Natural options for management of melasma, a review

ABSTRACT

A blemish free, even-toned skin is universally associated with healthy skin. This reasoning makes people desire to have a flawless skin. Melanin is a naturally occurring pigment in humans. This pigment is responsible for skin, hair, and eye color, therefore determines our race and phenotypic appearance. On darker skin types, it is common that melanin production processes malfunctions. These malfunctions often lead to overproduction and secretion of melanin. As a result, unwanted pigmentary problems such melasma occur. Due to unknown etiology and its recurrence in nature, melasma is challenging to treat. The current available melasma treatment options often produce undesired side effects and suboptimum results. First-line topical treatments usually involve hydroquinone or topical steroids. Apart from the irritant reactions, this treatment mode is not suitable for all skin types. Skin care specialists are in search of an effective long-term cosmetics and cosmeceuticals to address hypermelanosis problems. Understanding of naturally occurring depigmenting agents provides an opportunity for more effective ways to manage melasma in all skin types. This review considers the benefits of naturally occurring ingredients which could help address skin pigmentation problems and broaden the choice for skin-lightening treatments.

KEYWORDS:

• Melasma
• hyperpigmentation
• natural ingredients
• darker skin types
• pigmentation disorders

Introduction

A blemish free, even skin tone is desirable by everybody. Flawless skin is considered a universal indication of beauty and healthy skin (1). Melanin, a naturally occurring pigment in humans, is responsible for skin, hair, and eye color, therefore determines our race and phenotypic appearance (2). It plays a vital protection role from cytotoxic ultraviolet (UV) radiation and oxidative stress (3,4). Melanin is produced from the melanosomes and transferred from melanocytes to keratinocytes (2,5,6). Melanin production is controlled by the expression and activity of a copper containing enzyme, tyrosinase (7). Tyrosinase is a vital enzyme involved in melanin synthesis. Tyrosinase regulates the catalytic processes of hydrolysis of tyrosine to l-DOPA as well as oxidation of DOPA to DOPA quinine (2,7–9). When this process is malfunctioning, it often leads to overproduction of melanin. Over secretion of melanin causes unwanted skin problems such as post-inflammatory melanoderma, hyperpigmentation, and melasma (4).

Melasma is a common, acquired hypermelanosis (Table 1) of the face, which affects both sexes with a noticeable frequency in women (10–13). It is more common in people of darker skin phototypes due to high melanin content in these skin types (14,15). There seems to be an increased interest among people with skin of color requesting effective skin care treatments, this brings about great demand to investigate effective treatment modalities suitable for these skin types as the current literature is not sufficient. (16–20).

Table 1. Causes of acquired hypermelanosis (41).

Exogenous sources

Cosmetics

Photosensitizing agents (bergamot oil)

Drugs (Isotretinoin, tetracycline, Methotrexate, griseofulvin, sulphonamides)

UV exposure (melasma, solar lentigo, freckles)

Skin disorders and conditions

Melasma

Linea fusca

Poikeloderma of civatte

Erythromelanosis follicularis

Riehl’s malanosis

Post inflammatory hyperpigmentation

Other causes

Pregnancy

Hemochromatosis

Liver disease

Addison’s disease

Pituitary tumor

Melasma is characterized by light-to-dark brown symmetrical, homogeneous, irregular patches or macules (21). Although its etiology is not clearly understood, sun exposure, hormones, pregnancy, use of phototoxic drugs, genetic influences, use of cosmetics, and anticonvulsant drugs are among the predisposing factors (12,13). Melasma is reported to have a significant negative impact on many women. Tremendous emotional stress and psychological distress are chronic emotions brought about by melasma (22–25).

According to statistical data, The American Academy of Dermatology estimates that melasma affects 5–6 million women in the United States (26). Research shows that pigmentation disorders are the third (8, 8%) largest group of skin disorders in dermatology practices. In Brazil, pigmentary disorders are the second largest (11, 6%) complaint in women (27). In South Africa, there is paucity of data in statistics. As a developing country with its diversity similar to America, the statistics may suggest similar patterns in South Africa.

Classification of melasma

Four clinical patterns (Figure 1) of hypermelanosis are cited in patients with melasma (12,28). These include, but are not limited to, a centrofacial, malar, and mandibular pattern. Melasma is not involved in the mucous membranes (10,26). Centrofacial is the most common pattern of melasma. This pattern involves the cheeks, forehead, upper lip, nose and chin. The malar pattern involves the cheeks and nose. The mandibular pattern involves lesions that occur over the ramus of the mandible.

Figure 1. Fitzpatrick skin phototype V with total face involvement melasma. (a) Female full face melasma involvement. (b) Male pattern melasma involving upper mentonian lesions, mandibular, zygomatic, temporal, and frontal (researchers’ collection).

Studies conducted in Brazil on the incidence of topographies (Table 2) concur that the facial area was the most affected; melasma was more noticeable on forehead, upper lip, zygoma, nose, chin, and parotid regions (26,28,29). Other areas of the body such as forearms and neck may also be involved with melasma (7).

