|Grade||Level of Evidence|
|A||Multiple double-blind, controlled clinical trials.|
|B||1 double-blind, controlled clinical trial.|
|C||At least 1 controlled or comparative clinical trial.|
|D||Uncontrolled, observational, animal or in-vitro studies only.|
|Grade||Effect||Size of Effect||Comments|
Improves age spots and hyperpigmentation through inhibiting melanin synthesis and destroying melanocytes.
Very effective in clearing epidermal melasma, but less effective in treating dermal melasma.
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Table of contents:
Hydroquinone occurs in some plants as free hydroquinone or as arbutin (glycosylated hydroquinone). Food sources containing arbutin include wheat products, pears, coffee and tea. Free hydroquinone is also found in coffee, red wine, wheat cereals and broccoli.
Due to its lipophilicity, hydroquinone readily penetrates human skin following topical application. In one study, percutaneous absorption with human skin in vitro gave a bioavailability of 43.3% of the applied dose, while the in vivo bioavailability was 45.3% of the dose from a 2% cream formulation.
Penetration enhancers such as azone, dimethyl isosorbide (DMI) and diethylene glycol monoethyl ether (DGME) did not increase the skin uptake of hydroquinone. Fractional laser irradiation did not enhance the permeation of hydroquinone either. The addition of the sunscreen Escalol 507 on the other hand decreased the penetration of hydroquinone, though the reason for this is unclear.
However, emulsions containing liquid crystalline phases were found to aid the penetration of hydroquinone in experiments on human abdominal skin. This was attributed to an increased partitioning of hydroquinone into the skin. The use of co-drugs (derivatives of hydroquinone and another synergistic drug bound covalently) also seems to improve dermal delivery of the parent drugs, which includes hydroquinone. Furthermore, the co-drug strategy minimizes penetration of hydroquinone through the skin, which is important as systemic exposure to hydroquinone can cause serious side effects.
After hydroquinone reaches the bloodstream, 35% is present as free hydroquinone, another 35% is reversibly bound to protein, and the remainder is irreversibly bound to protein. Because its excretion via urine is slower than its uptake through the skin, it is reasonable to assume that daily topical application of hydroquinone will lead to accumulation.
3. Effects on the skin
3.1 Lightening effect
Hydroquinone is a very commonly used agent for skin lightening and for treating hyperpigmentation. An analysis of 24.7 million visits for dyschromia in the United States revealed that hydroquinone monotherapy was the top medication prescribed by dermatologists, and that combination therapy containing hydroquinone was the fourth most popular medication.
Studies as early as in the 1960s found hydroquinone to be an effective depigmenting agent. Moreover, a 2% hydroquinone-cyclodextrin has been shown to induce lightening of solar lentigines (age spots) when applied to the forearms for 2 months. However, in another study, 2% hydroquinone did not significantly lighten the skin compared to 2% lignin peroxidase creams (elure Advanced Skin Lightening), indicating that higher concentrations may be required.
Hydroquinone has been combined with retinoids to lighten the skin. One study investigated the effectiveness of a regimen containing tretinoin, hydroquinone and lactic acid for cosmetic improvement of the colour of the nipple-areola complex among 15 women. After an average treatment period of 16.6 weeks, 80% of the women had achieved an improvement, and 73% were satisfied with the results. 2 women however required a second course of treatment to treat postinflammatory hyperpigmentation induced by the first course. 3% hydroquinone was also found to be less effective than a topical solution containing 2% mequinol and 0.01% tretinoin in treating solar lentigines and other hyperpigmented lesions, but 4% hydroquinone was more effective than 0.05% tretinoin cream in diminishing photodamage (dyspigmentation, fine wrinkles and tactile roughness) when combined with 0.3% retinol. Another study found that tazarotene + hydroquinone was superior over tazarotene alone in improving photodamaged skin, specifically solar lentigines and mottled hyperpigmentation. A clinical trial of nanoscale tretinoin particles + hydroquinone also successfully improved hyperpigmentation in 96% of lesions, and nearly eliminated hyperpigmentation in 59% of lesions.
