Dr Anahita Vali
Dermatologist & venereologist
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Melasma, sometimes called
chloasma (which means
green skin), appears as
a symmetrical blotchy,
brownish pigmentation on
the face. The pigmentation
is due to overproduction of
melanin by the pigment
cells, melanocytes. It can
lead to considerable
embarrassment and
distress.
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Melasma is a very common patchy
brown, tan, or blue-gray facial skin
discoloration, almost entirely seen in
women in the reproductive years. It
typically appears on the upper cheeks,
upper lip, forehead, and chin of
women 20-50 years of age. Although
possible, it is uncommon in males.
Over 90% of those with melasma are
women.
primarily related to external sun
exposure, external hormones like
birth control pills, and internal
hormonal changes as seen in
pregnancy. Most people with melasma
have a history of daily or intermittent
sun exposure, although heat is also
suspected to be an underlying factor.
Melasma is most common among
pregnant women, especially those of
Latin and Asian descents. People with
olive or darker skin, like Hispanic,
Asian, and Middle Eastern
individuals, have higher incidences of
melasma.
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Melasma is most common in
women 20-50 years of age.
Melasma looks like brown, tan, or
blue-gray spots on the face
(hyperpigmentation).
Melasma is characterized by three
location patterns (central face,
cheekbone, and jawline).
Melasma is caused partly by sun,
genetic predisposition, and
hormonal changes.
The most common treatment is
topical creams containing
hydroquinone.
Melasma prevention requires sun
avoidance and sun protection with
hats and sunscreen.
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An estimated 6 million women are
living in the U.S. with melasma and
45-50 million women worldwide
live with melasma.
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Prevention is primarily aimed at
facial sun protection and sun
avoidance.
Treatment requires regular
sunscreen application, medications
such as 4% hydroquinone and
fading creams.
unknown.
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The exact cause of melasma remains
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triggered by several factors, including pregnancy, birth control pills, hormone
replacement therapy (HRT and progesterone), family history of
melasma, race, antiseizure medications, and other medications that make
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the skin more prone to pigmentation after exposure to ultraviolet (UV) light.
Uncontrolled sunlight exposure is considered the leading cause of melasma,
especially in individuals with a genetic predisposition. individuals typically develop
melasma in the summer months,. In the winter, the hyperpigmentation in
melasma tends to be less visible. Heat, such as that experienced in a bakery or
factory.
When melasma occurs during pregnancy, it is also called chloasma, or "the mask of
pregnancy." Pregnant women experience increased estrogen, progesterone, and
melanocyte-stimulating hormone (MSH) levels during the second and third
trimesters of pregnancy. Melanocytes are the cells in the skin that deposit pigment.
However, it is thought that pregnancy-related melasma is caused by the presence of
increased levels of progesterone and not due to estrogen and MSH. postmenopausal
women who receive progesterone hormone replacement therapy are more
likely to develop melasma. Postmenopausal women receiving estrogen alone seem
less likely to develop melasma.
products or treatments that irritate the skin may cause an increase in melanin
production and accelerate melasma symptoms.
People with a genetic predisposition or known family history of melasma are at an
increased risk of developing melasma. Important prevention methods for these
individuals include sun avoidance and application of extra sunblock to avoid
stimulating pigment production..
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Four types of pigmentation
patterns are diagnosed in
melasma: epidermal, dermal,
mixed, and an unnamed type
found in dark-complexioned
individuals. The epidermal type
is identified by the presence of
excess melanin in the superficial
layers of skin. Dermal melasma
is distinguished by the presence
of melanophages (cells that
ingest melanin) throughout the
dermis. The mixed type
includes both the epidermal and
dermal type. In the fourth type,
excess melanocytes are present
in the skin of dark-skinned
individuals.
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Occasionally, skin biopsy may
be performed to confirm the
diagnosis. Histology varies with
the type of melasma. But some
degree of each of the following
features is usually found.
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Melanin deposited in basal
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Highly dendritic (branched)
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and suprabasal keratinocytes
deeply pigmented melanocytes
Melanin in the dermis within
melanophages
Solar elastosis and elastic fibre
fragmentation
The extent and severity of
melasma can be described using
the Melasma Area and Severity
Index (MASI).
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Melasma is usually readily
diagnosed by recognizing the typical
appearance of brown skin patches
on the face. Dermatologists are
physicians who specialize in skin
disorders and often diagnose
melasma by visually examining the
skin. A black light or Wood's
light (340-400 nm) can assist in
diagnosing melasma, although is not
essential for diagnosis. In most cases,
mixed melasma is diagnosed, which
means the discoloration is due to
pigment in the dermis and
epidermis. Rarely, a skin biopsy may
be necessary to help exclude other
causes of this local skin
hyperpigmentation
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Melasma is characterized by discoloration or
hyperpigmentation primarily on the face. Three
types of common facial patterns have been
identified in melasma, including
centrofacial (center of the
face),
malar (cheekbones), and
mandibular (jawbone).
The centrofacial pattern is the most prevalent form
of melasma and includes the forehead, cheeks,
upper lip, nose, and chin. The malar pattern
includes the upper cheeks. The mandibular
pattern is specific to the jaw.
The upper sides of the neck may less commonly
be involved in melasma. Rarely, melasma may
occur on other body parts like the forearms. One
study confirmed the occurrence of melasma on the
forearms of people being given progesterone.
This was a unique pattern seen in a Native
American study.
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Type of melasma
Clinical features
Epidermal
Well-defined border
Dark brown colour
Appears more obvious under black light
Responds well to treatment
Dermal
The most common type
Ill-defined border
Light brown or bluish in colour
Unchanged under black light
Responds poorly to treatment
Mixed
Combination of bluish, light and dark brown patches
Mixed pattern seen under black light
Partial improvement with treatment
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Postinflammatory
pigmentation
Solar lentigines and
other forms of lentigo
Drug-induced
pigmentation, e.g. due
to minocycline
Lichen planus
Naevus of Ota.
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Scented or deodorant soaps,
toiletries and cosmetics may
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cause a phototoxic reaction
triggering melasma that may
then persist long-term.
