CME: Therapeutic Insights in Melasma and Hyperpigmentation Management

August 2019 | Volume 18 | Issue 8 | Original Article | 718 | Copyright © August 2019

Kimberly A. Huerth MD MEd,ª Shahzeb Hassan BA,B Valerie D. Callender MDa,c

ªDepartment of Dermatology, Howard University College of Medicine, Washington, DC
bNorthwestern University Feinberg School of Medicine, Chicago, IL
cCallender Dermatology & Cosmetic Center, Glenn Dale, MD


Methimazole (MMI) is best known for its role as an oral antithyroid agent. It first gained attention as a topical lightening agent after it produced cutaneous depigmentation in brown guinea pigs.69 Its antimelanogenic effects are derived from potent melanocyte peroxidase inhibition, which disrupts several steps of the melanogenesis pathway.69-71 It has also been shown to inhibit tyrosinase activity in mushrooms via copper ion chelation, though it is not clear whether this effect is reproduced in humans.72

There are several studies that have been devoted specially to comparing the skin lightening ability of 5% MMI with various concentrations of HQ, with varied results. In a double-blind randomized controlled trial involving 50 Iranian patients with melasma, 4% HQ was compared with 5% MMI once daily for 8 weeks.73 4% HQ exhibited a higher reduction in MASI coupled with higher satisfaction scores from patients and physicians at 8 weeks, but was associated with increased relapse 4 weeks after stopping therapy. A second double-blinded randomized controlled trial compared response and safety of 5% MMI to 2% HQ in the once daily treatment of 58 Iranian women with melasma.74 Although the subjects subjectively assessed their outcomes to be the same at 8 weeks, MASI and VisioFace ΔE scores attained by 5% MMI were significantly lower than 2% HQ. 5% MMI had no effect on serum TSH levels. In a case series of two women who had each failed 2 months of therapy with 4% HQ, switching to daily 5% MMI for 8 weeks improved their melasma, though how this outcome was quantified was not specified. Neither subject experienced an alteration in serum TSH.75 Seeking to determine the pharmacokinetics of 5% MMI on facial skin, another study found MMI to be undetectable in serum 15 minutes to 24 hours following a single topical application to the face.71 This was extended to 6-weeks of daily topical application, at which point no significant changes in serum TSH, free thyroxine, or free triiodothyronine levels could be detected. Topical MMI preparations were well tolerated in all of the aforementioned studies. 

There is one single-blind split face study that compared daily 5% MMI to 4% kojic acid, both in conjunction with twice daily sunscreen (SPF 30) use, in 45 Turkish patients with melasma.76 At 12-weeks both topicals obtained equivalent improvements in the MASI score, and melanin indices as measured by Mexameter®. 20% of patients treated with 5% MMI experienced redness, burning, and itching that largely tapered off after the first 2 weeks of treatment. 11% of patients treated with 4% kojic acid reported similar adverse effects, though these persisted longer into therapy. 


Melasma and PIH are common, difficult to treat disorders that greatly impair quality of life in those affected. With the high prevalence of these conditions, and the changing demographics of our nation, dermatologists should anticipate seeing increasing numbers of SOC patients who present seeking help with their management. To illustrate, the US Census Bureau has estimated that by 2050, individuals with SOC will comprise a majority of Americans.77 Both conditions require an individualized and multilayered approach to treatment that is built upon consistent photoprotection. When designing a given approach, one must carefully consider who their patient is, and what treatments are feasible and responsible in terms of safety, compliance, outcomes, and affordability.


Dr. Callender serves as a consultant for, and has received funding from, Allergan, Galderma, and Ortho Dermatologics.


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Valerie D. Callender MD