303 Indian J Dermatol 2009; 54(4)

Pathophysiology of Melasma
The pathophysiology of melasma remains elusive, but
multiple factors have been implicated. The role of female
hormonal activity has been suggested by the increased
frequency of occurrence of melasma in pregnancy and in those
on oral contraceptive pills, estrogen replacement therapy,
and estrogen treatment for prostatic cancer. The mechanism
of induction of melasma by estrogen may be related to
the presence of estrogen receptors on the melanocytes that
stimulate the cells to produce more melanin. Genetic factors
are indicated by familial occurrence of melasma and its
increased incidence in people of Asian and Hispanic origins.
Other factors implicated in the etiopathogenesis of melasma
are photosensitizing and anticonvulsant medications, mild
ovarian or thyroid dysfunction, and certain cosmetics. One
of the most important factors in the development of melasma
is ultraviolet exposure from sunlight or other sources.
Exacerbation of melasma is universally seen after prolonged
sunexposure but the pigmentation fades after periods of
avoidance of sunexposure. Whatever the mechanisms,
melasma results in an increased deposition of melanin in
the epidermis, in the dermis within melanophages, or both.
The number of melanocytes in the lesions has been variably
reported to be normal
[3]
or increased.
[4]
The melanosomes
within the melanocytes and keratinocytes have been reported
to be increased in size.
[3,4]

Types of Melasma
The lesions range in color from light brown to dark
brownish-black and affect the regions of the face in
Introduction
Melasma (from the Greek word, melas meaning black)
is a common, acquired, circumscribed hypermelanosis of
sun- exposed skin. It presents as symmetric, hyperpigmented
macules having irregular, serrated, and geographic borders.
The most common locations are the cheeks, upper lips, the
chin, and the forehead, but other sun-exposed areas may
also occasionally be involved. The term, chloasma (from
the Greek word, chloazein meaning to be green) is often
used to describe melasma developing during pregnancy;
however, as the pigmentation never appears to be green,
the term, melasma should be preferred.
Although melasma may affect any race, it is much more
common in constitutionally darker skin types (skin types IV
to VI) than in lighter skin types, and it may be more
common in light brown skins, especially in people of East
Asian, Southeast Asian, and Hispanic origin who live in
areas of the world with intense solar ultraviolet exposure.
Melasma is the most common pigmentary disorder among
Indians.
[1].
It is much more common in women during their
reproductive years but about 10% of the cases do occur in
men. The clinical and histological features of melasma
in men are the same as those of melasma in women.
[2]
Review Article
TOPICAL TREATMENT OF MELASMA
Debabrata Bandyopadhyay
Abstract
Melasma is a common hypermelanotic disorder affecting the face that is associated with considerable psychological
impacts. The management of melasma is challenging and requires a long-term treatment plan. In addition to avoidance
of aggravating factors like oral pills and ultraviolet exposure, topical therapy has remained the mainstay of treatment.
Multiple options for topical treatment are available, of which hydroquinone (HQ) is the most commonly prescribed agent.
Besides HQ, other topical agents for which varying degrees of evidence for clinical efcacy exist include azelaic acid,
kojic acid, retinoids, topical steroids, glycolic acid, mequinol, and arbutin. Topical medications modify various stages of
melanogenesis, the most common mode of action being inhibition of the enzyme, tyrosinase. Combination therapy is the
preferred mode of treatment for the synergism and reduction of untoward effects. The most popular combination consists
of HQ, a topical steroid, and retinoic acid. Prolonged HQ usage may lead to untoward effects like depigmentation and
exogenous ochronosis. The search for safer alternatives has given rise to the development of many newer agents, several
of them from natural sources. Well-designed controlled clinical trials are needed to clarify their role in the routine
management of melasma.
Key Words: Melasma, newer agents, topical treatment
Indian J Dermatol 2009:54(4):303-9 DOI: 10.4103/0019-5154.57602
From the Department of Dermatology, Venereology, and
Leprosy, R. G. Kar Medical College, Kolkata, India. Address
for correspondence: Dr. Debabrata Bandyopadhyay, Department
of Dermatology, Venereology, and Leprosy, R. G. Kar Medical
College, 1, Khudiram Bose Sarani, Kolkata - 700 004, India.
E-mail: dr_dban@yahoo.com
304 Indian J Dermatol 2009; 54(4)
Bandyopadhyay: Topical treatment of melasma
different patterns. Three clinical patterns of distribution of
the pigmentation may be recognized: Centrofacial, malar,
and mandibular.
[5]
The centrofacial pattern is the most common and involves
the cheeks, nose, forehead, upper lip, and chin. The malar
pattern involves the cheeks and nose. The ramus of the
mandible is involved in the mandibular pattern. Melasma
does not involve the mucous membrane.
With the help of Woods lamp examination, melasma
may be classied into four histological types according
to the depth of pigment deposition
[6]
. The epidermal type
is the most common in which the pigmentation appears
more intense under Woods lamp examination. Melanin
is distributed throughout the epidermis; topical treatment
may work best in this type of melasma. In the dermal
type, the pigmentation is not intensied with Woods light.
The pigmentation is due to plenty of melanophages in the
dermis. In the mixed type, Woods light intensies
pigmentation in some areas while other areas remain
unchanged. The pigmentation is due to increased epidermal
melanin as well as dermal melanophages. Woods lamp
examination is of no benet in very dark individuals, and
this type is classied as indeterminate. This classication
may partly work in lighter skin types but not in brown
or black skin types.
[7]
Moreover, there may not be
good correlation between the ndings of Woods lamp
examination and histological depth of pigmentation.
[7]

