Management of Facial Hyperpigmentation

Am J Clin Dermatol 2000 Sep-Oct; 1 (5): 261-268 DISEASE MANAGEMENT 1175-0561/00/0009-0261/$20.00/0

Ana Pérez-Bernal, Miguel A. Muñoz-Pérez and Francisco Camacho

Department of Dermatology, Faculty of Medicine, Virgen Macarena Hospital, Seville, Spain

Contents

Abstract ...... 261 1. Management of Facial Hyperpigmentation ...... 262 2. Riehl’s Melanosis and Related Conditions ...... 262 2.1 Poikiloderma of Civatte ...... 262 2.2 Erythromelanosis Follicularis of the Face and Neck ...... 262 2.3 Erythrose Peribuccale Pigmentaire of Brocq ...... 263 2.4 Linea Fusca ...... 263 3. Facial Hyperpigmentation Associated with Use of Cosmetics and Drugs ...... 264 4. Melasma (Chloasma) ...... 264 5. Treatment of Facial Hyperpigmentation ...... 265 5.1 General Instructions ...... 265 5.2 Hypopigmentation Agents ...... 265 5.2.1 Hydroquinone ...... 265 5.2.2 Hydroquinone and Tretinoin Combinations ...... 266 5.2.3. Other Phenolic Compounds ...... 266 5.2.4 Azelaic Acid ...... 266 5.2.5 Tretinoin ...... 266 5.2.6 Kojic Acid ...... 266 5.2.7 Ascorbic Acid (Vitamin C) and Tocopherol (Vitamin E) ...... 266 5.3 Chemical Peels ...... 266 5.4 Laser Therapy ...... 267 6. Conclusion ...... 268

Abstract Facial and neck pigmentations are the most cosmetically important. They are common in middle-aged women, and are related to endogenous (hormones) and exogenous factors (such as use of cosmetics and perfumes, and exposure to sun radiation). Melasma (chloasma) is the most common cause of facial pigmentation, but there are many other forms such as Riehl’s melanosis, poikiloderma of Civatte, erythrose peribuccale pigmentaire of Brocq, erythromelanosis follicularis of the face and neck, linea fusca, and cosmetic hyperpigmentations. Treatment of melasma and other facial pigmentations has always been challenging and discouraging. It is important to avoid exposure to the sun or to ultraviolet lamps, and to use broad-spectrum sunscreens. Several hypopigmenting agents have been used with differing results. Topical hydroquinone 2 to 4% alone or in combination with tretinoin 0.05 to 0.1% is an established treatment. Topical azelaic acid 15 to 20% can be as efficacious as hydroquinone, but is less of an irritant. Tretinoin is especially useful in treating hyperpigmentation of photoaged skin. Kojic acid, alone or in combination with glycolic acid or hydroquinone, has shown good results, due to its inhibitory action on tyrosinase. Chemical peels are useful to treat melasma: trichloroacetic acid, Jessner’s solution, Unna’s paste, α-hydroxy acid preparations, kojic acid, and salicylic acid, alone or in various combinations have shown good results. In contrast, laser therapies have not produced completely satisfactory results, because they can induce hyperpigmentation and recurrences can occur. New laser approaches could be successful at clearing facial hyperpigmentation in the future. 262 Pérez-Bernal et al.

