Dermatologic Therapy, Vol.

26, 2013, 6972 Printed in the United States All rights reserved

2013 Wiley Periodicals, Inc.

DERMATOLOGIC THERAPY
ISSN 1396-0296

THERAPEUTIC HOTLINE
Successful treatment of hydroquinone-resistant melasma using topical methimazole
Joelle 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 University Hospital, Geneva, Switzerland

ABSTRACT: Melasma is an acquired hyperpigmentation skin disorder in sun-exposed areas. It occurs almost exclusively over the face, and is most commonly seen in women. Several depigmenting agents have been used for the treatment of melasma among which hydroquinone has been the most widely used due to its efcacy and safety in short-term use. However, hydroquinone is recently reported to be a 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 the treatment of melasma in recent years. Methimazole is an antithyroid agent orally used in humans since several decades and has been shown that when applied topically, it inhibits melanin synthesis and causes skin depigmentation in lab animals as well as human subjects. Herein, we report two hydroquinone-resistant melasma patients who were successfully treated with methimazole cream. Application of 5% methimazole cream once daily resulted in signicant improvement of melasma in both patients after 8 weeks. The efcacy of methimazole for melasma treatment as well as its advantages over other known depigmenting compounds (non-mutagenicity, non-cytotoxicity and high tolerability prole) suggests that topical methimazole should be added to the armamentarium of anti-melasma treatment. KEYWORDS: hydroquinone, melasma, methimazole

Introduction
Melasma is an acquired hyperpigmentation disorder of the skin in sun-exposed areas. It occurs almost exclusively over the face, and is most comAddress correspondence and reprint requests to: Ossama Abbas, 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.com Funding sources: None. Conict of interest disclosure: None declared.

monly seen in women. Exacerbating factors include a positive family history, ethnicity, drug intake, oral contraceptive pills, hormone replacement, pregnancy, and sun exposure. Along with strict sun avoidance, topical therapies, such as depigmenting agents, have been used with variable success. Among these, 4% topical hydroquinone (HQ) remains the mainstay of treatment and generally yields the best results; however, its potential mutagenic risk limits its use to certain countries. Methimazole (MMI) is an oral antithyroid medication which has recently received attention due to its depigmenting effect if used topically. It has been

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described to produce depigmentation in guinea pigs and was successfully tried in humans for the treatment of post-inammatory pigmentation and melasma, with no change in the levels of the thyroid hormones after a 6-week treatment (13). The present authors describe two cases of melasma that failed HQ therapy but responded to topical 5% MMI.

Case report
Case 1 A 50-year-old Hispanic woman presented with several years of history of hyperpigmented patches over both cheeks (Fig. 1A). She was previously healthy without medications. She worked as a housemaid and did not report any skin rash or burn prior to the pigmentation. On physical examination, she was noted to have irregular hyperpigmented light brown patches surrounded by numerous smaller pigmented macules on both malar eminences. Woods light examination accentuated the pigmentation indicating a predominantly epidermal type of melasma. The patient was given 4% topical HQ along with a sunscreen daily for a 2-month period to treat her melasma without any signicant improvement. Three weeks after discontinuation of HQ, the patient was prescribed topical MMI. MMI cream was prepared by dissolving MMI (Cilag, Schaffhausen, Switzerland) in distilled water and then dispersing the solution in a vanishing cream vehicle to obtain a nal concentration of 5% MMI in the product. Butylated hydroxytoluene (BHT, Sigma, Buchs, Switzerland) was added at a

concentration of 0.04% as the preservative. The cream was applied only to the hyperpigmented lesions once daily at bedtime. The thyroidstimulating hormone (TSH) level was tested prior to the treatment and was within normal limits. Within 2 months of treatment, the patient noticed an 80% improvement of her melasma lesions (Fig. 1B). The treatment was well tolerated and no signicant side effects were reported. Furthermore, a repeat TSH level at 2 months of treatment remained within normal values. She was advised to continue her treatment for another month but was unfortunately lost to follow-up later. Case 2 A 34-year-old Middle Eastern woman was referred for hyperpigmented patches over the cheeks (Fig. 2A). The patient had already received a 2-month therapy of 4% HQ with little to no response. On physical examination, the patient was found to have brown hyperpigmented patches over the cheeks. Woods light examination revealed her melasma to be predominantly of the epidermal type. She started with 5% topical MMI and BHT 0.04% to be applied daily. After 8 weeks, near complete clearing of the lesions occurred (Fig. 2B). No signicant difference in TSH levels before and after the treatment was detected.

Discussion
Melanogenesis involves a series of steps starting from enzymatic oxidation of tyrosine until melanin pigments are produced. The enzyme tyrosinase is

