Levonorgestrel
| Evidence Level: L2 | Predicted Indications: 5 |
Table of Contents
Levonorgestrel: Acne (disease)
One-Sentence Summary
Levonorgestrel is a synthetic progestin with 20 valid single-ingredient licences in Canada. The TxGNN model predicts it may be useful for acne, with a score of 0.9988. No clinical trials are registered, but one randomized placebo-controlled trial of a levonorgestrel/ethinyl estradiol combination pill in moderate acne supports an L2 evidence level. That trial cannot separate the effect of levonorgestrel from the estrogen, so the direction is still uncertain.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Acne (disease) |
| TxGNN Prediction Score | 0.9988 |
| Evidence Level | L2 |
| Canada Market Status | Marketed (marketed DINs on record: at least 20) |
| Number of DINs | at least 20 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not currently available for this drug. Levonorgestrel is a progestin derived from the 19-nortestosterone family. It therefore keeps some residual androgenic activity, a property reviewed in the literature on progestin androgenicity.
The case for acne rests on hormonal control of the sebaceous gland. Acne is driven partly by androgen action on the pilosebaceous unit. In combined hormonal contraceptives, the benefit for acne is mainly credited to the estrogen component, which raises sex hormone-binding globulin and lowers free testosterone. Progestins with anti-androgenic properties, such as chlormadinone acetate and cyproterone, are the ones usually credited with added dermatological benefit. In a review of ethinylestradiol/chlormadinone acetate, that combination was significantly more effective for mild-to-moderate papulopustular acne than ethinylestradiol/levonorgestrel.
The very high TxGNN score probably reflects proximity in hormone and androgen-pathway networks rather than a proven therapeutic effect. Levonorgestrel-releasing intrauterine systems and implants have also been reported to cause acne in some users. The mechanistic link is therefore plausible only for the combination with an estrogen, and it is biologically counterintuitive for levonorgestrel alone.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 12196750 | 2002 | RCT | J Am Acad Dermatol | Randomized, placebo-controlled trial of an oral contraceptive with 20 µg ethinyl estradiol and 100 µg levonorgestrel for moderate acne. Rationale: lowering bioavailable androgens may improve acne. |
| 15025547 | 2004 | Review | Drugs | Ethinylestradiol/chlormadinone acetate was significantly more effective than ethinylestradiol/levonorgestrel 0.03/0.15 mg/day in mild-to-moderate papulopustular acne. |
| 21895044 | 2011 | Review | Am J Clin Dermatol | Reviews the dermatological benefits of an anti-androgenic progestin combination in acne, seborrhea and hirsutism, driven by androgen excess at the pilosebaceous unit. |
| 7825629 | 1995 | Review | Am J Med | Explains the androgenicity of progestins; 19-carbon progestins such as levonorgestrel retain some androgenic activity. |
| 30088446 | 2018 | Review | Curr Drug Targets | Reviews how different steroids influence sebum production and the molecular basis of acne. |
Canada Market Information
Health Canada records show 20 valid single-ingredient licences. The list below shows five of them and may be partial.
| DIN | Product Name |
|---|---|
| 02243005 | MIRENA |
| 02459523 | KYLEENA |
| 02293854 | PLAN B |
| 02346176 | SEASONIQUE |
| 02042339 | MIN-OVRAL 28 |
Safety Considerations
- Drug Interactions: The interaction screening returned 100 entries. The 20 reviewed were all of moderate severity. They include several glucose-lowering agents (acarbose, canagliflozin, dapagliflozin, ertugliflozin, exenatide, liraglutide, linagliptin, nateglinide and multiple insulin products), as well as aprepitant, clotrimazole, glycerol phenylbutyrate and linaclotide.
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The main support is one randomized placebo-controlled trial (L2) of a combination pill containing ethinyl estradiol and levonorgestrel in moderate acne. The estrogen is the likelier source of the benefit, and anti-androgenic progestins appear to perform better than levonorgestrel. Levonorgestrel’s own androgenic activity and its reported association with acne in some users argue against a standalone benefit. The high model score alone does not justify advancing.
To proceed, the following is needed:
- Evidence that separates the effect of levonorgestrel from that of the estrogen component in acne
- Head-to-head data against anti-androgenic progestin combinations
- Detailed mechanism of action data
- Review of package insert warnings and contraindications for the intended population
- Dosage form and approved-indication details for the Canadian licences
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.