Skin Pigmentation and Cosmetic Considerations for Even Skin Tone

Abstract

The pigment polymer, melanin is the major determinant of visible pigmentation of skin, hair, and eyes. Its synthesis within organelles called melanosomes in melanocytes and transfer to and distribution within keratinocytes in the epidermis regulates skin pigmentation. Sunlight and its ultraviolet radiation component have a well-established role in skin tanning, through increasing epidermal melanin. Additionally, linked to the pigmentary system are disorders of pigmentation, resulting in problems ranging from hypopigmentation to hyperpigmentation. This chapter provides an overview of the prominent hyperpigmentary manifestations such as post-inflammatory hyperpigmentation (e.g., that associated with acne), solar lentigo, melasma, and peri-orbital hyperpigmentation and recent advances in cosmetic interventions borne out of strong scientific understanding and consumer clinical studies.

1. Introduction

Visual appearance is the reflection of one’s inner self and is hence associated with self-esteem. To achieve skin devoid of imperfections has been an age-old quest, as it plays an important role in social acceptability. One such important aspect of appearance is skin color and its associated disorders. Skin color is determined by the amount and type of melanin (i.e., eumelanin and pheomelanin) synthesized in melanocytes and distributed within epidermal layers. It is also widely agreed that the type of melanin and its distribution in the epidermis are the most important factors in the protection of human skin from the detrimental effects of ultraviolet radiation (UVR). Constitutive skin color is what a person is born with and is genetically determined, while environmental factors such as UVR and pollution and physiological changes such as inflammation, hormonal changes, age, etc., influence facultative skin color.

Many constitutive pigmentation genes have been identified through spontaneous mutations causing a visible change in hair or skin color phenotype in mice or humans. All these genes are associated with either regulation of the pigmentation process in melanocytes or its development, survival, differentiation, and/or responses to stimuli [1]. In recent studies, using a genome-wide association approach complemented with targeted resequencing, scientists have identified previously unreported non-canonical skin pigmentation pathways in African populations, suggesting that the architecture of skin pigmentation can vary across humans subjected to different local evolutionary pressures [2, 3, 4]. Thus, novel variants in genes not previously linked to pigmentation are being discovered, and mounting evidence appears to suggest that there could be many more variants yet to be identified.

On the other hand, the molecular regulation of facultative pigmentation also called hyperpigmentation, has not been very well characterized. Limited knowledge exists on the etiology and the key genes/proteins involved in the induction, characteristics, and maintenance of the pathology of these conditions. Facial hyper-pigmentary conditions like melasma, post-inflammatory hyperpigmentation (PIH), periorbital darkening, and solar lentigines (SL, age spots) are common cosmetic concerns across populations, especially in individuals of skin of color. Some of these conditions are described in the next section with the latest understanding of their underlying biology.

2. Hyper pigmentary conditions and biology

The common facial melanotic conditions prevalent in humans are shown in Figure 1.

Figure 1.

Various facial hyper melanosis prevalent in humans. (A) Periorbital hyperpigmentation (POH); (B) solar/senile lentigines (SL); (C) post inflammatory hyperpigmentation (PIH); (D) melasma.

2.1 Solar lentigines

Solar lentigines (SL) is a common hyperpigmentary disease occurring in approximately 90% of old Caucasians and 70% of old Asians [5]. It is reported to develop more frequently in men than women [6, 7]. It presents a well-demarcated circumscribed yellow or brown macule with a diameter of 1–3 cm, predominantly on sun-exposed areas such as the face and the dorsal aspects of the hands and forearms [8]. However, unlike UV tanning, which may disappear with time in the absence of further sun exposure, SL is not known to resolve on its own, probably due to irreversible damage resulting from repeated sun exposure. Besides sun exposure, environmental factors such as constituents of ambient air pollution; may also contribute to SL development [9].

Histopathological assessment of SL has been carried out by several independent investigators. Prominent features include hyperpigmentation of the basal cell layer with a characteristic club-shaped elongation of rete ridges, numerous melanocytes, and increased melanin production without cellular atypia. A significant increase in both the epidermal area and the number of melanocytes, compared to that with a similar degree of photodamage, but frequently lacking the rete ridge hyperplasia classically associated with lentigines from other anatomic sites have been reported for facial SL [10, 11]. Classification of human SL progressive stages, based on the degree of melanin deposition and the depth and complexity of the rete ridges has been proposed with early stages of SL presenting with lower melanin levels as well as shorter and simpler rete ridges, whereas later stages show an accumulation of melanin and intricated rete ridges protruding into the thinning dermis and epidermis [12, 13, 14]. More recent studies have also pointed to the role of underlying inflammation in SL pathogenesis [15].

In recent years, insights generated through several qualitative and quantitative studies have significantly advanced our understanding of the underlying mechanisms in SL pathogenesis. Gene profiling studies reported upregulation of genes related to inflammation, fatty-acid metabolism, and melanogenesis, and downregulation of cornified envelope-related genes, indicating that solar lentigo is likely induced by mutagenic effects of repeated ultraviolet light exposures, thereby increasing melanin production, with a concomitant reduction in proliferation and differentiation of keratinocytes [14, 16]. The observed reduction in keratinocyte proliferation has been corroborated in a subsequent study, wherein the authors propose that early events may involve pigment-related genes, but with increasing time, increased levels of keratins 5 and 10 may put pressure on the basement membrane with basal keratinocytes loaded with melanin, pushing down toward the dermis to form rete ridges instead of moving upwards toward the stratum corneum as in normal skin [17]. Analysis of 160 skin biopsy samples from the lesional skin of SL showed a gradual increase in the expression of specific microRNAs from photo protected to peri-lesional skin to SL [18]. The profile reveals a significant change in microRNAs that regulate genes involved in lipid and fatty acid metabolism as well as inflammation.

