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Management of hyperpigmentation: Current
treatments and emerging therapies
Avni Nautiyal | Sarika Wairkar
Submit your next paper to PCMR online at http://mc.manuscriptcentral.com/pcmr
Pigment Cell Melanoma Res. 2021;00:1–15.
1 | INTRODUCTION
Hyperpigmentation of the skin is a common dermatological condi-
tion in which the color of the skin generally becomes darker. These
changes in skin coloration can be a result of various internal and
external factors including hormonal changes, inflammation, injury,
acne, eczema, certain medication, UV exposure, etc. (Pérez- Bernal
et al., 2000). Skin pigmentation and coloration are governed by
the biological processes involving the production of the skin pig-
ment called melanin produced by melanocytes in various layers of
skin. Thus, alterations in melanocyte production or distribution
of melanin result in skin hyperpigmentation disorders (Rossi &
Hyperpigmentation is an umbrella term that includes various
skin discoloration, pigmentation, and darkening- related disorders.
Various commonly observed hyperpigmentation disorders include
melasma, post- inflammatory hyperpigmentation, ephelides, lentig-
ines, and many more. Melasma refers to an acquired hypermelano-
sis skin condition in which irregular patches of light to dark brown
or gray– brown lesions appear on the sun- exposed parts of the skin
(Katsambas & Antoniou, 1995; Victor et al., 2004). It usually af-
fects the face and the neck regions and predominantly observed
in women (Handel et al., 2014). Post- inflammatory hyperpigmen-
tation (PIH) refers to another hypermelanosis skin condition in
which dark patches develop succeeding injury or inflammation of
the skin (Kaufman et al., 2018). Solar lentigines is a condition in
Received: 3 December 2020
Revised: 16 April 2021
Accepted: 10 May 2021
DOI : 10.1111/pcmr.1298 6
Management of hyperpigmentation: Current treatments and
Avni Nautiyal | Sarika Wairkar
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Shobhaben Pratapbhai Patel School of
Pharmacy & Technology Management,
SVKMs NMIMS, Mumbai, India
Sarika Wairkar, Shobhaben Pratapbhai
Patel School of Pharmacy & Technology
Management, SVKM’s NMIMS, V.L.Mehta
Road, Vile Parle ( W), Mumbai - 400 056,
This research did not receive any specific
grant from funding agencies in the public,
commercial, or not- for- profit sectors.
Hyperpigmentation of the skin refers to a dermatological condition which alters the
color of the skin, making it discolored or darkened. The treatments for hyperpigmen-
tation disorders often take very long to show results and have poor patient compli-
ance. The first- line treatment for hyperpigmentation involves topical formulations
of conventional agents such as hydroquinone, kojic acid, and glycolic acid followed
by oral formulations of therapeutic agents such as tranexamic acid, melatonin, and
cysteamine hydrochloride. The second- line approaches include chemical peels and
laser therapy given under the observation of expert professionals. However, these
therapies pose certain limitations and adverse effects such as erythema, skin peel-
ing, and drying and require long treatment duration to show visible effects. These
shortcomings of the conventional treatments provided scope for further research
on newer alternatives for managing hyperpigmentation. Some of these therapies in-
clude novel formulations such as solid lipid nanocarriers, liposomes, phytochemicals,
platelet- rich plasma, microneedling. This review focuses on elaborating on several
hyperpigmentation disorders and their mechanisms, the current, novel and emerging
treatment options for management of hyperpigmentation.
topical formulations, chemical peels, laser therapy, hyperpigmentation, novel therapies
NAUTIYAL ANd WAIRKA R
which patches of darkened macular lesions cause hyperpigmenta-
tion, commonly referred to as “Age spots” or “Sunspots” (Ortonne
et al., 2006). Another common disorder, Ephelides or Freckles is
darkened, reddish to light brown spots that typically develop on the
facial, neck, and arm areas. They develop during the childhood phase
and are more prevalent in lighter or fairer skin individuals (Ezzedine
et al., 2013). Although hyperpigmentation is a common cosmetic
complaint in most skin types, it is prominently found in middle- aged
women and the population with III– VI skin type (Woolery- Lloyd
& Kammer, 2011). El- Essawi et al reported that skin discoloration
and uneven skin tone are common skin problems faced by African
Americans, with almost 50% participants facing such concerns
(Silpa- Archa et al., 2017). Among the Arab Americans, PIH is mainly
reported by people of darker skin tone originating from Yemen and
the ones with lighter skin tone from Lebanon and Syria (Kaufman
et al., 2018). In another study comprising 3,000 Latinos, the occur-
rence of melasma and hyperpigmentation was reported to be 7.5%
and 6.0% , respectively (Silpa- Archa et al., 2017). In Asia, Malays and
Indians have a higher incidence of PIH compared with the Chinese
who are lighter skinned. A study conducted in the Netherlands re-
ported the occurrence of solar lentigines in 51.4% individuals in
the face and 83.3% on the back. (Bastiaens et al., 2004) Similarly,
Caucasian patients report incidences of pigmentary disorders,
other than vitiligo, which is the seventh most common dermatoses
(Callender et al., 2011).
Hyperpigmentation is not considered a harmful or lethal disor-
der; however, it can affect the quality of life of patients by affecting
their emotional and psychological health. Various treatment options
are available for hyperpigmentation. These agents are primarily
applied by topical route in the form of creams, gels, or ointments.
However, these topical treatments pose various side effects such as
skin drying, irritation, peeling, or hypopigmentation. The prolonged
treatment durations ranging from several months to years may lead
to poor patient compliance and satisfaction. The challenge of effec-
tive therapy to treat hyperpigmentation remains unresolved that
lays emphasis on the need for novel treatment options. This article
thus focuses on the therapeutic targets as well the various conven-
tional, novel and emerging therapies being approached for the bet-
ter, effective, and timely management of hyperpigmentation.
