THERAPEUTIC HOTLINE

Successful treatment ofhydroquinone-resistant melasma

using topical methimazoleJoelle Malek*, Adele Chedraoui*, Damian Nikolic†,Neda Barouti†, Samer Ghosn* & Ossama Abbas**Dermatology Department, American University of Beirut Medical Center,Beirut, Lebanon and †Department of Dermatology, Geneva UniversityHospital, Geneva, Switzerland

ABSTRACT: Melasma is an acquired hyperpigmentation skin disorder in sun-exposed areas. It occursalmost exclusively over the face, and is most commonly seen in women. Several depigmenting agentshave been used for the treatment of melasma among which hydroquinone has been the most widelyused due to its efficacy and safety in short-term use. However, hydroquinone is recently reported to bea cytotoxic and mutagenic compound in mammalian cells and is thus banned in several countries.Hydroquinone ban has caused investigators to search for alternative depigmenting agents for thetreatment of melasma in recent years. Methimazole is an antithyroid agent orally used in humans sinceseveral decades and has been shown that when applied topically, it inhibits melanin synthesis andcauses skin depigmentation in lab animals as well as human subjects. Herein, we report twohydroquinone-resistant melasma patients who were successfully treated with methimazole cream.Application of 5% methimazole cream once daily resulted in significant improvement of melasma inboth patients after 8 weeks. The efficacy of methimazole for melasma treatment as well as its advantagesover other known depigmenting compounds (non-mutagenicity, non-cytotoxicity and high tolerabilityprofile) suggests that topical methimazole should be added to the armamentarium of anti-melasmatreatment.

KEYWORDS: hydroquinone, melasma, methimazole

Introduction

Melasma is an acquired hyperpigmentation disor-der of the skin in sun-exposed areas. It occursalmost exclusively over the face, and is most com-

monly seen in women. Exacerbating factorsinclude a positive family history, ethnicity, drugintake, oral contraceptive pills, hormone replace-ment, pregnancy, and sun exposure. Along withstrict sun avoidance, topical therapies, such asdepigmenting agents, have been used with variablesuccess. Among these, 4% topical hydroquinone(HQ) remains the mainstay of treatment and gen-erally yields the best results; however, its potentialmutagenic risk limits its use to certain countries.Methimazole (MMI) is an oral antithyroid medica-tion which has recently received attention due toits depigmenting effect if used topically. It has been

Address correspondence and reprint requests to: OssamaAbbas, MD, Assistant Professor, Department of Dermatology,American University of Beirut Medical Center, Riad El Solh St,PO Box 11-0236 Beirut, Lebanon, or email:ossamaabbas2003@yahoo.comFunding sources: None.Conflict of interest disclosure: None declared.

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described to produce depigmentation in guineapigs and was successfully tried in humans for thetreatment of post-inflammatory pigmentationand melasma, with no change in the levels of thethyroid hormones after a 6-week treatment (1–3).The present authors describe two cases of melasmathat failed HQ therapy but responded to topical5% MMI.

Case report

Case 1

A 50-year-old Hispanic woman presented withseveral years of history of hyperpigmented patchesover both cheeks (Fig. 1A). She was previouslyhealthy without medications. She worked as ahousemaid and did not report any skin rash or burnprior to the pigmentation. On physical examina-tion, she was noted to have irregular hyperpig-mented light brown patches surrounded bynumerous smaller pigmented macules on bothmalar eminences. Wood’s light examination accen-tuated the pigmentation indicating a predomi-nantly epidermal type of melasma. The patient wasgiven 4% topical HQ along with a sunscreen daily fora 2-month period to treat her melasma without anysignificant improvement. Three weeks after discon-tinuation of HQ, the patient was prescribed topicalMMI. MMI cream was prepared by dissolving MMI(Cilag, Schaffhausen, Switzerland) in distilled waterand then dispersing the solution in a vanishingcream vehicle to obtain a final concentration of 5%MMI in the product. Butylated hydroxytoluene(BHT, Sigma, Buchs, Switzerland) was added at a

concentration of 0.04% as the preservative. Thecream was applied only to the hyperpigmentedlesions once daily at bedtime. The thyroid-stimulating hormone (TSH) level was tested prior tothe treatment and was within normal limits. Within2 months of treatment, the patient noticed an 80%improvement of her melasma lesions (Fig. 1B). Thetreatment was well tolerated and no significant sideeffects were reported. Furthermore, a repeat TSHlevel at 2 months of treatment remained withinnormal values. She was advised to continue hertreatment for another month but was unfortunatelylost to follow-up later.