Several independent studies have implicated cell types besides melanocytes in SL pathogenesis. In a study to decipher morphological and immunohistochemical changes of keratinocytes in facial SL, it was shown that individual keratinocytes were larger in size and showed increased p16 staining, pointing to a role for senescent changes underlying the pathogenesis [19]. More recently, in a study on 190 SL subjects, Notch1-dependent keratinocyte malfunction was suggested as the cause of the development of SL [20]. Besides the epidermal compartment, several independent studies have also reported changes in epithelial-mesenchymal crosstalk in SL pathogenesis. Prominent among these are endothelin-1 (ET-1), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), and stem cell factor (SCF) [21, 22]. An interesting difference between UVB melanosis and SL is that in the former, ET-1 and SCF are stimulated by interleukin-1 alpha (IL-1α), while in SL, they are stimulated by tumor necrosis factor-alpha (TNFα) [23]. Observed degradation of heparan sulfate chains owing to increased heparinase at the dermal-epidermal junction (DEJ), may exacerbate the transfer of growth factors and cytokines between the epidermis and dermis, contributing to hyperpigmentation in SL [24]. Studies have also pointed to increased blood flow and vasculature in SL using immunohistochemistry [25], 3D microvascular analysis [26], and optical coherence tomography angiography [27]. Most recently, a dysregulation of Nrf2 signaling has been shown to be associated with SL pathogenesis [28]. Taken together, these pieces of evidence point to a complex network of cells and secreted factors that are likely involved in the development and progression of SL.

2.2 Postinflammatory hyperpigmentation

Postinflammatory hyperpigmentation (PIH) is one of the most common causes of altered normal skin color [29]. It is an acquired hyper-melanosis and a common sequela of various inflammatory episodes. It primarily afflicts patients with darker skin types (Fitzpatrick types III–VI), although all skin types can develop PIH [30]. As compared to 25% in white patients, the prevalence of PIH in Hispanic and black patients is 48 and 65%, respectively [31]. Additionally, it has been reported to occur with equal incidence in males and females of all ages [32]. Although PIH is easily diagnosed from the patient’s history and the presence of inflammation, several dermatoses lead to PIH without noticeable inflammation. Hence, while visual assessment can aid in PIH evaluation, the use of non-invasive methods can further aid diagnosis [33].

PIH presents itself in two forms—epidermal (light to dark brown) which usually disappears spontaneously and dermal (blue-gray coloration) which has a more prolonged course and may either take years to resolve or may be permanent [33, 34]. Unfortunately, a vicious cycle may emerge leading to new areas of hyperpigmentation if the underlying inflammatory disorder is not resolved [34]. In many cases, the extent of damage to the skin may result in scars and keloids.

Causative factors can be divided into endogenous and exogenous factors. The former includes PIH from inherited diseases such as incontinentia pigmenti, cutaneous diseases such as acne, lichen planus, erythema dyschromia persistans, and facial melanoses, as well as systemic diseases such as morphea, porphyria, and biliary cirrhosis [29]. The latter on the other hand include mechanical trauma, extremes of temperature, ionizing and non-ionizing radiation, phototoxic reactions, laser resurfacing [35, 36], and cases of contact dermatitis [37]. Noteworthy is the PIH commonly accompanying acne, often considered more bothersome than acne itself [38] and that accompanying axillary darkening because of shaving, plucking, and/or antiperspirant use [39].

Different histological patterns of PIH emerge, depending on which skin layer is involved. For the epidermal type, there appears to be an increase in the number (hyperplasia), size (hypertrophy), and activity of melanocytes, leading to increased melanin content, with little dermal changes [40]. On the other hand, in the dermal type, melanin enters the dermis, contributing to dermal pigmentation, with an accompanying perivascular lymphocytic infiltrate [40, 41].

Likely pathogenic mechanisms underlying PIH include inflammatory mediators such as arachidonic acid metabolites, nitric oxide, etc., and crosstalk between melanocytes and neighboring keratinocytes and fibroblasts, resulting in the exchange of several melanogenic factors [42].

2.3 Periorbital hyperpigmentation

Periorbital hyperpigmentation (POH) is a common dermatological condition that presents as a dark periorbital area beneath or around the eyes. While it afflicts about 78% of the global population, the majority of the affected individuals are of Asian and African origin [43]. It is reported to occur in both sexes with a greater frequency in females with early onset at age 16–25 [44, 45]. It can also frequently be seen in multiple members of the same family [46].

While the etiology is multifactorial, prominent causative factors include familial, UV, inadequate sleep, post-inflammatory hyperpigmentation following atopic dermatitis, allergic contact dermatitis, lichen planus pigmentosus, erythema dyschromicum perstans [47] tear-trough depression, and periorbital edema [43, 48, 49]. Basis the clinical pattern of pigmentation and vasculature, POH can be classified into (a) constitutional, which involves the presence of a curved band of dark brown to black pigmentation on the skin of the lower eyelids, (b) postinflammatory pigmentation, marked by the presence of irregular patches of dark brownish or gray pigmentation on the skin of the lower, upper, or both the eyelids with lichenifed eczema in surrounding areas, (c) vascular, involving bluish discoloration of the lower eyelids and visible greenish blue veins that become more prominent on stretching of the overlying skin, (d) the shadow effect, involving the presence of deep tear trough over the medial aspect of the inferior orbital rim that disappears with direct lighting, and (e) mixed highlighted by presence of periorbital blue, purple, or pink hue with puffiness associated with palpebral bags, blepharoptosis, and loss of fat with bony prominence [43, 50, 51].

