Melasma

Etiologic and Therapeutic Considerations

Pearl E. Grimes, MD

Background: Melasma is a common acquired symmet-
richypermelanosis characterized by irregular light- to
gray-brown macules and patches involving sun-
exposed areas of skin. Etiologic factors in the pathogen-
esis of melasma include genetic influences, exposure to
UV radiation, pregnancy, hormonal therapies, cosmet-
ics, phototoxic drugs, and antiseizure medications.
Observations: Melasma is often a therapeutically chal-
lenging disease, and current treatments include hypopig-
menting agents, chemical peels, and lasers. Hypopigment-
ing agents include phenolic and nonphenolic derivatives.
Phenolic agents include hydroquinone and hydroqui-
none combination preparations. Despite controversies re-
garding the issue of hydroquinone-induced ochronosis, hy-
droquinone remains the most effective topically applied
bleaching agent approved by the Food and Drug Admin-
istration for the treatment of melasma. Nonphenolic bleach-
ing agents include tretinoin and azelaic acid. Superficial,
medium, and deep chemical peels are more often used in
lighter-complexioned patients. Such peels should be used
with caution in blacks. Although lasers have demon-
strated significant efficacy in the treatment of a variety of
hyperpigmentary disorders, their precise efficacy and place
in the therapy of melasma have yet to be established.
Conclusions: In the hierarchy of therapies for melasma, the
treating physician must consider the devastating psychoso-
cial impact of pigmentary imperfections within the realm
of the benefits and risks associated with each treatment.
(Arch Dermatol. 1995;131:1453-1457)

Melasma
relatively
IS a
common acquired
symmetric hypermela-
nosis characterized by
irregular light- to gray-
brown macules involving sun-exposed ar¬
eas (Figure I ). There is a predilection for
involvement of the cheeks, forehead, up¬
per lip, nose, and chin.1 The disease is most
commonly observed in women; men rep¬
resent only 10% of cases and demonstrate
the same clinicohistologic characteristics as
do women.2 Hormonal factors do not ap¬
pear to hold a causative significance in men.
The disease affects all racial groups but is
most prevalent in darker-complexioned in¬
dividuals (skin types IV through VI), espe¬
cially women of Hispanic descent who live
in areas with intense UV radiation.34 The
true incidence of melasma is unknown.
However, results of a survey conducted by
Haider et al5 of 2000 black patients seek¬
ing dermatologie care in a private practice
in Washington, DC, revealed that the third
most commonly cited skin disorders were
pigmentary problems other than vitíligo. Of
these patients, the majority had a diagno¬
sis of postinflammatory hyperpigmenta-
From the Division of tion, followed in frequency by melasma.
Dermatology, King-Drew Although the precise cause of melasma
Medical Center, is unknown, multiple factors have been im¬
Los Angeles, Calif. plicated in the etiopathogenesis of this con-
dition.4 These include genetic influences, ex¬
posure to UV radiation, pregnancy, oral con¬
traceptives, estrogen-progesterone therapies,
thyroid dysfunction, cosmetics, and photo-
toxic and antiseizure drugs. Of the aforemen¬
tioned factors, Pathak et al3 suggest that ge¬
netic influences and exposure to UV radia¬
tion are the most important. Melasma may
not resolve with parturition or discontinu¬
ance oforal contraceptive use. Perez et al6 per¬
formed extensive endocrinologie evaluations
in nine patients with melasma and found sig¬
nificantly increased levels of leutinizing hor¬
mone and lower levels of serum estradiol, ab¬
normalities suggesting subclinical evidence
of a mild ovarian dysfunction. In addition,
Lufti et al7 studied 108 nonpregnant wom¬
en and found a significant association between
thyroid autoimmunity and melasma, prima¬
rily in women whose condition developed
during pregnancy or after the ingestion of oral
contraceptive drugs. In their study, the fre¬
quency of thyroid disorders was four times
greater in the patients with melasma (n=84)
than in the matched controls (n=25).
Three clinical patterns of hyperpig-
mentation are recognized in patients with
melasma.3,4 These include a centrofacial, a
malar, and a mandibular pattern. Based on
Wood's light examination of the skin, me¬
lasma can be divided into four types. The
epidermal variety is characterized by in-

