Skin Depigmenter: What is it? Common and Alternative Topical Uses, Treatments

There is a wide variety of chemical peels available on the market today.

Almost all skin types and ethnicities can find a chemical treatment to restore a youthful appearance.

However, not all procedures will provide the same results. There are effective depigmentation treatments to control areas of hyperpigmentation, melasma, and blemishes or scars on the skin.

Depigmenting agents are commonly prescribed to treat hyperpigmentation disorders.

The information below presents a review of several notable depigmenting agents reported in the literature.

Although some of these topical agents are available only from certain research institutions, an increasing number of products may be used by physicians as part of an arsenal to treat hyperpigmentation disorders.

Recent advances in cosmetic dermatology have developed the laser as another modality for treating hyperpigmentation.


A basic understanding of the pigmentation pathway is helpful before discussing various skin lightening agents and their known mechanisms of action.

The type and amount of melanin synthesized by the melanocyte and its distribution pattern in the epidermis determine the actual color of the skin.

Melanin is formed through oxidative reactions involving the amino acid tyrosine and the enzyme tyrosinase.

The first step is critical because the rest of the reaction sequence can proceed spontaneously at physiological pH. Here, tyrosinase converts tyrosine to dihydroxyphenylalanine (DOPA) and then to dopaquinone.

Subsequently, dopaquinone is converted to dopachrome by autoxidation and finally to dihydroxyindole or dihydroxyindole-2-carboxylic acid (DHICA) to form eumelanin (black-brown pigment).

The latter reaction occurs in the presence of dopachrome tautomerase and DHICA oxidase.

In the presence of cysteine ​​or glutathione, dopaquinone is converted to cysteinyl DOPA or glutathione DOPA. Subsequently, pheomelanin, a yellow-red pigment, is formed.

One study suggests a novel method to test multiple topical skin lightening methods before starting therapy, using a UV-induced skin tan.

Concerns have been raised regarding some commercial lighting products related to mercury content.

Allergic contact dermatitis was attributed to mercury in one report, and high mercury concentrations were described in the ovaries of mice exposed to the skin lightening cream in another. Additional studies are required before conclusions can be drawn.


Determining the cause of hyperpigmentation is essential in selecting the best approach to treatment.

Depending on the patient’s history and clinical findings, the etiology of hyperpigmentation may include post-inflammatory hyperpigmentation, drugs, photosensitizing agents, ultraviolet light, or systemic disease (e.g., Addison’s disease, liver disease, pregnancy, pituitary tumors).

The causative agent must be determined and managed to treat the pigmentary disorder properly.

Hyperpigmentation is treated with the application of topical agents and with laser treatments. Topical skin lightening therapy and laser treatments can take weeks to several months before noticing a significant difference.

During the treatment phase, patients should avoid the sun by wearing protective clothing and sunscreen to decrease the likelihood of UV-induced pigment changes.

Common topical treatments


An important industrial chemical, hydroquinone is also a ubiquitous chemical readily available in cosmetic and over-the-counter forms for skin lightening. It is considered one of the most effective melanogenesis inhibitors in vitro and Vivo.

Hydroquinone causes reversible inhibition of cellular metabolism by affecting the synthesis of DNA and RNA.

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.

Therefore, hydroquinone can be considered a potent melanocyte cytotoxic agent with relatively high melanocyte-specific cytotoxicity.

Hydroquinone is also a poor tyrosinase substrate, thus competing with tyrosine oxidation inactive melanocytes.

Hydroquinone 2% is available over the counter in various cosmetic preparations. Evidence of improvement with hydroquinone (monotherapy) is generally seen at 4-6 weeks, with apparent improvement to plateau at approximately four months.

Concentrations as high as 10% can be combined extemporaneously for refractory cases. For best efficacy, hydroquinone is combined in various blends to treat hyperpigmentation.

Kligman’s original formula involves the combination of 5% hydroquinone with 0.1% retinoic acid and 0.1% dexamethasone in a hydrophilic ointment base. Tri-Luma is a popular skin lightening agent combination containing 0.01% fluocinolone, 4% hydroquinone, and 0.05% tretinoin in a cream formulation.

Despite hydroquinone’s excellent overall safety, be aware of potential adverse effects. Contact dermatitis occurs in a small number of patients and responds quickly to topical steroids.

