Hydroquinone

Although hydroquinone is one of the most effective skin lightening agents known so far, there are concerns over its safety when in prolonged contact with the skin. It may be best to minimize exposure until further studies can verify its safety.

Effects


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

C

Skin lightening

Strong

Improves age spots and hyperpigmentation through inhibiting melanin synthesis and destroying melanocytes.

C

Melasma treatment

Strong

Very effective in clearing epidermal melasma, but less effective in treating dermal melasma.

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Scientific Research


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Table of contents:

1. Sources

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.[1]

2. Bioavailability

Due to its lipophilicity, hydroquinone readily penetrates human skin following topical application.[2][3] 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.[4]

Penetration enhancers such as azone, dimethyl isosorbide (DMI) and diethylene glycol monoethyl ether (DGME) did not increase the skin uptake of hydroquinone.[2][5] Fractional laser irradiation did not enhance the permeation of hydroquinone either.[5] The addition of the sunscreen Escalol 507 on the other hand decreased the penetration of hydroquinone, though the reason for this is unclear.[2]

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.[6] 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.[7][8]

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.[9] 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.[10]

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.[11]

Studies as early as in the 1960s found hydroquinone to be an effective depigmenting agent.[12][13] Moreover, a 2% hydroquinone-cyclodextrin has been shown to induce lightening of solar lentigines (age spots) when applied to the forearms for 2 months.[14] However, in another study, 2% hydroquinone did not significantly lighten the skin compared to 2% lignin peroxidase creams (elure Advanced Skin Lightening),[15] 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.[16] 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,[17] 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.[18] Another study found that tazarotene + hydroquinone was superior over tazarotene alone in improving photodamaged skin, specifically solar lentigines and mottled hyperpigmentation.[19] A clinical trial of nanoscale tretinoin particles + hydroquinone also successfully improved hyperpigmentation in 96% of lesions, and nearly eliminated hyperpigmentation in 59% of lesions.[20]

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.[21] 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[22] and similar formulations also containing a broad spectrum sunscreen (Lustra-AF) or retinol (Alustra) also reduced blotchiness, hyperpigmentation and roughness of the skin.[23] 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.[24]

Hydroquinone also provides benefits when used after or alongside some dermatology procedures. It helps resolve hyperpigmentation following facial laser resurfacing, for instance.[25] 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,[26] and led to milder fine lines, wrinkles and hyperpigmentation in patinets previously treated with Botox.[27]

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.[28] 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.[29] 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.[30] 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.[31][32]

Hydroquinone exerts its whitening effect on the skin via 2 known mechanisms. It is selectively cytotoxic towards melanocyte-derived cells,[33][34] and suppresses melanogenesis by inhibiting the activity of tyrosinase, the rate-limiting enzyme in melanin synthesis.[35][34] 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.[36]

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.[37][38]

3.2 Melasma treatment

Hydroquinone is frequently prescribed as a topical treatment for melasma, a pigmentary disorder affecting the face.[39][40] It is particularly effective in treating epidermal melasma.[40]

Individually, 4% but not 2% hydroquinone is more efficacious than 20% azelaic acid in treating melasma.[41][42][43][44] The combination of 20% azelaic acid cream and a 15% or 20% glycolic acid lotion is as effective as 4% hydroquinone however.[45] 20% azelaic acid + 5% hydroquinone is also more effective than 5% hydroquinone alone, showing a quicker onset of the therapeutic response.[46]

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),[47] nor was 4% hydroquinone more effective than 3 new hydroquinone-free skin brightener formulations.[48] However, 4% hydroquinone was more effective than 5% ascorbic acid,[49] 4% niacinamide[50] and 10% topical zinc sulfate,[51][52] and as effective as 1% dioic acid, a new depigmenting agent, in improving melasma.[53] 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.[54]

Other comparisons demonstrated that 4% hydroquinone was superior to a cream containing 0.75% kojic acid and 2.5% ascorbic acid.[55] Like hydroquinone + azelaic acid, hydroquinone together with kojic acid and/or glycolic acid also has a synergistic effect in reducing melasma.[56][57][58][59]

