Managing

Melasma and Its Series Editor: Doris Hexsel, MD Newest Therapies Leslie Baumann, MD

wide range of options is included in the arma- Greek word meaning “to be black.”4 Given the actual color mentarium for melasma, but the condition is of the dyschromia, melasma is the preferred term. Although A recalcitrant. Sun-protective behavior is necessary, its appearance is most frequently linked to pregnancy or and patients should halt use of oral contraceptives and use of oral contraceptives, melasma is known to develop at avoid skin care products that facilitate pigmentation.1 The any time during a woman’s reproductive years. Melasma has author prefers using a regimen that combines hydroqui- been diagnosed in premenstrual girls as well as menopausal none 4% in the morning and a triple-combination cream women, but these instances are rare. Women with darker (fluocinolone acetonide 0.01%, hydroquinone 4%, treti- skin types are more often affected. Approximately 10% of noin 0.05%) in the evening. The hydroquinone product melasma presentations occur in men, more often in those contains Tyrostat™-09, which is derived from extracts of of Middle Eastern, Caribbean, or Asian descent. In an age- field dock (Rumex spp). Tyrostat-09 has been shown to be matched comparison of men with melasma and control sub- an effective tyrosinase inhibitor used alone or in combina- jects, the men with idiopathic melasma were found to have tion, outperforming hydroquinone and arbutin, according significantly higher levels of circulating luteinizing hormone to one study.2 This product also contains avobenzone, a and lower levels of testosterone.5 Melasma is a common pig- COS DERM 6,7 strong UVA-blocking sunscreen agent. mentary problem among Asians, particularly women. In recalcitrant patients, the previously mentioned regi- Melasma typically presents as discrete, irregularly shaped men can be combined with glycolic peels, Jessner peels, tan to dark-brown macules, appearing most often on the modified Jessner peels, or intense pulsed light therapies to upper lip, nose, cheeks, chin, forehead, and, occasionally, hasten resolution. Serial glycolic acid peels were found, in the neck. There are 3 identifiable patterns of presenta- one study, to provide additional improvement when com- tion, with a centrofacial distribution, involving the cheeks, bined with a modification of Kligman’s topical formulation forehead, upper lip, nose, and chin, being the most Do Not Copy8,9 (hydroquinone 5%, tretinoin 0.5%, hydrocortisone ace- common. The other distribution patterns seen are the tate 1% in a cream base).3 mandibular pattern, involving the chin line, and the malar Although there is no cure for melasma, the triple- pattern, which involves the nose and cheeks. Melasma combination products have been shown to at least tempo- most often emerges in skin regularly exposed to the sun, rarily treat the condition. Because they combine 3 effective but it reportedly has been observed on the nipples and ingredients in one cream, they likely improve patient com- around the external genitalia.10,11 pliance by simplifying the regimen. Patient education about sunscreen and sun avoidance is still paramount. Etiology The pathogenesis of melasma is not yet clearly understood. Melasma Solar exposure, genetic predisposition, and hormonal Known to be extremely refractory to treatment, melasma, influences are considered among the primary causal fac- also called chloasma and “the mask of pregnancy,” is a com- tors, but a precise etiology has not yet been ascertained.10,11 mon, chronic cutaneous discoloration typically affecting The hormones estrogen and progesterone, nutritional defi- women of childbearing age. Chloasma is derived from the ciency, and certain antiepilepsy drugs have been identified Greek word meaning “to be green”; melasma comes from the as playing significant causal or exacerbating roles in the development of melasma.12 Indeed, some authors con- Dr. Baumann is Chief, Division of Cosmetic , sider the root cause to be stimulation of melanocytes by University of Miami, Florida. endogenous or exogenous estrogen,13 implying that other Dr. Baumann has served as an advisory board member factors serve only to worsen the condition. Hydantoin and and investigator for Galderma Laboratories, LP, and Stiefel phenytoin have also been cited as contributing factors in Laboratories, Inc. both women and men.11,14

VOL. 20 NO. 6 • JUNE 2007 • Cosmetic Dermatology® 349 Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Managing Melasma