An uncommon but essential side effect of hydroquinone is exogenous ochronosis.

This disorder is characterized by a progressive darkening of the skin exposed to hydroquinone. Histologically, degeneration of collagen and elastic fibers occurs.

This degeneration is followed by the appearance of characteristic ochronotic deposits consisting of ocher-colored, crescent-shaped fibers in the dermis.

Exogenous ochronosis has generally been seen in black patients who have used high concentrations of hydroquinone for many years.

Cases occurring after using 2% hydroquinone have also been reported, but analyses of some of these products found that they contained much higher concentrations.

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 challenging to treat but can respond to topical steroids and chemical peels.

Tretinoin has been used to enhance the effectiveness of hydroquinone. In a large-scale, double-blind, placebo-controlled study, 0.05% tretinoin caused a decrease in melanin content at six months.

Two known glutathione inhibitors, cystamine and buthionine sulfoximine have also been reported to help increase the inhibitory effect of hydroquinone on pigmentation.

The study authors 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 the mice.

Hydroquinone monobenzyl ether

Like hydroquinone, hydroquinone mono benzyl ether (MBEH) belongs to the chemical agents’ phenol/catechol class. Unlike hydroquinone, MBEH almost always causes almost irreversible depigmentation of the skin.

Traces of MBEH have been found in disinfectants, antiseptics, rubber covered plate trays, duct tape, powdered rubber condoms, and rubber aprons.

In dermatology, MBEH should only be used to remove residual areas of skin with normal pigmentation in patients with refractory and generalized vitiligo.

The suggested mechanism of depigmentation of MBEH is selective melanocytic destructions through the free radical formation and competitive inhibition of the tyrosinase enzyme system.

Acido azelaic

A naturally occurring saturated dicarboxylic acid isolated initially from Pityrosporum ovale, azelaic acid is a relatively weak competitive inhibitor of tyrosinase in vitro. Furthermore, azelaic acid has an antiproliferative and cytotoxic effect on melanocytes.

The latter effect occurs due to relatively potent inhibition of thioredoxin reductase, an enzyme involved in activating mitochondrial oxidoreductase and DNA synthesis.

Although azelaic acid was initially prescribed to treat acne, it has been used successfully to treat lentigos, rosacea, and post-inflammatory hyperpigmentation.

It is prescribed topically as a 20% cream and combined with glycolic acid (15% and 20%). Its efficacy has been compared to 4% hydroquinone in treating facial hyperpigmentation in dark-skinned patients.

The combination formula was as effective as 4% hydroquinone 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 activity of the catecholase tyrosinase, which is the essential rate-limiting enzyme in the biosynthesis of melanin, a skin pigment.

Kojic acid is also widely consumed in the Japanese diet, believing it is beneficial for health.

It has been shown to improve neutrophil phagocytosis and phytohaemagglutinin-stimulated lymphocyte proliferation significantly.

Kojic acid-treated melanocytes become non-dermal, with a reduced melanin content. In addition, it removes reactive oxygen species released in excess from cells or generated in tissues or blood.

Kojic acid is used in concentrations ranging from 1-to 4%. Although effective as a skin lightening gel, it has been reported to have a high sensitization potential and can cause irritant contact dermatitis.

In a study comparing the combination of glycolic acid / kojic acid with glycolic acid/hydroquinone, no statistical differences in efficacy were reported between kojic acid and hydroquinone; however, the kojic acid preparation was said to be more irritating.

To decrease irritation from kojic acid, it is combined with a topical corticosteroid.

In a comparative study, 2% hydroquinone, 10% glycolic acid, and 2% kojic acid decreased hyperpigmentation in melasma patients better than the same combination without kojic acid.

Mequinol (4-hydroxyanisole)

Similar to hydroquinone, 4-hydroxyanisole (4HA) is cytotoxic to melanocytes. Reports indicate that it is clinically effective in inhibiting melanogenesis when used to combine 2% 4HA cream and 0.01% retinoic acid.

The authors reported minimal local skin irritation with this combination. Two percent of 4HA alone did not produce significant hypopigmentation.

Mequinol is used in Europe in concentrations ranging from 5 to 20% and is approved in the United States to treat solar lentigos.