Case 2

A 34-year-old Middle Eastern woman was referredfor hyperpigmented patches over the cheeks(Fig. 2A). The patient had already received a2-month therapy of 4% HQ with little to noresponse. On physical examination, the patientwas found to have brown hyperpigmented patchesover the cheeks. Wood’s light examination revealedher melasma to be predominantly of the epidermaltype. She started with 5% topical MMI and BHT0.04% to be applied daily. After 8 weeks, near com-plete clearing of the lesions occurred (Fig. 2B). Nosignificant difference in TSH levels before and afterthe treatment was detected.

Discussion

Melanogenesis involves a series of steps startingfrom enzymatic oxidation of tyrosine until melaninpigments are produced. The enzyme tyrosinase is

A B

FIG. 1. (A) Hispanic woman with hydroquinone-resistant hyperpigmented patches over both cheeks before treatment withmethimazole. (B) Significant improvement of treatment with daily topical methimazole after 2 months.

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assumed to be responsible for the hydroxylation oftyrosine into dopa and the oxidation of dopa intodopaquinone. Dopaquinone is subsequently con-verted to the indoles 5,6-dihydroxyindole and/or5,6-dihydroxyindole-2 carboxylic acid. Throughoxidative polymerization, indoles are then trans-formed into eumelanin pigments (4).

HQ is a phenol-derived depigmenting chemicaloriginally thought to mediate its effect by inhibit-ing the tyrosinase enzyme. However, studies haveshown that HQ is itself oxidized by tyrosinase andis transformed into 1,4-benzoquinone, a metabo-lite known to be cytotoxic to melanocytes (4). Thiscytotoxicity is not restricted to melanocytes; othercells such as keratinocytes can be affected as well.In vitro studies have also demonstrated mutageniceffects of HQ in Salmonella and in the ChinesehamsterV79 ovarian cells. These observationshave led some countries to ban the use of HQ andopt for alternative depigmenting compounds, saferhowever not as effective (2).

Based on the observation that some tyrosinase-free cells such as eosinophils, neutrophils, and mastcells are able to produce melanin pigments, analternative pathway of melanin synthesis involvingother enzymes was considered (4). Several studieshave implicated the peroxidase enzyme in the oxi-dation of dopa to dopaquinone (4–7). Furthermore,the peroxidase-hydrogen peroxide system displayshigher activity than tyrosinase in the final steps ofmelanogenesis, specifically in the oxidation of theindoles as well as in the production of pheomela-nins. In addition, peroxidase has been found to have

the highest activity in stages II and III premelano-somes and its levels were detectable in pigmentedmelanomas but not in amelanotic melanomas. Allthese studies clearly pointed out a crucial role forthe peroxidase enzyme in melanin synthesis (5).

The skin depigmenting effect of MMI was firstdiscovered in 2002, where the topical in vivo appli-cation of MMI, a potent peroxidase inhibitor, wasfound to cause visible cutaneous depigmentationin brown guinea pigs after 6 weeks. Histologically,the melanin content of the epidermis was signifi-cantly reduced and melanocytes exhibited mor-phological changes without a significant decreasein number (1).

To test for any possible cytotoxic effect, in vitrostudies were performed on B16 melanocytes towhich increasing concentrations of MMI wereadded. Even at the highest concentration (800 mm),MMI did not result in significant decrease in mel-anocyte number and lead to the inhibition of mel-anogenesis by more than 50% of controls. However,when other depigmenting agents such as HQ,arbutin, and kojic acid were added to B16 melano-cytes, they were found to be melanocytotoxic atconcentrations as low as 10, 100, and 100 mm,respectively (8).