The pathogenesis of POH may be due to one of many factors, notably, dermal melanocytosis [52], an extension of pigmentary demarcation lines of the face [45], postinflammatory hyperpigmentation, superficial location of the vasculature [53], tear-trough depression [52], and thinning of skin [54]. Ultraviolet-induced damage stimulates melanogenesis through multiple pathways [55] or melasma, if it appears on the eyelids, leading to dark eyelids and a tanned lower eyelid region [56].

Histological examination reveals that the most consistent features of POH are hyper melanization of the basal layer and lower malpighian layer with increased melanin granules together with dermal melanin incontinence, dermal melanophages, and perivascular lymphocytic infiltrate [53, 57, 58]. Additionally, the dilation of dermal blood vessels may contribute to the severity of POH [58]. In a study on Asian subjects, the group reported dermal melanocytosis along with melanophages in patients with POH as detected by immune-histochemical staining with S-100 antigen [59]. The almost universal presence of dermal melanin is likely to influence poor treatment outcomes of POH.

Recently, in a study on Caucasian, Asian, and African subjects, it was confirmed through various instrumental measurements that the three features associated with the occurrence of infraorbital dark circles, were hyperpigmentation, a tendency for more dilated, thicker, or increased number of capillaries and thinner skin in the under-eye area in Caucasian subjects. These trends were also observed in the African and far east Asian subjects [60]. However, detailed molecular mechanisms involved in POH continue to elude us.

2.4 Melasma

Melasma is defined as a chronic, acquired disorder of hyperpigmentation, presenting as symmetrical, light to dark brown and ashen gray-brown macules and patches on sun-exposed areas of the face and neck [61]. It is also sometimes referred to in medical literature as the “mask of pregnancy or chloasma,” the latter originating from the Greek word chloazein, meaning to be green [62]. It is primarily a disease of adult women, with reported cases in men being only 10% [63], presenting mostly in the facial area of darker-complexioned individuals (skin types IV–VI) of Hispanic, East Asian, and Southeast Asian origin exposed to intense ultraviolet radiation [62] and shorter wavelengths of visible light [64]. In a multicenter survey from nine countries, the mean onset of age was 34 years [65]. It negatively impacts the quality of life; often, poor therapeutic responses pose a huge challenge to dermatologists and escalate the cost of treatment for affected individuals [66]. Predisposing factors include pregnancy, hormonal therapies (including oral contraceptives), phototoxic and anti-epileptic medications, intense sun exposure [67], and genetic predisposition [68, 69]. Recent studies suggest that thyroid hormones may play a key role in melasma [70].

There are two broad ways to classify melasma: (a) based on the distribution of lesions, three clinical patterns of melasma have been recognized—Centro facial, malar, and mandibular; (b) based on the distribution of melanin in the epidermis and dermis using a Woods lamp into epidermal, dermal, mixed, and indeterminate types [62].

As with other hyperpigmentary conditions, the pathogenesis is multifactorial and poorly understood. Some of the prominently reported mechanisms underlying melasma pathogenesis include melanocyte activation, melanin and melanosome retention in the epidermis and dermis, basement membrane damage, solar elastosis, increased mast cell count and increased vascularization [71]. Overall, the epidemiological and pathophysiological data seem to suggest that melasma is a photoaging disorder [64].

Transcriptional profiling revealed that a subset of Wnt signaling modulators, including Wnt inhibitory factor-1 (WIF-1), secreted frizzled-related protein 2 (sFRP2), and Wnt5a, were upregulated in lesional melasma skin [72]. The downregulation of WIF-1 which may occur in keratinocytes and fibroblasts can influence melasma pathogenesis through the up-regulation of canonical and non-canonical Wnt signaling [73]. Given that UV is implicated in melasma pathogenesis, the upregulation of several of the UV-induced cytokines in melasma is not surprising.

Likewise, melanocytes in melasma can also be activated by hormones. Notably, lesional skin shows increased expression of progesterone receptors [74, 75] and estrogen receptor beta expression in the dermis [74]. Significant advances have been made in elucidating the influence of estrogens on melanogenesis [76].

The number of blood vessels, vessel size, and vessel density are greater in lesional melasma skin than in perilesional skin [77, 78, 79]. Factors that could influence vascularization and pigmentation in melasma are upregulated in lesional areas of melasma. Prominent among these are vascular endothelial growth factor (VEGF), stem cell factor (SCF), and inducible nitric oxide synthase (iNOs) [77, 80, 81]. Endothelin-1 (ET-1) released from endothelial cells stimulates pigmentation through endothelin receptor B activation at the surface of melanocytes [82]. Concerning solar elastosis, the current consensus is that 83–93% of melasma patients show a variable degree of solar elastosis with abnormal elastotic material [83, 84]. An increased number of mast cells, particularly around elastotic areas of the dermis in lesional melasma [83] is believed to exacerbate solar elastosis, besides promoting basement membrane disruption and extracellular matrix (ECM) degradation through the release of tryptase, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2, and transforming growth factor-beta (TGF-β) [85].