A phototoxic reaction to certain
medications may also trigger
melasma.
Melasma has been associated
with hypothyroidism (low levels
of thyroid hormone).
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Scented or deodorant
soaps, toiletries and
cosmetics may cause a
phototoxic reaction
triggering melasma
that may then persist
long-term.
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The most common melasma
therapies include 2% hydroquinone
(HQ) creams like the over-thecounter products Esoterica and
Porcelana and prescription-strength
4% creams like Obagi Clear, TriLuma, NeoCutis Blanche, and 4%
hydroquinone. Certain sunscreens
also contain 4% hydroquinone, such
as Glytone Clarifying Skin Bleaching
Sunvanish SPF 23 and Obagi's
Sunfader sunscreen. Products with
HQ concentrations above 2%
sometimes require a prescription or
are dispensed through physician's
practices. Clinical studies show that
creams containing 2% HQ can be
effective in lightening the skin and
are less irritating than higher
concentrations of HQ for melasma.
These creams are usually applied to
the brown patches twice a day.
Sunscreen should be applied over
the hydroquinone cream every
morning. There are treatments for
all types of melasma, but the
epidermal type responds better to
treatment than the others because
the pigment is closer to the skin
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Hydroquinone is the
compound most frequently
used in skin whitening
products. Due to concerns
about its side effects, it was
almost banned by the FDA
in 2006, as there were
medical issues of
carcinogenicity and reports
of disfiguring ochronosis.
In the European Union
Hydroquinone has been
banned in cosmetic creams
since 2000.
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Symptoms include:
yellow-brown,
banana-shaped fibers
caviar-like papules
brown-grey or blueblack
hyperpigmentation
The majority of the
lesions will be seen on
areas of the body that
get the most sun.
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Long term use of creams containing
this compound may lead to
exogenous ochronotic lesions. The
duration of the use is directly
proportional to the risk of
developing the condition with most
cases being after years of use.
Around 10-15 million skin
lightening products are sold
annually, with Japan being the
major buyer
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Exogenous ochronosis can be caused
from long term usage of certain
‘’skin lightening products’’,
even if the hydroquinone is
in amounts as small as 2%.
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Skin lightening products are still
prevalent in many parts of the
world.Reasons for this may be due
to aesthetic or social standing
reasons, in areas where a lighter
skin tone is considered to be a sign
of wealth or beauty.As well, skinlightening creams containing
compounds such as hydroquinone
are commonly used to help with
hyperpigmentation disorders such
as melasma
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Hydroquinone-induced exogenous
ochronosis is an avoidable dermatosis
that is exceedingly difficult to treat.
However, some studies show that
treatment may be possible with a Q-
switched alexandrite (755 nm)
laser.
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It is recommended that individuals with
this disorder stop using hydroquinone
containing compounds.It is important to
be aware of this as dermatologists may
think the symptoms a patient is exhibiting
are a melasma, and prescribe a
hydroquinone containing cream.
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Ochronosis is the syndrome
caused by the accumulation of
homogentisic acid in
connective tissues. The
phenomenon was first
described by Rudolf Virchow
in 1865.The condition was
named after the yellowish
(ocher-like) discoloration of
the tissue seen on microscopic
examination. However,
macroscopically the affected
tissues appear bluish grey
because of a light scattering
phenomenon known as the
Tyndall effect. The condition
is most often associated with
alkaptonuria but can occur
from exogenous
administration of phenol
complexes like hydroquinone.
THERE ARE THREE CLINICAL
STAGES OF EXOGENOUS
OCHRONOSIS:
ERYTHEMA AND MILD
HYPERPIGMENTATION
HYPERGIMENTATION AND
‘’CAVIAR-LIKE’’ LESIONS
PAPULO-NODULAR LESIONS
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temporary skin irritation. People who use
HQ treatment in very high concentrations for
prolonged periods (usually several months to
years) are at risk of developing a side effect
called ochronosis. Hydroquinone-induced
ochronosis is a permanent skin discoloration
that is thought to result from use of
hydroquinone concentrations above 4%.
Although ochronosis is fairly uncommon in the
U.S., it is more common in areas like Africa
where hydroquinone concentrations upward of
10%-20% may be used to treat skin
discoloration like melasma.
Regardless of the potential side
effects, HQ remains the most
widely used and successful
fading cream for treating
melasma worldwide. HQ
should be discontinued at the
first signs of ochronosis
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Melasma can be very slow to respond to treatment, so
patience is necessary. Start gently, especially if you have
sensitive skin. Harsh treatments may result in an irritant
contact dermatitis, and this can result in postinflammatory
pigmentation.
Generally a combination of the following measures is
helpful.
General measures
Discontinue hormonal contraception.
Year-round sun protection. Use broad-spectrum very high
protection factor sunscreen of reflectant type and apply it to
the whole face every day. Reapply every 2 hours if outdoors
during the summer months. Alternatively or as well, use a
make-up that contains sunscreen. Wear a broad-brimmed
hat.
Use a mild cleanser, and if the skin is dry, a light
moisturiser. This may not be suitable for those with acne.
Cosmetic camouflage (make-up) is invaluable to disguise
the pigment.
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Tyrosinase inhibitors are the mainstay of treatment. The aim is to prevent new pigment
formation by inhibiting formation of melanin by the melanocytes.
Hydroquinone 2-4% as cream or lotion, applied accurately to pigmented areas at night
for 2 to 4 months. This may cause contact dermatitis (stinging and redness in 25%). It
should not be used in higher concentration or for prolonged courses as it has been
associated with ochronosis (a bluish grey discolouration).
Azelaic acid cream, lotion or gel can be used longterm, and is safe even in pregnancy.
This may also sting.
Kojic acid is often included in formulations as they interact with copper, required by LDOPA (a cofactor of tyrosinase). Kojic acid can cause irritant contact dermatitis and less
commonly, allergic contact dermatitis.
Ascorbic acid (vitamin C) acts through copper to inhibit pigment production. It is well
tolerated but highly unstable, so is usually combined with other agents.
New agents under investigation include mequinol, arbutin and deoxyarbutin (from
berries), licorice extract, rucinol, resveratrol, 4-hydroxy-anisole, 2,5-dimethyl-4-hydroxy3(2H)-furanone and/or N-acetyl glucosamine
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Topical corticosteroids such as hydrocortisone, work
quickly to fade the colour and reduce the likelihood of
a contact dermatitis caused by other agents.
Soybean extract, which is thought to reduce the
transfer of pigment from melanocytes to skin cells
(keratinocytes) and inhibit receptors.
Tranexamic acid is a lysine analogue that inhibits
plasmin (this drug is usually used to stop bleeding)