Table 2. Frequency of facial features affected by melasma (adapted from Ref. (29)).

Topographies	Percentage
Mandibular	18
Temporal	24
Glabella	25
Mentonian	29
Parotid	30
Nasal	40
Supralabial	51
Zygomatic	84

Originally published in Handel AC, Lima PB, Tonolli VM, Miot LDB, Miot HA. Risk factors for facial melasma in women: a case-control study. Br J Dermatol. 2014 © British Association of Dermatologists. Reproduced by permission of British Association of Dermatologists. Permission to reuse must be obtained from the rightsholder.

Melasma is further classified according to the time it takes to resolve when treated. It is classified as either transient or persistent (10,30). Transient type is when melasma retracts within a year of termination of stimulus, e.g., post-pregnancy. Persistent melasma is seen when melasma persists more than a year after the stimulus has been removed (12,31).

Melasma is classified into four different histological types according to its depth in the skin (10,32). When melanin is distributed in the epidermis, it is illuminated more intense under the Wood’s lamp, a common tool for the diagnosis of melasma. This type is referred to as the epidermal type and is the most common. Dermal melasma is not as intense under Wood’s lamp and melanin is distributed in the dermis. In mixed type melasma, Wood’s lamp gives some interrupted intense illumination on some areas while others remain unchanged. On very dark individuals, Wood’s lamp cannot illuminate melasma due to the skin color acting as a competing chromophore. This type of melasma is classified as the intermediate melasma (10,30).

Histopathological studies have suggested a hyper functional effect on melanocytes (32–34). When compared to normal skin, the involved skin shows larger melanocytes which are extremely discolored with very noticeable dendrites and increased synthesis of eumelanin. Epidermal melanocytes were noticed to be filled with more mitochondria, Golgi apparatus, and rough endoplasmic reticulum. Ribosomes also reflected increased melanocytic activity (34). Electronic microscopy studies revealed almost a similar finding to histology. Microscopically, there were more keratinocytes, melanocytes, and dendrites when compared to the uninvolved skin (33).

South Africa is a country of multiple ethnicity and origin, covering a wide range of darker skin types (35). Melasma is found more frequently and noticeable on Fitzpatrick skin types III–VI (darker skin phototypes) (14,15). Most intervention procedures (topical treatments, lasers and light, chemical peels) have been used but with undesired side effects and suboptimal results on darker skin types (3,16). The darker skin types tend to be sensitive to treatment interventions. Side effects like ochronosis when using hydroquinone (HQ), skin irritations to glycolic acid peels are common reported undesired effects. Darker skin types are more prone to post-inflammatory hyperpigmentation and have a greater chance of relapse (14,36,37). Although medium depth peels, e.g., trichloroacetic acid, are recommended for management of melasma, they should be used with caution as there is a risk of developing hypertrophic scarring and unwanted permanent depigmentation (17,36,37). Use of deep peels is completely prohibited as they are not suitable for darker skin types (36,37). Treatment interventions such as laser, although recommended in literature for melasma treatment, are not suitable for darker skin types (14,36–38).

Diagnostic tools

Analysis of melasma is essential as it informs the treatment choice. There are few instruments that are used for melasma analysis. These include Wood’s lamp, dermoscopy, reflectance confocal microscopy, colimetry, mexametry, Melasma Area and Severity Index, and histology. Wood’s lamp examination is the most common melasma grading tool in which the skin is examined while exposed to the black light emitted by Wood’s lamp. This diagnostic tool was invented by a Caltimore physicist, Robert W. Wood, in 1903. Black light is invisible to the naked eye because it is in the UV spectrum with a wavelength just shorter than the color violet. The Wood’s lamp glows violet in a dark environment because it also emits some light in the violet part of the electromagnetic spectrum. A traditional Wood’s lamp is a low-output mercury arc covered by a Wood filter (barium silicate and 9% nickel oxide) and emits wavelength 320–450 nm (peak 365 nm). Wood’s lamp highlights the difference in pigmentation between affected and normally skin. Intensely seen pigmentation under this lamp responds better to topical treatment (39,40).

Treatment of melasma

Current modalities

Treatment of melasma is challenging to treat due to its recurrence nature. Current treatments of melasma include application of sunscreen, use of topical HQ alone or in combination with tretinoin, and or a corticosteroid (7,10,13,41). Superficial chemical peels and laser therapy are also common treatments (21). HQ is considered the gold standard among the topical treatments of melasma; however, its use is associated with many undesirable side effects. Skin irritations, cytotoxicity, mutagenicity of melanocytes, contact dermatitis, and exogenous ochronosis in ethnic phototypes are amongst reported side effects (42). Natural plant extracts have also been used in the treatment of melasma (Table 3).

Table 3. Studies evaluating the use of topical natural therapies as monotherapy versus other therapies used for treatment of Melasma.

