Skin Depigmenting Agents: Where Do We Stand?

Abstract

Skin hyperpigmentary disorders are frequent and psychologically disturbing conditions for patients. Skin depigmenting agents have been widely used for the treatment of such disorders. The most efficacious depigmenting agents, such as hydroquinone and the Kligman’s formula, are associated with long-term side effects, and safer skin depigmenting agents, such as kojic acid, arbutin, and niacinamide, might suffer from a significantly lower depigmenting efficacy. Therefore, there is still a need for safe and simultaneously efficacious skin depigmenting compounds. Tranexamic acid and cysteamine are two new and interesting molecules that seem to fulfill the majority of the needed characteristics of an acceptable skin depigmenting agent. In this chapter, a review of most important molecules as well as their side effects will be provided with a focus on the newest skin depigmenting molecules recently emerged into the armamentarium of hyperpigmentation treatments.

1. Introduction

As dermatologists, we often find ourselves confronted with patients suffering from hyperpigmentation disorders such as, post-inflammatory hyperpigmentation (PIH), melasma, solar lentigines as well as facial dyschromia. What we see as dark spots or patches on the skin is the result of altered melanin production and/or melanocyte density. Focal hyperpigmentation typically occurs after skin injury or other causes of inflammation including acne vulgaris and eczema. Chronic exposure to UV light also represents a risk factor for the development of skin hyperpigmentation as well as premature aging due to the oxidative stress and cellular damage caused by UVA and UVB rays. These conditions generally do not impact health of the patients; however, as they may significantly affect their appearance, they can be psychologically disturbing and have an impact on patient’s quality of life. According to a recent study, patients with pigmentary disorders have a high prevalence of psychological distress, including stress, anxiety, and depression [1]. Therefore, it is of utmost importance for patients’ psychological well-being to provide them with efficacious and safe treatments for short- as well as long-term use. Maintenance therapy is especially important in hyperpigmentation disorders such as melasma, which has a high recurrence rate. However, the most effective depigmenting agents that are currently available in the armamentarium of dermatologists often take long to show results, have poor patient compliance, and/or do not have a safety profile that allow long-term use due to the risk of causing unwanted side effects.

In this chapter, the most efficacious topical, oral, and injectable depigmenting agents for treating hyperpigmentation will be discussed, and special attention will be given to the most recent and promising ones.

2. Skin depigmenting agents throughout history

Skin whitening is an ancient practice with a long and complex history. In ancient Greece, women painted their faces with white lead to achieve a lighter and unblemished skin tone as at that time pale skin was a sign of beauty and prestige [2]. Ancient Egyptians, like other Mediterranean populations, used to lighten their skin as well. Corroborating this was the uncovering of a 3500-year-old mummy head in the area of the Theban necropolis that exhibited pathological signs typical of exogenous ochronosis, an inflammatory skin condition, which is currently linked to the long-term and unsupervised application of creams containing the depigmenting agent hydroquinone [3]. In ancient Rome, people used a mixture of vinegar and white lead (called cerussa, the lead sugar) with the purpose of whitening their faces. Another widely used skin lightening ingredient was mercury. Creams and ointments containing mercury have been used for centuries to treat infections as well as inflammatory skin diseases and more recently as topical skin whiteners or “freckle removers” [4]. Inorganic mercury compounds are absorbed through the skin and cause depigmentation by competing with copper and resulting in an inactivation of tyrosinase, the enzyme responsible for melanin synthesis. After World War II, the toxic effects of mercury and lead became more evident. Cases of nephrotic syndrome as well as gastrointestinal and neurotoxicity were associated to the use of mercury-containing skin lightening products [5]. Finally, in 1973, the FDA banned the use of mercury in cosmetics [6]. Mercury was therefore replaced by other active ingredients, i.e., hydroquinone, which became the gold standard depigmenting agent for the treatment of hyperpigmentation. Hydroquinone also encountered safety concerns in recent years due to its potential mutagenic effect and was banned in several countries. This let dermatologists and patients with few options for the treatment of hyperpigmentary disorders. Oral and injectable tranexamic acid and topical cysteamine entered into the scope of effective depigmenting options, and much research has been done on these two promising molecules in recent years.