Depending on the natural history of the lesions, melasma
may also be classied into transient and persistent types.
[7]

The transient type disappears within one year of cessation
of hormonal stimuli like pregnancy or oral contraceptive
pills. The persistent type continues to be present more
than one year after the hormonal stimulus is removed
and is caused by the action of UV rays and other factors,
highlighting the role of sun-avoidance in the management
of melasma.
Topical Treatment
By causing cosmetic disgurement of the face, melasma
is frequently associated with a signicant emotional
effect. There is no universally effective specic therapy
for the diseaseexisting agents have varying degrees
of effectiveness, and the condition, more often than not,
relapses.
[8]
Most cases are treated with topical agents, used
alone, or in combinations. Other modalities of treatment
utilized in the management of this hypermelanotic disorder
are chemical peels and physical therapies in the form of
various lasers or intense pulse light sources. All patients
with melasma should be counseled about the natural
course of the disease and the necessity for adherence to a
long- term treatment plan. Careful history about the possible
precipitating or aggravating factors must be taken with
special attention to the intake of oral contraceptives or
other hormonal preparations, phototoxic and anti-seizure
medications, and the usage of cosmetics. Discontinuation
of oral pills and avoidance of scented cosmetics is advised.
Recurrence of melasma occurs on exposure to sunlight
and other sources of ultraviolet rays. Photoprotective
measures like the avoidance of direct sun-exposure and
the regular use of a broad-spectrum sunscreen are always
advised, although clinical studies on their role are lacking.
Treatment with demelanizing agents must be continued for
several months before signicant clinical benets become
noticeable. Topical agents are much more effective in the
epidermal type of melasma.
[9]

Hydroquinone
Hydroquinone (HQ), also known as dihydroxybenzene, is
a hydroxyphenolic compound that is structurally similar to
precursors of melanin. It inhibits the conversion of DOPA to
melanin by inhibition of the enzyme, tyrosinase. HQ affects
not only the formation, melanization, and degradation of
melanosomes, but it also affects the membranous structures
of melanocytes and eventually causes necrosis of whole
melanocytes.
[10]
HQ is an oxidizing agent that can oxidize
in tubes or bottles, turning the color of formulations from
white to brown. Products that have undergone this color
change are ineffective and should be discarded.
[11]

