It is unfortunate that skin lightening and getting rid of brown spots is a long term slow process that does not produce results. The most popular skin lightening preparation used in the prescription realm is hydroquinone, but it has been mired in recent regulatory controversy. Hydroquinone is an unstable compound that has withstood the test of time, but may actually be toxic to pigment cells. What can be done to even skin pigmentation?
The most damaging activity for the skin is cleansing. Many patients with dark spots think they can scrub the pigment off their skin, much like dirt. Do not use aggressive particulate scrubs with fruit pigments, nut fragments, or polyethylene scrubbing beads if you have dark spots. You should also avoid home dermabrasion machines, aggressive facial brushes, and needling devices. A popular trend in the Orient and Europe is to apply pigment lightening products followed by use of a roller that contains smaller tapered stainless steel needles. The roller is pushed into the skin creating small wounds. This technique is known as needling.
Sunscreen-containing moisturizers are excellent if you have dark spots. A sunscreen-containing moisturizer should be selected with a minimum SPF 30 because lower SPF products may not have adequate UVA photoprotection, which causes facial pigmentation. Ideally, the sunscreen-containing moisturizer should combine both organic and inorganic filters to both absorb and reflect UV radiation. Further photoprotection can be achieved by applying a facial foundation followed by a facial powder.
Colored cosmetics can be an excellent source of sun protection. Facial foundation contains iron oxide, zinc oxide, and kaolin, all of which can block the sun. Many facial foundations now contain organic sunscreens, as well, using octyl methoxycinnamate and oxybenzone to provide an SPF rating.
Powders applied on top of the facial foundation can provide even more sun protection by allowing the facial foundation to remain and place while coating the skin with an additional layer of kaolin, talc, and iron oxide. Facial powders are also excellent at absorbing sweat and sebum that can destroy the facial foundation film and literally float the photoprotection right off the face. The face powder can be dusted with a loose brush over the facial foundation that has been placed over the sunscreen-containing moisturizer. Never forget to recommend a hat, scarf, umbrella, and big sunglasses in addition to cosmetics.
As mentioned previously, the gold standard for hyperpigmentation therapy in the US remains hydroquinone. This substance is actually quite controversial having been removed from the OTC markets in Europe and Asia. The maximum concentration in cosmetic formulations is 2% while most prescription formulations are 4%.
The most commonly used ingredient in skin lightening moisturizers is licorice extract. The botanical actives are known as liquiritin and isoliquertin, which are glycosides containing flavenoids. Liquiritin induces skin lightening by dispersing melanin. It is typically applied to the skin in a dose of one gram per day for 4 weeks to see a clinical result. Irritation is not a side effect and it can be easily combined with hydroquinone.
The second most common OTC skin lightening agent in the US and the most popular skin lightening agent in the Orient is kojic acid, chemically known as 5-hydroxymethyl-4H-pyrane-4-one). It is a hydrophilic fungal derivative obtained from Aspergillus and Penicillium species. Some studies indicate that kojic acid is equivalent to hydroquinone in pigment lightening ability. The activity of kojic acid is attributed to its ability to prevent tyrosinase activity by binding to copper.
Two other substances that are commonly combined are aleosin and arbutin. Aleosin is a low-molecular-weight glycoprotein obtained from the aloe vera plant. It is a natural hydroxymethylchromone functioning to inhibit tyrosinase by competitive inhibition at the DOPA oxidation site., In contrast to hydroquinone, it shows no cell cytotoxicity, however it has a limited ability to penetrate the skin due to its hydrophilic nature. It is sometimes mixed with arbutin. Arbutin is obtained from the leaves of the Vaccinicum vitis-idaca and is a naturally occurring gluconopyranoside that causes decreased tyrosinase activity without affecting messenger RNA expression. It also inhibits melanosome maturation. Arbutin is not toxic to melanocytes and is used in a variety of pigment lightening preparations in Japan at concentrations of 3%. Higher concentrations are more efficacious than lower concentrations, but a paradoxical pigment darkening may occur.
