tain tyrosinase, a copper-containing enzyme, that
catalyzes the conversion of L-tyrosine to L-dopa and
L-dopa to L-dopa-quinone in melanin synthesis.1
Melasma is a dysfunction of this pigmentary system,
resulting in an irregular brown or grayish-brown
facial hypermelanosis. Although it can occur in both
sexes and any skin type, it is more commonly seen
in women2 and those with darker complexions—
Fitzpatrick’s skin types IV to VI—especially those
living in areas of intense UV radiation, such as
Hispanics/Latinos, Asians, and African Americans.3-6
The condition usually develops slowly and symmet-
rically, and can last formany years, withworsening in
the summer and improvement during the winter.7
Melasma is sometimes used interchangeably with
the term ‘‘chloasma,’’ which is a hyperpigmentation
that often results from pregnancy or changes in
uterine and ovarian hormones; melasma, however,
can have a variety of possible causes. The common
HQ: hydroquinone
IPC: isopropylcatechol
IPL: intense pulsed light
MASI: Melasma Area and Severity Index
MKF: modified Kligman’s hydroquinone formula
PIH: postinflammatory hyperpigmentation
RA: retinoic acid
RCT: randomized controlled trial
SWC: skin-whitening complex
TCA: trichloroacetic acid
YAG: yttrium-aluminum-garnet
From the Division of Dermatology, Department of Medicine,
Sunnybrook and Women’s College Health Sciences Center
(Sunnybrook site) and the University of Torontoa; Mediprobe
Research Inc, London, Ontario, Canadab; Department of Der-
matology and Cutaneous Surgery, University of Miami School
of Medicinec; Skin of Color Center, New Yorkd and College of
Physicians and Surgeons, Columbia University, New York.e
Funding sources: None.
Disclosure: Dr Taylor has received previous honoraria/grants
or acted as a consultant or an investigator for the following
companies: Allergan, Astellas, Barrier Therapeutics, Bieresdorf,
Connetics, Dermik, Doak (Bradley), Galderma, Intendis, Johnson&
Johnson, L’Oreal, Medicis, Palomar, Stiefel.
Reprint requests: Aditya K. Gupta, MD, PhD, FRCP (C), 645
Windermere Rd, London, Ontario, Canada N5X 2P1. E-mail:
agupta@execulink.com.
Published online October 4, 2006.
0190-9622/$32.00
REVI
The treatment of m
of clinic
Aditya K. Gupta, MD, PhD, MBA/HCM,
Keyvan Nouri, MD,c an
Toronto and London, Ontari
and New Yor
Melasma is an irregular brown or grayish-brown facia
those living in areas of intense UV radiation. The pre
there are many possible contributing factors. Because
melasma is often difficult to treat. The use of broad-s
topical hydroquinone, the most common treatment fo
acid (tretinoin) and azelaic acid. Combination therap
roids have been used in the treatment of melasma, an
monotherapy. Kojic acid, isopropylcatechol, N-acet
other compounds that have been investigated for th
efficacy, safety, or trial design indicates that the interv
be recommended. Chemical peels, laser treatments, a
apeutic modalities that have been used to treat melas
M
elanin is produced in melanocytes and
stored in melanosomes within the kerati-
nocytes. The number, melanin content,
and location of these melanized cells (along with
oxygenated and deoxygenated hemoglobin) help
determine the color of the skin. Melanosomes con-
ª 2006 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2006.02.009
1048
EWS
elasma: A review
al trials
FRCP (C),a,b Melissa D. Gover, BSc,b
d Susan Taylor, MDd,e
o, Canada; Miami, Florida;
k, New York
l hypermelanosis, often affecting women, especially
cise cause of melasma remains unknown; however,
of its dermal component and tendency to relapse,
pectrum (UVA 1 UVB) sunscreen is important, as is
r melasma. Other lightening agents include retinoic
ies such as hydroquinone, tretinoin, and corticoste-
d are thought to increase efficacy as compared with
yl-4-cysteaminylphenol, and flavonoid extracts are
eir ability to produce hypopigmentation, but their
entions would need further study before they could
nd intense pulsed light therapy are additional ther-
ma. ( J Am Acad Dermatol 2006;55:1048-65.)