2.1 Topical treatments

The first-line treatment for hyperpigmentation involves topical application of formulations incorporating depigmenting agents. If such options do not prove to be efficacious in the patient, more invasive treatments such as microneedling, mesotherapy, microdermabrasion, chemical peels, or laser are often performed. These however might be associated with post-inflammatory hyperpigmentation especially in higher phototypes. On the other hand, these methods are rather invasive and costly, and a long-term maintenance treatment is usually not acceptable by the patients. Oral administration of drugs, e.g., tranexamic acid (TXA), is usually considered as last therapeutic option. Although TXA treatment is very effective, the risk of life-threatening side effects such as thrombus formation causes it to be hardly acceptable for the treatment of “cosmetic” problems. The optimal treatment for hyperpigmentary disorders would thus be a topical treatment employable by patients at home and not only effective, but also safe enough to be used long term as the maintenance therapy. The most well-known topical depigmenting molecules will be discussed in the next sections. Their efficacy as well as safety profile for long-term use will be addressed, and the most appropriate topical depigmenting agent available today will be discussed in more detail.

2.1.1 Hydroquinone and its derivatives

Hydroquinone (HQ) is a biphenol. Its widespread application in human and industrial activities made hydroquinone a ubiquitous molecule in the environment. In 1936, Oettel reported that black-haired cats turned gray when fed with HQ over a period of 6–8 weeks, and after stopping the treatment, the hair became repigmented as quick [7]. This finding was confirmed a few years later by Martin and Ansbacher [8].

In 1939, Oliver et al. published about an antioxidant (monobenzylether of hydroquinone) used in rubber gloves to reduce their deterioration, which was responsible for depigmentation of the skin of workers wearing the gloves [9]. In 1941, Peck and Sobotka found out that oral administration monobenzylether of hydroquinone to guinea pigs did not result in any depigmentation. However, when topically applied, it caused depigmentation of the epidermis [10].

HQ was shown to act as an inhibitor of tyrosinase in vitro, but in vivo it likely acts through the release of free radicals, which are toxic to melanocytes [11]. In 1981, Passi and Nazzaro-Porro showed that HQ acts as an alternative substrate for tyrosinase, whose oxidation product is the highly toxic metabolite 1,4-benzoquinone [12]. Other studies reported that the depigmenting activity of HQ results from its potent melanocytotoxic effects, which are mediated via its enzymatic oxidation to quinones [13, 14, 15]. Other enzymes, such as peroxidase, can metabolize hydroquinone resulting in toxic metabolites responsible for melanocytotoxicity [13, 16].

For many decades, hydroquinone has been recognized as the gold standard topical agent for skin lightening. Hydroquinone alone is of moderate to good efficacy for the treatment of most hyperpigmentary disorders. Epidermal melasma and post-inflammatory hyperpigmentation respond fairly well to topical hydroquinone, while dermal melasma and lentigines are not responsive. Efforts have been made to increase the efficacy of topical hydroquinone formulations by changing the vehicle as well as by adding other depigmenting agents. Alpha-hydroxy acids (AHAs), kojic acid, azelaic acid, etc., are examples of agents added to hydroquinone to enhance its depigmenting activity. A considerable increase in the depigmenting efficacy of hydroquinone was achieved by Kligman in 1975.

2.1.2 Kligman’s formula

In 1975, Kligman and Willis investigated ways to enhance the depigmenting effect of hydroquinone [17]. It was found that the skin of acne patients treated with topical retinoic acid occasionally showed a light hypopigmentation after several months of use and that intradermal injection of corticosteroids into darker skin types resulted in depigmentation. These observations brought to the idea of combining HQ with retinoic acid and corticosteroids [17]. Surprisingly, this combination was found to have a synergistic depigmenting action. Retinoic acid promotes skin desquamation, therefore increases melanin loss from the superficial epidermal layers. In recent years, retinoic acid was found to be an inhibitor of glutathione S-transferase resulting in melanocytes becoming more susceptible to the cytotoxic effects of HQ [18].

Several studies demonstrated the superior efficacy of KF over HQ alone, resulting in KF quickly becoming the new gold standard. The KF has been modified over the years. Modifications of the initial formula involved changes in the types of corticosteroids and vehicles used. Modified Kligman’s formulas (mKF) have become the most widely used HQ-based products for treatment of melasma [19, 20].

It is worth notice though that HQ nonresponsive pathologies, such as dermal melasma and lentigines, still remain unresponsive to the KF. The presence of retinoic acid in the KF counteracts to some extent the corticosteroid-induced skin atrophy. However, evident cases of skin atrophy after long-term use of KF have been reported [21]. In my hands, KF is an efficacious topical formula for the treatment of hyperpigmentary disorders, but at the expenses of a more irritant potential and of possible side effects with long-term use due to the presence of corticosteroids.

