Oral Therapies for the Treatment of Skin Hyperpigmentation

Oral Therapies for the Treatment of Skin Hyperpigmentation

Hyperpigmentation is a common complaint of dermatology patients. It may be viewed as cosmetically undesirable and has the potential to produce significant psychosocial distress. There are two important types of melanin: pheomelanin (yellow-red pigment) and eumelanin (black-brown pigment). The type and concentration of melanin pigment determines coloration of the skin.

Both types of melanin are made by melanocytes. Each melanocyte is surrounded by about 40 keratinocytes. Melanin is produced and stored inside melanocytes within specialized organelles known as melanosomes. These melanosomes are then transported to overlaying keratinocytes, which allows for distribution of pigmentation. The principal role of melanin is to protect the skin from ultraviolet (UV) damage by absorbing UV sunlight and removing reactive oxygen species (ROS) (Kim).

Melanin itself is formed through a complex series of chemical reactions involving the amino acid tyrosine in the presence of the copper-containing enzyme tyrosinase (Kim). The enzyme tyrosinase is necessary for the conversion of tyrosine to both eumelanin and pheomelanin. Interestingly, tyrosinase exists widely in plants as well and is responsible for enzymatic browning (Kim). Hyperpigmentation occurs when the body produces excess of eumelanin, pheomelanin, or both.

As might be expected, an increase of melanin pigmentation in the skin is most frequently caused by chronic sun exposure. However, it is also well known to occur in a variety of systemic conditions including Addison’s disease (adrenal gland insufficiency), Wilson’s disease (excess copper), hormonally-mediated factors (e.g. pregnancy), hemochromatosis (excess iron), thyroid disease, diabetes, and malnutrition, as well as exposure to certain medications. The existence of systemic causes of skin hyperpigmentation suggests that some types of hyperpigmentation may improve with systemic treatments.

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A number of orally administered natural extracts, vitamins and supplements, as well as foods, are frequently promoted for the treatment of hyperpigmentation. While most scientific studies have examined the skin lightening effects of topical agents, a growing number have begun to review the benefits of some of these oral therapies for decreasing tyrosinase production and efficacy, inflammatory mediators of hyperpigmentation, and keratinocyte uptake of melanin. We examine evidence supporting the use of oral supplements such as glutathione, amino acids, vitamins, flavonoids, carotenoids, and metformin in treating idiopathic, actinic, and some types of metabolically induced skin hyperpigmentation.

Glutathione

The most commonly used systemic skin lightening agent is glutathione (Malathi). It is an important tri-peptide antioxidant synthesized in plants, animals, fungi, and some bacteria from the amino acids glutamate, cysteine, and glycine. Fruits and vegetables have moderate to high amounts of glutathione and freshly prepared meats are relatively rich as well (Jones). Glutathione is thought to work through several mechanisms to inhibit melanin synthesis. These include interrupting the activity of tyrosinase by binding and chelating copper, as well as quenching the free radicals and peroxides that contribute to tyrosinase activation (Villarama).

In a single randomized, double-blind, placebo-controlled study of 60 participants, orally administered glutathione at 500mg daily for 4 weeks decreased melanin and resulted in the lightening of skin color measured on the face and forearm (Arjinpathana). Oral glutathione is in the “generally regarded as safe” category of the Food and Drug Administration and is usually marketed as a food or dietary supplement. However, long-term safety requires extensive clinical trials.

Amino Acids

Cysteine

Cysteine is a semi-essential amino acid, which means it can be biosynthesized in humans. As already noted, it is a precursor of glutathione. Cysteine is found in most high-protein foods, including poultry, yogurt, egg yolks, red peppers, garlic, onions, broccoli, Brussels sprouts, oats, and wheat germ. High concentrations of the L-enantiomer of cysteine have been found to reduce tyrosinase activity in cultured melanocytes (Smit). On the contrary, cysteine deprivation has been found to promote eumelanogenesis in human melanoma cells (Del Marmol).

Tranexamic acid

Tranexamic acid is a synthetic derivative of the amino acid lysine. It is commonly used in medicine to prevent bleeding by inhibiting the activation of plasminogen to plasmin. Plasmin degrades fibrin, a protein that forms the framework of blood clots. The World Health Organization lists tranexamic acid as an essential medicine.

Treatment of melasma with oral tranexamic acid has been described as an effective and safe therapy. In one study, a dosage of 250mg twice daily for 6 months was found to provide 65% patients with excellent or good improvement (Wu). The skin lightening effects of tranexamic acid are believed to work by way of its antiplasmin activity, which depletes the keratinocyte pool of arachidonic acid involved in ultraviolet induced melanogenesis (Malathi). The use of tranexamic acid for lightening dark spots on the skin has a potential risk of thrombosis.