and reduces production of prostaglandins (the
precursors of tyrosine). Tranexamic acid has been used
experimentally for melasma as a cream or injected into
the skin (mesotherapy), showing some benefit. It may
cause allergy or irritation.
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Superficial or epidermal pigment can be peeled off. Peeling can also allow
tyrosinase inhibitors to penetrate more effectively. Agents to achieve this
include:
Topical alpha hydroxyacids including glycolic acid and lactic acid, as
creams or as repeated superficial chemical peels, not only remove the
surface skin but their low pH inhibits the activity of tyrosinase.
Topical retinoids, such as tretinoin are prescription medicines. They can
be hard to tolerate and sometimes cause contact dermatitis. Do not use
during pregnancy.
Salicylic acid , a common peeling ingredient in skin creams and can also
be used for chemical peels but it is not very effective in melasma.
Currently, the most successful formulation has been a combination of
hydroquinone, tretinoin, and moderate potency topical steroid, which has
been found to result in improvement or clearance in up to 60-80% of those
treated. Many other combinations of topical agents are in common use, as
they are more effective than any one alone. However, these products are
often expensive.
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In order to treat melasma, combination or specially
formulated creams with hydroquinone, a phenolic
hypopigmenting agent, azelaic acid, and retinoic
acid (tretinoin), nonphenolic bleaching agents,
and/or kojic acid may be prescribed. For severe
cases of melasma, creams with a higher
concentration of HQ or combining HQ with other
ingredients such as tretinoin, corticosteroids, or
glycolic acid may be effective in lightening the skin.
Azelaic acid 15%-20% (Azelex, Finacea)
Retinoic acid 0.025%-0.1% (tretinoin)
Tazarotene 0.5%-0.1% (Tazorac cream or gel)
Adapalene 0.1%-0.3% (Differin gel)
Kojic acid
Lactic acid lotions 12% (Lac-Hydrin or Am-Lactin)
Glycolic acid 10%-20% creams (Citrix cream,
NeoStrata)
Glycolic acid peels 10%-70%
Other proprietary ingredients and mixtures of
ingredients as in Elure, Lumixyl, and SkinMedica's
Lytera products
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1) Light, circadian rhythms and
melatonin: (1) UV or visible light from the
sun is sensed by the retina, which signals
the suprachiasmatic nucleus (SCN)
region of the brain, enabling entrainment
of circadian rhythms throughout the
body;
(2) UV light induces skin damage.
Both
melatonin and Vitamin
D3 have protective effects
against this damage, through the
inhibition of reactive oxygen species
(ROS) formation as well as other
mechanisms;
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(3) UVB light exposure can cause
disruption of the circadian rhythms in
normal skin, but also has the protective
effect of producing Vitamin D3; and
(4) in addition to its protective effects
against UVB skin damage, melatonin also
plays a role in the regulation of circadian
rhythms, through its inhibition of the
HDAC SIRT1
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Although UV exposure is detrimental to
skin health and key to the carcinogenesis
process, it does not explain all skin
cancers, including the increase in
melanoma incidences of indoor workers.
There has been speculation to tie this in
with vitamin D production and/or the
breakdown of vitamin D stores within the
skin which is more common in indoor
workers. With all the lifestyle changes we
have seen over the past century, there has
also been an increase in the incidences of
many cancers. Many variables could
contribute to the causes of these increases.
However, the role that changes in
environmental stressors play cannot be
ignored. Further understanding of
circadian regulations is needed to develop
novel strategies towards circadian related
conditions and diseases which encompass
a wide range from behavioral conditions
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Melatonin was first discovered in connection to the
mechanism by which some amphibians and reptiles
change the color of their skin.
discovered that feeding extract of the pineal glands
of cows lightened tadpole skin by contracting the
dark epidermal melanophores.
dermatology professor Aaron B. Lerner and
colleagues at Yale University, in the hope that a
substance from the pineal might be useful in treating
skin diseases, isolated the hormone from bovine
pineal gland extracts and named it melatonin.
production of melatonin exhibits a circadian rhythm
in human pineal glands. The discovery that
melatonin is an antioxidant was made in 1993.The
first patent for its use as a low dose sleep aid was
granted to Richard Wurtman at MIT in 1995.
Around the same time, the hormone got a lot of press
as a possible treatment for many illnesses.The New
England Journal of Medicine editorialized in 2000: "The
hype and the claims of the so-called miraculous
powers of melatonin several years ago did a great
disservice to a scientific field of real importance to
human health. With these recent careful and precise
observations in blind persons, the true potential of
melatonin is becoming evident, and the importance
of the timing of treatment is becoming clear. Our 24hour society, with its chaotic time cues and lack of
natural light, may yet reap substantial benefits."
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Many biological effects of
melatonin are produced
through activation of melatonin
receptors, while others are due
to its role as a pervasive and
powerful antioxidant, with a
particular role in the protection
of nuclear and mitochondrial
DNA.
Melatonin is categorized by the
US Food and Drug
Administration (FDA) as a
dietary supplement and is not
regulated as a pharmaceutical
drug.
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In mammals, melatonin is
biosynthesized in four enzymatic steps
from the essential dietary amino acid
tryptophan, with serotonin produced at
the third step. Melatonin is secreted into
the blood by the pineal gland in the
brain. Known as the "hormone of
darkness," it is secreted in darkness in
both day-active (diurnal) and nightactive (nocturnal) animals.
It may also be produced by a variety of
peripheral cells such as bone marrow
cellslymphocytes, and epithelial cells.
Usually, the melatonin concentration in
these cells is much higher than that
found in the blood, but it does not seem
to be regulated by the photoperiod.
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Melatonin has been identified in many plants
including feverfew (Tanacetum parthenium), St
John's wort (Hypericum perforatum), rice, corn,
tomato and other edible fruits. The
physiological roles of melatonin in plants
involve regulation of their response to
photoperiod, defense against harsh
environments, and the function of an
antioxidant. Melatonin also regulates plant
growth by its ability to slow root formation,
while promoting above ground growth.
Melatonin has been reported in foodstuffs
including cherries to about 0.17–
13.46 ng/g,bananas and grapes, rice and
cereals, herbs, olive oil, wineand beer.
When birds ingest melatonin-rich plant feed,
such as rice, the melatonin binds to melatonin
receptors in their brains. When humans
consume foods rich in melatonin such as
banana, pineapple and orange the blood
levels of melatonin significantly increase.
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Pomegranate Fruit Extract Inhibits UVB-induced
Inflammation and Proliferation by Modulating NFκB and MAPK Signaling Pathways in Mouse Skin
