Treatment of melasma_ a review of less commonly used antioxidants

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Review
Treatment of melasma: a review of less commonly used
antioxidants
Kayla M. Babbush1, BS, Remy A. Babbush2, and Amor Khachemoune3,4, MD, FAAD, FACMS
1Division of Dermatology, Department of
Medicine, Albert Einstein College of
Medicine/Montefiore Medical Center, Bronx,
NY, USA, 2Department of Food Science,
Cornell University, Ithaca, NY, USA,
3Department of Dermatology, State
University of New York Downstate,
Brooklyn, NY, USA, and 4Department of
Dermatology, Veterans Health
Administration, Brooklyn, NY, USA
Correspondence
Amor Khachemoune, MD, FAAD, FACMS
Veterans Affairs Medical Center
State University of New York Downstate
800 Poly Place
Brooklyn, NY 11209
USA
E-mail: amorkh@gmail.com
Conflict of interest: None.
Funding source: None.
doi: 10.1111/ijd.15133
Abstract
Melasma, a common cause for seeking dermatologic care, is a chronic condition of skin
hyperpigmentation. With a poorly understood pathogenesis, and no universal cure,
melasma is a challenge for many dermatologists. For decades, there has been
investigation into the role of oxidative stress in melasma. In this literature review, we
introduce the role of oxidative stress in melasma and discuss the function of various topical
and oral antioxidant therapies for patients suffering from melasma. Numerous studies have
shown efficacy of various antioxidant therapies for treatment of hyperpigmentation, and in
this review, we focus primarily on those with less widespread use. Vitamin E, niacinamide,
polypodium leucotomos, pycnogenol, grape seed extract, amino fruit acids, phytic acid,
zinc, silymarin, Korean red ginseng powder, plant extracts, and parsley all have well-
demonstrated evidence of antioxidant properties, and these substances have been studied
in the context of skin hyperpigmentation. Although there is conflicting evidence of their
therapeutic efficacy, the use of these naturally occurring substances is promising for
patients and medical providers seeking alternative therapeutic options.
INTRODUCTION
Pigmentary disorders can be divided into acquired, congenital,
hypopigmentary, hyperpigmentary, or mixed disorders. Pig-
mentary disorders have a well-demonstrated impact on patient
quality of life, and as a result, they are a common cause for
seeking dermatologic care.1-3 Melasma is a chronic, acquired
pigmentary disorder that presents with hypermelanosis of sun-
exposed areas of skin. Female predominance has been
demonstrated in various studies, and this disorder, also known
as the “mask of pregnancy,” often plagues gravid women. Mel-
asma, along with other disorders of hyperpigmentation, occurs
more commonly in skin of color.4 There is evidence of mel-
asma in all population groups; however, epidemiological stud-
ies have found a higher prevalence among populations of East
Asians (Japanese, Korean, and Chinese), Indians, Pakistanis,
Middle Easterners, Mediterranean-Africans, and Hispanics with
increased exposure to ultraviolet radiation.5 Genetic predispo-
sition plays a role in the development of the disease, and
familial occurrence of melasma has been reported to be as
high as 61%.6
The diagnosis of melasma is clinical, and biopsy is rarely
necessary. The severity of melasma can be estimated using the
Melasma Area and Severity Index (MASI) score, the modified
MASI (mMASI) score, colorimetry, and mexametry. The Mel-
asma Quality of Life scale (MelasQoL) can also be used to
guide treatment and track improvement. This 10-item scale can
assess the level of impairment individuals suffer from due to
their melasma.5,7
The pathogenesis of melasma is multifactorial and incom-
pletely understood, and this poses a challenge for disease man-
agement. Ultraviolet light exposure, which induces reactive
oxygen species (ROS), altered cutaneous vasculature, family
history, and hormonal influences are all known to play a role in
development of melasma.8,9 Biopsies of melasma skin show an
increased number of melanocytes, melanosomes in ker-
atinocytes, and dendrites.10,11 There is also evidence of
increased activity of melanogenic enzymes in affected skin and
