Disorders related to melanin, the pigment responsible for most of the color of our skin, are one of the major reasons people seek aesthetician or dermatologist care. This article will help the skin care professional identify specific types of pigmentation disorders, review common treatments for pigmentation and compare common cosmetic ingredients that are used to help minimize the appearance of irregular pigmentation.

The Pigmentation Process
Like blemishes that take a few weeks before they become visible on the skin, irregular pigment that appears on the skin surface has to undergo a complex, multi-step process before you can perceptibly see the lesion [Figure 1]. In fact, sun exposure damage can take many years to become visibly apparent in the skin. Consider an 18-year-old with very little visible pigmentation other than tanned skin, and fast forward 17 years when she finally comes in to take care of all the “sun spots” she starts to see at age 35.
A study conducted by the U.S. Food and Drug Administration in 2003 states that we actually only receive 25 percent of our lifetime sun exposure by age 18.1 Because the body is still developing, the cells in children are programmed to produce visible damage and skin cancer five to 50 years later. In adult years our skin becomes progressively less able to protect itself, and coupled with the additional years of exposure dooms humans to extrinsic aging.
Pigment synthesis occurs in 14 separate steps. Three occur outside the melanocyte, while the remaining eleven steps happen within the melanocyte. Topical product application can pharmacologically affect 10 of these steps, while the remaining steps happen so quickly they are not impacted by our current externally applied technology. The process happens like this:

1. Activation of inflammation sends a message to epidermal cells to release endothelin and pre-formed α-MSH.
2. Endothelin then increases the transfer of melanosomes to keratinocytes and increases the production of α-MSH. Hormones will increase production of α-MSH by activating the pituitary gland to make more α-MSH.
3. α-MSH begins activating the synthetic cascade of tyrosinase by binding to a melanocyte receptor.
4. The enzymes of the tyrosinase synthetic pathway are upregulated.
5. Tyrosinase activates the binding of tyrosine to copper.
6. The tyrosine/copper complex oxidizes to DOPA.
7. DOPA becomes DOPAquinone.
8. DOPAquinone is enzymatically processed into two types of melanin: Pheomelanin and eumelanin.
9. Melanosomes transfer into keratinocytes via octopus-like tentacles (dendrites from the melanocyte), creating darker color in the skin.
10. The pigment continues upward to the stratum corneum via epidermal basal cell turnover and epidermal cell migration/maturation for desquamation.

Intrinsic (internal, unavoidable) processes activate hyperpigmentation, as with hormones and certain diseases. Extrinsic (environmental, preventable) causes are frequently associated with an inflammatory response in the skin. These factors include ultra violet light exposure, a disrupted skin barrier from any cause including chemicals in skin care products, and other insults that create harmful chronic inflammation in the skin. These chronic inflammatory factors combined with a compromised, unhealthy skin barrier will trigger the abnormal process of irregular, or mottled, hyperpigmentation, as seen in photoaging and diseases such as lupus erythematosus.

