Hyperpigmentation Therapeutics: From Hydroquinone Alternatives to Lasers and Oral Tranexamic Acid
Andrew F. Alexis, MD, MPH, delivered a comprehensive review of hyperpigmentation management during his Masterclasses in Dermatology session, “Hyperpigmentation: Treatment Considerations,” emphasizing combination therapy, procedural advances, and emerging non–hydroquinone agents.
Hydroquinone remains a mainstay but carries limitations, including irritant contact dermatitis, “halo” hypopigmentation, and risk of exogenous ochronosis. These concerns have fueled interest in alternative topical agents.
Thiamidol, identified through screening of 50,000 compounds against recombinant human tyrosinase, emerged as a potent human tyrosinase inhibitor. In comparative studies, 0.2% thiamidol twice daily achieved modified Melasma Area and Severity Index (mMASI) reductions comparable to 4% hydroquinone when paired with sunscreen.
Cysteamine 7.5% has also demonstrated efficacy in melasma, performing favorably against triple-combination therapy in mMASI reduction. Additional formulations incorporating 2-mercaptonicotinoyl glycine, niacinamide, and botanical extracts have shown clinical improvement in post-inflammatory hyperpigmentation.
Photoprotection remains foundational. Mineral sunscreens with zinc oxide, titanium dioxide, and iron oxide provide coverage against UV and visible light, which are relevant in melasma pathogenesis. Antioxidants are increasingly integrated into therapy, given evidence of oxidative imbalance in melasma, including elevated malondialdehyde levels correlating with severity.
Oral tranexamic acid has gained traction for recalcitrant melasma. In a randomized trial, 250 mg twice daily for 3 months resulted in a 49% mMASI reduction vs 18% with placebo. Contraindications include thromboembolic risk and oral contraceptive use; screening for deep venous thrombosis (DVT), stroke, and hypercoagulable states is essential. A 5-year retrospective review of 206 patients reported no documented DVT, pulmonary embolism, myocardial infarction, or stroke events.
Polypodium leucotomos, a tropical fern extract with antioxidant properties, improved melasma when added to topical hydroquinone (480 mg daily).
Procedural therapies play a growing role. In Fitzpatrick skin types III–V, 4 sessions of nonablative fractional 1927 nm laser achieved approximately 50% mMASI improvement at 4 and 12 weeks. Retrospective data in skin types IV–VI showed a mean 43% improvement without complications. Microneedling combined with topical therapy yielded large effect sizes (>0.8) at 12 weeks in meta-analysis data.
Chemical peels, including 44% glycolic acid combined with kojic acid and arbutin topicals, also demonstrated benefit.
Dr Alexis emphasized diagnostic precision. Not all facial hyperpigmentation is melasma; conditions such as lichen planus pigmentosus (LPP) and acquired dermal macular hyperpigmentation require alternative strategies. In LPP, 90.4% of patients improved with oral isotretinoin (20 mg/day), with durable responses at 6 months.
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Reference
Alexis AF. Hyperpigmentation: treatment considerations. Presented at: Masterclasses in Dermatology; February 19–22, 2026; Sarasota, FL.