Most recently HQ became object of controversy as regulatory agencies around the world began questioning its safety. In Europe and in some Asian countries, hydroquinone has become unavailable due to concerns regarding carcinogenesis and melanocyte toxicity [22]. A study demonstrated that large amounts of oral hydroquinone caused cancer in rodents [23]. However, human being exposed to hydroquinone dust in hydroquinone factories showed a lower cancer rate compared with the normal population adding to the complexity of hydroquinone controversy. Adverse effects, such as skin irritation, contact dermatitis, and exogenous ochronosis, may occur with the unsupervised use of this compound. As a result of the controversy around the use of HQ, there exists a large and growing market for alternative products that are as effective in depigmenting the skin. Meanwhile, other formulations containing already existing depigmenting molecules, such as arbutin, kojic acid and azelaic acid, remained available, but unfortunately with a far less efficacy profile compared with hydroquinone formulations.

2.1.3 Arbutin

Arbutin is a HQ glycoside in which one molecule of D-glucose is bound to HQ. Its depigmenting effects result from the inhibition of tyrosinase. Many in vitro studies can be found in the literature showing arbutin’s inhibitory effects on melanin synthesis [24, 25, 26]; however, the efficacy observed could hardly reach that of HQ. Several clinical studies have been performed in which arbutin was combined with other agents in formulations, e.g., niacinamide, bisabolol, retinyl aldehyde [27], or with tranexamic acid [28], showing to be as effective as 4% HQ in reducing pigmentation. According to some authors, arbutin is thought to work following its decomposition to HQ. Bang et al. report that arbutin can be hydrolyzed by the natural skin microbiota (Staphylococcus epidermidis and Staphylococcus aureus) leading to its conversion to HQ [29]. Others reported that arbutin can be converted into HQ by effect of UV radiation [30]. Thus, arbutin-containing skin lighteners are not totally HQ free. In addition, there are reports arguing that arbutin has pro-melanogenic effects in vitro, which obviously conflict with others reporting a depigmenting activity of arbutin [31]. Even if arbutin was as effective as 4% HQ , it is because it is actually converted to HQ. Therefore, there is no advantage in using arbutin instead of HQ.

On the other hand, as a dermatologist, arbutin-containing products in my hands are far less effective than HQ-containing formulations.

2.1.4 Kojic acid

Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyrone) is a naturally occurring, hydrophilic fungal product obtained from various genera of fungi, such as the ones belonging to the genus Aspergillus and Penicillium [32]. It is a potent antioxidant, a tyrosinase inhibitor and a copper chelator, showing depigmenting effects in vitro [33]. A quick search on the literature confirms that at the moment there are no vehicle-controlled studies confirming the depigmenting action of kojic acid alone, in animal or in human trials. In an in vivo animal study on black Guinea pig skin, kojic acid did not show any depigmenting action when applied topically at 4% for 6 weeks (unpublished data).

When combined with other actives, kojic acid has been demonstrated to be effective in reducing hyperpigmentation, including melasma. A double-blind, split face study compared the efficacy of a gel containing 2% kojic acid in combination with 10% glycolic acid and 2% HQ to the same preparation without kojic acid for the treatment of epidermal melasma. Improvement of melasma was observed on both the facial sides, but higher efficacy was obtained with the gel containing the kojic acid [34]. Kojic acid is often combined with HQ for a synergistic depigmenting effect [32, 35]. Combination therapy including kojic acid may be an option in case a patient shows tolerability issues with other first-line therapies. However, kojic acid may be irritant and having sensitizing potential. Side effects reported following its topical application are contact dermatitis and erythema [36, 37].