Common Disorders and Treatments

Types of Hyperpigmentation
Determining the depth of pigmentation improves diagnosis and treatment planning. A Wood’s Lamp evaluation of skin shows increased color contrast compared to normal skin color for purely epidermal pigmentation. Less contrast indicates deeper, or dermal, pigmentation, which translates to more difficult and
longer treatment.
Lentigos result from local accumulation of melanocytes and are commonly found on the face, neck, upper trunk, dorsal arms and hands. Although not related to any specific internal disease, they are sometimes referred to as “liver spots,” along with thick, scaly seborrheic keratoses. These hyperpigmented macules are evenly colored and usually over 0.5 cm in size. Treatments include the prescription and non-prescription topical medications used to treat other forms of hyperpigmentation as discussed in detail later. Also effective are destructive liquid nitrogen, intense pulsed light (IPL) or chemical peel series.
Ephelides, or freckles, are sharply defined tan to light brown flat macules that tend to increase in color when exposed to sunlight. Ephelides are usually less than 0.5 cm in diameter and are found on the face, arms and upper trunk. Ephelides show increased amount of basal cell melanin. Treatments include those that were mentioned for lentigos.
Poikiloderma of Civatte (PC) appears as mild hyperpigmentation in a horse-shoe pattern on the sides of the neck and under the chin, sometimes on the décolleté area, and rarely on the arms. The word poikiloderma gets its meaning from the combination of small telangiectasias, skin atrophy and irregular pigmentation (hypo- and hyperpigmentation).2 Tolerable treatments are often difficult, so look for therapies that do not aggravate inflammation in the skin while still providing lightening properties. Best results for treatment include chemical peel series, IPL, and long-wave LED to help calm the inflammation. Pulsed dye laser performed in a physician’s office is also promising.3
Mottled Hyperpigmentation and Dyschromia is characteristic of photoaging and marked by surface spots or blotches of different colors or shades. The word “dyschromia” describes an abnormal discoloration of the skin, and includes mottled hyperpigmentation and diffuse darkening with aging in higher Fitzpatrick types. Dyschromia can also be confused with melasma. Treatments for both include those
discussed above.
Hormonal Associated Melasma and Chloasma – Chloasma, also known as the “mask of pregnancy,” is melasma that appears during pregnancy and lactation. Melasma also occurs post-pregnancy, when taking certain forms of birth control pills, and during perimenopause, especially when estrogens are ingested. The appearance of both is the same: A stain-like pattern on the cheeks, forehead, jaw line, chin and/or upper lip. The spots almost have a symmetrical look; if you see a splotchy, distinct pattern on one side of the face, you will see it on the other side as well [Figure 2]. The best way to treat melasma/chloasma is with gentle prescription or OTC topicals. Light microdermabrasion or non-aggressive chemical peels may also be used, but the trick is to keep treatments as non-aggressive as possible, to avoid causing any further inflammatory response in the skin, resulting in deeper, more difficult to treat post-inflammatory type. IPL or laser treatments are not recommended, since heat, not just sun exposure, can aggravate this type of hyperpigmentation. Oral Pycnogenol® (pine bark extract) at 300 mg daily and Heliocare® (golden fern extract) three times daily are very helpful in treating and prevention.
Post Inflammatory (PIH) – Darker Fitzpatrick types, IV and higher, have a particularly high tendency to experience hyperpigmentation after any sort of skin lesion has healed. Fortunately, when acute onset within weeks of a procedure, this type of pigmentation abnormality does not occur deep enough to damage melanocytes, and will improve gradually over time, especially with treatment. It is always a good plan to prepare your client with a skin brightening regimen four to six weeks before and after undergoing any type of procedure that may cause a post-inflammatory reaction, such as skin resurfacing (whether mechanical, chemical or laser) or any type of surgical procedure.4
Erythema Ab Igne is a heat-induced condition, clinically similar to Poikiloderma of Civatte, except there is underlying firmness or sclerosis. It usually occurs on the lower back and lower legs in response to chronic heating devices. Treatment is to avoid heat, as well as using the treatments recommended for PC, plus a high potency prescription corticosteroid (fluocinonide).
Medications or other ingested elements can cause unwanted pigmentation. The most common prescription medicines inducing hyperpigmentation include minocycline, antimalarials (hydroxychloroquine) and amiodarone. Therapeutic results are poor and there is little spontaneous resolution with the drug-in-
duced type.
Natural Tonics - Many people are ingesting natural tonics – containing minerals such as silver, iron, bismuth and gold. These can be deposited into the skin, producing abnormal coloration.