2 | PATHOPHYSIOLOGY OF
Melanocytes responsible for the tegument color in skin is pro-
duced embryonically from neural crest cells. They are melanosome-
producing cells present in the basal layer at the dermal and
epidermal junction (Duval et al., 2014). Melanosomes are intracel-
lular, lysosome- like organelles that host the production and stor-
age of the skin pigments like melanin. These pigments are further
distributed to the neighboring keratinocytes, giving skin its color
(Yamaguchi & Hearing, 2009). The amino acid L- Tyrosine acts as the
precursor for melanin biosynthesis and produces melanin through
various spontaneous enzymatic reactions, also known as the Raper
Mason pathway, as described in Figure 1. The melanogenesis path-
way occurs within a melanosome leading to the production of black–
brown Eumelanin and/or the yellow– red Pheomelanin. L- Tyrosine
increases melanosome production and L- Dopachrome increases
tyrosinase activity. Thus, regulating the L- Tyrosine and L- DOPA
levels plays a major role in homeostasis of melanogenic systems
(Yamaguchi & Hearing, 2009).
Tyrosinase, a glycoprotein (60– 70 kDa), contains copper and acts
as the rate- limiting enzyme of the melanin biosynthesis pathway
and, therefore, considered as a potential target for several therapeu-
tic agents. The tyrosinase, T YRP- 1 and T YRP- 2, enzymes involved
in melanogenesis are regulated by the master transcription factor
known as the microphthalmia transcription factor (MITF). The α-
melanocyte- stimulating hormone (α- MSH) and the adrenocortico-
tropic hormone (ACTH) are present in the epidermis and dermis and
act as major regulators of the melanogenesis pathway.
Melanosomes undergo degradation differently in diverse
skin types during the keratinocyte differentiation process. They
either reach the outermost epidermal layers intact, as seen in
darker skin, or form melanin dust like in fairer skin types. The
vast variations in skin color and complexions seen in humans are
thus a result of these complex processes (D’Mello et al., 2016).
Various factors, intrinsic or extrinsic, can be responsible for dis-
rupting the normal melanogenesis process and result in many hy-
perpigmentation disorders. Signals and factors such as UV, cAMP,
and IL1 can enhance and regulate the pro- opiomelanocortin
(POMC) peptides, which act as precursors of alpha- MSH (Duval
et al., 2014). Upon UV exposure, melanosomes are distributed to
the surrounding keratinocytes and the upper epidermis for DNA
photoprotection. It causes the apoptosis of melanin- containing
keratinocytes in the upper epidermis to prevent cell growth with
unrepaired DNA damage. Keratinocytes further release several
growth factors such as alpha- MSH, Endothelin- 1 (ET- 1), and
aid in the UV- induced hyperpigmentation (Eichner et al., 2014;
Yamaguchi & Hearing, 2009). Various intrinsic factors involved
in hyperpigmentation include signals from fibroblasts, endothe-
lial cells, keratinocytes, several hormones, inflammatory cells,
and the nervous system. These cells may release ET- 1 and NO
(Nitric oxide) which potentiate melanogenesis (Yamaguchi &
Hearing, 2009). Inflammation brings about an increase in the
release of arachidonate- related chemical mediators such as PGs
(PGE2, PGF2a), leukotrienes (LTC4, LTD4), and thromboxanes,
which are known to enhance tyrosinase activity. Additionally,
muscarinic, and alpha and beta estrogen receptors have been
found to be involved in adenyl cyclase and cAMP production.
The elevated estrogen levels in pregnancy can thus contribute to
hyperpigmentation disorders such as melasma and areolar hyper-
pigmentation (Eichner et al., 2014).
The histopathology of hyperpigmentation can vary with the vari-
ous pigmentation disorders. The histopathological features of melasma
include epidermal thinning and rete ridge flattening. Increased mela-
nin content in both the epidermis and dermis and mild perivascular
NAUTIYAL ANd WAI RKAR
lymphohistiocytic infiltrate is observed here. Immunohistochemistry
analysis suggests enlarged melanocytes with prominent dendrites, a
larger number of dermal melanophages, and their melanin deposition.
Electron microscopy studies reported increased melanosomes in the
melanocytes and keratinocytes. In PIH mainly, increased epidermal
melanin content is observed in the lymphocytes surrounding blood
vessels in dermal papilla and dermal melanophages. Perifollicular, peri-
vascular lymphocytic infiltration, and dermal fibrosis can also be ob-
served with increased expression of several markers such as [CD]- 68,
c- kit, and MMP- 2 emphasizing the role of skin inflammation. Two his-
topathological patterns of PIH can be distinguished as epidermal type
and dermal type. In prior, increased melanogenesis, melanin deposition
in the epidermis is observed, whereas the latter is characterized by en-
hanced pigment deposition in the dermis in spite of enhanced melano-
genic activity in the epidermis (Nicolaidou and Katsambas, 2014; Kang
et al., 2002; Silpa- Archa et al., 2017; Isedeh et al., 2016).
3 | CURRENT TREATMENTS FOR
The potential targets for the depigmenting and hyperpigmentation
control agents include various cell receptor antagonists, inhibitors
of melanocyte stimulation, tyrosinase enzyme inhibitors, inhibitors
of melanosome transfer, and degraders of formed melanin in ke-
ratinocytes as described in Figure 2. The widely targeted approach
includes the inhibition of tyrosinase, most important rate- limiting
enzyme of the melanogenesis pathway.
3.1 | Topical treatments
Topical agents are widely used for the treatment or management
of site- specific skin hyperpigmentation and were formulated into
topical dosage forms such as creams and gels. Hydroquinone, a gold
standard for hyperpigmentation treatment, has been in topical use
since the 1960s that acts by inhibiting tyrosinase to interfere with
the melanin synthesis. The strength of the available products ranges
up to 4% (Haddad et al., 2003). Another agent, Arbutin, is a deriva-
tive of hydroquinone, but with much lesser melano- toxic effects. Its
depigmenting activity is due to its tyrosinase inhibition along with
melanosome maturation inhibition activity. The anti- tyrosinase
activity of arbutin is dose dependent; however, the use of higher
concentrations should be monitored as it may cause paradoxical hy-
perpigmentation (Piamphongsant, 1998).