1. Management of Facial Hyperpigmentation mainly affects perimenopausal women. There is an irregular dark pigmentation with a reticulate distribution over a slight erythem- Normal skin color is dependent on the quantity and type of atous field, located on the lateral and low neck. melanin pigment in the melanocytes and keratinocytes. The thick- Histologically, there is hyperkeratosis and epidermal atro- ness of the stratum corneum, the dermal vasoconstriction or vaso- phy, liquefaction degeneration of the basal layer, numerous der- dilatation and the occasional presence of endogenous or exoge- mal melanophages, and a perivascular or band-like lymphocytic nous pigments, may also modify the skin color. infiltrate. Exposure to light, photodynamic substances in cosmet- Several factors may be responsible for the numerous hyper- ics, and an unknown endocrine factor are important factors. It is chromatic processes affecting the epidermis and/or dermis: he- necessary to use sunscreens and avoid precipitating factors.[5] reditary, endocrine, nutritional, neoplastic, inflammatory, drugs, physical and chemical.[1] Due to their visibility, facial and neck pigmentations (cervicofacial pigmentations) are the most cosmetically important. They 2.2 Erythromelanosis Follicularis of the Face and Neck are more common in middle-aged women and are related to endo- Erythromelanosis follicularis of the face and neck is an ery- genous and exogenous factors, such as use of cosmetics and per- thematous and pigmentation disorder affecting the follicles. His- fumes, and exposure to sun radiation.[2] tologically, there is follicular dilatation with infundibular keratotic Among the most common cervicofacial hyperpigmentations are Riehl’s melanosis, which is difficult to conceptually differen- tiate from other disorders such as poikiloderma of Civatte, erythrose peribuccale pigmentaire of Brocq, erythromelanosis follicularis of the face and neck, because they share clinical and etiologic factors. Currently, all of them are considered variants of Riehl’s melanosis.[3] In addition to these forms of hyperpigmentations, the management of cosmetic hyperpigmentations, linea fusca, and melasma (chloasma) will also be discussed.

2. Riehl’s Melanosis and Related Conditions Riehl’s melanosis occurs in middle-aged women. Brownish gray reticulate pigmentation develops over the face and neck, on the temples, cheeks, chin, supraciliary, dorsum of nose, lateral surfaces of neck, and low neck (fig. 1). It was first described in the First World War, and endogenous factors may be involved, such as digestive disorders, neurovegetative lability, vitamin de- ficiency, and toxic factors. However, in most currently observed cases the condition has been induced by use of cosmetics containing coal tar derivatives, which have a high propensity to cause photosensitivity.[4] Histologically, there is a pigmentary overload in the dermal melanophages, occasional epidermic edema and hyperfunction of melanocytes. Riehl’s melanosis shows a long evolution over time and the recognition and removal of causal agents will lead to a gradual improvement in the condition. The use of sunscreens, and creams containing hydroquinone 2 to 5% plus tretinoin or glycolic acid, also produce a slow improvement.

2.1 Poikiloderma of Civatte Poikiloderma of Civatte is a very common disorder that Fig. 1. Riehl’s melanosis: brownish reticulate pigmentation on neck.

Therapy with tretinoin cream, ammonium lactate 12% lotion, metronidazole gel, or hydroquinone cream is ineffective. No effective therapy is currently available.

2.3 Erythrose Peribuccale Pigmentaire of Brocq

Erythrose peribuccale pigmentaire of Brocq typically appears as a reddish brown pigmentation around the mouth as far as the nasolabialis sulcus, and sometimes presents as a narrow perioral ring. It may be the result from the use of topical corticosteroids of the treatment of rosacea,[7] and from photodynamic substances present in cosmetics. The pigmentation persists for a long time, even after the cause is eliminated. Elimination of the cause, camouflage, sunscreens, and depigmentation using the different techniques that will be described for melasma (see section 3), have been used to treat this condition.

2.4 Linea Fusca

In linea fusca, brownish yellow pigmentation develops near the hair implantation line in an arch disposition, affecting the forehead (fig. 3) and temporal areas. Similar dark plaques can be observed all over the face. Histologically, there is liquefaction degeneration of the basal layer, perivascular chronic inflammatory infiltrate, follicular hyperkeratosis and melanin deposition in dermis and melanophages.[7] It is necessary to rule out the possibility of exogenous factors as a cause for the condition (e.g. use of cosmetics, hat ribbons, Fig. 2. Erythromelanosis follicularis of the face and neck: reddish brown pigmentation on face and neck. plugging, the sebaceous glands are enlarged, and a periadnexial lymphocytic infiltrate and vasodilatation may be observed. Clinically, there is a symmetric, well defined, reddish brown pigmentation affecting preauricular and maxillary areas, with follicular papules and erythema (fig.2). Using the pressure of a glass the reddish brown area becomes pale, and then it is possible to see brown pigmentation and some telangiectasia. First described in Japan, cases in Caucasians have been reported.[6] This condition can be differentiated from ulerythema ophryogenes, erythromelanosis peribuccale pigmentaire of Brocq and poikiloderma, due to its typical location, the presence of pigment and telangiectasia. Of unknown etiology, some cases are inherited as an autosomal recessive disorder. No photosensitivity relationship has been found. Fig. 3. Linea fusca: brownish pigmentation affecting forehead.

etc), because typical linea fusca can be associated to central nerv- ous system disorders such as encephalitis, tumors, and syphilis.