International Journal of Dermatology 2021, 60, 166–173 ª 2020 the International Society of Dermatology
166
increased melanin deposition in both the epidermis and der-
mis.10,11
Combination therapy is often recommended for patients, as
there is no universally efficacious treatment. Topical therapies
include, but are not limited to, hydroquinone, retinoids, and
numerous bleaching combination formulas. Superficial peels,
microdermabrasion, and various laser and light therapies are
often used in conjunction with topical therapies. Oral tranexamic
acid has also been used. It is critical for patients to avoid exac-
erbating factors, which include ultraviolet light exposure, hor-
monal therapy, and various oral medications.8 Antioxidants are
commonly part of this treatment method, as they are functional
in controlling oxidative stress linked with skin aging and pigmen-
tation disorders. Furthermore, recent investigation has explored
the use of topical cytidine, which is believed to play a role in
melanogenic pathways.12-14
Oxidative stress in dermatology
The skin is the site of numerous biochemical reactions, many of
which result in the generation of free radicals including ROS.15-17
Oxidative stress occurs with a disturbance in the balance
between free radicals and antioxidant defenses.18 This imbalance
exists in photodamage, non-melanoma skin cancers, psoriasis,
vitiligo, scleroderma, lichen planus, acne vulgaris, alopecia
areata, seborrheic dermatitis, and pemphigus foliaceus.17,19,20
Sunlight, a primary trigger of oxidative damage, results in features
of premature skin aging, namely rhytids, dyspigmentation, telang-
iectasias, and xerosis.21
Oxidative stress in melasma
There is clear evidence of oxidative stress in melasma. Seckin
et al.22 reported significantly elevated levels of malondialdehyde
(MDA), nitric oxide (NO) and enzyme activity of superoxide dis-
mutase (SOD) and glutathione peroxidase (GSH-Px) in serum
of melasma patients compared with controls. Elevated MDA, a
product of lipid peroxidation, NO, a free radical secreted by
endothelial cells, and SOD and GSH-Px, intracellular antioxi-
dants, are markers of oxidative damage. Paradoxically, the
authors found significantly lower protein carbonyl levels in the
patient group.22 Protein carbonyl is an indicator of oxidative
stress in amino acids and is used to evaluate oxidative protein
damage.
In addition to reporting elevated oxidative markers in mel-
asma patients, Choubey et al.23 identified a significant positive
correlation between MASI score and serum MDA.
ANTIOXIDANT THERAPY IN MELASMA
There is evidence of oxidative stress in melasma pathogenesis.
We have previously reported on a number of well-known antiox-
idants that play a role in control of skin pigmentation.24 These
antioxidants include vitamin C,25-47 azelaic acid,48-52 cys-
teamine,53,54 glutathione,55-57 carotenoids,58,59 curcuma
longa,60,61 ellagic acid,62,63 kojic acid,64,65 and reservatrol.66-69
However, in addition to the previously mentioned antioxidants,
there are a number of other compounds with antioxidant proper-
ties that may have therapeutic value for melasma and hyperpig-
mentation (Table 1). These antioxidant compounds show
efficacy in both topical and oral routes of administration.
Vitamin E
Vitamin E has a number of health benefits, and its numerous
isoforms have the ability to neutralize free radicals.70 Because
of its antioxidant abilities, oral and topical applications of vitamin
E have been investigated for treating hyperpigmentation.
Hayakawa et al.25 conducted a double-blind trial in which
patients received an oral combination of vitamins C and E or
single preparation of one vitamin. Combined treatment had sta-
tistically better improvement for patients with chloasma and pig-
mented contact dermatitis. Handoget al.26 studied a test drug
containing procyanidin and vitamins A, C, and E. Patients
showed significant improvement in MASI score and a significant
decrease in pigmentation. Guevara et al.71 investigated a cream
containing hydroquinone, buffered glycolic acid (GA), vitamins C
and E, and sunscreen and found a significant decrease in pig-
mentation compared with sunscreen alone.
