Levonorgestrel
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Levonorgestrel: From Contraception to Acne
One-Sentence Summary
Levonorgestrel is a synthetic progestin generally used in hormonal contraception (combined oral contraceptives, emergency contraception, and intrauterine systems). The TxGNN model predicts potential efficacy for Acne, with 5 clinical trials and 20 publications currently associated with this direction — but the underlying mechanistic evidence is contested rather than clearly supportive.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not documented in this evidence pack (Levonorgestrel is a well-established hormonal contraceptive; no Danish approved-indication text is on file since the drug is not currently marketed in Denmark) |
| Predicted New Indication | Acne (disease) |
| TxGNN Prediction Score | 99.88% |
| Evidence Level | L3 |
| Denmark Market Status | Not marketed |
| Number of Marketing Authorisations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data for Levonorgestrel is currently unavailable. Based on known pharmacology, Levonorgestrel is a second-generation progestin used in combined oral contraceptives, emergency contraception, and intrauterine delivery systems.
The link to acne is mechanistically ambiguous rather than clearly supportive. Levonorgestrel has comparatively high intrinsic androgenic activity relative to other progestins (see literature below), which in theory could aggravate rather than improve acne — the opposite of the mechanism used by antiandrogenic progestins (e.g., chlormadinone acetate, drospirenone, cyproterone acetate) that are established acne treatments when combined with ethinylestradiol. Comparative literature indicates that ethinylestradiol/chlormadinone combinations were significantly more effective than ethinylestradiol/levonorgestrel for papulopustular acne.
That said, one placebo-controlled RCT found that a low-dose combined pill containing ethinylestradiol 20 µg + levonorgestrel 100 µg improved moderate acne, likely because the estrogen component raises sex hormone-binding globulin and lowers bioavailable androgens systemically — an effect of the combination product, not evidence that levonorgestrel itself is the active driver. This means any acne benefit observed to date is confounded by the estrogen component, and the signal should be interpreted as weak and drug-combination-dependent rather than a levonorgestrel-specific effect.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00480532 | N/A | Completed | 131 | Studied doxycycline added to continuous combined oral contraceptives to reduce breakthrough bleeding; acne is only mentioned as a general indication for doxycycline, not a study endpoint, and the contraceptive’s progestin component is not confirmed as levonorgestrel (Grade B relevance). |
| NCT01650168 | N/A | Completed | 101,498 | Large safety cohort comparing nomegestrol acetate/estradiol vs. levonorgestrel-containing combined oral contraceptives; endpoint is general safety (e.g., thromboembolic risk), not acne (Grade C relevance). |
| NCT00161226 | N/A | Terminated | 44 | Levonorgestrel intrauterine system studied for endometrial cancer prevention in obese women; acne is mentioned only as a known side effect of oral progestins, unrelated to the study’s primary endpoint (Grade C relevance). |
| NCT05570786 | Phase 2 | Completed | 100 | Subdermal gestrinone implant (not levonorgestrel) for endometriosis-related pelvic pain; acne relevance unconfirmed from available title/summary (Grade C relevance). |
| NCT05492487 | Phase 2 | Unknown | 60 | Pilot study comparing Mirena (levonorgestrel-IUS) vs. megestrol for atypical endometrial hyperplasia in women wanting fertility preservation; not acne-related (Grade C relevance). |
None of the five registered trials directly tests levonorgestrel for an acne endpoint; the clinical-trial evidence base for this indication is indirect.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 12196750 | 2002 | RCT | J Am Acad Dermatol | Placebo-controlled RCT: ethinylestradiol 20 µg + levonorgestrel 100 µg improved moderate acne, attributed to lowered bioavailable androgens. |
| 15025547 | 2004 | Review (drug evaluation) | Drugs | Ethinylestradiol/chlormadinone acetate was significantly more effective than ethinylestradiol/levonorgestrel for mild-to-moderate papulopustular acne. |
| 6084924 | 1984 | Clinical study | Acta Derm Venereol | Compared testosterone/SHBG changes in acne patients on desogestrel- vs. levonorgestrel-containing pills; baseline androgen abnormalities were common. |
| 16796485 | 2006 | Review | J Womens Health | Drospirenone reduced acne vulgaris and hirsutism compared with medroxyprogesterone acetate and levonorgestrel, implying levonorgestrel is comparatively less favorable for these outcomes. |
| 7825629 | 1995 | Review | Am J Med | Establishes levonorgestrel’s relatively high androgenic activity among progestins — the mechanistic basis for the contradiction noted above. |
| 21895044 | 2011 | Review | Am J Clin Dermatol | Reviews dermatological benefits of antiandrogenic hormonal therapy for acne/hirsutism; levonorgestrel is not an antiandrogenic progestin. |
| 14688179 | 2004 | Cohort | Hum Reprod | Levonorgestrel-IUS evaluated for endometriosis symptom control (systemic exposure data; not acne-related). |
| 11727177 | 2001 | Review | Semin Reprod Med | General pharmacology of levonorgestrel-releasing intrauterine systems. |
| 11091988 | 2000 | Review | Obstet Gynecol Clin North Am | Overview of levonorgestrel implantable contraceptives. |
| 32909630 | 2020 | Systematic review (Cochrane) | Cochrane Database Syst Rev | Levonorgestrel-IUS evaluated for endometrial hyperplasia; high-quality general LNG evidence, not acne-specific. |
Denmark Market Information
Levonorgestrel is currently not marketed in Denmark under this evidence pack, and no marketing authorisations (national Lægemiddelstyrelsen or centralised EMA) are on record (0 licenses).
Safety Considerations
Please refer to the approved Summary of Product Characteristics (SmPC) for safety information. Key warnings, contraindications, and drug-drug interaction data were not available in this evidence pack — this is flagged as a blocking data gap (see Conclusion below), meaning a formal safety assessment cannot currently be completed.
Conclusion and Next Steps
Decision: Hold
Rationale:
- The acne signal is not levonorgestrel-specific: it derives from an estrogen/progestin combination RCT, while comparative and mechanistic literature suggests levonorgestrel’s relative androgenicity works against, rather than for, acne improvement.
- The drug has zero marketing authorisations in Denmark, and critical safety/labelling data (SmPC warnings, contraindications) are missing — classified as a Blocking data gap (DG001), which precludes a safety pre-assessment (S1).
To proceed, the following is needed:
- Official SmPC warnings and contraindications (DG001, Blocking)
- Confirmed mechanism-of-action / androgenicity profile via DrugBank (DG002)
- Clarification of whether the acne benefit is attributable to levonorgestrel or to the co-administered estrogen component
- Evaluation of route/dosage-form compatibility for a dermatology-oriented indication
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.