Treatment of Hyperpigmentation Heather Woolery-Lloyd, MD,*,† and Jenna N. Kammer, BA‡ Hyperpigmentation is a common dermatologic condition that is seen in all skin types but is most prominent in skin of color. In skin of color, any inflammation or injury to skin can almost immediately be accompanied by alterations in pigmentation, either hyperpigmen- tation or hypopigmentation. Post-inflammatory hyperpigmentation can be observed in many skin conditions including acne, eczema, and contact dermatitis and treatment can be challenging. The goal is to reduce the hyperpigmentation without causing undesirable hypopigmentation or irritation in the surrounding area. This review will discuss current research on treatments for hyperpigmentation and approaches to treating this condition. Semin Cutan Med Surg 30:171-175 © 2011 Elsevier Inc. All rights reserved. KEYWORDS hyperpigmentation, hydroquinone, dyschromia, ochronosis, melasma yperpigmentation is a common dermatologic condition none is available over-the-counter in the United States and Hthat is found in all skin types but is most prominent in Canada. Four percent hydroquinone is available by prescrip- skin of color. Any inflammation or injury to the skin can tion.3 The Kligman formula combines hydroquinone with a almost immediately be accompanied by alterations in pig- retinoid and a steroid, which enhances efficacy.3 mentation, either hyperpigmentation or hypopigmentation. A common side effect when one uses hydroquinone to Postinflammatory hyperpigmentation appears in many skin treat dyschromia attributable to acne is the “hydroquinone conditions, including acne, eczema, and contact dermatitis, halo.” This occurrence is characterized by a halo of hypopig- and treatment can be challenging. The goal is to reduce the mentation surrounding the dark macule attributable to the hyperpigmentation without causing undesirable hypopig- bleaching of the surrounding normal skin. This is frequently mentation or irritation in the surrounding area. observed when patients apply hydroquinone with their fin- A variety of topical agents are available to treat hyperpig- gertips to small macules. More common side effects with mentation. These topical agents can interfere with the pig- hydroquinone include irritation and erythema. When pre- mentation process at several different levels. The gold stan- scribing hydroquinone, one should warn patients of possible dard for treatment is a hydroxyphenolic chemical called irritation and recommend that patients discontinue the treat- hydroquinone. Hydroquinone acts by inhibiting the conver- ment if any significant redness or inflammation occurs. Irri- sion of dihydroxyphenylalanine to melanin by inhibiting the tation from hydroquinone is frequently caused by the hydro- activity of tyrosinase.1 Other mechanisms of action include quinone itself or by sodium metabisulfite, a common interfering with DNA and RNA synthesis, degrading melano- preservative in hydroquinone preparations.4 Continued use somes, and destroying melanocytes.2 Two percent hydroqui- of hydroquinone when irritation is present may lead to postinflammatory hyperpigmentation. *Department of Ethnic Skin Care, University of Miami Cosmetic Medicine A rare side effect of hydroquinone is exogenous ochronosis, and Research Institute, Miami Beach, FL. which is paradoxical darkening of the skin. It usually begins †University of Miami Department of Dermatology and Cutaneous Surgery, with erythema followed by blue-black patches on the face where Miami, FL. the hydroquinone was applied. In severe cases, blue-black ma- ‡Drexel University College of Medicine, Philadelphia, PA. cules can progress to papules and nodules on sun-exposed areas Conflict of Interest Disclosures: Both authors have completed and submitted 5 the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr after long-term usage of hydroquinone. It may be triggered Woolery-Lloyd is a shareholder in Sanabella LLC; has been an investi- from inhibition of homogentisic acid oxidase locally by hydro- gator for Johnson & Johnson, Allergan, Loreal and Galderma; and has quinone. This rare side effect was common in South Africa, received payment for service on speakers’ bureaus and serving on the where long-term hydroquinone use was widespread. In the Advisory Boards from Johnson & Johnson and Allergan. Dr Kammer has United States, ochronosis is less common; approximately 30 nothing to disclose. 3 Address reprint requests to Heather Woolery-Lloyd, MD, University of Mi- cases have been reported in North America, and typically it ami Department of Dermatology and Cutaneous Surgery, 1295 NW 14th occurs with long-term continued use of hydroquinone over de- Street, Suite K, Miami, FL 33136. E-mail: [email protected] cades. This risk may be reduced with sunscreen because the 1085-5629/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. 