HQ is the most frequently prescribed depigmenting agent
worldwide and it has remained the gold standard for the
treatment of melasma, particularly of the epidermal type.
HQ preparations are commonly used in the treatment of
melasma at concentrations varying from 2 to 5% applied
once daily. Variably good yet reversible results are obtained
in most of the patients treated with HQ. The depigmenting
effects of the HQ treatment become evident after 5-7 weeks.
Treatment should be continued for at least three months, up
to one year.
[9]
HQ is also formulated in combination with
other agents like sunscreens, topical steroids, retinoids, and
glycolic acids for added benets.
Adverse reactions of HQ are related to its dose and the
duration of treatment. Irritation is the most common
complication; other adverse effects include erythema,
stinging, colloid milium, irritant and allergic contact
dermatitis, nail discoloration, transient hypochromia,
and paradoxical postinammatory hypermelanosis.
[9,12]

The so-called confetti-like depigmentation or guttate
hypomelanosis is characterized by mottled depigmented
spots that develop on the macules of melasma. This
is observed in association with the use of HQ at
concentrations higher than 2%. Exogenous ochronosis
[13,14]

a blue-black pigmentation of the treated areas, has been
mainly reported in darker skin from prolonged use of a
strong concentration, but has also been reported in whites
after short- or long-term use of 2% HQ preparations.
[15]

The etiology of hydroquinone-induced hyperpigmentation
in exogenous ochronosis remains speculative; improvement
occurs very slowly after avoidance of the offending
agent.
[16]
The monobenzy lether of HQ should never be used
305 Indian J Dermatol 2009; 54(4)
Bandyopadhyay: Topical treatment of melasma
in the treatment of melasma as it can produce a permanent
loss of melanocytes, causing a disguring confetti-like
leukoderma.
Regulatory agencies in Japan, Europe, and most recently
the USA, have raised questions about the safety of HQ
[17]

and it has been banned in cosmetic preparations in many
countries. This has encouraged research into alternative
agents for the topical management of melasma.
Azelaic acid
Azelaic acid is a naturally occurring, nonphenolic, saturated,
nine-carbon dicarboxylic acid that competitively inhibits
tyrosinase. Azelaic acid was initially developed as a topical
anti-acne agent but because of its effect on tyrosinase, it
has also been used to treat hyperpigmentary disorders like
melasma. Its mechanisms of action include the inhibition
of DNA synthesis and mitochondrial enzymes, thereby
inducing direct cytotoxic effects toward the melanocyte.
[18]

Topical azelaic acid has no depigmentation effect on
normally pigmented skin; this specicity may be attributed
to its selective effects on abnormal melanocytes.
[19]
It can be
used for postinammatory hyperpigmentation in acne. Free
radicals are believed to contribute to hyperpigmentation,
and azelaic acid acts by reducing free radical production.
[20]

A double-blind randomized study has shown that a
20% concentration of azelaic acid was equivalent to 4%
hydroquinone in the treatment of melasma, but without its
side effects.
[21]
Another controlled study has found azelaic
acid to be superior to 2% hydroquinone.
[22]
A combination
of azelaic acid with 0.05% tretinoin or 15-20% glycolic
acid may produce earlier, more pronounced skin lightening.
Adverse effects of azelaic acid include pruritus, mild
erythema, and burning.
[23]

Kojic acid
Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyrone) is a
naturally occurring, hydrophilic fungal product derived
from certain species of Acetobacter, Aspergillus, and
Penicillium.
[19]
It acts by inhibiting the production of free
tyrosinase; it is also a potent antioxidant.
[24]
It is generally
univalent to other therapies but may be more irritating.
Kojic (KA) acid is used at concentrations ranging from 1 to
4%. In one double-blind study, KA 2% combined with HQ
2% was shown to be superior to glycolic acid (GA) 10%
and HQ 2%
[25]
Another double-blind study compared GA
5% with either HQ 4% or KA 4% for three months. Both
combinations proved equally effective with a reduction of
pigmentation in 52% of the patients.
[26]
KA may be effective
if a patient has difculty tolerating other rst-line therapies.
It may cause contact dermatitis and erythema.
[27]
Retinoids
Retinoids, such as tretinoin, were rst used in combination
with HQ as penetration enhancers, but were later recognized
to have their own effect on melanogenesis.
[28]
Retinoids
affect multiple steps in the melanization pathway. Tretinoin
promotes the rapid loss of pigment through epidermopoiesis
and increased epidermal turnover decreases the contact time
between keratinocytes and melanocytes.
[8]
Retinoic acid
(RA) suppresses UVB-induced pigmentation by reducing
tyrosinase activity. The acid acts at a posttranscriptional
level on tyrosinase and tyrosinase-related protein.
[12]

