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108doin of dihydroxyphenylalanine to melanin by inhibiting theivity of tyrosinase.1 Other mechanisms of action includeerfering with DNA and RNA synthesis, degrading melano-es, and destroying melanocytes.2 Two percent hydroqui-

tation from hydroquinone is frequently caused by the hydro-quinone itself or by sodium metabisulfite, a commonpreservative in hydroquinone preparations.4 Continued useof hydroquinone when irritation is present may lead topostinflammatory hyperpigmentation.

A rare side effect of hydroquinone is exogenous ochronosis,which is paradoxical darkening of the skin. It usually beginswith erythema followedbyblue-blackpatches on the facewherethe hydroquinone was applied. In severe cases, blue-black ma-cules can progress to papules and nodules on sun-exposed areasafter long-term usage of hydroquinone.5 It may be triggeredfrom inhibition of homogentisic acid oxidase locally by hydro-quinone. This rare side effect was common in South Africa,where long-term hydroquinone use was widespread. In theUnited States, ochronosis is less common; approximately 30cases have been reported in North America,3 and typically it

epartment of Ethnic Skin Care, University of Miami Cosmetic Medicineand Research Institute, Miami Beach, FL.niversity of Miami Department of Dermatology and Cutaneous Surgery,Miami, FL.rexel University College of Medicine, Philadelphia, PA.flict of Interest Disclosures: Both authors have completed and submittedthe ICMJE Form for Disclosure of Potential Conflicts of Interest. DrWoolery-Lloyd is a shareholder in Sanabella LLC; has been an investi-gator for Johnson & Johnson, Allergan, Loreal and Galderma; and hasreceived payment for service on speakers bureaus and serving on theAdvisory Boards from Johnson & Johnson and Allergan. Dr Kammer hasnothing to disclose.dress reprint requests to Heather Woolery-Lloyd, MD, University of Mi-reatment of Hyperpigmenather Woolery-Lloyd, MD,*, and Jenna N. K

Hyperpigmentation is a common dermatologimost prominent in skin of color. In skin ofalmost immediately be accompanied by altetation or hypopigmentation. Post-inflammatorskin conditions including acne, eczema, anchallenging. The goal is to reduce the hyphypopigmentation or irritation in the surrouresearch on treatments for hyperpigmentatioSemin Cutan Med Surg 30:171-175 2011

KEYWORDS hyperpigmentation, hydroquinone, dy

yperpigmentation is a common dermatologic conditionthat is found in all skin types but is most prominent in

n of color. Any inflammation or injury to the skin canost immediately be accompanied by alterations in pig-ntation, either hyperpigmentation or hypopigmentation.stinflammatory hyperpigmentation appears in many skinnditions, including acne, eczema, and contact dermatitis,d treatment can be challenging. The goal is to reduce theperpigmentation without causing undesirable hypopig-ntation or irritation in the surrounding area.A variety of topical agents are available to treat hyperpig-ntation. These topical agents can interfere with the pig-ntation process at several different levels. The gold stan-occcad

ami Department of Dermatology and Cutaneous Surgery, 1295NW14thStreet, Suite K, Miami, FL 33136. E-mail: woolerylloyd@yahoo.com

5-5629/11/$-see front matter 2011 Elsevier Inc. All rights reserved.:10.1016/j.sder.2011.06.004ioner, BA

ition that is seen in all skin types but isany inflammation or injury to skin cans in pigmentation, either hyperpigmen-rpigmentation can be observed in manytact dermatitis and treatment can beentation without causing undesirablearea. This review will discuss currentapproaches to treating this condition.

ier Inc. All rights reserved.

mia, ochronosis, melasma

ne is available over-the-counter in the United States andnada. Four percent hydroquinone is available by prescrip-n.3 The Kligman formula combines hydroquinone with ainoid and a steroid, which enhances efficacy.3