3. Facial Hyperpigmentation Associated with Use of Cosmetics and Drugs Photosensitizers can act by a phototoxic, or by a photoal- lergic mechanism. Some photodynamic substances that induce phototoxic contact dermatitis can produce severe hyperpigmentation. This is the case of berloque dermatitis occurring after the application of eau de cologne or perfumes containing bergamot oil, an ultraviolet sensitizer. Some plants containing furocoumarines may induce prairie dermatitis (phytophotodermatitis) when patients are exposed to sun after contact with the particular plant. The photosensitizer capacity of furocoumarines induces Fig. 4. Melasma (chloasma) in a woman affecting cheeks and upper lip. pigmentation, and this capacity is used for vitiligo repigmentation therapy. Other compounds act as photoallergens, although many of Although the etiology is unknown, several etiogenic factors them may only develop a phototoxic action: sulfonamides, ani- have been implicated, including genetic factors, UV exposure, lines, p-aminobenzoic acid, chlorothiazides, some oral antidia- pregnancy, oral contraceptives, hormonal replacement therapies, betics, phenothiazines, chlorpromazine, hexachlorophene, and thyroid disturbances, cosmetics, and some photosensitizer drugs.[11] salicylamides, are also present in some cosmetic products. Tetra- The sun exposure is the most important factor, and is present in cyclines induce an erythema followed by pigmentation of un ex- all patients,[12] who improve or worsen with sun exposure. Im- posed areas by a phototoxic mechanism, as do griseofulvin and provements have been reported at the end of pregnancy or at the minocycline.[8] end of oral hormonal therapy, although melasma do not always Lichenoid toxic melanodermitis of Hoffman and Habermann disappear. It can appear during menopause or in men who take is an example of occupationally-induced hyperpigmentation. It estrogens to treat prostate cancer. Some papers show the exist- occurs in people whose work brings them into contact with lubri- [13] cant oils and derivatives over a long period of time. It also may ence of a subclinical ovarian dysfunction, and that it is more [14] occur in men and women who have applied creams or prepara- common in patients with autoimmune thyroiditis. Melanocyte [4] tions containing petrolatum with photodynamic additives. Irreg- stimulating hormone is not relevant in the etiology of melasma. ular areas of brownish violet pigmentation will appear after a There are 3 clinical models: (i) centrofacial, the most com- transitory inflammatory reaction in photoexposed areas, some- mon, in which the nose, chin, upper lip and forehead are affected; times with lichenoid papules and blisters. Histologically, there is (ii) malar, where the nose and cheeks are affected and; (iii) man- acanthosis, perivascular inflammatory infiltrate, and melanin de- dibular, the most rare, where the lower jaw is affected. posits in upper dermis and melanophages. It will slowly disappear Using Wood’s light examination it is possible to classify when the cause is eliminated, although the use of sunscreens and melasma into 4 types:[15] therapy similar to that used for melasma (see section 3) may ac- 1. Epidermal type: melanin increased in all the epidermal layers [9] celerate healing. with sparse melanophages in the upper dermis. It is the most common type, and the pigmentation increases under Wood’s light 4. Melasma (Chloasma) examination. 2. Dermal type: pigmentation does not increase under Wood’s Melasma is a brown or gray hyperpigmentation, with an ill- defined periphery, more or less symmetrical, and localized to the light examination. Histologically, there are many melanophages forehead, cheeks, chin, and upper lip. It is quite common in women throughout the whole dermis. (fig. 4), and rare in men (who comprise only 10% of the cases of 3. Mixed type: there is an increase of melanin in epidermis melasma)[10] (fig. 5). It appears in people of all races, but is more and in dermal melanophages, and Wood’s light examination in- common in people with skin phototypes IV to VI who live in areas creases pigmentation only in some areas, whereas in other areas of high ultraviolet (UV) radiation. no changes are observed.