Abbreviations used:
AEs: adverse effects
AzA: azelaic acid
CO2: carbon dioxide
FA: fluocinolone acetonide
GA: glycolic acid
contributing factors include genetic predisposi-
tion,4,8 pregnancy,9 use of oral contraceptives,10
J AM ACAD DERMATOL
endocrine dysfunction or hormone treatments,11,12
and exposure to UV light.4,8,13 In addition, cosmetics
and drugs containing phototoxic agents (eg, antisei-
zure medications) have also been linked to me-
lasma.3 Interestingly, Wolf et al14 suggests that some
cases of melasma could be stress induced, because
the release of melanocyte-stimulating hormone can
be influenced by stress.
When melasma occurs with pregnancy, also
termed ‘‘themaskof pregnancy,’’ it can resolvewithin
a few months after delivery and treatment may not
be necessary. However, there are many cases in
which the disorder persists indefinitely.15 Pregnancy-
associated melasma may be caused by an increase
in placenta, ovarian, and pituitary hormones.16 Me-
lasma has also been attributed to an elevation of
melanocyte-stimulating hormone, estrogen, and pro-
gesterone leading to increased melanogenesis.10
Vazquez et al8 reports that melasma in men
shares the same clinicohistologic characteristics as
in women, with the exception that hormonal factors
may not play a major role. The main associated fac-
tors among men appear to be sun-induced aggrava-
tion and a significant family history of the condition.8
A study of melasma in Indian men implicated sun
exposure and cosmetic use including topical mus-
tard oil.17
It is helpful, before treatment, to perform an
examination using Wood’s lamp; this will identify
the depth of the melanin pigmentation, thus, helping
to delineate the type of melasma.18 Generally, me-
lasma is classified into one of 3 histologic types: epi-
dermal, dermal, and mixed.13 However, some also
include a fourth type known as Wood’s light inap-
parent.4 UnderWood’s light the epidermal type often
shows a darkening of color when examined, as the
light emitted by Wood’s lamp is absorbed by the
excess melanin. The dermal type, however, will not
show this accentuation.1,4 The mixed type involves a
deposition of melanin in both the epidermis and the
dermis and color enhancement with Wood’s light is
seen is some places of the skin, but not others.4
It is interesting to note that when histologically
assessing 56 patients, Kang et al13 did not find any
cases of entirely dermal-based melasma. Further-
more, Sanchez et al4 describe dermal type me-
lasma as having melanin-laden macrophages in the
perivascular array, both in the papillary and retic-
ular dermis. Epidermal hyperpigmentation in the
dermal type was found to be similar to the epider-
mal type, but not as prominent.4 It has, thus, been
suggested that there may be no truly pure dermal
type of melasma.13
There are 3 clinical patterns recognized on the
VOLUME 55, NUMBER 6
basis of clinical examination. These include a
centrofacial, malar, and mandibular pattern. The
centrofacial is the most common pattern of melasma
and involves the cheeks, forehead, upper lip, nose,
and chin. The malar pattern has lesions limited to the
cheeks and nose, and the mandibular pattern has
lesions that occur over the ramus of the mandible.4
Other sites (eg, forearm and neck) may also be
involved in any of these patterns.7
METHODS
MEDLINE (1966-2005) was searched using the key
words melasma, chloasma, hyperpigmentation, and
hypermelanosis. This article outlines published ran-
domized controlled trials (RCTs) of the interventions
that have been studied for use in the treatment
melasma.When RCTs were not present, nonrandom-
ized or open clinical trials were reviewed.
