Understanding the Science Behind Melasma

By Dr Faisal Ali and Professor Firas Al-Niaimi / 12 Mar 2021

Dr Firas Al-Niaimi and Dr Faisal Ali outline why melasma occurs and how it can be approached with treatments based on the current science

Melasma is undoubtedly a ubiquitous condition presenting to many dermatologists. While the clinical diagnosis appears relatively unchallenging, satisfactory cure often evades patients and their practitioners. Let’s look at the image in Figure 1. Most readers will have little difficulty in making this diagnosis and proposing a treatment plan. It could be considered insouciant to approach this as simple ‘excess pigmentation’. In the last few years significant advances have been made in the understanding of melasma and its pathophysiology, which we endeavour to summarise in this article.

Causes of melasma

Let’s start from the upper part of the skin – the epidermis. In addition to the melanocytes which produce melanin through melanogenesis, there are keratinocytes and important receptors which play a role in the process of melasma.1

Keratinocytes produce a multiplicity of factors implicated in melasma, including vascular endothelial growth factors (VEGF), melanocyte stimulating hormone (MSH), and inducible nitric oxide synthase (iNOS). Moreover, there is greater understanding of the direct role of visible light (in particular the blue spectrum) on melanocyte stimulation and, as a consequence, melanogenesis particularly in the darker skin types.1

The next level from the epidermis deeper into the skin is the essential basement membrane which separates the epidermis from the dermis. Numerous histological studies have demonstrated damage and insufficiency in the basement membrane (particularly collagen type IV component), leading to ‘dropping’ of the melanin into the dermis only to be encapsulated later by macrophages, giving rise to the term melanophages.2,3 It is the defect in the basement membrane that is responsible for the term ‘dermal melasma’ commonly recounted in dermatology literature.

Arriving at the dermis is where a number of important changes occur that are instrumental for the pathogenesis of melasma. These include senescent fibroblasts, solar elastosis, increased vascularity and the increased presence of a particular inflammatory cell; the mast cell.2,4,5

It is in fact the mast cell that is increasingly recognised as being instrumental in the pathogenesis of melasma through a number of mechanisms. The mast cell secretes a substance called histamine, which has a direct melanin stimulatory effect through the H2 receptors, in addition to another secreted substance called tryptase that upregulates matrix metalloproteinase (MMP)-9.6 This is partly responsible for the basement membrane damage, as well as the upregulation of other MMPs and Granzyme-B, which are responsible for extracellular matrix degradation, giving rise to the solar elastosis observed in the upper dermis in lesional melasma skin compared to uninvolved skin.2 Furthermore, the mast cell increases the dermal vascularity through the mediation of VEGF and transforming growth factor beta-2 (TGF-beta2).7

The observed increased vascularity in many melasma cases (termed angiogenic melasma) is responsible for the ongoing increased hyperpigmentation through the secretion of certain factors, in particular endothelin-1. These factors stimulate the melanocytes through activation of the melanogenesis process.2,7,8

The role of the senescent fibroblasts is increasingly recognised through the secretion of melanogenic factors such as proteins, growth factors and, more importantly, stem cell factor (known as SCF) which directly activates c-kit, the ligand of the tyrosine kinase receptor responsible for melanogenesis in the melanocytes.4,6

Translating this to clinical practice

Indisputably, the melanocyte is the lynchpin in the pathophysiology of melasma through the production of melanin. The stimulatory effects on melanocytes are multifactorial and not limited to the ultraviolet rays. As explained earlier, the role of visible light is being increasingly recognised, as well as the stimulatory effects from the mast cells and endothelin from the dermal vasculature through endothelin-specific receptors on the melanocytes. In clinical practice, treatment and control of the vascular component (through vascular lasers and tranexamic acid) can lead to improvement in the melasma independent from direct melanocyte action.8-10

Notably, the effects of tranexamic acid extend beyond the inhibition of the vascular component and include the blockade of plasmin conversion to plasminogen, which in turn stimulates the production of prostaglandins (a powerful melanocyte stimulator) through the arachidonic acid metabolites. Plasmin is upregulated by ultraviolet exposure and is one pathway of many inhibited by the use of sunblock.7-10

It could be considered insouciant to approach this as simple ‘excess pigmentation’  

Strengthening the basement membrane with topical treatments (niacinamide and retinol) or energy-based devices limits the melanin ‘drop’ from the basal layer to the dermis, thereby limiting the formation of melanophages. Similar benefits are derived from treating the upper dermal solar elastosis and senescent fibroblasts with analogous interventions.1-3,11


Melasma is a common condition with varying degrees of severity and proclivity to recrudescence. Treatment has traditionally been preoccupied with ultraviolet radiation protection, along with melanin removal and inhibition. In recent years a greater and deeper understanding of the pathophysiology of melasma has delineated the roles of three crucial components; namely the mast cells, basement membrane, and vascular component. Whilst some or all components might be involved in varying degrees of severity, it is apparent that melasma is a complex interplay of the aforementioned factors, for which optimal control and treatment should be taken into consideration. The surge of popularity and efficacy of tranexamic acid in melasma is testimony to the increasingly recognised roles the mast cells, endothelin and plasmin activation play in this challenging condition to treat.

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