|Year : 2015 | Volume
| Issue : 1 | Page : 21-27
Etiopathogenesis of melasma
Sidharth Sonthalia1, Rashmi Sarkar2
1 SKINNOCENCE: The Skin Clinic and Research Centre, Gurgaon, Haryana, India
2 Department of Dermatology and STD, Maulana Azad Medical College, Lok Nayak Hospital, University of Delhi, New Delhi, India
|Date of Web Publication||26-Jun-2015|
SKINNOCENCE: The Skin Clinic and Research Centre, C-2246 (Ground Floor), 'Suhridaya,' Sushant Lok-1, Block-C, Gurgaon - 122 009, Haryana
Source of Support: None, Conflict of Interest: None
Melasma is a notoriously recidivist condition with yet unclear etiopathogenesis. It seems to have a multifactorial origin with both genetics and environment playing an important role. A genetic predisposition is suggested by a high reported incidence in family members in certain racial groups. Among the environmental factors, exposure to ultraviolet and visible light constitutes the biggest risk factor. Onset or worsening of melasma during pregnancy and during or following intake of hormonal oral contraceptive pills suggest the involvement of hormonal factors. The role of cutaneous vasculature in its pathogenesis is suggested by presence of clinically appreciable telangiectatic erythema confined to the melasma lesional skin in many patients, a finding reinforced by dermatoscopic evaluation and detection of upregulated expression of vascular endothelial growth factor, in the lesional skin. Various other factors such as thyroid disorder, drugs, cosmetics, stress may exacerbate existing melasma in a subset of patients. Although the precise molecular pathogenesis of melasma remains mysterious, up regulation of inducible nitric oxide synthase and many melanogenesis-related genes and melanocyte markers such as TYR, MITF, SILV, and TYRP1, Wnt pathway modulator genes, genes of prostaglandin metabolic processes, and those regulating lipid metabolism seem to be operative. In summary, though the exact etiopathogenesis of melasma remain appalling, newer studies have provided corporeal evidence in favor of certain previously suspected and some novel factors. Further research in this area will not only provide more evidence for their involvement in the pathophysiology of melasma, but also offer attractive targets for development of newer treatment modalities. This article exhaustively reviews the validity of the previously postulated etiological factors based on hitherto-accrued evidence, and explores the newer suggested pathogenetic mechanisms, which may pave way for development of novel therapeutic strategies.
Keywords: Etiopathogenesis, hormonal, melasma, ultraviolet light, vascular
|How to cite this article:|
Sonthalia S, Sarkar R. Etiopathogenesis of melasma. Pigment Int 2015;2:21-7
| Introduction|| |
Melasma is an acquired, symmetrical hypermelanosis of the face presenting as light brown to dark, muddy brown macules on the face. This intriguing disorder of hyperpigmentation is fairly common with millions of people affected across the globe. Individuals with Fitzpatrick skin phototypes III through V, living in areas of intense ultraviolet (UV) light exposure are more commonly affected. Several clinical patterns of melasma are encountered in clinical practice, namely centrofacial [Figure 1], malar [Figure 2] and the rare mandibular pattern [Table 1].  There is a significant overlap in many patients. While the centrofacial pattern is the most common, especially in women, the mandibular pattern commonly encountered in postmenopausal women is considered by some to be a form of poikiloderma of civatte.  Although melasma is primarily considered to be a pigmentation disorder of the female gender, occurrence in men is not uncommon. In a study of 200 Indian patients with melasma, 41 (20.5%) were men.  Melasma is a notoriously recidivist condition, with a significant negative impact on the patients' quality-of-life. Relapse is invariable despite optimum preventive measures and dermatologists can only ensure "treatment and maintenance" of effect rather than "permanent cure." With unimpeded sun exposure, this condition has a chronic progressive course. Treatment is difficult, often unsatisfactory and needs to be continued indefinitely to maintain the initial therapeutic response. The treatment of melasma is sometimes confounded with the occurrence of exogenous ochronosis due to prolonged use of hydroquinone (HQ)-based topicals agents. Thus, a better understanding of the condition's pathogenesis is warranted for development of non-HQ-based therapeutics agents to avoid this rare yet disturbing adverse effect of the "gold standard" of melasma treatment.