Glycolic acid is a white crystalline alpha hydroxy acid extracted
from sugarcane (Van Scott et al., 1996). The effect of glycolic acid is
concentration dependent. It works by causing desquamation of ke-
ratinocytes at lower concentrations and by producing epidermolysis
at higher concentrations (Fischer et al., 2010). Kojic acid is commonly
used for hyperpigmentation disorders owing to its various mecha-
nisms including tyrosinase inhibition. It acts mainly by inhibiting the
catecholase activity of tyrosinase. Another study suggested that its
depigmenting and anti- melanogenesis effect is due to the forma-
tion of interleukin- 6 protein by kojic acid in keratinocytes (Cabanes
et al., 1994; Choi et al., 2012). However, various clinical studies have
suggested contact dermatitis as a common side effect of kojic acid
therapy (Nakagawa et al., 1995).
FIGURE 1 The melanogenesis
NAUTIYAL ANd WAIRKA R
Retinoids comprise of Vitamin A or Retinol and its structural and
functional derivatives. They have multiple mechanisms that lead to
depigmentation including effects on cell proliferation, differentia-
tion, and inflammation (Jacyk, 2001). Retinoids inhibit the induction
of melanogenesis process by the melanocyte- stimulating hormone
(MSH) or L- tyrosine, but do not affect the growth and morphology
of the melanocytes, tyrosinase enzyme, or dopachrome tautomer-
ase (Ebanks et al., 2009). Tretinoin, a first- generation retinoid, is a
natural derivative of retinol and has been suggested to be effective
against hyperpigmentation due to photoaging (Bhawan, 1998; Weiss
et al.,1988) Formulating lower concentrations of tretinoin (up to
1%) in creams or gels can help in reducing its side effects (Embil &
Nacht, 1996). Certain third- generation synthetic retinoids such as
adapalene (0.1 to 0.3%) and tazarotene (0.05 to 1%) creams and gels
have also been found to be safe and effective in treating PIH (Grimes
& Callender, 2006; Jacyk, 2001).
Azelaic acid inhibits tyrosinase and produces a direct anti-
proliferative effect on the melanogenesis pathway (Bergman &
Luke, 2017). It does not affect the normal melanocytes and does not
lead to ochronosis on prolonged use as seen in 4% hydroquinone
(Baliña & Graupe, 1991). Niacinamide is the physiologically active
analog of Vitamin B3, which inhibits the transfer of melanosomes to
the surrounding keratinocytes and also to disrupt the cell- signaling
pathway between melanocytes and keratinocytes as suggested by
various in vitro studies. It, however, does not inhibit tyrosinase activ-
ity or cell proliferation to affect melanogenesis (Matts et al., 2002).
The melanin synthesis pathway is a complex, multistep process;
therefore, several topical agents can be employed together to act
upon different steps of the pathway suggesting a rationale for combi-
nations of topical agents for synergistic effects, or could sometimes
alleviate t he undesirable side effec ts of the other. Hence, seve ral top-
ical combinations have been studied and even marketed by various
pharmaceutical companies. Hydroquinone is the most widely used
component for combinations with several agents such as kojic acid,
glycolic acid, azelaic acid, or corticosteroids. These combinations
have shown to be therapeutically more effective than hydroquinone
alone (Ferreira Cestari et al., 2007). The “Triple combination” of 5%
hydroquinone with 0.1% tretinoin and 0.1% dexamethasone was sug-
gested to be effective in treatment of PIH, melasma, and ephelides.
Tretinoin was found to prevent the oxidation of hydroquinone and
also enhance its epidermal penetration and the corticosteroid re-
duced skin irritation and side effects (Kligman & Willis, 1975). This
combination, however, posse ssed the side effe ct of skin irritation due
to high tretinoin concentration, and thus instead, the combination
of 4% hydroquinone with 0.05% tretinoin and 0.01% fluocinolone
acetonide was studied and found to be effective (Torok et al., 2005).
FIGURE 2 Process of hyperpigmentation, potential targets and agents for control of hyperpigmentation
NAUTIYAL ANd WAI RKAR
Various clinical studies performed on these topical agents to eluci-
date their efficacy have been described in Table 1.
3.2 | Oral treatments
Oral drugs are considered as second- line treatment for hyperpig-
mentation, and Tranexamic acid is one of them. Studies in guinea pig
skin suggested that it reduces tyrosinase enzyme activity by inhibit-
ing UV- induced plasmin activity which in turn leads to reduction in
both arachidonic acid and prostaglandins, eventually affecting ty-
rosinase (Cho et al., 2013; Kato et al., 2011).
Melatonin, a hormone secreted by the pineal gland, possesses
free radical scavenging and antioxidant properties and stimulates
various antioxidant enzymes like glutathione peroxidase, and in-
hibits the α- MSH receptor. According to a study, topical melatonin
alone, as well as combined with 4% hydroquinone and oral mela-
tonin, was shown to significantly decrease the pigmentation in all
melasma patients. It also caused an increase in glutathione levels and
a decrease in malondialdehyde levels, showing alleviation in oxida-
tive stress (Hamadi, 2009). Cysteamine hydrochloride occurs natu-
rally in the body as the degradation product of the L- cysteine amino
acid. A randomized, double- blind study showed that 5% cysteam-
ine significantly improved pigmentation in melasma patients than
placebo owing to its hydroxy radicals scavenging activity (Besouw
et al., 2013). Glutathione, a tripeptide produced in the body, acts as
a strong antioxidant. It has skin- lightening activity via various mech-
anisms like tyrosinase enzyme inhibition and the ability to switch
production of eumelanin to pheomelanin (Sonthalia et al., 2016).
In a clinical study, 50 mg glutathione lozenge was shown to mod-
erately lighten or reduce hyperpigmentation in 90% of the subjects
(Handog et al., 2016). Another randomized, double- blind clinical
study suggested that both oral and topical glutathione significantly
reduced the melanin index in patients with melasma (Hashizume &
3.3 | Chemical peels
Chemical peels are a prevalent option for several hyperpigmenta-
tion disorders, second to topical ones. Chemical peels work by caus-
ing desquamation and remove the superficial topmost layers of the
stratum corneum. They further enhance the penetration if and when
used in combination with other topical agents.