The absolutely most crucial part of treating any pigmentation disorder is to include daily application of at least SPF 30 broad-spectrum sunscreen, containing anti-inflammatory and antioxidant properties, along with using cosmeceutical products that help to repair skin barrier strength and calm chronic inflammatory effects. Oral photoprotection ingredients can be added to the daily regimen including black tea, berries, cocoa, coffeeberry, feverfew, ginseng, grape seed, milk thistle, oat, olive, peanut, pomegranate, soy, tamarind, tomato, white sandalwood and wine.5

Current Treatment Philosophies and Side Effects
When you consider how long it took for spots to become visible in your skin (remember our 18-year-old mentioned above), resolution of unwanted pigmentation requires diligent adherence to home care and/or clinical regimens, and lots of patience. Unfortunately, there is no quick fix for long term remission.
Most cosmeceutical products on the market today focus on tyrosinase inhibition, or destruction of pigment cells. Over 100 ingredients have demonstrated tyrosinase inhibition in a test tube (in-vitro), while 37 have been reported to affect living human skin (in-vivo). This methodology does work to some degree, but there are flaws to this technique.
For example, ingredients that affect the pigmentation processes happening within the melanocyte often penetrate poorly through the skin barrier, and must be delivered via methods that harshly break open the skin barrier (which can trigger an inflammatory response and ultimately induce more pigmentation). Hydroquinone is being formulated with botanically-derived ingredients to improve tyrosinase inhibition, but many of these botanical ingredients are known to be irritating (another inflammatory trigger). Some formulas have also incorporated antioxidants and corticosteroids to help reduce inflammation and increase efficacy of these formulas, but it has only had a mild impact on these effects. Tyrosinase inhibiting or pigment destroying formulas are only able to affect up to three of the steps within the hyperpigmentation induction process. More important, patients who suffer from negative side effects such as redness, irritation and thinning of the skin are forced to stop using these types of products, which minimizes the chance of successful treatment. In the last three years, 11 products have been published to have efficacy in topically treating one or more types of hyperpigmentation. All but one product incorporated hydroquinone into its formulation.
Tretinoin, hydroquinone, kojic acid and arbutin are common active ingredients that are used in skin lightening formulas – however they are known to damage the skin barrier and are pro-inflammatory. Consider, that in 2006 the FDA proposed banning the use of over-the-counter hydroquinone here in the U.S., due to unfortunate side effects.6 Hydroquinone has been banned in the EU, Canada (in skin care products), Japan, South Africa and Australia due to safety concerns of increasing risk of skin cancer and activating dermatitis, as well as the irreversible side effects of ochronosis, a bluish-black pigmentation.
What are the alternatives to hydroquinone? The key to stopping irregular pigmentation lies in using cosmeceutical products that stop more than one or two of the hyperpigmentation steps, while at the same time build barrier strength without creating ancillary inflammation response. There are a number of ingredients on the market that show promising in-vivo data for diminishing the appearance of unwanted pigmentation, including ascorbic acid, arbutin, kojic acid, soy, trypsin inhibitor, Soy Bowman Birk inhibitor, aloesin, 4-butylresorcinol (rucinol), N-acetylglucosamine, niacinamide + retinylpalmitate, linoleic acid, bearberry, paper mulberry, licorice, white water lily (nymphaea alba flower extract), lactic acid, phenylethyl resorcinol and undecylenoyl phenylalanine.
Other ingredients were tested in-vitro; however it is important to state that less than 1 percent of positive test tube results translate into positive clinical study results when mixed into a finished formulation to apply on human skin. These include coffeeberry, coriander, pomegranate, Zn-2-glycoprotein, emblicanin, gentistic acid, ellagic acid, blueberry and cranberry.7 Many of these have been added to products that are commercially available and claim benefit even though a human clinical trial was not performed with the marketed product.