Vitamins

Hyperpigmentation has been associated with nutritional deficiencies. Nutritional deficiencies may be due to inadequate intake, abnormal absorption, or medications. Therefore, it is important to recognize patterns of hyperpigmentation that may be suggestive of specific nutritional deficiencies.

Vitamin B12

Hyperpigmentation has been observed as a sign of Vitamin B12 deficiency (Simsek). Typically, it is most pronounced on the hands and feet and maximally over the fingers and toes (Baker). This is most likely to occur in vegan or strict vegetarian populations where the animal content of the diet is inadequate. Pigmentation usually resolves with administration of vitamin B12 (Baker). Improvement may noted within two weeks, but some cases require 6 to 12 weeks of treatment (Baker).

Folic Acid

A decrease in the folic acid levels in the body is most commonly associated with chemotherapy medications but may also be brought about by pregnancy and contraceptive pills. Hyperpigmentation of the palms, soles, and tongue has been reported as a consequence of folic acid deficiency induced megaloblastic anemia of pregnancy (Baumslag).

Several cases of generalized hyperpigmentation have also been noted in patients with acute leukemia receiving folic acid antagonists, with another case reported from folate deficiency in a malnourished alcoholic patient (Waisman, Downham). Folate naturally occurs in a wide variety of foods. Avocado, spinach, liver, asparagus, and Brussels sprouts are among those with the highest levels of folate. Effective treatment requires a diet high in folic acid or vitamin supplementation.

Vitamin A and β-carotene

Vitamin A deficiency “phrynoderma” may be associated with skin hyperpigmentation (Bleasel). It is caused by a combination of inadequate dietary intake of Vitamin A and/or β-carotene in patients at risk for malnutrition, including those on a strict weight-loss program and those who have undergone bariatric surgery.

A diet rich in vitamin A should be recommended as first-line treatment. The main sources of vitamin A are liver, eggs, and butter. Beta-carotene is converted to vitamin A after absorption. Beta-carotene is found in highest concentration in green leaves and most orange and yellow fruit, as well as vegetables such as carrots, watermelon, papaya, and tomatoes.

Flavonoids

Flavonoids are a group of organic compounds thought to provide health benefits through cell signaling pathways and antioxidant effects. They are often used to explain some of the health benefits associated with fruit and vegetable-rich diets. In recent years, it has been revealed that flavonoids possess inhibitory effects on tyrosinase.

In addition to the flavonoids described below, a variety of anecdotal reports suggest that acerola (West Indian cherry), morus nigra (black mulberry), soy germ, and bearberry may also improve skin hyperpigmentation when absorbed systemically.

Osmanthus fragrans

Osmanthus fragrans is a common flavor additive for tea and other beverages. It has many potential applications in biomedical science because of its anti-inflammatory and anti-oxidative properties. When tested on mouse melanoma cells in the laboratory setting, it demonstrated anti-tyrosinase and anti-melanin production properties (Wu).

Quercetin

Quercetin is a flavonoid found in many fruits and vegetables, including capers, radish leaves, carob, dill, cilantro, fennel leaves, red onion, radicchio, watercress, buckwheat, and kale. It has demonstrated tyrosinase inhibitory activity on experiments with mushroom tyrosinase and may induce insulin secretion by activation of L-type calcium channels in pancreatic β-cells (Arung, Bardy).

It is important to note that quercetin is contraindicated with some antibiotics such as fluoroquinolones, as it binds to bacterial DNA gyrase, although it is unclear whether it may inhibit or enhance antimicrobial action (Hilliard). Furthermore, it may have harmful interactions with the chemotherapy agents taxol/paclitaxel (Bun).

Proanthocyanidin

Proanthocyanidin is found in a variety of plants including apples, cinnamon, and grapes. Cocoa beans are thought to contain the highest concentration. In one study, proanthocyanidin-rich grape seed extract was orally administered to 12 Japanese women with melasma for 6 months (Yamakoshi). Melasma improved in 10 of the 12 women.

In another study, a significant decrease in pigmentation of age spots was demonstrated following 12 weeks of supplementation with the maritime pine bark extract Pycnogenol, which contains 65-75% proanthocyanidins (Furumura). Proanthocyanidins from grape seeds have also been found to effectively inhibit ultraviolet-induced melanogenesis of human melanocytes in vitro (Lian).

Rose Hip

Rose hip is the fruit of the rose plant. It is used in herbal teas, jam, jelly, and syrup and is known as one of the richest plant sources of vitamin C. Oral administration of rose hip to guinea pigs has been shown to inhibit skin melanogenesis, suggesting usefulness as a systemic therapy for hyperpigmentation (Fujii).