4. Indeterminate type: patients with VI phototype who show α-hydroxy acid preparations, chemical peels, and laser therapies no differences under Wood’s light examination. are also used. This classification has a prognostic value: patients with epi- In the following sections we will discuss the efficacy, advan- dermal type melasma show a better response to hypopigmenting tages, and disadvantages of these different therapeutic options. agents. In the case of dermal pigmentation, the response to hypopigmenting agents will depend on macrophage transport and 5.1 General Instructions elimination.[5] All women at risk of developing melasma should avoid sun 5. Treatment of Facial Hyperpigmentation exposure and not sue UV lamps. They should use appropriate clothes and broad-spectrum sunscreens. Treatment of melasma and other facial pigmentations has If melasma has been induced by the use of oral contracep- always been challenging, and at many times discouraging. It in- tives, they must be stopped. If melasma appears during pregnancy cludes general instructions that patients must follow exactly, and it is necessary to use sunscreens, with an improvement seen at the the use of hypopigmenting agents, like hydroquinone and kojic end of gestation. acid, with or without the addition of exfoliative agents (tretinoin, glycolic acid or trichloroacetic acid). In addition, azelaic acid, 5.2 Hypopigmentation Agents

5.2.1 Hydroquinone Hydroquinone is a hydroxyphenolic chemical classically used in melasma treatment. It inhibits the conversion of dopa to melanin by inhibiting the tyrosinase enzyme. Other proposed mechanisms of action are inhibition of DNA and RNA synthesis, degradation of melanosomes, and destruction of melanocytes.[16] Hydroquinone efficacy depends on its concentration, the ve- hicle used, and the chemical stability of the final product. Com- monly used concentrations range from 2 to 5%. As a higher concentration is used, a higher efficacy is reached, but more skin irritation is caused. In addition, concentrations higher than 5% do not produce better results.[17] Good results are obtained with a concentration of a 3% concentration. Use of a 2% concentration, without the use of additional substances, is only useful as a main- tenance therapy, as is recommended by the US Food and Drug Administration and European Regulation of Cosmetics Prod- ucts.[5] Hydroquinone must not be prepared as a monobencyl-ether, because it can induce confetti-like depigmentation, and also a delayed-type hypersensitivity reaction. It must be formulated as a hydroalcoholic solution by adding an antioxidant such as so- dium bisulphite 0.1% and ascorbic acid (vitamin C) 0.1%. Adverse effects of hydroquinone are irritative dermatitis, contact dermatitis, postinflammatory pigmentation, nail bleach- ing, and there have been some published cases of exogenous ochronosis, appearing as a dark and reticulated pigmentation of the face after using hydroquinone preparations,[18] although this adverse effect is infrequent, in relation to the common use of hydroquinone products. Hydroquinone can provide permanent depigmentation if the lesion is treated with a high concentration and Fig. 5. Melasma (chloasma) in a man affecting the forehead and cheeks. for a long time.

5.2.2 Hydroquinone and Tretinoin Combinations 5.2.6 Kojic Acid Hydroquinone in combination with other chemical products Kojic acid has recently been used as a 2% cream, alone or in has been used for many years, with more therapeutic success than combination with glycolic acid or hydroquinone, due to its inhib- hydroquinone alone. Hydroquinone 2 to 5% plus tretinoin 0.05 itory action on tyrosinase. In a comparative study in Chinese to 0.1% cream is commonly used, and sometimes dexamethasone women with epidermal melasma, half of the face was treated with 0.1% or hydrocortisone 0.5% is also added. Tretinoin acts by pre- kojic acid 2% gel plus glycolic acid 10% and hydroquinone 2%, venting the oxidation of hydroquinone, improving epidermal pen- and the other half of the face with just glycolic acid 10% and etration, allowing pigment elimination, and increasing keratin- hydroquinone 2%.[25] Better results were obtained on the half of ocyte proliferation. Corticosteroids decrease the irritative effects the face treated with the cream including kojic acid. of hypopigmenting agents, and also inhibit melanin synthesis by decreasing cellular metabolism, but they must not be used for long 5.2.7 Ascorbic Acid (Vitamin C) and Tocopherol (Vitamin E) periods of time to avoid adverse effects. Good results are usually Ascorbic acid and tocopherol (vitamin E) have a synergistic obtained with these combinations, used twice a day for 8 to 10 action. In mild forms of melasma, ascorbic acid may be useful weeks.[19] due to its ability to transform melanin to leucomelanin, which is without color.[14]