2.1.5 Azelaic acid

In 1978, Dr. Nazzaro-Porro studied the mechanism of hypopigmenting effects in Pityriasis versicolor. At that time, a causative relation between the fungus Pityrosporum and hypopigmentation was suggested. It was postulated that certain metabolites secreted by the fungus might penetrate down the skin reaching the basal layer and damage melanocytes resulting in hypopigmentation [38, 39]. This hypothesis was confirmed, observations by electron microscopy revealed that melanocytes in the hypopigmented areas were highly damaged. Additional investigations followed showing that when Pityrosporum cultures were fed with unsaturated fatty acids with double bonds in 6–12 positions, dicarboxylic acids were produced. These metabolic products, including azelaic acid, were found to competitively inhibit tyrosinase in vitro [38]. Important observations suggest that medium chain-length dicarboxylic acids could be useful for treating hyperpigmentary disorders. Azelaic acid formulated in a cream was then used and showed good results in clinical studies on melasma patients first and later on patients affected by lentigo maligna [39, 40]. Histological analysis performed in the latter study shed light on the mechanism of action of azelaic acid, evidencing a progressive destruction of abnormal melanocytes followed by their replacement by normal ones. Further in vitro studies elucidated that azelaic acid has no depigmenting effect on normal melanocytes; instead, it has selective cytotoxic effect (inhibition of DNA synthesis and mitochondrial enzymes) in abnormal melanocytes [41].

Azelaic acid is a naturally occurring nine carbon C₈–C₁₄ dicarboxylic acid produced by Malassezia furfur (formerly known as Pityrosporum ovale). Obtained from whole grain cereals, rye, wheat, and barley, azelaic acid has multiple functions; it scavenges reactive oxygen species, it has anti-inflammatory, antibacterial, comedolytic as well as anti-keratinizing properties, and last but not least, it inhibits tyrosinase as well as thioredoxin activities [39, 40, 42, 43, 44]. It is precisely because of these many properties that azelaic acid has been and is still used as a topical anti-acne agent [45]. Despite the fact that azelaic acid showed no depigmenting action in animal studies performed by Dr. Pathak et al. in 1985, [46] some human studies showed that very long treatment protocols (up to 24 weeks) could induce some depigmenting action in melasma lesions. In some of these studies, azelaic acid used for at least 6 months could show comparable effects to topical 4% HQ. The efficacy of a cream containing 20% azelaic acid has been compared with one containing 2% HQ in one study and with one containing 4% HQ in a second study involving 155 and 329 patients, respectively, both studies being 24-weeks long. Results showed that azelaic acid provides at least equivalent or, in the first study, even higher efficacy to HQ in the treatment of melasma [47, 48]. Side effects documented with topical use of azelaic include pruritus, mild erythema, and burning. Since azelaic acid is not cytotoxic to normal melanocytes, adverse events such as exogenous ochronosis or leukoderma are not associated with its use [48]. In addition, azelaic acid is not known to have mutagenic and carcinogenic potential.

In my experience, topical azelaic acid has a very long onset of action, which is not comparable with HQ or other effective depigmenting compounds, and this is associated with a very low compliance of patients who expect a depigmenting effect at least during the first weeks of application.

3. Newly emerging depigmenting agents

3.1 TXA in different forms

Tranexamic acid (TXA)—IUPAC name: trans-4-aminomethyl cyclohexane carboxylic acid—is a synthetic lysine analog well known for its anti-fibrinolytic activity. TXA has been used for several years to treat heavy bleedings, e.g., during menstruation or surgery as well as in case of trauma and bleeding disorders [49]. In recent years, TXA became more and more popular as a depigmenting agent. The first report describing the depigmenting effects of TXA dates back to 1979 [50]. The skin-whitening effects of oral TXA were accidentally found by Nijo Sadako, a Japanese investigator who had used TXA to treat patients with urticaria and observed improvements in their melasma. It has been postulated and later on reported that TXA is effective by modulating the vascular component of melasma [51, 52]. Recent studies have shown promising results on TXA for the treatment of melasma due to its ability to block melanin synthesis. Maeda investigated the mechanism of action of TXA in cultured human melanocytes. It was suggested that TXA inhibits melanin synthesis without interacting directly with melanocytes, but by interfering with the interaction between melanocytes and keratinocytes through the inhibition of plasminogen activator and therefore interfering with the plasminogen/plasmin pathway [53]. This results in a decrease of free arachidonic acid production and as a consequence melanogenic factors, such as prostaglandin and leukotrienes—which are known to stimulate tyrosinase activity—are reduced [54].

The paracrine melanogenic factor Endothelin-1 (ET-1) is generally increased in patients affected by melasma. In 2016, Kim at al. published about a possible mechanism of action of topical TXA in melasma patients. Topical application of 2% TXA resulted in ET-1 downregulation as shown in skin biopsies taken from the patients [55]. In addition, a slight decrease in the number of CD 31⁺ blood vessels was also found in patients applying TXA. Additional literature aiming at elucidating the mechanism of action of TXA showed that it reduces tyrosinase protein expression as well as tyrosinase-related protein 1 and 2 (TRP1/2) levels [56].