Solar UV radiation, particularly its UVB component
(280–320 nm), causes adverse cellular and molecular
events leading to skin cancer. Therefore, additional
approaches are needed to define novel agents to
prevent skin cancer which results as a consequence of
UVB exposure. In this study, we investigated the
photochemopreventive effects of pomegranate fruit
extract (PFE) after multiple UVB irradiations to the skin
of SKH-1 hairless mice. Our data show that PFE
consumption afforded protection to mouse skin by
inhibiting UVB-induced inflammation and
proliferation via modulation of nuclear factor kappa B
and mitogen-activated protein kinases pathways. This
study suggests the potential efficacy of PFE as a
photochemopreventive agent for skin cancer
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Oral medications for
melasma are under
investigation,
including tranexamic
acid (a prescription
medicine in New
Zealand). None can be
recommended at this
time.
Oral vit c,e
antioidants
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Machines can be used to remove epidermal pigmentation but with
caution – over-treatment may cause postinflammatory
pigmentation. Fractional lasers are preferred and have been
approved by the FDA for treating melasma. Patients should be
pretreated with a tyrosinase inhibitor .
The ideal treatment for a quick result is just to destroy the
pigment, while leaving the cells alone. Intense pulsed light (IPL)
appears to be the most effective light therapy investigated so far.
The topicals described above should also be used before and after
treatment. Pigmentation may recur. Several treatments may be
necessary and postinflammatory hyperpigmentation may
complicate recovery.
Conventional carbon dioxide or erbium:YAG resurfacing lasers
and pigment lasers (Q-switched ruby and Alexandrite devices) are
sometimes used, but they have a high risk of making melasma
worse. Dermabrasion and microdermabrasion are not
recommended, as they may also cause postinflammatory
hyperpigmentation.
Intense pulse light
IPL was developed in the late 1990s and involves the use of a xenon-chloride lamp that emits
light that is non-coherent not collimated and has a wide spectrum (500–
1200 nm).
The advantage of IPL lies in the flexibility of parameters. The wavelength, fluence, number,
duration, and delay of pulses can be changed for each patient to effectively target
chromophore. Hence, it can be used for the treatment of a variety of conditions like
vascular lesions, hair removal, and melanocytic lesions. However, there are
very few studies on the treatment of melasma with IPL.
Rebound hyperpigmentation
treated five Chinese patients with melasma with laser toning. There was no significant
improvement in melasma and all five patients developed laser-induced depigmentation.
Possible pathogenic mechanisms for this depigmentation could be high fluences causing direct
phototoxicity and cellular destruction of melanocyte, subthreshold additive effect of multiple
doses, intrinsic unevenness of skin pigmentation, and non-uniform laser energy output.Several
other side effects mentioned in the literature include rebound
hyperpigmentation,
physical urticaria, acneiform eruption, petechiae, and herpes simplex
reactivation.
Rebound hyperpigmentation could be due to the multiple subthreshold exposures that
can stimulate melanogenesis in some areas.
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Results take time and the above measures are
rarely completely successful. About 30% of
patients can achieve complete clearance with a
prescription agent that contains a combination of
hydroquinone, tretinoin and a topical
corticosteroid.
Unfortunately, even in those that get a good result
from treatment, pigmentation may reappear on
exposure to summer sun and/or because of
hormonal factors. New topical and oral agents are
being studied and offer hope for effective
treatments in the future.
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Topical alpha
hydroxyacids including
glycolic acid and lactic
acid, as creams or as
repeated superficial
chemical peels, not only
remove the surface skin
but their low pH
inhibits the
activity of
tyrosinase.
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Tri-Luma is a combination prescription cream
containing fluocinolone acetonide 0.01%,
hydroquinone 4%, and tretinoin
0.05%.
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It is used to treat melasma and other skin
discoloration. Results may be seen in usually about
six to eight weeks from starting treatment. Tri-Luma
should not be used for prolonged periods exceeding
eight weeks without your doctor's recommendation.
It should not be used by pregnant or breastfeeding
women unless specifically instructed by your
physicianit must also be refrigerated.
Other combination creams include the Kligman
formula which is a triple cream including a retinoid,
a hydroquinone, and a topical steroid (for example,
fluocinolone acetonide 0.01%, hydroquinone 8%, and
tretinoin 0.1%). These triple combination creams may
be compounded in different strengths by specialty
pharmacists according to a physician's prescription.
Triple creams are highly effective for
melasma.
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It has been suggested that taking an
oral
proanthocyanidin (a class of
flavonols) along with a vitamin regimen
may significantly reduce pigmentation. At this
time, the mechanism for this treatment method
is not fully understood. Significantly more
study is necessary before this method of
treatment could be deemed effective. One
major benefit to this mode, however, is that the
use of proanthocyanidin is a natural treatment
method, and it is a safe alternative in patients
who exhibit a moderate or severe adverse
reaction to a topical treatment.[25]
In an attempt to search for a new treatment for
melasma, Wu et al studied oral administration
of tranexamic acid (TA) in Chinese
patients. Tranexamic acid tablets
were prescribed to 74 patients at a
dosage of 250 mg twice daily for 6
months. At follow-up, more than half of
patients (54%) showed good results. This
treatment may be effective for some patients,
but further study is needed.[26]
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Communication between the
nervous system and epidermal
melanocytes has been proven .
The observation that epidermal
melanocytes molecularly differ
from dermal melanocytes seems
to support the hypothesis about
double origin of skin
melanocytes Thus, melanocytes
in the skin either derive directly
from NCC populating the skin
via a dorsolateral migratory
pathway or arise from ventrally
migrating precursors forming
the myelin around the
cutaneous nerves .
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Sometimes melasma may be
preventable by avoiding facial sun
exposure. In most cases, prevention
is difficult. Individuals who have a
family history of melasma must take
extra precautions to prevent
melasma. The most
important way to prevent
the onset of melasma and
premature aging is to
avoid the sun. If exposure to
sunlight cannot be avoided, then
hats, sunglasses, and sunblock with
physical blockers should be worn.
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A daily sun protection factor
(SPF) of at least 15 that
contains physical blockers,
such as zinc oxide and
titanium dioxide, is
recommended to block UV
rays, but it is important to
have a sunblock that also
covers for UVA protection.
Chemical blockers may not
fully block both types of UVA and UV-B as effectively as
zinc or titanium. The regular
use of sun protection
enhances the effectiveness of
melasma treatments