5.2.3. Other Phenolic Compounds Isopropylcatechol metabolites 1 to 3% induce toxic radicals which target melanocytes. They produce confetti-like depigmen- 5.3 Chemical Peels tation, contact and allergic dermatitis. The combination of 4- Chemical peels, mainly medium peels, are useful to treat melas- hydroxyanisole 2% plus 0.01% tretinoin is better tolerated. ma: trichloroacetic acid, Jessner’s solution, Unna’s paste, α-hydroxy Jimbow[20] proposed the use of a phenolic thioether (N-acetyl-4- acid preparations, kojic acid, and salicylic acid, alone or in com- S-cysteaminylphenol, in 4% oil/water emulsion, twice a day for bination are used. 6 months) for the treatment of epidermal melasmas, inducing less Complete blanching of diffuse melasma was observed in irritation than hydroquinone. 30% of patients treated with glycolic acid 50% plus kojic acid 10%, partial blanching in 60% and no effect in 10% of patients. 5.2.4 Azelaic Acid The same results were obtained with trichloroacetic acid 15 to Azelaic acid is a dicarboxylic acid (1,7-heptanedicarboxylic 25%.[26] acid) isolated from Pityrosporum ovale, that has been found to be Glycolic acid peels (50 to 70%) are becoming increasingly effective on hyperactive melanocytes, and was used in the 1980s popular in the treatment of melasma. They can be safely used in as an adjuvant treatment for melanoma.[21] The antiproliferative dark skinned patients due to a quite low risk of hyperpigmenta- and cytotoxic effects of azelaic acid are mediated via inhibition tion.[27] of mitochondrial oxidoreductase activity and DNA synthesis. It is used as a cream at a concentrations of 15 to 20%, showing a greater efficacy than hydroquinone 2%,[22] but not greater than hydroquinone 4%.[23] In addition, it only induces slight irritation, and can be used for a long time.

5.2.5 Tretinoin Tretinoin induces dispersion of pigment granules inside the keratinocyte, and accelerates the turn over of epidermal cells, facilitating the elimination of dispersed pigment. It is used to treat hyperpigmentation of photoaged skin, postinflammatory hyperpigmentation, and melasma. Tretinoin 1% has been used to suc- cessfully treat melasma in Black patients; improvements of up to 73% were seen after 40 weeks of treatment.[24] Erythema and peeling in the area of application are adverse effects of tretinoin

0.05 to 0.1%; postinflammatory hyperpigmentation is can also Fig. 6. Chemical peel that contains resorcinol, kojic acid, hydroquinone and α- occur. hydroxy acid for treating melasma (chloasma).

Table I. Facial hyperpigmentation: clinical features and recommended therapy Pigmentary condition Clinical features Recommended therapy Riehl’s melanosis Reticulate pigmentation Sunscreens Neck and face Hydroquinone creams plus tretinoin or Photosensitivity? glycolic acid Poikiloderma of Civatte Perimenopause women Sunscreens Reticulate dark pigmentation Avoid precipitating factors (cosmetics, Lateral and low neck hormones) Erythromelanosis follicularis of the face and neck Affecting follicules Ineffective Preauricular, maxillary areas Symmetric pigmentation Erythrose peribucale pigmentaire of Brocq Around the mouth Eliminate the cause Result of corticosteroid therapy and Sunscreens and melasma therapies photodynamic cosmetics Linea fusca Forehead and temporal areas If possible eliminate the cause (cosmetics, Exogen factors ribbons) CNS disorders Cosmetic and drugs associated facial hyperpigmentation Berloque dermatitis Eliminate the cause Prairie dermatitis Sunscreens and melasma therapies Photoallergens Lichenoid toxic melanodermitis of Hoffman and Habermann Melasma (chloasma) Women (phototypes IV to VI) Avoid sun exposure Hormonal factors Sunscreens Wood’s light classification Hypopigmentation agents Chemical peels Lasers?