Retinoids, such as tretinoin and adapalene, are derived from vitamin A. Mechanisms for reducing pigmentation include inhibition of tyrosinase induction, interference with pigment transfer, and acceleration of epidermal turnover.

They also can disperse pigment granules within keratinocytes. Retinoids can act as penetration enhancers with other lightening agents such as hydroquinone and mequinol.

The most common adverse effects include burning, stinging, erythema, dryness, and peeling. Although the adverse effects are reversible, retinoid dermatitis can lead to hyperpigmentation, especially in dark-skinned people.

Tretinoin is available in different concentrations ranging from 0.01% to 0.1%. In a study of a white population, 0.


Niacinamide is the biologically active form of vitamin B-3. Suppresses melanosome transfer to epidermal keratinocytes.

The first studies show a 35-68% inhibition of melanosomes in culture models with one mmol of niacinamide L -1 for 12 days.

Niacinamide with retinyl palmitate has improved hyperpigmentation and increased skin lightening after four weeks of treatment compared to vehicle alone.


Soy proteins contain serine protease inhibitors that inhibit the activation of the protease-activated receptor-2 (PAR-2) pathway. The PAR-2 ​​path is essential for keratinocyte phagocytosis of melanosomes and melanosome transfer.

By inhibiting this pathway, reducing melanin transfer produces a soothing effect. Improvement of hyperpigmentation was observed after 12 weeks of twice daily application of unpasteurized soy milk, with minimal adverse effects.

chemical peels

The mechanism of action of chemical exfoliating agents is to accelerate epidermal turnover and eliminate melanized keratinocytes, leading to the loss of melanin granules.

Post-inflammatory hyperpigmentation is the most common complication, especially in dark-skinned individuals. Other adverse reactions include erythema following inflammation, infection, and aggravation of melasma.

Exfoliants, such as alpha-hydroxy acids have been shown to lighten melasma, solar lentigines, and post-inflammatory hyperpigmentation. Glycolic acid is derived from sugar cane and is used as an ingredient in skin lightening products in low concentrations.

It can also be used as a peeling agent in concentrations of 30 to 70% to increase the effectiveness of other lightening agents such as hydroquinone by removing the epidermis, which improves the penetration of hydroquinone.

Repeated peels are required every 2-3 weeks to achieve significant lightening.

In an Indian study of 40 patients with skin types, III-IV with moderate to severe melasma, glycolic acid peels were used in addition to a modified Kligman hydroquinone formula in a 21-week open-label pilot study.

Eighty percent of the patients in the cascara group noted excellent improvement.

Other chemical peels include 50% trichloroacetic acid (TCA) peels and 20-30% salicylic acid peels used for various pigment disorders, including melasma, on darker skin types.

A clinical trial of TCA peels in 20 patients with melasma reported that 55% of patients experienced a good clinical response, with no significant complications being reported.

Shallow and medium-depth peels with salicylic acid are adequate and were well tolerated on darker skin types when combined with hydroquinone.

Alternative treatments

Arbutina (hidroquinona-beta-D-glucopiranosida)

Arbutin, glycosylated hydroquinone found in high concentrations in certain plants and capable of surviving extreme and sustained dehydration, has been shown to inhibit melanin synthesis by inhibiting tyrosinase activity.

Inhibition of melanosomal tyrosinase activity, rather than suppressing the synthesis and expression of this enzyme, appears to be the mechanism of action.

Because arbutin does not hydrolyze to release hydroquinone, the latter agent is not responsible for the inhibitory effect of arbutin on melanogenesis.

Inhibition of melanin synthesis (approximately 39%) occurs at a concentration of 5 X 10 5 mol / l.

Although the effective topical concentration for treating hyperpigmentation disorders has not been formally evaluated and published, several manufacturers are marketing arbutin as a depigmenting agent.

Several studies have shown that arbutin is less effective than kojic acid in treating hyperpigmentation. Some manufacturers report that arbutin is an effective depigmenting agent at a concentration of 1%.

Mulberry paper

This tyrosinase inhibitor was isolated from a herbal extract of plants. The roots of the plants from which the paper berry was isolated were collected in Korea.

A comparison of blackberry tyrosinase inhibition with kojic acid and hydroquinone reveals that the IC50 (i.e., the concentration causing 50% inhibition of tyrosinase activity) is 0.396%, compared with 5.5% for hydroquinone and 10% for kojic acid.

