Levonorgestrel

證據等級: L5

預測適應症: 6 個

Levonorgestrel: From Contraceptive Use to Acne

One-Sentence Summary

Levonorgestrel is a synthetic progestin used globally in contraceptive products (oral contraceptives, IUDs, subdermal implants, and emergency contraception), though it holds no market authorization in New Zealand. The TxGNN model's top-ranked prediction (rank 1611 overall) proposes potential relevance to Acne (disease), but the evidence is thin and mechanistically ambiguous — 5 clinical trials (none designed to test levonorgestrel monotherapy for acne) and 20 literature records (6 directly discussing acne or progestin androgenicity), rated at evidence level L4.

Quick Overview

Item	Content
Original Indication	Not available — no approved license record in New Zealand. Based on the literature in this evidence pack, levonorgestrel is known internationally as a progestin used in contraception (combined oral contraceptives, IUDs, subdermal implants, emergency contraception)
Predicted New Indication	Acne (disease)
TxGNN Prediction Score	99.88%
Evidence Level	L4
New Zealand Market Status	✗ Not Marketed
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available (DG002, High severity gap). Based on the literature in this evidence pack, levonorgestrel is a 19-nortestosterone-derived progestin used across multiple contraceptive delivery forms — oral pills, intrauterine systems, and subdermal implants — where its efficacy in preventing pregnancy is well established.

The link to acne is mechanistically contested rather than straightforward. One review in the evidence pack (PMID 7825629, "The androgenicity of progestins") classifies levonorgestrel as one of the more strongly androgenic progestins, which theoretically stimulates sebum production and could worsen acne — the opposite of a therapeutic direction. Separately, a placebo-controlled RCT (PMID 12196750) and a randomized multicenter study (PMID 10717776) show that low-dose combined oral contraceptives containing ethinyl estradiol + levonorgestrel improve acne, but this benefit is attributed to the estrogen component raising SHBG and lowering free testosterone — a combination-product effect, not an action of levonorgestrel in isolation.

This creates a genuine directional ambiguity: levonorgestrel's own androgenic activity works against an anti-acne effect, while the estrogen it is typically co-formulated with works in favor of one. None of the identified trials isolate levonorgestrel's independent contribution, so the TxGNN prediction should be read as flagging a drug-class association (progestin-containing combined contraceptives and acne) rather than a validated single-agent mechanism.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00161226	N/A	Terminated	44	LNG-releasing IUS (Mirena) trial for endometrial cancer prevention in obese women; notes acne as a known side effect of oral progestins, but was not designed to test acne treatment
NCT01650168	N/A	Completed	101,498	Large safety cohort comparing nomegestrol acetate/estradiol vs. LNG-containing combined oral contraceptives; focused on VTE and general safety, not acne efficacy
NCT05492487	Phase 2	Unknown	60	Fertility-sparing treatment of atypical endometrial hyperplasia (Mirena vs. megestrol); unrelated to acne
NCT00480532	N/A	Completed	131	Continuous combined oral contraceptive + doxycycline for bleeding control; doxycycline (not levonorgestrel) is the acne-relevant component, so LNG's independent contribution cannot be isolated
NCT05570786	Phase 2	Completed	100	Subdermal gestrinone implant for endometriosis-related pelvic pain; title truncated in source data, no confirmed link to acne

None of these trials were designed to evaluate levonorgestrel specifically for acne treatment.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
12196750	2002	RCT	J Am Acad Dermatol	Placebo-controlled RCT: low-dose ethinyl estradiol/levonorgestrel (EE/LNG) combined OC improved moderate acne, attributed to lowered bioavailable androgens
10717776	1999	RCT	Contraception	Multicenter, open-label, randomized comparison of two low-dose EE oral contraceptives with different progestins (incl. LNG); compared androgenic marker and acne outcomes
7825629	1995	Review	Am J Med	Classifies levonorgestrel among the more androgenic progestins — mechanistic basis for concern that LNG alone could aggravate rather than treat acne
15025547	2004	Review	Drugs	Drug evaluation of EE/chlormadinone acetate; reports EE/CMA was significantly more effective than EE/levonorgestrel for mild-to-moderate papulopustular acne
21895044	2011	Review	Am J Clin Dermatol	Reviews dermatological benefits (acne, hirsutism, seborrhea) of antiandrogenic hormonal therapy, providing comparative context to LNG's androgenic profile
16796485	2006	Review	J Womens Health	Reviews drospirenone vs. medroxyprogesterone acetate, levonorgestrel, and micronized progesterone; notes LNG's association with acne vulgaris as a side effect rather than a treatment benefit

The remaining 14 literature records in this evidence pack (contraceptive efficacy, IUD/implant reviews, VTE risk, lipid effects) are general levonorgestrel/contraception literature not specific to acne and were excluded from this table.

New Zealand Market Information

Levonorgestrel currently holds no market authorization in New Zealand (0 licenses on file).

Safety Considerations

Please refer to the package insert for safety information. (Key warnings, contraindications, and drug interaction data are marked as data gaps in this evidence pack — DG001, Blocking severity — and were not available at the time of this review.)

Conclusion and Next Steps

Decision: Hold

Rationale: The mechanistic direction is contradictory — levonorgestrel's androgenic activity could worsen rather than treat acne, and the only supportive clinical evidence comes from combined estrogen+LNG contraceptives, not levonorgestrel alone. Evidence level is L4 (mechanism/preclinical-level), no dedicated single-agent trials exist, and the drug is unmarketed in New Zealand with a blocking safety data gap (package insert warnings/contraindications not yet obtained).

To proceed, the following is needed:

Resolve DG001 (TFDA/NZ package insert warnings and contraindications) — blocking for S1 safety review
Resolve DG002 (levonorgestrel mechanism of action detail) — needed to properly assess mechanistic plausibility
Dedicated trial or pharmacoepidemiologic data isolating levonorgestrel's independent effect on acne (vs. combination-product confounding)
Clarification of any New Zealand regulatory pathway or market-entry plan, given 0 current authorizations
Completion of "pending" study-type/relevance classification for the remaining literature records
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.