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3/8/2019 8:04:27 AM


Hydroquinone cream is the standard depigmentation or skin lightening agent. Clinically it is used to treat areas of dyschromia, such as in:

  • Melasma
  • Chloasma
  • Solar lentigines
  • Freckles
  • Post-inflammatory hyperpigmentation

Its most common use is in patients with post-inflammatory hyperpigmentation and melasma.

Post-inflammatory hyperpigmentation

Postinflammatory hyperpigmentation results from cutaneous inflammation, causing increased melanin production. Common causes of postinflammatory hyperpigmentation are acne vulgaris, eczematous dermatoses, contact dermatitis, psoriasis, lichen planus, and burns.[1] The most common cause of hyperpigmentation results from photodamage from sunlight exposure.[2] Inflammation increases the release and oxidation of arachidonic acid to prostaglandins and leukotrienes resulting in increased melanin production.[3] Hydroquinone is used to treat postinflammatory hyperpigmentation along with photoprotection. Improvement with hydroquinone occurs over several weeks to months.[4]


Melasma is an acquired hyperpigmentation and presents on sun-exposed areas of the face, commonly the forehead, cheeks, and chin.[5] It presents as symmetrically distributed pigmented macules and patches.[6] Factors that play a role in the pathogenesis of melasma are darker skin, UV radiation, hormones, genetics, and antiepileptic medications. Exposure to UV radiation is the main factor in pathogenesis as UV radiation increases the levels of alpha-melanocyte-stimulating hormone and adrenocorticotropic hormone, which increases the proliferation of melanocytes.[7] Also, at the dermal layer, increased expression of stem cells of fibroblasts and tyrosine kinase receptor c-kit is resent in melasma lesions. Also noted in lesions are upregulation of vascular endothelial growth factor (VEGF), Wnt, and reactive oxygen species seen after UV induced dermal inflammation. Vascularization and melanocyte hyperreactivity results from this UV induced inflammation leading to increased melanin production and hyperpigmentation. Patients who are pregnant or use oral contraceptives are also at risk because the expression of estrogen receptors seems to rise in melasma lesions as well.[8][6] Estrogen also induces the release of melanocyte-stimulating hormone (MSH), which stimulates tyrosinase leading to increased production of melanin. For this reason, melasma occurs more frequently in females vs. males [6]. Treatment is similar to postinflammatory hyperpigmentation, with photoprotection and hydroquinone being the first line.

Photoprotection is a significant key in maximal benefit from hydroquinone use. Melanocytes are stimulated from UVB, UVA, and even visible light leading to pigmentation. Therefore, broad-spectrum sunscreens are recommended.[6]

Hydroquinone is not FDA approved due to its unknown safety profile. It is banned in the EU, Australia, and Japan.

Mechanism of Action

Hydroquinone acts as a skin depigmentation agent by inhibiting melanin synthesis. It inhibits the conversion of L-3,4- dihydroxyphenylalanine (L-DOPA) to melanin by inhibiting tyrosinase due to its structural similarity to an analog of melanin precursors.[6]

The pathway of melanin synthesis[9]:

  1. Hydroxylation of L-phenylalanine to L-tyrosine
  2. Tyrosinase hydroxylates L-tyrosine to 3,4 L-dihydroxyphenylalanine (L-DOPA)
  3. L-DOPA oxidized to dopaquinone
  4. Production of eumelanin and pheomelanin resulting in black to brown and yellow to red color of skin


Hydroquinone is only used topically as a depigmentation agent. A thin layer is applied with fingertips and rubbed into the face (or other affected areas) 1 to 2 times a day for 3 to 6 months. If there are no results after 2 to 3 months, hydroquinone should be discontinued. It is important to evenly apply hydroquinone over the entire face to prevent uneven pigmentation and use concurrently with sunscreen to protect from damaging UV light, which increases pigmentation.  Physicians recommended stopping treatment after this time for a few months before restarting to decrease the risk of side effects. It can also be applied during weekends only or three times a week for more extended maintenance therapy with minimal complications.[6]

Hydroquinone is available in 2% over the counter or as 4% prescribed.[2]  It comes in the following dose forms: cream, emulsion, gel, or solution.

Multiple studies have shown that maximum results occur when using hydroquinone as combination therapy with a retinoid and corticosteroid. The most widely used triple combination cream is composed of hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01%.[6] Use in combination with other agents requires a prescription by a dermatologist.

Results vary among each patient.

About 35% to 45% of hydroquinone is absorbed systemically after topical use.[10]

Adverse Effects

Adverse Effects[11][6][2]:

  • Irritation
  • Allergic contact dermatitis
  • Erythema
  • Inflammation
  • Xeroderma
  • Stinging
  • Rarely ochronosis - ochronosis is a blue-black or gray-blue discoloration; it is rare and more commonly seen in patients that use a high concentration of hydroquinone for a long period on large areas of the body

Studies also suggest that hydroquinone can falsely elevate capillary glucose when measured with a glucometer.[12]

Concerns that hydroquinone cream is carcinogenic have not been confirmed in clinical practice or human research.[6]


  • Allergic reaction or hypersensitivity hydroquinone 
  • Sun exposure
  • Be cautious when using with other medications that cause photosensitivity

Pregnancy Category C

About 35 to 45% of the topical hydroquinone dose is absorbed systemically. Current studies have not shown an increased risk of malformations or adverse effects in pregnant women, but it is recommended to minimize exposure due to the substantial absorption.[10] The safety of breastfeeding mothers and in children is yet to be established and as such should be avoided.