TXA is a relatively new depigmenting agent, and it is used topically, by intradermal microinjection, and as oral agent for the treatment of melasma. TXA is an amino acid derivative, thus it does not adequately penetrate into the epidermis. A limited number of studies compared the efficacy of topical TXA at concentrations of 2% up to 5% to that of HQ (2–3%) alone or in combination with dexamethasone showing a comparable MASI score reduction with no statistical difference between groups [57, 58, 59]. The efficacy of the topical forms of tranexamic acid is rather controversial, and there is a need for large-scale, randomized controlled clinical trials comparing the efficacy of topical TXA versus oral or intradermal TXA [60]. However, the intradermal injection as well as the oral form of TXA tends to work as efficient depigmenting method for hyperpigmentary disorders.

A concern associated with the use of TXA for melasma has been the risk of developing arterial and venous thrombosis. The reported cases of thrombosis with oral TXA for the treatment of heavy bleeding refer to patients with risk factors for hypercoagulability, including clotting disorders, history of pulmonary emboli, prolonged immobility, hormone therapy, active bleeding, etc. [61, 62, 63]. This might be considered as a prohibiting factor for long-term use of TXA especially the oral form in patient with hyperpigmentary disorders.

To date, there are no studies comparing directly the efficacy of TXA with the one of triple combination cream (modified Kligman’s formula).

In my hands, the topical form of TXA when not combined with other depigmenting molecules did not show any significant depigmenting results in patients with hyperpigmentary disorders. The intradermal form is quite effective, but is associated with pain, and most patients do not wish to continue the intradermal injections further than 4–6 months. The oral form of TXA is significantly effective in most patients with melasma, but is associated with a recurrence as soon as the treatment is stopped. Topical treatments proved to be ineffective in prohibiting such a recurrence.

3.2 Cysteamine

Cysteamine is the simplest aminothiol present in nature. It is an endogenous molecule resulting from the degradation of L-cysteine in mammalian cells during the Coenzyme A metabolic pathway [64]. Plasma concentrations of cysteamine are low, but it is highly concentrated in human milk. Cysteamine plays several key roles in human biology [65]. It acts as an intracellular antioxidant and has protective properties [65, 66, 67]. Cysteamine is orally administered to treat different pathologies, such as cystinosis and neurodegenerative disorders [67, 68].

The first evidence of the depigmenting activity of cysteamine dates back to 1966 when Chavin injected cysteamine hydrochloride into the skin of black gold fish model and observed a discoloration of the fish [69]. The higher depigmenting properties of cysteamine compared to HQ were demonstrated by two independent studies on animal models published by Frenk et al. and Bleehen et al., a couple of years later [70, 71]. Qiu et al. demonstrated that cysteamine exerts no cytotoxic effects on melanocytes and that it acts through melanogenesis inhibition [72]. Despite the high efficacy and high safety profile, two problems have precluded the use of cysteamine as a depigmenting agent: its instability and its offensive odor upon oxidation [65, 73]. These problems were overcome in 2012, and the first topical product containing cysteamine came to the market.

The first clinical evidences of the efficacy of topical stabilized cysteamine for the treatment of melasma were demonstrated in two double-blind, randomized, vehicle-controlled trials [74, 75]. The first trial involved 50 female melasma patients. At 2 and at 4 months, a statistically significant reduction in mMASI score (41.8% reduction at 2 months and 58.1% reduction at 4 months) as well as melanin index (47.2% at 2 months and 65.1% at 4 months) was observed in the group treated with stabilized cysteamine compared with placebo vehicle (mMASI: 7.1% reduction at 2 months and 10.8% reduction at 4 months; melanin index: 7.1% reduction at 2 months and 10.8% reduction at 4 months) [74]. The second vehicle-controlled study involved 40 melasma patients. mMASI scores were significantly reduced in the cysteamine group (55.6% reduction at 4 months) compared with placebo (7.6% reduction at 4 months). Melanin index measured by Mexameter and by Dermacatch was also reduced by 59.2% (versus 10% for placebo) and by 63.6% (versus 5.5% for placebo), respectively. Recent double-blind and randomized clinical trials compared the efficacy and tolerability of topical cysteamine with that of 4% HQ, TXA, and triple combination cream. When compared with Hydroquinone and TXA mesotherapy, stabilized cysteamine was shown to be as effective and better tolerated [76, 77, 78, 79].