A necessary precondition for the pathogenesis of melasma systemic disease—cause no shortage of stress and anxiety appears to be a history of frequent, protracted exposure to among their sufferers. At the cellular level, pigmentation the sun, which is also well known to aggravate the condi- disorders are engendered, endogenously or exogenously, tion.9,12 Indeed, UV exposure is believed to be the leading by a rise in the production of melanin by melanocytes, exogenous factor in the development of melasma.12,15 In a the increased transfer of melanosomes from melanocytes study of 56 Korean patients, the lesional skin of melasma to basal and suprabasal keratinocytes, or both.15,18 The was shown histologically to be characterized by more hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine prominent solar elastosis than was normal skin, with mela- through the enzymatic action of tyrosinase and the nosomes greater in number and more diffusely spread in subsequent oxidation of 3,4-dihydroxyphenylalanine to keratinocytes.16 It is not surprising, then, that melasma is dopaquinone produces the 2 chemically discrete types of usually less conspicuous in the winter months, when there the pigment melanin (the brown-black eumelanin and red- tends to be less sun exposure.11 A few familial melasma yellow pheomelanin).19,20 Melanin is transferred to kerati- cases have been reported, suggesting that there may be a nocytes or into the through 3 different processes: genetic etiologic component, but there are not many sup- (1) damage to melanocytes in the basal layer renders the portive data on this point.12 cells susceptible to phagocytosis by melanophages, which The application of hot wax for the removal of unwanted results in release of melanin into the dermis; (2) melano- hair has been reported to precede the appearance of somes are directly deposited, through their dendrites, into melasma on the upper lip in some women. In fact, this the dermis; or (3) macrophages migrate into the phenomenon occurs frequently enough that the author and phagocytize melanosomes, returning them to the postulates that heat might influence the development of dermis. Treatments for melasma are aimed at preventing melasma in a fashion similar to ab igne (a reticu- the production of melanin, inhibiting the transfer of mela- lated erythematous hyperpigmented eruption induced by nosomes, or hastening the removal of melanosomes and chronic heatCOS exposure). DERMmelanin from the epidermis.21 This article will focus on the Some authors have suggested that women who use treatment of melasma using combination therapy contain- oral contraceptives are the patients who most often pre- ing a corticosteroid, a , and a tyrosinase inhibitor. sent with this painless but stressful pigmentary condi- tion.11,12 Melasma also frequently affects pregnant women. Treatment With a Corticosteroid, Together, these groups comprise the majority of patients a Retinoid, and a Tyrosinase Inhibitor with melasma. Estrogen by itself is an unlikely source Introduced in 1975 and popular since then for the treat- of origin,Do as suggested by the lowNot incidence of melasma ment of Copymelasma, the “Kligman formula” consists of treti- among postmenopausal women on estrogen replacement noin 0.1%, hydroquinone 5%, dexamethasone 0.1%, and therapy,12 but estrogen clearly plays a role in the pathogen- hydrophilic ointment.19 Complete depigmentation of esis of melasma. In fact, it is believed that 17b-estradiol is normal adult skin in black males treated for melasma, partially responsible for maintaining the pigmentary disor- ephelides, and postinflammatory der.17 Melasma is exceedingly idiopathic, characterized by resulted from the daily application of this formulation differences from patient to patient and within individuals, for 5 to 7 weeks. Kligman and Willis19 found that omis- even from pregnancy to pregnancy.12 Melasma is also char- sion of any one component of the regimen resulted in acterized by a high degree of recalcitrance and, after sub- failure to achieve depigmentation. The combination is siding in the months succeeding a patient’s pregnancy or no longer available commercially but can be formulated after cessation of an oral contraceptive regimen, can recur, by a pharmacy. The success of the Kligman formula, taking years to resolve.11,14 Some authors have speculated however, laid the foundation for melasma treatment, as about an endocrine etiology,10 but such a pathogenesis has topical combination remains the mainstay therapy for not been established.14 Likewise, no causal relationships this vexing pigmentary disorder despite the advent of have been attributed to ovarian disorders being correlated new approaches stemming from technologic innovation. with an increased incidence of melasma. The likelihood The 3 components of the Kligman formula have been of experiencing a recurrence of this dyschromia among used both individually and in combination to success- patients with melasma is greater than the likelihood of fully treat pigmentation disorders. initial onset of melasma among a general population. Disorders of pigmentation, although not usually rep- Corticosteroids resentative of serious threats to health—though they Corticosteroids have been combined with other agents are sometimes manifestations of significant underlying in the treatment of melasma for years. They exert an