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

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

assumed to be responsible for the hydroxylation of tyrosine into dopa and the oxidation of dopa into dopaquinone. Dopaquinone is subsequently converted to the indoles 5,6-dihydroxyindole and/or 5,6-dihydroxyindole-2 carboxylic acid. Through oxidative polymerization, indoles are then transformed into eumelanin pigments (4). HQ is a phenol-derived depigmenting chemical originally thought to mediate its effect by inhibiting the tyrosinase enzyme. However, studies have shown that HQ is itself oxidized by tyrosinase and is transformed into 1,4-benzoquinone, a metabolite known to be cytotoxic to melanocytes (4). This cytotoxicity is not restricted to melanocytes; other cells such as keratinocytes can be affected as well. In vitro studies have also demonstrated mutagenic effects of HQ in Salmonella and in the Chinese hamsterV79 ovarian cells. These observations have led some countries to ban the use of HQ and opt for alternative depigmenting compounds, safer however not as effective (2). Based on the observation that some tyrosinasefree cells such as eosinophils, neutrophils, and mast cells are able to produce melanin pigments, an alternative pathway of melanin synthesis involving other enzymes was considered (4). Several studies have implicated the peroxidase enzyme in the oxidation of dopa to dopaquinone (47). Furthermore, the peroxidase-hydrogen peroxide system displays higher activity than tyrosinase in the nal steps of melanogenesis, specically in the oxidation of the indoles as well as in the production of pheomelanins. In addition, peroxidase has been found to have

the highest activity in stages II and III premelanosomes and its levels were detectable in pigmented melanomas but not in amelanotic melanomas. All these studies clearly pointed out a crucial role for the peroxidase enzyme in melanin synthesis (5). The skin depigmenting effect of MMI was rst discovered in 2002, where the topical in vivo application of MMI, a potent peroxidase inhibitor, was found to cause visible cutaneous depigmentation in brown guinea pigs after 6 weeks. Histologically, the melanin content of the epidermis was signicantly reduced and melanocytes exhibited morphological changes without a signicant decrease in number (1). To test for any possible cytotoxic effect, in vitro studies were performed on B16 melanocytes to which increasing concentrations of MMI were added. Even at the highest concentration (800 mm), MMI did not result in signicant decrease in melanocyte number and lead to the inhibition of melanogenesis by more than 50% of controls. However, when other depigmenting agents such as HQ, arbutin, and kojic acid were added to B16 melanocytes, they were found to be melanocytotoxic at concentrations as low as 10, 100, and 100 mm, respectively (8). Because the peroxidase enzyme is also involved in the biosynthesis of thyroxine, it was imperative to study the transdermal absorption of topical MMI and to determine its effect on thyroid function in order to detect any change in thyroid hormone levels. Animal studies have yielded controversial results for MMIs percutaneous

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absorption. Studies using ex vivo rabbit skin as well as repeated application in hyperthyroid cats were rather suggestive of systemic absorption. On the other hand, other experiments using more accurate detection techniques revealed barely detectable serum levels of MMI after topical application and failed to show any effect on thyroid function tests. The serial high-performance liquid chromatography analysis of sera from individuals who applied the 5% MMI cream to a 50 cm2 surface area of their face revealed no detectable serum MMI levels (3). Topical MMIs safety was also tested in vivo in melasma patients. A study by Kasraee et al. involving 20 patients with melasma showed no change in serum TSH, free thyroxine, and free triiodothyronine levels after a 6-week period of once daily application (3). MMI shows many advantages over HQ, arbutin, and other depigmenting agents. In contrast to other known depigmenting drugs, it is odorless, very well tolerated, not associated with cytotoxic and/or mutagenic effects, and does not readily undergo auto-oxidation. In addition, MMI was shown to reduce ultraviolet-induced erythema in the skin, adding to its depigmenting effect a potential sun protective action. Being an inhibitor of both tyrosinase and peroxidase, it acts on several steps in the melanogenesis pathway, enabling it to exert its actions at multiple levels, suggesting its role not only as monotherapy but also as a potential adjuvant to other topical treatments (8). In addition to melasma, MMI was successfully tried in one case of post-inammatory hyperpigmentation in a patient with acid burn injury (2).

The present authors hence report the successful management of two HQ-resistant patients with MMI. The efcacy of MMI for the treatment of melasma and its advantages over other known depigmenting compounds suggest that topical MMI should be added to the available armamentarium of anti-melasma treatments.

References
1. Kasraee B. Depigmentation of brown guinea pig skin by topical application of methimazole. J Invest Dermatol 2002: 118: 205207. 2. Kasraee B, Handjani F, Parhizgar A, et al. Topical methimazole as a new treatment for postinammatory hyperpigmentation: report of the rst case. Dermatology 2005: 211: 360 362. 3. Kasraee B, Safaee Ardekani GH, Parhizgar A, et al. Safety of topical methimazole for the treatment of melasma. Transdermal absorption, the effect on thyroid function and cutaneous adverse effects. Skin Pharmacol Physiol 2008: 21: 300 305. 4. Okun MR, Donnellan B, Pearson SH, Edelstein LE. Melanin: a normal component of human eosinophils. Lab Invest 1974: 30: 681685. 5. Kasraee B. Peroxidase-mediated mechanisms are involved in the melanocytotoxic and melanogenesis-inhibiting effects of chemical agents. Dermatology 2002: 205: 329339. 6. Okun MR. The role of peroxidase in mammalian melanogenesis: a review. Physiol Chem Phys Med NMR 1996: 28: 91 100. 7. Okun MR, Schley L, Ziegelstein R, Blair H. Oxidation of tyrosine to dopachrome by peroxidase isolated from murine melanoma. Physiol Chem Phys 1982: 14: 812. 8. Kasraee B, Hgin A, Tran C, Sorg O, Saurat JH. Methimazole is an inhibitor of melanin synthesis in cultured B16 melanocytes. J Invest Dermatol 2004: 122: 13381341.

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