			Treatment measurements
Ref.	Natural intervention	Study design	Objective	Subjective	No. of subjects	Results	Mechanism of action	Side effects	Comments
(43)	Topical VIT C iontophoresis	Randomized, double-blind, placebo-controlled trial, 12 weeks treatment	Colorimeter	Self-assessment	29 Female participants	Gradual reduction of colorimeter L values compared to the placebo. Self-assessment indicated >75% improvement	Inhibit melanin formation and reduce oxidized melanin	Mild electric shock, itching, erythema, burning sensation, and facial dryness	VIT C needs to be stabilized its inability to permeate the skin may result in skin irritations
(51)	Topical VIT L-ascorbic acid versus HQ	A double-blind, randomized trial of 5% ascorbic acid versus 4% HQ in melisma, 16 weeks	Colorimetry, digital photography, and regular color slides	Patient assessment	16 Female participants	Lightening effect of HQ was evident in the first month of treatment; effect of l-ascorbic acid was noted in the third month. Colorimetric measures showed no statistical differences	Suppresses melanin synthesis through its antioxidant effect or by the inhibition of tyrosinase	Fewer, tolerable side effects on the l-ascorbic side compared to the HQ side	l-Ascorbic acid has less side effects, therefore could be used for longer periods
(54)	Topical KA acid	Comparative study of 4% HQ and 0.75% kojic acid cream (containing 0.75% KA and 2.5% VIT C) applied once daily application at night, 12 weeks	MASI, Wood’s light examination	Color photographs	60 Participants of either sex	HQ proved to be highly efficacious, with faster onset of action compared to KA	Anti-tyrosinase	No reported side effects	Broad SPF was used. Poor KA effects could be that KA is a lighter agent compared to HQ. The efficacy of KA in this study may have been potentiated by VIT C
(52)	KA 1% alone, vis-a-vis its separate combinations	A randomized, single blind, comparative study group A—kojic acid 1% cream, group B—kojic acid 1% and hydroquinone 2% cream, group C—kojic acid 1% and betamethasone valerate 0.1% cream, and group D—kojic acid 1%, hydroquinone 2%, and betamethasone valerate 0.1% cream, 3 months	MASI	Photographs, global assessment scale	80 Participants of either sex	Improvement in MASI from all four groups	Tyrosinase inhibition and suppression of melanogenesis	No reported side effects	Combination of KA with HQ is a superior depigmenting agent, use of daily SP was enforced. Wood’s lamp unreliable to examine depth of pigmentation in Indian skin types IV and V
(56)	Topical soybean and soya milk paste applied daily for 8–9 weeks	Both in vivo and in vitro	F&M staining of histologic sections	–	–	STI treated Co-cultures demonstrate reduced tyrosinase activity Decreased pigment deposition was observed	Inhibit melanosome transfer to tokeratinocytes, antioxidant properties	No visual irritation, histologic analyses revealed no markers of irritation or other pathological signs	Soybean could be a promising agent for treatment of melasma. Soybean extracts did not require the addition of any delivery vehicle to exert their depigmenting activity
(58)	Topical liquiritin 2% with a vehicle cream	Split face clinical trial, 4 weeks	–	5 point scale, millimeter grid scale, color photographs and clinical evaluation	20 Female participants	60% with reduction in lesion size, 75%, 70% with reduction in pigment intensity by 3 levels	Melanin dispersibility via the amelanodermic and epidermal stain removing property	Mild skin irritation in the form of erythema and burning sensation	Good response with sun protection and no reported chronic toxicity
(59)	Topical licorice	Efficacy study, 12 weeks	MASI	PGA	34 Female participants	Significant improvement	Inhibits tyrosinase enzyme and anti-inflammatory effects	No side effects recorded	Safe lightening agent due to its anti-inflammatory properties
(60)	Topical licorice, 4%	Randomized, double-blind, placebo-controlled clinical trial, 12 weeks	MMASI	Classification of efficacy of the interventions in four levels	40 Female participants	Notable decrease in MMASI	Solid lipid nanoparticles technology	Minimal side effects	Nanoparticles technology allows large use of large amounts of licorice and increases efficacy
(62)	Topical solution of mequinol	Pilot small case series study. 2% mequinol and 0.01% tretinoin applied twice daily, 12 weeks	–	Digital photographs	5 Male participants	Complete clearance of melasma at 12 weeks	Competitive inhibitor of tyrosinase	Minimal tolerable side effects such as stinging	Sample size very small
(63)	Topical niacinamide	A double-blind, randomized clinical trial of niacinamide 4% versus HQ 4% for 8 weeks	MASI, Colorimeter assessment, Histopathology, Spectrophotometry	Two independent blinded observers	27 Female participants	Niacinamide induces a decrease in pigmentation, inflammatory infiltrate	Serine protease inhibitors	Mild tolerable side effects on niacinamide reported as erythema, pruritus, and burning	Niacinamide is a safe and effective therapeutic agent
