Summary and Key Features
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Hyperpigmentation is a common skin problem that is particularly prevalent in middle-aged and elderly individuals and in individuals with darker skin complexion; its impact on appearance can detract from quality of life.
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Hydroquinone is only available through a prescription. It depigments skin by inhibiting tyrosinase activity, inhibiting DNA and RNA synthesis, and degrading melanosomes.
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Kojic acid is used in concentrations between 1% and 4% and is often more effective in combination with other ingredients, but it has been reported to have a high sensitizing potential and may cause irritant contact dermatitis.
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Soy induces interference with the PAR-2 pathway and has been shown to reduce dyspigmentation by reducing the phagocytosis of melanosomes by keratinocytes, thus reducing melanin transfer. Niacinamide also reduces skin pigmentation by inhibiting melanosome transfer.
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Tranexamic acid inhibits tyrosinase expression and modifies pigmentation by inhibiting ultraviolet-induced plasminogen activation, reducing inflammatory mediators.
See and .
Introduction
Hyperpigmentation is a common skin problem that is particularly prevalent in middle-aged and elderly individuals and in individuals with higher Fitzpatrick skin type. It is cosmetically important and can greatly detract from both appearance and quality of life, particularly in cultures where smooth and even skin is valued as a sign of health or in cultures that are beauty conscious. Environmental factors, particularly ultraviolet (UV) light exposure, are a common contributor in pigmentary abnormalities such as melasma, solar lentigines, and ephelides ( Fig. 12.1 ). Exposure to certain drugs and chemicals as well as the existence of certain disease states can result in hyperpigmentation ( Box 12.1 ). Postinflammatory hyperpigmented skin lesions may develop as a consequence of acne, trauma, or side effects from aesthetic procedures such as chemical peels or laser therapy for some patients.
Skin Diseases and Conditions
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Melasma
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Riehl’s melanosis
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Poikiloderma of Civatte
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Erythromelanosis follicularis
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Linea fusca
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Postinflammatory hyperpigmentation
Exogenous Causes
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Ultraviolet exposure (e.g., melasma, solar lentigines, ephelides)
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Photosensitizing agents (e.g., berloque dermatitis due to bergamot oil, furocoumarins)
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Drugs (e.g., estrogens, tetracyclines, amiodarone, phenytoin, phenothiazines, sulfonamides)
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Cosmetics
Other Causes
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Pregnancy
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Liver disease
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Addison’s disease
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Hemochromatosis
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Pituitary tumors
The treatment of acquired hyperpigmentation has traditionally been challenging, and the results are frequently discouraging. Many of the treatment agents can trigger skin irritation, require long-term regular use before results are apparent, or can be only partly effective. Insufficient compliance with therapy also limits effectiveness. Sun avoidance and the diligent use of broad-spectrum, high sun protection factor (SPF) sunscreen are mandatory for successful treatment.
Skin-Lightening Cosmeceuticals
Multiple depigmenting cosmeceuticals are currently available, although published clinical evidence to support their effectiveness is often lacking. These skin-lightening compounds work by acting at one or more steps in the pigmentation process, reducing pigment in the skin ( Box 12.2 ). Since tyrosinase is the rate-limiting enzyme for melanin biosynthesis, many of the cosmeceuticals for skin lightening exert their effect on this enzyme.
Before Melanin Synthesis
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Tyrosinase transcription:
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Tretinoin
During Melanin Synthesis
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Tyrosinase inhibition:
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Hydroquinone
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4-Hydroxyanisole
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4-S-Cystaminylphenol and derivatives
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Arbutin
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Aloesin
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Azelaic acid
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Kojic acid
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Resveratrol/oxyresveratrol
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Resorcinol derivatives
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Product reduction and ROS scavengers:
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Ascorbic acid and ascorbic acid derivatives
After Melanin Synthesis
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Tyrosinase degradation:
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Linoleic acid
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α-Linolenic acid
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Inhibition of melanosome transfer:
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Serine protease inhibitors
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Lectins and neoglycoproteins
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Soybean/milk extracts
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Niacinamide
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Skin turnover acceleration:
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Glycolic acid
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Lactic acid
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Linoleic acid
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Liquiritin
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Retinoic acid
Hydroquinone
For many years, the phenolic compound hydroquinone has been the most widely and successfully used skin-lightening agent for the treatment of melasma, postinflammatory hyperpigmentation, and other hyperpigmentation disorders ( Fig. 12.2 ). Hydroquinone occurs naturally in many plants as well as in coffee, tea, beer, and wine. Hydroquinone has demonstrated the efficacy of depigmenting skin through various mechanisms, such as inhibiting the conversion of tyrosine to melanin, suppressing tyrosinase activity, inhibiting DNA and RNA synthesis, and degrading melanosomes.