350 Cosmetic Dermatology® • JUNE 2007 • VOL. 20 NO. 6 Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Managing Melasma

antimetabolic effect, resulting in decreased epidermal turn- to be the rate-limiting enzyme for the biosynthesis of over and, thus, may produce a mild depigmenting effect. In melanin in epidermal melanocytes. Therefore, tyrosinase early studies by Kligman and Willis,19 topical dexametha- activity is thought to be a major regulatory step in mela- sone as monotherapy produced little depigmentation, even nogenesis. Hydroquinone has been shown to decrease the after 3 months of therapy. A significant concern is that activity of tyrosinase by 90%.20 In addition, hydroquinone topical corticosteroids used alone in this setting, especially is cytotoxic to melanocytes.30 Jimbow et al31 elucidated on the face, may result in epidermal atrophy, telangiecta- the mechanism of hydroquinone via electron microscopy sia, rosacealike erythema, , and perioral dermatitis. and histochemistry studies on guinea pigs and showed Several studies have demonstrated that epidermal atrophy that the melanosome structure is disturbed after treatment does not occur when topical corticosteroids are com- with hydroquinone. This may lead to complete melano- bined with .22-25 When used in combination with cytic degradation; however, keratinocytes are spared and tretinoin and hydroquinone in the treatment of melasma, show no apparent injury. Hydroquinone is known to cause fluocinolone acetonide 0.01% suppresses biosynthetic and reversible inhibition of cellular metabolism by affecting secretory functions of melanocytes and, thus, melanin both DNA and RNA synthesis. Although it is useful as a production, leading to early response in melasma, synergy sole agent, hydroquinone is often combined with other among the 3 agents, and no significant side effects over an agents such as tretinoin, glycolic acid, kojic acid, and 8-week period.23 azelaic acid. Other products on the market contain ingre- dients that inhibit tyrosinase and thus decrease melanin Tretinoin formation, but hydroquinone seems to be the most popu- Topical retinoids were first used in 1960 for the treatment lar. It is found in over-the-counter products, usually at a of epidermal keratinization diseases, and a significant level of 2%, and in prescription products at a level of 5%. improvement was observed in patients suffering from Pharmacies have been known to compound formulations .COS1 Since then, retinoids have been used for everyDERM- with a level of 12% or higher. thing from cancers to wrinkles. Many studies have shown There have been many concerns about the safety of the efficacy of retinoids in treating pigmentation disorders hydroquinone, and, in fact, its use has been banned in as seen in and melasma.26 Europe and is highly regulated in Asia. This is due, in part, Retinoids have not been found to suppress melanogen- to the fact that it is a metabolite of benzene and has poten- esis in pigmented skin equivalents and monolayer cultures tial mutagenic properties. However, adverse effects related of murine and human melanocytes.27 It is thought that the to topically applied hydroquinone are infrequent and pre- role Doof retinoids in bleaching treatmentsNot appears to be in dominantly Copy occur with formulation levels greater than 4%. other specific actions, such as promotion of keratinocyte They tend to be temporary and resolve on discontinuation. proliferation and acceleration of epidermal turnover. The most common problems caused by hydroquinone are Evaluations of tretinoin 0.1% as monotherapy for irritant and allergic .32 A small number of melasma have been favorable,22,23 but this approach can cases of exogenous ochronosis, which presents as asymp- take a long time before the condition shows any improve- tomatic blue-black macules in the area of hydroquinone ment. A 10-month, randomized, vehicle-controlled clinical application, have been reported.33,34 It usually occurs after study did show that topical tretinoin 0.1% was effective prolonged use of even low concentrations of hydroquinone in lightening the melasma in 28 black patients, with only (eg, 2%). The topical hydroquinone products are thought mild side effects.28 to cause this disorder by inhibiting the enzyme homogen- In a recent study, 10 Indian patients with melasma tisic acid oxidase in the skin. This results in the local accu- were treated in a split-face fashion with either a tretinoin mulation of homogentisic acid that then polymerizes to 1% solution applied for 4 hours once weekly or a weekly form ochronotic pigment.35 Exogenous ochronosis seems 70% glycolic acid peel for 12 weeks.29 It was concluded to occur more commonly among patients with darker that the tretinoin 1% solution was well tolerated and skin types.36 As a monotherapy, hydroquinone remains as effective a therapy for melasma in dark-skinned the most effective topically applied hypopigmenting agent individuals as a standard and well-tried chemical peel approved for treating melasma by the US Food and Drug (70% glycolic acid). Administration (FDA).36

