Ramirez N | MDedge

Cutaneous melasma is a relatively common dermatologic disease, occurring most commonly in Asian and Hispanic women of childbearing years.1-5 Exposure to solar UV radiation is the most important environmental factor in the pathogenesis of melasma.2,3 Therapy for melasma remains a challenge. Pharmacologic treatments are the mainstay.2,6,7 Hydroquinone, azelaic acid, tretinoin, and topical corticosteroids have been used as monotherapy7-11 or in various combinations.12-15 Kligman and Willis15 found that monotherapy with hydroquinone, tretinoin, or the topical corticosteroid dexamethasone did not produce substantial hypopigmentation within a 3-month treatment period. However, they did observe satisfactory results with a combination of tretinoin 0.1%, hydroquinone 5.0%, and dexamethasone 0.1% in a hydrophilic ointment.15 Furthermore, Kligman and Willis,15 as well as other researchers, have noted efficacy and safety benefits with use of hydroquinone, tretinoin, and various topical corticosteroids. In experimental and clinical studies, the use of tretinoin and other retinoids has been found to abrogate the epidermal atrophy that can occur with topical corticosteroids.16,17 This could be due to the ability of tretinoin and other retinoids to induce hyperplasia of epidermal cells and to induce dermal collagen synthesis.16,17 The objective of the 2 well-controlled trials featured in this article was to compare the efficacy and safety of the combination of hydroquinone, tretinoin, and the fluorinated topical corticosteroid fluocinolone acetonide, in a hydrophilic cream formulation, with 3 dual-combination products in the clearing of melasma. back to top

METHODS Study Design—The 2 pivotal trials used similar multicenter, randomized, investigator-blind, active-control, parallel-group protocols. Thirteen centers were involved in these trials. Both studies compared a triple-combination hydrophilic cream vehicle containing tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone acetonide 0.01% (RA+HQ+FA) with the dual-combination products tretinoin plus hydroquinone (RA+HQ), tretinoin plus fluocinolone acetonide (RA+FA), and hydroquinone plus fluocinolone acetonide (HQ+FA). All products involved the same drug concentrations and vehicle. All formulations were used once daily at night. A total of 641 adult patients were randomized to the various treatment groups. Objective evaluation of melasma severity at baseline and at various points after treatment involved investigator assessment of global improvement from baseline using an 8-point scale (0=completely clear to 7=worse) at each follow-up visit. A baseline photograph was used for comparison. Patient Population—Patients enrolled in the study were predominantly white women (aged 21 to 75 years) with Fitzpatrick skin types I through IV. For enrollment into the study, all patients had to demonstrate a stable hyperpigmentation on the face for at least 3 months’ duration, macular lesions that were neither depressed nor atrophic, and melasma severity scores of at least 2 (ie, hyperpigmentation that was at least moderately darker than the surrounding normal skin). There were no significant differences in demographic parameters or skin phototypes among patients in each of the 4 treatment groups. The degree of hyperpigmentation in all patients was moderate to severe. Efficacy and Safety Analysis—The primary efficacy end point involved the investigators’ assessment of the proportion of intent-to-treat patients in each treatment group who achieved complete clearing at week 8. The secondary end point (secondary success) involved the proportion of intent-to-treat patients in each treatment group who achieved complete clearing (score=0) or near-complete clearing (ie, mild residual hyperpigmentation, score=1) by week 8 (Table 1).

