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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 dictate skin’s actual colour. The formation of Melanin lies into a sequence of oxidative reactions which involve the enzyme tyrosinase and the amino acid tyrosine.

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.

Hydroquinone is remarkably safe however, keep in mind that there is the possibility of side effects. Particularly, a few patients presented with contact dermatitis responded immediately to topical steroids. Exogenous Ochronosis, is on the other hand a not so very common side effect of hydroquinone, where there is a progressive darkening of the area due to exposure to hydroquinone as well as elastic fibres and collagen degeneration occurs, histologically speaking. Following this degeneration is the appearance of crescent-shaped, ochre-colored fibres in the dermis, a typical characteristic of exogenous ochronosis. In general, black patients as well as in South Africa are more likely to be diagnosed with exogenous ochronosis, due to the long-term use of hydroquinone in high concentration. Additionally, there are reported cases of exogenous ochronosis as a result of 2% hydroquinone use, however, assays of the before mentioned products demonstrated that the concentrations of hydroquinone were much higher. In the light of these facts, discontinuation of hydroquinone 4-6 months in cases of no improvement is generally recommended. Ochronosis as a result of the use of hydroquinone is not easy to treat, however, it’s possible to respond to chemical peeling & topical steroids.

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)

Kojic acid is a fungal metabolic product, which has the ability to restrain tyrosinase’s activity. The latter is a significant enzyme that inhibits the rate of skin pigment’s melanin biosynthesis. Kojic Acid is greatly preferred, thus widely consumed in the Japanese diet, as they believe that it has beneficial attributes for the health. Actually, it has been demonstrated to greatly enhance lymphocyte proliferation and neutrophil phagocytosis which are intrigued by phytohemagglutinin. When treated with kojic acid, melanocytes present a decrease in their melanin content, as they become non-dendritic. Additionally, it searches 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.


Derivatives of vitamin A such as adapalene & tretinoin are amongst the retinoids. To reduce pigmentation certain mechanisms such as interference with pigment transfer, acceleration of epidermal turnover and inhibition of tyronsinase induction should be applied. Retinoids are able to spread the pigment particles within keratinocytes. Retinoids, when used with mequinol and hydroquinone (lightening agents), have the ability to function as penetration amplifier. However, they do have side effects, amongst which are stinging, burning, dryness, scaling, and erythema. Reversible as they are, hyperpigmentation may occur more often in individuals with dark skin complexion. In a study conducted on Caucasian population, there was a reduction by 36% of the overall severity of melasma compared with its vehicle when 0,1% tretinoin was used as monotherapy. Tretinoin can be found in several strengths ranging from 0.01%-0.1%.


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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