Although not a clinical trial, one study found significant inhibi-
tion of melanization in human melanocytes with a compound of
alpha-tocopherol (a form of vitamin E) and ferulic acid.72
Niacinamide/nicotinamide
Niacinamide, or nicotinamide, is an amide of vitamin B3. Nicoti-
namide suppresses ROS in human cells and effectively reduces
oxidative damage.73 Topical niacinamide has been investigated
in various dermatologic conditions including acne, rosacea,
aging, atopic dermatitis, blistering disorders, and skin cancer
prevention.74
Navarrete-Solis et al.75 conducted a split-face study of mel-
asma patients who applied sunscreen and either niacinamide
or hydroquinone cream. All patients showed pigment improve-
ment; however, a greater percentage observed good to excel-
lent results with hydroquinone. Of note, a greater number of
patients reported side effects with hydroquinone. Hakozaki
et al.76 conducted both in vitro and in vivo studies with niaci-
namide and found a significant decrease in cutaneous hyper-
pigmentation and an increase in skin lightness compared with
vehicle alone. Campuzano-Garcia et al.77 considered DNA
hypermethylation in melasma lesions and determined treat-
ment with sunscreen and niacinamide, retinoic acid, or placebo
resulted in a significant reduction in DNA methyltransferase 1
expression.
Others have investigated niacinamide, in conjunction with
other therapies, for skin pigmentation. Hakozaki et al.32 studied
a gel containing vitamin C and niacinamide, in conjunction with
ultrasound radiation. Desai et al.78 studied a topical facial serum
containing tranexamic acid, kojic acid, and niacinamide.
ª 2020 the International Society of Dermatology International Journal of Dermatology 2021, 60, 166–173
Babbush, Babbush, and Khachemoune Antioxidant treatment for melasma Review 167
Table 1 Summary of clinical investigations discussed in this manuscript
Antioxidant
Route of
administration Type of study Conclusion References
Amino fruit acids Topical Randomized single-blind
right–left comparison trial
Amino fruit acid peel is less irritating and better tolerated
than glycolic acid peel for melasma, but there is significant
melasma regression with both peeling methods
86
Korean red
ginseng powder
Oral Uncontrolled observational
study
Korean red ginseng powder shows good tolerability and
beneficial effects for melasma
100
Niacinamide/
nicotinamide
Topical Randomized double-blind
clinical trial
Niacinamide (compared with hydroquinone) is a safe and
effective therapeutic agent for melasma
75
Topical Randomized double-blind
split-face trial
Niacinamide significantly decreased hyperpigmentation
and increased skin lightness compared with vehicle alone
76
Topical Randomized double-blind
controlled trial
After treatment with niacinamide, retinoic acid, or placebo,
expression of DNA methyltransferase (DNMT) 1 is decreased,
which correlates with clinical improvement of melasma
77
Topical Clinical trial A tranexamic acid, kojic acid, and niacinamide containing
serum is an effective and well-tolerated treatment option
for addressing hyperpigmentary conditions
78
Topical Randomized split-face
clinical trial
High-frequency ultrasound radiation together with
skin-lightening gel (ascorbyl glucoside and niacinamide)
is effective to reduce hyperpigmentation
32
Petroselinum
crispum
Topical Randomized double-blind
clinical trial
The effect of petroselinum crispum on melasma severity
is the same as that of hydroquinone
103
Phytic acid Topical Clinical trial Easy phytic peel (commercial product composed of
phytic acid, glycolic acid, lactic acid, and phenyl glycolic
[mandelic] acid) is effective, safe, and well-tolerated
for melasma
88
Topical Split-face study Triple combination (20% azelaic acid + 10%
resorcinol + 6% phytic acid) is as effective as 50%
glycolic acid peel for melasma
89
Topical Randomized clinical trial Glycolic acid and salicylic–mandelic acid peels are more
effective than phytic acid peels for melasma
90
Plant extracts Topical Split-face study Orchid-rich plant extracts possess similar efficacy to
vitamin C derivative for skin whitening
101
Polypodium
leucotomos
Oral Randomized double-blind
placebo-controlled clinical trial
Oral PLE is not significantly better than placebo as an
adjunct to topical sunscreen for melasma
80
Oral Randomized double-blind
placebo-controlled clinical trial
Oral polypodium leucotomos extract appears to be a safe
and effective adjunctive treatment in combination with
topical hydroquinone and sunscreen for melasma
81
Pycnogenol/grape
seed extract
Oral Clinical trial Pycnogenol 75 mg is therapeutically effective and safe in