Basement membrane damage has been reported in melasma patients via periodic acid-Schiff-diastase (D-PAS) staining and anti-collagen type IV immunohistochemistry, respectively [84]. This predisposes melanocytes to hang into the dermal compartment—the characteristic pendulous melanocytes observed in histology leading to dermal incontinence [86]. Increased expression of matrix metalloproteinases such as MMP2 and 9 in response to chronic UV exposure is likely to contribute to basement membrane damage [87]. The outcomes of these events result in melanin or melanophages in the dermis [84, 88]. Recently, melanin content, location and distribution in melasma, and elastosis severity were confirmed using multiphoton microscopy [89]. Dermal incontinence is a challenge across hyperpigmentation and one, that is likely to significantly contribute to the recalcitrant nature of these conditions.

While we continue to investigate the pathology and biology of various hyperpigmentary conditions, the other key question that needs to be addressed is the factors that make an individual susceptible to a particular hyperpigmentary disorder, besides family history. An in-depth analysis of the epidemiology and population genetics data may help in identifying key population or individual biology, which will in turn support the designing of better preventive options.

3. Role of UV and visible light in skin pigmentation

From the discussion on hyperpigmentary disorders prevalent in humans in the previous section, the role of UV is quite evident and seems to be central to all conditions, so it is worthwhile to discuss the effects of UV and solar spectrum on the skin in the following section.

Ultraviolet radiation on the earth’s surface, both UVB and UVA radiation, constitutes about 5% of total sunlight received. In skin phototypes I–II, exposure to UVB radiation, leads to erythema and sunburns [90]. Skin pigmentation or tanning induced by UV radiation in skin phototypes III–IV, occurs in three different phases-immediate pigment darkening (IPD) and persistent pigment darkening (PPD), both thought to be the result of oxidation or redistribution of melanin while delayed tanning (DT), a characteristic of UVB is because of new melanin synthesis [91, 92]. There is limited data on the skin types V–VI and their response behavior to UV. While erythema, IPD, and DT are the noticeable effects of UV-induced damage to the skin in a short period, repeated exposure may result in one of the chronic effects of sun exposure such as photo-aging which results in the development of deep wrinkles and spots on the exposed skin [93].

UVB (290–320 nm) being more energetic directly damages DNA by causing cyclobutane pyrimidine dimerization and the formation of 6–4 photoproducts. UVA rays (320–400 nm) on the other hand generate reactive oxygen species (ROS) that, in turn, cause indirect DNA damage and activation of several cellular pathways [94]. At the molecular level, UV has been shown to cause DNA damage with subsequent accumulation of p53 protein which regulates the expression of the transcription factor hepatocyte nuclear factor-1α in melanocytes, which in turn regulates MITF and tyrosinase levels [95] and the transcription of the pro-opiomelanocortin (POMC) gene in keratinocytes which eventually regulates MC1R induced melanogenesis in melanocytes [96]. GWAS, linkage, and association-based studies on European and non-European populations suggest the role of distinct genes like glutamate metabotropic receptor 6 (GRM6), activating transcription factor 1 (ATF1), WNT1, and pre melanosome protein 17 (SILV/Pmel17) in observed differential tanning response [1, 97] pointing to the fact that the genetic makeup of the population could drive the nature and the molecular events leading to a tan.

In the past decade, the focus has shifted to the other wavelengths of light namely visible light (400–700 nm) and infrared radiation (IR; 700–1400 nm) which form a major part of the solar spectrum, 45 and 54%, respectively. These longer wavelengths penetrate deeper into the skin and can induce ROS and potentially cause erythema in light skin and pigmentary changes in individuals with darker skin types [92, 98, 99, 100, 101]. Furthermore, susceptibility to pigmentation by visible and IR radiation was shown to reside in darker skin types more than Caucasian skin [92, 102, 103]. Visible light and IR activate metalloproteinases and decrease collagen production by inducing oxidative stress [104, 105]. Damodaran et al. [106] demonstrated that among variable parts of the visible light spectrum, blue wavelength contributes maximally to pigmentation in human subjects (Figure 2A and B). As the blue region is adjacent to UV radiation in terms of wavelength and frequency, blue light is expected to induce photobiological effects like UV radiation, including photoaging and skin pigmentation [101, 107]. In the field of ophthalmology, researchers have identified that “excessive blue light exposure” may cause photokeratitis and retinal injury [108]. Interestingly, the prevalence of photoreceptors like opsins, which recognize blue and green wavelengths of visible light in the eye, have been demonstrated in human skin [109, 110] including in melanocytes, which could be modulated by light exposure.

Figure 2.

Effect of visible light on skin pigmentation—clinical evidence. (A) Effect of different wavelengths of light on skin pigmentation; (B) effect of visible light on color (L*, b*, and a*), hydration, TEWL, antioxidants (catalase, total antioxidants [TOAX], superoxide dismutase [SOD], and free fatty acids [faa]), and inflammation markers (IL-1a) as measured from tape strips.

Multiple studies also suggest that sun exposure (UVA, B, and visible light) could have a role in the induction or exacerbation of hyperpigmentary conditions like freckles, solar lentigines, PIH, melasma, and dark circles [45, 111, 112, 113]. In a randomized study with melasma subjects, Castanedo-Cazares et al. [114] showed that UV sunscreens with visible light protection along with 4%HQ treatment significantly improve MASI scores as against just UV protection with HQ treatment [114, 115].

Therefore, it can be assumed that protection is mandatory not only against UV but against the whole spectrum of light as an adjuvant to regular therapy for hyperpigmentation [99, 116]. In addition to UV, the role of blue light /high-energy visible light from non-solar sources like digital devices also needs to be investigated for its contribution to the exacerbation of hyperpigmentation.