Compared with phenolic compounds like HQ, RA takes a
much longer time to act; clinically signicant lightening
becomes.evident after 24 weeks.
Tretinoin monotherapy has produced a good therapeutic
response in clinical trials
[29,30]
but better results are
obtained in combination with other agents like HQ and
corticosteroids. The most common side effects include
erythema, burning, stinging, dryness, and scaling. The
inammation may cause hyperpigmentation, particularly in
people with dark skin.
[28]
Patients must be advised to use
sunscreens during treatment with retinoic acid. Adapalene,
a naphthoic acid derivative with retinoid activity, was
found to be equally efcacious in a randomized trial in
Indian patients but with signicantly less untoward effects
than tretinoin.
[31]

Topical steroids
Reversible hypopigmentation of normal skin is a well-
known untoward effect of prolonged potent steroid
application. The mechanism of the skin-lightening effect
of topical corticosteroids is ill-understood. Melanocytes
respond to a wide variety of chemical mediators. The
inhibitory effects of corticosteroids on the synthesis of
mediators like prostaglandin and leukotriene may partly
explain their effects on melanogenesis.
[28]
Potent or
superpotent steroids, when used alone, have been associated
with good therapeutic responses,
[32,33]
but monotherapy is
not recommended due to their frequent untoward effects.
Topical steroids are used in combination products for their
synergistic effects and for the reduction of irritation from
other products like tretinoin. Various combinations with
HQ and retinoic acid have given good cosmetic results in
clinical trials.
[34]
Adverse effects of topical steroids include
irritation, rosacea-like dermatosis, atrophy, telangiectasia,
and hypertrichosis.
Glycolic acid
Glycolic acid is an alpha-hydroxy acid that is usually
combined with other agents at a concentration of 5-10%
for its skin-lightening property. The mechanism of
its effect might be due to epidermal remodeling and
accelerated desquamation, which would result in quick
pigment dispersion on pigmentary lesions. It also directly
reduces melanin formation in melanocytes by tyrosinase
inhibition.
[35]

A randomized controlled trial has demonstrated that a
formulation containing 10% glycolic acid and 4% HQ
had good clinical efcacy in treating melasma in a group
306 Indian J Dermatol 2009; 54(4)
Bandyopadhyay: Topical treatment of melasma
of Hispanic patients. Irritation was a common side effect
which resolved with the temporary cessation of application
and application of moisturizers.
[36]

Mequinol
Mequinol (4-hydroxyanisole, hydroquinone monomethyl
ether) is a derivative of HQ. Its mechanism of action is
unclear; however, being a substrate of tyrosinase, it may
act as a competitive inhibitor of the formation of melanin
precursors
[11]
. It is currently marketed in the USA at a
concentration of 2% in combination with 0.01% tretinoin
as a penetration enhancer. In a randomized, parallel-group,
double-masked study involving 216 subjects, a mequinol
2%/ tretinoin 0.01% solution was found to be highly
effective and well-tolerated treatment for solar lentigines
and related hyperpigmented lesions, being superior to HQ
3% for lesions on the forearm and of similar efcacy for
lesions on the face.
[37]
The results of a trial with a case
series of male patients with melasma has shown that
four out of ve patients achieved complete clearance at
12 weeks, and one patient showed moderate improvement.
Side effects were minimal and consisted of stinging in one
patient. All patients maintained results at the 16-weeks
follow-up visit.
[38]

An open-label study was conducted to determine the rate
of adverse events of topical mequinol/tretinoin, twice
daily application for up to 24 weeks with concomitant
sunscreen in the treatment of solar lentigines and related
hyperpigmented lesions. The untoward effects of this
topical combination were in the form of erythema, burning/
stinging/tingling, desquamation, pruritus, skin irritation,
halo hypopigmentation, and hypopigmentation. The authors
concluded that when used with sunscreen of SPF 25 or
greater, the combination was safe and well tolerated and did
not produce any unexpected or unusual adverse events.
[39]