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 Figure 1. Light-brown patches involving the forehead
creased melanin in the basal, suprabasal, and stratum cor-
neum layers. The pigmentation is intensified by Wood's light
examination. Dermal melasma reveals a preponderance of
melanophages in the superficial dermis and in the deep der¬
mis, which is not enhanced with Wood's light. Epidermal
and dermal pigment alterations are present in the mixed
variety. Indeterminate melasma is described in individu¬
als with skin type VI, in whom Wood's light examination
is of no benefit.
Three histologie patterns of pigmentation have been
described: epidermal, dermal, and mixed. The latter is
characterized by deposition of both dermal and epider¬
mal pigment.
Historically, the treatment of melasma has been chal¬
lenging. Therapies have included the routine use of broad-
spectrum sunscreens and various concentrations of hy-
droquinone with or without the addition of tretinoin,
salicylic acid, or glycolic acid. In addition, azelaic acid;
a-hydroxy acid preparations, including glycolic acid; reti-
noic acid (tretinoin); chemical peels; and laser thera¬
pies are used (Table). Cosmetics (such as Dermablend,
by Flori Roberts) also assume an important role in the
management of this condition as a temporary means of
camouflage. These preparations provide heavy, tempo¬
rary coverage, which is objectionable to some patients.
PHENOLIC HYPOPIGMENTING AGENTS
Hydroquinone
Hydroquinone is a hydroxyphenolic chemical that in¬
hibits the conversion of dopa to melanin by inhibiting
the tyrosinase enzyme." Other proposed mechanisms are
inhibition of DNA and RNA synthesis, degradation of
melanosomes, and destruction of melanocytes. Hydro-
quinone-containing bleaching creams are used exten¬
sively worldwide for pigmentary imperfections charac¬
terized by hyperpigmentation. It is the most commonly
used product in the therapy of melasma. Concentra¬
tions of hydroquinone vary from 2% (over the counter)
to 3% and 4% (by prescription) in the United States. In
addition, higher concentrations are often extemporane¬
ously compounded by dermatologists for treatment of me¬
lasma and other hyperpigmentary conditions.
Arndt and Fitzpatrick1' compared the efficacy of 2%
and 5% hydroquinone for treatment of hypermelanosis
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(top) and cheek (bottom), typical of melasma.
in 56 patients and found no difference in therapeutic ef¬
ficacy. Hydroquinone was moderately effective in 80%
of cases. Two percent hydroquinone was less irritating.
Fitzpatrick et al10 subsequently reported the efficacy of
a 2% cream of stabilized hydroquinone in decreasing hy-
permelanosis in 64% of 93 patients studied. Ensuing re¬
ports have continued to confirm the efficacy of hydro¬
quinone as a hypopigmenting agent.
Sanchez and Vazquez ' treated 46 women with melasma
'
using two versions of a 3% hydroalcoholic solution of hy¬
droquinone. Overall improvement was noted in 88% of the
patients and moderate to marked improvement in 36%. Side
effects were minimal. The use of a sunscreen was thought
to enhance the therapeutic efficacy of this regimen. More
recently, Glenn et al,12 in a double-blind 12-week clinical
trial, evaluated the clinical and light microscopic effects of
hydroalcoholic solutions of 3% and 6% hydroquinone in treat¬
ing a variety of hyperpigmentary disorders, including me¬
lasma. No significant differences were observed in the clini¬
cal efficacy of the two preparations, and both were effective
in causing marked lightening of hyperpigmented skin. How¬
ever, compared with placebo, there was a greater statistically
significant difference induced by 6% hydroquinone com¬
pared with 3% hydroquinone. Side effects were minimal with
each preparation. In addition, the authors reported that sig¬
nificant clinical improvement can be induced by hydroqui¬
none in the treatment of hyperpigmentation characterized
by epidermal and dermal pigment deposition via the induc¬
tion of a decrease in epidermal melanin.