A common side effect when one uses hydroquinone toat dyschromia attributable to acne is the hydroquinonelo. This occurrence is characterized by a halo of hypopig-ntation surrounding the dark macule attributable to theaching of the surrounding normal skin. This is frequentlyserved when patients apply hydroquinone with their fin-tips to small macules. More common side effects withdroquinone include irritation and erythema. When pre-ibing hydroquinone, one should warn patients of possibleurs with long-term continued use of hydroquinone over de-es. This risk may be reduced with sunscreen because the

171

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172 H. Woolery-Lloyd and J.N. Kammerttern of ochronosis clinically is photodistributed. Long-termtinued use of hydroquinone should be avoided.For patients with chronic conditions, such as melasma, hy-quinone should be switched to an alternative therapy after amonths or once significant improvement is achieved. Theremany alternative agents, and until recently, there were fewvivo trials in which authors examined alternatives to hy-quinone to support claims of efficacy. This article williew alternatives to hydroquinone and will focus on evi-nced-based data to support their usage.

nimal, In Vitro, and Openabel Studiesnoleic Acidibitors of tyrosinase are believed to suppress melanogen-s and have led to the development of products that usese skin-lightening agents.6,7 Liposome-encapsulated lino-c acid has demonstrated a whitening effect in ultravioletV)-stimulated hyperpigmented human upper arm skin.8

animal studies, investigators evaluated the lightening ef-ts of unsaturated fatty acids on ultraviolet B (UVB)-in-ced pigmentation of dorsal brown guinea pig skin. Allilies of unsaturated fatty acids examined inhibited mela-production and tyrosinase activity. Interestingly, linoleicd was most effective in lightening UVB-induced hyperpig-ntation in vivo, whereas -linolenic acid was most effec-e in inhibiting melanin production in vitro.9

lagic Acid and Arbutinagic acid (EA), an antioxidant, inhibits skin pigmentationulting from UV irradiation. The results of in vitro experi-nts indicate that EA suppresses melanogenesis by inhibit-tyrosinase activity. In one study of 30 subjects with

lasma authors compared the effects EA, synthetic EA, andutin10 and demonstrated a statistically significant reduc-n inMexameter (CK Electronic, Ramstein, Germany) read-s in all three groups.

erola Fruit Extracterola fruit extract, another tyrosinase inhibitor, has beenown to lighten UVB-induced skin pigmentation in browninea pig skin.11

ethimazolethimazole (1-methyl-2-mercaptoimidazole; MMI) is anl antithyroid medication that clinically causes hypopigmen-ion in some patients by inhibiting tyrosinase.12 A study wasducted with 11 uniformly pigmented guinea pigs treated

thMMI topically to one randomly chosen ear for six weeks.13e results revealed hypopigmentation in six of 11MMI-treateds versus no alterations in any of the control sites.13

Totorlinded Clinical Trialsioic Acidecent blinded study enrolled 96 Mexican female patientsth melasma; one-half of the patients received 1% dioicd, and the other half received 2% hydroquinone cream.14

ere was a significant improvement in the Melasma Areaverity Index scores from baseline to the end of the studyen dioic acid or hydroquinone were used; however, theres no significant difference between the two treatments. Indition, the side effects were similar with both, except pru-us was more common in patients using hydroquinone.

yy interferes with melanin transfer by inhibiting the pro-n-activated receptor 2 (PAR-2) pathway. PAR-2 is a G pro-n-coupled receptor that controls the ingestion of melano-es by keratinocytes.15 Two soybean-derived proteins,

mely soybean trypsin inhibitor and the Bowman-Birk in-itor, interfere with melanosome transfer by inhibiting theR-2 activation. The lightening activity of these agents andir ability to prevent UV-induced pigmentation suggestst inhibition of the PAR-2 pathway by soybean extractsy be used as a natural alternative to skin lightening.16 In anded controlled 12-week study, authors evaluated the ef-acy of a soy moisturizer containing soybean trypsin inhib-r and Bowman-Birk Inhibitor on 65womenwithmoderateial photodamage. There was significant improvement inttled pigmentation, blotchiness, dullness, fine lines, over-texture, and overall skin tone.17

cinola prospective, single-center, double-blind, randomized,icle-controlled, bilateral (split-face) comparative trial, 32men with melasma were provided with two identicales containing rucinol serum 0.3% or vehicle.18 Rucinolum demonstrated significant improvement in melasmaen compared with the vehicle control after three monthstreatment.

