Hyperpigmentation is a common and distressing problem caused by
various inflammatory skin disorders, such as eczema, allergic contact
dermatitis, and irritant contact dermatitis Acne is also a frequent
cause. Papulosquamous disorders in general commonly predispose a patient
to postinflammatory hyperpigmentation. Melasma is a common form of
noninflammatory hyperpigmentation.
Sun exposure often reverses the results of therapy, compromising the
lengthy treatment process. Consequently, the first line of therapy for
hyperpigmentation is a broad-spectrum sunscreen used in conjunction with
a phenolic agent such as a hydroquinone, or with a nonphenolic agent
such as tretinoin, azelaic acid, or kojic acid. There are hundreds of
sunscreen formulations with different UV absorbing chemicals in various
concentrations.
1 The UVB and UVA absorbing chemicals used in
the formulation of topical sunscreens include paraaminobenzoic
acid-related products, salicylates, cinnamates, benzophenones, zinc
oxide, and titanium oxide. Almost all sunscreen products contain a
mixture of one or more UVB absorbing chemicals.
1
Hydroquinone and related compounds reduce the production of melanin
by their inhibition of the enzyme tyrosinase. Topical corticosteroids
also inhibit tyrosinase activity and affect endoplasmic reticulum
secretory function of melanocytes. Agents such as salicylic acid and
glycolic acid act to remove melanin in the epidermis by their peeling
action. Tretinoin, which has a mild peeling effect, acts in a similar
manner. It may also inhibit tyrosinase.
Hydroquinone
Hydroquinone, which is a hydroxyphenolic chemical, has been the gold
standard for treatment of hyperpigmentation for over 50 years. It acts
by inhibiting the enzyme tyrosinase, thereby reducing the conversion of
DOPA to melanin. Some of the other possible mechanisms of action are the
destruction of melanocytes,degradation of melanosomes, and the
inhibition of the synthesis of DNA and RNA.
Hydroquinone can be compounded into 5%-10% concentrations, but at
these strengths, may be irritating and unstable. The 2% concentrations
of hydroquinone available over the counter in the US and Canada are not
as efficacious as the 3% and 4% prescription formulations, as their
onset of action is later than with the higher concentrations.
Antioxidants, such as vitamin C and retinoids, as well as alpha-hydroxy
acids may be used as additives to increase penetration and enhance
efficacy. Exogenous ochronosis with the use of hydroquinone has been
reported in dark-skinned patients, in particular South African women who
frequently use very high concentrations of hydroquinone over large
surface areas.
3 Although hydroquinone is used extensively in
North America, there have only been about 30 reported cases of exogenous
ochronosis from hydroquinone use in North America.
Adverse reactions from hydroquinone use include irritant and allergic
contact dermatitis, and nail discoloration. Postinflammatory
hyperpigmentation may occur from the contact dermatitis.
Hypopigmentation of the normal skin surrounding the treated areas may
also occur. These usually resolve with the discontinuation of the
hydroquinone treatment.
2
Other Phenolic Agents
Monobenzone, the monobenzyl ether of hydroquinone, is a special
topical phenolic agent, which is indicated only for the final
depigmentation of disfiguring vitiligo. It is applied topically to
permanently depigment normal skin surrounding vitiliginous areas in
patients with disseminated vitiligo (greater than 50% body surface
area). The cream is applied in a thin layer, rubbed into the normally
pigmented areas two or three times daily. Depigmentation is usually
achieved after 6-12 months with 20% monobenzone treatment. It should
then be applied only as often as required to maintain depigmentation.
Monobenzone cream can produce satellite depigmentation at sites distant
from the site of initial application.
N-acetyl-4-cysteaminylphenol (NCAP) is another phenolic agent that is
currently being developed and is not yet available in North America.
NCAP acts to decrease intracellular glutathione by stimulating
pheomelanin rather than eumelanin.
4 It also inhibits
tyrosinase activity, has been found to be more stable, and causes less
irritation than hydroquinone. In a retrospective study of 12 patients
with melasma using 4% NCAP, 66% showed marked improvement, and 8% showed
complete loss of melasma lesions. Changes of melanoderma were evident
after 2-4 weeks of daily topical application of NCAP.
5
Azelaic Acid
Azelaic acid is a naturally occurring non-phenolic, saturated,
nine-carbon dicarboxylic acid. Its use originated from the finding that
Pityrosporum species can oxidize unsaturated fatty acids to dicarboxylic
acids, which competitively inhibit tyrosinase. Azelaic acid was
initially developed as a topical drug with therapeutic effects for the
treatment of acne. However, because of its effect on tyrosinase, it has
also been used to treat melasma, lentigo maligna and other disorders of
hyperpigmention.
2,6 Azelaic acid has been reported to be
effective for hypermelanosis caused by physical or photochemical agents,
and lentigo maligna melanoma as well as other disorders characterized
by abnormal proliferation of melanocytes. Its mechanism of action is to
inhibit DNA synthesis and mitochondrial enzymes, thereby inducing direct
cytotoxic effects toward the melanocyte.
