Macules (medical terminology – melasma) are more extended skin lesions as compared to spots, usually showing vague boundaries and a brown or brown-yellow colour.

Macules – Melasma – Chloasma

In most cases they are superficial (not deep) lesions and they are due to the increased levels of melanin and the effect of certain enzymes.


UV radiation is a really significant factor, which is why the problem is more common in areas with plenty of sunshine.

In women with predisposition hormonal changes play an important role, such as in cases of polycystic ovary symptom, when contraceptives are used, and during pregnancy (Chloasma), leading to increased melanin activity and the appearance of discolourations on the face.


The management of melasma – chloasma is not an easy process. Sometimes it is necessary to apply for many months combined treatment to achieve the best possible result.

Special treatments, medical peelings and microdermabration constitute the main treatment methods, while in certain cases specialised LASER devices may also be used.

Need for constant sun protection should be highlighted

We have the most advanced and modern therapeutic methods so that to choose – depending on each occasion – the most appropriate treatment for the best individualised method of treatment.

Lightening and depigmentation agents

Depigmentation agents are mainly recommended for the treatment of depigmentation conditions. It is important to understand the main pigmentation root. The type and quantity of melanin composed by the melanocytes and its distribution pattern on the skin determines the actual colour of the skin. Melanin is formed through a series of oxidative reactions involving the amino acid tyrosine and the enzyme tyrosinase.

Hyperpigmentation can be treated through the application of local agents and/or through laser treatment. Treatment with local lightening agents and laser may last from some weeks to months in order to achieve significant improvement. During the treatment period patients should avoid sun exposure and always use sunscreen to reduce chances of pigmentation changes due to ultraviolet radiation.

Common topical treatments


An important industrial chemical, hydroquinone is also a ubiquitous chemical readily available in cosmetic and non-prescription forms for skin lightening. It is considered one of the most effective inhibitors of melanogenesis in vitro and in vivo. Hydroquinone causes reversible inhibition of cellular metabolism by affecting both DNA and RNA synthesis. The cytotoxic effects of hydroquinone are not limited to melanocytes, but the dose required to inhibit cellular metabolism is much higher for non-melanotic cells than for melanocytes. Thus, hydroquinone can be considered a potent melanocyte cytotoxic agent with relatively high melanocyte-specific cytotoxicity. Hydroquinone is also a poor substrate of tyrosinase, thereby competing for tyrosine oxidation in active melanocytes.

The 2% hydroquinone is readily available over the counter in various cosmetic preparations. Evidence of improvement with hydroquinone (monotherapy) is usually observed at 4-6 weeks, with improvement appearing to plateau at approximately 4 months. Concentrations as high as 10% can be compounded extemporaneously for refractory cases. For better efficacy, hydroquinone is compounded into various mixtures for the treatment of hyperpigmentation. The original Kligman formula involves compounding 5% hydroquinone with 0.1% retinoic acid and 0.1% dexamethasone in a hydrophilic ointment base. Tri-Luma is a popular combination skin-lightening agent that contains 0.01% fluocinolone, 4% hydroquinone, and 0.05% tretinoin in a cream formulation.

Despite the remarkable overall safety of hydroquinone, bear in mind the potential adverse effects. Contact dermatitis occurs in a small number of patients and responds promptly to topical steroids. An uncommon, yet important, adverse effect of hydroquinone is exogenous ochronosis. This disorder is characterized by progressive sooty darkening of the skin area exposed to hydroquinone. Histologically, degeneration of collagen and elastic fibres occurs. This degeneration is followed by the appearance of characteristic ochronotic deposits consisting of crescent-shaped, ochre-coloured fibres in the dermis.

Exogenous ochronosis has generally been observed in black patients who have used high concentrations of hydroquinone for many years. Cases occurring after the use of 2% hydroquinone have also been reported, but assays of some of these products found that they actually contained much higher concentrations. An exogenous ochronosis due to hydroquinone has been reported from South Africa. For this reason, the general recommendation is that hydroquinone should be discontinued if no improvement occurs within 4-6 months. Hydroquinone-induced ochronosis is often difficult to treat, but it may respond to topical steroids and chemical peeling.

Tretinoin has been used to enhance the efficacy of hydroquinone. In a large-scale, double-blind, placebo-controlled study, 0.05% tretinoin caused a decrease in melanin content at 6 months. Two known inhibitors of glutathione, cystamine and buthionine sulfoximine, have also been reported useful for their enhancement of the inhibitory effect of hydroquinone on pigmentation. The authors of the study reported a synergistic decrease in hair pigmentation when a combination of hydroquinone (2% or 4%) and buthionine sulfoximine (5%) was applied to the dorsal skin of mice.

Monobenzyl ether of hydroquinone

Similar to hydroquinone, monobenzyl ether of hydroquinone (MBEH) belongs to the phenol/catechol class of chemical agents. Unlike hydroquinone, MBEH almost always causes nearly irreversible depigmentation of the skin. Traces of MBEH have been found in disinfectants, germicides, rubber-covered dish trays, adhesive tape, powdered rubber condoms, and rubber aprons. In dermatology, MBEH should only be used to eliminate residual areas of normally pigmented skin in patients with refractory and generalized vitiligo. The suggested mechanism of depigmentation of MBEH is selective melanocytic destruction through free-radical formation and competitive inhibition of the tyrosinase enzyme system.