patients suffering from melasma
84
Oral Clinical trial Grape seed extract is safe and useful for improving chloasma 85
Silymarin Topical Randomized double-blind
placebo-controlled clinical trial
Silymarin shows improvement melasma in a
dose-dependent manner
98
Topical Comparative study There are no significant differences in the therapeutic
response between topical silymarin (0.7% and 1.4%)
versus hydroquinone 4% for melasma
99
Vitamin E Oral Multiclinical double-blind trial Vitamin C + E combination treatment has significantly
better results than vitamin C alone for chloasma
25
Oral Randomized double-blind
placebo-controlled trial
Oral procyanidin + vitamins A, C, and E is safe and
effective for epidermal melasma
26
Topical Randomized double-blind
placebo-controlled trial
Cream containing 4% hydroquinone, 10% buffered
glycolic acid, vitamins C + E, and sunscreen is
safe and effective for melasma
71
International Journal of Dermatology 2021, 60, 166–173 ª 2020 the International Society of Dermatology
Review Antioxidant treatment for melasma Babbush, Babbush, and Khachemoune168
Polypodium leucotomos
Polypodium leucotomos (PL) is used for the management of
various skin conditions, and this species of fern acts as a direct
scavenger of various ROS.79 Two randomized, double-blind,
placebo-controlled trials investigated oral PL extract (PLE) for
treatment of melasma. In a study of Hispanic women, the PLE
treatment group and placebo group both had improvment in
melanin index and MASI score, but there was no significant
intergroup difference.80 Additionally, a study of Asian patients
resulted in a significant decrease in mMASI scores for both
treatment and placebo groups with a significantly lower mMASI
score and an improvement in the MelasQoL score in the PLE
group compared with placebo.81
Pycnogenol/grape seed extract
Pycnogenol is an extract from French maritime pine. It contains
various flavonoids, namely phenolic acids and procyandins, and
it has been used as a therapeutic remedy for various conditions
including circulatory dysfunction and wound healing. It has
strong antioxidant capacity and interacts with other cellular
antioxidants.82 Grape seed extract also contains many flavo-
noids, including proanthocyanidin, with similar antioxidant
effects against oxygen free radicals and oxidative stress.83
Ni et al.84 conducted a study in which women with melasma
took oral tablets of pycnogenol tri-daily. After 30 days, overall effi-
cacy rate was 80%, and there was a significant decrease in pig-
mentary intensity and average melasma area. Yamakoshi et al.85
studied the efficacy of oral grape seed extract for melasma treat-
ment and found a significant decrease in melanin index.
Amino fruit acids
Amino fruit acids are carboxylated acidic amino acids with
strong antioxidant properties and evidenceof anti-aging and
anti-photopigmenting agents.86 Ilknur et al.86 conducted a sin-
gle-blind randomized study of melasma patients to compare GA
peels with amino fruit acid peels. There was significant
melasma regression for both peeling methods but no significant
difference between groups; however, the amino fruit acid peel
was less irritating and better tolerated.
Phytic acid
Phytic acid, unlike other antioxidants, is a stable plant antioxidant
that is not consumed by reacting with activated oxygen species.
Phytic acid has a high iron affinity, enabling it to effectively inhibit
various oxidative reactions, block hydroxyl radical formation and
diminish lipid peroxidation.87 Combination peels containing phytic
acid have been investigated in various studies.
Al-Mokadem et al.88 investigated a chemical peel containing
phytic acid, GA, lactic acid, and mandelic acid in melasma
patients. The reduction in MASI score was significant; however,
pigmentation recurred because of unprotected sun exposure
and lack of patient compliance. Faghihi et al.89 determined a tri-
ple-combination peeling agent consisting of azelaic acid, resor-
cinol, and phytic acid was safe and as effective as GA peel for
melasma treatment. However, Sarkar et al.90 found GA and sal-
icylic–mandelic acid peels equally more efficacious than phytic
acid combination peels.
Zinc
Zinc is an essential trace element critical for the structure and
function of many macromolecules and enzymes in humans.91
There are numerous mechanisms by which zinc functions as an
antioxidant; however, zinc deficiency and excess can cause an
increase in oxidative stress.92 Many studies have investigated
the efficacy of zinc in treating melasma, but there is conflicting
evidence about whether or not this trace metal provides thera-
peutic value.