coriceo licorice extracts, glabridin and liquiritin, have demon-ated topical lightening effects. Glabridin is the main activeredient in licorice extract derived fromGlycyrrhiza glabra andpears to exert its anti-inflammatory effect via inhibition oferoxide anion production and cyclooxygenase activity. Ine in vitro study, authors investigated the inhibitory effects ofbridin onmelanogenesis and inflammation byusing cultured6 murine melanoma cells and guinea-pig skin and foundt glabridin inhibits tyrosinase activity in these cells but hadeffect on DNA synthesis.19

The licorice extract, licochalcone A, is derived from a lic-ce plant grown in northwest China, Glycyrrhiza inflata.ochalone A has anti-inflammatory as well as antimicrobialects in randomized vehicle-controlled clinical trials.20pical licochalone A has also demonstrated anti-inflamma-y properties by causing a significant reduction in redness

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Treatment of hyperpigmentation 173ative to the vehicle control in both the shave- and UV-uced erythema tests.20

In a study of 20 women ages 18-40 years with a clinicalgnosis of bilateral and symmetric idiopathic epidermallasma, liquiritin cream was applied on one side of the faced a vehicle cream on the other side twice daily for foureks.21 Sixteen of the patients were rated as exhibiting an excel-t response, with no discernible differences between the nor-l skin and previously pigmented areas. Two patients showedair response, and two showed a good response. In addition,% of patients in the liquiritin group showed at least a 75%uction in lesion size compared tonone in the vehicle group.21

e skin lightening effects of licorice extract is demonstrated in. 1.

tamin Ccorbic acid (vitamin C) is known to inhibit melanin forma-n by reducing o-quinone formation. The antioxidant ef-ts of ascorbic acid prevent the production of free radicals,ich trigger melanogenesis,22 and reduce oxidizedmelanin,anging the pigmentation from black to tan. Moreover, its a photoprotective effect, by preventing UV-induced freeical damage.23 Ascorbic acid is retained in the epidermis,ich is an advantage over sunscreens because they are easilyoved.24

A split-face, double-blind study was conducted to evaluate

ure 1 Top: Baseline hyperpigmented macule Bottom: After 6eks of treatment with a topical serum containing licorice rootract, retinol and antioxidants.therapeutic effect of topical 5%L-ascorbic acid versus topicalhydroquinone in patients withmelasma by the use of color-

triaanetry, digital photography, regular color slides, and subjectiveluations.25 The best subjective improvement was observedthe hydroquinone side with 93% good and excellent results,pared with 62.5% on the l-ascorbic acid side.25 However,

orimetric measures demonstrated no statistical differencestween the two groups. The lightening effect of hydroquinones apparent as early as the first month of treatment, whereast of l-ascorbic acid was not observed until the third month.hough less effective thanhydroquinone, patients in the ascor-acid group experienced fewer side effects. Sixty-eight per-t of patients in the hydroquinone group had side effectspared with 6.2% in the ascorbic acid group.25 Therefore,

orbic acid may be a good adjunct when treating hyperpig-ntation. In addition, the authors suggested that 10% ascorbicdmight bemore effective. Further clinical studies are neededassess the efficacy of ascorbic acid in melasma.Iontopheresis has been used to enhance epidermal absorp-nof vitaminC.Twenty-nine femalepatientswithmelasmawereolled in a randomized,double-blind,placebo-controlled studyvitamin C iontophoresis and demonstrated a significant de-ase in pigmentation compared to placebo.26

