Melasma pathogenesis and influencing factors – an overview of the latest research
T. Passeron, E-mail:email@example.com
Melasma is an acquired, symmetrical hypermelanosis of the face. The pathogenesis of melasma is complex and the treatment is often challenging with frequent relapses. Genetic background, exposure to ultraviolet radiation, and female sex hormones are classical influencing factors. To the light of the recent literature, other factors could promote melasma lesions. Moreover, there are increasing evidences showing that melanocytes are not the only cells involved, and that other players probably have a key role in the development and the relapses of melasma. Identifying those associated factors should provide new targets for a more efficient treatment of melasma and a better prevention of the relapses.
Melasma is an acquired, symmetrical hypermelanosis of the face. The pathogenesis of melasma is complex and the treatment remains challenging. The evolution of melasma is chronic for 10–20 years and without a strict avoidance of sunlight, the relapses are almost constant. Genetic background, exposure to ultraviolet (UV) radiation, and female sex hormones are classical influencing factors. To the light of the recent literature, other factors could promote melasma lesions. Moreover, there are increasing evidences showing that melanocytes are not the only cells involved, and that other players probably have a key role in the development and the relapses of melasma.
Old causative factors with an overestimated role?
A large survey performed in 324 patients from 12 centres of nine countries has been conducted to better understand the UV radiation and hormonal influences in the development of melasma.1 Almost half of the patients had a familial history of melasma. Melasma affects most patients in the 3rd or the 4th decade of life, but onset of the lesions after 40, or 50 year-old is observed in 14% and 6% of cases respectively. The onset of the disease is found to be earlier in light skin types, whereas dark skin types (V and VI) are usually associated with a late onset of melasma (even post-menopausal). Only 20% of melasma occurred in the peri-pregnancy period. The risk of onset during pregnancy was associated with having spent more time outdoors. Interestingly, the contraceptive pills appear to have a weak impact on the evolution of melasma. Moreover, the impact of the hormonal treatment is even weaker in case of familial history of melasma. Finally, the vast majority of patients who had used sunscreen before the diagnosis of melasma felt that an increased use of sunscreen improved their melasma. However, only one-third of patients changed their behaviour regarding sun exposure and protection after the onset of melasma. Those data support the role of sun exposure in melasma. The hormonal influence, although playing some role, at least in some patients, appears to be weaker than previously thought. These results do not support a systematic change in hormonal contraception in melasma patients, especially in those with familial history of melasma.
Visible light and melasma
Ultraviolet radiations are considered the main causative factor of the relapses in melasma and a strict avoidance of sun exposure is recommended. However, despite the use of very effective sunscreens against UV radiations, many patients have relapses of the hyperpigmented lesions after the summer period. Interestingly, it has been recently shown that the visible light was also able to induce an increase of skin pigmentation, at least in dark skin types. Indeed, the effect on pigmentation of visible light was compared with UVA exposure in the back of healthy volunteers. In dark skin patients (skin type IV–VI), both UVA and visible light were able to increase pigmentation, but the pigmentation was more intense and more stable after visible light exposure as compared with UVA.2 Those results demonstrate that visible light is also able to modulate the pigmentation process. According to these results, we cannot conclude that visible light plays a role in melasma relapses, but it is tempting to hypothesize that it could explain the only partial protective effect of most sunscreens. Thus, the use of tinted mineral sunscreens could protect both against UV and visible light, and might be more effective for preventing the melasma relapses. Prospective comparative trials should be performed to answer to this very practical but crucial question.
One clinical phenotype but many cellular players and pathways involved
To better understand the complex pathophysiology of melasma, a transcriptional analysis was performed in melasma skin samples as compared with the surrounding healthy skin. A total of 279 genes were stimulated and 152 were found to be down-regulated.3 Up-regulation of many melanin bio-synthesis-related genes as well as melanocytes markers such as TYR, MITF, SILV and TYRP1 were found to be up-regulated in melasma skin. Interestingly, several genes, involved in other biological processes and/or expressed by other cells than melanocytes, were found to be differentially expressed as compared with the surrounding unaffected skin. Increased expression of a subset of Wnt pathway modulator genes, up-regulation of prostaglandin metabolic process and genes that regulate fatty and metabolism are some of the most interesting differentially expressed pathways that were found in this study.
Non-coding RNA could also participate to the melasma pathogenesis. One of them, the H19 gene which transcribes a non-coding RNA was recently found to be significantly down-regulated in melasma lesions.4 Interestingly, the decreased transcription of H19 in melanocyte–keratinocyte co-culture induces a stimulation of melanogenesis and an increased transfer of melanin to keratinocytes. Interestingly, the increase of melanin production under H19 silencing was only found in melanocyte–keratinocyte co-culture and not with melanocytes alone. Those results suggest that H19 could play a role in melasma development and underlines the crucial role of keratinocyte in this disorder.
The activation of inducible nitric oxide synthase (iNOS) within keratinocytes was shown to have a role in melanogenesis process, especially after UV radiations. Recently, an increased expression of iNOS was observed in melasma lesions.5 According to this study, this increased could be linked to an activation of the AKT/NFkB pathway. iNOS and NF-kB pathway could thus be also implicated in melasma pathogenesis, and could be interesting targets for developing more effective treatments. These results also emphasize the role of keratinocytes in the pathophysiology of melasma.
Targeting the vascularization for treating melasma
Histological studies have clearly shown a significant increase of the vascularization within melasma lesions as compared to the surrounding healthy skin.6 Those results were confirmed by using laser confocal microscopy examination.7 The exact role of the vascularization in the hyperpigmentation observed in melasma still remains to be elucidated. However, two studies, using two different therapeutic approaches, but sharing the same aim of targeting the vascular component of melasma, have been recently reported. Thus, a prospective comparative split face randomized study has shown that the combination of stabilized Kligman’s trio and pulsed dye laser was significantly more effective than the stabilized Kligman’s trio alone.8 More interestingly, the combination approach prevented at least partially the relapses after the summer period, while the cream alone did not. The second study assessed the effect on melasma of the tranexamic acid, an anti-fibrinolytic used to prevent and to treat some haemorrhagic events. The combined use of this agent topically and orally during 8 weeks lead to a decrease of the hyperpigmentation in melasma lesions. Histological examinations showed a decrease in melanin content and in vascularization.9 Those pilot studies clearly need to be confirmed, but they both underline the potential interest of targeting the vascular component for treating melasma.
Thus, melasma is confirmed to be a complex disorder and appears not to be only restricted to the melanocytes. Identifying those associated factors should provide new targets for a more efficient treatment of melasma and a better prevention of the relapses.