(66)	Glucosamine cream A (4% N-acetyl glucoseamine and 2% nicotinamide) cream B (4% HQ)	A randomized, double-blinded, split-face clinical trial. Treatment creams applied twice daily, 12 weeks	MMASI	Digital photography; patient’s rating	30 Female participants	Efficacy of N-acetyl glucosamine + nicotinamide was slightly more	Prevents thyrosinase glycosylation	Erythema, pruritus, and burning were reported less in cream A compared to cream B	Cream A treatment could be a good alternative to hydroquinone
(71)	Arbutin 1% topical gel and plant extract containing Ea	A randomized, prospective, open-label study for 4 weeks with a 6-month follow-up period	Mexameter	Clinical photographs	20 Female participants	A significant response was obtained from all of 10 patients who used arbutin	Whitening agent	No side effects were reported	Possible treatment intervention, use of sun protection remains key
(80)	Topical mulberry extract	Randomized, single-blind, placebo-controlled trial comparative study 75% mulberry (Morus alba) extract oil versus placebo, 8 weeks	MASI, Mexameter, MELASQoL	–	50 Participants	MASI score, significantly improved Mexameter readings showed a significant drop MELASQoL score also improved tremendously for the mulberry group	Whitening agent with antioxidant properties	Mild itching in four patients from the 75% mulberry extract oil group and 12 cases of either itching or erythema reported from the placebo group	Safe and effective skin-lightening ingredient
(66)	Glucosamine cream A (4% N-acetyl glucoseamine and 2% nicotinamide) and cream B (4% HQ)	A randomized, double-blinded, split-face clinical trial. Treatment creams applied twice daily, 12 weeks	MMASI	Digital photography; patient’s rating	30 Female participants	Efficacy of N-acetyl glucosamine + nicotinamide was slightly more	Prevents thyrosinase glycosylation	Erythema, pruritus, and burning were reported less in cream A compared to cream B	Cream A treatment could be a good alternative to hydroquinone
(71)	Arbutin 1% topical gel and plant extract containing Ea	A randomized, prospective, open-label study, 4 weeks with a 6-month follow-up period	Mexameter	Clinical photographs	20 Female participants	A significant response was obtained from all of 10 patients who used arbutin	Whitening agent	No side effects were reported	Possible treatment intervention, use of sun protection remains key
(80)	Topical mulberry extract	Randomized, single-blind, placebo-controlled trial comparative study 75% mulberry (Morus alba) extract oil versus placebo, 8 weeks	MASI, Mexameter, MELASQoL	–	50 Participants	MASI score significantly improved. Mexameter readings showed a significant drop; MELASQoL score also improved tremendously for the mulberry group	Whitening agent with antioxidant properties	Mild itching was reported in 4 patients from the 75% mulberry extract oil group while there were 12 cases of either itching or erythema reported from the placebo group	Safe and effective skin-lightening ingredient
(84)	Hesperidin	Efficacy study to determine the anti-melanogenic effect of hesperidin, in vitro	PASW statistics ver.18.0	–	–	Hesperidin decreased tyrosinase activity leading to melanin decrease expression of MITF and MITF’s downstream melanogenesis-related proteins	Inhibits melanogenesis through scavenging (ROS) and interacting with melanogenic intermediates	–	Hesperidin could be a promising, safe, and healthy skin depigmenting agent with added antioxidant and skin barrier strengthening effects
(88)	Oral ginseng—3 g	Open-label, prospective clinical study	MASI, Mexameter, MELASQoL	Global improvement scale	25 Female participants	MASI decreased and MELASQoL showed improvement 74% of the patients showed some improvement on the patient- and investigator-rated global improvement scales	Inhibition of key enzymes of melanogenesis and enhancing production of antimelanogenic factor	Mild gastrointestinal discomfort and nausea	Novel skin whitening ingredient
(89)	Topical AA	Randomized, double-blind comparison of azelaic acid (20%) and hydroquinone (2%) applied twice daily, 24 weeks	–	5 point grading scale, millimeter grid and color photographs	155 Female participants	AA results categorized as being good to excellent improvement	Tyrosinase inhibitor	Mild side effects reported as burning, itching, and stinging. These were associated with improper cleansing of the face	Therapeutic response compared to HQ group
(94)	Oral grape seed extract rich with proanthocyanidin	Efficacy study, 6 months	Colorimetry Focal macule size	–	12 Female participants	Improvement maximally achieved after 6 months and there was no further improvement after this period	Antioxidant, reduces melanin, biosynthesis as well as UV-induced hyperpigmentation	No adverse effects reported	No clear distinction from melasma