View this table

Table 1. Melasma Severity Rating Scale Used in Primary and Secondary Efficacy Analysis

All patients randomized to the various treatment groups were analyzed for adverse events. Statistical analysis involved the Cochran-Mantel-Haenszel test, stratified by center. back to top

RESULTS Efficacy—Significantly more of the patients treated with RA+HQ+FA (26.1%) experienced complete clearing compared with each of the dual-therapy groups at week 8 (9.5% for RA+HQ, 1.9% for RA+FA, and 2.5% for HQ+FA, P

References

Grimes PE. Melasma: etiologic and therapeutic considerations. Arch Dermatol. 1995;131:1453-1457.
Mosher DB, Fitzpatrick TB, Ortonne J-P, et al. Hypomelanoses and hypermelanoses. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. Vol 1. New York, NY: McGraw-Hill; 1999:945-1017.
Barankin B, Silver SG, Carruthera A. The skin in pregnancy. J Cut Med Surg. 2002;6:236-240.
Sober AF, Fitzpatrick TB. Disturbances of pigmentation. section I. mechanisms of pigmentation in man. In: Moschella SL, Pillsbury DM, Hurley HJ Jr, eds. Dermatology. Vol 2. Philadelphia, Pa: WB Saunders Co; 1975:1085.
Vasquez M, Maldonado H, Benmaman C, et al. Melasma in men. Int J Dermatol. 1988;27:25-27.
Pathak MA, Fitzpatrick TB, Kraus EW. Usefulness of retinoic acid in the treatment of melasma. J Am Acad Dermatol. 1986;15:894-899.
Giannotti B, Melli MC. Current approaches to the treatment of melasma. Clin Drug Invest. 1995;10(suppl 2):57-64.
Griffiths CEM, Finkel LJ, Ditre CM, et al. Topical tretinoin (retinoic acid) improves melasma. a vehicle-controlled, clinical trial. Br J Dermatol. 1993;129:415-421.
Verallo-Rowell VM, Verallo V, Graupe K, et al. Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma. Acta Derm Venereol. 1989;143(suppl):58-61.
Sanchez JL, Vazquez M. A hydroquinone solution in the treatment of melasma. Int J Dermatol. 1982;20:55-58.
Kimbrough-Green CK, Griffiths CEM, Finkel LJ, et al. Topical retinoic acid (tretinoin) for melasma in black patients. Arch Dermatol. 1994;130:727-733.
Gano SE, Garcia RL. Topical tretinoin, hydroquinone, and betamethasone valerate in the therapy of melasma. Cutis. 1979;23:239-241.
Kang WH, Chun SC, Lee S. Intermittent therapy for melasma in Asian patients with combined topical agents (retinoic acid, hydroquinone and hydrocortisone): clinical and histological studies. J Dermatol. 1998;25:587-596.
Katsambas A, Antoniou CH. Melasma: classification and treatment. J Eur Acad Dermatol Venereol. 1995;4:217-223.
Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol. 1975;111:40-48.
Kligman LH, Schwartz E, Lesnik RH, et al. Topical tretinoin prevents corticosteroid-induced atrophy without lessening the anti-inflammatory effect. Curr Probl Dermatol. 1993;21:79-88.
McMichael AJ, Griffiths CE, Talwar HS, et al. Concurrent application of tretinoin (retinoic acid) partially protects against corticosteroid-induced epidermal atrophy. Br J Dermatol. 1996;135:60-64.
Sanchez PN, Pathak MA, Sato S, et al. Melasma: a clinical, light microscopic, ultrastructural, and immunofluorescence study. J Am Acad Dermatol. 1981;4:698-710.
Denton CR, Lerner AB,

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Author and Disclosure Information

Susan C. Taylor, MD; Helen Torok, MD; Terry Jones, MD; Nicholas Lowe, MD; Phoebe Rich, MD; Eduardo Tschen, MD; Alan Menter, MD; Leslie Baumann, MD; Joshua J Wieder, MD; Michael M. Jarratt, MD; David Pariser, MD; Dale Martin, MD; Jonathan Weiss, MD; Joel Shavin, MD; Nini Ramirez, MD