The authors also performed a patch test with 1% paper mulberry extract and found no significant irritation at 24 hours or 28 hours.

Glabridin (liquorice extract)

Glabridin is the main ingredient in licorice extract. The authors investigated glabridin for its inhibitory effect on pigmentation and reported that glabridin inhibited melanocyte tyrosinase activity without cytotoxicity.

Furthermore, they demonstrated that UV-B-induced pigmentation and erythema were inhibited by topical application of 0.5% glabridin. The anti-inflammatory properties of glabridin were attributed to the inhibition of superoxide anion production and cyclooxygenase activity.

A combination product of 0.4% licorice extract, 0.05% betamethasone, and 0.05% retinoic acid effectively treated melasma. This treatment is not currently available in the United States.

Arctostaphylos patula and Arctostaphylos viscida

The leaves of these 2 Arctostaphylos plants have been reported to be potent tyrosinase inhibitors. These two extracts inhibited melanin production from dopachrome and showed dismutase superoxide-like activity.

The effective topical concentration of these two plants in hyperpigmentation disorders is currently not known.

Magnesium Ascorbyl Phosphate

Magnesium-L -fascial-2-phosphate (MAP) is a stable derivative of ascorbic acid. When used as a 10% cream, MAP suppressed melanin formation. A clinically significant relieving effect was observed in 19 of 34 patients with melasma and solar lentigos.

Furthermore, MAP is protective against UV-B radiation-induced skin damage. The last protective effect is theorized to be due to the conversion of MAP to ascorbic acid.

A Japanese study of 110 patients showed a 25% decrease in hyperpigmentation after six months of using a 3% MAP skin lightening moisturizer.


A hydroquinone derivative, 4-isopropylcatechol, has been used to treat hyper melanosis at 1-3% concentrations. Its melanocytotoxic effect causes the loss of functional melanocytes, causing depigmentation.

Like other phenolic compounds, it is a known irritant and can cause contact allergy. It also causes confetti areas of depigmentation at the treatment site.


Allison is a low molecular weight glycoprotein and a natural derivative of aloe vera. Unlike hydroquinone, it inhibits tyrosinase by competitive inhibition and does not show cellular cytotoxicity.

Due to its hydrophilic nature, it has a reduced ability to penetrate the skin. An experimental product has been used with arbutin or deoxyabutin to decrease tyrosinase activity.

Phenolic Thioethers

N -acetyl-4-S-cysteaminylphenol and N -propionyl-4-S-cysteaminylphenol are derived from phenol homologs with melanocytotoxic activity. N-Acetyl-4-S-cysteaminylphenol is a derivative analog of tyrosine-amine that is less irritating than hydroquinone.

Therefore, it can inhibit tyrosinase as an alternative substrate for tyrosinase activity. Decreasing intracellular glutathione favors the pathway for pheomelanin formation instead of eumelanin.

A clinical study with a 4% N -acetyl-4-S-cysteaminophenol preparation for melasma showed moderate improvement after 2-4 weeks of application, with minimal adverse effects. N-propionyl-4-S-cysteaminylphenol is more potent and has more cytotoxic properties than the N -acetyl form.

N-acetyl glucosamine

N-Acetylglucosamine is an amino-monosaccharide that was developed as a cosmeceutical to lighten pigments. It decreases melanin production by inhibiting tyrosinase glycosylation.

A double-blind, randomized study reported that the application of 2% N-acetyl glucosamine twice daily for five weeks provided a relieving effect.

Tranexamic acid

Tranexamic acid (trans -4-aminomethylcyclohexanecarboxylic acid) is a lysine analog that has been shown to prevent UV-induced pigmentation.

It decreases the activity of melanocytic tyrosinase by preventing the binding of plasminogen to keratinocytes, resulting in the reduction of prostaglandins and arachidonic acid, which are inflammatory mediators involved in melanogenesis.

In an open-label pilot study, 100 women with melasma were given intradermal microinjection of tranexamic acid for 12 weeks. The treatment was well-tolerated, and 76.5% of the subjects reported just lightening of their melasma.



The treatment of laser hyperpigmentation techniques (amplification of light by emission of stimulated radiation) is a rapidly growing field.