VIT: Vitamin; AA: azelaic acid, MASI, PGA, MMASI: Modified Melasma Area and Severity Index; Ea: ellagic acid; ROS: reactive oxygen species; MITF: microphthalmia-associated transcription factor; p-Erk1/2: phospho-extracellular signal-regulated kinase 1/2; MELASQoL: Melasma Quality of Life Scale.

Naturally occurring remedies for melasma treatment

The goal of treating melasma is to reduce hypermelanosis without causing hypopigmentation or irritation on the surrounding skin. There are many modalities available on the market; however, the side effects associated with them are significant. Naturally occurring depigmenting ingredients, e.g., kojic acid, vitamin C, soybean, licorice, arbutin, mequinol, niacinamide, glucosamine, aloesin, mulberry, hesperidin, ginseng, azelaic acid, umbelliferone (UMB), and grape seed, are presented in this study (Table 3).

Vitamin C (ascorbic acid)

Vitamin C is extracted from green leafy vegetables and citrus fruits. It is a water soluble vitamin with potent functions (42). It has the ability to reduce dopaquinone to DOPA, therefore acting as an antioxidant found in large quantities in human skin (3,10,43–45). Vitamin C has an added benefit of photo protective effects by preventing absorption of both UVA and UVB harmful radiation as well as promotion of collagen synthesis (46).

Literature provides evidence of the instability of vitamin C in the form of a solution. Many studies have concurred that it is quick to oxidize and decomposes in solution (3,45). Vitamin C obtained from fruits and vegetables has limited stability and permeability; this may result in unwanted skin irritations and allergy (47). Ascorbate esters such as magnesium ascorbyl-2-phosphate are always added to any Vitamin C solution to stabilize it (1,3,10,45).

Recent literature demonstrates that the success of topical vitamin C is based on combination therapy. Vitamin C has been combined with iontophoresis (43,46,48), with mesotherapy (47), with laser Q-Switched ND:YAG laser (49), or fractional Q-Switched Ruby Laser (50). Due to its limited permeability being a charged molecule, combination therapies are aimed to assist vitamin C penetration ensuring better efficacy (47). Clinical trials investigating efficacy of vitamin C with iontophoresis (43) or comparing it with HQ (51) have both revealed excellent results with minimal tolerable side effects (Table 3).

Solano et al. (3) acknowledge vitamin C as an excellent antioxidant due to its ability to reduce back o-dopaquinone to dopa, thereby inhibiting melanin formation. Smit et al. (6) suggest that vitamin C is a popular depigmenting agent currently used in most skin whitening formulations. Draelos (1) echoes the same effects of vitamin C in the inhibition of melanin production, however contends that it is a poor lightening product when used alone; better results are achieved when combined with licorice extracts. Bandyopadhyay (10) and Rendon and Gavira (41) suggest that vitamin C is effective when used with MAP cream.

Kojic acid

Kojic acid is a naturally occurring hydrophilic fungus derivative, which acts as a tyrosinase inhibitor and an antioxidant (52). It is best combined with corticosteroids to reduce irritation (10,41). It is commonly used in Asia and Japan with concentrations between 1% and 4%. Application of kojic acid creams is usually twice a day (41,53).

In recent studies, efficacy of topical kojic acid on melasma has been investigated by comparing it with HQ (54), used as monotherapy comparing it with its separate different combinations (52). On both studies, no side effects were observed and results suggested its action as a possible tyrosinase inhibitor. Results achieved on both studies suggested that kojic acid has limited efficacy when used as monotherapy, being a hydrophilic molecule, encounters greater resistance by the cutaneous barrier; however, combination therapies have resulted in significant skin-lightening effects (Table 3).

Soybean

Stimulation of collagen synthesis, protection against photodamage induced by UVB, antioxidant, anti-inflammatory, and moisturizing effects are among other properties of soybean (55). Natural soybeans contain two serine protease inhibitors, Bowman–Birk inhibitor and the soybean trypsin. The two proteases act by interfering with the protease activated receptor 2 pathway (keratinocyte phagocytosis of melanosomes and melanosome transfer). The therapeutic effect of this process is the pigment lightening effect (1,41).

In an in vivo study (Table 3), Yucatan dark-skinned swine were treated with soybean and soya milk paste for a period of 9 weeks (56). Histopathology of the sites treated showed that both soybean and soya milk reduced melanin deposits into the epidermis through phagocytosis of melanosomes, which resulted in reduced color; additionally, both soybean and soya milk extract demonstrated the ability to prevent sun-induced pigmentation (56). It is interesting to note that these results were achieved without an additional vehicle to exert their depigmenting properties. This is an added advantage as the thick stratum corneum is the primary barrier to transdermal treatments (57).

Licorice

Licorice extract has the ability to inhibit tyrosinase activity through its principal active compound glabridin which results in the suppression of melagonesis (4). Liquiritin and isoliquirtin are other two popular active agents of licorice, both act as melanin disperser or removal of epidermal melanin (58,59).

In a clinical trial studies, topical liquiritin has been compared with a vehicle cream (58), used as monotherapy on an efficacy study (59,60). The results of all three studies (Table 3) proved licorice as safe, lightening agent with added anti-inflammatory benefits (59). Nano technology demonstrated a possibility of loading large amounts of licorice for enhanced efficacy (60).