Accepted for publication March 17, 2003. Dr. Taylor is from Dermatology Associates, St. Luke’s-Roosevelt Hospital, New York, New York. Dr. Torok is from HMT Dermatology Associates, Inc, Medina, Ohio. Dr. Jones is from J&S Studies, Bryan, Texas. Dr. Lowe is from Clinical Research Specialists, St. John’s Hospital, Santa Monica, California. Dr. Rich is from Dermatology Specialists Northwest, Portland, Oregon. Dr. Tschen is from Academic Dermatology Associates, Albuquerque, New Mexico. Dr. Menter is from Texas Dermatology Associates, Dallas, Texas. Dr. Baumann is from University of Miami, Florida. Dr. Wieder is in private practice, Los Angeles, California. Dr. Jarratt is from DermResearch, Inc, Austin, Texas. Dr. Pariser is from Eastern Virginia Medical School and Virginia Clinical Research, Inc, Norfolk. Dr. Martin is from Skin Surgery Medical Group, Inc, San Diego, California. Drs. Weiss and Shavin are from Gwinnett Clinical Research Center, Snellville, Georgia. Dr. Ramirez is from Hill Dermaceuticals, Inc, Sanford, Florida.
This article was supported by an educational grant from Galderma Laboratories, L.P. Dr. Taylor is a member of advisory boards and speaker’s programs and has received a research grant from Galderma. Dr. Rich is a member of the advisory board and speaker’s program for Novartis Pharmaceuticals Corporation. Dr. Menter is involved in a clinical research study for Galderma. Dr. Baumann has performed clinical trials for Hill Dermaceuticals. Dr. Weiss is a member of the speaker’s program and has received research grants from Galderma.
All other authors report no conflict of interest.

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Susan C. Taylor, MD; Helen Torok, MD; Terry Jones, MD; Nicholas Lowe, MD; Phoebe Rich, MD; Eduardo Tschen, MD; Alan Menter, MD; Leslie Baumann, MD; Joshua J Wieder, MD; Michael M. Jarratt, MD; David Pariser, MD; Dale Martin, MD; Jonathan Weiss, MD; Joel Shavin, MD; Nini Ramirez, MD

Accepted for publication March 17, 2003. Dr. Taylor is from Dermatology Associates, St. Luke’s-Roosevelt Hospital, New York, New York. Dr. Torok is from HMT Dermatology Associates, Inc, Medina, Ohio. Dr. Jones is from J&S Studies, Bryan, Texas. Dr. Lowe is from Clinical Research Specialists, St. John’s Hospital, Santa Monica, California. Dr. Rich is from Dermatology Specialists Northwest, Portland, Oregon. Dr. Tschen is from Academic Dermatology Associates, Albuquerque, New Mexico. Dr. Menter is from Texas Dermatology Associates, Dallas, Texas. Dr. Baumann is from University of Miami, Florida. Dr. Wieder is in private practice, Los Angeles, California. Dr. Jarratt is from DermResearch, Inc, Austin, Texas. Dr. Pariser is from Eastern Virginia Medical School and Virginia Clinical Research, Inc, Norfolk. Dr. Martin is from Skin Surgery Medical Group, Inc, San Diego, California. Drs. Weiss and Shavin are from Gwinnett Clinical Research Center, Snellville, Georgia. Dr. Ramirez is from Hill Dermaceuticals, Inc, Sanford, Florida.
This article was supported by an educational grant from Galderma Laboratories, L.P. Dr. Taylor is a member of advisory boards and speaker’s programs and has received a research grant from Galderma. Dr. Rich is a member of the advisory board and speaker’s program for Novartis Pharmaceuticals Corporation. Dr. Menter is involved in a clinical research study for Galderma. Dr. Baumann has performed clinical trials for Hill Dermaceuticals. Dr. Weiss is a member of the speaker’s program and has received research grants from Galderma.
All other authors report no conflict of interest.

