Irregular pigmentation of the face is one of the most common signs of photo-aging. Pigmentation is due to the uneven production of melanin, a brown pigment produced by melanocytes in the skin. Many different patterns can be seen on the faces of people of different ages. Small localized brown spots in the form of freckles across the cheeks, medically known as lentigenes, usually appear around the age of 25–30, depending on cumulative sun exposure. Pigmentation can also present in the form of melasma, a diffuse darkening of the skin over the sides of the forehead, lateral jawline and upper lip. This type of skin darkening is hormone dependent, most commonly seen during pregnancy, around menopause and with the use of oral contraceptives. Lastly, increased facial pigmentation can present as overall darkening in people after 50 years from a combination of melanin pigment and fragmented elastin fibers.
Other factors also influence facial pigmentation, such as gender. Since men do not experience the same hormonal issues as women, increased facial pigmentation from melasma is uncommon. While male testosterone may cause some skin issues, it is female estrogen that produces facial pigmentation. The coarse skin texture of the male face from hair growth camouflages fine freckling that is often seen on the female face. Finally, the male facial skin is more resistant to UVA damage due to its increased thickness from the terminal hairs present as a beard on the face. UVA radiation penetrates deeply within the skin, but not as readily into thicker male skin as it does into thinner female skin. Because UVA damage is the primary cause of pigmentary abnormalities, pigment lightening products are more commonly used by females than males.1
There are also differences in skin pigmentation problems based on race. Individuals with darker skin are more prone to skin darkening. This is due to an enhanced ability of darker skin to produce melanin. Pigment may be produced in response to sun exposure, skin disease and skin trauma. It is distinctly more difficult to lighten skin in darker-complected individuals. While pigmentation problems may be more visible in persons with lighter skin, OTC skin-lightening preparations are more successful in this population.
There is no doubt that the best method of skin lightening is avoiding sun damage. In fact, all OTC skin-lightening treatments (Table 1) should include a sunscreen. Sunlight contains visible light and invisible ultraviolet B (UVB) and ultraviolet A (UVA) radiation. Visible light and UVB radiation do not tan the skin. Skin tanning in people of all skin colors is due to UVA radiation. Most sunscreens focus on preventing sunburn, which is due to UVB radiation. They do not prevent tanning, since UVA radiation still strikes the skin. Thus, sunscreens selected for skin-lightening purposes should contain UVA photoprotectants such as avobenzone, oxybenzone, zinc oxide and/or titanium dioxide.
Topical treatments for facial pigmentation are problematic. A successful treatment must remove existing pigment from the skin, shut down the manufacture of additional melanin pigment and prevent the transfer of existing melanin pigment to the melanosomes. No currently available topical product is able to accomplish all three of these functions. This review article examines various actives for topical skin-lightening products on the OTC markets.
The gold standard for topical skin lightening in the United States remains hydroquinone. This substance is controversial having been removed from the OTC markets in Europe and Asia. Concern arose from reports that oral hydroquinone caused cancer in mice that were fed large amounts of the substance. While oral consumption probably is not related to topical application, hydroquinone remains controversial because it actually is toxic to melanocytes.
Hydroquinone, a phenolic compound chemically known as 1,4 dihydroxybenzene,functions by inhibiting tyrosine, a key substance in melanin pigment production.2 Specificially, it covalently binds to histidine or interacts with copper at the active site of tyrosinase. It also inhibits RNA and DNA synthesis and may alter melanosome formation, thus selectively damaging melanocytes. These activities suppress the melanocyte, causing gradual decrease of melanin pigment production.3
Hydroquinone is available in both the OTC and prescription US markets. While controversy has arisen about its availability, no restrictions on hydro-
quinone use have been issued by the United States Food and Drug Administration (FDA) as of this writing. Hydroquinone is a medication that received grandfather status from the FDA, as it was in common use when the FDA was founded. Thus, some hydroquinone formulations have never undergone the testing required for today’s drug approval.