Grimes[28] used a series of 5 peelings with salicylic acid 20 have failed. Even with the availability of more sophisticated la- to 30% at 2 weeks intervals in dark skinned patients (phototypes sers, the results obtained are not completely satisfactory. Lasers V to VI), after initial treatment with hydroquinone 4% for 2 induce hyperpigmentation, and recurrence of melasma after laser weeks, obtaining good results for melasma and other types of treatment is the usual outcome. hyperpigmentation. Several types of lasers have been used to treat pigmented le- Peels are commercially available that combine resorcinol, kojic sions: argon laser, Q-switched Nd:YAG (1064nm) laser (used to α acid, hydroquinone, salicylic acid, and -hydroxy acid prepara- remove tattoos), Q-switched Nd:YAG (532nm) and Q-switched tions with a pH of 2.5; peels without hydroquinone or without ruby laser.[29] These lasers have been used to treat epidermal resorcinol are also available (fig. 6). Layers of solution are ap- hyperpigmentations such as ephelides, lentigo, and café-au-lait plied on the skin every 3 weeks, and neutralisation is not required. spots, but results with melasma have not been satisfactory. Resorcinol, a classic therapeutic agent in dermatology, is an iso- The erbium-YAG laser is probably the best one to treat mer of catechol and hydroquinone. It is used as Jessner’s solution, melasma. Manaloto and Alster[30] treated 10 women with melasma which consists of 14g resorcinol, 14g of salicylic acid, 14g of resistant to other forms of treatment with erbium-YAG laser re- lactic acid 85%, and enough 95% ethanol to make up 10ml. Resor- cinol is also used in Unna’s paste: up to 50% resorcinol plus zinc surfacing, obtaining a good improvement of hyperpigmentation oxide and ceisatite, used for 30 minutes, making a deeper peel.[5] immediately after the treatment. However, 3 to 6 weeks after The use of trichloroacetic acid 35% followed by hydroqui- treatment, all of them had a postinflammatory hyperpigmenta- none hydroalcoholic 4% solution or tretinoin 0.05% plus hydro- tion, that could be resolved with glycolic acid peels every 2 cortisone acetate 1% cream has produced excellent results in weeks. They concluded that laser therapy should be only used in White patients with lighter complexions.[14] refractory melasmas. Nouri et al.[31] obtained good results using a pulsed carbon dioxide laser to destroy melanocytes, followed by a Q-switched 5.4 Laser Therapy alexandrite laser to eliminate dermal melanin, in patients with Laser therapy is of little use for treating melasma and laser dermal type melasma. In the future, the combined use of several therapy should only be considered when other therapeutic options types of lasers may become the key weapon for melasma therapy.