Several investigators have reported that the efficacy
of hydroquinone is improved when it is used in combina¬
tion with other chemicals. Kligman and Willis15 noted an
enhanced efficacy of 5% hydroquinone, 0.1% tretinoin, and
0.1% dexamethasone in hydrophilic ointment for the treat¬
ment of melasma, ephelides, and postinflammatory hyper¬
pigmentation. In contrast, they experienced poor results
with each of the aforementioned drugs as monotherapies.
Gano and Garcia,14 in an open-label trial, applied succes¬
sive applications of 0.05% tretinoin, 0.1% betamethasone
valerate, and 2% hydroquinone in 20 women with me¬
lasma. After 10 weeks of therapy, objective improvement
was noted in 65% of the subjects,whereas subjective im¬
provement was noted by 95% of the subjects.
Pathak et al3 conducted clinical trials involving 300 His¬
panic women with melasma using various depigmenting for-
 Therapeutic Modalities for Melasma
Hypopigmenting agents Chemical
Phenolic derivatives
Hydroquinone
Hydroquinone/tretinoin
Hydroquinone/salicylic acid
Hydroquinone/glycolic acid
Isopropylcatechol
Acetyl-4-S-cystaminylphenol
Nonphenolic compounds
Tretinoin
Azelaic acid*
*Not approved for use in the United States.
mulations containing hydroquinone to determine the ideal
concentrations of hydroquinone, retinoic acid, and cortico-
steroid. They concluded that cream or lotion formulations
of 2% hydroquinone and 0.05% to 0.1% retinoic acid pro¬
vided the most favorable results. In view of the significant
effects of UV íadiation in the pathogenesis of melasma, Pathak
et al3 and others15 strongly emphasize the prolonged use of
broad-spectrum sunscreens in the treatment of this disor¬
der. When the clinical efficacy of hydroquinone is assessed
according to the findings of the aforementioned studies, it
can be seen that methodological techniques, drug formu¬
lations and concentrations, data interpretation, and results
vary considerably. Despite these discrepancies, hydroqui¬
none remains the most effective topically applied bleaching
agent for the treatment of melasma.
Many dermatologists prescribe higher extempora¬
neously compounded concentrations of hydroquinone
for difficult cases.The formulations contain concentra¬
tions as high as 10% combined with nonfluorinated ste¬
roid creams with or without the additional use of treti¬
noin or salicylic acid. Extemporaneously compounded
preparations are often effective in patients that have failed
to respond to lower concentrations of hydroquinone. With
controlled use and monitoring, side effects from these
preparations have proved minimal.
Adverse reactions associated with hydroquinone use
include acute and chronic complications. Acute reac¬
tions include irritant and allergic contact dermatitis, nail
discoloration, and postinflammatory hyperpigmenta-
tion.16 Hydroquinone use can also induce hypopigmen-
tation and, rarely, depigmentation of treated and sur¬
rounding normal skin. In my experience, these changes
are temporary and resolve on cessation of hydroqui¬
none treatment, in contrast to monobenzone (Beno-
quin) use, which can cause permanent depigmenta¬
tion.17 Hence, the only indication for monobenzone
therapy is in the treatment of severe vitíligo.
A more recent concern regarding the use of hydroqui¬
none is the occurrence of hydroquinone-induced ochrono-
sis, a chronic disfiguring condition resulting, in general, from
the prolonged use of strong concentrations of hydroquinone
(Figure 2). The condition was initially described by Find-
ley et al1K among South African Bantu women who had ap¬
plied strong concentrations of hydroquinone for many years.
Myriad cases are continually being reported in Africa, and
the overwhelming majority of sufferers are black women.
Clinically, ochronosis is characterized by a reticulated, ripple-
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peels Lasers
Deep Pigmented lesion dye laser
Buffered phenols Cooper vapor laser
Medium Q-switched ruby laser
Unbuffered phenol Argon laser
Superficial
Trichloracetic acid
a-Hydroxy acids