Despite continuous quest for the etiological factors and pathogenetic mechanisms contributing to melasma, its pathophysiology remains elusive and treatment challenging. Over the last one decade, new findings based on advanced techniques like dermoscopy, in vivo reflectance confocal microscopy (RCM), and immunohistochemistry from biopsy specimens have provided sufficient insight into its pathogenesis. ,,, While old time-tested theories regarding its pathophysiology have not yet been discarded, recent and emerging postulates need further confirmation. Overall, two groups of factors seem to be instrumental - endogenous factors, most importantly genetic predisposition and cutaneous vasculature, and exogenous stimuli such as sex hormones and UV irradiation. In this article, we review the major as well as certain newly recognized factors implicated in the etiopathogenesis of melasma.
| Clues from Histopathological, Electron Microscopic and Immunohistochemical Studies|| |
Epidermal hyperpigmentation: The main culprit
Sanchez et al. proposed the subdivision of melasma into epidermal, dermal and mixed types, depending on the depth of skin involvement.  This differentiation by Wood's lamp examination has been in vogue, wherein, accentuation of pigmentation is supposedly suggestive of increased epidermal melanin content whereas lack of enhancement of lesional pigment suggests increase in dermal melanin content. Lesions with both enhancing and nonenhancing areas are said to have a mixed pattern. Although this typing has had enormous significance in the development of management strategies in melasma, it suffers from serious flaws. Such differentiation is difficult to appreciate in dark-complexioned individuals. While it has been well-established that Wood's light examination is not accurate in determining the level or the depth of melanin pigment, , it has been recently reported that single skin biopsy-based histological classification may also not be comprehensive.  Most recently, this concept has been rendered redundant with an in vivo RCM study that demonstrated heterogenous distribution of melanophages between different regions of melasma. Such heterogenous distribution of melanophages was evident even within different foci of individual lesions of melasma. These findings raise serious doubts about the existence of "true epidermal" or "true dermal" melasma and suggest that all melasma are indeed mixed.  Epidermal hyperpigmentation through increased melanogenesis in epidermal melanocytes is now considered to be the hallmark of melasma lesional skin. A new classification of melasma may better be based on the ratio of epidermal to dermal melanin involving the whole lesional skin. Thus, melasma is chiefly characterized by epidermal hyperpigmentation with or without melanophages. The role of small amount of dermal melanin in the melasma lesional skin remains speculative. In a study involving 56 Korean patients with melasma, an 83% increase in epidermal pigmentation was reported in the lesional skin. ,
Melanogenesis, melanocytosis, and hyperactive melanocytes
Histopathology of melasma lesions has offered valuable insights to understand its etiopathogenesis. In the study by Kang et al. (vide supra) comparing the histology of melasma lesions and normal facial skin, the following features were more pronounced in the former-solar elastosis, greater number of epidermal melanocytes, free dermal melanin and melanophages, elastic fiber fragmentation, and significantly increased epidermal melanin.  The melanocytes in lesional skin have been found to be biologically more active than their counterparts in normal skin with increased dendriticity and presence of greater quantities of mitochondria, Golgi bodies, and rough endoplasmic reticulum.  Hitherto considered to arise primarily due to increased local melanogenesis (increase in melanin formation), it is being realized that there is an additional component of melanocytosis that is, increased number of pigment cells in lesions of melasma. While enhanced melanogenesis within these melanocytes of melasma lesions has been conclusively proven by recent findings of upregulation of many melanin biosynthesis-related genes and melanocyte markers such as tyrosinase, TYRP1, TYRP2, and MITF, whether melanocytosis contributes to it is still controversial with contradictory immunostaining results. ,,
| Multifactorial Etiopathogenesis of Melasma|| |
The major etiological factors implicated in melasma seem to act in concert [Figure 3]. In a study of 210 patients, the incidence of different causative factors was: 100% for sunlight exposure, 27% for pregnancy, 14% for cosmetics, 13% for familial factors, and 6.3% for oral contraceptive pill (OCP) use.  The results of a recent global survey by Ortonne et al. in 324 women with melasma also suggest that a combination of hormonal factors such as pregnancy and OCP use, and sun exposure is involved. 