In a study by Sharquie et al.,93 melasma patients were trea-
ted with topical zinc sulfate solution and displayed significant
improvement in MASI score, with most patients maintaining
improvement 3 months after therapy cessation. Iraji et al.94 and
Yousefi et al.95 also conducted studies to assess the efficacy of
Table 1 Continued
Antioxidant
Route of
administration Type of study Conclusion References
Zinc Topical Clinical trial Topical 10% zinc sulfate solution is safe and
effective for melasma
93
Topical Randomized double-blind
comparative trial
Topical zinc is not highly effective in reducing
the severity of melasma
94
Topical Randomized double-blind
controlled trial
10% zinc sulfate is not as effective as 4% hydroquinone
cream in the treatment of melasma
95
Topical Pilot study A combination of tazarotene 0.075%, azelaic acid 20%,
tacrolimus 0.1%, and (microfine) zinc oxide 10% could
potentially be an effective, safe, and tolerable treatment
for moderate-to-severe melasma
96
Other antioxidants used for treatment of melasma include: azelaic acid, carotenoids, curcuma longa (turmeric), cysteamine, ellagic acid, glu-
tathione, kojic acid, resveratrol, and vitamin C.
ª 2020 the International Society of Dermatology International Journal of Dermatology 2021, 60, 166–173
Babbush, Babbush, and Khachemoune Antioxidant treatment for melasma Review 169
topical zinc, and both concluded zinc was not as effective in
reducing melasma severity compared with hydroquinone. Kirsch
et al.96 studied a combination cream containing tazarotene, aze-
laic acid, tacrolimus, and zinc oxide and found this compound
to be effective and safe for melasma.
Silymarin
Silymarin is a polyphenolic antioxidant from the milk thistle
plant, and it functions as both a free radical scavenger and lipid
peroxidation inhibitor.97
In a study by Altaei,98 melasma patients used silymarin
cream and were 100% satisfied with significant pigment
improvement and lesion size reduction. Likewise, in a study by
Nofal et al.,99 melasma patients received 0.7 or 1.4% silymarin
cream versus 4% hydroquinone cream. MASI scores were sig-
nificantly reduced in all groups with no significant difference
between groups. Unlike with hydroquinone, there were no signif-
icant adverse events with silymarin treatment.
Korean red ginseng powder
Korean red ginseng powder has therapeutic value for antioxi-
dant, anti-aging, anti-inflammatory, and immunomodulatory pro-
cesses.100 It contains phenolic compounds, which inhibit
tyrosinase and ginsenoside, and prevent elevated intracellular
ROS Song et al.100 found that oral Korean red ginseng powder
leads to a reduction in MASI score, improvement in MelasQoL,
reduced pigmentation, and improved global improvement scales
in melasma patients.
Plant extracts including orchid extract
The Orchidaceae plant kingdom family consists of thousands of
species. The antioxidant and scavenging abilities of orchids
contribute to their pharmacological use. Tadokoro et al.101 con-
ducted a study of Japanese females to investigate the whitening
efficacy of topical orchid extracts in patients with melasma and
lentigo senilis. Their study, which had no adverse events, con-
cluded that topical application of the orchid-containing plant
extract has similar efficacy to vitamin C in skin whitening.101
Petroselinum crispum
Petroselinum crispum, or English parsley, is a common food sub-
stance with hypoglycemic, hypolipidemic, hepatoprotective, diure-
tic, antimicrobial, anticoagulant, and antioxidant properties.102
Khosravan et al.103 conducted a double-blind, randomized trial to
assess the efficacy of topical petroselinum crispum compared
with hydroquinone cream for melasma. Patients receiving either
therapy achieved significant reductions in MASI score; however,
there was no significant difference between groups.
CONCLUSION
Oxidative stress has been shown to play a role in the patho-
physiology of melasma. This has resulted in exploration of the
therapeutic value of various antioxidants for those suffering from
this chronic disease. Vitamin E, niacinamide, polypodium leuco-
tomos, pycnogenol, grape seed extract, amino fruit acids, phytic
acid, zinc, silymarin, Korean red ginseng powder, plant extracts,
and parsley all have clear evidence of antioxidant properties
and have been studied for treatment of hyperpigmentation and
melasma.
Although these compounds do not all have substantial evi-
dence of benefit for patients with melasma, the investigation of
numerous naturally occurring antioxidant compounds is encour-
aging for dermatologists and patients suffering from this skin
condition with a well-demonstrated impact on quality of life.
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