Glycolic acid
Resorcinol
like, sooty pigmentation of the face, commonly affecting the
cheeks, forehead, and periorbital regions.
Histologie studies reveal changes in the papillary and
sometimes the reticular dermis. Banana-shaped, yellow-
brown pigment globules of the papillary dermis are de¬
posited in and around collagen bundles. Elastosis, tel-
angiectasia, foreign body multinucleated giant cells,
sarcoidal granulomas, and transfollicular elimination of
ochronotic fibers have been described.19
Industrial sources reveal that there are 5 to 6 million
users of hydroquinone in the United States. Six ounces of
over-the-counter hydroquinone preparations are purchased
per customer per year. Although hydroquinone is used ex¬
tensively in the United States, to my knowledge there have
been only 14 cases of exogenous ochronosis reported in the
American literature to date, and the majority of these cases
occurred after short- and long-term use of 2% hydroquinone
preparations.20"22 In light of the vast quantities of hydroqui¬
none used in the United States, the incidence of reported cases
of ochronosis complicating hydroquinone use is rare.
Other Phenolic Depigmenting Agents
Bleehen23 treated 68 patients with 1% or 3% isopropylcat-
echol for 3 months. Fifty of the patients had melasma; 66%
showed significant improvement. Twenty patients had vary¬
ing degrees of irritation as a result of the isopropylcat-
echol use, and four patients developed an allergic contact
dermatitis. Confetti-like depigmentation occurred in the
treated areas in one patient. Because isopropylcatechol
proved to be melanocytotoxic in Bleehen's study, he has
recommended that it be used only with extreme caution.
In 1991, Jimbow24 described the efficacy of a new de¬
pigmenting agent, N-acetyl-4-S-cysteaminylphenol, in the
treatment of 12 patients with melasma. Marked improve¬
ment or complete clearing of lesions was noted in 75% of
cases. Side effects were minimal. The efficacy of this drug
for the treatment ofmelasma warrants further investigation.
NONPHENOLIC COMPOUNDS
Azelaic Acid
Azelaic acid is a naturally occurring dicarboxylic acid (1,7-
heptanedicarboxylic acid) that has demonstrated benefi¬
cial therapeutic effects in the treatment of acne and sev¬
eral disorders of hyperpigmentation, including melasma and
lentigo maligna. Among its many pharmacodynamic prop-
 erties, azelaic acid appears to have selective effects on hy¬
peractive and abnormal melanocytes.25 There are minimal
effects on normally pigmented human skin, freckles, se¬
nile lentigines, and nevi. The cytotoxic and antiprolifera-
tive effects of azelaic acid may be mediated via inhibition
of mitochondrial oxidoreductase activity and DNA syn¬
thesis. Disturbance of tyrosinase synthesis by azelaic acid
may also influence its therapeutic effects.
Several studies have reported the efficacy of a topical
20% azelaic acid in the treatment ofmelasma. Rigoni et al,26
in a noncomparative study, noted significant overall improve¬
ment in 39 women. Verallo-Rowell et al,27 in a double-blind
comparative study, treated 132 Filipino women, and found
20% azelaic acid to be significantly more effective than 2%
hydroquinone. Seventy-three percent of the patients com¬ Figure 2. Hydroquinone-induced ochronosis after prolonged use of 2%
pleting the 6-month azelaic acid trial achieved good to ex¬ hydroquinone.
cellent response, compared with 19% of the patients treated
with 2% hydroquinone. In addition, Balina and Graupe28 com¬
pared the efficacy of 20% azelaic acid and 4% hydroquinone
in a 24-week, multicenter, double-blind study involving 329
women with melasma. They reported no significant differ¬
ences in the results. Good to excellent responses were ob¬
served in 72% of the patients in the hydroquinone group and
in 65% of those in the azelaic acid group.
Azelaic acid at concentrations of 15% to 20% ap¬
pears to be well tolerated in humans. Allergic sensitiza-
tion and/or phototoxic reactions are uncommon. Ad¬
verse reactions include pruritus, mild transient erythema,