Jessner's solution is a chemical peel consisting of 14% salicylic
acid, 14% lactic acid, and 14% resorcinol in alcohol solution. It has
been widely used for several years, with good safety and efficacy
as a medium depth chemical peel, de- keratinizing agent, and even
as a penetration enhancer. Amer and Metwalli, 2000 studied the
effect of Jessner's solution chemical peel on 60 Asian melasma
patients in a randomized study. After 12 weeks of treatment, the
melasma area severity index (MASI) scores were significantly de-
creased from the initial 6.5 ± 3.84 to 2.9 ± 3.03. (Ejaz et al., 2008).
Tretinoin peel s have been explore d due to their capa bility of caus-
ing similar therapeutic and histological effects as topical Tretinoin,
but in a reduced span of 2.5 weeks instead of 4– 6 months (Cucé
et al., 2001). A study suggested that increasing the concentration
of Tretinoin peel from 1% to 10% decreased the time for skin con-
tact from 4 to 8 hr to just 1 hr, while still maintaining the same effi-
cacy (Ghersetich et al., 2010). Similarly, glycolic acid peels have been
found to be beneficial in hyperpigmentation disorders like melasma
and post- inflammatory hyperpigmentation (Fischer et al., 2010).
Salicylic acid peels (20%– 30%) cause peeling of the superficial
skin layer, however, have shown mixed results. In a randomized,
double- blind study conducted by Ejaz et al., 2008, salicylic acid peel
was found to be as effective in melasma patient s as that of Jessners's
solution (Ejaz et al., 2008). Another randomized study suggested no
significant improvement in the pigmentation of patients with post-
inflammatory hyperpigmentation treated with salicylic acid peel
(Joshi et al., 2009). In the same way, lactic acid peels study revealed
its safety and efficacy in reducing the hyperpigmentation in dark-
skinned patients with melasma by decreasing MASI scores to 56%
(Monheit , 2005). Trichloroacetic acid is known to penetrate between
superficial papillary and mid- reticular dermis and cause medium-
depth chemical peeling on the skin (Otley & Roenigk, 1996). The
use of higher concentration of trichloroacetic acid (10%– 65%) as a
deeper peel poses a risk of causing post- inflammatory hyperpigmen-
tation in patients with darker skin (Chun et al., 2004).
Although peels are effective in various hyperpigmentation dis-
orders, their high concentrations and related side effects are often
3.4 | Laser therapy
Light amplification by stimulated emission of radiation (Lasers) is a
source of high- intensity monochromatic coherent light. The intro-
duction of laser therapy transfigured the treatment options for many
skin disorders, especially hyperpigmentation. The safety and effi-
cacy of lasers remains debatable; however, many hyperpigmentation
disorders have reported good results with this therapy.
Intense pulsed light (IPL) has shown promising improvements in
the treatment of hyperpigmentation. It involves the use of a xenon-
chloride lamp that emits light with a wide spectrum. Due to possible
alterations in parameters such as wavelength and fluence, it is fre-
quently used for melanocytic lesions, hair removal, vascular lesions,
and melasma (Sarkar et al., 2012). Another widely used option for
hyperpigmentation is Q- Switched neodymium- doped yttrium alumi-
num garnet (QS Nd:YAG) laser. This laser is highly selective, having a
longer wavelength and hence does not damage the epidermis but is
very well absorbed by melanin cel ls at low doses. (Lee, 20 03). Pulsed-
dye laser or PDL is believed to reduce melanocyte stimulation by
targeting the vascular components in lesions (Plonka et al., 2009).
Furthermore, Q- switched ruby laser or QSRL has been widely stud-
ied for hyperpigmentation; however, its efficacy remains question-
able although its mechanism is similar to QS Nd:YAG laser. Since the
NAUTIYAL ANd WAIRKA R
TABLE 1 Clinical studies on topical agents for hyperpigmentation
Topical agent Study group Study type Outcome/s References
Hydroquinone (4%) 30 melasma patients with skin types
A double- blind, randomized, prospective
Improvement in hyperpigmentation in
76.9% patients treated with 4% topical
hydroquinone as compared to placebo,
adverse effects such as itching and
eruptions reported in 25% of patients
(Haddad et al., 2003)
Arbutin (3%) 50 Caucasian and dark- skinned patients
with solar lentigines
A paired comparison, vehicle- controlled,
double- blind study
Effective in treating solar lentigines in
patients with lighter skin but failed to
show therapeutic response in darker-
(Boissy et al., 2005)
Tretinoin (0.1%) 40 Caucasian patients A randomized, double- blind, vehicle-
More effective against photoaging-
related hyperpigmentation in dark-
skinned patients as compared to vehicle
but reported retinoid dermatitis as a
(Weiss et al., 1988)
Azelaic Acid (20%) 155 patients of Indo- Malay and
A randomized double- blind study 20% azelaic acid cream found to be more
effective than 2% hydroquinone cream
(Verallo- Rowell et al.,1989).
Azelaic Acid (20%) 329 female patients A randomized double- blind study 20% azelaic acid cream found to be
equally effective as 4% hydroquinone
cream against hyperpigmentation
(Baliña & Graupe, 1991)
Niacinamide (5%) 18 Japanese women with multiple types
of brown pigmentation
A randomized split- face double- blind
paired design study
Significant decrease in facial
hyperpigmentation spots in the patients
as compared to vehicle
(Hakozaki et al., 2002)
Fluocinolone acetonide (0.01%),
Hydroquinone (4%), Tretinoin
228 patients with facial melasma A long- term, multicenter, open- label,
12- month study
Melasma either completely or mostly
cleared in more than 90% patients, no
notable safety concerns
(Torok et al., 2005)
NAUTIYAL ANd WAI RKAR
QSRL has a wavelength of 694 nm, it was thought to be highly se-
lective toward melanosomes compared with QS Nd:YAG laser with
a wavelength of 1,064 nm (Sarkar et al., 2012). The erbium:YAG is a
laser having wavelength of 2,940 nm which ablates skin with least
thermal damage and thus, reduces the risk of post- inflammatory hy-
perpigmentation. (Manaloto & Alster, 1999). Several clinical studies
have been carried out for laser therapies suggesting varied results
and details are described in Table 2.