Lasers work by emitting a high intensity, monochromatic, coherent source of energy that is absorbed by water, hemoglobin, and melanin in the skin, known as chromophores. The absorption of energy destroys the chromophores.

The wavelength of the laser determines the depth of penetration of the laser and the selected chromophores.

Based on the absorption spectrum of melanin, the ruby ​​Q-switch laser (694 nm) and the Nd: YAG Q (Q) laser (1064 nm) are the lasers of choice for the treatment of hyperpigmented lesions such as lentigos. And post-inflammatory hyperpigmentation.

In a randomized controlled trial of 27 patients with dorsal solar lentigines, the best treatment was with the Nd: YAG Q-switch laser compared to a krypton laser, a 532 nm diode-pumped laser, or liquid nitrogen.

In a Chinese study, a Q-Switch laser (755 nm) was used to treat 602 patients with nevus of Ota and was reported to achieve good results with minimal adverse effects.

Adverse effects were transient hyperpigmentation and worsening of pre-existing melasma. The success rate depended on the number of treatments. More treatments achieved better response rates in most patients.

Adverse effects of laser treatment include discomfort, redness, mild swelling, and post-inflammatory hyperpigmentation. Patients should always undergo a test point before completing treatment.


For more refractory hyperpigmentation disorders, ablative lasers (pulsed/scanned carbon dioxide or Er: YAG laser) have been reported to remove superficial skin parts, including abnormal melanocytes.

However, this therapeutic approach is not considered a first-line treatment due to the adverse effects of hyperpigmentation, scarring, and the rapid recurrence of primary hyperpigmentation.

A split-face study in 6 patients with refractory dermal-type melasma showed complete resolution by the combined treatment of the pulsed carbon dioxide laser and the Q-Switch Alexandrite laser compared to the pulsed carbon dioxide laser alone.

Although effective, this approach is unpredictable and can cause scarring and infection.

The Er: YAG laser (2490nm) removes the skin and disrupts the melanin granules in the upper dermis.

It has been shown to improve refractory melasma; however, most cases develop transient post-inflammatory hyperpigmentation, making this helpful approach only for selected patients with refractory/recalcitrant melasma.

Intense pulsed light

A recent derivative of laser treatment is intense pulsed light, in which high-intensity pulses of a broad wavelength (515-1200 nm) of light deliver energy to the skin. The power of the intense pulsed light is sent to the dermis and absorbed by the chromophores.

Intense pulsed light has been shown to work well for the treatment of lentigos, but the therapy has not been optimized for the treatment of melasma.

A Japanese study showed a 50% improvement in solar and ephelid lentigines in 48% of patients after 3-5 treatments and a 75% improvement in 20% of patients.

Adverse effects of intense pulsed light treatment include pain, local irritation, and post-inflammatory hyperpigmentation.

Fractional photothermolysis

Fractional photothermolysis (Fraxel) is a recent development in laser technology. It was approved by the US Food and Drug Administration.

For the treatment of dyspigmentation in 2005. Fraxel acts by thermal damage in the microscopic areas of the epidermis and dermis.

With a single Fraxel treatment, approximately 15-20% of the skin undergoes laser resurfacing, and the surrounding normal skin is postulated to aid the healing process.

Based on the fraction of skin that experiences thermal damage, it is hypothesized that the skin will have minor wear and therefore require less healing (“downtime”) between treatments.

A case report describing Fraxel treatment showed a marked reduction in hyperpigmentation in a white woman after two treatments, and no adverse effects were reported.

In addition, a case series of 10 melasma patients documented a 75-100% improvement in melasma in 5 of 10 patients based on physician and patient evaluations.

Patients with skin type V showed little or no improvement with treatment. One patient experienced post-inflammatory hyperpigmentation from Fraxel treatment, and, overall, patients reported pain of 6.3 on a scale of 0-10.

Further comparative studies of laser treatments and depigmenting agents will determine the optimal treatment for patients with different skin tones with hyperpigmentation.



Although not a standard treatment modality for melasma, dermabrasion has been reported as a possible alternative treatment for recalcitrant melasma.

In an Asian study, 97% of 410 patients had a melasma clearance without recurrence.

Adverse reactions include post-inflammatory hyperpigmentation, erythema, pruritus, milia formation, loss of skin texture, and scarring.