Many prescription products have made submissions to the FDA and completed the required safety and efficacy testing but OTC formulations and some generic formulations were never tested. It is these untested formulations that have created concern. The maximum concentration in OTC products is 2%, while most prescription formulations are 4%. In general, 4% hydroquinone is more effective than 2% hydroquinone, but neither concentration will lighten pigment that is deep in the skin due to penetration issues. Current hydroquinone preparations are unable to reach the middle to deep dermis where post-inflammatory acne pigmentation may lie; therefore, its pigment-lightening abilities are limited. Deep penetration of hydroquinone also raises unresolved safety issues.
In all formulations, hydroquinone is highly unstable and turns brown on contact with air, which oxidizes the hyroquinone molecule. Once the hydroquinone has oxidized, it is no longer active and should be discarded. It would be advisable to label OTC products with a warning that brown, discolored cream is unsuitable for use.
With the regulatory issues surrounding hydroquinone, a new pigment lightener known as mequinol has been introduced. At present, mequinol is only available by prescription but has been approved for use in the United States and Europe. It is chemically known as 4-hydroxyanisole and is chemically synthesized. Other names include methoxyphenol, hydroquinone monomethyl ether, and p-hydroxyanisole.
Mequinol is available in the United States in a 2% concentration and is commercially marketed as a prescription skin lightener in combination with 0.01% tretinoin as a penetration enhancer; vitamin C in the form of ascorbic acid; and ascorbyl palmitate, to enhance skin lightening. These active agents are dissolved in an ethyl alcohol vehicle. It is unknown exactly how mequinol lightens skin, but it is a competitive inhibitor in the formation of melanin precursors. It does not damage the melanocyte as hydroquinone does.
Many dermatologists combine hydroquinone with prescription vitamin A formulations such as tretinoin to improve skin-lightening results. Tretinoin has an effect on skin pigmentation as seen by a decrease in freckling.4 Freckling is created by the irregular grouping of melanocytes,5 which can be normalized with retinoids through alterations in pigment transfer.6 While this effect is more dramatic with topical prescription tretinoin, topical OTC retinol has been thought to provide similar effects.
Retinoids, such as retinol or retinaldehyde, can also be used as penetration enhancers for other skin lightening agents. Ingredient combinations where each ingredient affects a different portion of the skin pigmentation pathway may be more beneficial for skin lightening than single ingredient formulations. Since there are many steps in pigment formation, skin lighteners can interrupt melanin production and transfer at multiple sites. Formulations that have activity at multiple sites have a better chance of stopping pigment production. For further reading, see Ingredient Combinations for Skin Lightening.
Ascorbic acid, also known as vitamin C, is used in OTC pigment-lightening formulations. It interrupts the production of melanin by interacting with copper ions to reduce dopaquinone, an important intermediate in pigment production.7 It is a potent antioxidant sometimes combined with hydroquinone to prevent oxidation of the hydroquinone.
By itself, low concentration ascorbic acid is a poor skin-lightening agent. In higher concentrations, ascorbic acid can be a strong skin irritant due to its low pH, but may induce pigment lightening by inducing skin peeling in lighter-skinned individuals. High concentrations of ascorbic acid must be avoided in persons of color, as the irritation paradoxically will darken the skin.
Licorice extracts are used in many OTC products to lighten skin. The active agents are liquiritin and isoliquertin, which are glycosides containing flavonoids.8 Liquiritin induces skin lightening by dispersing melanin pigment and enhancing more even pigment distribution. It must be applied to the skin in a dose of 1 g/day for four weeks to see a clinical result. This may not be practical in OTC formulations due to the expense of such a high concentration. Since the liquiritin is an anti-inflammatory, irritation is not a side effect with licorice extract, whereas irritation is the dose-limiting problem with hydroquinone, retinoids and ascorbic acid.
Alpha Lipoic Acid
Alpha lipoic acid is found in some OTC pigment-lightening preparations. It is a disulfide derivative of octanoic acid, which is able to inhibit tyrosinase, a key enzyme in pigment production. However, its ability to lighten skin is doubtful, as it is a large molecule with questionable penetration to the level of the melanocyte where tyrosinase is present. Effective pigment lightening agents must reach their target in order to induce the desired effect. Molecular size and molecular charge are two key considerations in pigment lightening efficacy.
Kojic acid, chemically known as 5-hydroxymethyl-4H-pyrane-4-one, is one of the most popular skin lightening agents found globally in OTC skin lightening creams. It is a hydrophilic fungal derivative obtained from the Aspergillus and Penicillium species. It is frequently employed in Asia for the treatment of melasma.9
Some studies indicate that kojic acid is equivalent to hydroquinone in pigment-lightening ability.10 The activity of kojic acid is attributed to its ability to prevent tyrosinase activity by binding to copper. The problem with kojic acid is again the ability to penetrate the skin and reach its copper target. It is possible that penetration enhancers might overcome some of this difficulty; however, damage to the skin barrier and product irritation are a common side effect.
Aleosin is a botanical low-molecular-weight glycoprotein obtained from the aloe vera plant. It is a natural hydroxymethylchromone that functions by inhibiting tyrosinase.11, 12 In contrast to hydroquinone, it shows no cell cytotoxicity; however, it has a limited ability to penetrate the skin due to its hydrophilic nature. It is sometimes mixed with arbutin, described next, to enhance its skin-lightening abilities.
Arbutin is obtained from the leaves of the Vaccinicum vitis-idaea (lingonberry) and other related plants such as bearberry, cranberry, mulberry or blueberry shrubs. It is a naturally occurring gluconopyranoside with a form of hydroquinone that causes decreased tyrosinase activity without affecting messenger RNA expression.13 It also inhibits melanosome maturation.
Arbutin is not toxic to melanocytes and is used in a variety of pigment lightening preparations in Japan at concentrations of 3%. Higher concentrations are more efficacious than lower concentrations, but a paradoxical pigment darkening may occur due to skin irritation. Synthetic versions of arbutin, such as deoxyarbutin, may offer enhanced efficacy.
The most effective skin lightening agents are ingredient combinations that use complementary mechanisms of action to lighten the skin. One of the most effective prescription combinations contains hydroquinone, tretinoin and a topical corticosteroid. The synergistic effect of the ingredients results in the superior results. Hydroquinone functions to inhibit tyrosinase while tretinoin acts as a penetration enhancer, inducing stratum corneum sloughing to allow the hydroquinone to fully reach the melanocytes. In addition, tretinoin decreases pigment transfer.
Unfortunately, both hydroquinone and tretinoin are irritants, thus the addition of a topical corticosteroid increases the tolerability of the formulation while decreasing inflammation. Since inflammation is a driving force for skin pigmentation, the effect of the corticosteroid is also additive.
Skin lightening is a definite challenge. Many substances have been reported to inhibit melanin production in vitro but these same results are not seen in vivo. Melanocytes are extremely difficult cells to grow in culture, and it is possible that many skin-lightening ingredients that did not produce clinical results were toxic to the cultured melanocytes. It is important that skin-lightening ingredients only suppress pigment production and do not destroy the melanocytes. Melanocyte destruction results in permanent skin lightening, which must be avoided at all costs.
Melanocytes are present at birth and do not divide or reproduce during an individual’s lifespan, making cell preservation extremely important. Furthermore, cell cultures do not have the stratum corneum barrier to prevent penetration of skin lightening ingredients. For a pigment-lightening preparation to be effective, it must reach the melanocyte deep within the skin. This is the limiting factor in most skin lighteners.
There is no doubt that pigment lightening will be a consumer need that continues to grow during the next decade. Attractive youthful skin is even in color without discrete areas of darkening. Sun avoidance is the best preventive measure but the human desire to seek the sun, especially during youth, will make skin lightening a challenge that must be overcome.
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