In the United States, hydroquinone was available over the counter (OTC) in strengths up to 2%. However, with the recent change in regulation, it is now available through prescription only, usually at 3–4%, but concentrations as high as 10% may be available through compounding pharmacies. Hydroquinone is also available in a combination with other agents. For the treatment of melasma, a prescription drug containing 4% hydroquinone, tretinoin, and a low-potency fluorinated steroid, fluocinolone acetonide, is effective and safe. Other combination products contain glycolic acid, vitamin C, and/or retinol, which function as penetration enhancers for the hydroquinone activity.
Common side effects of hydroquinone are skin irritation or contact dermatitis, which can be treated with topical steroids. A rare but serious side effect of hydroquinone is the development of exogenous ochronosis, a sooty hyperpigmentation in the treatment area that may be difficult to reverse. Exogenous ochronosis appears to be prevalent among individuals with a darker complexion when hydroquinone is used at high concentrations or for prolonged periods even at low concentrations.
These side effects are the reason hydroquinone is banned or highly restricted in several African countries, Europe, and many Asian countries. In the United States, hydroquinone is banned as an OTC depigmenting agent, and only one prescription drug containing hydroquinone is approved for use by the US Food and Drug Administration (FDA). As a result of the restrictions, alternative depigmenting agents are increasingly being used as monotherapy, in combination with other skin depigmenting agents, or in combination with hydroquinone under medical supervision. Alternating the use of hydroquinone with one of these alternative agents in 4-month cycles will help prevent side effects such as irritation as well as decreasing the risk of exogenous ochronosis.
Tranexamic Acid
Tranexamic acid (TXA) is derived from the amino acid lysine, and it functions as a plasmin inhibitor used to reduce bleeding. Effectiveness of TXA in melasma was first reported in Japan in 1979, and increasingly more products with TXA have become available to treat melasma and hyperpigmentation. The exact mechanism of action is not well understood. TXA effectively suppresses ultraviolet (UV)-induced erythema and pigmentation by inhibiting UV-induced plasminogen activation, thereby decreasing inflammatory mediators. Additionally, TXA inhibits the expression of tyrosinase through suppression of a melanogenesis regulator known as microphthalmia-associated transcription factor (MITF).
TXA is available through a prescription to take orally to treat bleeding. Although clinical studies demonstrate efficacy in treating melasma, it is currently off-label use. For topical products, TXA is used between 1% and 5% and is often combined with other cosmeceutical ingredients, such as niacinamide and kojic acid.
Resorcinol and Derivatives
Resorcinol is used to treat skin conditions such as acne, calluses, and warts. However, it is a skin irritant and sensitizer, and percutaneous absorption can have systemic effects, especially in the central nervous system. Due to its effectiveness, resorcinol derivatives are developed to overcome the negative impacts of resorcinol, and there are several resorcinol derivatives found in skin lightening products. Examples are 4-n-butyl resorcinol (rucinol), hexylresorcinol, phenylethyl resorcinol, and isobutylamido thiazolyl resorcinol. These resorcinol derivatives are potent inhibitors of tyrosinase activity, leading to suppression of melanin production in skin. In a clinical study for melasma, a topical product with 0.3% rucinol was compared to a vehicle control. After 12 weeks, the rucinol treatment resulted in a significant reduction in skin pigmentation over the placebo treatment, with good tolerance of the products.
Natural Cosmeceuticals for Dyspigmentation
Increasing interest in the use of natural ingredients, as well as the need to find an alternative to hydroquinone, has led to research on a variety of dyspigmentation treatment cosmeceuticals derived from natural ingredients ( Box 12.3 ).
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