Although melasma tends to be a
chronic disorder with periodic
ups and downs, the prognosis
for most cases is good. Just as
melasma develops slowly,
clearance also tends to be slow.
The gradual disappearance of
dark spots is based on
establishing the right treatment
combination for each individual
skin type. Melasma cases
that do not successfully
respond to treatment are
due to excessive sun
exposure.



After 30 years of age 10-20% of epidermal
melanocytes are lost every decade .
In the older people, apart from a
decreased number of melanocytes
morphology is changed (melanocytes are
larger, more dendritic) and tyrosinase
activity is reduced.
The relationships between ageing and
the proliferative activity of melanocytes
have been observed. In vitro, adult
melanocytes proliferate less times than
fetal and neonatal melanocytes . Also,
melanocytes from patients with a
premature ageing disorder have reduced
proliferative potential

Melanoblasts migrate
over very long distances
throughout the embryo,
proliferate and promote
their own survival.
Thus, melanoblast
development is a highly
dynamic process, which
requires rapid
activation of different
signaling pathways.


Recent developmental studies using model
organisms and lineage tracing have been
able to trace melanocytes arising from
migration of a multipotent precursor cell
along nerve projections. With great
probability there could be cells with stem
cell's properties located in the cutaneous
nerves, but if only ?
These cells are retained in a stem cell-like
state until the signal sent by the end of the
cutaneous nerve promotes these cells to
differentiate into melanocytes . But there are
also observations that some melanoblasts
from the dorsal way of NCC migration stay
in the dermis after the end of epidermis
inoculation, up to the second trimester
during fetal time

a, Haematoxylin and eosin stain of normal human skin. Cells of the upper layer of the
epidermis (keratinocytes) contain large nuclei, which stain blue, and the dermis appears
pink as a result of staining of its abundant protein, collagen (muscle and nerve fibres
may also stain pink). Normal melanocytes (arrows) have smaller nuclei and
inconspicuous cytoplasm compared with the surrounding keratinocytes. Melanocytes
are typically located in the basal layer of the epidermis, at the junction with the dermis.
Differences in human pigmentation reflect variations in the number of melanosomes in
keratinocytes and different melanin granule phenotype (depending on the
eumelanin/pheomelanin ratio) rather than variation in the number of melanocytes.
(Image courtesy of S. R. Granter, Brigham and Women's Hospital, Massachusetts.) b,
Immunohistochemical analysis of the same human tissue as shown in a identifies
melanocytes by using the immunohistochemical marker D5, which stains the MITF
transcription factor located in their nuclei (Image courtesy of S. R. Granter.) c, Medaka
goldfish are valuable in pigmentation studies. The wild type, B/B, is the lower of the two.
Compared with this, b/b (top), which is bred for its golden colour, lacks melanin except
in the eyes. The b locus is highly homologous with the locus for oculocutaneous albinism
4 (OCA-4) in humans, MATP or AIM1. MATP seems to be involved in melanocyte
differentiation and melanosome formation. (Image reprinted, with permission, from ref.
82.) d, The yellow pigmentation in golden labradors is recessively inherited and results
from an amino-acid substitution in Mc1r that produces a premature stop codon6. The
same pigmentation can be seen in mice (Mc1re/e), horses and cats with hypomorphic
Mc1r variants. (Image courtesy of Terra Nova.) e, Furred animals such as mice lack
epidermal melanocytes (except in non-hair-bearing sites such as the ear, nose and paws).
f, Polar bears have hollow unpigmented fur to blend in with the environment but, unlike
other furred animals, have a high density of epidermal melanocytes, which aid in heat
retention and produce black skin most notable in non-furred areas. (Image courtesy of
First People.)

In the human skin, melanocytes are present in the epidermis
and hair follicles. The basic features of these cells are the
ability to melanin production and the origin from neural
crest cells. This last element is important because there are
other cells able to produce melanin but of different
embryonic origin (pigmented epithelium of retina, some
neurons, adipocytes). The life cycle of melanocyte consists of
several steps including differentiation of melanocyte
lineage/s from neural crest, migration and proliferation of
melanoblasts, differentiation of melanoblasts into
melanocytes, proliferation and maturation of melanocytes at
the target places (activity of melanogenic enzymes,
melanosome formation and transport to keratinocytes) and
eventual cell death (hair melanocytes). Melanocytes of the
epidermis and hair are cells sharing some common features
but in general they form biologically different populations
living in unique niches of the skin.

Melanocytes form a heterogeneous group
of cells in the human body. Although all
of them have ability to produce melanin
and originate from embryonic cells
named neural crest cells (NCC), their
particular functions in all target places
are much wider than the melanin
synthesis only [1]. In the human body
melanocytes’ presence does not confirm
only epidermis, hair and iris where they
give a color of these structures.
Melanocytes have been also found in the
inner ear, nervous system, heart and
probably it is not the end of a list where
these cells exist [2, 3]. It is necessary to
stress that not only melanocytes have
ability to produce melanin but also other
cells e.g. cells of pigmented epithelium of
retina, epithelia of iris and ciliary body of
the eye, some neurons, adipocytes
The life cycle of melanocytes consists of
several steps including lineage specification
from embryonic neural crest cells
(melanoblasts), migration and proliferation
of melanoblasts, differentiation of
melanoblasts into melanocytes, maturation of
melanocytes (melanin production in special
organelles – melanosomes, dendritic
morphology), transport of mature
melanosomes to keratinocytes and eventual
cell death. Several populations of neural crest
cells (cranial, dorsal trunk, ventral trunk)
give melanocytes of the skin. The embryonic
origin of epidermal and hair melanocytes is
the same but development is different [6, 7].
The problem of melanocyte stem cells’
localization in the adult skin is still a matter
of debate. The first such place was a hair
bulge, but if only…? [8]. Experimental data
clearly show that the trunk NCC migrating
through a ventral pathway could remain in a
myelin sheath of the cutaneous nerves and in
particular situations give melanoblasts [9,
10]. The embryonic development of
melanocytes give an opportunity to better
understand the skin diseases e.g. melanoma
and its heterogeneity, vitiligo. Thus, in this
review the epidermal and hair melanocytes’
biology and development are characterized.


