ORIGINAL ARTICLE

Melasma pathogenesis and influencing factors anoverview of the latest research

T. Passeron*

Department of Dermatology, University Hospital of Nice, Nice, France

*Correspondence: T. Passeron, E-mail: passeron@unice.fr

AbstractMelasma 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.

Conflicts of InterestNone declared.

IntroductionMelasma 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

1020 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 evi-

dences 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 overestimatedrole?A large survey performed in 324 patients from 12 centres of nine

countries has been conducted to better understand the UV radia-

tion and hormonal influences in the development of melasma.1

Almost half of the patients had a familial history of melasma. Mel-

asma 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 associ-

ated with having spent more time outdoors. Interestingly, the con-

traceptive 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 mel-

asma. 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 hor-

monal contraception in melasma patients, especially in those with

familial history of melasma.

Visible light and melasmaUltraviolet 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 sunsc-

reens 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 IVVI), 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

2012 The AuthorJEADV 2013, 27 (Suppl.1), 56 Journal of the European Academy of Dermatology and Venereology 2012 European Academy of Dermatology and Venereology

DOI: 10.1111/jdv.12049 JEADV

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 playersand pathways involvedTo 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, sev-

eral genes, involved in other biological processes and or expressedby 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 dif-

ferentially 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 melanocytekeratinocyte co-culture induces a stimulation

of melanogenesis and an increased transfer of melanin to keratino-

cytes. Interestingly, the increase of melanin production under H19

silencing was only found in melanocytekeratinocyte co-culture

and not with melanocytes alone. Those results suggest that H19

could play a role in melasma development and underlines the cru-

cial 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 bealso 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 treatingmelasmaHistological studies have clearly shown a significant increase of the

vascularization within melasma lesions as compared to the sur-

rounding healthy skin.6 Those results were confirmed by using

laser confocal microscopy examination.7 The exact role of the vas-

cularization in the hyperpigmentation observed in melasma still

remains to be elucidated. However, two studies, using two differ-

ent 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 Kligmans trio and

pulsed dye laser was significantly more effective than the stabilized

Kligmans 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 com-

bined use of this agent topically and orally during 8 weeks lead to

a decrease of the hyperpigmentation in melasma lesions. Histolog-

ical 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 vas-

cular 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 effi-

cient treatment of melasma and a better prevention of the

relapses.

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