3.3 Mechanism of action

Cysteamine inhibits melanin production at different levels of the melanogenesis pathway by inhibiting tyrosinase and peroxidase, both essential enzymes leading to the conversion of tyrosine into dopaquinone and the further polymerization of indoles into melanin. Cysteamine is also a chelator of iron and copper ions, thus preventing Fenton-type reactions [80]. As an antioxidant and scavenger of free radicals, cysteamine suppresses all oxidation steps in the melanogenesis pathway also preventing photo-oxidation. Another interesting feature of cysteamine is that it is also able to increase levels of intracellular glutathione, amplifying natural depigmenting effects [81, 82]. In addition, cysteamine has the ability to cleave keratin disulfide bonds, thus enhancing the shedding of melanin in the corneal layer promoting epidermal turnover [76].

3.4 New formulations based on cysteamine

New formulations combining cysteamine with other molecules, such as certain vitamin B3 derivatives as well as with alpha hydroxy acids (AHAs) (cysteamine triple combination), recently entered the market. This triple combination was aimed at increasing the efficacy and accelerating the onset of action of cysteamine through the inhibition of melanosomal transfer by vitamin B3 derivatives and by increasing the epidermal penetration of cysteamine by AHA.

A very recent double-blind, randomized, and placebo-controlled 16-week long clinical trial has been performed to compare the efficacy, safety, and tolerability of the cysteamine triple combination with that of modified Kligman’s formula for the treatment of melasma. Results are about to be published and showed an equivalent onset of action in terms of mMASI reduction and melasma/normal skin contrast reduction at 4 weeks post initiation of the treatment. Similar efficacy was shown at 16 weeks with no significant differences between the group applying the cysteamine triple combination and the group applying the modified Kligman’s formula. No severe adverse events were reported in any groups.

Vitamin B3 group of chemicals in general confers anti-inflammatory, anti-pruritic, antimicrobial, and lightening effects. The latter results from the inhibition of melanosomal transfer. The combination of a vitamin B3 derivative with cysteamine exploits the complementary depigmenting action of the two molecules to achieve an additive depigmenting effectiveness.

An important advantage of cysteamine, in contrast to the gold standard triple combination (Kligman’s formula), is the possibility of long-term use as a maintenance therapy. In addition, topical cysteamine is shown to be efficacious for the treatment of lentigines, which are usually resistant to most topical depigmenting agents [65].

It is possible that cysteamine triple combination could in the near future serve as a safe and effective long-term treatment for hyperpigmentary disorders in humans.

3.5 New oral and/or injectable treatments

3.5.1 Polypodium

Polypodium leucotomos (PL) is an anti-inflammatory, antioxidant, and photoprotective agent extracted from fern species [83, 84, 85]. These activities are attributed to the presence of several compounds in the extract, among others p-cumaric, ferulic, caffeic, and vanillic acids [86]. In 2004, it was shown that oral administration of PL (7.5 mg/kg) provided photoprotective effects in patients who were previously exposed to photochemotherapy [87]. The effect of oral PL extract (480 mg daily) was also assessed on pigmentation following visible light exposure in patients with Fitzpatrick skin type IV–VI for a period of 28 days. A significant decrease in persistent pigment darkening and delayed tanning were observed accompanied by a decrease in markers for cellular damage, suggesting that PL has depigmenting and cytoprotective effects [88, 89]. The clinical efficacy of PL was demonstrated also for the prevention and treatment of melasma. At 12 weeks, mean MASI score was significantly decreased in patients treated with PL as compared with placebo [90]. Another randomized and placebo-controlled clinical trial was performed with 40 Hispanic female patients with moderate to severe melasma, who were given either Polypodium (240 g doses, three times daily) or placebo for 12 weeks, both groups applied topical sunscreen (SPF 55). Both melanin index and MASI scores were reduced in both groups, and PL was found to have no significant depigmenting effect [91]. Another study was performed on 40 Asiatic patients with melasma comparing the combination of PL (twice daily, total daily dose of 480 mg) with topical 4% HQ and SPF50 sunscreen to the combination of HQ and sunscreen alone over a period of 12 weeks. Significant improvement in mMASI scores was observed for both groups, and at day 56, PL treatment was significantly better than placebo. The authors of this study suggested that PL is a useful adjunctive for treatment of melasma [92].