-Acetylglucosamined Niacinamide

acetylglucosamine (NAG) is a monosaccharide derivativeglucose. NAG reduces hyperpigmentation by inhibitingconversion of protyrosinase to tyrosinase, a key step inproduction of melanin.27 Niacinamide is a biologically

ive amide of vitamin B3 inhibiting the transfer of melano-es to keratinocytes.28 A study with 18 Japanese womenealed the depigmentary effect of niacinamide was not theult of a direct impact on melanin synthesis by melano-es, but a reduction in melanosome transfer from melano-es to surrounding keratinocytes.28 An eight-week, double-nd, randomized, split-face clinical trial showed that 2%G reduced the appearance of facial hyperpigmentation,d a combination of 2% NAG with 4% niacinamide dem-strated an even greater improvement.29

ecapeptide 12capeptide 12, a synthetic, 10-amino acid peptide, has beenestigated for its skin-lightening effects. A split-face, random-d, double-blind and placebo-controlled pilot was performeddetermine the effect of twice-daily topical application of thisgopeptide (0.01%).30 Five participants with moderate, recal-rant melasma were enrolled in this 16-week study, and alljects demonstrated statistically significant improvements inappearance of their melasma and overall facial aesthetics.30

mbination Therapymenew combination therapies have been introduced that areven to be as effective as hydroquinone. A combination ofcolic acid, antioxidants and licorice root was shown to be asective as 4% hydroquinone in an 8-week blinded split-face

l.31 Another combination of kojic acid, alpha hydroxy acids,d emblica was effective as 4% hydroquinone at 12 weeks.32

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174 H. Woolery-Lloyd and J.N. Kammermbination therapy may provide a new approach to treatingperpigmentation with significant results.

emical Peelse adjunctive use of chemical peels or microdermabrasionalso be helpful when treating hyperpigmentation. These

erventions work best in a series; typically three to fiventhly treatments are required to attain the greatest results.sorption studies prove that these procedures not only re-ve superficial layers of the stratum corneum but also en-nce penetration of topical therapies when treating hyper-mentation.33,34 A recent single-blinded randomized studywhich the authors compared the therapeutic effects ofcolic acid peels and amino fruit acid peels in patients withlasma illustrated that both are efficacious but amino fruitd peels were found to be less irritating and better toler-d.35 Two split-face studies examined a series of four chem-l peels with hydroquinone versus hydroquinone alone inwomen with melasma.36,37 In one study authors examinedicylic acid peels, whereas in the other they examined gly-lic acid peels. Neither study demonstrated a significantference between chemical peels used with hydroquinonesus hydroquinone alone. However, a larger trial of 40ian patients with melasma did demonstrate a statisticallynificant improvement when chemical peels were added toodified Kligman daily. In this study a series of six peelsre performed every three weeks.38 The results of thesedies suggest that more than four peels may be required toieve significant results when treating hyperpigmentation.

eatment Recommendationshen treating hyperpigmentation, it is important to categorizetients into acute or chronic hyperpigmentation. Acute causes,h as acne hyperpigmented macules, can be treated with agmanformulationanddailysunscreentopreventnewlesions. Inn of color, a Kligman formula with hydroquinone, 6-8%, treti-in, 0.025%, and dexamethasone, 0.1% is very effective. Com-ation therapies with hydroquinone alternatives are also use-as adjunctive therapies. Sunscreens that contain antioxidantsd other agents targeting pigment, such as licorice extract and, are especially useful to prevent and treat pigment.For more chronic causes of hyperpigmentation, initial treat-nt with hydroquinone is useful but alternatives to hydroqui-ne are essential for maintenance. Hydroquinone should bed for one to three months and then as needed. During hy-quinone holidays, alternatives should be used once or twiceily for best results.Manyof the agents discussed in this review,h as licorice extract, soy, emblica, and niacinamide, can bed to maintain patients while off hydroquinone.Hyperpigmentation can be a common, yet challenging,uelae of cutaneous inflammation, especially in those withrker skin. Post inflammatory hyperpigmentation andlasma are difficult conditions for many patients generatingegative impact on their quality of life. There are many safed effective agents available, including a variety of topical

n-lightening products. In addition, procedures, such asemical peels can serve as adjuncts to topical therapy. Newer 24.bination therapies have provided novel and effectiveatment options for hyperpigmentation. More research iseded to identify additional agents that achieve the same, ift better efficacy of hydroquinone with fewer side effects.