Abstract
Biologically, light including ultraviolet (UV) radiation is vital
for life. However, UV exposure does not come without risk,
as it is a major factor in the development of skin cancer.
Natural protections against UV damage may have been
affected by lifestyle changes over the past century, including
changes in our sun exposure due to working environments,
and the use of sunscreens. In addition, extended “day time”
through the use of artificial light may contribute to the
disruption of our circadian rhythms; the daily cycles of
changes in critical bio-factors including gene expression.
Circadian disruption has been implicated in many health
conditions, including cardiovascular, metabolic and
psychiatric diseases, as well as many cancers. Interestingly,
the pineal hormone melatonin plays a role in both circadian
regulation as well as protection from UV skin damage, and is
therefore an important factor to consider when studying the
impact of UV light. This review discusses the beneficial and
deleterious effects of solar exposure, including UV skin
damage, Vitamin D production, circadian rhythm disruption
and the impact of melatonin. Understanding these benefits
and risks is critical for the development of protective
strategies against solar radiation.


Introduction
The electromagnetic solar spectrum, which
includes visible light and ultraviolet (UV)
radiation among other radiation, plays a
significant role in a variety of biological functions
within a living system. In earth’s natural
environment, we are exposed to the solar radiation
in a regular 24 h cycle which varies according to
the season. This radiation may have beneficial as
well as harmful effects to living organisms. For
example, UV radiation has many effects on the
environment and the organisms inhabiting the
planet. The most beneficial impact of UV light in
humans is its essential role in the production of
Vitamin D3 in the skin. Calcitriol, the active form
of vitamin D3, participates in a variety of the
body’s protective functions, including DNA
damage repair and immune function. However,
excessive exposure to UV radiation can have a
variety of adverse effects on the skin, including
cancers of the skin. Studies have suggested that
solar radiations are important regulators of
“circadian rhythms,” which by definition are
physical, mental and behavioral changes that
follow a ∼ 24 h cycle that primarily responds to
light and dark in an organism’s environment

Unfortunately, the lifestyle factors of the modern era such as the widespread use
of artificial lights to extend our “daylight” time contribute adversely to the
biological processes leading to unwanted conditions and responses. For
example, excessive UV exposure to skin can cause skin aging, precancerous skin
conditions and melanoma and nonmelanoma skin cancers. The modern research
is suggesting that circadian rhythms may be involved in the development
and/or progression of cancer because it is believed that ∼10% of the genes
oscillate according to the body’s circadian clock. Their functions are widely
varied but are connected with the normal cell cycle, metabolic functions and
DNA damage repair. Normal circadian rhythms are therefore essential for the
body’s natural defense against diseases such as cancer. It is believed that a
deregulation of oscillatory expression and function of circadian rhythm
regulatory genes over the 24 h period enhances the risk of carcinogenesis. Light
and dark cycles influence the circadian clock and the daily oscillations of the
genes controlled by the circadian rhythms. Although artificial light can also
contribute to the circadian network, solar light is its major regulator. With
increased exposure to artificial light, there is an increase in the probability of
disrupting these rhythms, as circadian rhythm gene expression has been shown
to be lower in artificial light relative to natural light.

Altered circadian rhythm disrupts the DNA damage
responses and cell cycle regulations as well as the
expression of the pineal hormone melatonin. Like other
circadian factors, the circadian control of melatonin
secretion is regulated by the circadian clock machinery
which depends on a network of genes and their rhythmic
oscillations driven by the circadian timing system located
in the suprachiasmatic nucleus (SCN) of the hypothalamus
as well as peripheral oscillators located in cells.
Dysregulated circadian control of melatonin can contribute
to the adverse effects of UV radiation on the skin, as
melatonin has been shown to have a protective role against
UVB skin damage. Further, melatonin is a strong
antioxidant and can attenuate UV radiation mediated
oxidative stress. Indeed, low levels of melatonin have been
associated with increased risk or shown to play a role in
the development of several cancers

Choosing the
appropriate laser and
the correct settings is
vital in the treatment of
melasma. The use of
latter should be
restricted to cases
unresponsive to topical
therapy or chemical
peels. Appropriate
maintenance therapy
should be selected to
avoid relapse of
melasma.

A selective window for
targeting melanin lies between
630 and 1100 nm, where there is
good skin penetration and
preferential absorption of
melanin over
oxyhaemoglobin.[2] Absorption
for melanin decreases as the
wavelength increases, but a
longer wavelength allows
deeper skin penetration. Shorter
wavelengths (<600 nm) damage
pigmented cells with lower
energy fluencies, while longer
wavelengths (>600 nm)
penetrate deeper but need more
energy to cause melanosome
damage.