6. Conclusions 15. Sánchez NP, Pathak MA, Sato S, et al. Melasma. A clinical, light microscopic, ultrastructural and immunofluorescence study. J Am Acad Dermatol 1981; 4: The treatment of facial hyperpigmentation is still challeng- 698-710 ing. The use of sunscreens is recommended in all conditions. 16. Palumb A, Dischia M, Misuraca G. Mechanism of inhibition of melanogenesis by hydroquinone. Biochem Biophys Acta 1991; 1073: 85-90 Elimination of precipitating factors could be beneficial in 17. Arndt KA, Fitzpatrick TB: Topical use of hydroquinone as a depigmenting agent. poikiloderma of Civatte, erythromelanosis follicularis of the face JAMA 1965; 194: 965-7 and neck, erythrose peribucale pigmentaire of Brocq, linea fusca, 18. Snider RI, Theirs BH. Exogeneous ochronosis. J Am Acad Dermatol 1993; 28: and cosmetic- and drug-associated facial hyperpigmentation (ta- 662-4 ble I). New laser approaches could be successful at clearing facial 19. Salopek TG, Jimbow K. New treatment options for the patient with facial hyperpigmentation. Curr Opin Dermatol 1995; 61-8 hyperpigmentations in the future, but at the present time combi- 20. Jimbow K. N-acetyl-cysteaminylphenol as a new type of depigmenting agent for nations of hypopigmentation agents and chemical peels are the the melanoderma of patients with melasma. Arch Dermatol 1991; 127: 1528-34 most useful therapies for melasma and other facial hyper- 21. Camacho F, Sotillo I, Moreno JC. Melanoma. Introducción. Inmunoterapia del pigmentations. melanoma con BCG. Acido azelaico como tratamiento complementario del melanoma maligno. Symposium de Inmunología y Dermatología. Madrid: Grupo Jarpyo Ed., 1987: 38-48 References 22. Fitton A, Goa KL. Azelaic acid. A review of its pharmacological properties and 1. Diaz-Pérez JL, Mitxelena J, Diaz-Ramón L, et al. Discromías. Medicine 1999; therapeutic efficacy in acne and hyperpigmentary skin disorders. Drugs 1991; 136: 6425-30 41: 780-98 2. Serrano S, Fernández-Vozmediano JM. Hiperpigmentaciones por medicamentos. 23. Balina LM, Graupe K. The treatment of melasma 20% azelaic acid versus 4% Monogr Dermatol 1996; 9: 45-55 hydroquinone cream. Int J Dermatol 1991; 30: 893-5 3. Armijo M, Ortega RM. Discromías. In: Armijo M, Camacho F, editors. 24. Kimbrough-Green CK, Griffiths CE, Finkel LJ. Topical retinoic acid (tretinoin) Dermatología. 3rd ed. Madrid: Aula Médica Ed., 1998: 353-80 for melasma in black patients. Arch Dermatol 1994; 130: 727-33 4. Kaminsky CA, Kaminsky AR. Discromías. Monogr Dermatol 1992; 5: 81-93 25. Lim JT. Treatment of melasma using Kojic Acid in a gel containing Hydroquinone 5. Camacho F, Pathak MA. Hipermelanosis cervicofaciales. Monogr Dermatol 1996; and Glycolic Acid. Dermatol Surg 1999; 25: 282-4 5: 279-90 26. Cotellesa C, Peris K, Onorati MT, et al. The use of chemical peelings of different 6. Warren FM, Davis LS. Erythromelanosis follicularis faciei in women. J Am Acad cutaneous hyperpigmentations. Dermatol Surg 1999; 25: 450-4 Dermatol 1995; 32: 863-6 27. Pandya AG, Guevara IL. Disorders of hyperpigmentation. Dermatol Clin 2000; 7. Litt JZ. Steroid induced rosacea. Am Fam Physician 1993; 48: 67-71 1891-8 8. Henmdrix Jr JD, Greer KE. Cutaneous hyperpigmentation caused by systemic drugs. Int J Dermatol 1992; 31: 458-66 28. Grimes PE. The safety and efficacy of salycilic acid chemical peels in darker 9. Hoffmann E, Habermann R. Arzneiliche und gewerbliche Dermatosen durch racial-ethnic groups. Dermatol Surg 1999; 25: 18-22 Kriegsersatzmittel (Vaseline, Schmieröl) und eigenartige Melanodermatiden. 29. Gupta G, McKay IR, McKay RM. Q-switched ruby laser in the treatment of labial Dtsch Med Wochenschr 1918; 44: 261-4 melanotic macules. Lasers Surg Med 1998; 25: 219-22 10. Vazquez M, Maldonado H, Benaman C. et al. Melasma in men; a clinical and 30. Manaloto RS, Alster T. Erbium: YAG Laser resurfacing for refractory Melasma. histologic study. Int J Dermatol 1988; 27: 25-7 Dermatol Surg 1999; 25: 121-3 11. Pandya AG, Guevara IL. Disorders of hyperpigmentation. Dermatol Clin 2000; 31. Nouri K, Bowes L, Chartier T, et al. Combination treatment of melasma with 18: 91-8 pulsed CO2 Lase followed by Q-Switched Alexandrite Laser: a pilot study. 12. Katsambas A, Antoniou Ch. Melasma. Classification and treatment. J Eur Acad Dermatol Surg 1999; 25: 494-7 Dermatol Venereol 1995; 4: 217-23 13. Pérez NP, Sánchez JL, Aquilo F. Endocrinologic profile of patients with idiopathic melasma. J Invest Dermatol 1983; 81: 543-5 14. Lufti RJ, Fridmanis M, Misrunas AL. Association of melasma with thyroid auto- Correspondence and offprints: Professor Francisco Camacho, Departo. immunity and other thyroidal abnormalities and their relationship to the origin Dermatología, Hospital Virgen Macarena, Avda Dr Fedriani s/n. 41009 Se- of melasma. J Clin Endocrinol Metab 1985; 61: 28-31 ville, Spain.

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP 图书馆。图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页文献云下载图书馆入口外文数据库大全疑难文献辅助工具