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.[60][61][62] 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.[63][64] 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.[65]

Triple combination cream containing 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide is even more effective than hydroquinone alone[66][67] or the dual combination of hydroquinone and tretinoin in clearing melasma.[39][68][69][70][71] However, relapses are common -- in 1 study, 21 out of 70 patients relapsed during maintenance therapy and had to resume daily treatment.[72] 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.[73]

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.[74][75] 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.[76] 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.[77]

Other hydroquinone-containing combination treatments that have been investigated for treating melasma include 0.1% tretinoin, 5% hydroquinone and 1% hydrocortisone,[78] and 4% hydroquinone + 10% ascorbic acid (Obagi-C Rx System).[79]

Finally, because topical agents like hydroquinone is not as effective in reducing dermal pigmentation,[40][80] it has been combined with laser-based treatments to treat acquired dermal melanocytosis.[81] This has been shown to be effective in ameliorating dark circles around the eyes.[82]

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.[4] 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.[83] Hydroquinone has also been linked to renal toxicity and renal tumours in rats and mice when administered orally,[84][85] though not topically.[86] The relevance to humans is however uncertain;[87] no reports have demonstrated carcinogenesis or nephrotoxicity in humans resulting from the application of hydroquinone-containing creams.[10]

A single study has been published involving the use of hydroquinone in 99 pregnant women.[88] No increase in adverse events were seen, agreeing with the observations of an earlier 2-generation reproduction study in rats.[89] This suggests that hydroquinone use during pregnancy may not be associated with increased risk of malformations or other adverse effects.[88]

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.[87]

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.[90][91][92] First discovered in South Africans back in 1975,[93] it has since been observed in African Americans,[94] Indians,[92][95] Hispanics and Caucasians,[96] and Chinese.[97][98][99]

4.3 Other side effects

Discolouration of the fingernails also occurs occasionally with hydroquinone use.[100][101][102] Fortunately, it resolves within a few months after cessation of hydroquinone use.[101][102]

A few cases of skin atrophy and mild telangiectasia have also been reported during treatment of melasma with hydroquinone-containing triple combination cream.[103][104][105]