scaling, and burning.25 These effects usually subside in

2 to 4 weeks. Azelaic acid has virtually no systemic tox-
icity when used to treat melasma.
Tretinoin Figure 3. Hyperpigmentation of the face induced by 0.05% tretinoin cream.

The efficacy of 0.1% tretinoin has been reported in the treat¬
ment of postinflammatory hyperpigmentation2g and me¬
lasma.30"32 Griffiths et al,30 in a 40-week clinical trial in¬
volving 38 patients with melasma, observed improvement
or significant improvement in 68% of 19 tretinoin-treated
patients, compared with only 5% of 19 vehicle-treated pa¬
tients. Moderate cutaneous side effects of erythema and des¬
quamation were observed in 88% of the patients. Kim-
brough-Green et al31 reported the efficacy of topical 0.1%
tretinoin in a 40-week double-blind clinical trial involv¬
ing 28 black patients with melasma. Seventy-three per¬
cent of 15 tretinoin-treated patients were improved or much
improved at the end of the study, compared with 46% of
13 controls. Statistically significant lightening was first noted
at 24 weeks. The study failed to provide follow-up data re¬
garding the persistence of pigment loss induced by treti¬
noin. Cutaneous side effects noted throughout the study
were limited to erythema and/or peeling in the area of ap¬
plication. In contrast, Tadaki et al32 treated 15 Japanese
patients with 0.1% tretinoin and found no improvement
in melasma. In addition, side effects were severe.
Although side effects were minimal in Kimbrough-Green
and colleagues' study, the routine use of 0.05% and 0.1% treti¬
noin is often associated with dermatitis and distressing hy-
perpigmentation (Figure 3). Therefore, the prescribing phy¬
sician must establish a risk-benefit ratio. In addition, the ef¬
ficacy of tretinoin should be assessed in relation to other
bleaching agents. The results of published studies review-
the efficacy of varying concentrations of hydroquin¬
ing 9"14
one revealed moderate to significant improvement in 64%
to 88% of the cases at 12 weeks of treatment. These figures
contrast significantly
with the 68% to 73% improvement in¬
duced by tretinoin at 40 weeks of treatment.30"32
CHEMICAL PEELS
Chemical peels have become an established technique for
improving or erasing wrinkles, reducingsuperficial acne scar¬
ring, removing kératoses, and treating pigment imperfec¬
tions.33 Superficial, medium, and deep chemical peels are
often used to treat melasma in lighter-complexioned whites.
Buffered and unbuffered phenol peels, trichloroacetic acid
peels, resorcinol paste, and a-hydroxy acids have been used,
with mixed results. There is a tendency for pigmentation
changes, including areas of hypopigmentation and hyper-
pigmentation, to develop in black patients after chemical
peels.34 In dark-complexioned individuals, phenol peels are
more likely to induce depigmentation and hypopigmenta¬
tion. The more superficial peels tend to induce hyperpig-
mentation. In addition, deeper peels are occasionally com¬
plicated by keloid formation and hypertrophie scarring. Other
side effects of peels include atrophy, bacterial and viral in¬
fections, milia, telangiectasia, and pore enlargement.35
Glycolic acid peels (50% to 70%) are becoming increas¬
ingly popular in the treatment of melasma. Moy et al35 de¬
scribed some improvement in patients treated with this mo-

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dality. They also recommend the use of 10% glycolic acid
and 2% hydroquinone in the treatment of melasma. Myriad
combinations of glycolic acid-hydroquinone bleaching
agents are now being marketed in the United States.
LASER THERAPY
Laser therapy for melasma represents a novel approach
to a vintage condition. Although studies have demon¬
strated some success with laser therapy in the treatment
of diseases of hyperpigmentation, such as solar lentigi-
nes and cafe-au-lait macules, its efficacy and place in the
treatment of melasma have yet to be established.
Grekin et al36 treated 10 patients with melasma with
a 510-nm pigmented lesion dye laser at an
energy level of
2.0 to 4.0 J/cm for a total of three treatments. No improve¬
ment was observed in eight of the patients, and less than
50% improvement was noted in the other two. Fitzpatrick
et al37 used the same laser, with a 300-nanosecond pulse,
and found it to be effective in the treatment of postinflam¬
mation hyperpigmentation but ineffective for melasma.
The copper vapor laser, although efficacious in the treat¬
ment of pigmented lesions according to Dinehart et al,38 has
also failed to provide some measure of success in patients
with melasma. Goldberg39 and McBurney40 have been able
to obtain favorable results with the Q-switched ruby laser
(94 nm) and the argon laser (514 nm), respectively. Light-
skinned patients showed a greater response than their darker-
complexioned counterparts when treated with the Q-switched
ruby laser. However, soon after treatment, there was recur¬
rence of the disease. Although the argon laser is more widely
used, its efficacy in the treatment of melasma is, for now, an¬
ecdotal, since there have been no large studies conducted
to show otherwise. Taylor and Anderson4' treated eight pa¬
tients with melasma or postinflammatory hyperpigmenta¬
tion by Q-switched ruby laser. No permanent improvement
was noted. Some cases worsened. Side effects oflaser therapy
include atrophy, hypertrophie scarring, hypopigmentation,
and hyperpigmentation.
CONCLUSIONS
"My skin is black upon me; and my bones are burned with
heat ! (Job 30:30). In summary, the treating physician must
"
be constantly aware of the psychosocial impact of pigmen¬
tary imperfections, including those caused by melasma. Cur¬
rent therapeutic approaches are beneficial for many patients.
However, they remain ineffective for some and cause sig¬
nificant side effects. Therefore, in the hierarchy of therapies
for melasma, the treating physician must attempt to estab¬
lish a risk-benefit ratio for each therapeutic modality.
Accepted for publication April 25, 1995.
Reprint requests to Division of Dermatology, King-
Drew Medical Center, 12021 S Wilmington Ave, Los An¬
geles, CA 90059 (Dr Grimes).
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