Besides wavelength,
pigment specificity of
lasers also depends on
pulse width.[2] With an
estimated TRT of 250–
1000 ns, melanosomes
require submicrosecond
laser pulses (<1 μs) for
their selective
destruction, but longer
pulse durations in the
millisecond domain do
not appear to cause
specific melanosome
damage.[


Laser was compared with pre- or posttreatment TCC. The authors found that
pre-treatment with TCCs was more
effective as this decreases melanin
production before laser injury, hence
chances of PIH are reduced and the
melasma is improved. If TCC is used
after laser treatment, melanin is being
produced at full capacity, hence
increasing chances of PIH and slowing
improvement of melasma. Hence, the
authors recommend medical treatment
for hyperpigmentation for at least 8
weeks before laser treatment to achieve
optimal results.
This technique used in the above studies
has recently been referred to as “laser
toning” or “laser facial” and has become
increasingly popular. It is widely used in
Asian countries for skin rejuvenation and
melasma. Laser toning involves the use of
a large spot size (6–8 mm), low fluence
(1.6–3.5 J/cm2), multiple passed QS 1064
nm Nd:YAG laser performed every 1-2
weeks for several weeks.[
Rebound hyperpigmentation
treated five Chinese patients with melasma with laser toning. There was no significant
improvement in melasma and all five patients developed laser-induced depigmentation.
Possible pathogenic mechanisms for this depigmentation could be high fluences causing direct
phototoxicity and cellular destruction of melanocyte, subthreshold additive effect of multiple
doses, intrinsic unevenness of skin pigmentation, and non-uniform laser energy output.Several
other side effects mentioned in the literature include rebound
hyperpigmentation,
physical urticaria, acneiform eruption, petechiae, and herpes simplex
reactivation.
Rebound hyperpigmentation could be due to the multiple subthreshold exposures that
can stimulate melanogenesis in some areas.
They found that only 532 and 1064 nm at threshold and suprathreshold dose produced permanent
leukotrichia. At subthreshold exposure, none of these wavelengths caused hypopigmentation but they
accelerated melanogenesis.
To avoid serious side effects, it is recommended that too many (>6-10) or too frequent (every week)
laser sessions with QS Nd:YAG should be avoided. Hypopigmentation should be looked for after
every session and further treatments should be stopped.
The PIH could be due to the inflammatory dermal reaction induced by laser
that stimulated the activity of melanocytes in treated skin.
The occurrence of PIH limits the use of this laser for recalcitrant melasma.
Moreover, there are hardly any studies documenting its efficacy in melasma.
FRACTIONAL LASERS
Fractional phtothermolysis is a new concept in laser therapy in which multiple
microscopic zones of thermal damage are created leaving the majority of the
skin intact. The latter serves as a reservoir for healing. These multiple columns
of thermal damage are called microthermal treatment zones (MTZ) and lead to
extrusion of microscopic epidermal necrotic debris (MENDs) that includes
pigment in the basal layer. The viable keratinocytes at the wound margins
facilitate the migration of MENDs. The depth and diameter of MTZ are
determined by the energy levels used. 6 mJ/MTZ corresponds to a diameter of
80 μm and depth of 360 μm in each MTZ.[6] The density used and the number
of passes determine the proportion of surface area treated.
IPL and melanocytic lesions, treated two patients with epidermal melasma and
achieved 76–100% clearance with fluence of 34 J/cm2, pulse width of 3.8 ms, double
mode, and pulse delay of 20 ms.[52] However, three patients with mixed melasma
showed less than 25% clearance with 615 nm filter, fluence 38 J/cm2, pulse width of
4.5 ms, double mode, and delay of 20 ms. Patients developed PIH.
The only RCT done in this domain is that by Wang et al. in which patients with refractory
melasma were treated with IPL and hydroquinone and compared with hydroquinone
alone.[50] 570 nm cutoff filter was used in the first session and 590–615 nm filters for
subsequent sessions to target deeper melanin. Fluence used varied from 26 to 33 J/cm2, double
mode and pulse length of 3–4 and 4–5 ms, respectively. However, in this study the authors
preferred to use long delay between pulses (30–35 ms) which is higher compared to other
studies. The IPL group achieved a significant response (39.8% clearance) compared to control
group (11.6% clearance). Treatment efficacy did not correlate with any variables, such as age,
duration of melasma, or skin phototype. Also, there was recurrence 6 months after therapy
indicating the need for additional treatments to maintain results.


The laser settings play an important role in the treatment.
500–550 nm filters can be used initially and for epidermal
lesions, whereas higher wavelength filters can be used to
target deeper melanin hence patients with dermal/mixed
melasma. The fluence can be modulated in relation to the
anatomic sites. Higher fluence can be used for cheek and
zygoma, whereas perioral region and neck need lower
fluencies. Higher fluencies are useful for deeper lesions but
cause PIH in dark skinned patients. Therefore, for darker skin,
lower fluence should be used. Single pulses heat pigment
well, but double or triple pulses should be used as they
reduce the thermal damage by allowing the epidermis to cool
while the target stays warm. The pulse duration used in the
studies varied from 3 to 5 ms. Average pulse delay used was
10–20 ms. However, Wang et al. used long delay between
pulses (30–35 ms) with good results.[50] It is important that
delay time between pulses should not be below 10 ms as this
increases the risk of thermal damage as the targeted tissue
cannot reduce its temperature within that time. Average
number of sessions used in these studies was 2–5 at an
interval of 4–8 weeks. However, more number of sessions is
required for maintenance and it decreases the chances of
recurrence.
It is a good approach to do a pre-test session before starting
treatment to assess the efficacy of settings and look for any
cutaneous hyper-reactivity.


The studies show that IPL is effective for
epidermal melasma. Dermal or mixed or
refractory melasma can be targeted with higher
fluencies though the risk of PIH should be kept
in mind in darker skin. It is a good approach to
use low fluences and long delay between pulses
in such cases as done by Wang et al.[50] Also,
sun protection and hydroquinone should be
used throughout treatment and thereafter.
Patients treated in these studies also had
additional benefits of brighter skin colour,
smoother skin texture, and uniform
pigmentation.[

Zoccali and colleagues used
dermoscopy to assess the area
immediately after treatment
session to choose the correct
parameters: a transient
hyperpigmentation (colour
change to grey) indicating a
correct IPL setting.[51] Postdermoscopy is helpful in
evaluating the IPL efficacy and
healing process. Post IPL
dermoscopic finding can be
classified into three patterns: (1)
spotty/small dotted, (2)
reticulated, and (3) complex
(clumped). These clinical
patterns represent clinical
pictures of microcrust formed
during the process.[

Kono and colleagues
conducted a prospective
direct comparison study
of fractional resurfacing
using different fluences
and densities for skin
rejuvenation and found
that greater density was
more likely to produce
erythema, swelling, and
hyperpigmentation.[