Luteolin

Luteolin has been observed to inhibit pigmentary changes associated with UVB-induced photoaging using hairless mice and human keratinocytes (Lim). It has also demonstrated inhibitory effects on the activity of mushroom tyrosinase (Xie). Luteolin is primarily found in leaves, but dietary sources of luteolin include chili, onion, broccoli, celery and carrot.

Carotenoids

Carotenoids are organic pigments found in plants, as well as some bacteria and fungi. Humans are incapable of synthesizing carotenoids. Similar to flavonoids, a number of studies have revealed that carotenoids possess inhibitory effects on melanogenesis.

Fucoxanthin

Fucoxanthin is a carotenoid derived from edible sea algae. Oral administration to mice has been found to display anti-pigmentary activity in UVB-induced melanogenesis (Shimoda). It is hypothesized that this effect may be due to the suppression of melanogenic stimulants such as neurotrophin and prostaglandin E2, as well as melanocyte stimulating hormone expression. Of note, considerable interest in fucoxanthin has been generated by research suggesting that it may promote fat metabolism by increasing the expression of thermogenin (Maeda).

β-cryptoxanthin

β-cryptoxanthin is a carotenoid that is widely contained in fruits of citrus plants. Similar to fucoxanthin, oral administration of β-cryptoxanthin to mice has been shown to suppress UVB-induced melanogenesis. Suppression of inflammatory melanogenic stimulants and melanocytic stimulating hormone expression are thought to be involved in this mechanism (Shimoda).

Metformin

Metformin is the most widely prescribed anti-diabetic medication. It has been shown to modulate the level of the signal transductor cyclic adenosine monophosphate (cAMP), an important promoter of melanin synthesis (Miller). The cAMP-dependent pathway has been long presumed to play a critical role in mediating α-melanocyte-stimulating hormone-induced pigmentation (Ao).

Anti-melanogenic effects have been confirmed on reconstituted human epidermis and on human skin biopsies incubated with metformin (Lehraiki). However, while systemic treatment of mice with metformin has demonstrated regression of melanoma tumors, no change of skin pigmentation in metformin-treated mice was observed (Lehraiki). This suggests that that the depigmenting effect of metformin may be limited to topical application. Nevertheless, improvement of hyperpigmentation associated with acanthosis nigricans secondary to insulin resistance has been observed with oral metformin therapy (Hw).

Miscellaneous

Consumption of coffee, which has high concentrations of antioxidant polyphenols, showed a statistically significant correlation towards a decrease in pigmented spot scores in a cross-sectional survey (Fukushima). Subjects with the highest total polyphenol consumption from all sources showed the lowest score of ultraviolet-pigmented spots. Other foods abundant with polyphenols include cloves, peppermint, star anise, cocoa powder, and oregano.

Simultaneous oral administration of Vitamin C, L-cysteine, and Vitamin E decreased the number of melanocytes in guinea pigs (Fujiwara). Similarly, separate studies also in guinea pigs found that the oral administration of traditional Chinese oolong tea and pomegranate extract inhibited UVB-induced pigmentation (Aoki, Yoshimura). The mechanism of action for both the oolong tea and pomegranate extract is thought to be due to a decrease of intracellular tyrosinase at the mRNA transcription level.

Conclusion

HYPERPIGMENTATION TREATMENT

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Numerous systemic, orally administered therapies have been proposed for the treatment of skin hyperpigmentation. It is reasonable to expect that the most effective systemic therapies will address known underlying causes such as thyroid disease, diabetes, malnutrition, and hormonal imbalance. Improvement of otherwise unresponsive skin hyperpigmentation, or hyperpigmentation of unknown cause, with systemic therapy is less predictable. Based on existing research, the most promising remedies appear to be glutathione, tranexamic acid, and proanthocyanidin. Additional studies to better establish safety and efficacy are necessary.

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Brandon Kirsch, MD
Brandon Kirsch
brandon.kirsch@clearifirx.com

Brandon Kirsch, MD, FAAD, is a board-certified dermatologist specializing in clinical drug development and medical innovation. He is the founder of Kirsch Dermatology in Naples, Florida (www.KirschDerm.com) and is also the Chief of Dermatology at the Naples Community Hospital.

Dr. Kirsch started his career as a lawyer and holds law degrees from the University of Western Ontario (LL.B.) and Georgetown (LL.M. Securities and Financial Regulation). Dr. Kirsch completed his pre-medical studies at the University of Pennsylvania, medical school at Brown University, internship at the Mayo Clinic (Florida) and dermatology residency at the University of North Carolina. In partnership with the Mayo Clinic, he filed to patent a novel topical composition for the treatment of skin hyperpigmentation that he co-developed and also oversaw a successful pilot study of the formulation.

Dr. Kirsch has experience with therapeutic drug development programs from pre-clinical to Phase 3 studies. He is licensed to practice medicine in California, Colorado, Florida, and North Carolina and law in New York and Ontario.



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