ferencesPalumbo A, dIschia M, Misuraca G, et al: Mechanism of inhibition ofmelanogenesis byhydroquinone. BiochimBiophysActa 1073:85-90, 1991JimbowK,Obata H, PathakMA, et al: Mechanism of depigmentation byhydroquinone. J Invest Dermatol 62:436-449, 1974Halder RM, Richards GM: Topical agents used in the management ofhyperpigmentation. Skin Ther Lett 9:1-3, 2004Huang PY, Chu CY: Allergic contact dermatitis due to sodium meta-bisulfite in a bleaching cream. Contact Dermatitis 56:123-124, 2007Lawrence N, Bligard CA, Reed R, et al: Exogenous ochronosis in theUnited States. J Am Acad Dermatol 18:1207-1211, 1988Akiu S, Suzuki Y, Asahara T, et al: Inhibitory effect of arbutin onmelanogenesis-biochemical study using cultured B16 melanoma cella.J Dermatol 101:609-613, 1991Kahn V: Effect of kojic acid on the oxidation of DL-DOPA, norepineph-rine, and dopamine by mushroom tyrosinase. Pigment Cell Res 8:234-240, 1995Shigeta Y, Imanaka H, Ando H, et al: Skin Whitening Effect of linoleicacid Is Enhanced by liposomal Formulations. Biol Pharm Bull 27:591-594, 2004Ando H, Ryu A, Hashimoto A, et al: Linoleic acid and alpha-linolenicacid lightens ultraviolet-induced hyperpigmentation of the skin. ArchDermatol Res 290:375-381, 1998Ertam I, Mutlu B, Unal I, et al: Efficiency of ellagic acid and arbutin inmelasma: A randomized, prospective, open-label study. J Dermatol35:570-574, 2008Hanamura T: Skin lightening effect of polyphenol extract of Acerolafruit on UVB induced pigmentation. Biosci Biotechnol Biochem 72:3211-3218, 2008Kasraee B, Handjani F, Parhizgar A, et al: Topical methimazole as a newtreatment for postinflammatory hyperpigmentation: Report of the firstcase. Dermatology 211:360-362, 2005Kasraee B: Depigmentation of brown Guinea pig skin by topical appli-cation of methimazole. J Invest Dermatol 118:205-207, 2002Tirado-Snchez A, Santamara-Romn A, Ponce-Olivera RM: Efficacyof dioic acid compared with hydroquinone in the treatment ofmelasma. Int J Dermatol 48:893-895, 2009Babiarz-Magee L, Chen N, Seiberg M, et al: The expression and activa-tion of protease-activated receptor-2 correlate with skin color. PigmentCell Res 17:241-251, 2004Paine C, Sharlow E, Liebel F: An alternative approach to depigmenta-tion by soybean extracts via inhibition of the PAR-2 pathway. J InvestDermatol 116:585-595, 2001Wallo W, Nebus J, Leyden JJ: Efficacy of a soy moisturizer in photoag-ing: A double-blind, vehicle-controlled, 12-week study. J Drugs Der-matol 6:917-922, 2007Khemis A, Kaiafa A, Queille-Roussel C, et al: Evaluation of efficacy andsafety of rucinol serum in patients with melasma: A randomized con-trolled trial. Br J Dermatol 156:997-1004, 2007Yokota T, Nishio H, Kubota Y, et al: The inhibitory effect of glabridinfrom licorice extracts on melanogenesis and inflammation. PigmentCell Res 11:355-361, 1998Kolbe L, Immeyer J, Batzer J, et al: Anti-inflammatory efficacy of lico-chalcone A: Correlation of clinical potency and in vitro effects. ArchDermatol Res 298:23-30, 2006Amer M, Metwalli M: Topical liquiritin improves melasma. Int J Der-matol 39:299-301, 2000Catani MV, Rossi A, Costanzo A, et al: Induction of gene expression viaactivator protein-1 in the ascorbate protection against UV-induceddamage. Biochem J 15:77-85, 2001Dreher F, Maibach H: Protective effects of topical antioxidants in hu-