Author and Disclosure Information

Susan C. Taylor, MD; Helen Torok, MD; Terry Jones, MD; Nicholas Lowe, MD; Phoebe Rich, MD; Eduardo Tschen, MD; Alan Menter, MD; Leslie Baumann, MD; Joshua J Wieder, MD; Michael M. Jarratt, MD; David Pariser, MD; Dale Martin, MD; Jonathan Weiss, MD; Joel Shavin, MD; Nini Ramirez, MD

Accepted for publication March 17, 2003. Dr. Taylor is from Dermatology Associates, St. Luke’s-Roosevelt Hospital, New York, New York. Dr. Torok is from HMT Dermatology Associates, Inc, Medina, Ohio. Dr. Jones is from J&S Studies, Bryan, Texas. Dr. Lowe is from Clinical Research Specialists, St. John’s Hospital, Santa Monica, California. Dr. Rich is from Dermatology Specialists Northwest, Portland, Oregon. Dr. Tschen is from Academic Dermatology Associates, Albuquerque, New Mexico. Dr. Menter is from Texas Dermatology Associates, Dallas, Texas. Dr. Baumann is from University of Miami, Florida. Dr. Wieder is in private practice, Los Angeles, California. Dr. Jarratt is from DermResearch, Inc, Austin, Texas. Dr. Pariser is from Eastern Virginia Medical School and Virginia Clinical Research, Inc, Norfolk. Dr. Martin is from Skin Surgery Medical Group, Inc, San Diego, California. Drs. Weiss and Shavin are from Gwinnett Clinical Research Center, Snellville, Georgia. Dr. Ramirez is from Hill Dermaceuticals, Inc, Sanford, Florida.
This article was supported by an educational grant from Galderma Laboratories, L.P. Dr. Taylor is a member of advisory boards and speaker’s programs and has received a research grant from Galderma. Dr. Rich is a member of the advisory board and speaker’s program for Novartis Pharmaceuticals Corporation. Dr. Menter is involved in a clinical research study for Galderma. Dr. Baumann has performed clinical trials for Hill Dermaceuticals. Dr. Weiss is a member of the speaker’s program and has received research grants from Galderma.
All other authors report no conflict of interest.

Article PDF

072010067.pdf

Article PDF

072010067.pdf

Cutaneous melasma is a relatively common dermatologic disease, occurring most commonly in Asian and Hispanic women of childbearing years.1-5 Exposure to solar UV radiation is the most important environmental factor in the pathogenesis of melasma.2,3 Therapy for melasma remains a challenge. Pharmacologic treatments are the mainstay.2,6,7 Hydroquinone, azelaic acid, tretinoin, and topical corticosteroids have been used as monotherapy7-11 or in various combinations.12-15 Kligman and Willis15 found that monotherapy with hydroquinone, tretinoin, or the topical corticosteroid dexamethasone did not produce substantial hypopigmentation within a 3-month treatment period. However, they did observe satisfactory results with a combination of tretinoin 0.1%, hydroquinone 5.0%, and dexamethasone 0.1% in a hydrophilic ointment.15 Furthermore, Kligman and Willis,15 as well as other researchers, have noted efficacy and safety benefits with use of hydroquinone, tretinoin, and various topical corticosteroids. In experimental and clinical studies, the use of tretinoin and other retinoids has been found to abrogate the epidermal atrophy that can occur with topical corticosteroids.16,17 This could be due to the ability of tretinoin and other retinoids to induce hyperplasia of epidermal cells and to induce dermal collagen synthesis.16,17 The objective of the 2 well-controlled trials featured in this article was to compare the efficacy and safety of the combination of hydroquinone, tretinoin, and the fluorinated topical corticosteroid fluocinolone acetonide, in a hydrophilic cream formulation, with 3 dual-combination products in the clearing of melasma. back to top

