A New Approach to Treating Hyperpigmentation
by Diana L. Howard Ph.D.
Vice President Technical Development, The International Dermal Institute
Reprinted from Les Nouvelles Esthetiques (Sept. 2002), published in the United States.

In the past five years skin lightening and brightening products have become increasingly popular throughout the world. While traditionally these products were popular in Asian-Pacific and African communities the current market trend finds them increasing in popularity across the globe. As technology in skin care soars to new heights, and the global population continues to age, this category of skincare products will undoubtedly flourish with increasing demand by consumers. Perhaps this is just another indication of what happens to an aging population as their skin finally shows years of sun damage while under the influence of fluctuating hormones. As professional skin therapists, our focus should not only be on what effectively lightens or brightens skin, but more importantly, factors such as safety and mildness must be crucial considerations when exploring options. At The International Derrmal Institute we have not only studied the newest technology for the treatment of hyper-pigmentation but have updated our understanding of its underlying causes.

What determines skin color?
Skin color is mainly determined by the amount of melanin present in the skin. Melanin, a brown or reddish form of pigment, is synthesized in octopus shaped, dendritic cells called melanocytes and is bound to a protein matrix to form the melanosome. After the melanosome is produced in the melanocyte, it is transferred to a keratinocyte cell where it begins it s journey through the different layers of epidermis while giving skin its visible color.

Regardless of skin color, the number of melanocytes does not vary among humans. There is approximately one melanocyte for every thirty-six keratinocytes found in the epidermis. The amount of melanin, the type of melanin produced (whether it is eumelanin, a brownish-black or phaeomelanin, a yellowish-red pigment), the size of the melanosomes and the distribution of melanosomes in the epidermis all contribute to the skin's color and intensity-light vs. dark. In black skin, we not only see larger melanosomes with more melanin present, but more of them. They are seen as larger, individual, jelly bean-like structures surrounded by a membrane, where as melanosomes in Caucasian, Asian and Hispanic skin, are smaller, vary in size and shape, with many melanosomes clustered in a single membrane jacket.

While the amount of melanin synthesized in our skin is determined by genetics, there is also an over-riding effect of the environment, such as exposure to UV radiation, that determines skin pigmentation levels. Due to its ability to absorb UV light, the primary function of melanin is believed to be to protect the skin from sunlight. Not only does skin tan in response to exposure to sunlight as a result of synthesis of melanin , studies have shown that melanosomes actually cluster, forming a protective cap over the nucleus of the cell when incident sunlight is detected. In addition to the development of an overall tan, exposure to UV light may also stimulate hyperpigmentation in specific areas such as the hands, face and neck. These dark spots are often referred to as age spots or liver spots and are a nuisance for fair skinned and darker complexions as well. Age spots usually become evident in our early forties and become increasingly more evident as we age. Unfortunately, we do not fully understand why melanocytes start producing melanin in an erratic pattern as we age. On a more positive note, sun induced hyperpigmentation appears to be the easiest form of pigmentation to effect with topically applied skin lighteners or brighteners.

Because light colored skin has less melanosomes, less melanin and lower levels of eumelanin than darker skin, there is less protection against exposure to UV radiation. Likewise, in individuals with lighter skin, the majority of the melanin is confined to the lower layers of the epidermis; in darker skin, the melanin is evident throughout the layers of the epidermis. The darker the skin, the greater the incidence of melanin in the outermost layers of the stratum corneum. It is believed that the enzymatic process whereby the usual protein/melanin complex is broken down as it transits through the epidermis during keratinization is not as active in dark skin. This is most likely part of the protective role that melanin plays in the skin. While it stands to reason that darker skin would be easier to treat, due to the melanin being closer to the surface of the skin, the overall abundance of melanin in dark skin actually makes it more difficult to treat. Do not think for one minute that dark skin with its preponderance of melanin is exempt from the ravages of UV exposure. It may be better equipped to protect itself but it is still vulnerable to sun induced hyperpigmentation as well as post inflammatory hyperpigmentation, and photodamage.

In addition to genetics and environmental influences, skin pigmentation is effected by endocrine or hormonal factors, usage of prescription drugs, stress, topically applied products including cosmetics, and wound healing to the skin tissue. The latter incidence gives rise to post-inflammatory hyperpigmentation (PIH), a phenomenon that is more problematic for individuals with darker skin color. PIH stems from the melanocytes exaggerated response to cutaneous insult, which results in an increased or abnormal distribution of melanin in the tissues. Interestingly, melanocyte activity is stimulated by the same inflammatory mediators that are activated when the skin’s immune response is activated. What effects the skin’s Langerhans cells, generally will stimulate the melanocytes, and vice versa. When inflammation subsides, the inflammatory mediators revert to normal levels and so does the production of melanin. In due course the cells causing hyperpigmentation rise to the stratum corneum and slough-off causing the hyper-pigmentation to disappear. Recent studies have shown however, that depending on the depth of the inflammation or wound, hyper-pigmentation can not only be evident in epidermal cells but in the dermis as well. This may very well account for the difficulty in treating post inflammatory pigmentation associated with deeper scar tissue.