3.5.2 Grape seed extract

Grape seed extract (GSE) contains proanthocyanidin, a powerful antioxidant. Although there are no studies on the topical use of grape seed extract, oral intake for 6 months has been found beneficial in patients with melasma in a study conducted by Yamakoshi, et al. [93] L* value and melanin index were measured. Both indices increased after 6 months of grape seed extract intake confirming the depigmenting action of GSE. The study suggested that GSE is effective in reducing hyperpigmentation in melasma patients. The depigmenting effects were only observed after 6 months with no further improvements afterward. The extract was shown to be safe and well tolerated. Another recent study on 30 women with mild-to-moderate facial melasma assessed the depigmenting efficacy of oral supplementation including GSE in combination with Pinus pinaster, vitamins, and minerals, used concomitantly with a high SPF sunscreen. MASI score decreased significantly at days 28, 56, and 84. A significant decrease in the melanin index between melasma affected skin and adjacent area was observed. Also a reduction in the number and areas of UV pigmented spots and in the areas of melasma was seen overtime [94].

Regarding the very slow onset of action, GSE might only be interesting as an adjuvant treatment for melasma in addition to topical agents and not as a monotherapy.

3.5.3 Glutathione

Glutathione (GSH) is a tripeptide of glutamate, cysteine, and glycine and is a powerful endogenous antioxidant. Endogenous GSH produces depigmentation by inhibiting tyrosinase and bypassing the production of eumelanin to that of pheomelanin [95]. At the time of authoring this chapter, only a few published clinical studies evaluated the efficacy of oral and topical glutathione as depigmenting agent. An open-label, 8-week study published in 2016 involved 30 healthy Filipino women, who were treated with a 500-mg buccal (sublingual lozenge) glutathione. The results showed a significant reduction in the melanin index (determined by Mexameter), and moderate lightening was observed in 90% of the subjects [96]. Topical oxidized glutathione (GSSG) at 2% was tested on 30 healthy women in a randomized, double-blind, split-face, and placebo-controlled study. Changes in melanin index values determined by Mexameter, moisture content of the stratum corneum determined by corneometry, smoothness, wrinkle formation, and elasticity of the skin were measured. The study lasted 10 weeks and showed a significant reduction of the melanin index in the GSSG-treated side [97]. The findings of these studies, however, need to be interpreted with caution due to some important limitations, such as the small samples size, the short study period, and no follow-up, no evidence of GSH efficacy on patients having hyperpigmentation but studies performed only on healthy subjects and lack of measurement of blood levels of glutathione. To date, there is no in vivo evidence on the efficacy of GSH on the treatment of hyperpigmentary disorders.

Systemic GSH through IV injection has been used as an off-label treatment for hyperpigmentary disorders and general skin whitening. This practice is forbidden by the FDA due to its hazardous side effects, such Stevens-Johnsons syndrome associated with IV injection of glutathione. The depigmenting action of IV GSH is not yet shown in any studies.

4. Conclusions

Topical cysteamine and tranexamic acid (intradermal and oral forms) are newer options that physicians can incorporate into their armamentarium. TXA, because of its demonstrated efficacy, is a good tool in hands of dermatologists for stubborn lesions.

The depigmenting efficacy of TXA and cysteamine has been evidenced in several clinical trials; however, additional larger studies are needed. To date, cysteamine has never been associated to severe adverse effects and thus represents an interesting alternative treatment to the Kligman’s formula. If the results of the current studies showing the comparable efficacy of cysteamine with HQ and especially the Kligman’s formula are confirmed in further clinical trials, cysteamine can be considered as one of the primary treatments for hyperpigmentary disorders. The absence of side effects associated with long-term use of cysteamine preparations suggests that it could be safely employed in the maintenance phase, since the Kligman’s formula, although very effective for the acute treatment, is not a long-term option.

The existing risk of hazardous side effects such as thrombosis makes the long-term use of oral TXA risky. This causes TXA not to be considered as a long-term tool for the treatment of patients with recurring pigmentary disorders as melasma.

The other agents presented in this chapter, such as arbutin, kojic acid, and azelaic acid, are generally well tolerated, but appear having low efficacy and/or slow onset of action, although combinations of two or more depigmenting agents could improve that. More research and evidences are needed to demonstrate their individual benefits as well as optimal formulations.

Conflict of interest

Dr. Behrooz Kasraee is currently the president, shareholder, and the Chief Scientific Officer of Scientis SA.