Azelaic acid

A naturally occurring, saturated dicarboxylic acid originally isolated from Pityrosporum ovale, azelaic acid is a rather weak competitive inhibitor of tyrosinase in vitro. In addition, azelaic acid has an anti-proliferative and cytotoxic effect on melanocytes. The latter effect occurs because of a rather potent inhibition of thioredoxin reductase, an enzyme involved in mitochondrial oxidoreductase activation and DNA synthesis.

Although azelaic acid was initially prescribed for the treatment of acne, it has been successfully used in the treatment of lentigines, rosacea, and post inflammatory hyperpigmentation. It is prescribed topically as a 20% cream and has been combined with glycolic acid (15% and 20%). Its efficacy has been compared with hydroquinone 4% in the treatment of facial hyperpigmentation in dark-skinned patients. The combination formula reportedly was as effective as hydroquinone 4% cream, although with a slightly higher rate of local irritation.

Kojic acid (5-hydroxy-4-pyran-4-one-2-methyl)

A fungal metabolic product, kojic acid inhibits the catecholase activity of tyrosinase, which is the rate-limiting, essential enzyme in the biosynthesis of the skin pigment melanin. Kojic acid is also consumed widely in the Japanese diet, with the belief that it is of benefit to health. Indeed, it has been shown to significantly enhance neutrophil phagocytosis and lymphocyte proliferation stimulated by phytohemagglutinin. Melanocytes treated with kojic acid become non dendritic, with a decreased melanin content. Additionally, it scavenges reactive oxygen species released excessively from cells or generated in tissue or blood.

Kojic acid is used in concentrations ranging from 1-4%. Although effective as a skin-lightening gel, it has been reported to have high sensitizing potential and may cause irritant contact dermatitis. In a study comparing glycolic acid/kojic acid combination with glycolic acid/hydroquinone, no statistical difference in efficacy was reported between kojic acid and hydroquinone; however, the kojic acid preparation was reported to be more irritating.

To decrease the irritation from kojic acid, it is combined with a topical corticosteroid. In a comparison study, 2% hydroquinone, 10% glycolic acid, and 2% kojic acid decreased hyperpigmentation in patients with melasma better than the same combination without kojic acid.

Mequinol (4-hydroxyanisole)

Similar to hydroquinone, 4-hydroxyanisole (4HA) is cytotoxic to melanocytes. Reports indicate it is clinically effective in inhibiting melanogenesis when used as a combination of 2% 4HA cream and 0.01% retinoic acid. The authors reported minimal local skin irritation with this combination. Two percent 4HA alone did not produce significant hypopigmentation. Mequinol is used in Europe in concentrations ranging from 5-20% and is approved in the United States for the treatment of solar lentigines.


Retinoids such as tretinoin and adapalene are derivatives of vitamin A. The mechanisms for reducing pigmentation include inhibition of tyrosinase induction, interference with pigment transfer, and acceleration of epidermal turnover. They also have the ability to disperse pigment granules within keratinocytes. Retinoids may act as penetration enhancers when used with other lightening agents such as hydroquinone and mequinol. The most common adverse effects include burning, stinging, erythema, dryness, and scaling. Although the adverse effects are reversible, retinoid dermatitis may itself lead to hyperpigmentation, especially in dark-skinned individuals. Tretinoin is available at different strengths ranging from 0.01% to 0.1%. In a study on a white population, 0.1% tretinoin used as monotherapy reduced the over all severity of melasma by 36% compared with its vehicle.


Niacinamide is the biologically active form of vitamin B-3. It suppresses the transfer of melanosomes to the epidermal keratinocytes. Early studies show 35-68% inhibition of melanosomes in culture models with 1 mmol L-1 niacinamide for 12 days. Niacinamide with retinyl palmitate has been shown to improve hyperpigmentation and increase skin lightening after 4 weeks of treatment compared with vehicle alone.


Soy proteins contain serine protease inhibitors that inhibit the activation of the protease activated receptor–2 pathway (PAR-2). The PAR-2 pathway is important for keratinocyte phagocytosis of melanosomes and melanosome transfer. By inhibiting this pathway, reduction of melanin transfer produces a lightening effect. Improvement of hyperpigmentation was seen after 12 weeks of twice-daily application of unpasteurized soy milk, with minimal adverse effect

About the author:

Christofer Tzermias

Specialised in the UK (Oxford & London) and in North America (New York & San Diego) in the field of LASER Dermatology, Dr Tzermias, has been providing dermatological state-of-the-art treatments using cutting-edge LASER and Energy based Devices for over 20 years. He has been Director of Interventional and LASER Dermatology Department at the Athens Medical Center for over 18 years and for the last 9 years is the Scientific Director of IQ - Intensive Quality Dermatology & Cosmetic Surgery Clinics, which at the 2017 Healthcare Awards won the ‘Innovation Award for Innovative Services’ for their pioneering contributions. Since 2018, IQ Dermatology & Cosmetic Surgery Clinics has also been operating in London, UK and in Muscat, Oman. Dr Tzermias is a Fellow of the world-renowned American Society for LASER Medicine and Surgery (ASLMS), a Founder Member of the European Society LASER Dermatology (ESLD), the Vice President of the ‘Open Health Alliance’ and he is also on the Board of Directors of Elitour - Greek Medical Tourism Council.

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