Controlled clinical trials with large numbers of patients are
needed to clarify the role of this promising new agent in
the routine management of melasma.
Arbutin
Arbutin, the beta-D-glucopyranoside derivative of
hydroquinone, is a naturally occurring plant product
which has been used successfully in the treatment of
hyperpigmentary disorders. The glycosidic bond is
hydrolyzed in vivo leading to the controlled release of
hydroquinone.
[12]
Arbutin acts by the inhibition of tyrosinase,
thereby decreasing melanin formation. The normal skin
microora may also hydrolyze arbutin; the hydrolyzed
hydroquinone shows more potent free-radical scavenging
activity and tyrosinase inhibition than arbutin.
[40]
The action of arbutin is dose-dependent and less toxic
than hydroquinone. Deoxyarbutin is a recently developed
derivative of arbutin that has been produced by removing
the hydroxyl groups from the molecule. This produces
reversible skin-lightening by direct inhibition of
tyrosinase.
[41]
Although good controlled clinical trials are
lacking, initial in vitro and in vivo experimental studies
have demonstrated that it could be a safe and effective
treatment for hypermelanotic disorders.
[42,43]

Other New and Experimental Agents
A number of agents, both synthetic and those derived from
natural sources like plants, have been investigated for their
potential role in reducing melanin pigmentation. Although
experimental evidence suggests their possible benets,
dependable controlled clinical trials are mostly lacking.
Some of the compounds are formulated in combination
products and marketed by pharmaceutical companies;
many are available as ingredients of over-the-counter
preparations.
N-acetyl-4-S-cysteaminylphenol
NCAP is a phenolic agent which acts as an alternative
substrate for tyrosinase, thus inhibiting the enzymes activity.
It has been reported to be more stable and causes less
irritation than hydroquinone. In a study of 12 patients with
melasma, using 4% NCAP, 66% of patients showed marked
improvement and 8% showed a complete resolution of
melasma lesions. With daily topical application, clinical
changes were evident after 2-4 weeks.
[44]

Alpha-tocopheryl Ferulate
The compound of alpha-tocopherol and ferulic acid, also an
antioxidant connected with an ester bond, alpha-tocopheryl
ferulate (alpha-TF), can absorb ultraviolet (UV) radiation and
thus maintain tocopherol in a stable state. In experimental
studies, this agent was found to have signicant effect in the
retardation of melanogenesis, possibly by inhibiting tyrosine
hydroxylase activity in an indirect manner.
[45,46]

Ascorbic acid
Ascorbic acid has antioxidant properties and affects
melanogenesis by reducing dopaquinone to DOPA and
preventing free-radical production and absorption of
ultraviolet radiation.
[12]
Comparing the efcacy of 5%
ascorbic acid and 4% hydroquinone in 16 patients with
melasma in a double-blind clinical trial, the authors
concluded that although hydroquinone showed a better
response, ascorbic acid may play a role in the therapy
of melasma as it is almost devoid of side effects and it
could be used alone or in combination therapy.
[47]
In an
open-label trial, 25% L-ascorbic acid formulated with
a penetration enhancer, was found to have a signicant
effect in the treatment of melasma.
[48]
Ascorbic acid,
however, is highly unstable in aqueous solution and stable
esters like magnesium ascorbyl-2-phosphate (MAP) have
been synthesized. MAP has a protective effect against
UVB radiation
[49]
and it inhibits melanogenesis in vitro
and in vivo. Experiments demonstrated that MAP cream
was absorbed into the epidermis and that 1.6% remained
307 Indian J Dermatol 2009; 54(4)
Bandyopadhyay: Topical treatment of melasma
48 hours after application. The lightening effect was
signicant in 19 of 34 patients with melasma or senile
freckles and in 3 of 25 patients with normal skin.
[50]

Niacinamide
Niacinamide (nicotinamide), the biologically active amide
form of niacin (vitamin B
3
), can reduce pigmentation
by reversibly preventing the transfer of melanosomes
from melanocytes to the keratinocytes.
[51]
It has no effect
on tyrosinase activity. In clinical studies, niacinamide
signicantly decreased hyperpigmentation and increased
skin lightness compared with vehicle alone after four
weeks of use.
[52]
Liquorice derivatives
Liquorice is the root of the perennial herb Glycyrrhiza
glabra. Glabridin is an oil-soluble derivative of liquorice
extract. Glabridin has been shown to have tyrosinase
inhibitory as well as anti-inammatory properties in
experimental studies.
[53]
A clinical trial with Liquiritin,
another liquorice derivative, has also shown benet in
treating melasma.
[54]