|Figure 3: Major etiological factors of melasma with mechanisms associated with them|
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| Genetics and Racial Factors|| |
A genetic predisposition is suggested by a high reported incidence in family members in certain racial groups. It has ranged from 10-70% in studies from Iran, Singapore and in Latino men.  In Southeast Asia, the prevalence ranged from 40% in females to 20% in males.  The global survey by Ortonne et al. comprising women from nine countries reinforced the susceptibility of Fitzpatrick skin phototypes III and IV and a higher likelihood of a positive family history in African-Americans.  The underlying molecular mechanisms need to be elucidated. There seems to be an insignificant difference in the predominance of a particular type of melasma in people of different ethnicities. By and large, the centrofacial pattern has been reported to be the most common, followed closely by the malar pattern. This fact was reinforced in a recent cross-sectional, multicentric clinico-epidemiological study of melasma in India.  In contrast to Indian women, Indian men displayed a higher percentage of malar pattern than centrofacial (61% vs. 29.3%) pattern.  The pattern of outdoor activity of working Indian men may be responsible for this difference.
| Role of Sun Exposure|| |
Facts suggesting the relationship of melasma with sun exposure
Sun exposure, especially UV radiation (UVR) is undoubtedly the most important etiological factor for melasma. Occurrence of lesions in predominantly sun-exposed areas of the face, and delay in relapse after successful reduction with regular use of broad-spectrum sun screens support the role of unimpeded sun exposure in evolution and progression of melasma. In the study by Sarkar et al. on male melasma, more than 50% of the patients were outdoor workers and around 30% belonged to hilly regions.  In addition, studies have also revealed that features of solar damaged skin, typically solar elastosis on histology are often present in lesions of melasma.
Cellular and humoral mechanisms underlying ultraviolet-induced melasma
Complex cellular interactions and interplay of cytokines and hormones contribute to the effect of UVR in melasma. Latest evidence has implicated cells other than melanocytes notably, keratinocytes, dermal fibroblasts, and cutanenous vasculature. 
Effects of ultraviolet radiation on keratinocyte- melanocyte interaction
Melanocyte proliferation, migration, and melanogenesis are upregulated by UVR directly, as well as indirectly by the cytokines like interleukin-1 and endothelin-1, and peptides especially α-melanocyte-stimulating hormone, and adrenocorticotropic hormone produced by UV-stimulated keratinocytes. These peptides stimulate melanocyte proliferation as well as melanin synthesis via stimulation of tyrosinase activity and tyrosinase-related protein 1.  The enhanced expression of inducible nitric oxide synthase (iNOS) in melasma within keratinocytes also contributes to the melanogenesis process. 
Effects of ultraviolet radiation on dermal inflammation and fibroblast activation
Kang et al. have reported significantly increased expression of both stem cell factor (SCF) from fibroblasts and c-kit in the melasma lesional skin.  The cytokines derived from fibroblasts stimulate the proliferation and melanogenesis of melanocytes. Thus, the UV-induced dermal inflammation leading to fibroblast activation resulting in upregulation of SCF in the dermis of melasma lesions, culminating into increased melanogenesis sounds like a plausible explanation. Other inflammatory events operating at the cellular level may also have a role. UV-stimulated synthesis of prostaglandins (PGs) and upregulation of cyclo-oxygenase-2 in lesional skin resulting in epidermal hyperpigmentation has been reported.  The emergence of PG analogs as a therapeutic option for vitiligo lends further support to this speculation.