6 Topical azelaic
acid has no depigmentation effect on normally pigmented skin, freckles,
senile lentigines, and nevi. This specificity may be attributed to its
selective effects on abnormal melanocytes. Azelaic acid can be used for
postinflammatory hyperpigmentation in acne.
7 Free radicals are believed to contribute to hyperpigmentation, and azelaic acid acts by reducing free radical production.
8
Azelaic acid 20% is currently available in the US and is only indicated
for the treatment of acne, although it has off-label use for
hyperpigmentation. In the treatment of melasma, a 24-week study in South
America found that a 20% concentration of azelaic acid was equivalent
to 2% hydroquinone.
9 In the Philippines, a study found that 20% azelaic acid was better than 2% hydroquinone.
10
Kojic Acid
Kojic acid (5-hydroxy-2-(hydroxy methyl)-4-pyrone), a naturally
occurring hydrophilic fungal derivative evolved from certain species of
Acetobacter, Aspergillus and Penicillium, is used in the treatment of
hyperpigmentation disorders.
11 It acts by inhibiting the
production of free tyrosinase with efficacy similar to hydroquinone. In
Japan, kojic acid has been increasingly used in skin care products. This
is because, until recently, topically applied kojic acid at 1%
concentration had not exhibited any sensitizing activity.
12
However, more recent long-term Japanese studies have shown that kojic
acid has the potential for causing contact dermatitis and erythema.
12
Arbutin
Arbutin, which is the b-D-glucopyranoside derivative of hydroquinone,
is a naturally occurring plant derived compound that has been used for
postinflammatory hyperpigmentation.
13 It is effective in the treatment of disorders of hyperpigmentation characterized by hyperactive melanocytes.
13
The action of arbutin is dependent on its concentration. Higher
concentrations are more efficacious than lower concentrations, but they
may also result in a paradoxical hyperpigmentation.
13 In
comparative in vitro studies of various compounds used to improve the
appearance of disorders of hyperpigmentation, arbutin was found to be
less toxic than hydroquinone. A dose-dependent reduction in tyrosinase
activity, as well as melanin content in melanocytes, was also
demonstrated.
14
Licorice Extract
Licorice extract is not yet available in North America, but has been
used in other parts of the world, particularly in Egypt. Its mechanism
of action is similar to that of kojic acid. The main component of the
hydrophobic fraction of licorice extract is glabridin, which has an
effect on the skin. Studies investigating the inhibitory effects of
glabridin on melanogenesis and inflammation have shown that it inhibits
tyrosinase activity of melanocytes. No effect on DNA synthesis was
detectable.
15
Topical Retinoids
The efficacy of topical tretinoin 0.05-0.1% as monotherapy for postinflammatory hyperpigmentation has been reported.
16
Tretinoin was also used as monotherapy in a study on 38 African-
American patients with melasma and 68%-73% of patients improved. In 88%
of the patients, moderate side-effects of desquamation and erythema were
observed.
17,18 Darker skinned patients who develop a
dermatitis from tretinoin may develop postinflammatory hyperpigmentation
secondary to the dermatitis.
The mechanism of action of tretinoin in the treatment of melasma is
poorly understood. Clinical improvement has been found to be associated
with a reduction in epidermal melanin, possibly as a result of the
inhibition of tyrosinase by the action of tretinoin.
19
Although tretinoin can be effective as monotherapy for
hyperpigmentation and melasma, it requires 20 to 40-week treatment
periods. Tretinoin can also be used in conjunction with hydroquinone or
other depigmenting agents to improve efficacy. The first published study
of combination therapy used tretinoin 0.1%, hydroquinone 5%, and
dexamethasone 0.1% for postinflammatory hyperpigmentation.
20
Tretinoin was shown to reduce the atrophy of the corticosteroid and
facilitated the epidermal penetration of the hydroquinone. The
tretinoininduced irritation was reduced by the corticosteroid. The first
triple combination topical therapy approved by the US FDA for melasma
is a modified formulation comprising fluocinolone acetonide,
hydroquinone 4% and tretinoin 0.05%. In studies of patients with
melasma, 78% had complete or near clearing after 8 weeks of therapy.
Similar results and favorable safety profile were seen in a 12-month
study.
21
In a randomized clinical trial, the efficacy of adapalene 0.1% was
found to be comparable to that of tretrinoin 0.05% cream in the
treatment of melasma (mainly epidermal type). The results showed fewer
side-effects and greater acceptability among patients using adapalene.
19
Conclusion
The treatment of hyperpigmentation disorders can be a long process.
The psychosocial impact of these disorders should be taken into
consideration. There are several topical treatment options available,
the most common of which is hydroquinone. The use of combination therapy
and monotherapy with nonphenolic agents is increasingly common. These
treatment options are primarily for epidermal disorders
ofhyperpigmentation. Dermal disorders of hyperpigmentation are difficult
to treat, and have not been effectively managed using currently
available therapy.
