Levonorgestrel
| Evidence Level: L4 | Predicted Indications: 6 |
Table of Contents
Levonorgestrel: From Contraception to Acne
One-Sentence Summary
Levonorgestrel is a progestin marketed in the US as an intrauterine device and as oral tablets, including emergency contraception, so its original use is contraception. The TxGNN model predicts it may be effective for acne, but none of the 5 clinical trials found tests acne, and the acne literature mostly concerns combination pills. This direction is not well supported, and the mechanism may even point the opposite way.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Contraception (inferred from product types, because the label indication text was not provided) |
| Predicted New Indication | Acne (disease) |
| TxGNN Prediction Score | 99.88% |
| Evidence Level | L4 |
| US Market Status | ✓ Marketed |
| Number of NDAs | 20 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available. Levonorgestrel is a 19-nortestosterone-derived progestin used for contraception. The literature describes contraceptive effects such as ovulation inhibition and changes to cervical mucus and the endometrium.
The link to acne is indirect and contradictory. Acne is driven partly by androgens. Some combined oral contraceptives improve it by raising SHBG and lowering free testosterone, and this benefit is usually attributed to the ethinyl estradiol component. Levonorgestrel itself retains some androgenic activity (PMID 7825629), so it could worsen acne rather than treat it.
The high TxGNN score is a graph-based prediction. It may simply reflect the class-wide association between hormonal contraceptives and acne. It is not clinical evidence of benefit from levonorgestrel.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00161226 | N/A | Terminated | 44 | Levonorgestrel intrauterine system for endometrial cancer prevention in women with high BMI. Acne is mentioned only as a side effect of oral progestins. |
| NCT01650168 | N/A | Completed | 101,498 | Cohort safety study of a nomegestrol acetate/estradiol pill versus levonorgestrel-containing combined pills. Not an acne study. |
| NCT00480532 | N/A | Completed | 131 | Doxycycline to reduce unplanned bleeding during continuous combined oral contraceptive use. Not acne-directed. |
| NCT05570786 | Phase 2 | Completed | 100 | Gestrinone implant for endometriosis pelvic pain. No link to levonorgestrel or acne is shown, so this is a likely false match. |
| NCT05492487 | Phase 2 | Unknown | 60 | Mirena versus megestrol for fertility-sparing treatment of atypical endometrial hyperplasia. No acne relevance. |
All five trials were graded C (low relevance) for acne.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 12196750 | 2002 | RCT | J Am Acad Dermatol | Randomized, placebo-controlled trial of a low-dose pill (20 µg ethinyl estradiol + 100 µg levonorgestrel) in moderate acne. The abstract provided does not include results, and the effect cannot be attributed to levonorgestrel alone. |
| 10717776 | 1999 | Randomized study | Contraception | Compared androgen profiles and clinical outcomes of two 20 µg ethinyl estradiol pills with different progestins, one of them levonorgestrel. |
| 15025547 | 2004 | Drug review | Drugs | Ethinylestradiol/chlormadinone acetate was significantly more effective than ethinylestradiol/levonorgestrel in mild-to-moderate papulopustular acne. Levonorgestrel appears here as the weaker comparator. |
| 21895044 | 2011 | Review | Am J Clin Dermatol | Dermatological benefits of an antiandrogenic pill (ethinylestradiol/chlormadinone acetate) in acne, hirsutism and related disorders. |
| 16796485 | 2006 | Review | J Womens Health | Drospirenone, with antiandrogenic properties, may reduce acne and hirsutism, unlike more androgenic progestins such as levonorgestrel. |
| 7825629 | 1995 | Review | Am J Med | Progestins derived from 19-carbon androstane, including those used in most contraceptives, retain androgenic activity. |
| 14688179 | 2004 | Clinical study | Hum Reprod | Levonorgestrel intrauterine system for symptomatic treatment of endometriosis (a different indication). |
| 32909630 | 2020 | Systematic review | Cochrane Database Syst Rev | Levonorgestrel-releasing intrauterine system for endometrial hyperplasia (a different indication). |
| 11727177 | 2001 | Review | Semin Reprod Med | Progestin-releasing intrauterine systems: contraceptive efficacy and antiproliferative endometrial effect. |
US Market Information
The source data lists 20 authorizations but gives no approved-indication text. The five main ones are:
| Authorization Number | Product Name | Dosage Form | Manufacturer |
|---|---|---|---|
| NDA206229 | LILETTA | Intrauterine device | Allergan, Inc. |
| ANDA202508 | My Way | Tablet | Lupin Pharmaceuticals, Inc. |
| NDA203159 | Skyla | Intrauterine device | Bayer HealthCare Pharmaceuticals Inc. |
| ANDA206867 | Julie Morning After Pill | Tablet | Julie Products Inc. |
| ANDA202635 | AfterPlan | Tablet | Sun Pharmaceutical Industries, Inc. |
Available routes are intrauterine (device) and oral (tablet).
Safety Considerations
Please refer to the package insert for safety information. No drug interactions were found in the queried data.
- Relevant to this prediction: levonorgestrel’s residual androgenic activity (PMID 7825629) is a theoretical concern for acne.
Conclusion and Next Steps
Decision: Hold
Rationale: The 99.88% TxGNN score is not backed by clinical evidence. No registered trial tests acne. The acne studies involve combination pills, where the benefit is likely due to ethinyl estradiol. Levonorgestrel’s androgenic activity may work against the prediction. The other five predictions (Worth syndrome, pregnancy-associated osteoporosis, autosomal dominant neovascular inflammatory vitreoretinopathy, apocrine adenosis of the breast and blunt duct adenosis of the breast) are L5 with no trials or literature, and were also rated Hold.
To proceed, the following is needed:
- Package insert warnings and contraindications (a blocking gap for safety screening)
- Mechanism of action data from DrugBank
- Reading the full text of PMID 12196750 and PMID 10717776 to see whether the acne results can be separated from the ethinyl estradiol effect
- Head-to-head or levonorgestrel-only acne data, ideally including androgenic acne worsening
- Manual check of NCT05570786 for a possible false match
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.