Visible light and melasma
Apart from the effect of UVR, the role of visible light is being increasingly recognized. Visible light is known to induce hyperpigmentation especially in skin types IV-VI.  It could explain the only partial protective effect of most UV-A and UV-B protective sunscreens and higher efficacy of tinted mineral sunscreens that additionally protect against visible light in prevention of melasma relapses.
| Role of Hormones|| |
The relationship of melasma with female sex hormones, OCPs and pregnancy has been perplexing and needs further elucidation.
Pregnancy and melasma
Many patients note the onset or worsening of melasma during pregnancy; often christened as "chloasma gravidarum" and "the mask of pregnancy;" with typical onset during the second half of the gestational period. However, melasma may appear before pregnancy or many years after delivery. The reported incidence of melasma appearing during pregnancy has ranged from 2.5% to 75% with genetic and racial factors contributing to this wide variation. Major studies on epidemiology of melasma in Indian women are lacking; however, two studies have reported an incidence of 2.5-8.5% during pregnancy in Indian women. ,
Hormones, hormone receptors and melasma
Though results of existing studies support the role of a hormonal component in the pathogenesis of melasma, the evidence is not robust enough due to the wide variation in their results, perhaps owing to the varied genetic backgrounds of different study population. In the study by Pérez et al. comparing basal state serum levels of multiple steroidal and female hormones between 9 women with idiopathic melasma (unrelated with pregnancy or OCP intake), and their age-and sex-matched normal controls, the only discernible difference was a significantly increased levels of luteinizing hormone and relatively lower levels of serum estradiol in melasma patients.  With lack of clarity on the role of circulating hormonal levels in the pathogenesis of melasma, the role of hormone receptors has become an active area of research. Immunohistochemical studies have shown that compared to the melanocytes of nonlesional skin, cells from melasma lesions exhibit increased estrogen receptor expression. However, the response of these receptors to different hormones in melanocyte-incubation studies has also been conflicting with variable changes in melanocyte proliferation and tyrosinase activity. Thus, factors such as heightened sensitivity of melanocytes of melasma lesions to estrogens (and possibly other hormones) and additional synergistic influences such as UVR, cutaneous vasculature, activity of sebaceous glands, and oxidative stress also need to be considered. 
Oral contraceptive pills and melasma
The onset of melasma following intake of OCPs is well-documented. In the global survey by Ortonne et al., 25% of 324 women with melasma reported disease onset with OCP use.  The accrued evidence from different studies studying the epidemiology of OCP-induced melasma suggests it to be more common in patients lacking family history of melasma and a higher risk of recurrence or worsening of melasma during pregnancy in such patients. Thus, while patients who develop melasma while taking OCPs may benefit by stopping them and avoiding them in future, a systematic change in hormonal contraception in melasma patients seems unwarranted. ,
| Vascular Factors|| |
The demonstration of more prominent solar elastosis in lesional melasma skin compared with perilesional skin, and UV-induced dermal inflammation leading to fibroblast activation and resultant increase in melanogenesis makes a strong case for the role of dermal environment in the development of melasma. , There is a newfangled interest in the role of cutaneous vasculature in its pathogenesis. Though hyperpigmented patches predominate the clinical presentation of melasma, many patients demonstrate additional distinguishing features like pronounced telangiectatic erythema confined to the melasma lesional skin [Figure 4], more evident on dermatoscopy [Figure 5]. Evidence from recent research including results of colorimetric analysis, immunohistochemical studies, and laser confocal microscopy examination has shown that melasma lesions are more vascularized than the perilesional skin. , The investigative study conducted by Kim et al. in 50 women with newly-diagnosed melasma has provided robust evidence to support the vascular theory of melasma and the probable events involved in it. They demonstrated a significant increase in both the number and size of dermal blood vessels, and upregulated expression of vascular endothelial growth factor (VEGF), in the lesional skin compared to the perilesional normal skin.  It has been speculated that UV irradiation induces an angiogenic switch, associated with the up-regulation of proangiogenic factors such as VEGF, basic fibroblast growth factor, and interleukin-8. VEGF is the major putative angiogenic factor and it seems to enhance melanogenesis by interaction with VEGF receptors present in epidermal keratinocytes followed by release of mediators, most importantly metabolites of arachidonic acid, and plasminogen from the proliferated vessels. , The reports of efficacy of two newer treatment modalities that is, tranexamic acid, a plasminogen inhibitor, and pulsed dye laser that primarily targets vascular components of the skin, further lend support to the vascular theory of melasma. 