Mequinol

Mequinol is used as an alternative to HQ due to fewer properties that lead to irritation of the skin. Mequinol is the formulation of 0.01% tretinoin and a penetration enhancer (61). This is a scheduled concentration and, therefore, requires a prescription. Though its pathway is unclear, mequinol is thought to be a tyrosinase inhibitor (62). Mequinol has been found to be effective in treating dyspigmentation, even on darker skin types, without causing any side effect (1). A pilot study investigated the efficacy of topical 2% mequinol and 0.01% tretinoin for melasma on men (62). The study demonstrated positive results as complete clearance was noted in 12 weeks with minimal tolerable side effects (Table 3).

Niacinamide

Niacinamide is the active form of vitamin B₃ found in yeasts and root vegetables. It is an important precursor of nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate (42). A recent clinical trial investigated topical niacinamide; the study results demonstrated its efficacy in both subjective and objective measures (63). Additionally, side effects were mild and tolerable (Table 3). Other studies conducted both in in vitro and in humans have found niacinamide to have inhibitory mechanism on melanosome transfer to keratinocytes (34,64). Additionally to depigmenting effects, topical niacinamide has antiaging properties as it decreased collagen oxidation and improved ageing-induced sallowness (65).

Glucosamine

Glucosamine is an amino-monosaccharide which is found in all human tissues. When an amino acid group is added to glucose, the result is the production of the sugar. The molecule product is then acetylated to N-acetyl glucosamine (66). N-acetyl glucosamine has been found to have lightening effects on hypermelanosis due to its reduction of melanin in the melanocytes by prevention of tyrosinase glycosylation (51,66). A recent randomized clinical trial (66) indicated that N-acetyl glucosamine combined with nicotinamide could be a good alternative to HQ when treating melasma. Results of this study demonstrated efficacy in both subjective and objective measures (Table 3). Subjects were instructed against direct sun exposure and daily use of sun protection factor, SPF 15. Combination of niacinamide and glucosamine has been found to have even better results compared to use of glucosamine alone (67).

Arbutin

Arbutin is a HQ derivative found in cranberries, pears, wheat, and blueberries (68). Its mechanism of action is based on inhibition of melanogenesis by binding tyrosinase without influencing the messenger RNA transcription of tyrosinase (45). Its efficacy is dependent on its concentration; the higher the concentration, the better the results. In melasma management, arbutin has been used in combination with lasers (69) as an ingredient in a hydrogel mask (70) or combined with Ellagic acid (71). In all these studies, there have been no undesirable side effects. In a randomized single-blind placebo study (71), 1% topical arbutin brought about a significant response with no side effects.

In vitro studies have shown improvement in the appearance of hyperpigmentation, reduction in melanin content in melanocytes as well as reduction in tyrosinase activity; when compared to HQ, arbutin had demonstrated less toxic effects, making it a better choice (53). Chawla et al. (72) observed that tyrosinase hydroxylation and DOPA activity of tyrosinase inhibition effect are dose dependent. This effect may be due to the chemical structure of dA as de-oxysugars have the ability to increase skin penetration and binding affinity for tyrosinase (3,72).

Researchers endorse that α arbutin has an enhanced efficacy compared to arbutin itself and is less toxic when compared to HQ (73,74). Its action is achieved without affecting the mRNA expression enzymes. This has been demonstrated in cultured human melanoma cells. Its effects are further demonstrated by its effectiveness of inhibition of mushroom tyrosinase in vitro (75,76).

Aloesin

Aloesin is a compound which is derived from aloe extracts. In an in vitro study conducted by Jones et al. (77), aloesin proved to have the ability of inhibiting melanin production from mushroom and murine sources. Choi et al. (78) investigated aloesin pigmentary inhibition effects on UV-induced pigmentation on human skin. The study involved topical application of aloesin on the human forearm that has been exposed to UV radiation four times daily for 15 days. Aloesin was found to have suppressed pigmentation by 34%. This result suggested that aloesin could be used for hypermelanosis which is due to UV radiation. Melasma could also benefit as the literature has cited sun exposure to stimulate the formation of melasma. There is dearth of data regarding its efficacy on melasma.

Mulberry extract

Mulberry extract is a Morus alba L. derivative plant from Moraceae family. The root bark has been found to have skin depigmenting effects due to its inhibitory action of dopa oxidase activity of tyrosinase and its superoxide scavenging activity (53). An in vitro investigative study looked at the effects of compounds found in dried mulberry leaves on melanin biosynthesis (79). The result of this study was significant as cultured melan-a cells responded positively. It was discovered that dried mulberry leaves have an inhibitory effect on tyrosinase action and on melanin formation in melan-a cells (79). A randomized clinical trial investigated 75% topical mulberry oil compared to a placebo in the treatment on melasma (80). Results demonstrated that mulberry was a safe and effective lightening agent with added antioxidant benefits with mild side effects such as itching (Table 3).