Clinical Study Data
Do we know if looking at the whole hyperpigmentation process while reducing inflammation and barrier damage is actually effective for the most difficult types of hyperpigmentation?
A blinded human clinical trial of 12-weeks with six week regression study of a novel topical treatment was released in 2010 by Stephens and Associates of Colorado Springs, Colo. They tested a non-prescription herbal formulation against a regimen which included prescription tretinoin 0.05 percent combined with hydroquinone 4 percent on 45 panelists. At the end of 12 weeks, panelists reported that erythema had increased 66.6 percent with the prescription system verses only 21 percent with the herbal regimen, and scaling and dryness were worsened by 200 percent with the prescription regimen, but 100 percent improved with the herbal regimen.
Efficacy results with the non-prescription formula included a 37.6 percent improvement in whole face lentigines, 43.6 percent with melasma, 30.3 percent with mottled hyperpigmentation and dyschromia at 37.5 percent verses the prescription regimen: Lentigines improved by 37.5, melasma improved by 36.7, mottled hyperpigmentation improved by 39.2 and dyschromia by 38.6 percent.
Lentigines treated with the prescription regimen rebounded to worse than baseline while the herbal formula-treated panelists remained improved from baseline. The dermatological researchers found that the non-prescription herbal regimen offered a viable alternative treatment to the prescription regimen, with better safety and continued resolution of visible hyperpigmentation in the long term.8
The pigment in our skin does provide an important protective shield to our inner bodies. But too much, or unwanted, pigmentation can affect an individual’s self-esteem. As skin care professionals we have the opportunity to provide compelling options for treating irregular or unwanted pigmentation to help add to our patient’s quality of life.

Defining Terms:
Melanin – The dark coloration, or pigment, that appears in the hair, skin and eyes. It consists of two types: Eumelanin for brown/black color and Pheomelanin for yellow/red color.
Melanocyte – A cell contained within the epidermis that produces melanin in the skin. Melanocytes are formed at the base of the dermal/epidermal junction and connect to other cells around them. Skin injury or defects in metabolism or developmental migration may result in melanocytes being deposited in the dermis. Examples include post-inflammatory hyperpigmentation, hemochromatosis and nevi (moles), respectively. [See Figure 5]
Melanosomes – Oval shaped granules of color contained within the melanocyte that synthesize melanin. Every human on the planet has the same number of melanocyte cells; however darker skinned individuals have a larger number of melanosomes that create darker pigment. [See Figure 6]
Alpha-MSH (α-MSH) – A melanocyte-stimulating hormone synthesized and released by the pituitary gland.
Endothelin – A class of peptide hormones, consisting of a chain of amino acids that are synthesized by endothelial cells.
Tyrosine – A non-essential amino acid that is a metabolic precursor to melanin.
Tyrosinase – An enzyme that upregulates the conversion of tyrosine to the pigment melanin.

Resources:
1http://www.ncbi.nlm.nih.gov/pubmed/12733658?dopt=Abstract
2 http://emedicine.medscape.com, assessed 11/30/2010.
3 http://emedicine.medscape.com, assessed 11/30/2010.
4 Thornfeldt C and Bourne K. The New Ideal in Skin Health:
Separating Fact from Fiction, Allured Books, 2010:113.
5 Thornfeldt C and Bourne K. The New Ideal in Skin Health:
Separating Fact from Fiction, Allured Books, 2010:113.
6 wais.access.gpo.gov [DOCID:fr9au06-17], assessed 3/20/2010
7 Thornfeldt C and Bourne K. The New Ideal in Skin Health:
Separating Fact from Fiction, Allured Books, 2010:114.
8 Study information available on file. Episciences, Inc.
www.epionce.com

Dr. Carl R. Thornfeldt is president, CEO and chief scientific officer of Episciences, Inc. He is a practicing dermatologist with 24 years of skin research experience, 21 U.S. patents granted, and over 19 scientific publications in the area of treatment of skin diseases and conditions, including chapters in five dermatological textbooks. Along with these accomplishments, he has also spent nearly two decades focusing on researching the skin barrier and cutaneous inflammatory conditions. Thornfeldt received his M.D. from the Oregon Health Sciences University, and completed his dermatology residency at University Hospital, San Diego, Calif.