Scientific References


  1. Deisinger PJ, Hill TS, English JC. Human exposure to naturally occurring hydroquinone. J Toxicol Environ Health. (1996)
  2. Bucks DA, et. al. Percutaneous absorption of hydroquinone in humans: effect of 1-dodecylazacycloheptan-2-one (azone) and the 2-ethylhexyl ester of 4-(dimethylamino)benzoic acid (Escalol 507). J Toxicol Environ Health. (1988)
  3. Barber ED, Hill T, Schum DB. The percutaneous absorption of hydroquinone (HQ) through rat and human skin in vitro. Toxicol Lett. (1995)
  4. Wester RC, et. al. Human in vivo and in vitro hydroquinone topical bioavailability, metabolism, and disposition. J Toxicol Environ Health. (1998)
  5. Lee WR, et. al. Skin permeation of small-molecule drugs, macromolecules, and nanoparticles mediated by a fractional carbon dioxide laser: the role of hair follicles. Pharm Res. (2013)
  6. Otto A, et. al. Effect of emulsifiers and their liquid crystalline structures in emulsions on dermal and transdermal delivery of hydroquinone, salicylic acid and octadecenedioic acid. Skin Pharmacol Physiol. (2010)
  7. Hsieh PW, et. al. The co-drug of conjugated hydroquinone and azelaic acid to enhance topical skin targeting and decrease penetration through the skin. Eur J Pharm Biopharm. (2012)
  8. Hsieh PW, et. al. Co-drug strategy for promoting skin targeting and minimizing the transdermal diffusion of hydroquinone and tranexamic acid. Curr Med Chem. (2013)
  9. Corley RA, et. al. Development of a physiologically based pharmacokinetic model for hydroquinone. Toxicol Appl Pharmacol. (2000)
  10. Westerhof W, Kooyers TJ. Hydroquinone and its analogues in dermatology - a potential health risk. J Cosmet Dermatol. (2005)
  11. Kang SJ, et. al. Dyschromia in skin of color. J Drugs Dermatol. (2014)
  12. Spencer MC. Topical use of hydroquinone for depigmentation. JAMA. (1965)
  13. Arndt KA, Fitzpatrick TB. Topical use of hydroquinone as a depigmenting agent. JAMA. (1965)
  14. Petit L, Piérard GE. Analytic quantification of solar lentigines lightening by a 2% hydroquinone-cyclodextrin formulation. J Eur Acad Dermatol Venereol. (2003)
  15. Mauricio T, Karmon Y, Khaiat A. A randomized and placebo-controlled study to compare the skin-lightening efficacy and safety of lignin peroxidase cream vs. 2% hydroquinone cream. J Cosmet Dermatol. (2011)
  16. Yoshimura K, et. al. Cosmetic color improvement of the nipple-areola complex by optimal use of tretinoin and hydroquinone. Dermatol Surg. (2002)
  17. Jarratt M. Mequinol 2%/tretinoin 0.01% solution: an effective and safe alternative to hydroquinone 3% in the treatment of solar lentigines. Cutis. (2004)
  18. Draelos ZD. Novel approach to the treatment of hyperpigmented photodamaged skin: 4% hydroquinone/0.3% retinol versus tretinoin 0.05% emollient cream. Dermatol Surg. (2005)
  19. Lowe N, et. al. Tazarotene versus tazarotene plus hydroquinone in the treatment of photodamaged facial skin: a multicenter, double-blind, randomized study. J Cosmet Laser Ther. (2006)
  20. Sato K, et. al. A clinical trial of topical bleaching treatment with nanoscale tretinoin particles and hydroquinone for hyperpigmented skin lesions. Dermatol Surg. (2007)
  21. Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol. (1975)
  22. Gladstone HB, et. al. Efficacy of hydroquinone cream (USP 4%) used alone or in combination with salicylic acid peels in improving photodamage on the neck and upper chest. Dermatol Surg. (2000)
  23. Gupta AK, Ryder JE. Lustra, Lustra-AF and Alustra. Skin Therapy Lett. (2003)
  24. Leyden JJ, Parr L. Treating photodamage of the décolletage area with a novel copper zinc malonate complex plus hydroquinone and tretinoin. J Drugs Dermatol. (2010)
  25. Goldman MP. The use of hydroquinone with facial laser resurfacing. J Cutan Laser Ther. (2000)
  26. Woodhall KE, et. al. Benefits of using a hydroquinone/tretinoin skin care system in patients undergoing intense pulsed light therapy for photorejuvenation: a placebo-controlled study. J Drugs Dermatol. (2009)
