Topical Metformin for Hyperpigmentation

There are numerous causes of hyperpigmentation, such as post-inflammatory etiologies, hormonally mediated factors, cosmetics, drug-induced causes, and UV radiation in addition to systemic conditions such as Addison’s disease and Wilson’s disease. These pigmentation disorders have traditionally been a relatively difficult condition to treat, and currently used depigmentation agents have little effect with sometimes severe side effects.

Metformin is primarily an antidiabetic drug but has been found to play an important role in a number of cutaneous disorders. By improving hyperinsulinemia, metformin has helped hormonal acne, hidradenitis suppurativa and acanthosis nigricans. Its antiandrogenic properties further serve as an add-on to the conventional management of hirsutism associated with polycystic ovarian syndrome (PCOS). Metformin has also been topically used in hyperpigmentary disorders with significant improvement.

Metformin acts on the melanogenic proteins tyrosinase, tyrosine-related protein (TRP)-1 and TRP-2 bringing about a reduction in their expression. This downregulates the expression of microphthalmia-associated transcription factor (MITF), which has been referred to as the master gene for melanocyte survival.

Only topical metformin (not oral) has resulted in improvement of hyperpigmentation disorders. Topical metformin solution was originally tested on the tails of mice for 8 weeks., and induced tail whitening. Then, researchers confirmed the antimelanogenic effect of metformin on reconstituted human epidermis and on human skin biopsies. These data emphasize the depigmenting effect of metformin and suggest a clinical strategy for using metformin in the topical treatment of hyperpigmentation disorders. In animal studies, metformin exerted an antagonistic role in pigmentation only as a topical preparation. Recently, there have been encouraging reports of the benefits of using metformin in treatment of cutaneous malignancies.

Several reports have demonstrated the inhibitory effect of metformin on the proliferation of many cancers including melanoma. Recently, it has been shown that metformin is able to modulate the cAMP level in the liver. As cAMP has a crucial role in melanin synthesis and skin pigmentation, the effect of metformin on melanogenesis was investigated both in vitro and in vivo. Treatment with topical metformin led to reduced melanin content in melanoma cells and in normal human melanocytes by decreasing cAMP accumulation and cAMP-responsive element–binding protein phosphorylation. This inhibitory effect is correlated with decreased expression of master genes of melanogenesis.

Indian J Pharmacol. 2016 Jan-Feb; 48(1): 4–10.

Metformin – For the dermatologist

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J Invest Dermatol. 2014 Oct;134(10):2589-2597.

Inhibition of melanogenesis by the antidiabetic metformin

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Topical metformin has also been used in hyperpigmentation disorders. Metformin acts on three melanogenic proteins and reduces their expression, and also inhibits the activity of PKC-β.5 Inhibiting PKC activity in vivo selectively blocks tanning and reduces basal pigmentation in the epidermis and in anagen hair shafts.

J Invest Dermatol. 2004 Jan; 122(1):159-66.

Topical application of a protein kinase C inhibitor reduces skin and hair pigmentation

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Pyogenic granuloma (PG)

Pyogenic granuloma (PG) is a common, acquired, benign vascular neoplasm of the skin and mucous membranes. It occurs most often in children and adolescents. First-line treatment options for PG are based on destructive approaches. Pain, permanent scarring, and pigmentation are potential complications of these therapies. Topical propranolol 1% ointment with occlusion was found to be effective in consecutive patients; 59.0% completely regressed in a mean of 66 days, 18.2% remained stable, and 22.7% did not respond. No side effects (e.g., skin irritation, allergy, bleeding) were observed. Early treatment was associated with a more favorable outcome.

Pediatr Dermatol. 2018 Jan;35(1):117-120.

Topical 1% propranolol ointment with occlusion in treatment of pyogenic granulomas: An open-label study in 22 children.

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Topical Tranexamic Acid for Melasma

Topical tranexamic acid is a promising treatment for melasma. Tranexamic acid (TA) has been reported to have whitening effects especially for ultraviolet-induced hyperpigmentation including melasma.The aim of a 12-week double-blind split-face trial was to evaluate a topical solution of TA and compare it with combined solution of hydroquinone and dexamethasone as the gold standard treatment of melasma. A significant decreasing trend was observed in the Melasma Area and Severity Index (MASI) score of both groups with no significant difference between them during the study. No differences were seen in patients’ and investigators’ satisfaction of melasma improvement between two groups. However, the side effects of hydroquinone + dexamethasone were significantly prominent compared with TA. This study’s results suggest that topical tranexamic acid may be preferred over hydroquinone + dexamethasone for the treatment of melasma.

J Res Med Sci. 2014 Aug;19(8):753-7.

Topical tranexamic acid as a promising treatment for melasma.

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Topical tranexamic acid has been studied as an adjuvant treatment in melasma.

The main objective of the following study was to evaluate the benefits of topical TA combined with intense pulsed light (IPL) treatment in Asians with melasma. Thirteen subjects completed the study without serious adverse events. MI and mMASI decreased significantly from baseline to 12 weeks after the last IPL treatment on the topical TA side but not on the vehicle side. The prevention of rebound pigmentation by topical application of TA after IPL treatment was also statistically significant. Topical TA can be considered as an adjuvant to conventional treatment for melasma.