4. Cosmetic agents for hyperpigmentation

The consumer desire to achieve uniform skin tone or complexion has been actively supported and promoted by the cosmetic industry for several decades. The commonly used agents for the treatment of hyperpigmentation are hydroquinone, arbutin, kojic acid, and their derivatives, various derivatives of vitamin C, tretinoin, and natural extracts [117] besides chemical peels, lasers, and light-based therapies. This section will focus on topical solutions recommended for hyperpigmentation.

Hydroquinone (HQ) has been the gold standard in the treatment of hyperpigmentation for over five decades although due to its adverse effects (including toxicity and mutagenicity), it is now banned from use in cosmetics or for over-the-counter (OTC) sales in many countries. Currently, HQ is banned in OTC and available only under prescriptions [118, 119], Considering its deleterious effects, consumer interest is shifting to safer and naturally derived actives.

Over time, HQ has been combined with other drugs, with the intent of improving its efficacy. It was Albert Kligman who first developed and demonstrated the efficacy of a formula containing 0.1% tretinoin, 5% hydroquinone, and 0.1% dexamethasone in 1975. A modified Kligman’s formula containing 4% HQ , 0.05% tretinoin, and 0.01% fluocinolone acetonide is currently in use, with the backing of successful clinical on melasma patients [120, 121, 122]. This mix is popularly called Tri-Luma or the triple combination, can be used across all Fitzpatrick phototypes, and is reported to be better tolerated.

Hydroquinone’s action is mostly suggested to be via its ability to inhibit melanin formation by blocking tyrosinase enzyme activity [123, 124]. Deri et al. [125], by visualization studies of HQ in the active site of tyrosinase protein crystals, together with molecular modeling, binding constant analysis, and kinetic experiments, have confirmed that HQ can act both as a tyrosinase enzyme substrate and as an inhibitor. As a substrate, instead of forming melanin, it gets metabolized to quinones and free radicals which cause lipid peroxidation, damaging the melanocyte membrane and leading to melanocyte cytotoxicity and depigmentation [126, 127]. However, in a recent study designed to compare the effects of arbutin, HQ , and kojic acid with numerous resorcinol vis-à-vis inhibition of recombinant human tyrosinase [128, 129], HQ was found to be ineffective against tyrosinase enzyme as compared to resorcinol (Figure 3). Thus, although considered to be a tyrosinase inhibitor for a long, it appears that the cytotoxic potential of HQ may largely contribute to its depigmentation effect.

Figure 3.

Inhibition of recombinant human tyrosinase enzyme activity by different resorcinols and known tyrosinase inhibitors. Dose-dependent inhibition of tyrosinase enzyme activity was performed using synthetic recombinant human tyrosinase enzyme protein and DOPA as the substrate.

Other tyrosinase inhibitors like arbutin, a derivative of hydroquinone, and kojic acid, have lesser adverse effects, unlike hydroquinone. Glycolic acid, on the other hand, works by causing the desquamation of keratinocytes or epidermolysis when used at higher concentrations [130].

A range of vitamins and their derivatives with enhanced stability or improved dermal penetration are also in use in various cosmetic and pharmaceutical products for skin tone benefits [131, 132].

Vitamin C (VC), also known as ascorbic acid, is a water-soluble vitamin, essential for several processes in human skin, such as dermal collagen synthesis, cell turnover, ROS scavenging, and many more [133]. Emerging evidence indicates that VC and its derivatives can exert therapeutic effects on recalcitrant melasma and facial hyperpigmentation, especially with improved dermal delivery [134, 135]. Vitamin C and its derivatives, magnesium ascorbyl phosphate, and 3-O-ethyl-L-ascorbic acid, exert their depigmenting effect by acidification of the melanocyte cytoplasm, which in turn suppresses the catalytic activity of tyrosinase. Cytoplasmic pH is critical for the catalytic activity of tyrosinase and for the assembly of Pmel17 protein fibrils in the melanosome to form the scaffold upon which melanin is deposited, and any change would therefore influence the melanogenesis process in melanocytes [136, 137]. Vitamin C seems to induce the expression of sodium-dependent VC transporter-2 that further facilitates the transmembrane transport of VC which in turn leads to acidification of the cytoplasm [138]. In addition, 3-O-ethyl-L-ascorbic acid was also shown to modulate the function through Nrf2-mediated α-MSH inhibition in UVA-irradiated keratinocytes and by autophagy induction and inhibition of α-MSH-stimulated melanogenesis in melanocytes [139].

The amide form of vitamin B3, niacinamide has been shown to inhibit melanosome transfer from the melanocytes to the epidermal keratinocytes [140, 141, 142]. Various other functions of niacinamide, including improved immunity, barrier function, etc., make it a popular ingredient in multiple cosmetic preparations [132, 143].

Oral and topical tranexamic acid is a recent addition to dermatologists’ treatment options to tackle recalcitrant conditions such as melasma and PIH, in combination with other skin tone agents, though more successful studies are needed to back its topical use [144, 145]. In addition, superficial chemical peeling alone or in combination with other topical procedures is also key in the treatment of hyper-pigmentary conditions [146]. In such treatment, avoidance of sun exposure and the use of sunscreens is a must for a successful outcome. Then there are laser and light-based therapies like intense pulsed light, low fluence Q-switched lasers, and non-ablative fractionated lasers that are currently prevalent for use for melasma. Though effective these are also associated with an increased risk of recurrence and PIH [146].