METHODS Study Design—The 2 pivotal trials used similar multicenter, randomized, investigator-blind, active-control, parallel-group protocols. Thirteen centers were involved in these trials. Both studies compared a triple-combination hydrophilic cream vehicle containing tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone acetonide 0.01% (RA+HQ+FA) with the dual-combination products tretinoin plus hydroquinone (RA+HQ), tretinoin plus fluocinolone acetonide (RA+FA), and hydroquinone plus fluocinolone acetonide (HQ+FA). All products involved the same drug concentrations and vehicle. All formulations were used once daily at night. A total of 641 adult patients were randomized to the various treatment groups. Objective evaluation of melasma severity at baseline and at various points after treatment involved investigator assessment of global improvement from baseline using an 8-point scale (0=completely clear to 7=worse) at each follow-up visit. A baseline photograph was used for comparison. Patient Population—Patients enrolled in the study were predominantly white women (aged 21 to 75 years) with Fitzpatrick skin types I through IV. For enrollment into the study, all patients had to demonstrate a stable hyperpigmentation on the face for at least 3 months’ duration, macular lesions that were neither depressed nor atrophic, and melasma severity scores of at least 2 (ie, hyperpigmentation that was at least moderately darker than the surrounding normal skin). There were no significant differences in demographic parameters or skin phototypes among patients in each of the 4 treatment groups. The degree of hyperpigmentation in all patients was moderate to severe. Efficacy and Safety Analysis—The primary efficacy end point involved the investigators’ assessment of the proportion of intent-to-treat patients in each treatment group who achieved complete clearing at week 8. The secondary end point (secondary success) involved the proportion of intent-to-treat patients in each treatment group who achieved complete clearing (score=0) or near-complete clearing (ie, mild residual hyperpigmentation, score=1) by week 8 (Table 1).

View this table

Table 1. Melasma Severity Rating Scale Used in Primary and Secondary Efficacy Analysis

All patients randomized to the various treatment groups were analyzed for adverse events. Statistical analysis involved the Cochran-Mantel-Haenszel test, stratified by center. back to top

RESULTS Efficacy—Significantly more of the patients treated with RA+HQ+FA (26.1%) experienced complete clearing compared with each of the dual-therapy groups at week 8 (9.5% for RA+HQ, 1.9% for RA+FA, and 2.5% for HQ+FA, P

Cutaneous melasma is a relatively common dermatologic disease, occurring most commonly in Asian and Hispanic women of childbearing years.1-5 Exposure to solar UV radiation is the most important environmental factor in the pathogenesis of melasma.2,3 Therapy for melasma remains a challenge. Pharmacologic treatments are the mainstay.2,6,7 Hydroquinone, azelaic acid, tretinoin, and topical corticosteroids have been used as monotherapy7-11 or in various combinations.12-15 Kligman and Willis15 found that monotherapy with hydroquinone, tretinoin, or the topical corticosteroid dexamethasone did not produce substantial hypopigmentation within a 3-month treatment period. However, they did observe satisfactory results with a combination of tretinoin 0.1%, hydroquinone 5.0%, and dexamethasone 0.1% in a hydrophilic ointment.15 Furthermore, Kligman and Willis,15 as well as other researchers, have noted efficacy and safety benefits with use of hydroquinone, tretinoin, and various topical corticosteroids. In experimental and clinical studies, the use of tretinoin and other retinoids has been found to abrogate the epidermal atrophy that can occur with topical corticosteroids.16,17 This could be due to the ability of tretinoin and other retinoids to induce hyperplasia of epidermal cells and to induce dermal collagen synthesis.16,17 The objective of the 2 well-controlled trials featured in this article was to compare the efficacy and safety of the combination of hydroquinone, tretinoin, and the fluorinated topical corticosteroid fluocinolone acetonide, in a hydrophilic cream formulation, with 3 dual-combination products in the clearing of melasma. back to top