General management
Because of its refractory and recurrent nature,
melasma is often difficult to treat. The goals of
treatment often include prevention or reduction in
the severity of recurrence, reduction of the affected
area, improvement in the cosmetic defect, and re-
duced time to clearance, all with the fewest possible
side effects.19 The principles of therapy include pro-
tection from UV light, inhibition of melanocyte
activity and melanin synthesis, and the disruption
and removal of melanin granules.20
General management recommendations that
assist in the clearing of melasma include discontinu-
ation of birth control pills, scented cosmetic products,
and phototoxic drugs, coupled with UV protection
with use of broad-spectrum (UVA 1 UVB) sun-
screens.20 Solar exposure exacerbates melasma, and
its avoidance is fundamental for the successful man-
agement of the disease.21 Most patients using bleach-
ing agents can expect a recurrence of the disease on
exposure to sunlight and artificial UVA and UVB
light.21 This supports the importance of the use of
broad-spectrum sunscreens (SPF[ 30) in melasma
therapies. Broad-spectrum sunscreens must be ap-
plied daily throughout the year and continued indef-
initely to minimize the reactivation of melanocytes
by incidental exposure to the sun.21
Although sunscreens are a vitally important com-
ponent of therapy, other forms of treatment are
nonetheless necessary.22 Topical treatments include
the application of creams such as hydroquinone
(HQ). Although some negative reactions have been
described, HQ remains one of the most prescribed
agents for melasma and is considered the gold
standard of therapy, especially for epidermal me-
lasma. The epidermal type generally has a good
Gupta et al 1049
response to topical therapy, whereas skin with
mainly dermal deposition of melanin responds
poorly.4 Alternative therapies such as chemical peel-
ing agents or laser therapy are sometimes also used.
Table I outlines the various treatments for melasma
and their proposed mechanism of action. Table II
outlines efficacy studies for the most common forms
of topical treatment, whereas Table III focuses on the
efficacy studies for chemical peeling agents.
Hydroquinone
Mechanism of action. HQ (1,4-dihydroxyben-
zene) is a hydroxyphenol, which, in the presence of
catalytic amounts of dopa, will compete with tyro-
sine, the natural substrate of tyrosinase. This process
prevents the enzymatic oxidation of tyrosine to
dopa, thus, preventing the synthesis of melanin.
This is consistent with the selective mode of action
toward cells with active tyrosinase activity.23
Efficacy. Amer and Metwalli24 assessed the effi-
cacy of HQ 4% cream used in conjunction with
broad-spectrum sunscreen in patients with various
pigmentary disorders. Of the 70 patients entered into
the study, 50 had melasma, 10 freckles, and 10
postinflammatory hyperpigmentation (PIH). The
pigment intensity relative to nonaffected areas of
skin was determined on a 4-point scale with 1 being
no difference, 2 mild pigmentation, 3 moderate pig-
mentation, and 4 severe pigmentation. From week
0 to 12 (treatment end) the number of patients with
melasma and moderate pigmentation decreased
from 28 (56%) to 1 (2.1%), and patients with severe
pigmentation decreased from 22 (44%) to 4 (8.4%).
In addition, the number of patients with melasma
with no difference between affected and nonaffected
areas increased from none at week 0 to 41 patients
(85.4%) at week 12. The study deemed that there was
Table I. The mechanisms by which various
treatments for melasma achieve their
depigmenting effect
Mechanism of action Therapy
Tyrosinase inhibitor Hydroquinone
Tretinoin*
Azelaic acid
Kojic acid
Nonselective suppression
of melanogenesis
Corticosteroids
Inhibition of ROS Azelaic acid
Removal of melanin Chemical peels
Thermal damage Laser treatments
ROS, Reactive oxygen species.
*Tretinoin may also disperse keratinocyte pigment granules and
accelerate epidermal turnover.31
1050 Gupta et al
a good to excellent response achieved in 89.5% of
patients with melasma and that treatment with HQ is
beneficial in patients with hyperpigmentary disor-
ders.24 However, these results should be considered
with caution, as this study is not randomized or
placebo controlled. Furthermore, the study seems to
lack a detailed description of the methods under-
taken and there appears to have been no statistical
analysis of the results.
Haddad et al25 in a double-blind, randomized,
placebo-controlled study of 30 patients with me-
lasma, assessed the efficacy of a skin-whitening
complex (SWC) 5% cream versus HQ 4% cream.