Flavonoids
[12]
Flavonoids are naturally occurring polyphenolic compounds
that have well-known anti-inammatory, antioxidant,
antiviral, and anticarcinogenic properties. Many
plant- derived avonoid compounds have hypopigmentary
effects and their roles are still under investigation. These
include catechin conjugated with gallic acid (from green
tea leaves), ellagic acid (from green tea, strawberry,
eucalyptus etc), and aloesin (from aloe tree).
Other agents known to affect melanin pigmentation and
sometimes used in formulations are N-acetyl glucosamine,
thiotic acid (alpha-lipoic acid), gentisic acid, soybean
extract, and paper mulberry extract.
Combination Treatment
Melanogenesis is a complex, multi-stage process in
which precursor molecules are acted upon by the enzyme
tyrosinase to produce the complex biopolymer named
melanin in specic organelles called melanosomes.
Melanized melanosomes are then transferred from
melanocytes to the keratinocytes, eventually producing the
visually apparent skin color. Various topical agents act on
different stages of this process, thus providing a rationale
for combinations of agents for better therapeutic effect. In
addition to having a synergistic effect, a particular drug
may abrogate untoward effects of another drug formulated
in the same vehicle. For example, topical steroids may
reduce the irritant effects of HQ or retinoids. On the other
hand, retinoids may prevent steroid-induced cutaneous
atrophy. Combinations of hypomelanotic agents with
sunscreens are also available in the market.
Various combinations of different topical agents have
been studied and many are marketed by pharmaceutical
companies. Hydroquinone is generally the main
component of formulations. It is combined with drugs
like glycolic acid, azelaic acid, kojic acid, retinoic acid, or
corticosteroids. In addition, arbitrary mixtures of various
other demelanizing agents are marketed although efcacy
and safety have not been established by controlled clinical
trials for most of them.
However, the most extensively studied and widely
used combination is the so-called triple combination,
a formulation containing HQ, retinoic acid, and
corticosteroids. First proposed by Kligman and Willis,
[55]

the original combination utilized 5% HQ, 0.1% tretinoin,
and 0.1% dexamethasone and was found to be effective in
the treatment of melasma, ephelides, and postinammatory
hyperpigmentation. Concerned about the irritant potential
of this combination for its high tretinoin concentration,
modications of the theme have been tried (HQ 4%,
tretinoin 0.05%, and uocinolone acetonide 0.01%) and
have been found to be highly effective in long-term clinical
studies.
[34]
It has been suggested that rst-line therapy
for melasma should consist of effective topical therapies,
mainly in the form of triple combinations, and only when
triple combinations are unavailable or when patients have
hypersensitivity to them, should dual ingredients or single
agents be considered.
[34]
Treatment During Pregnancy
[23]
Melasma is more resistant to treatment during pregnancy
because of the persistent hormonal trigger for development
of the disease. For this reason, treatment for melasma is
routinely deferred until after delivery. Moreover, treatment
may be unnecessary because melasma in pregnancy may
be a transient affair; removal of the hormonal trigger after
parturition may result in signicant improvement.
Conclusion
Management of melasma can be challenging and requires
long-term treatment with topical agents. The results are
often unsatisfactory and topical agents may sometimes
cause signicant adverse reactions. Hydroquinone has
remained the gold standard of topical treatment but concerns
regarding its side effects remain. A triple combination
of hydroquinone, retinoic acid, and corticosteroids has
been suggested to be the rst-line topical treatment for
this pigmentary disorder. Many new agents that inhibit
melanogenesis have been developed. Although in vivo and
in vitro experimental studies have suggested their potential
role in the management of melasma, controlled clinical
trials are mostly lacking and are urgently needed in the
future.
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Received: April, 2009. Accepted: April, 2009.
Source of support: Nil, Conict of Interest: Nil.
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