Levonorgestrel
| Evidence Level: L4 | Predicted Indications: 6 |
Table of Contents
Levonorgestrel: From Hormonal Contraception to Acne
One-Sentence Summary
Levonorgestrel is a progestin (a synthetic female sex hormone) that is marketed in South Africa as oral tablets. The TxGNN model predicts it may be effective for acne, but this comes from a knowledge-graph prediction. Only 1 probable randomised trial, of a combination pill with ethinylestradiol, supports the direction, and none of the 5 registered clinical trials tests levonorgestrel for acne.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not stated in the registration data (levonorgestrel is a progestin used in contraception) |
| Predicted New Indication | Acne |
| TxGNN Prediction Score | 99.88% |
| Evidence Level | L4 |
| South Africa Market Status | Marketed |
| Number of SAHPRA Registrations | 11 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available. Based on known information, levonorgestrel is a 19-nortestosterone-derived progestin used in hormonal contraceptives, either alone or combined with ethinylestradiol. Its mechanistic fit for acne is indirect and its direction of effect is uncertain.
Acne is driven partly by androgens acting on the pilosebaceous unit. Combined oral contraceptives can improve acne by raising sex hormone binding globulin (SHBG) and lowering free testosterone. This benefit is usually attributed to the ethinylestradiol component. Levonorgestrel is relatively androgenic, so on its own it may worsen acne. Any acne benefit therefore comes from the combination product, not from the drug alone.
The very high TxGNN score reflects graph-based association only and does not establish clinical benefit.
Clinical Trial Evidence
No SANCTR or PACTR registrations were retrieved. None of the trials below directly tests levonorgestrel for acne.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00480532 | N/A | Completed | 131 | Continuous combined oral contraceptive plus doxycycline, aimed at reducing unplanned bleeding. It is not an acne study, so it is indirect evidence at best. |
| NCT01650168 | N/A | Completed | 101,498 | Safety cohort comparing a nomegestrol acetate/estradiol pill with levonorgestrel-containing pills. It is a safety study, not an acne study. |
| NCT00161226 | N/A | Terminated | 44 | Levonorgestrel intrauterine system for endometrial cancer prevention in women with obesity. Wrong disease. |
| NCT05570786 | Phase 2 | Completed | 100 | Randomised, placebo-controlled gestrinone implant for endometriosis pelvic pain. Its link to levonorgestrel and acne is unconfirmed and needs manual checking. |
| NCT05492487 | Phase 2 | Unknown | 60 | Mirena (levonorgestrel IUS) versus megestrol for atypical endometrial hyperplasia. Wrong disease. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 12196750 | 2002 | RCT (probable) | J Am Acad Dermatol | Placebo-controlled trial of a low-dose pill (20 µg ethinylestradiol + 100 µg levonorgestrel) in moderate acne. This is the most relevant item, but it tests a combination product. |
| 15025547 | 2004 | Drug review | Drugs | Ethinylestradiol/chlormadinone acetate was significantly more effective than ethinylestradiol/levonorgestrel for mild-to-moderate papulopustular acne. |
| 6084924 | 1984 | Clinical study | Acta Derm Venereol | In 54 women with acne, pills containing desogestrel or levonorgestrel were compared on total and unbound testosterone and SHBG over 6 months. |
| 21895044 | 2011 | Review | Am J Clin Dermatol | Dermatological benefits of ethinylestradiol/chlormadinone acetate in androgen-related skin conditions, including acne. It concerns a different progestin. |
| 7825629 | 1995 | Review | Am J Med | Reviews the androgenicity of progestins. It supports the concern that 19-carbon progestins such as levonorgestrel have androgenic activity. |
| 16796485 | 2006 | Review | J Womens Health | Drospirenone versus other progestins, including levonorgestrel, with a focus on acne and hirsutism. |
South Africa Market Information
Approved indication text is not available in the registration data.
| Registration Number | Product Name | Dosage Form |
|---|---|---|
| Reg. No. 44/21.8.2/0808 | Medilevo 1,5 Mg | Tablet |
| Reg. No. 51/21.8.2/0584 | Femilevo 1,5Mg | Tablet |
| Reg. No. 49/21.8.2/0574 | Vonel | Tablet |
| Reg. No. 33/18.8/0054 | Loette 28 | Tablet |
| Reg. No. A40/18.8/0747 | Hy-an | Tablet |
Available registrations are all oral tablets. Of the 11 registrations, 5 are listed here.
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 acne prediction rests on a graph score plus one probable RCT of a combination pill. The benefit there is usually attributed to ethinylestradiol, and levonorgestrel itself is androgenic. No trial tests levonorgestrel alone for acne. The other five predictions (Worth syndrome, pregnancy-associated osteoporosis, autosomal dominant neovascular inflammatory vitreoretinopathy, and two benign breast adenoses) have no trials or literature and no plausible mechanistic link, so they are also on Hold.
To proceed, the following is needed:
- SAHPRA Professional Information warnings and contraindications (a blocking gap for safety screening)
- Mechanism of action data
- Confirmation of the design and full text of the 2002 EE/LNG acne trial, and whether it isolates a levonorgestrel effect
- Manual verification of NCT05570786
- A comparison against existing acne treatments in the South African setting
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.