | Elagolix alone or with add-back therapy vs placebo for fibroid-related heavy menstrual bleeding. Norethisterone is not the primary agent. |
| NCT01441635 | Phase 2 | Completed | 271 | Elagolix proof-of-concept study in fibroid-related heavy bleeding. Norethisterone involvement is not evident. |
| NCT06953076 | N/A | Recruiting | 111 | MySaturn: ultrasound appearance of fibroids during relugolix/oestradiol/norethisterone treatment. No amenorrhea efficacy endpoint. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37863160 | 2024 | RCT (post hoc subgroup) | Am J Obstet Gynecol | Relugolix combination (with oestradiol and norethindrone acetate) improved fibroid-related heavy bleeding over 52 weeks in Black/African American women. |
| 38530848 | 2024 | Randomised trial | PLoS One | WHICH trial (South African authors): compares DMPA-IM and NET-EN injectables on oestradiol levels and menstrual effects. |
| 6786825 | 1981 | Phase I trial | Contraception | 20 women on norethisterone enanthate or acetate. Menstrual disorders, including amenorrhea, were reported, and the pre-ovulatory LH/FSH peaks were abolished. |
| 37103532 | 2023 | Overview | Obstet Gynecol | Efficacy and safety of oral GnRH antagonists with add-back steroids for uterine leiomyomas. |
| 23641480 | 2013 | Cochrane review | Cochrane Database Syst Rev | Combination injectable contraceptives: effective, with bleeding-pattern changes limiting acceptability. |
| 18843662 | 2008 | Cochrane review | Cochrane Database Syst Rev | Earlier version of the review above. |
| 2660092 | 1989 | Review | Pediatr Clin North Am | Principles of hormonal contraception in adolescents. |
| 3071312 | 1988 | Review | Aust Fam Physician | Choosing an oral contraceptive. |
Most of the remaining literature is older contraception reviews with little direct relevance to amenorrhea.
South Africa Market Information
Approved indication text was not available for any of these registrations. The Essential Medicines List status was not assessed.
| Registration Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| Reg. No. B/18.8/135 | Micro-Novum | Tablet | Not stated in data received |
| Reg. No. 29/21.8.2/0763 | Estro-Pause N | Tablet | Not stated in data received |
| Reg. No. 29/21.8.2/0764 | Estro-Pause N Forte | Tablet | Not stated in data received |
| Reg. No. 27/21.8.2/0021 | Estracombi TTS | Pad (patch) | Not stated in data received |
| Reg. No. S/18.8/124 | Trinovum Tablets | Tablet | Not stated in data received |
Showing 5 of 9 registrations.
Safety Considerations
Please refer to the SAHPRA-approved Professional Information (PI) for safety information. Report adverse drug reactions to SAHPRA.
Conclusion and Next Steps
Decision: Hold
Rationale: The high TxGNN score and the plausible progestogenic mechanism justify keeping this as a research question. However, no trial or publication tests norethisterone for amenorrhea, and the relugolix/elagolix trials answer a different question (bleeding suppression in fibroids). The safety screening cannot start because the SAHPRA package insert data is missing.
To proceed, the following is needed:
- SAHPRA package insert warnings and contraindications for the registered products (blocking gap)
- Approved indications for each registration, to establish the true original indication
- Mechanism of action data (e.g. from DrugBank)
- A targeted literature search for norethisterone used to treat amenorrhea, as distinct from bleeding suppression
- Confirmation that the regulatory data reflects SAHPRA sources, since the pack lists TFDA as an input source
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.