Because the peroxidase enzyme is also involvedin the biosynthesis of thyroxine, it was imperativeto study the transdermal absorption of topicalMMI and to determine its effect on thyroid func-tion in order to detect any change in thyroidhormone levels. Animal studies have yieldedcontroversial results for MMI’s percutaneous

A B

FIG. 2. (A) Middle Eastern woman with hydroquinone-resistant hyperpigmented patches over both cheeks before methimazoletreatment. (B) Remarkable improvement after using topical methimazole daily for 2 months.

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absorption. Studies using ex vivo rabbit skin as wellas repeated application in hyperthyroid cats wererather suggestive of systemic absorption. On theother hand, other experiments using more accu-rate detection techniques revealed barely detect-able serum levels of MMI after topical applicationand failed to show any effect on thyroid functiontests. The serial high-performance liquid chroma-tography analysis of sera from individuals whoapplied the 5% MMI cream to a 50 cm2 surface areaof their face revealed no detectable serum MMIlevels (3). Topical MMI’s safety was also tested invivo in melasma patients. A study by Kasraee et al.involving 20 patients with melasma showed nochange in serum TSH, free thyroxine, and free tri-iodothyronine levels after a 6-week period of oncedaily application (3).

MMI shows many advantages over HQ, arbutin,and other depigmenting agents. In contrast toother known depigmenting drugs, it is odorless,very well tolerated, not associated with cytotoxicand/or mutagenic effects, and does not readilyundergo auto-oxidation. In addition, MMI wasshown to reduce ultraviolet-induced erythema inthe skin, adding to its depigmenting effect a poten-tial sun protective action. Being an inhibitor ofboth tyrosinase and peroxidase, it acts on severalsteps in the melanogenesis pathway, enabling it toexert its actions at multiple levels, suggesting itsrole not only as monotherapy but also as a poten-tial adjuvant to other topical treatments (8). Inaddition to melasma, MMI was successfully tried inone case of post-inflammatory hyperpigmentationin a patient with acid burn injury (2).

The present authors hence report the successfulmanagement of two HQ-resistant patients withMMI. The efficacy of MMI for the treatment ofmelasma and its advantages over other knowndepigmenting compounds suggest that topicalMMI should be added to the available armamen-tarium of anti-melasma treatments.

References

1. Kasraee B. Depigmentation of brown guinea pig skin bytopical application of methimazole. J Invest Dermatol 2002:118: 205–207.

2. Kasraee B, Handjani F, Parhizgar A, et al. Topical methima-zole as a new treatment for postinflammatory hyperpigmen-tation: report of the first case. Dermatology 2005: 211: 360–362.

3. Kasraee B, Safaee Ardekani GH, Parhizgar A, et al. Safety oftopical methimazole for the treatment of melasma. Transder-mal absorption, the effect on thyroid function and cutaneousadverse effects. Skin Pharmacol Physiol 2008: 21: 300–305.

4. Okun MR, Donnellan B, Pearson SH, Edelstein LE. Melanin: anormal component of human eosinophils. Lab Invest 1974:30: 681–685.

5. Kasraee B. Peroxidase-mediated mechanisms are involved inthe melanocytotoxic and melanogenesis-inhibiting effects ofchemical agents. Dermatology 2002: 205: 329–339.

6. Okun MR. The role of peroxidase in mammalian melanogen-esis: a review. Physiol Chem Phys Med NMR 1996: 28: 91–100.

7. Okun MR, Schley L, Ziegelstein R, Blair H. Oxidation oftyrosine to dopachrome by peroxidase isolated from murinemelanoma. Physiol Chem Phys 1982: 14: 8–12.

8. Kasraee B, Hügin A, Tran C, Sorg O, Saurat JH. Methimazole isan inhibitor of melanin synthesis in cultured B16 melano-cytes. J Invest Dermatol 2004: 122: 1338–1341.

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