Norethisterone
| 證據等級: L5 | 預測適應症: 1 個 |
目錄
Norethisterone: From Hormonal Contraception to Amenorrhea
One-Sentence Summary
Norethisterone is a synthetic progestin used globally in hormonal contraceptive and hormone-therapy regimens; no SAHPRA-approved indication is currently on file for this product in South Africa. The TxGNN model predicts it may be effective for Amenorrhea, with 8 clinical trials and 20 publications currently identified, though most of this evidence reflects norethisterone acting as an “add-back” component within combination regimens rather than as a directly studied monotherapy.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not documented in this evidence pack — norethisterone is not currently SAHPRA-registered, so no approved indication text is on file |
| Predicted New Indication | Amenorrhea |
| TxGNN Prediction Score | 99.60% |
| Evidence Level | L2 |
| South Africa Market Status | Not Marketed |
| Number of SAHPRA Registrations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data for norethisterone is not available in this evidence pack, and no original approved indication is on file since the product is not currently registered with SAHPRA. Based on known pharmacology, norethisterone is a well-characterised synthetic progestin (a 19-nortestosterone derivative) used worldwide as a component of combined and progestin-only contraceptives, hormone-replacement regimens, and menstrual-disorder therapy.
Progestins act on endometrial progesterone receptors to regulate proliferation and shedding of the uterine lining, and clinically norethisterone acetate (NETA) is used as an “add-back” agent alongside GnRH antagonists (e.g., relugolix) to modulate withdrawal bleeding and menstrual/amenorrhea outcomes during hormone-suppression treatment of uterine fibroids.
This existing role as a menstrual-cycle-modulating agent is mechanistically consistent with the TxGNN-predicted link to amenorrhea. However, it is worth flagging that most of the supporting evidence below (the LIBERTY trial programme) studies norethisterone as an add-back component of a relugolix combination, not as a standalone investigational agent for amenorrhea — this distinction is why the evidence pack rates this L2 rather than higher despite several completed Phase 3 trials.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03049735 (LIBERTY 1) | Phase 3 | Completed | 388 | Relugolix + estradiol + norethindrone acetate vs placebo for heavy menstrual bleeding in fibroids; amenorrhea was a secondary efficacy measure. Relevance: B — NETA is the add-back component, not the primary study drug. |
| NCT03103087 (LIBERTY 2) | Phase 3 | Completed | 382 | Replication of LIBERTY 1 design and results, reinforcing add-back NETA’s role in menstrual/amenorrhea control. Relevance: B. |
| NCT03412890 (LIBERTY Extension) | Phase 3 | Completed | 477 | Long-term open-label extension confirming durability of amenorrhea/menstrual control with relugolix + E2 + NETA. Relevance: B. |
| NCT03751124 | Phase 3 | Completed | 229 | Randomized withdrawal study evaluating long-term efficacy/safety of relugolix + E2 + NETA, including recovery from induced amenorrhea after treatment. Relevance: B. |
| NCT05620355 | Phase 3 | Unknown (follow-up status unconfirmed) | 312 | BG2109 alone and combined with add-back therapy for heavy menstrual bleeding in fibroids. Relevance: B. |
| NCT01441635 | Phase 2 | Completed | 271 | Elagolix (not norethisterone) vs placebo for heavy uterine bleeding/fibroids. Relevance: C — low, drug mismatch. |
| NCT01817530 | Phase 2 | Completed | 571 | Elagolix Phase 2b study on heavy menstrual bleeding in fibroids. Relevance: C — low, drug mismatch. |
| NCT06953076 | N/A | Recruiting | 111 | Observational ultrasound study of fibroid morphology during relugolix/estradiol/norethisterone treatment; does not directly assess amenorrhea outcomes. Relevance: C. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 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 substantially improved fibroid-associated heavy menstrual bleeding over 52 weeks — directly relevant to South African patient demographics |
| 38530848 | 2024 | RCT | PLoS One | WHICH trial: compared norethisterone enanthate (NET-EN) vs DMPA-IM injectable contraception, evaluating effects on estradiol levels and menstrual/psychological/behavioral measures relevant to HIV risk |
| 6786825 | 1981 | Phase I Clinical Trial | Contraception | Phase I trial of norethisterone enanthate and norethisterone acetate in 20 women; suppressed LH/FSH peaks in all treated women, with amenorrhea and spotting recorded as menstrual disorder outcomes |
| 37103532 | 2023 | Review | Obstetrics and Gynecology | Reviews oral GnRH antagonists (co-administered with add-back steroids including norethindrone) for management of uterine leiomyomas |
| 23641480 | 2013 | Systematic Review (Cochrane) | Cochrane Database of Systematic Reviews | Combination injectable contraceptives (including norethisterone-containing products) reviewed for efficacy and bleeding-pattern effects |
| 18843662 | 2008 | Systematic Review (Cochrane) | Cochrane Database of Systematic Reviews | Earlier version of the combination injectable contraceptives review |
| 2660092 | 1989 | Review | Pediatric Clinics of North America | General overview 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 |
| 6508652 | 1984 | Review | Australian Family Physician | General review of oral contraceptives |
South Africa Market Information
Norethisterone is currently not registered with SAHPRA (market status: Not Marketed) — no SAHPRA registration numbers, product names, or approved indication text are on file for this evidence pack.
Safety Considerations
Please refer to the SAHPRA-approved Professional Information (PI) for safety information. Report adverse drug reactions to SAHPRA.
Note: this evidence pack flags a Blocking data gap (DG001 — TFDA/SAHPRA-equivalent PI warnings and contraindications not available), meaning a formal safety pre-assessment cannot currently be completed for this candidate.
Conclusion and Next Steps
Decision: Hold
Rationale:
- Norethisterone has no current SAHPRA registration in South Africa, and a Blocking data gap (missing PI warnings/contraindications) prevents safety pre-assessment.
- The strongest clinical trial evidence (LIBERTY programme) studies norethisterone acetate as an add-back component within a relugolix combination regimen, not as a directly investigated monotherapy for amenorrhea, limiting the strength of the L2 evidence rating despite a high TxGNN score (99.60%).
To proceed, the following is needed:
- SAHPRA-approved Professional Information (PI) — warnings, contraindications (resolves DG001, Blocking)
- Confirmed mechanism-of-action documentation from DrugBank (resolves DG002, High)
- Identification of a South African norethisterone-containing product (standalone or combination) to establish a market pathway
- Direct clinical evidence of norethisterone monotherapy (rather than as an add-back agent) for amenorrhea
- Given PMID 37863160’s Black/African American subgroup data, a population-specific applicability review for South African patients is recommended
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.