Other combinations of active ingredients with hydroquinone have been evaluated, too. A forumla of 0.1% tretinoin, 5% hydroquinone and 0.1% dexamethasone was therapeutically effective in treating freckles, melasma and postinflammatory hyperpigmentation, but not senile lentigines. Meanwhile, a cream containing 4% hydroquinone + 2% glycolic acid (Lustra) improved photodamage, hyperpigmentation, texture, fine lines, dryness, skin tone and skin clarity of the neck and upper chest in a study on 19 women and similar formulations also containing a broad spectrum sunscreen (Lustra-AF) or retinol (Alustra) also reduced blotchiness, hyperpigmentation and roughness of the skin. In another study, a copper zinc malonate lotion, a 4% hydroquinone cream and a tretinoin cream together improved skin roughness, mottled hyperpigmentation, lentigines, wrinkling, skin laxity and crepiness on the neck and chest.
Hydroquinone also provides benefits when used after or alongside some dermatology procedures. It helps resolve hyperpigmentation following facial laser resurfacing, for instance. Further, a 4% hydroquinone skin care system (Obagi Condition and Enhance System) + 0.05% tretinoin enhanced improvements in hyperpigmentation and skin laxity when used as an adjunct to intense pulsed light (IPL) therapy, and led to milder fine lines, wrinkles and hyperpigmentation in patinets previously treated with Botox.
The controversy over the safety of hydroquinone has in recent years stimulated research to develop alternative skin lightening agents and formulations. One novel formulation consisting of kojic acid, emblica extract and glycolic acid was discovered to be as effective as 4% hydroquinone in reducing mild to moderate facial dyschromia. Likewise, another topical product with 0.5% ellagic acid and 0.1% salicyclic acid appears to provide comparable skin depigmentation benefit to 4% hydroquinone, in addition to having better esthetics. Another formulation of hydroxyphenoxy propionic acid, ellagic acid, yeast extract, and salicylic acid (SkinCeuticals Advanced Pigment Corrector) was also as effective as 4% hydroquinone + 0.025% tretinoin in evening out the skin tone, decreasing the size and the intensity of spots, and at improving overall pigmentation. 2 studies have also shown that a 4-product, hydroquinone-free regimen (SkinMedica Hyperpigmentation System) was as effective as a 7-product hydroquinone-based regimen (Obagi Nu-Derm) at improving facial hyperpigmentation and global photoaging.
Hydroquinone exerts its whitening effect on the skin via 2 known mechanisms. It is selectively cytotoxic towards melanocyte-derived cells, and suppresses melanogenesis by inhibiting the activity of tyrosinase, the rate-limiting enzyme in melanin synthesis. A 2013 study also indicated that hydroquinone inhibits the early stage of differentiation of embryonic stem cells, promoting their differentiation into cells other than melanocyte lineage cells, as well as inhibits the late stage of differentiation where melanogenesis becomes active.
Oxidization of hydroquinone in melanocytes releases highly toxic compounds such as the quinones, which destroy pigment cells and hence cause depigmentation. Cells protect against these toxic compounds through the action of glutathione-s-transferase (GST), a detoxifiying enzyme. Because tretinoin is a potent inhibitor of GSTs, it makes cells more susceptible to the cytotoxic effect of chemicals like the quinones. This is believed to be behind the synergistic decrease of pigmentation observed when hydroquinone is combined with tretinoin.
3.2 Melasma treatment
Individually, 4% but not 2% hydroquinone is more efficacious than 20% azelaic acid in treating melasma. The combination of 20% azelaic acid cream and a 15% or 20% glycolic acid lotion is as effective as 4% hydroquinone however. 20% azelaic acid + 5% hydroquinone is also more effective than 5% hydroquinone alone, showing a quicker onset of the therapeutic response.
In another comparative study, 2% hydroquinone alone was also not more effective than a cream containing an association of emblica, licorice and belides (Clariderm Clear), nor was 4% hydroquinone more effective than 3 new hydroquinone-free skin brightener formulations. However, 4% hydroquinone was more effective than 5% ascorbic acid, 4% niacinamide and 10% topical zinc sulfate, and as effective as 1% dioic acid, a new depigmenting agent, in improving melasma. 4% hydroquinone cream was also more effective than a skin whitening complex containing uva-ursi extract, biofermented Aspergillus, grapefruit extract and rice extract, providing an improvement of 77% versus an improvement of 67% for the skin whitening complex, though the latter was better tolerated and resulted in no side effects.