Monitor for any hypersensitivity or long term irritation, in which case the medication should be discontinued. Also, in the rare case ochronosis develops, stop using hydroquinone and consult a physician.


No significant toxicity has been found with the topical use of the hydroquinone cream.

Some studies report malignancies in animals treated for an extended period with large oral doses.[2]

Hydroquinone in the environment

In the environment, hydroquinone is a chemical and can be toxic in the setting of human and industrial activities by promoting the generation of reactive oxygen species, oxidative stress and hence the potential for DNA damage. It is a major benzene metabolite and is known to be hepatotoxic and carcinogenic in these settings. Some studies suggest it can promote tumor cell growth and suppress the immune response. It is used in photography and is present in dyes, paints, varnishes oils, and motor fuels. In its oxidized form, it is more toxic and less degradable. It demonstrates high toxicity to aquatic organisms, and rodents and may induce leukemia, renal tubular cell tumor, and liver cancer. It has also been found to influence immune cell responses and causes an increase in an allergic response by increasing interleukin-4 production and immunoglobulin E levels.[13]

Enhancing Healthcare Team Outcomes

The health care team, such as physicians, nurses, and pharmacists play an important role in monitoring patients on hydroquinone. It is important to monitor patients to ensure that they only use the medication as prescribed for no more than 5 to 6 months to limit side effects. Also, it is important to follow instructions for the medication application, its frequency, keep a watchful eye for any adverse effect, which should be clearly explained to the patient. Patients should be instructed to cease using the medication if any sort of irritation, hypersensitivity, or allergic reaction occurs. The rare, yet most potentially harmful, side effect of ochronosis needs to be explained to patients using hydroquinone, and they should be instructed to discontinue this medication immediately if this occurs. 

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Hydroquinone - References


Epstein JH, Postinflammatory hyperpigmentation. Clinics in dermatology. 1989 Apr-Jun;     [PubMed]
Stephens TJ,Babcock M,Bucay V,Gotz V, Split-face Evaluation of a Multi-ingredient Brightening Foam Versus a Reference Control in Women with Photodamaged Facial Skin. The Journal of clinical and aesthetic dermatology. 2018 Oct;     [PubMed]
Tomita Y,Maeda K,Tagami H, Mechanisms for hyperpigmentation in postinflammatory pigmentation, urticaria pigmentosa and sunburn. Dermatologica. 1989;     [PubMed]
Katsambas AD,Stratigos AJ, Depigmenting and bleaching agents: coping with hyperpigmentation. Clinics in dermatology. 2001 Jul-Aug;     [PubMed]
Sofen B,Prado G,Emer J, Melasma and Post Inflammatory Hyperpigmentation: Management Update and Expert Opinion. Skin therapy letter. 2016 Jan;     [PubMed]
Kauh YC,Zachian TF, Melasma. Advances in experimental medicine and biology. 1999;     [PubMed]
Mahmoud BH,Ruvolo E,Hexsel CL,Liu Y,Owen MR,Kollias N,Lim HW,Hamzavi IH, Impact of long-wavelength UVA and visible light on melanocompetent skin. The Journal of investigative dermatology. 2010 Aug;     [PubMed]
Lieberman R,Moy L, Estrogen receptor expression in melasma: results from facial skin of affected patients. Journal of drugs in dermatology : JDD. 2008 May;     [PubMed]
Speeckaert R,Van Gele M,Speeckaert MM,Lambert J,van Geel N, The biology of hyperpigmentation syndromes. Pigment cell     [PubMed]
Bozzo P,Chua-Gocheco A,Einarson A, Safety of skin care products during pregnancy. Canadian family physician Medecin de famille canadien. 2011 Jun;     [PubMed]
Rendon MI,Barkovic S, Clinical Evaluation of a 4% Hydroquinone 1% Retinol Treatment Regimen for Improving Melasma and Photodamage in Fitzpatrick Skin Types III-VI. Journal of drugs in dermatology : JDD. 2016 Nov 1;     [PubMed]
Choukem SP,Efie DT,Djiogue S,Kaze FF,Mboue-Djieka Y,Boudjeko T,Dongo E,Gautier JF,Kengne AP, Effects of hydroquinone-containing creams on capillary glycemia before and after serial hand washings in Africans. PloS one. 2018;     [PubMed]
Enguita FJ,Leitão AL, Hydroquinone: environmental pollution, toxicity, and microbial answers. BioMed research international. 2013;     [PubMed]


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