Among multiple hyperpigmentation treatments, 4% hydroqui-
none topical formulations was a gold standard, but US- FDA pro-
posed a ban overall OTC preparations of hydroquinone in 2006 due
to its potential carcinogenicity. After its ban, many topical drugs
such as azelaic acid, tretinoin, and kojic acid have entered the mar-
ket. Although these drugs are effective, they have long treatment
durations, poor stratum corneum penetration, and poor epidermal
targeting. Oral treatments, which are still newer and under assess-
ment, compared with the traditional topical medications. Oral drugs
have also been reported to cause lesser adverse effects such as
spot- specific skin irritation, burning, and erythema than the topical
treatments, however, are not very widely marketed as standalone
treatment. Later, chemical peels were employed as they cause the
complete removal of the damaged skin, allowing regeneration of the
skin cells. Yet, they have a risk of inflammation, scarring and changes
in natural skin color. A wide variety of lasers too can be employed
in the treatment of hyperpigmentation along with drugs; however,
the safety aspect of using lasers remains questionable. Considering
all the conventional therapies, there is an underlying need for safe,
more evolved therapeutics for hyperpigmentation.
4 | NOVEL THERAPIES FOR
4.1 | Novel formulations
4.1.1 | Solid lipid nanoparticles (SLN)/
Nanostructured lipid carriers (NLC)
Solid lipid nanoparticles and NLC were explored as attractive choices
for topical delivery as they form an occlusive layer on the skin surface
leading to hydration of the stratum corneum and enhanced drug pen-
etration. Also, they have many advantages such as high drug loading,
improved stability, and bioavailability. Therefore, several agents for
hyperpigmentation, especially tyrosinase inhibitors have been formu-
lated as lipid nanocarriers. Ghanbarzadeh et al., 2015 prepared hyd-
roquinone SLNs gel that showed greater hydroquinone deposition in
skin epidermis (46.5% ± 2.6%) than hydroquinone gel (15.1% ± 1.8%)
and thus, improved drug localization and better skin targeting
(Ghanbarzadeh et al., 2015). Kojic acid SLNs reported for controlled
release and higher t yrosinase inhibit ion activity t han conventional kojic
acid (Khezri et al., 2020). A popular phytoconstituent, curcumin, was
formulated into solid lipid nanoparticles (CUR- S LNs) for skin pigmenta-
tion. Drug deposition studies further indicated greater drug retention
in skin with the CUR- SLN gel (82.32% ± 0.39%) after 24 hr, than plain
CUR gel (28% ± 0.24%). Skin irritation tests showed no erythema or ir-
ritation with the CUR- SLN gel, marking it safe for topical use (Shrotriya
et al., 2018). Wu et al., 2017 formulated hydroquinone- NLC wherein
the rate of tyrosinase inhibition by hydroquinone- NLC was found to be
42.39%% ± 0.63% as compared to 28.40%% ± 1.12% of hydroquinone
solution, suggesting improved light stability of hydroquinone by NLC
and thus showed better tyrosinase inhibition assay (Wu et al., 2017).
Such promising results of SLN and NLC could be taken ahead for in-
depth study and its use in managing hyperpigmentation Figure 3.
4.1.2 | Liposomes/Nanosomes
Liposomes are microscopic, spherical vesicles made up of a concen-
tric phospholipid and cholesterol bilayer and can incorporate the hy-
drophobic and the hydrophilic drug. They can easily merge with the
cell membrane and alter membrane fluidity to effectively deliver the
drug and enhance stratum corneum penetration. Arbutin liposomes
displayed slower skin permeation and higher skin deposition than
arbutin solution in in vitro study that finally results in reduced sys-
temic absorption of the drug (Wen et al., 2006). Liposomal serum
contaṇining a combination of azelaic acid, 4- n- butylresorcinol, and
retinol was studied in patients with melasma. After treatment, the
MASI score was enhanced from 41.7% to 85%, and melasma severity
scale (MSS) improved from “moderate” to “mild.” Microneedling was
sugges ted to enhance the ef fects of lipos omal serum (Kusum awardani
et al., 2019). Similar observations were reported by Ghafarzadeh and
Eatemadi, 2017 in a double- blinded, randomized clinical study on
the efficacy of topical liposome- encapsulated aloe vera on melasma
patients with 32% improvement in the MASI score (Ghafarzadeh &
Nanosomes are very similar to liposomes but have only a single-
lipid monolayer. A single- blind clinical study evaluated the safety and
efficacy of topical vitamin C nanosome with iontophoresis and com-
pared it with 70% glycolic acid peel for the melasma patients. The re-
sults were evaluated using baseline comparison and photographs, and
the nanosome was found to be better than glycolic acid peel in improv-
ing hyperpigmentation. Also, vitamin C nanosomes reported fewer and
more transient adverse effects such as burning, irritation, and dryness
of the skin (Sobhi & Sobhi, 2012). Therefore, liposomes and nanosomes
formulations can be used clinically in future for hyperpigmentation.
4.1.3 | Nano/Micro emulsions
Nanoemulsions and microemulsions are nanocarriers having two im-
miscible phases— the aqueous phase mixed with an oil phase with
the help of surfactants. These carriers are potential vehicles in cos-
meceuticals and for topical administration of drugs due to their size,
solubility enhancement of both hydrophilic and lipophilic drugs etc.
The microemulsion of hydroquinone was studied for me-
lasma and hyperpigmentation. The in vitro drug release, 87.405%
NAUTIYAL ANd WAIRKA R
TABLE 2 Laser Therapies for Hyperpigmentation
Type of laser the rapy
laser Study gro up Study type Outcome/s References
Intense Pulsed Light (IPL)
500– 1200 nm 33 Taiwanese women
A prospective, case– control
IPL with 4% hydroquinone cream reported an
improvement of 39.8% in relative melanin index
as compared to 11.6% improvement by 4%
hydroquinone alone. Complete resolution of
melasma in 35% patients seen in the IPL group.
(Wang et al., 2004)
56 Patient s with
lesions, with skin
types I- IV
A split- face, randomized,
evaluator blinded, open- label
57% of melasma patients treated with IPL
combined with Triple combination cream showed
clear to almost clear skin as compared to 23%
of patients treated with IPL combined with a
(Goldman et al., 2011)
Q- Switched Neodymium-
Doped Yttrium Aluminum
Garnet (QS Nd: YAG) Laser
1,064 nm 22 Thai Melasma
patients with skin
types III- V
A split- face, randomized study QS Nd: YAG laser with 2% hydroquinone showed
an improvement of 92.5% in the relative lightness
index compared to 19.7% in control. The laser
group reported improvement of 75.9% in
modified MASI scores.