Other comparisons demonstrated that 4% hydroquinone was superior to a cream containing 0.75% kojic acid and 2.5% ascorbic acid. Like hydroquinone + azelaic acid, hydroquinone together with kojic acid and/or glycolic acid also has a synergistic effect in reducing melasma.
The efficacy of formulations containing hydroquinone and retinoids has also been evaluated. 4% hydroquinone with 0.15% retinol improved melasma severity and pigmentation intensity in 3 separate studies. A 4% hydroquinone skin care system (Obagi Nu-Derm) + 0.025% tretinoin cream has also been demonstrated to reduce melasma area and severity in multiple studies. Yet another study showed that silicone sheets containing 5% hydroquinone + 1% tretinoin improved epidermal melanosis to the same extent as conventional treatment with hydroquinone and tretinoin, but led to fewer cases of irritant dermatitis.
Triple combination cream containing 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide is even more effective than hydroquinone alone or the dual combination of hydroquinone and tretinoin in clearing melasma. However, relapses are common -- in 1 study, 21 out of 70 patients relapsed during maintenance therapy and had to resume daily treatment. A novel skin-lightening cream with hydroquinone and 4 other skin-brightening active ingredients was also found to be comparable in efficacy to the triple combination cream.
Hydroquinone has also been used as an adjunct topical agent for chemical peeling in patients suffering from melasma, where it acts as a priming agent to minimize postinflammatory hyperpigmentation, a frequently encountered side effect. In this respect, it has been demonstrated to be more effective than 0.025% tretinoin. Serial glycolic acid peels also provided additional improvement in melasma when combined with a topical regimen of 5% hydroquinone, 0.05% tretinoin and 1% hydrocortisone acetate. Furthermore, sequential treatment with triple combination cream and glycolic acid peels showed positive results in a pilot study, although the efficacy compared to treatment with triple combination cream alone is not clear.
Other hydroquinone-containing combination treatments that have been investigated for treating melasma include 0.1% tretinoin, 5% hydroquinone and 1% hydrocortisone, and 4% hydroquinone + 10% ascorbic acid (Obagi-C Rx System).
Finally, because topical agents like hydroquinone is not as effective in reducing dermal pigmentation, it has been combined with laser-based treatments to treat acquired dermal melanocytosis. This has been shown to be effective in ameliorating dark circles around the eyes.
4. Side Effects
4.1 Risks of systemic exposure
It has been estimated that 35% to 45% of hydroquinone is systematically absorbed following topical use in humans. For this reason, it is important to understand the potential systemic side effects that may result from exposure to hydroquinone.
There has been 1 case report of neuropathy (nerve damage) in a 30-year old woman following the use of hydroquinone-based skin bleaching creams. Hydroquinone has also been linked to renal toxicity and renal tumours in rats and mice when administered orally, though not topically. The relevance to humans is however uncertain; no reports have demonstrated carcinogenesis or nephrotoxicity in humans resulting from the application of hydroquinone-containing creams.
A single study has been published involving the use of hydroquinone in 99 pregnant women. No increase in adverse events were seen, agreeing with the observations of an earlier 2-generation reproduction study in rats. This suggests that hydroquinone use during pregnancy may not be associated with increased risk of malformations or other adverse effects.
Because of the appreciable absorption of hydroquinone, it may be best to minimize exposure until further studies can confirm its safety in humans. Indeed, according to a safety assessment, hydroquinone should not be used in leave-on cosmetics.
4.2 Exogenous ochronosis
Long-term use of topical hydroquinone can in rare cases result in exogenous ochronosis, a condition that manifests clinically as gray-brown or blue-black hyperpigmentation in sun-exposed areas of the skin, and histologically as banana-shaped ochre-coloured deposits in the dermis. First discovered in South Africans back in 1975, it has since been observed in African Americans, Indians, Hispanics and Caucasians, and Chinese.
4.3 Other side effects
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