Hydroquinone Triple-Combination Cream Tyrosinase, the enzyme that controls the synthesis of mela- The Kligman formula was used for many years but nin, is a unique product of melanocytes. It is considered required compounding by a pharmacy because it was

VOL. 20 NO. 6 • JUNE 2007 • Cosmetic Dermatology® 351 Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Managing Melasma

not FDA approved. A triple-combination cream using a clearing of hyperpigmentation was observed in 77% of the set of agents similar to those in the Kligman formula has aggregate triple-combination group compared with 46.8% received FDA approval for the treatment of melasma. for tretinoin plus hydroquinone, 42.2% for hydroquinone This medication combines tretinoin 0.05%, hydroqui- plus fluocinolone acetonide, and 27.3% for tretinoin plus none 4%, and fluocinolone acetonide 0.01% (a mild anti- fluocinolone acetonide. Erythema at the application site, inflammatory corticosteroid). Studies have demonstrated desquamation, burning, xerosis, and pruritus were the that combining a mild corticosteroid with a retinoid pre- adverse effects most often cited in response to applica- vents corticosteroid-induced atrophy without lessening tion of the triple-combination cream, but overall, side the anti-inflammatory effect.22,24 effects were mild and of brief duration. The development In the 2 phase 3 trials that led to FDA approval of of ochronosis has been associated with the use of hydro- the triple-combination cream, a total of 641 predomi- quinone in high concentrations. There were no reported nantly white women (aged 21–75 years, Fitzpatrick skin occurrences of ochronosis in this study among patients types I–IV) with moderate to severe hyperpigmenta- using any of the treatments containing hydroquinone 4%. tion were randomized into various treatment groups Some authors have argued against the use of topical cor- in two 8-week, multicenter, investigator-blind studies.25 ticosteroids for melasma because of a correlation with skin There were 3 arms of each study that compared dual- atrophy and .37 However, the combination combination formulations of tretinoin plus hydroquinone, of a retinoid with a corticosteroid is thought to mitigate tretinoin plus fluocinolone acetonide, and hydroquinone the mineralocorticoid effects of glucocorticoids, thereby plus fluocinolone acetonide. In both studies, all formula- decreasing the risk of corticosteroid-inducing atrophy.22 tions were applied once nightly, and the same drug concen- The distinctive triple-combination formulation is believed trations and vehicles were used. to have worked in this fashion in preventing skin atrophy. Of the study population, only one patient, in the hydroqui- Results andCOS Conclusion DERMnone plus fluocinolone acetonide group, developed skin At the end of 8 weeks, 26.1% of the patients treated with atrophy. It is important to note that this patient did not the triple-combination cream exhibited complete resolu- receive the formulation containing the retinoid. tion compared with 4.6% of the patients in the 3 dual- The combined results of the 2 studies of the triple- combinationDo therapy groups. 25 CompleteNot or near-complete combination Copy cream strongly suggest that the use of

Figure Not Available Online Figure Not Available Online

A B

Patient with moderate melasma at baseline (A) and with mild melasma after 8 weeks of treatment with a triple-combination formulation of fluocinolone acetonide 0.01%, hydroquinone 4%, and tretinoin 0.05% (B).