Hormonally induced pigmentation manifests itself in various forms, such as hyperpigmentation spots and melasma, better known as the mask of pregnancy. It is believed that both estrogen and progesterone influence melanocyte activity, driving the production of melanin. When compared to melanocyte activity that is stimulated by sun exposure, hormonally induced melanocytes are considered to be hyperactive. Hormonally induced melanin may be confined to the epidermis but it may also be found in the dermis making treatment especially difficult. Once hormonal fluctuations subside, such as the end of pregnancy or discontinuance of hormone supplements, the hyperpigmentation gradually disappears.

How is melanin made?
In order to understand how we can effectively treat hyper-pigmentation we need to review how melanin is made in the skin.
The production of pigment within the melanocyte is a multi-step process. The first step is mediated by the enzyme, Tyrosinase, and it involves the conversion of the amino acid Tyrosine to L-DOPA. In the second step, L-DOPA is converted to Dopaquinone, a dihydroxybenzene derivative; this step is also mediated by the Tyrosinase enzyme but it now requires copper as an enzyme co-factor. Once Dopaquinone is made, the biosynthetic pathway splits and several subsequent reactions lead to either eumelanin, the brown and black melanin, or phaeomelanin, the yellow and red melanin pigments. Scientists are continually studying this biosynthetic pathway in an effort to better understand and control the process of melanin formation.

How can we control hyperpigmentation?
The most obvious means of controlling pigmentation, especially sun induced, would be to apply a broad-spectrum sunscreen with a minimum SPF of 15 regularly. This will help control future pigmentation.

But what about existing hyperpigmentation ? For years Hydroquinone has been considered to be the most effective ingredient for lightening hyperpigmentation. It is classified as an over-the-counter-drug in the USA and may be used in concentrations up to 2%. There are various theories on how hydroquinone works to effect hyperpigmentation; some researchers claim that it denatures the melanin-protein complex thereby, causing a decoloration of skin. Others claim it inhibits the Tyrosinase enzyme, while some claim it inhibits the synthesis of the protein associated with the melanin. While hydroquinone may be an effective pigment lightener, there are many concerns regarding its safety. It has been estimated that one third of the population is allergic to hydroquinone. Serious contact dermatitis has been noted and skin may be photosensitized with prolonged use. Hydroquinone has been classified as "an extreme sensitizer". In some cases, a condition known as onchronosis can result, leading to actual hyperpigmentation and acne-like lesions. Others report that hypopigmentation results when used on an olive skin color. The Occupational Safety and Health Administration in the USA states that hydroquinone is, “mutagenic and has cancer causing potential”. The Addendum to the Final Report on the Safety Assessment of Hydroquinone published in the Journal of the American College of Toxicology in 1994 concludes that hydroquinone is a potent cytotoxic agent that causes mutations and alterations to DNA and that it should not be used in any leave-on type of product; it is safe for rinse-off products when used in concentrations less than 1%. Remember, most OTC products marketed to lighten pigmentation use hydroquinone at a 2% concentration. Bearing in mind the results of these studies, it should really come as no surprise that the use of hydroquinone has been banned in many countries throughout the world.

Hydroquinone is the only ingredient recognized as a lightening agent by the US FDA . Consequently, any other ingredient used to lighten skin must be referred to as a brightening agent and not a lightener. In the past few years as hydroquinone has fallen out of favor and even banned in most of the world, there has been an onslaught of alternative brightening agents that are now marketed to combat hyperpigmentation.

Are there safe alternatives to hydroquinone?
At The International Dermal Institute, our scientists have studied the various mechanisms that are known to impact melanin formation. We know that we can control the process by influencing various steps along the pathway. Perhaps the best-studied step involves that of the Tyrosinase enzyme. For years, scientists have been looking for ways to regulate this enzyme and therefore, slow melanin formation. One can regulate Tyrosinase by either slowing down its activity or competing for its substrates, either Tyrosine in step one (see figure 1) or L-DOPA in step two. An example of a mechanism that controls Tyrosinase activity would be the use of rice extract-- the phytic acid found in rice, binds the copper metal ion slowing down step two of the Tyrosinase mediated reaction. Kojic acid, Aspergillus (a fungus) ferment, Rumex extract and ergothioneine (a plant amino acid) are other examples of Tyrosinase inhibitors that chelate or bind copper. There are many other botanical extracts that have been studied for their ability to inhibit Tyrosinase. These include: Sophora angustifolia, Kiwi fruit, Nasturtium, Rumex (Yellow Dock), Phyllanthus emblica fruit, Mulberry, Ascorbic acid, Bearberry and Licorice.