METHODS Study Design—The 2 pivotal trials used similar multicenter, randomized, investigator-blind, active-control, parallel-group protocols. Thirteen centers were involved in these trials. Both studies compared a triple-combination hydrophilic cream vehicle containing tretinoin 0.05%, hydroquinone 4.0%, and fluocinolone acetonide 0.01% (RA+HQ+FA) with the dual-combination products tretinoin plus hydroquinone (RA+HQ), tretinoin plus fluocinolone acetonide (RA+FA), and hydroquinone plus fluocinolone acetonide (HQ+FA). All products involved the same drug concentrations and vehicle. All formulations were used once daily at night. A total of 641 adult patients were randomized to the various treatment groups. Objective evaluation of melasma severity at baseline and at various points after treatment involved investigator assessment of global improvement from baseline using an 8-point scale (0=completely clear to 7=worse) at each follow-up visit. A baseline photograph was used for comparison. Patient Population—Patients enrolled in the study were predominantly white women (aged 21 to 75 years) with Fitzpatrick skin types I through IV. For enrollment into the study, all patients had to demonstrate a stable hyperpigmentation on the face for at least 3 months’ duration, macular lesions that were neither depressed nor atrophic, and melasma severity scores of at least 2 (ie, hyperpigmentation that was at least moderately darker than the surrounding normal skin). There were no significant differences in demographic parameters or skin phototypes among patients in each of the 4 treatment groups. The degree of hyperpigmentation in all patients was moderate to severe. Efficacy and Safety Analysis—The primary efficacy end point involved the investigators’ assessment of the proportion of intent-to-treat patients in each treatment group who achieved complete clearing at week 8. The secondary end point (secondary success) involved the proportion of intent-to-treat patients in each treatment group who achieved complete clearing (score=0) or near-complete clearing (ie, mild residual hyperpigmentation, score=1) by week 8 (Table 1).

View this table

Table 1. Melasma Severity Rating Scale Used in Primary and Secondary Efficacy Analysis

All patients randomized to the various treatment groups were analyzed for adverse events. Statistical analysis involved the Cochran-Mantel-Haenszel test, stratified by center. back to top

RESULTS Efficacy—Significantly more of the patients treated with RA+HQ+FA (26.1%) experienced complete clearing compared with each of the dual-therapy groups at week 8 (9.5% for RA+HQ, 1.9% for RA+FA, and 2.5% for HQ+FA, P

References

Grimes PE. Melasma: etiologic and therapeutic considerations. Arch Dermatol. 1995;131:1453-1457.
Mosher DB, Fitzpatrick TB, Ortonne J-P, et al. Hypomelanoses and hypermelanoses. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. Vol 1. New York, NY: McGraw-Hill; 1999:945-1017.
Barankin B, Silver SG, Carruthera A. The skin in pregnancy. J Cut Med Surg. 2002;6:236-240.
Sober AF, Fitzpatrick TB. Disturbances of pigmentation. section I. mechanisms of pigmentation in man. In: Moschella SL, Pillsbury DM, Hurley HJ Jr, eds. Dermatology. Vol 2. Philadelphia, Pa: WB Saunders Co; 1975:1085.
Vasquez M, Maldonado H, Benmaman C, et al. Melasma in men. Int J Dermatol. 1988;27:25-27.
Pathak MA, Fitzpatrick TB, Kraus EW. Usefulness of retinoic acid in the treatment of melasma. J Am Acad Dermatol. 1986;15:894-899.
Giannotti B, Melli MC. Current approaches to the treatment of melasma. Clin Drug Invest. 1995;10(suppl 2):57-64.
Griffiths CEM, Finkel LJ, Ditre CM, et al. Topical tretinoin (retinoic acid) improves melasma. a vehicle-controlled, clinical trial. Br J Dermatol. 1993;129:415-421.
Verallo-Rowell VM, Verallo V, Graupe K, et al. Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma. Acta Derm Venereol. 1989;143(suppl):58-61.
Sanchez JL, Vazquez M. A hydroquinone solution in the treatment of melasma. Int J Dermatol. 1982;20:55-58.
Kimbrough-Green CK, Griffiths CEM, Finkel LJ, et al. Topical retinoic acid (tretinoin) for melasma in black patients. Arch Dermatol. 1994;130:727-733.
Gano SE, Garcia RL. Topical tretinoin, hydroquinone, and betamethasone valerate in the therapy of melasma. Cutis. 1979;23:239-241.
Kang WH, Chun SC, Lee S. Intermittent therapy for melasma in Asian patients with combined topical agents (retinoic acid, hydroquinone and hydrocortisone): clinical and histological studies. J Dermatol. 1998;25:587-596.
Katsambas A, Antoniou CH. Melasma: classification and treatment. J Eur Acad Dermatol Venereol. 1995;4:217-223.
Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol. 1975;111:40-48.
Kligman LH, Schwartz E, Lesnik RH, et al. Topical tretinoin prevents corticosteroid-induced atrophy without lessening the anti-inflammatory effect. Curr Probl Dermatol. 1993;21:79-88.
McMichael AJ, Griffiths CE, Talwar HS, et al. Concurrent application of tretinoin (retinoic acid) partially protects against corticosteroid-induced epidermal atrophy. Br J Dermatol. 1996;135:60-64.
Sanchez PN, Pathak MA, Sato S, et al. Melasma: a clinical, light microscopic, ultrastructural, and immunofluorescence study. J Am Acad Dermatol. 1981;4:698-710.
Denton CR, Lerner AB,