Patients were randomized into two groups; group
1 received HQ 4% and placebo, and group 2 received
SWC and placebo, each to be applied to opposite
sides of the face. Efficacy was measured based on
two independent investigator evaluations and a
patient questionnaire. Of the 30 patients enrolled,
25 completed the study. Group 1 (HQ vs placebo)
showed an improvement of 76.9% and group 2 (SWC
vs placebo) showed an improvement of 66.7%. This
difference was not statistically significant (Fisher’s
test, P = .673). Patient satisfaction levels were 66.7%
for group 1 and 69.2% for group 2. Despite being
a RCT, this study opts to evaluate the compounds
involved through amore qualitative approach, rather
than using measures of pigment intensity or Melasma
Area and Severity Index (MASI) scores. Furthermore,
the study fails to provide a description of what
comprises SWC. Nonetheless, with a 76.9% improve-
ment rate in those treated with HQ, this study does
support earlier evidence that HQ is effective in
treating hyperpigmentation.
Interestingly, while testing glycolic acid (GA)
peels for melasma, Hurley et al26 discovered that
4% HQ monotherapy with daily application of sun-
screen not only improves melasma, but is as effective
as their proposed peeling regimen plus HQ. In this
randomized, investigator-blind, split-face prospec-
tive trial, 21 Hispanic women (18 of whom com-
pleted the study) were treated with 4% HQ and 4 GA
peels (20% concentration on first two visits then 30%
at next two) on one side and 4% HQ only on the
other. Both sides had a statistically significant treat-
ment effect (P\ .001). However, between the two
groups, there was no significant difference in either
the degree of pigmentation lightening or in the MASI
scores from baseline to treatment end. HQ 4% cream
as a monotherapy was concluded to be an adequate
agent for treating melasma.26
The available concentrations of HQ vary from
1.5% to 4% (Table IV). Concentrations of 2% or less
are available in the United States in over-the-counter
preparations and those with concentrations greater
J AM ACAD DERMATOL
DECEMBER 2006
that 2% are available only by prescription. In the
J AM ACAD DERMATOL Gupta et al 1051
Table II. Studies involving commonly used topical agents for the management of melasma
No. of patients
Treatment Study Design E C R1 R2 Duration Results
Sunscreen Vazquez
et al
(1983)22
R, DB 59 53 Sunscreen 1 Placebo 1 3 mo R1: 96.3% showed
improvement.HQ HQ
R2: 80.8% showed
improvement.
No significant
difference
between R1 and R2.
HQ Amer
et al
(1998)24
O 50* 48* HQ 4% 12 wk Good to excellent
response in 89.5% of
those with melasma.
Haddad
et al
(2003)25
R, DB,
SF
30 25 HQ 4% vs
placebo
SWC 5% vs
placebo
3 mo R1: improvement of
76.9% on HQ side.R1 = 15 R1 = 12
R2: improvement
of 66.7% on
SWC side.
R2 = 15 R2 = 13
Tretinoin Griffiths
et al
(1993)32
R, DB 50 38 Tretinoin 0.1% Vehicle 40 wk R1: 68% improved;
significant over
baseline (P = .0003).
R1 = 26 R1 = 19
R2: 5% improved.
R2 = 24 R2 = 19
Epidermal pigment
reduced by 36% in
R1, but increased by
50% in R2 (P = .002).
Kimbrough-
Green et al
(1994)33
R, DB 30 28 Tretinoin 0.1% Vehicle 40 wk R1: 73% improved.
R1 = 15 R1 = 15 R2: 46% improved;
15% worsened.R2 = 15 R2 = 13
R1 marginally
significant better
than R2
(P = .07).
Steroid Neering
(1975)38
R, O 17 16 Betameth-
asone
17-valerate
0.2%
3 mo Depigmentation in 12
patients, attributed
to betamethasone
(P\ .05).
25% Showed no
depigmentation.
Combination Gano et al
(1979)15
O 20 Tretinoin 0.05% 1
betamethasone
valerate 0.1% 1
10 wk 65% Showed
improvement.
35% Showed no
improvement.HQ 2%
Taylor
et al
(2003)40
R, SB 641 HQ 4%
Tretinoin 0.05% 1
FA 0.01%
HQ 4% 1
tretinoin
0.05% or
tretinoin
0.05% 1 FA
0.01% or
HQ 4% 1 FA
0.01%
8 wk Significantly more
patients (28.6%)
in R1 cleared
completely
(P\ .001).