One may also use competing substrates that literally compete for the active site on the Tyrosinase enzyme. Many of the plant based extracts that contain a dihydroxybenzene derivative compete with L-DOPA for the site on the enzyme thus, slowing melanin production. Examples of botanical extracts that compete for the substrate site include: Bearberry, Mulberry, Licorice, Mulberry, and ascorbic acid (vitamin C). Studies have been conducted looking at the flavonoid components of these plants and their similarity in chemical structure to L-DOPA. These flavonoids are dihydroxybenzene derivatives, which are thought to compete with the substrate in either of the tyrosinase mediated steps. Many of these botanical extracts may in fact work on two fronts--not only do they inhibit the Tyrosinase enzyme but they compete with the enzyme’s substrate as well.

Figure 1: Initial steps in melanin biosynthesis
A different approach to controlling pigmentation is illustrated with the use of yeast extract, which has been studied for its ability to shunt melanogenesis toward the lighter phaeomelanins. This gives the perception of a lighter pigmentation although actual production of melanin is really not turned off.

More recently it has been discovered that a 5% concentration of the alpha hydroxy acid, lactic acid, will inhibit the formation of the Tyrosinase enzyme, thereby slowing the process of melanin synthesis. This new approach to effecting melanin synthesis is unique to lactic acid and does not occur with other alpha hydroxy acids such as glycolic acid.
Kojic acid at up to 1% concentrations has also been used to treat hyperpigmentation; its ability to bind the copper metal and inhibit tyrosinase enzyme accounts for its effectiveness. However, best results are obtained in an anhydrous base (no water) which is not generally how it is marketed. Recent studies on kojic acid show that topical application may induce contact dermatitis and that it has a high sensitizing potential.

And finally, another means to control hyper-pigmentation is to control inflammation. The use of anti-inflammatory agents such as licorice, Green Tea and Mulberry, will help address the connection between inflammation and pigment formation.

Table: Ingredients used to treat Hyperpigmentation

Ingredient or plant extract:	What it does:
Sophora angustifolia root	Anti-inflammatory; inhibits Tyrosinase
Actinidia chinensis (kiwi) fruit	Inhibits Tyrosinase
Nasturtium officinale	Inhibits Tyrosinase
Rumex crispus (Yellow Dock)	Inhibits Tyrosinase
Phyllanthus emblica fruit	Inhibits Tyrosinase
Morus alba root (Mulberry)	Inhibits Tyrosinase; anti-inflammatory
Ascorbic acid; or Sodium Ascorbyl Phosphate; or Magnesium Ascorbyl Phosphate	Inhibits Tyrosinase; acts as a reducing agent on intermediates
Lactic acid	Suppresses formation of Tyrosinase enzyme
Glycyrrhiza glabra (Licorice)	Anti-inflammatory; Inhibits Tyrosinase
Arctostaphylos uva ursi (Bearberry)	Inhibits Tyrosinase;
Aspergillus ferment (fungus)	Inhibits Tyrosinase (binds copper)
Oryza sativa (rice)	Inhibits Tyrosinase (binds copper)
Citrus grandis (Grapefruit)	Inhibits Tyrosinase
Mitracarpus scaber	Inhibits Tyrosinase; reducing agent
Kojic acid	Inhibits Tyrosinase (binds copper)

A word to the wise
My first consideration in selecting which type of product I would use on my client has to be first for their safety, then for the effectiveness of the product. Regardless of which brightening agents one selects for treating hyperpigmentation the key thing to remember is that you must consistently use the product every morning and night for at least eight weeks before you will detect an improvement. Even if you could shut down all new melanin biosynthesis in the skin, remember it still takes about forty-five days for the existing melanin to naturally sloughed off. At the same time you are treating existing pigmentation you must use a minimum SPF 15 on the skin whenever outdoors. Too often, someone is religious about application of his or her pigment lightener/brightener products but then they forget to apply a sunscreen and within 24 hours the hyperpigmentation spots reappear.
Remember also, the depth of the pigmentation will dictate the degree of effectiveness when treating hyperpigmentation. Dermal pigmentation is obviously more difficult to treat than epidermal pigment. For obvious reasons, hormonally induced pigmentation and deeper post-inflammatory hyperpigmentation are often more difficult to treat than sun induced pigmentation. And remember, you and your client should have realistic expectations as to the degree of lightening that you will achieve. It is highly unlikely that you will make a spot disappear but you can reduce its intensity and help to even-out the overall pigmentation of the skin. Not all hyperpigmentation spots will respond favorably--if 75% of your clients get significant lightening to hyperpigmentation that is considered a very good result.

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