  27. Schlessinger J, Kenkel J, Werschler P. Further enhancement of facial appearance with a hydroquinone skin care system plus tretinoin in patients previously treated with botulinum toxin Type A. Aesthet Surg J. (2011)
  28. Draelos ZD, et. al. Evaluation of a kojic acid, emblica extract, and glycolic acid formulation compared with hydroquinone 4% for skin lightening. Cutis. (2010)
  29. Dahl A, Yatskayer M, Raab S, Oresajo C. Tolerance and efficacy of a product containing ellagic and salicylic acids in reducing hyperpigmentation and dark spots in comparison with 4% hydroquinone. J Drugs Dermatol. (2013)
  30. Draelos ZD, et. al. Dyspigmentation, skin physiology, and a novel approach to skin lightening. J Cosmet Dermatol. (2013)
  31. Fabi S, Massaki N, Goldman MP. Efficacy and tolerability of two commercial hyperpigmentation kits in the treatment of facial hyperpigmentation and photo-aging. J Drugs Dermatol. (2012)
  32. Fabi SG, Goldman MP. Comparative study of hydroquinone-free and hydroquinone-based hyperpigmentation regimens in treating facial hyperpigmentation and photoaging. J Drugs Dermatol. (2013)
  33. Smith CJ, O'Hare KB, Allen JC. Selective cytotoxicity of hydroquinone for melanocyte-derived cells is mediated by tyrosinase activity but independent of melanin content. Pigment Cell Res. (1988)
  34. Hu ZM, et. al. Effects of hydroquinone and its glucoside derivatives on melanogenesis and antioxidation: Biosafety as skin whitening agents. J Dermatol Sci. (2009)
  35. Palumbo A, et. al. Mechanism of inhibition of melanogenesis by hydroquinone. Biochim Biophys Acta. (1991)
  36. Inoue Y, et. al. Analysis of the effects of hydroquinone and arbutin on the differentiation of melanocytes. Biol Pharm Bull. (2013)
  37. Bolognia JL, et. al. Enhancement of the depigmenting effect of hydroquinone by cystamine and buthionine sulfoximine. Br J Dermatol. (1995)
  38. Kasraee B, Handjani F, Aslani FS. Enhancement of the depigmenting effect of hydroquinone and 4-hydroxyanisole by all-trans-retinoic acid (tretinoin): the impairment of glutathione-dependent cytoprotection? Dermatology. (2003)
  39. Rajaratnam R, et. al. Interventions for melasma. Cochrane Database Syst Rev. (2010)
  40. Bandyopadhyay D. Topical treatment of melasma. Indian J Dermatol. (2009)
  41. Verallo-Rowell VM, et. al. Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma. Acta Derm Venereol Suppl (Stockh). (1989)
  42. Ibrahim Galadari. A comparison of the effect of topical azelaic acid (20%) and hydroquinone (2%) in the treatment of melasma. The Gulf Journal of Dermatology. (1994)
  43. Baliña LM, Graupe K. The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream. Int J Dermatol. (1991)
  44. Farshi S. Comparative study of therapeutic effects of 20% azelaic acid and hydroquinone 4% cream in the treatment of melasma. J Cosmet Dermatol. (2011)
  45. Kakita LS, Lowe NJ. Azelaic acid and glycolic acid combination therapy for facial hyperpigmentation in darker-skinned patients: a clinical comparison with hydroquinone. Clin Ther. (1998)
  46. Tehrani S, et. al. Efficacy and safety of azelaic acid 20% plus hydroquinone 5% in the management of melasma. Iran J Dermatol. (2012)
  47. Costa A, et. al. Association of emblica, licorice and belides as an alternative to hydroquinone in the clinical treatment of melasma. An Bras Dermatol. (2010)
  48. Makino ET, et. al. Clinical efficacy and safety of a multimodality skin brightener composition compared with 4% hydroquinone. J Drugs Dermatol. (2012)
  49. Espinal-Perez LE, Moncada B, Castanedo-Cazares JP. A double-blind randomized trial of 5% ascorbic acid vs. 4% hydroquinone in melasma. Int J Dermatol. (2004)
  50. Navarrete-Solís J, et. al. A Double-Blind, Randomized Clinical Trial of Niacinamide 4% versus Hydroquinone 4% in the Treatment of Melasma. Dermatol Res Pract. (2011)
  51. Yousefi A, et. al. Is topical zinc effective in the treatment of melasma? A double-blind randomized comparative study. Dermatol Surg. (2014)
  52. Iraji F, Tagmirriahi N, Gavidnia K. Comparison between the efficacy of 10% zinc sulfate solution with 4% hydroquinone cream on improvement of melasma. Adv Biomed Res. (2012)