Significantly more
patients (77%) R1
experienced
complete/near-
complete clearing
(P\ .001).
AzA Lowe et al
(1998)46
R, DB,
PG
52 45 AzA 20% Vehicle 24 wk R1: treatment response
in 55% of patients.R1 = 25 R1 = 21
R2: treatment response
in 12.5%.
R2 = 27 R2 = 24
Continued
VOLUME 55, NUMBER 6
1052 Gupta et al
treatment of melasma, it is recommended that
the HQ preparations be applied uniformly and twice
daily to the affected area. It has been recommended
that if no improvement is evident after an initial
discontinued27; however, in some cases it can take
as long as 6 months for a change to appear.
Safety and tolerability. The most frequently
observed reactions are mild skin irritation and sen-
Verallo-
Rowell
et al
(1989)29
R, DB 155 132 AzA 20% HQ 2% 24 wk R1: 56.9% achieved
good overall
improvement; 16.9%
excellent; 23% fair.
R1 = 77 R1 = 65
R2: 17.9% good;
1.5% excellent;
50.8% fair; 29.8%
treatment failures.
R2 = 78 R2 = 67
R1 differed
significantly from
R2 (P\ .001).
Balina
et al
(1991)47
R, DB 329 243 AzA 20% HQ 4% 24 wk R1: 64.8% good/
excellent overall
result; 7.4%
treatment failures.
R1 = 164 R1 = 122
R2: 72.5% good/
excellent; 8.3%
failures.
R2 = 165 R2 = 121
No significant
difference between
R1 and R2.
Kakita
et al
(1998)48
R, DB,
PG
65 59 AzA 20% 1 HQ 4% 24 wk R1 and R2
produced
equivalent overall
improvement
scores; no
significant
difference.
R1 = 31 R1 = 29 GA 15%-20% GA vehicle
R2 = 34 R2 = 30
KA Garcia
et al
(1996)50
R, O,
SF
39 39 KA 1 HQ 1 3 mo 51% Had equal
reduction with
both regimens.
GA GA
28% Had more
reduction with R1.
21% Had more
reduction with R2.
R1 and R2 not
significantly
different (P[ .05).
Lim (1999)49 R, DB,
R/L
43 40 KA 2% 1 HQ 2% 1 12 wk R1: more than half
clearance in 60%
of cases.
HQ 2% 1 GA 10%
R2: more than
half clearance
in 47.5% of cases.
GA 10%
Improvement not
statistically
different (P = .9).
AzA, Azelaic acid; C, completed; DB, double-blind; E, enrolled; FA, flucinolone acetonide; GA, glycolic acid; HQ, hydroquinone; KA, kojic acid;
O, open; PG, parallel group; R, randomized; R1, regimen 1; R2, regimen 2; R/L, right/left comparison; SB, single-blind; SF, split-face; SWC, skin-
whitening complex.
*The study enrolled 70 patients with various pigmentary disorders, only 50 possessed melasma.
Table II. Cont’d
No. of patients
Treatment Study Design E C
2 months of use, then the drug should be
R1 R2 Duration Results
J AM ACAD DERMATOL
DECEMBER 2006
sitization, characterized by itching, burning, stinging,
et al SF showed significant1 GA peel 30% 1
and allergic dermatitis, and have been reported to
occur more frequently with 4% than 2% concentra-
tions. Chronic use of high concentrations of HQ
($5%) have been reported to produce ochronosis
and colloid milium.27
In the study by Amer and Metwalli,24 local irrita-
tion was noted in most patients, but exogenous
ochronosis was not observed. The randomized,
controlled study by Haddad et al25 reported that
the incidence of side effects was greater among the
HQ group than the SWC group, where 25% of the
HQ group reported an itchy eruption. This was not
statistically significant from the SWC group, which
had no reports of side effects.
Bentley-Phillips and Bayles28 conducted a 6-year
investigation designed to assess the safety of HQ in
an optimal concentration. Through the use of open
and closed patch testing of 840 volunteers (resulting
in 7000 test areas) they determined that HQ is a
suitable for use in cosmetics, provided that the
content is kept below a certain limit. HQ 3% concen-
tration was determined to be the optimal strength.
Interestingly, their impr