|Figure 4: Clinical appearance of a treatment-naïve patient with melasma showing pronounced telangiectatic erythema in a background of hyperpigmented macules|
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|Figure 5: Dermoscopic appearance of the patient in Figure 4, demonstrating background of hyperpigmentation with prominent interspersed erythema and telangiectasias (original magnification ×10)|
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| Other Factors|| |
Melasma skin is characterized by impaired stratum corneum integrity and a delayed barrier recovery rate.  Various other factors have been implicated in the pathophysiology of melasma [Table 2]. However, the evidence supporting their definitive role is weak and controlled studies are warranted to establish their contribution to the causation of melasma.
| Molecular Pathogenesis|| |
The precise molecular pathogenesis of melasma remains mysterious. Results of a transcriptional analysis study performed in lesional skin samples compared with normal skin have provided interesting insights into its complex pathophysiology. Of the total 279 genes stimulated in this study, 152 were found to be down-regulated, with upregulation of many melanogenesis-related genes and melanocyte markers such as TYR, MITF, SILV, and TYRP1.  Interestingly, certain genes involved in other biological processes and/or expressed by cells other than melanocytes were found to be differentially expressed in lesional skin, especially a subset of Wnt pathway modulator genes (Wnt nhibitory factor 1, secreted frizzled-related protein 2, and Wnt5a), genes of PG metabolic processes, and those regulating lipid metabolism. Noncoding RNA also seems to participate in the pathogenesis of melasma. In a recent melanocyte-keratinocyte culture study, the H19 gene which transcribes a noncoding RNA was found to be significantly down-regulated in lesional skin.  Stimulation of melanogenesis and increased transfer of melanin to keratinocytes were associated with decreased transcription of H19 suggesting the role of this gene in evolution of melasma.
The most affected biological process in melasma is lipid metabolism which seems to be the most affected biological process in the pathogenesis of melasma. , Genes involved with lipid metabolism, such as peroxisome proliferator-activated receptor (PPAR) alpha, arachidonate 15-lipoxygenase, PPAR gamma coactivator 1 alpha, type B (ALXO 15B), diacylglycerol o-acyltransferase 2-like 3 were found to be down regulated; seemingly down regulated by chronic UV exposure.  Another change observed in melasma skin is thinning of the stratum corneum; which coupled with disturbed lipid metabolism is responsible for the impaired integrity of stratum corneum resulting in the delayed barrier recovery rate seen in melasma skin. 
Other molecular pathways have also been implicated. UVR-induced activation of iNOS expression within keratinocytes (vide supra) contributing to the melanogenesis process could be linked to an activation of the AKT ⁄ nuclear factor-kappa B pathway. ,
| Conclusion|| |
In summary, though the exact role of etiological factors in the causation of melasma and its precise pathogenesis remain puzzling, newer studies have provided corporeal evidence in favor of certain previously suspected and some novel factors. Further research in this area will not only provide more evidence for their involvement in the pathophysiology of melasma, but also offer attractive targets for development of newer treatment modalities.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]