Hesperidin

Hesperidin is a bioflavonoid which is fund mostly in peels and membranes of citrus fruits (81); it known for its anti-inflammatory and antioxidant effects (82). In vitro studies conducted have demonstrated good result when treating hypermelanosis due to its ability to inhibit melanin without causing cytotoxicity (82,83). A recent efficacy in vitro demonstrated hesperidin to decrease tyrosinase activity with added antioxidant and skin barrier strengthening effects (84). Other benefits of hesperidin are antiaging; it protects against UVA-induced fibroblast damage as well as protection of collagen damage induced by oxidation (85).

Ginseng

For thousands of years, ginseng has been traditionally used eastern Asia due to its versatility to treat various diseases such as hypertension, liver and kidney dysfunction, diabetes mellitus, and wound healing (86). Red ginseng and white ginseng are the two traditional preparations of ginseng having a ginsenosides as the most important constituent of ginseng (87). White ginseng comes from peeled, dried ginseng root while the red ginseng is produced by steaming fresh ginseng root and then drying it to acceptable moisture content, red ginseng is more potent than the white ginseng (86). In vitro and observational studies investigated its melanogenic effect demonstrated that ginseng reduced melanin content, tyrosinase activity as well as perception of UVB-induced ROS (21,88,89). Efficacy of oral ginseng has been investigated in a clinical study (88). Both subjective and objective measurements showed significant improvement at completion of the study (Table 3). In the study, mild side effects were controlled as soon as ginseng was stopped.

Azelaic acid

Azelaic acid is a nine carbon, naturally occurring, nontoxic saturated non-phenolic dicarboxyl acid. Original use of azelaic acid was on the treatment of acne (53). Due to effects on tyrosinase, it has been used to treat hypermelanosis of the skin (90,91). Azelaic acid works on the mitochondrial enzymes resulting in direct cytotoxic effect towards melanocytes; it also inhibits DNA synthesis. It also has an effect on reduction of free radicals production (53). Studies done in Indo-Malay-Hispanic studies discovered that 20% concentration of azelaic acid is equivalent to those of 2% HQ (90). Baliña and Graupe (91) indicate a similar efficacy for 20% azelaic acid compared to 4% HQ, both in terms of lesion size reduction, pigmentary intensity, and overall response. Azelaic acid is well tolerated with minimal side effects such as a burning sensation, mild erythema, pruritis, cutaneous irritations, and scaling (90,91). There is dearth of data pertaining recent studies in azelaic acid on melasma; this topic requires more studies.

Umbelliferone

UMB is a phenolic compound of plant origin from the Apiaceae (Umbelliferae) family such as carrots and coriander (92,93). Due to its ability to absorb UV light in at several wavelengths (300, 305, 325 nm), this compound is mainly used in sun protection factors as the key ingredient (92). Other effects include non-toxicity to the skin, antioxidant, and anti-inflammatory properties (93). The use of this ingredient in melasma requires more research on its efficacy as there is paucity of data regarding its effectiveness.

Grape seed extract

Grape seed extract contain an antioxidant proanthocyanidin (94). Oral intake of grape seed (Table 3) extract for 6 months resulted in lightening effects of melasma (94). There is however dearth of data regarding its efficacy on topical use.

Limitations of these treatments

Natural therapies have a potential to be used as alternative management for melasma; however, paucity of data regarding their efficacy and potential side effect profile needs to be addressed. More controlled clinical trials are lacking to determine their role. Only a few natural ingredients have been incorporated into topically applied cosmetics or cosmeceuticals often due to lack of parallel human studies (10,26,41,42).

Preventative measures

Although its etiology is not clearly understood, sun exposure, hormones, pregnancy, use of phototoxic drugs, genetic influences, use of cosmetics, and anticonvulsant drugs are cited among predisposing factors (12,13). UV radiation is cited as being the main cause of melasma as it induces the increase in melanogenic activity (12,32). Melasma has been found to reduce during cold winter months and worsens with hot summer climates. In intertropical regions, melasma incidence is observed to have an increased tendency (95,96).

Melasma is also thought to be induced by heat. Authors identified nighttime workers, who are exposed to heat of ovens, e.g., bakers, and professionals exposed to high intensity of light, e.g., dentists, experience great resistance when treating melasma. Worsening of the melasma is also reported as being worse after being exposed to their working condition (97,98).

All these studies suggest that safe sun practice is key to all individuals. If melasma is common among other family members, children should be taught about safety sun exposures. Being a female categorizes one as being at risk due to pregnancy hormones. Use of depigmenting cosmetics as preventative therapy would be proper when pregnant even before melasma starts to appear. Genetic predisposition has been noted in melasma studies (26,27). This reasoning suggests that whenever there is family history, members at risk should try and avoid melasma triggers.