Vitamin C is used in some OTC formulations as a pigment lightening active or as an antioxidant or as a pH adjustor. It can be hard to determine from the jar label its exact role, however if ascorbic acid is listed in the last 3-5 ingredients, it probably is not effective for hyperpigmentation. Ascorbic acid interrupts the production of melanogenesis by interacting with copper ions to reduce dopaquinone and blocking dihydrochinindol-2-carboxyl acid oxidation. High concentrations of ascorbic acid might be more effective, but will lower the skin cream pH possibly causing irritation.
Facial hyperpigmentation is one of the most common signs of photoaging. Many different patterns can be seen. Focal hyperpigmentation in the form of small lentigenes across the lateral cheeks usually begins about age 25-30, depending on cumulative sun exposure, with continued accumulation of lesions throughout life. Pigmentation can also present in the form of melasma with reticulated pigment over the sides of the forehead lateral jawline and upper lip. Lastly, hyperpigmentation can present as overall darkening of the skin from a combination of melanin pigment, fragmented elastin fibers, and residual hemosiderin. Topical treatments for hyperpigmentation are problematic. A successful treatment must remove existing pigment from the skin, shut down the manufacture of melanin, and prevent the transfer of existing melanin to the melanosomes. No currently available topical product is able to accomplish all three of these functions. This article examines the various mechanisms of action for the topical hyperpigmentation formulations that have been identified in the prescription and OTC markets.
The gold standard for hyperpigmentation therapy in the US remains hydroquinone. This substance is actually quite controversial having been removed from the OTC markets in Europe and Asia. Concern arose because oral hydroquinone has been report to cause cancer in mice fed large amounts of the substance. While oral consumption probably is not related to topical application, hydroquinone remains controversial because it actually is toxic to melanocytes. Hydroquinone, a phenolic compound chemically known as 1,4 dihydroxybenzene, functions by inhibiting the enzymatic oxidation of tyrosine and phenol oxidases. It covalently binds to histidine or interacts with copper at the active site of tyrosinase. It also inhibits RNA and DNA synthesis and may alter melanosome formation, thus selectively damaging melanocytes. These activities suppress the melanocyte metabolic processes inducing gradual decrease of melanin pigment production.
Hydroquinone is available in both the OTC and prescription US markets. The maximum concentration in OTC formulations is 2% while most prescription formulations are 4%. It is possible to compound hydroquinone creams as high as 8%, but the formulations are unstable with rapid oxidation represented by browning of the product. In all formulations, hydroquinone is unstable turning brown upon contact with air. Once the hydroquinone has oxidized, it is no longer active and should be discarded.
Prescription hydroquinone formulations have tried to increase the potency of formulations by adding penetration enhancers such as glycolic acid, sunscreens, and tretinoin as a supplemental pigment lightening agent. Other prescription formulations have added microsponges to create time delivery of hydroquinone to the skin while others have placed the hydroquinone in a special canister dispenser.
Mequinol is the most recent new skin lightening agent to be approved in the US. It has also received approval in Europe. It is chemically known as 4-hydroxyanisole. Other names include methoxyphenol, hydroquinone monomethyl ether, and p-hydroxyanisole. Mequinol is available in the US in a 2% concentration and is commercially marketed as a prescription skin lightener in combination with 0.01% tretinoin as a penetration enhancer and Vitamin C, in the form of ascorbic acid and ascorbyl palmitate, to enhance skin lightening. These active agents are dissolved in an ethyl alcohol vehicle. The exact mechanism of action accounting for the skin lightening properties of mequinol is unknown, however it is a substrate for tyrosinase thereby acting as a competitive inhibitor in the formation of melanin precursors. It does not damage the melanocyte like hydroquinone.
Topical tretinoin is used alone and in combination with hydroquinone as prescription pigment lightening treatment. Tretinoin has an effect on skin pigmentation as seen by a decrease in cutaneous freckling and lentigenes. It is the irregular grouping and activation of melanocytes that accounts for the dyspigmentation associated with photoaging, but normalization of this change has been histologically demonstrated with retinoids. While this effect is more dramatic with topical tretinoin, topical retinol has been thought to provide similar effects as a cosmeceutical.