In the next section, we will focus on currently popular cosmetic ingredients such as niacinamide, resorcinol, and retinoids and their potential for the future.

4.1 Niacinamide

Niacinamide has been reported to possess numerous properties, for instance, anti-inflammatory, antimicrobial, immunity booster, bioenergetics modulator, and antioxidant, which makes it suitable for various dermatological uses [132, 143, 147]. Niacinamide can effectively treat various skin conditions viz. aging, hyperpigmentation, acne, rosacea, psoriasis, pruritus, dermatitis, etc. [132, 143]. It increases the biosynthesis of ceramides, as well as other stratum corneum lipids and thus enhances epidermal permeability barrier function [148]. Studies have shown that niacinamide modulated NFkB-mediated inflammatory response, which could support its anti-aging activity [149]. In addition, niacinamide protected against collagen loss in the dermis by preventing its glycation and activation of fibroblast function [150].

Niacinamide is also a well-established and commonly used skin-brightening agent and has been reported to have a significant effect on various hyperpigmentary conditions [142, 151, 152]. Navarrete-Solis et al. [152] showed significant improvement in MASI scores in melasma subjects treated with 4% niacinamide same as for 4% hydroquinone, with less melanin and inflammatory infiltration on histological evaluation of biopsies. However, the lightening effect of hydroquinone was evident as early as the first month of treatment, albeit with some adverse events, whereas with niacinamide, it was noted only in the second month of treatment The effect of niacinamide on melasma was attributed to its anti-inflammatory, melanosome transfer inhibition, and antiaging effects on elastosis [152].

Another study was carried out by a group from Iran [153], on the efficacy of topical 4% niacinamide and 1% clindamycin gels in a randomized, double-blind clinical trial on acne patients with moderate inflammatory acne vulgaris. The mean grade of acne and mean count of papules in patients were comparable in both treatments at the end of the study. In a double-blind study carried out on Indian subjects with acne marks, the application of 1.25% of niacinamide significantly reduced acne marks within 6 weeks as compared to baseline, assessed visually using a skin color scale by an expert dermatologist (Figure 4A and B) [154].

Figure 4.

Clinical benefits of niacinamide for acne marks. (A) The average extent of lightening of blemishes after product usage for week 2/4/6/8. Statistically significant reduction in the intensity of blemish color at week 2/4/6/8. The negative y-axis values indicate a brightening effect. (B) The facial images of subjects at weeks 0 and 8, after the application of a niacinamide-containing formulation. These photographs are true evidence from the study and are representative of some of the best responders from the study.

In an axillary depigmentation trial in phototype III–V, the treatment of 4% niacinamide and desonide 0.05%, significantly reduced the hyperpigmentation of the axillae in 9 weeks versus the placebo group. However, the efficacy of the topical steroid was significantly better than niacinamide treatment and the effect was apparent in desonide-treated subjects by 6 weeks of application. There were also reduced mononuclear and phagocytic cell infiltrates, as well as melanin expression in niacinamide-treated subjects, compared with baseline as determined from the biopsies. However, desonide, in addition, improved the basement membrane as seen in histopathology [155].

Studies have supported the use of anti-inflammatory and depigmenting agents for treatments of PIH, however very few have objectively evaluated PIH development. Damodaran et al. [154] used the sodium dodecyl sulfate (SDS) occluded patch test human trial model of irritation [156] to evaluate the effects of inflammation on pigmentation and the efficacy of niacinamide on inflammation and PIH. The study showed that the pigment or L* value increased with an increasing irritation score (Figure 5A). Pre-application of niacinamide reduced inflammation resulting from SDS and the subsequent development of pigmentation (Figure 5B and C).

Figure 5.

SDS-induced human occluded patch test. (A) Irritation score induced by SDS follows the trends as with pigmentation (L* increase); (B) inhibition of SDS-induced inflammation by pre-application of niacinamide in a dose-dependent manner; (C) niacinamide-containing formulation reduced PIH induced by SDS.

A possible molecular mechanism in the efficacy of niacinamide on PIH could be attributed to the modulation of a protein called SERPINB3 in the skin [157]. Serpin Family B Member 3 (SERPINB3) is an endogenous protease inhibitor known for its role in maintaining epidermal barrier homeostasis and is implicated in inflammatory skin conditions including acne [158, 159]. Nair et al. [157] demonstrated that the dermal fibroblasts secrete SERPINB3 in response to inflammatory cytokine interleukin-1 alpha, that in turn induced melanin production in melanocytes (Figure 6A). Niacinamide could blunt the SERPINB3 secretion by fibroblasts (Figure 6B) suggesting the novel role of SERPINB3 in its anti-inflammatory and anti-PIH activity for the potential amelioration of acne and acne marks.

Figure 6.

Effect of SERPINEB3 on pigmentation and its modulation by niacinamide. (A) 24 h of IL-1α treatment increased SERPINB3 protein secretion (25% vs. control) from dermal fibroblasts. (B) Pre-treatment of cells with 5 mM niacinamide significantly reduced (29% vs. IL-1α) the SERPINB3 secretion of cells. The values are mean ± SE of cells from three independent donors. *p < 0.05 vs. control, #p < 0.05 vs. IL-1α.

4.2 Resorcinol

The synthesis and distribution of melanin contribute to skin and hair color in mammals. In human melanocytes, melanin is synthesized within melanosomes by the enzyme tyrosinase, which catalyzes the rate-limiting reaction ie. the conversion of tyrosine to DOPA quinone [160, 161, 162].