352 Cosmetic Dermatology® • JUNE 2007 • VOL. 20 NO. 6 Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Managing Melasma

this agent is more effective than the 3 evaluated dual- 13. Stulberg DL, Clark N, Tovey D. Common hyperpigmentation disorders combination agents in reversing the hyperpigmentation in adults: part II. , seborrheic keratoses, acanthosis nigricans, characteristic of melasma. Apparently safe, effective, and melasma, diabetic dermopathy, , and postinflammatory hyperpigmentation. Am Fam Physician. 2003;68:1963-1968. well tolerated for the treatment of melasma, this topical 14. Champion RH, Burton JL, Ebling FJG, eds. Rook/Wilkinson/ formulation combines 3 components already established as Ebling Textbook of Dermatology. Vol 3. 5th ed. Oxford: Blackwell relatively effective agents in monotherapy or dual-therapy Science; 1992. regimens (Figure). The 2 multicenter studies evaluated the 15. Barankin B, Silver SG, Carruthers A. The skin in pregnancy. J Cutan Med Surg. 2002;6:236-240. use of the triple-combination formulation over an 8-week 16. Kang WH, Yoon KH, Lee ES, et al. Melasma: histopathological char- period, but a 12-month open-label extension trial also acteristics in 56 Korean patients. Br J Dermatol. 2002;146:228-237. demonstrated the safety and tolerability of the product.25 17. Hassan I, Kaur I, Sialy R, et al. Hormonal milieu in the maintenance Another recent study buttresses the findings of this of melasma in fertile women. J Dermatol. 1998;25:510-512. 18. Baumann LS. Cosmetic Dermatology: Principles and Practice. New research. Investigators assessed the efficacy of a formula York: McGraw-Hill; 2002. containing tretinoin 0.1%, hydroquinone 5%, and hydro- 19. Kligman AM, Willis I. A new formula for depigmenting human skin. cortisone 1% used to treat 25 female Korean patients Arch Dermatol. 1975;111:40-48. with melasma recalcitrant to therapy.6 Patients applied the 20. Nordlund JJ. Postinflammatory hyperpigmentation. Dermatol Clin. 1988;6:185-192. triple-combination formulation to their faces for 4 months. 21. Pandya AG, Guevara IL. Disorders of hyperpigmentation. Dermatol They were evaluated before treatment, then assessed Clin. 2000;18:91-98. 4 weeks and 4 months after treatment. Statistically signifi- 22. Kligman LH, Schwartz E, Lesnik RH, et al. Topical tretinoin pre- cant depigmentation in clinical and histologic studies was vents corticosteroid-induced atrophy without lessening the anti- inflammatory effect. Curr Probl Dermatol. 1993;21:79-88. found, as was elevated subepidermal collagen synthesis, 23. Menter A. Rationale for the use of topical corticosteroids in melasma. results that were noted as early as 4 weeks after treatment. J Drugs Dermatol. 2004;3:169-174. 24. McMichael AJ, Griffiths CE, Talwar HS, et al. Concurrent application References of tretinoin (retinoic acid) partially protects against corticosteroid- 1. Pathak MA,COS Fitzpatrick TB, Kraus EW. Usefulness of retinoic acidDERM in induced epidermal atrophy. Br J Dermatol. 1996;135:60-64. the treatment of melasma. J Am Acad Dermatol. 1986;15:894-899. 25. Taylor SC, Torok H, Jones T, et al. Efficacy and safety of a new 2. Simonot D, McColl J, Thome D. Tyrosinase inhibitors: activity of a triple-combination agent for the treatment of facial melasma. Cutis. rumex extract in combination with kojic acid and arbutin. Cosmetics 2003;72:67-72. & Toiletries. 