  53. Tirado-Sánchez A, Santamaría-Román A, Ponce-Olivera RM. Efficacy of dioic acid compared with hydroquinone in the treatment of melasma. Int J Dermatol. (2009)
  54. Haddad AL, et. al. A clinical, prospective, randomized, double-blind trial comparing skin whitening complex with hydroquinone vs. placebo in the treatment of melasma. Int J Dermatol. (2003)
  55. Monteiro RC, et. al. A Comparative Study of the Efficacy of 4% Hydroquinone vs 0.75% Kojic Acid Cream in the Treatment of Facial Melasma. Indian J Dermatol. (2013)
  56. Garcia A, Fulton JE Jr. The combination of glycolic acid and hydroquinone or kojic acid for the treatment of melasma and related conditions. Dermatol Surg. (1996)
  57. Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Dermatol Surg. (1999)
  58. Deo KS, et. al. Kojic Acid vis-a-vis its Combinations with Hydroquinone and Betamethasone Valerate in Melasma: A Randomized, Single Blind, Comparative Study of Efficacy and Safety. Indian J Dermatol. (2013)
  59. Guevara IL, Pandya AG. Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of melasma. Int J Dermatol. (2003)
  60. Grimes PE. A microsponge formulation of hydroquinone 4% and retinol 0.15% in the treatment of melasma and postinflammatory hyperpigmentation. Cutis. (2004)
  61. Cook-Bolden FE, Hamilton SF. An open-label study of the efficacy and tolerability of microencapsulated hydroquinone 4% and retinol 0.15% with antioxidants for the treatment of hyperpigmentation. Cutis. (2008)
  62. Grimes PE. An efficacy study of 3 commercially available hydroquinone 4% treatments for melasma. Cutis. (2007)
  63. Grimes P, Watson J. Treating epidermal melasma with a 4% hydroquinone skin care system plus tretinoin cream 0.025%. Cutis. (2013)
  64. Gold M, et. al. Open-label treatment of moderate or marked melasma with a 4% hydroquinone skin care system plus 0.05% tretinoin cream. J Clin Aesthet Dermatol. (2013)
  65. Iida S, et. al. Silicone sheet containing all-trans retinoic acid and hydroquinone for the treatment of epidermal melanosis. Dermatol Surg. (2013)
  66. Chan R, et. al. A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma. Br J Dermatol. (2008)
  67. Ferreira Cestari T, et. al. A comparison of triple combination cream and hydroquinone 4% cream for the treatment of moderate to severe facial melasma. J Cosmet Dermatol. (2007)
  68. Taylor SC, et. al. Efficacy and safety of a new triple-combination agent for the treatment of facial melasma. Cutis. (2003)
  69. Torok HM, et. al. Hydroquinone 4%, tretinoin 0.05%, fluocinolone acetonide 0.01%: a safe and efficacious 12-month treatment for melasma. Cutis. (2005)
  70. Grimes P, et. al. Community-based trial of a triple-combination agent for the treatment of facial melasma. Cutis. (2006)
  71. Rendon MI. Utilizing combination therapy to optimize melasma outcomes. J Drugs Dermatol. (2004)
  72. Grimes PE, et. al. Continuous therapy followed by a maintenance therapy regimen with a triple combination cream for melasma. J Am Acad Dermatol. (2010)
  73. Monheit GD, Dreher F. Comparison of a skin-lightening cream targeting melanogenesis on multiple levels to triple combination cream for melasma. J Drugs Dermatol. (2013)
  74. Nanda S, Grover C, Reddy BS. Efficacy of hydroquinone (2%) versus tretinoin (0.025%) as adjunct topical agents for chemical peeling in patients of melasma. Dermatol Surg. (2004)
  75. Garg VK, Sarkar R, Agarwal R. Comparative evaluation of beneficiary effects of priming agents (2% hydroquinone and 0.025% retinoic acid) in the treatment of melasma with glycolic acid peels. Dermatol Surg. (2008)
  76. Sarkar R, et. al. The combination of glycolic acid peels with a topical regimen in the treatment of melasma in dark-skinned patients: a comparative study. Dermatol Surg. (2002)
  77. Rendon M, et. al. Successful treatment of moderate to severe melasma with triple-combination cream and glycolic acid peels: a pilot study. Cutis. (2008)