Tyrosinase, also known as polyphenol oxidase (PPO), is a copper-containing mixed-function oxidase, widely distributed in micro-organisms, animals, and plants. These oxidases catalyze two distinct reactions of melanin synthesis: hydroxylation of a tyrosine a monophenol (monophenolase activity) and the oxidation of DOPA-an o-diphenol to the corresponding o-quinone (diphenolase activity). The quinones formed being highly reactive, polymerize spontaneously to form high molecular weight compounds or pigments—melanin [163]. Melanin is then secreted by melanocyte cells, which are distributed in keratinocytes in the basal layer of the epidermis in the skin. However, abnormal accumulation of melanin has been associated with hyper-pigmentary conditions, including melasma, freckles, and senile lentigines as covered in the earlier section.

Identification of potent and specific tyrosinase inhibitors has been ongoing for several decades due to its wider implications for the food, pharmaceutical, and cosmetic industries [164, 165]. However, most of the initial discoveries were made using mushroom tyrosinase as a model system [166, 167]. It is only in recent times that more potent tyrosinase inhibitors have been identified using enzymes sourced from human melanocytes or recombinant human tyrosinase protein with superior efficacy on melanotic conditions like solar lentigines and melasma, [129, 168]. The commonly used compounds in the class of tyrosinase inhibitors include hydroquinone, arbutin, kojic acid, thiols, and resorcinol and among them, resorcinol derivatives are the most potent in enzyme inhibition [128, 129]. It has been shown that resorcinol is a mono-oxygenase substrate and gets oxidized to hydroxy intermediate; 3-hydroxy-ortho-quinone, which results in irreversible elimination of Cu (0) of tyrosinase enzyme leading to inactivation of the enzyme [169, 170]. Tyrosinase inhibition activity, though, is mainly attributed to its resorcinol moiety, the efficacy can be further modulated by the various substitution at the 4-position of resorcinol [129, 168, 170]. The levels of tyrosinase inhibition by various 4-resorcinols vary with respect to their alkyl chain length (Figure 3).

Phenylethyl resorcinol (PER, 4-(1-phenylethyl)1,3-benzenediol) is a potent inhibitor of tyrosinase [171, 172, 173]. PER has been in use as a skin lightener in cosmetics for more than a decade, but the clinical demonstration of its efficacy on hyperpigmentation is limited by its chemical instability to UV light [174, 175].

The clinical efficacy of 4-butyl resorcinol (BR) on the other hand, has been very well established in multiple human trials [173, 176, 177, 178, 179]. A randomized, single-blind clinical study was conducted on female subjects with 0.3% 4-butyl resorcinol, 0.3% 4-hexyl resorcinol, and 0.5% 4-phenylethy resorcinol for 12 weeks. 4-butyl resorcinol significantly reduced the appearance of age spots on the forearm after 8 weeks, while others did in 12 weeks. Thereafter, 1% 4-butyl resorcinol was clinically evaluated on age spots on the forearm again; enhancement in skin tone was noticeable by the end of the 16 weeks and was judged to be significant after 4 weeks [173]. The 0.1% 4-butyl resorcinol cream showed rapid efficacy with excellent tolerability in patients with melasma [177, 180]. Liposome-encapsulated 4-butyl resorcinol had a significantly improved effect on the melanin index after 8 weeks of application, without any occurrence of adverse events [178]. In a study on Indian subjects to assess the efficacy, safety, and tolerability of 0.3% 4-butyl resorcinol in melasma patients, a significant decrease in MASI score was observed with no evidence of adverse effect [179].

Another alkyl resorcinol in the skin tone benefit market is 4-hexyl resorcinol (4-HR), an effective tyrosinase inhibitor that was used earlier in the food and medical industries [181, 182, 183]. 4-HR has been demonstrated through in-vitro and human trials to improve hyperpigmentation through its tyrosinase inhibition activity and its anti-inflammatory potential [184, 185]. 4-HR could regulate collagen and elastin production by inhibiting NF-kB activity in fibroblasts and improving photodamaged skin and clinical signs of aging [186]. Chaudhuri [187] reported multiple benefits of 4-HR, including evidence for its anti-microbial, antioxidant, and anti-glycation effects, along with its effect on extracellular matrix proteins. In a face study by Won et al. [188], 4-HR successfully improved overall skin tone when used in an emulsion over 12 weeks.

The most recent entrant in the skin tone market is the imidazolyl derivative of resorcinol, thiamidol, identified through a high throughput screening of a large compound library on human tyrosinase protein. With an IC50 of 1 μM for tyrosinase enzyme inhibition, it is the most potent inhibitor known so far [129, 168]. The group has also demonstrated the efficacy of thiamidol on various hyperpigmentary conditions like melasma [189, 190, 191], solar lentigines [192], PIH [193], and UV-induced skin damage [194] and demonstrated its efficacy to be superior to HQ [190].

The availability of recombinant human tyrosinase protein [128, 129] combined with new platforms that allow for structure-active site prediction based on amino acid sequence [168] will hopefully promote further investigations on tyrosinase chemistry, leading to the identification of inhibitors with greater potency and reduced safety concerns.

In general, as apparent with hydroquinone, the efficacy of a molecule gets compromised when safety becomes paramount. The usage of high doses of ingredients is also a concern in terms of formulation compatibility, sensory, and cost. In such cases, efficacy could be boosted by combining it with other potent agents with a different mode of action and examples do exist where combination therapies have been shown to work for the treatment of recalcitrant hyperpigmentary conditions such as melasma, with a clear example being Kligman’s triple combination.