In order to treat melasma, combination or specially
formulated creams with hydroquinone, a phenolic
hypopigmenting agent, azelaic acid, and retinoic
acid (tretinoin), nonphenolic bleaching agents,
and/or kojic acid may be prescribed. For severe
cases of melasma, creams with a higher
concentration of HQ or combining HQ with other
ingredients such as tretinoin, corticosteroids, or
glycolic acid may be effective in lightening the skin.
Azelaic acid 15%-20% (Azelex, Finacea)
Retinoic acid 0.025%-0.1% (tretinoin)
Tazarotene 0.5%-0.1% (Tazorac cream or gel)
Adapalene 0.1%-0.3% (Differin gel)
Kojic acid
Lactic acid lotions 12% (Lac-Hydrin or Am-Lactin)
Glycolic acid 10%-20% creams (Citrix cream,
NeoStrata)
Glycolic acid peels 10%-70%
Other proprietary ingredients and mixtures of
ingredients as in Elure, Lumixyl, and SkinMedica's
Lytera products




In conjunction with home cream applications, in-office treatments include
chemical peels (chemical exfoliation), microdermabrasion (mechanical
exfoliation), and laser therapy. These additional treatments may be useful
for some cases of melasma, although laser still has issues with
reproducibility.
Many types and strengths of chemical peels are available for different skin
types. The type of peel should be tailored for each individual and selected
by the physician. In treating melasma, 30%-70% glycolic acid peels are very
common. Various combinations, including a mix of 10% glycolic acid and
2% HQ, can be used to treat melasma.
Microdermabrasion utilizes vacuum suction and an abrasive material like
fine diamond chips or aluminum oxide crystals to exfoliate the top layers of
the skin. The vacuum pressure is adjusted depending on the sensitivity and
tolerance of the skin. Typical microdermabrasion sessions can last anywhere
from a few minutes to one hour. Minimal to no recovery time is needed
after microdermabrasion. Microdermabrasion techniques can improve
melasma, but dramatic results are not generally seen or expected after one
or two treatments. Multiple treatments in combination with sunscreen and
other creams yield best results.
There is no guarantee that melasma will be improved with these
procedures. In some cases, if treatments are too harsh or abrasive, melasma
can be induced or worsen. Additionally, these procedures are almost
always considered cosmetic and may not be covered by medical insurance
providers.


Lasers may be used in melasma, but they
generally produce only temporary
results. Laser therapy is not the primary
choice to treat melasma as studies reveal
little to no improvement in the
hyperpigmentation for most patients.
Lasers may actually worsen some types
of melasma and should be used with
caution. Multiple laser treatments may be
necessary to see results, as treatments are
most effective when they are repeated.
To ensure that treatment doesn't fail,
people must minimize sun exposure.
People who treat their melasma report a
better quality of life because they feel
better about themselves. As with any
treatment, people should consult their
physician. Pregnant women or mothers
breastfeeding may need to wait to treat
melasma. Many melasma creams need to
be discontinued in pregnancy and
breastfeeding because of possible risks to
the developing fetus and newborn. These
people may consider cosmetics to
temporarily conceal the skin
discoloration.

Researchers believe
that the
hydroxyphenolic
chemical (HQ) blocks
a step in a specific
enzymatic pathway
that involves
tyrosinase. Tyrosinase
is the enzyme that
converts dopamine to
melanin. Melanin
gives skin its color.



Azelaic acid is a non-hydroquinone cream that
can be used to treat melasma. Studies have
reported that 15%-20% azelaic acid was very
effective and safe in melasma, although the
overall results are significantly less impressive
than 4% hydroquinone. There are no major
complications reported with azelaic acid.
Possible minor side effects include itching
(pruritus), redness (erythema), scaling (dry
patches), and a temporary burning sensation
that tends to improve after 14-30 days of use.
Tretinoin cream (Retin A, Renova, Retin A
Micro) is a non-hydroquinone cream used to
treat melasma. Most often, tretinoin is used in
combination with other creams like azelaic acid
or hydroquinone. Mild localized side effects are
fairly common and include peeling, dry skin,
and irritation. Overall, melasma may respond
slower to treatment with tretinoin alone than
with hydroquinone. The Obagi system combines
tretinoin with Obagi Blender.
Other retinoid creams include tazaratone and
adapelene. These are prescription creams used
much like tretinoin (Retin A).

[19] In
fact, the only topical
ointment currently approved by
the US Food and Drug
Administration (FDA) for the
treatment of melasma is the
Triple Combination Cream, a
composite of hydroquinone 4%,
tretinoin 0.05%, and
fluocinolone acetonide 0.01%.
Comparative studies of the
effectiveness of the Triple
Combination cream vs topical
HQ suggest that the
combination cream is faster and
more effective at reducing
melasma pigmentation, but it
does carry a slightly increased
risk of an adverse reaction.[20]

This is consistent with
the theory of selective
photothermolysis,
which states that the
pulse duration of an
emitted laser
wavelength must be less
than the thermal
relaxation time of the
targeted object. A
typical 1-µm
melanosome has a
thermal relaxation time
of 0.5-1 microseconds.

Tissue repair following laser-induced
melanosomal disruption demonstrates a 2staged initial transient cutaneous
depigmentation followed by subsequent
repigmentation weeks later. Black guinea pig
skin irradiated with 40-nanosecond Q-switched
ruby pulses at a radiant exposure of 0.4 J/cm2 or
greater whitens immediately, fades in 20
minutes, depigments 7-10 days later, and then
repigments 4-8 weeks after treatment. The
repigmented guinea pig skin displays a
persistent leukotrichia, which can last up to 4
months after laser irradiation. Guinea pig skin
exposed to a radiant exposure of less than that of
the threshold exposure (< 0.3 J/cm2) undergoes
paradoxical melanogenesis. This may be due to
either a sublethal change in the melanosome
(interfering with the normal feedback inhibition
of melanogenesis) or simply postinflammatory
hyperpigmentation. Further studies are required
to evaluate the therapeutic implications of this
paradoxical reaction.

More recent guidelines
advise against lasering
"benign pigmented
lesions" in tattoos, as 13
cases of melanoma have
been reported at such
sites. Thus, one must
remove tattoos with
pigmented lesions
underneath with
extreme caution.[82]