(Wattanakrai et al., 2010)
50 Chinese Melasma
An open- labeled, prospective
QS Nd: YAG laser showed an improvement
of 35.8% from the baseline in patients with
melasma. Concluding that results of laser therapy
depend on the severity of the disease at baseline.
(Xi et al., 2011)
Pulsed- Dye Laser (PDL) 585 nm 17 Melasma patients
with skin types II- IV
A prospective, randomized,
single- blind, split- face study
PDL with triple combination therapy reported
a decrease in the MASI score from 6.20 to
2.79 as compared to 6.76 to 4.35 seen in triple
combination therapy alone.
(Passeron et al., 2011)
Q- Switched Ruby Laser
694 nm 20 patients with benign
A prospective, randomized
Treatment response better with QSRL in the
removal of pigmented lesions with lesser bleeding
than the 1,064 QS Nd: YAG laser.
(García García, 2010)
4 patients with
and 4 with post-
- Treatment with QSRL pulses of 694 nm, at
fluences 1.5– 7.5 was ineffective in treating
patients with melasma and post- inflammator y
(TAYLOR & ANDERSON, 1994)
Erbium: YAG Laser 2,940 nm 10 female melasma
patients with skin
types II - V
- Marked improvement in the hyperpigmentation in
melasma patients immediately on treatment
(Manaloto & Alster, 1999)
NAUTIYAL ANd WAI RKAR
hydroquinone was released from microemulsion after 24 hr. as com-
pared to 30% release from hydroquinone cream. This microemulsion
did not contribute to any skin irritation or disruption of epidermal
layers as confirmed in histopathology (Üstündağ Okur et al., 2019).
Kojic monooleate, a tyrosinase inhibitor, was formulated into na-
noemulsion (KMO) indicated 54.76% sur vival rate of 3T3 cells
(Afifah et al., 2018). Likewise, azelaic acid and hyaluronic acid na-
noemulsion was studied for tyrosinase inhibition along with in-
creased drug retention. The in vitro mushroom tyrosinase inhibition
assay showed that the formulation significantly reduced tyrosinase
activity and also exhibited good skin permeation in vitro (Jacobus
Berlitz et al., 2019). Thus, nanoemulsions and microemulsions could
be explored for the treatment of melasma and hyperpigmentation.
Lipid based carriers exhibited high stratum corneum penetration
and drug bioavailability and, hence, have been widely studied over
the course of time. Yet, the ultimate aim was to improve efficacy and
reduce toxicity of treatment to satisfy the patient.
4.2 | Phytochemicals
Phytochemicals are natural compounds extracted or derived from
plants and have been re ported for skin hyperpigme ntation treatme nt
owing to various mechanisms inhibiting melanogenesis. Aloesin, a
glycoprotein extracted from aloe vera, was reported to show anti-
tyrosinase activity in a dose- dependent way. It works by inhibiting
L- DOPA oxidation and has shown better affinity than kojic acid, ar-
butin etc. However, it has poor stratum corneum penetration due
to its hydrophilicity and high molecular weight, suggesting the need
for novel delivery systems to be more effective (Choi et al., 2002).
Hesperidin is a flavonoid obtained from various citrus fruits and pos-
sesses anti- tyrosinase, anti- inflammatory, photoprotective, and anti-
oxidant properties. Studies on human melanocyte cells showed the
melanin synthesis inhibition by hesperidin through dose- dependent
tyrosinase enzyme inhibition (Zhu & Gao, 2008). In contrast, Usach
et al reported that hesperidin was found to rather induce melano-
genesis in human melanocyte cells by enhancing tyrosinase activity
in a dose- dependent manner (Usach et al., 2015). Hence, there is a
need for further evaluation and in- depth study of the depigmenta-
tion property of hesperidin.
Ellagic acid, a polyphenol, reported to possess inhibition of ty-
rosinase and melanogenesis. In a study involving 30 female melasma
patients, ellagic acid was stated to significantly reduce the melanin
production (Ertam et al., 2008). Pycnogenol, a procyanidin, is the
bark extract of the French maritime pine which has been found to
act by protecting the skin against UV- induced erythema by inhib-
iting the nuclear factor (NF)- B- dependent gene expression (Saliou
et al., 2001). Polypodium leucotomos is extracted from fern species
and acts as an anti- inflammatory, antioxidant, and photoprotective
agent. A clinical study showed that oral Polypodium leucotomos de-
creased the cutaneous pigmentation response in patients who were
earlier exposed to PUVA (Middelkamp- Hup et al., 2004). In another
study, the effect of oral polypodium leucotomos extracts on visible
light- induced pigmentation in 22 patients with Fitzpatrick skin type
IV- VI was studied with a daily dose of 480 mg for 28 days. The spec-
troscopic analysis suggested a significant decrease in persistent pig-
ment darkening and delayed tanning, post- polypodium leucotomos
extract administration, and a decrease in markers for cellular damage
was also observed in immunohistochemistry results. (Mohammad
et al., 2019). Likewise, flavonoids silymarin and resveratrol exhibit
photoprotective properties through various mechanisms like sup-
pressio n of UV- induced ox idative stres s, DNA damage, ap optosis, and
anti- inflammatory properties (Choo et al., 2009; Kasai et al., 20 06).
Similar activities were reported for isoimperatorin and imperatorin
(Lin et al., 2008), glabridin, and liquirtin (Amer & Metwalli, 2000;
Yokota et al., 1998), alpha- bisabolol (Lee et al., 2010).
FIGURE 3 Novel therapies for
NAUTIYAL ANd WAIRKA R
Thus, further studies on phytochemicals could explore their po-
tential integrated with the standard therapies for effective manage-
ment of hyperpigmentation. It is also important to note that natural
agents often pose several risks of allergic and phototoxic reactions
and are sometimes adulterated with corticosteroids.