mans. Curr Probl Dermatol 29:157-164, 2001Darr D, Combs S, Dunston S, et al: Topical vitamin C protects porcine

skin from ultraviolet radiation-induced damage. Br J Dermatol127:247-251, 1992

25. Espinal-Perez LE, Moncada B, Castanedo-Cazares JP: A double-blindrandomized trial of 5% ascorbic acid vs. 4% hydroquinone in melasma.Int J Dermatol 43:604-607, 2004

26. Huh CH, Seo KI, Park JY, et al: A randomized, double-blind, placebo-controlled trial of vitamin C iontophoresis in melasma. Dermatology206:316-320, 2003

27. Bissett DL, Farmer T, McPhail S, et al: Genomic expression changesinduced by topical N-acetyl glucosamine in skin equivalent cultures invitro. J Cosmet Dermatol 6:232-238, 2007

28. Hakozaki T, Minwalla L, Zhuang J, et al: The effect of niacinamide onreducing cutaneous pigmentation and suppression of melanosometransfer. Br J Dermatol 147:20-31, 2002

29. Bissett DL, Robinson LR, Raleigh PS, et al: Reduction in the appearanceof facial hyperpigmentation by topical N-acetyl glucosamine. J CosmetDermatol 6:20-26, 2007

30. Hantash BM, Jimenez F: A split-face, double-blind, randomized andplacebo-controlled pilot evaluation of a novel oligopeptide for the treat-ment of recalcitrant melasma. J Drugs Dermatol 8:732-735, 2009

31. McDaniel DH,Wu J: Efficacy of a natural-based bleaching cream versus

hydroquinone 4% bleaching gel in the treatment ofhyperpigmentation. Cosmet Dermatol 21:596-602, 2008

32. Draelos ZD, Yatskayer M, Bhushan P, et al: Evaluation of a kojic acid,emblica extract, and glycolic acid formulation compared with hydro-quinone 4% for skin lightening. Cutis 86:153-158, 2010

33. Lee WR, Shen SC, Kuo-Hsien W, et al: Lasers and microdermabrasionenhance and control topical delivery of vitamin C. J Invest Dermatol121:1118-1125, 2003

34. P, Rajan PE: Grimes Skin barrier changes induced by aluminum oxide andsodium chloride microdermabrasion. Dermatol Surg 28:390-393, 2002

35. Ilknur T, Biak MU, Demirtasoglu M, et al: Glycolic acid peels versusamino fruit acid peels in the treatment of melasma. Dermatol Surg36:490-495, 2010

36. Hurley ME, Guevara IL, Gonzales RM, et al: Efficacy of glycolic acid peelsin the treatment of melasma. Arch Dermatol 138:1578-1582, 2002

37. Kodali S, Guevara IL, Carrigan CR et al: A prospective, randomized, split-face, controlled trial of salicylic acid peels in the treatment ofmelasma in LatinAmerican women. J AmAcad Dermatol 63:1030-1035, 2010

38. Sarkar R, Kaur C, Bhalla M, et al: The combination of glycolic acid peelswith a topical regimen in the treatment of melasma in dark-skinned pa-tients: A comparative study. Dermatol Surg 28:828-832, 2002; discussion:832

Treatment of hyperpigmentation 175

Treatment of HyperpigmentationAnimal, In Vitro, and Open Label StudiesLinoleic AcidEllagic Acid and ArbutinAcerola Fruit ExtractMethimazole

Blinded Clinical TrialsDioic AcidSoyRucinolLicoriceVitamin C

N-Acetylglucosamine and NiacinamideDecapeptide 12Combination TherapyChemical PeelsTreatment Recommendations

References