Patient counseling

Melasma is not just a cosmetic concern but rather a medical concern due to its disfiguring nature. It has been associated with significant negative psychological and emotional effects. Decrease in social functioning, reduced productivity at work, and low self-esteem are reported side effects due to melasma (7,22). Tremendous emotional stress and psychological distress are chronic emotions brought about by melasma (7,22–25). Grimes (33) indicates that these symptoms lead to unnecessary stress, ailments, disorders, and often disease.

In Brazil, studies of quality of life on patients suffering from melasma have been conducted from all geographic regions. It was found that quality of life of these patients was affected by melasma which was related to emotional well-being, skin appearance, embarrassment, and frustration. In response to the Melasma Quality of Life Scale (MelasQol) questionnaire, it was observed that most of the time patients reported discomfort, expressed feelings of frustration, agreed to being embarrassed about their skin appearance. Patients further indicated that facial lesions caused great dissatisfaction, low self-esteem lower productivity at work or school as well as withdrawal from social life (99,100).

The findings of the studies of quality of life on patients suffering from melasma suggest that melasma is more than just a cosmetic concern. These MelasQol findings propose that melasma treatments should not be only clinical-based treatments but rather also addressed the psychological aspect as well.

Discussion and conclusion

New, effective, treatment products for melasma are in huge demand. Until melasma can be treated successfully, and its cause identified, researchers work tireless on this subject matter. Development of effective bleaching preparations for hyperpigmented lesions remains a challenge in the cosmetic industry (2,6). This brings about a necessity for development of effective treatment products with no or fewer side effects for management of melasma for all skin phototypes.

Although HQ has remained the gold standard in treating hypermelanosis of the skin, various naturally occurring alternatives are being investigated, due to their lack of side effects. Alternative melasma management is required for darker skin phototypes as these skin phototypes are intolerant to use HQ. Prolonged use of HQ leads to worse pigmentary changes. Besides temporal relief, use of HQ on darker skin types is not the best choice and should be avoided (10,13).

Plant extracts have a potential to relieve symptoms of skin discoloration with minimal tolerable side effects. This suggests that naturally occurring ingredients or plant extracts ingredients could be used successfully in treating melasma even on darker skin types without risk of aggravating the condition. There have been no detrimental side effects reported on long-term use of the naturally occurring ingredients reviewed.

Stability of the depigmenting product choice should play a vital role. Vitamin C from fruits and vegetables has to be stabilized for it to be effective. This should alert the patients to familiarize themselves with efficacy of ingredients listed on the packaging as only proper actives will have a desired effect of the treatment. Most depigmenting creams and solutions have Vitamin C in the list of their active ingredients. It is concerning which form of vitamin C is usually used as the packaging does not always state clearly.

Counseling of patients is of importance during the treatment. Treatment time is an important factor to consider when dealing with melasma cases. In the researcher’s experience in skin care practice, patients who suffer from melasma tend to be impatient and request rapid treatment intervention. Some ingredients such as liquiritin have proved to be effective in a short period of time (58). Discontinuation of use of cosmetics which contain perfume is also another important factor that patients should be aware. Patient compliance is of utmost important for optimum results when treating melasma.

Lack of proper sun protection practices has remained a challenge. This challenge is notable especially on darker skin phototypes. They have a misconception that their skin does not get sun damage; hence, no sun tan is noticed on these skin types. It is imperative that during therapy, sun exposure is limited. Lack of sun protection practice reverses the result of the therapy. Photo protection should play an integral part in the skin care regimen of all individuals. Its importance should not be underestimated or overlooked. An American study analyzing data dating from 1992 National Health Interview survey regarding sun protection behaviors found that out of 1583 African-Americans, only minority respondents were aware of sun protection. The findings suggested that only 3 in 10 adults practiced sun protection, while in adolescents 69% were sunburnt while less than 40% practiced sun protection. Parents did not adequately protect their children from the sun and imitation tanning practices were found to be common among females and young adults (101). Good sun protection habits are vital for a desired outcome to be achieved for all skin phototypes.

Current skin pigment analysis tools are not suitable for use on darker skin types. A universal melasma analysis tool, Wood’s lamp, cannot detect melasma on darker skin types. Due to high epidermal melanin content in darker skin types acting as a competing chromophore, it is challenging to contrast melasma from normal skin (10,30). This necessitates updated skin analysis tools which will enable analysis of all skin types.

Literature has demonstrated melasma to have negative impact on quality of life (22–25). It is significant that all studies looking at effectiveness of treating melasma should also consider measuring the difference on quality of life as well. Studies cited in this review reported the use of natural therapies in melasma management and the possibility that naturally occurring depigmenting ingredients offer potential to expand the choices for treating hypermelanosis and a better choice of effective antimelanogesis topical treatments when dealing with all skin phototypes inclusive of the darker skin phototypes as they get affected the most by melasma.

Disclosure statement

The authors indicate no potential conflict of interest.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work is based on the research supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa (Grant Number 98337).