J Dermatolog Treat. 2016 Aug;27(4):373-7.

Topical tranexamic acid as an adjuvant treatment in melasma: Side-by-side comparison clinical study.

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Silymarin for Melasma

Melasma is a common acquired pigmentary disorder that occurs usually in women (more than 90% of cases) of all racial and ethnic groups. Melasma is an acquired increased pigmentation of the skin characterized by symmetrical and confluent grey-brown patches usually on the areas of the face exposed to the sun. Silymarin (also known as milk thistle) strongly prevents photocarcinogenesis, and significantly prevented melanin production. A study assessed the benefits of topical Silymarin (SM) cream in a double-blind placebo controlled study for treatment of 96 adult melasma patients seen at an outpatient clinic.

Clinically, patients treated with topical silymarin showed significant excellent pigment improvement & lesion size reduction from the 1st week. Silymarin significantly prevented melanin production in a dose-dependent manner. Silymarin showed tremendous improvement of melasma in a dose-dependent manner and was effective in the prevention of skin damage caused by U.V. sunlight. Patients’ satisfaction was recorded as 100%. During the period of treatment, no local or systemic adverse effects were observed.

BMC Dermatol. 2012; 12: 18.

The treatment of melasma by silymarin cream

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Pseudocatalase Cream for Vitiligo

Vitiligo is a spontaneous irregular depigmentation of skin. Patients with vitiligo have low catalase levels in their epidermis with high levels of hydrogen peroxide. Pseudocatalase cream is an externally applied UVB-activated product that can lead to recovery of the oxidative damage in the epidermis and remarkable repigmentation.

Skin Pharmacol Appl Skin Physiol 1999 May-Jun;12(3):132-8

Successful treatment of oxidative stress in vitiligo.

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J Pathol 2000 Aug;191(4):407-16

Melanocytes are not absent in lesional skin of long duration vitiligo.

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J Investig Dermatol Symp Proc 1999 Sep;4(1):91-6

In vivo and in vitro evidence for hydrogen peroxide (h4 O2) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase.

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Dermatology 1995;190(3):223-9

Treatment of vitiligo with a topical application of pseudocatalase and calcium in combination with short-term UVB exposure: a case study on 33 patients.

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Topical Phenylalanine for Vitiligo

Melanocytes may still be present in long-standing (>25 years) depigmented skin of patients with vitiligo. L-phenylalanine uptake and turnover in the pigment forming melanocytes is vital for initiation of melanogenesis. Phenylalanine hydroxylase activities increase linearly with inherited skin color yielding eightfold more activities in black skin compared to white skin. Camacho and Mazuecos performed an uncontrolled retrospective survey of a group of 193 patients (171 participants after screening) with evolving vitiligo who were treated with oral (50 or 100 mg/kg daily) and topical (10% gel) phenylalanine plus sun exposure. When the study closed, 100% repigmentation was achieved in 122 patients on the face, 35 on the trunk, and 33 on the limbs. Patients who were treated during the months of high solar radiation (and therefore also used the topical phenylalanine) achieved greater repigmentation. No side effects were reported.

Arch Dermatol. 1999;135:216-217

Treatment of vitiligo with oral and topical phenylalanine: 6 years of experience.

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J Drugs Dermatol 2002 Sep;1(2):127-31

Oral and topical L-phenylalanine, clobetasol propionate, and UVA/sunlight–a new study for the treatment of vitiligo.

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Mol Genet Metab 2005 Dec;86(4):27-33

Decreased phenylalanine uptake and turnover in patients with vitiligo.

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Researchers concluded that “although hydroquinone showed a better response, ascorbic acid may play a role in the therapy of melasma as it is almost devoid of side-effects; it could be used alone or in combination therapy.”

Int J Dermatol. 2004 Aug;43(8):604-7.

A double-blind randomized trial of 5% ascorbic acid vs. 4% hydroquinone in melasma.

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Melasma is a circumscribed brown macular hyperpigmentation of areas of the face and neck that are exposed to light, and is aggravated by sunlight, birth control pills, and pregnancy. This study demonstrates that a cream containing hydroquinone, glycolic acid, vitamins C and E, and sunscreen is a safe and effective treatment therapy for melasma.

Int J Dermatol. 2003 Dec;42(12):966-72.

Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of melasma.

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The antioxidant N-acetyl cysteine (NAC) has an antiproliferative effect on human keratinocytes and NAC has been used topically to satisfactorily treat lamellar ichthyosis.

Lancet. 1999 Nov 27;354(9193):1880.

Topical N-acetylcysteine for lamellar ichthyosis.

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Topically applied NAC can prevent skin irritation resulting from radiotherapy and protects from sun-induced erythema.

Semin Oncol. 1983 Mar;10(1 Suppl 1):86-92.

Topical use of N-acetylcysteine for reduction of skin reaction to radiation therapy.

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