171 doi:10.1016/j.sder.2011.06.004 172 H. Woolery-Lloyd and J.N. Kammer pattern of ochronosis clinically is photodistributed. Long-term Blinded Clinical Trials continued use of hydroquinone should be avoided. For patients with chronic conditions, such as melasma, hy- Dioic Acid droquinone should be switched to an alternative therapy after a A recent blinded study enrolled 96 Mexican female patients few months or once significant improvement is achieved. There with melasma; one-half of the patients received 1% dioic are many alternative agents, and until recently, there were few acid, and the other half received 2% hydroquinone cream.14 in vivo trials in which authors examined alternatives to hy- There was a significant improvement in the Melasma Area droquinone to support claims of efficacy. This article will Severity Index scores from baseline to the end of the study review alternatives to hydroquinone and will focus on evi- when dioic acid or hydroquinone were used; however, there denced-based data to support their usage. was no significant difference between the two treatments. In addition, the side effects were similar with both, except pru- ritus was more common in patients using hydroquinone. Animal, In Vitro, and Open Soy Label Studies Soy interferes with melanin transfer by inhibiting the pro- Linoleic Acid tein-activated receptor 2 (PAR-2) pathway. PAR-2 is a G pro- tein-coupled receptor that controls the ingestion of melano- Inhibitors of tyrosinase are believed to suppress melanogen- somes by keratinocytes.15 Two soybean-derived proteins, esis and have led to the development of products that use namely soybean trypsin inhibitor and the Bowman-Birk in- 6,7 these skin-lightening agents. Liposome-encapsulated lino- hibitor, interfere with melanosome transfer by inhibiting the leic acid has demonstrated a whitening effect in ultraviolet PAR-2 activation. The lightening activity of these agents and 8 (UV)-stimulated hyperpigmented human upper arm skin. their ability to prevent UV-induced pigmentation suggests In animal studies, investigators evaluated the lightening ef- that inhibition of the PAR-2 pathway by soybean extracts fects of unsaturated fatty acids on ultraviolet B (UVB)-in- may be used as a natural alternative to skin lightening.16 In a duced pigmentation of dorsal brown guinea pig skin. All blinded controlled 12-week study, authors evaluated the ef- families of unsaturated fatty acids examined inhibited mela- ficacy of a soy moisturizer containing soybean trypsin inhib- nin production and tyrosinase activity. Interestingly, linoleic itor and Bowman-Birk Inhibitor on 65 women with moderate acid was most effective in lightening UVB-induced hyperpig- facial photodamage. There was significant improvement in mentation in vivo, whereas ␣-linolenic acid was most effec- mottled pigmentation, blotchiness, dullness, fine lines, over- tive in inhibiting melanin production in vitro.9 all texture, and overall skin tone.17 Rucinol Ellagic Acid and Arbutin In a prospective, single-center, double-blind, randomized, Ellagic acid (EA), an antioxidant, inhibits skin pigmentation vehicle-controlled, bilateral (split-face) comparative trial, 32 resulting from UV irradiation. The results of in vitro experi- women with melasma were provided with two identical ments indicate that EA suppresses melanogenesis by inhibit- tubes containing rucinol serum 0.3% or vehicle.18 Rucinol ing tyrosinase activity. In one study of 30 subjects with serum demonstrated significant improvement in melasma melasma authors compared the effects EA, synthetic EA, and when compared with the vehicle control after three months arbutin10 and demonstrated a statistically significant reduc- of treatment. tion in Mexameter (CK Electronic, Ramstein, Germany) read- ings in all three groups. Licorice Two licorice extracts, glabridin and liquiritin, have demon- Acerola Fruit Extract strated topical lightening effects. Glabridin is the main active ingredient in licorice extract derived from Glycyrrhiza glabra and Acerola fruit extract, another tyrosinase inhibitor, has been appears to exert its anti-inflammatory effect via inhibition of shown to lighten UVB-induced skin pigmentation in brown superoxide anion production and cyclooxygenase activity. In guinea pig skin.11 one in vitro study, authors investigated the inhibitory effects of glabridin on melanogenesis and inflammation by using cultured Methimazole B-16 murine melanoma cells and guinea-pig skin and found that glabridin inhibits tyrosinase activity in these cells but had Methimazole (1-methyl-2-mercaptoimidazole; MMI) is an no effect on DNA synthesis.19 oral antithyroid medication that clinically causes