Shariff et al. [128] successfully adopted a combinatorial approach to demonstrate the superior clinical efficacy of a cosmetic formula containing 4-hexyl resorcinol and niacinamide. Based on the in vitro evaluation, appropriate ingredients, and doses were selected to develop a formulation which was then evaluated for spot lightening and anti-aging on Chinese subjects. In the double-blind split-face study comparing 3% niacinamide with 0.4% 4-HR+ 3% niacinamide over 12 weeks of application, significant improvement was achieved for spot lightening and fine lines and wrinkles in crow’s feet and perioral areas by the combination of 4HR+ niacinamide over niacinamide alone. This highlighted that combining molecules with different modes of action on pigmentation, resorcinol as a tyrosinase inhibitor and niacinamide as a melanosome transfer and anti-inflammatory molecule, may lead to better and safer skin tone formulas with efficacy on par or better than prescription drugs like hydroquinone.

Another ingredient with a different and established mode of action is retinoid and will be covered in the next section.

4.3 Retinoids

Topical retinoids are recommended by the American academy of dermatology as the first line of treatment for acne and hyperpigmentation, based on strong levels of evidence from well-controlled clinical trials [195, 196]. For issues related to irritation from retinoids, the use of moisturizers is recommended. Dermatologists use tretinoin along with other topical agents and procedures such as superficial chemical peels, to treat hyperpigmentation and improve outcomes [197].

Retinoids have been shown to bind and activate retinoid X nuclear receptors and mediate their cellular function which includes inhibition of keratinocyte proliferation and normalization of follicular differentiation which restores normal desquamation and helps to unclog pores [198]. Retinoids are also anti-inflammatory and suppress toll-like receptors, cytokine, and nitric oxide production [199, 200]. It also corrects pigmentation by inhibiting melanosome transfer and the rate of epidermal turnover [196].

Though tretinoin is recommended for the treatment of dark circles [201], melasma [202], and acne [203], some new retinoid derivatives such as adapalene, tazarotene, and trifarotene have also come into the market for dermatological usage [204, 205].

The effects of retinoids on hyperpigmentation have been evaluated in various studies, either for efficacy or safety assessment, with favorable results [195]. Tretinoin was the first retinoid specifically evaluated on hyperpigmentation in patients with melanin-rich skin. Tretinoin reduced hyperpigmented lesions mostly due to PIH in phototype IV–VI skin subjects, with improvement evident as early as week 4 [206]. However, irritation continued to be an issue and was managed by emollients and moisturizers.

The new derivative, tazarotene has FDA approval at 0.1% levels for use as an adjunct for the treatment of fine lines and wrinkles, mottled hyperpigmentation, and lentigines on the face [207]. In an acne-induced PIH or marks study with skin types III-VI, statistically significant reductions were achieved with tazarotene versus vehicle on hyperpigmented lesions, [208]. However, adverse events were still observed with tazarotene as in the case of tretinoin. Trifarotene 0.005% cream is a fourth-generation retinoid approved for the treatment of facial and truncal acne [209], but its clinical effects on PIH in patients with skin of color have not yet been reported.

Combination therapies are the mainstay of retinoid therapies which also help counteract associated irritation issues, essentially either with other topical drugs like HQ , clindamycin or light/laser therapies [196, 197].

Retinyl esters, such as retinyl propionate, are known to be less irritating and less efficacious than retinol or tretinoin and this was hypothesized to be the result of rapid degradation of retinoic acid generated endogenously from esters, by P450 (CYP) protein. Adamus et al. [210] demonstrated the use of climbazole a weak pan-inhibitor P450 (CYP) to prevent loss due to the degradation of retinoic acid thus boosting the efficacy of retinyl propionate in vitro. This was followed by a human trial which confirmed the hypothesis and demonstrated that retinyl propionate alone, and in combination with climbazole, was significantly less irritating than a similar serum containing retinol. The retinyl propionate with climbazole serum treatment also showed equal, or better efficacy than retinol alone serum on fine and coarse lines and wrinkles, as well as pigmentation. Additionally, the combined retinol/climbazole was shown to modulate histological biomarkers of skin aging viz. epidermal thickness, procollagen-1 protein, Ki-67, and retinoid activity (CRABP2, KRT4) [211].

Thus, milder but efficacious retinoids like retinyl propionate with climbazole could be another ingredient with a different mode of activity for the exploration of potential combinations in the future.

5. Conclusion

Melanin in the skin provides better photoprotection to melanated skin. However, abnormal accumulation of melanin as seen in hyperpigmentary conditions, viz. melasma, freckles, senile lentigines, etc. is undesirable. Hyperpigmentary conditions are by and large refractory and recurrent in nature, particularly to traditional cosmetic actives. Multiple risk factors, together with the complex and less understood biology of these conditions, largely contribute to poor treatment outcomes. The most effective interventions for their management are mostly drug-based preparations and physical methods such as lasers that are not very well tolerated, particularly in skin of color.

A comprehensive understanding of hyperpigmentation biology combined with the development of potent mixes that target multiple pathogenic mechanisms is likely the way to provide prescription strength efficacy for its control, without associated safety concerns and side effects. Also, as our understanding of the impact of sunlight and its various components (besides UV) on skin pigmentation and health improves, it is imperative to educate consumers on the diligent use of more comprehensive sun protection measures, regardless of skin phototype.