Azelaic acid is available currently as a 15% gel approved in the US for the treatment of rosacea. It is a 9-carbon dicarboxylic acid obtained from cultures of Pityrosporum ovale that may be a treatment alternative for individuals allergic to hydroquinone. Although its lightening effects are mild, several large studies done with a diverse ethnic background population have compared its efficacy to that of hydroquinone., It too interferes with tyrosinase activity, but may also interfere with DNA synthesis. It appears to have a specificity for abnormal melanocytes and for this reason has been used to suppress the progression of lentigo maligna to lentigo maligna melanoma.
There are a number of other skin lightening agents that have not reached the prescription market in the US. 4-isopropylcatechol is a potent tyrosinase inhibitor that was studied in the 1970s. N-acetyl-4-S-cystalminylphenol (NA-CAP) is a phenolic thioether amine that affects tyrosinase. It is slightly less irritating than hydroquinone. A pigment lightening agent known as 4-N-burylresorcinol is approved in Japan, but not in the US, for the treatment of melasma. It is commonly used to treat post-inflammatory hyperpigmentation following laser therapy in melasma patients.
There are a variety of nonprescription hyperpigmentation topical agents that are used in cosmeceuticals and cosmetics. None of these are as efficacious as hydroquinone, however they are considered safe for use both in the US and worldwide.
Ascorbic acid, also known as Vitamin C, is used in the treatment of hyperpigmentation. It interrupts the production of melanogenesis by interacting with copper ions to reduce dopaquinone and blocking dihydrochinindol-2-carboxyl acid oxidation. Ascorbic acid, an antioxidant, is rapidly oxidized when exposed air and is of limited stability. High concentrations of ascorbic acid must be used with caution as the low pH can be irritating to the skin.
Licorice extracts are being used as topical anti-inflammatories to decrease skin redness and hyperpigmentation. The active agents are known as liquiritin and isoliquertin, which are glycosides containing flavenoids. Liquiritin induces skin lightening by dispersing melanin. It is typically applied to the skin in a dose of one gram per day for 4 weeks to see a clinical result. Irritation is not a side effect
Alpha lipoic acid is found in a variety of anti-aging cosmeceuticals to function as an antioxidant, but it may also have very limited pigment lightening properties. It is a disulfide derivative of octanoic acid that is able to inhibit tyrosinase. However, it is a large molecule and cutaneous penetration to the level of the melanocyte is challenging.
Kojic acid, chemically known as 5-hydroxymethyl-4H-pyrane-4-one) is one of the most popular cosmeceutical skin lightening agents found in cosmetic counter skin lightening cream distributed worldwide. It is a hydrophilic fungal derivative obtained from Aspergillus and Penicillium species. It is the most popular agent employed in the Orient for the treatment of melasma. Some studies indicate that kojic acid is equivalent to hydroquinone in pigment lightening ability. The activity of kojic acid is attributed to its ability to prevent tyrosinase activity by binding to copper.
Aleosin is a low-molecular-weight glycoprotein obtained from the aloe vera plant. It is a natural hydroxymethylchromone functioning to inhibit tyrosinase by competitive inhibition at the DOPA oxidation site., In contrast to hydroquinone, it shows no cell cytotoxicity, however it has a limited ability to penetrate the skin due to its hydrophilic nature. It is sometimes mixed with arbutin, our next topic of discussion, to enhance its skin lightening abilities.
Arbutin is obtained from the leaves of the Vaccinicum vitis-idaca and other related plants. It is a naturally occurring gluconopyranoside that causes decreased tyrosinase activity without affecting messenger RNA expression. It also inhibits melanosome maturation. Arbutin is not toxic to melanocytes and is used in a variety of pigment lightening preparations in Japan at concentrations of 3%. Higher concentrations are more efficacious than lower concentrations, but a paradoxical pigment darkening may occur.
Pigment lightening for the treatment of lentigenes, melasma, and post-inflammatory hyperpigmentation is a challenge for the dermatologist. Hydroquinone remains the gold standard in the US, even though there are concerns in Europe and Asia regarding its safety. Many cosmeceutical pigment lightening agents exist, but current formulations are of limited efficacy.