Melasma is a common hyperpigmentary disorder. The impact on the quality of life of affected individuals is well demonstrated, demanding new therapeutic strategies. However, the treatment of melasma remains highly challenging.

Melasma and female hormones
Melasma is an acquired and chronic disorder characterized by a localized symmetrical hypermelanosis of the face or, less frequently, involving the neck and forearms. It occurs with a high prevalence during pregnancy, especially during the second half of the gestational period, and in women taking exogenous female hormones. Melasma has also rarely been described in males, especially those affected by primary hypogonadism or taking estrogens for prostatic cancer.

Melasma thus appears to be pathologically related to female sex hormones, but this is not consistently reflected in high circulating levels of estrogens or progesterone. This implies that other factors are likely to be relevant, including genetic predisposition, exposure to ultraviolet light, cosmetics and some medications.
More recent research has revealed several other key players and brought new pieces to the complex puzzle of the pathophysiology of melasma.

Melasma is a photoaging disorder
Interestingly both epidemiological and pathophysiological data published in the last 10 years provide evidence to support the hypothesis that melasma is a photoaging disorder and not just a pigmentation disorder of the melanocytes.

A transcriptional analysis performed in melasma lesions compared to surrounding healthy skin then clearly emphasized the complexity of this disorder by revealing almost 300
genes to be significantly differentially regulated, affecting not only melanocytes but also the dermis component (Kang et al., 2011).

These results further demonstrate that fibroblast-secreted
factors, such as WIF1 (Kim, Lee, & Lee, 2013) or sFRP2 (Kim, Han, Kim, Park, & Kang, 2016), are involved in the pathophysiology of melasma.

In addition endothelial cells were demonstrated to stimulate pigmentation through the production of endothelin 1 (Regazzetti et al., 2015). These results showed that increased vascularization in melasma lesions participates in the hyperpigmentation observed clinically.

While the face is widely exposed to the sun, only specific areas, such as malar, the forehead, and upper lips, are usually involved in melasma. However, these areas are rich in sebaceous glands, which are capable of synthesizing vitamin D and secreting several cytokines, including IL1α and IL6, as well as growth factors, such as angiopoietin and adipokine that directly or indirectly further modulate melanocyte function.

The coculture between a sebocyte cell line (SZ95) and human melanocytes induces the appearance of dendrites and melanogenesis, suggesting that among the growth factors and cytokines that the sebocyte can produce, there are also some capable of inducing melanogenesis (Abdel-Naser, Seltmann, & Zouboulis, 2012; Zouboulis et al., 2016). Moreover, sebocytes are also under the control of αMSH. Thus, an overexpression of this factor can influence both melanocytes and sebocytes.

In addition, UV-oxidized skin surface lipids, in particular of squalene, could be involved in the pathogenesis of the clinical manifestation of melasma, given that they are capable of activating melanin synthesis in cultured melanocytes and organ tissue (Picardo et al., 1991).

Therapeutic Options
Topical bleaching agents with Hydroquinone have until now been considered as the gold standard treatment for melasma. The most famous being Kligman formula (corticosteroid, retinoic acid and hydroquinone mixture) is available normally only on prescription. However unbeknown to users, many other brands containing secretly hidden Hydroquinone in their formulations are widely available on the internet. Today the safety of Hydroquinone has been called into question by the majority of regulatory and health authorities worldwide due to the significant risks and side effects associated with its use. The safety of Kligman formulation on skin types IV-V has never been tested. It does not prevent relapses and is not suitable for long term use of a chronic condition such as melasma (https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021112s009lbl.pdf)

Q-switched lasers have been proposed but they lead to almost constant relapses and frequent PIH (Rodrigues & Pandya, 2015). Usually, the treatments are associated with photoprotection using a high SPF index. However, these approaches often fail to clear melasma lesions and do not prevent relapses.

A Holistic Scientific Approach
Interestingly, all the treatments mentioned above target only the melanocytes, and the preventive photoprotection focuses mostly on UVB, neglecting UVA1 and visible light radiation. According to the accumulating data showing the impact of other cells and of the solar radiations beyond UVB in the pathophysiology of melasma, the treatments should adopt a holistic approach, recognizing melasma as a photoaging disorder rather than simply a pigmentation disease, in order to provide optimal clearance of the lesions and prevention against relapse.

Thanks to data gathered in recent years via NUNII Laboratoire’s fundamental research programme, new therapeutic targets have emerged for preventing or treating melasma, some are already available, and others will hopefully be developed soon.

In addition to more effective less toxic depigmenting agents in our Expert Pigment Corrector Formulation and the use of photoprotection covering the solar spectrum from UVB to blue light, the combination of agents helps restore the altered basal membrane and acting on the factors secreted by fibroblasts, mast cells, sebocytes, and endothelial cells. This unique patented combination of 10 active ingredients helps to contribute to the optimal treatment of this disabling skin disorder and is safe to use both short and long term even on skins of colour.

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