DOI: 10.1111/jdv.

12049 JEADV

ORIGINAL ARTICLE

Melasma pathogenesis and influencing factors – an

overview of the latest research
T. Passeron*
Department of Dermatology, University Hospital of Nice, Nice, France
*Correspondence: T. Passeron, E-mail: passeron@unice.fr

Abstract
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.

Conflicts of Interest
None declared.

Introduction weaker in case of familial history of melasma. Finally, the vast

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 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 overestimated
role?
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
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 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 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 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

ª 2012 The Author

JEADV 2013, 27 (Suppl.1), 5–6 Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology

6 Passeron
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, sev-
eral 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 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 melanocyte–keratinocyte 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 melanocyte–keratinocyte 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 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 sur-
rounding healthy skin.6 Those results were confirmed by using
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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 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 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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