4.3 | Fractional photothermolysis
It is a newer type of laser therapy which forms several microscopic
thermal damage zones on skin, leaving most of it intact which then
acts as a reservoir for healing. The thermal damage zones are also
called microthermal treatment zones (MTZ) and are responsible for
extruding out the microscopic epidermal necrotic debris (MENDs)
which contains the pigmentation in the basal layer. The movement of
MENDs is then facilitated by the keratinocytes at the wound corners
(Katz et al., 2010). A randomized study reported that fractional pho-
tothermolysis was equally effective in improving the MASI scores as
5% trichloroacetic acid in patients with melasma. About one- third
of the patients exhibited post- inflammatory hyperpigmentation,
which got resolved by the end of the treatment duration (Hong
et al., 2012). Another study evaluated fractional photothermolysis
in ten female patients of melasma with 4– 6 sessions at an interval of
1– 2 weeks and results reported that 75%– 100% lightening in original
pigmentation was observed in 60% of the patients and less than 25%
improvement was recorded in only 30% of the patients. (Rokhsar &
4.4 | Microneedling
Microneedling is a process in which an instrument studded with mi-
croneedles is rolled over the skin to penetrate the epidermis and reach
the upper dermis (0.5 mm) to induce a wound- healing response. It was
studied as a means to augment trans- epidermal delivery of various
agents for the treatment of hyperpigmentation disorders. In a clini-
cal study, a Rucinol and sophora- alpha serum was evaluated with and
without microneedling. The microneedle combination group showed
a significant decrease in MASI score as compared to the serum alone
(Fabbrocini et al., 2011). Similar results were stated using a combi-
nation of microneedling with triple combination cream containing
0.05% tretinoin, 4% hydroquinone, and 1% fluocinolone acetonide
(Lima 2015). In a randomized study, treatment with microinjections
of tranexamic acid combined with microneedling showed greater im-
provement in the hyperpigmentation in melasma patients than control
group. (Budamakuntla et al., 2013). Assessment of microneedling ther-
apy for the improvement of acne pigmentation scars was done in 39
patients with dark skin. The results showed substantial improvement
from baseline scores after microneedling treatment when reviewed
after 2 and 4 weeks subsequently. (Al Qarqaz & Al- Yousef, 2018).
Thus, microneedling could be explored as an effective and promising
augmenting therapy for deeper and more uniform penetration of the
depigmenting agents for treatment of hyperpigmentation disorders.
5 | OUTCOME MEASURES AND
EVALUATION MODELS FOR
Various studies have been conducted to measure the effectiveness
of treatment options for pigmentation disorders. However, most
of these methods or scales are non- validated and sometimes do
not give a clear indication of the satisfactory results of the study.
Validated outcome measures can act as standards for evaluating
treatments, such as the Psoriasis Area and Severity Index (PASI)
used for Psoriasis. Hence, similar methods and tools for hyperpig-
mentation disorders are employed to improve the evaluation and
comparison of the treatments being studied.
Colorimetry is standard measurement tool used to evaluate the out-
comes in patients with facial and axillary hyperpigmentation, melasma,
vitiligo, etc. Tristimulus colorimetry employing a chromameter CR 200
(Minolta) employs a specific combination of three stimuli— green, blue,
and red lights for the in vivo quantitative evaluation of hyperpigmen-
tation. Three parameters are taken into account: L* representing color
brightness, a* parameter expressing changes from red to green surface
and, b* parameter representing changes from yellow to a blue surface.
The mean value of three chromameter measurement readings is eluci-
dated for sk in pigmentation de termination. In a r andomized, doubl e- bl ind
study on niacinamide and desonide, the improvement in facial axillary
pigmentation was evaluated using chromameter. Improvement was indi-
cated by an increase in the L* value, depicting lightening of the skin pig-
mentation. The DermaSpectrometer consists of diodes that emit light at
specific wavelengths of 568 nm- green and 655 nm- red. It also involves
a photodetector for measuring the light reflected by skin. The absorbed
and reflected light at different wavelengths is measured by the meter,
green for hemoglobin, and red for melanin. The absorbed and reflected
light intensities project the melanin index and erythema index at 568 and
655 nm, respectively. Mexameter works on a similar principle involving 16
diodes that emit light at three different wavelengths of 568 nm— green,
660 nm— red, and 880 nm— infrared, arranged circularly. The intensities
of the absorbed and the reflected light at 660 and 880 nm give the mela-
nin index, whereas the erythema index is obtained from the light intensi-
ties at 568 and 660 nm. On comparison of the sensitivity performances,
it is observed that all the three colorimetric methods detect minor quan-
titative differences in skin pigmentation effectively. The mexameter,
however, showed lesser sensitivity in melanin index, and the strongest
sensibility for the erythema index was shown by the DermaSpectrometer
(Castanedo- Cazares et al., 2013; Clarys et al., 2000).
Spectrophotometric inputs from the skin have been analyzed using
complex algorithms to give back high- resolution data about the total
melanin content of the epidermis. Spectrophotometric intracutaneous
analysis (SIA) produces eight narrow band spectrally filtered images of
the skin over an area of 24 × 24 mm with radiation ranging from 400 to
1,000 nm. Certain highly replicable features such as the collagen holes
and dermal melanin identified by this technique are specific when stud-
ied using receiver operator characteristic curves with dermatoscopy.
This method provides valuable and credible information which can be
utilized in diagnosing pigmented skin lesions (Moncrieff et al., 2002).
NAUTIYAL ANd WAI RKAR
In image analysis, digital camera mounted on a microscope is
employed to scan the epidermis and dermis and tissue images are
captured under high magnification. The camera is connected to a
computer, and the images captured can be processed using Image J
v 1.44 software. Further, the captured epidermal images are treated
by deconvolution and binary processing to quantify the melanin con-
tent. The area of pigmentation involved can also be estimated and
expressed as % per mm2 (Castanedo- Cazares et al., 2013).
Hyperpigmentation area and severity index (HASI) or melasma
area and severity index (MASI) were developed by Kimbrough-
Green et al. It is an objective scoring system commonly used for ac-
curate quantification of facial hyperpigmentation and its treatments.