  78. Kang WH, Chun SC, Lee S. Intermittent therapy for melasma in Asian patients with combined topical agents (retinoic acid, hydroquinone and hydrocortisone): clinical and histological studies. J Dermatol. (1998)
  79. Bruce S, Watson J. Evaluation of a prescription strength 4% hydroquinone/10% L-ascorbic acid treatment system for normal to oily skin. J Drugs Dermatol. (2011)
  80. Kurita M, Kato H, Yoshimura K. A therapeutic strategy based on histological assessment of hyperpigmented skin lesions in Asians. J Plast Reconstr Aesthet Surg. (2009)
  81. Momosawa A, et. al. Combined therapy using Q-switched ruby laser and bleaching treatment with tretinoin and hydroquinone for acquired dermal melanocytosis. Dermatol Surg. (2003)
  82. Momosawa A, et. al. Combined therapy using Q-switched ruby laser and bleaching treatment with tretinoin and hydroquinone for periorbital skin hyperpigmentation in Asians. Plast Reconstr Surg. (2008)
  83. Karamagi C, Owino E, Katabira ET. Hydroquinone neuropathy following use of skin bleaching creams: case report. East Afr Med J. (2001)
  84. Shibata MA, et. al. Induction of renal cell tumors in rats and mice, and enhancement of hepatocellular tumor development in mice after long-term hydroquinone treatment. Jpn J Cancer Res. (1991)
  85. Whysner J, et. al. Analysis of studies related to tumorigenicity induced by hydroquinone. Regul Toxicol Pharmacol. (1995)
  86. David RM, et. al. Lack of nephrotoxicity and renal cell proliferation following subchronic dermal application of a hydroquinone cream. Food Chem Toxicol. (1998)
  87. Andersen FA, et. al. Final amended safety assessment of hydroquinone as used in cosmetics. Int J Toxicol. (2010)
  88. Mahé A, et. al. The cosmetic use of skin-lightening products during pregnancy in Dakar, Senegal: a common and potentially hazardous practice. Trans R Soc Trop Med Hyg. (2007)
  89. Blacker AM, et. al A two-generation reproduction study with hydroquinone in rats. Fundam Appl Toxicol. (1993)
  90. Charlín R, et. al. Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy. Int J Dermatol. (2008)
  91. Martins VM, et. al. Exogenous ochronosis: case report and literature review. An Bras Dermatol. (2012)
  92. Gandhi V, Verma P, Naik G. Exogenous ochronosis After Prolonged Use of Topical Hydroquinone (2%) in a 50-Year-Old Indian Female. Indian J Dermatol. (2012)
  93. Findlay GH, Morrison JG, Simson IW. Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams. Br J Dermatol. (1975)
  94. Hoshaw RA, Zimmerman KG, Menter A. Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks. Arch Dermatol. (1985)
  95. Singh A, Ramesh V. Exogenous ochronosis. Indian J Med Res. (2014)
  96. Levin CY, Maibach H. Exogenous ochronosis. An update on clinical features, causative agents and treatment options. Am J Clin Dermatol. (2001)
  97. Tan SK, Sim CS, Goh CL. Hydroquinone-induced exogenous ochronosis in Chinese--two case reports and a review. Int J Dermatol. (2008)
  98. Zawar V, Chuh A. Exogenous ochronosis in Asians. Int J Dermatol. (2010)
  99. Tan SK. Exogenous ochronosis in ethnic Chinese Asians: a clinicopathological study, diagnosis and treatment. J Eur Acad Dermatol Venereol. (2011)
  100. Mann RJ, Harman RR. Nail staining due to hydroquinone skin-lightening creams. Br J Dermatol. (1983)
  101. Ozluer SM, Muir J. Nail staining from hydroquinone cream. Australas J Dermatol. (2000)
  102. Parlak AH, Aydoğan I, Kavak A. Discolouration of the fingernails from using hydroquinone skin-lightening cream. J Cosmet Dermatol. (2003)
  103. Torok HM. A comprehensive review of the long-term and short-term treatment of melasma with a triple combination cream. Am J Clin Dermatol. (2006)
  104. Torok H, et. al. A large 12-month extension study of an 8-week trial to evaluate the safety and efficacy of triple combination (TC) cream in melasma patients previously treated with TC cream or one of its dyads. J Drugs Dermatol. (2005)
  105. Bhawan J, et. al. A histological examination for skin atrophy after 6 months of treatment with fluocinolone acetonide 0.01%, hydroquinone 4%, and tretinoin 0.05% cream. Am J Dermatopathol. (2009)