2002;117:51-56. 26. Gupta AK, Gover MD, Nouri K, et al. The treatment of melasma: a 3. Sarkar R, Kaur C, Bhalla M, et al. The combination of glycolic review of clinical trials. J Am Acad Dermatol. 2006;55:1048-1065. acid peels with a topical regimen in the treatment of melasma 27. Yoshimura K, Tsukamoto K, Okazaki M, et al. Effects of all-trans retinoic in dark-skinned patients: a comparative study. Dermatol Surg. acid on melanogenesis in pigmented skin equivalents and monolayer 2002;28:828-832. culture of melanocytes. J Dermatol Sci. 2001;27(suppl 1):S68-S75. Do Not28. Kimbrough-GreenCopy CK, Griffiths CE, Finkel LJ, et al. Topical retinoic 4. Montemarano AD. Melasma. Available at: http://www.emedicine.com /derm/topic260.htm. Accessed May 15, 2007. acid (tretinoin) for melasma in black patients: a vehicle-controlled 5. Sialy R, Hassan I, Kaur I, et al. Melasma in men: a hormonal profile. clinical trial. Arch Dermatol. 1994;130:727-733. J Dermatol. 2000;27:64-65. 29. Cuce LC, Bertino MC, Scattone L, et al. Tretinoin peeling. Dermatol 6. Kang WH, Chun SC, Lee S. Intermittent therapy for melasma in Surg. 2001;27:12-14. Asian patients with combined topical agents (retinoic acid, hydro- 30. Penney KB, Smith CJ, Allen JC. Depigmenting action of hydroqui- quinone and hydrocortisone): clinical and histological studies. J none depends on disruption of fundamental cell processes. J Invest Dermatol. 1998;25:587-596. Dermatol. 1984;82:308-310. 7. Lim JT, Tham SN. Glycolic acid peels in the treatment of melasma 31. Jimbow K, Obata H, Pathak MA, et al. Mechanism of depigmenta- among Asian women. Dermatol Surg. 1997;23:177-179. tion by hydroquinone. J Invest Dermatol. 1974;62:436-449. 8. Mandry Pagan R, Sanchez JL. Manibular melasma. P R Health Sci J. 32. Guevera JL, Pandya AG. Safety and efficacy of 4% hydroquinone 2000;19:231-234. combined with 10% glycolic acid, antioxidants, and sunscreen in 9. Sanchez NP, Pathak MA, Sato S, et al. Melasma: a clinical, light the treatment of melasma. Int J Dermatol. 2003;42:966-972. microscopic, ultrastructural, and immunofluorescence study. J Am 33. Levitt J. The safety of hydroquinone: a dermatologist’s response to Acad Dermatol. 1981;4:698-710. the 2006 Federal Register. J Am Acad Dermatol. In press. 10. Baran R, Maibach HI, eds. Textbook of Cosmetic Dermatology. 2nd ed. 34. Zawar VP, Mhaskar ST. Exogenous ochronosis following hydroqui- London: Martin Dunitz Ltd, 1998. none for melasma. J Cosmet Dermatol. 2004;3:234-236. 11. Arnold HL Jr, Odom RB, James WD, eds. Andrews’ Diseases of the Skin: 35. Kramer KE, Lopez A, Stefanato CM, et al. Exogenus ochronosis. J Clinical Dermatology. 8th ed. Philadelphia, Pa: WB Saunders; 1990. Am Acad Dermatol. 2000;42:869-871. 12. Mosher DB, Fitzpatrick TB, Ortonne J-P, et al. Hypomelanoses and 36. Grimes PE. Melasma: etiologic and therapeutic considerations. Arch hypermelanoses. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Dermatol. 1995;131:1453-1457. Fitzpatrick’s Dermatology in General Medicine. Vol 1. 5th ed. New 37. Giannotti B, Melli MC. Current approaches to the treatment of York, NY: McGraw-Hill; 1999:945-1017. melasma. Clin Drug Invest. 1995;10(suppl 2):57-64. n

VOL. 20 NO. 6 • JUNE 2007 • Cosmetic Dermatology® 353 Copyright Cosmetic Dermatology 2010. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher.