Treatment of hyperpigmentation problems / skin lightening

Hydroquinone is one of the best-established topical agents for reducing skin pimgentation, often viewed as the golden standard of skin lightening. Its effectiveness, both alone and in combination with other treatments, has been documented in a large number of clinical studies. It works by inhibiting the enzyme tyrosinase, thus blocking a critical step in the synthesis of melanin (dark skin pigment). Hydroquinone does not bleach skin in the sense that it does not destroy previously synthesized melanin. Hydroquinone treatment usually takes several weeks to produce results because even though the synthesis of new melanin is blocked quickly, the existing melanin takes a relatively long time to migrate out of the skin in the process of natural exfoliation. To speed up the effects, hydroquinone or other melanin synthesis inhibitors are sometimes combined with exfoliating agents, such as alpha-hydroxy acids. However, since both hydroquinone and many exfoliants are potential skin irritants, combining then increases the risk of skin irritation.

Hydroquinone is available in concentrations of 0.5 - 2% over-the-counter and 4% or even higher by prescription. Side effects of short-term use tend to be mild and non-systemic, especially for low-to-medium strength formulations.

Unfortunately, animal studies of very high doses indicated the potential of hydroquinone to cause cancer. Also, hydroquinone has been reported to cause ochronosis, a bluish black discoloration of tissue. This complication is relatively rare with short-term use of low-to-medium concentrations. However, prolonged use of high concentration, especially in dark skinned people, appears to cause ochronosis relatively frequently. For example, a South African study reported that up to 69% of long-term users of high strength (6-8%) hydroquinone developed some degree of ochronosis. As a result of these concerns, hydroquinione has been banned or restricted in several countries.

Clearly, more research is needed to better evaluate the above risks and better define appropriate use of hydroquinone. On one hand, the fact that high-dose long-term hydroquinone may cause cancer in mice does not automatically indicate that humans receiving typical hydroquinone treatments are also at risk. Hydroquinone has been the most used skin lightener for decades. Any marked carcinogenicity would probably have been noticed. On the other hand, a small increase in cancer risk is much easier to overlook, especially in the absence of large scale, long-term studies focusing on the issue.

Until more safety studies are performed, the use of high strength hydroquinone formulations, especially long-term, may be unwise without compelling indications and close medical supervision. As of the time of this writing, there is no clear evidence of serious risks associated with typical short-term use of low-to-medium strength hydroquinone formulations. Still, it is important to follow further research developments in this area.

Arbutin

While some promoters hail arbutin as a completely novel skin-lightening agent, it is actually hydroquinone in disguise. Arbutin is glycosylated hydroquinone (b-D-glucopyranoside derivative of hydroquinone to be exact), i.e. its molecule consists of hydroquinone connected to glucose. It is believed to work by slowly releasing hydroquinone through hydrolysis, which, in turn, suppresses melanin synthesis by inhibiting the enzyme tyrosinase. Arbutin appears to have fewer side effects than hydroquinone at similar concentrations - presumably due to the more gradual release. The range of arbutin concentrations reported in the literature is 3-7%.

Arbutin clearly has some pigmentation reducing effect. Yet, it remains unclear how well it stacks up against hydroquinone and what the equivalent concentrations (in terms of effectiveness) of these two agents might me. Arbutin appears to be gentler than hydroquinone as far as typical side effects like skin irritation are concerned. However, it is unclear whether the concerns recently raised regarding hydroquinone (risk of ochronosis and possible cancer risk) may apply to arbutin as well.

Finally, due to patenting issues, many skin care companies use arbutin-containing plant extracts (such as bearberry, blueberry, cranberry and other extract) instead of pure arbutin. Whether such products contain sufficient amount of arbutin is unclear. Even if they do, it is unclear whether arbutin in plant extract is equipotent to standard arbitin. (For example, plant extracts may contain other substances interfering with absorption or activity of arbutin).

All in all, arbutin appears to be a promising hydroquinone alternative, but many uncertainties remain.

Kojic acid

Kojic acid is a naturally occurring substance produced by some species of fungi. Similarly to hydroquinone, it suppresses the production of melanin by inhibiting the enzyme tyrosinase. Kojic acid appears to be comparable in effectiveness to hydroquinone as a skin-lightening agent. However, kojic acid is relatively unstable in skin care formulations. It easily oxidizes on contact with air and also reacts with other chemicals if exposed to sunlight.

To bypass this problem, some skin care companies use kojic acid dipalmitate, a more stable derivative. It remains unclear whether kojic acid dipalmitate is equivalent or even close to kojic acid in effectiveness. Kojic acid dipalmitate needs to be studied head-to-head against kojic acid and/or hydroquinone.

Finally, some controversial research has raised the issue of carcinogenicity of kojic acid. A special cancer susceptible strain of mice developed liver tumors when fed large amounts of kojic acid for 26-weeks. The relevance of this finding to topical use in humans, if any, remains unclear.

Azelaic acid

Azelaic acid is a naturally occurring chemical belonging to the class of dicarboxylic acids. In skin care, it is most commonly used to treat acne. However, azelaic acid also reduces melanin production by inhibiting (largely indirectly) the enzyme tyrosinase. It also suppresses the proliferation of abnormal melanin producing cells (melanocytes), apparently by reducing the rate of DNA synthesis. Azelaic acid has been used to treat melasma, lentigo maligna and other hyperpigmentation problems. Topical azelaic acid has no or little depigmentation effect on normally pigmented skin, freckles, age spots (solar lentigines), and nevi. Apparently, azelaic acid is much more active against abnormal melanin synthesis and abnormal melanocytes.

In the US, azelaic acid (20%) is approved as acne treatment but is sometimes used off-label for hyperpigmentation. A 24-week study in South America found that a 20% concentration of azelaic acid was equivalent to 2% hydroquinone in the treatment of melasma. A study in the Philippines found that 20% azelaic acid was superior to 2% hydroquinone. Some individuals who develop irritation on hydroquinone may tolerate azelaic acid. Recent safety concerns regarding hydroquinone, whether substantiated or not, make azelaic acid a more attractive skin lightening alternative for melasma and some other hyperpigmentation disorders. However, as opposed to hydroquinone, azelaic acid is not very effective against freckles and age spots.

Glabridin (Licorice extract)

Glabridin, the main compound in the hydrophobic fraction of licorice extract, inhibits melanin production, apparently by inhibiting tyrosinase activity. It has been used as a skin-lightening agent in some parts of the world. It appears to have a good side effect profile. Unfortunately, as of the time of this writing, there are no clinical studies as to how glabridin compares to the more established skin lighteners or what its optimal concentrations may be.

Topical retinoids

Topical retinoids, such are tretinoin 0.05-0.1%, have been used in the treatment of melasma and other hyperpigmentation problems. When used alone, retinoids appear to be considerably less effective than hydroquinone and they may take up to six month or more to achieve visible results. Retinoids seem to reduce hyperpigmentation by accelerating epidermal exfoliation (sloughing off of epidermal cells), which leads to a greater loss of epidermal melanin. It has been suggested that retinoids may also reduce melanin synthesis by indirectly inhibiting tyrosinase, but this is not well supported by evidence. In fact, if retinoids were strong inhibitors of tyrosinase one would expect their lightening effects to be seen in weeks (similarly to hydroquinone) not months.

In patients who do not sufficiently respond to tyrosinase inhibitors like hydroquinone, adding tretinoin appears to improve effectiveness, possibly because their mechanisms of action are complementary. On the other hand, both retinoids and hydroquinone are potential irritants. Skin irritation, especially if intense and/or prolonged, may actually worsen pigmentation problems by causing to so-called postinflammatory hyperpigmentation. Hence the combination of retinoids and hydroquinone should be used with particular caution.

In some melasma treatment studies, researchers combined a retinoid (e.g. tretinoin or adapalene), hydroquinone and a corticosteroid (e.g. dexamethasone or fluocinolone acetonide). The role of a corticosteroid was to reduce the skin irritation. This triple combination appears to be highly effective as a melasma treatment. However, it should be considered only in refractory cases because corticosteroids may cause skin atrophy.

Alpha hydroxy acids

Alpha hydroxy acids used at typical OTC strengths (5-15%) are ineffective as hyperpigmentation treatment. However, exfoliation that AHA produce increases the turnover of epidermal cells causing more melanin to wash out of the skin. As a result, AHA may enhance the effectiveness of other treatments, such as hydroquinone or other tyrosinase inhibitors. High strength AHA peels applied by a physician may be somewhat effective in reducing skin discolorations.

Chemical peels and laser resurfacing

Skin resurfacing, whether with a laser or a chemical agent, may significantly reduce pigmented lesions. However, these treatments are rarely used to treat hyperpigmentation alone due to cost, inconvenience and side effects, including hypopigmentation and hyperpigmentation.

Nonablative laser and intense pulsed light

Melanin absorbs light predominantly in the green-yellow range. Hence high intensity directed light in that range may heat up and eliminate hyperpigmented lesions without too much damage to the surrounding skin. This approach is more for localized lesions such as age spots. The devices used to treat hyperpigmentation include Intense Pulsed Light (IPL) systems, pulsed dye lasers and others. These treatments are expensive and, while the effect on localized lesions may be quick and dramatic, the outcome is somewhat unpredictable (hypopigmentation or hyperpigmentation may develop).

Cryotherapy

Cryotherapy is useful only for small, well-localized hyperpigmented lesions, such as age spots. For such problems, cryotherapy (freezing off the lesion) is as effective as laser treatments but more reliable, less expensive and less likely to cause side effects.