It depicts the severity of hyperpigmentation, and thus, the higher
the HASI score, the more severe or worse is the pigmentation. While
using HASI evaluation, the face is divided into four zones: the fore-
head (F), right malar region (MR), left malar region (ML), and the chin
(C). A (area of involvement), D (darkness), and H (homogeneity) are
the main factors assessed. MASI is then calculated by the adding
severity ratings of darkness and homogeneity factors, multiplied by
the area involved for all four areas.
MASI total score = 0.3A(f)[D(f)+H(f)] + 0.3A(lm) [D(lm) + H(lm)] +
0.3A(rm) [D(rm) + H(rm)] + 0.1A(c) [D(c) + H(c)].
The range of the MASI score can be from 0 to 48. The study
conducted by Pandya et al assessed the reliability and validity of
this MASI scoring method (Pandya et al., 2011; Sarkar et al., 2017).
Similarly, investigators at the Henry Ford Hospital, Detroit, USA, de-
veloped a six- point IGA scale for the determination of hyperpigmen-
tation and erythema (Isedeh et al., 2016).
Post- acne hyperpigmentation index (PAHPI) involves three main
important characteristics of PIH: the size, number, and intensity of
the lesions. A focus group of PIH patients ranks these factors in
order of importance. These factors are weighted based on focus
group feedback and the PAHPI score is calculated as the total of the
weighted variables, ranging between 6 and 22. A study conducted by
Savory et al on 15 PIH patients employed four rater s who were asked
to independently rank the photographs of PIH- affected patients and
assign them a PAHPI score according to the severity. Excellent inter-
rater and intra- rater reliability was observed and hence produced
encouraging preliminary results (Savory et al., 2014).
Several models of pigmentation have been developed for assess-
ment of agents for their inhibitory effects on the hyperpigmenta-
tion processes. In vitro cell- line studies are very commonly used for
the evaluation of tyrosinase inhibitors in reducing melanin content.
Other more complex assays using melanocytes, three- dimensional
skin equivalent cultures, or reconstructed skin which may contain
both dermal and epidermal cells such as the fibroblasts, keratino-
cytes, and melanocytes can be similarly performed in multiwell
plates (Ortonne and Bissett, 2008). In human models, the trichlo-
roacetic acid (TCA)- induced PIH model has been extensively stud-
ied for clinical, histological, and spectroscopic characteristics.
Here, studies comparing TCA- induced PIH with acne- induced PIH
in human patients have suggested that a better comparison among
the sites is possible with the TCA- induced PIH lesions as compared
to acne lesions, as they are more uniform in pigment intensity and
size. However, it is also observed that the TCA- induced lesions
and the acne- induced PIH are clinically, histologically, and spectro-
scopically indistinguishable after 28 days, suggesting that the TCA-
induced PIH model could be a reproducible and reliable alternative
for the assessment of acne- induced PIH. (Isedeh et al., 2016; Lyons
et al., 2020). Another model focuses on inducing PIH by employing
repeated hapten application of 2,4- dinitrofluorobenzene in hairless
transgenic mice (hk14- SCF Tg/HRM) having human- type epidermis
containing melanin. Its histopathological analysis revealed epidermal
hyperplasia, infiltrated inflammatory cells, and melanin- containing
cells in the dermis. Increased melanin without spongiosis and in-
creased dermal melanophages are observed which are similar char-
acteristics detected in PIH. Hence, suggesting that this mouse model
replicates the human PIH characteristics and could be employed to
assess novel treatments targeting PIH (Nakano et al., 2021).
6 | FUTURE PERSPECTIVE
The need and demand for newer, safer, and more effective treat-
ments for various hyperpigmentation disorders have paved the way
for researchers to explore treatment options continuously. Various
compounds and combinations are currently being tested and have
shown promising results in the initial phases of clinical trials and are
currently being considered for further evaluation.
Established anti- diabetic drug metformin tested topically in an-
imals that show whitening of tails and exhibited anti- melanogenic
effects when evaluated on human skin biopsies and reconstituted
human skin (Lehraiki et al., 2014). Methimazole topical cream was
evaluated for its depigmenting efficacy in melasma patients showing
hydroquinone- resistance and was found to be effective in reduc-
ing the hyperpigmentation through inhibition of melanin synthe-
sis (Malek et al., 2013). These candidates, though found to be safe
and well- tolerated, require more studies to establish their efficacy.
Topical serums can be explored for treating hyperpigmentation dis-
orders. A topical serum of 2.0% (w/w) cetyl tranexamate mesylate, a
tranexamic acid derivative, evaluated for its depigmenting and anti-
inflammatory ac tivity in patient s revealed improved skin tone and re-
duction in pigmentation spots and redness (Silva Souza et al., 2020).
A similar observation was shown by 0.3% rucinol serum in melasma
patients (Khemis et al., 2007).
7 | CONCLUSION
Although topical agents are considered as the first- line treatment for
hyperpigmentation, they also cause adverse effects such as skin irri-
tation and peeling with higher concentrations. Chemical peels come
next as second- line treatment, which have shown good efficacy
but poses a greater risk of side effects and is more expensive. Oral
therapies have usually demonstrated mixed results and more relapse
rate. Laser and microneedling therapies are approached as third- line
NAUTIYAL ANd WAIRKA R
treatment options due to limited data and usage history and high
risks of side effects. Additionally, prevention or maintenance
therapy with sunscreens for sun/UV protection remains crucial.
Unfortunately, existing treatments demonstrate limited safety and
efficacy, with prolonged treatment durations. Thus, several newer
therapeutic agents, novel formulations, and promising therapies are
under development for timely management of hyperpigmentation
with short duration and reduced adverse effects. However, a guar-
anteed therapy is still a dream for researchers relentlessly working
on the clinical therapeutics of hyperpigmentation.
CONFLICT OF INTEREST
Avni Nautiyal has contributed to acquisition, interpretation of data,
and drafting of the manuscript. Sarika Wairkar has contributed to
the conception and design of the review and approved final draft of
Sarika Wairkar https://orcid.org/0000-0002-0124-1741
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How to cite this article: Nautiyal A, Wairkar S. Management
of hyperpigmentation: Current treatments and emerging
therapies. Pigment Cell Melanoma Res. 2021;00:1– 15.