References

Grimes PE. Melasma: etiologic and therapeutic considerations. Arch Dermatol. 1995;131:1453-1457.
Mosher DB, Fitzpatrick TB, Ortonne J-P, et al. Hypomelanoses and hypermelanoses. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s Dermatology in General Medicine. Vol 1. New York, NY: McGraw-Hill; 1999:945-1017.
Barankin B, Silver SG, Carruthera A. The skin in pregnancy. J Cut Med Surg. 2002;6:236-240.
Sober AF, Fitzpatrick TB. Disturbances of pigmentation. section I. mechanisms of pigmentation in man. In: Moschella SL, Pillsbury DM, Hurley HJ Jr, eds. Dermatology. Vol 2. Philadelphia, Pa: WB Saunders Co; 1975:1085.
Vasquez M, Maldonado H, Benmaman C, et al. Melasma in men. Int J Dermatol. 1988;27:25-27.
Pathak MA, Fitzpatrick TB, Kraus EW. Usefulness of retinoic acid in the treatment of melasma. J Am Acad Dermatol. 1986;15:894-899.
Giannotti B, Melli MC. Current approaches to the treatment of melasma. Clin Drug Invest. 1995;10(suppl 2):57-64.
Griffiths CEM, Finkel LJ, Ditre CM, et al. Topical tretinoin (retinoic acid) improves melasma. a vehicle-controlled, clinical trial. Br J Dermatol. 1993;129:415-421.
Verallo-Rowell VM, Verallo V, Graupe K, et al. Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma. Acta Derm Venereol. 1989;143(suppl):58-61.
Sanchez JL, Vazquez M. A hydroquinone solution in the treatment of melasma. Int J Dermatol. 1982;20:55-58.
Kimbrough-Green CK, Griffiths CEM, Finkel LJ, et al. Topical retinoic acid (tretinoin) for melasma in black patients. Arch Dermatol. 1994;130:727-733.
Gano SE, Garcia RL. Topical tretinoin, hydroquinone, and betamethasone valerate in the therapy of melasma. Cutis. 1979;23:239-241.
Kang WH, Chun SC, Lee S. Intermittent therapy for melasma in Asian patients with combined topical agents (retinoic acid, hydroquinone and hydrocortisone): clinical and histological studies. J Dermatol. 1998;25:587-596.
Katsambas A, Antoniou CH. Melasma: classification and treatment. J Eur Acad Dermatol Venereol. 1995;4:217-223.
Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol. 1975;111:40-48.
Kligman LH, Schwartz E, Lesnik RH, et al. Topical tretinoin prevents corticosteroid-induced atrophy without lessening the anti-inflammatory effect. Curr Probl Dermatol. 1993;21:79-88.
McMichael AJ, Griffiths CE, Talwar HS, et al. Concurrent application of tretinoin (retinoic acid) partially protects against corticosteroid-induced epidermal atrophy. Br J Dermatol. 1996;135:60-64.
Sanchez PN, Pathak MA, Sato S, et al. Melasma: a clinical, light microscopic, ultrastructural, and immunofluorescence study. J Am Acad Dermatol. 1981;4:698-710.
Denton CR, Lerner AB,