Amongst the definitions for healthy skin appearance is an even complexion. Unfortunately, there are many causes of uneven pigmentation, and one of the most common is melasma. This is a hyperpigmentation disorder that results in the appearance of flat, dark brown-to-greyish patches on both sides of the face. 

Hydroquinone has been the go-to treatment for melasma for decades. Following its initial discovery, research on this powerhouse ingredient has continued, leading to more effective and safer ways to reap its benefits. 

So how exactly does hydroquinone work to lighten melasma? To answer that, we must first understand how melasma develops.

Melasma 101

In simple terms, melasma occurs when melanocytes produce more melanin than usual. This pigment could be deposited in the epidermis, the superficial layer of the skin, or dermis, the layer right underneath it. To the naked eye, it appears as flat, dark brown to greyish-brown patches that appear symmetrically on the face. There are different patterns of distribution, but the most common locations include the forehead, cheeks, nose, and chin.

There appears to be no singular cause for melasma, rather, it is a multifactorial medical condition (Bandyopadhyay, 2009). There appears to be some abnormality in the processes that controls melanin production. Genetics, family history, and hormonal imbalances clearly play a role. External influences include administration of certain kinds of medications, cosmetics, and skincare products. Last but most importantly, sun/light exposure and a lack of sun protective measures is a likely culprit in the exacerbation of melasma, as well as many other hyperpigmentation disorders. 

Approximately 1% of the global population suffers from this condition, but within certain populations, it can be much higher. Those with darker skin types (Fitpatrick IV to VI) and Asian, African, or Latino descent are more likely to have melasma (Pichardo et al., 2009). It is more common in women than in men, particularly those of reproductive age (Shankar et al., 2014). In pregnant women, melasma is also called “chloasma” or the “mask of pregnancy”.

Though melasma itself does not pose a health risk, both anecdotal and scientific evidence has shown it has a considerable effect on one’s psycho-emotional wellbeing (Fatma et al., 2016; Jiang et al., 2017). In an effort to improve the quality of life of melasma patients, decades of research have been dedicated to understanding the disorder and finding its cure.

There are a number of ingredients used to lighten melasma marks, but the top choice for many dermatologists remains hydroquinone, either as an agent on its own, or combined with other ingredients. 

How does hydroquinone work?

Hydroquinone’s effectiveness as a skin lightening agent relies primarily on its molecular structure. It is very similar to that of L3,4-diphenylalanine, (L-DOPA) a melanin precursor. So similar in fact, that the enzyme that usually binds to L-DOPA, which is called tyrosinase, ends up binding to hydroquinone instead. This is bad news for skin pigment production, as this particular enzyme is responsible for converting L-DOPA to melanin. As a tyrosinase inhibitor, hydroquinone effectively ambushes the production of melanin.

There is another way that hydroquinone throws a wrench into the process of skin pigmentation: it damages the cells responsible for producing melanin, called melanocytes. Over time, the number of microscopic pigment-making factories decrease, vastly slowing down the darkening of skin. 

Hydroquinone’s two-fold approach to inhibiting melanin deposition makes it excellent at treating melasma. It has retained the top spot as the drug of choice for melasma, with studies showing upwards of 70% of patients seeing significant improvements within 3 months of twice daily use. It is particularly effective at addressing melasma cases wherein the melanin is deposited in the epidermis, or topmost layer of the skin.

What are the indications for hydroquinone use?

Hydroquinone’s potency as a depigmenting agent makes it ideal for use in a wide variety of hyperpigmentation disorders. Melasma is one important example, but there are others.

Post-inflammatory hyperpigmentation is caused by excessive melanin production in response to an injury or infection. Thermal burns, acne, skin infections, and razor bumps may leave behind a darkened area that persists for much longer than it took to heal the initial insult. Hydroquinone has been used to speed up skin lightening to great effect, as soon as the inflammation has already been controlled. 

Solar lentigines, also known as sun spots or liver spots, occur because of intense or prolonged sun exposure without proper protection. This may occur because of decades of sun damage, as in older individuals, or among those who regularly use the tanning bed. Hydroquinone can address existing spots, but nothing beats sun protection measures in preventing new ones from appearing.

Certain drugs, such as the ones used in chemotherapy, may cause changes to the skin. Dryness, irritation, inflammation, and hyperpigmentation can occur. For the latter, hydroquinone may be used in the cases where the dark spots persist after cessation of therapy.

Hydroquinone has also been used to prevent and treat hyperpigmentation caused by laser treatments. Since one complication of these types of resurfacing techniques is increased melanin production, bleaching creams have been used to reduce the chance of occurrence.

It is common clinical practice to apply hydroquinone for a period of time before laser treatment, but some studies show that this has no effect. The plausible reasoning is because the skin layers that grow after laser resurfacing include melanocytes that were not exposed to the topical bleaching agent. However, the skin-lightening effects of hydroquinone use after laser therapy is well-documented.

What are factors to consider before using hydroquinone for melasma?

Hydroq uinone use can sometimes cause side effects.  It appears that the adverse side effects are more likely to occur when patients use more concentrated formulations, and increase the frequency of application outside of their doctor’s orders. 

Hydroquinone use has been associated with irritant or contact allergy dermatitis, causing dryness, redness, itchiness, increased sensitivity to the sun, and a painful stinging sensation when applied. However, these are often mild and transient. Use of hydroquinone in tandem with other skincare or cosmetic products with irritating ingredients, exacerbating the irritation of already sensitised skin.

More lasting effects on the skin include the formation of colloid milium and milia, which are small bumps on the skin that may or may not be pigmented. Discoloration of the nails and skin may also occur, but these are rare occurrences. 

Exogenous ochronosis, or the formation of bruise-colored patches on the skin, has long been associated with hydroquinone use, but it appears this condition develops when high concentrations of the ingredient are used frequently over a long period of time. The risk of this occurring when doctor’s orders about concentration and dosage are followed is very slim.  A systematic review of exogenous ochronosis case reports found that it is most likely to occur in patients who use over 4% hydroquinone products over an average of 5 years (Ischak and Lipner, 2021).

Perhaps the most worrying safety issue associated with hydroquinone use is carcinogenicity. Use on lab animals has shown that the ingredient appears to trigger the development of cancerous growths (Kooyers and Westerhoff, 2004). However, this result has not been found in the many human studies on hydroquinone use, nor have there been reports of its occurrence in clinical practice despite half a century of use (McGregor, 2007; Sofen et al., 2016).

The safety of hydroquinone use in lactating women is not yet known and hence should not be used in this setting. So far, no studies have shown that hydroquinone is teratogenic. That doesn’t mean that it is considered safe in pregnancy, however.  Since 35-45% of the drug gets absorbed into the bloodstream through topical administration, it is advised that pregnant and lactating patients err on the side of caution and opt for other skin lightening measures. 

As with any drug, it is best to consult a health professional prior to using hydroquinone. To ensure that this medication is the appropriate treatment, a dermatologist should confirm the diagnosis, take a thorough history, examine the patient’s skin, and conduct other diagnostic tests, if necessary. 

How is hydroquinone used?

Hydroquinone is administered topically by applying a thin layer on hyperpigmented areas. To treat melasma, dermatologists will usually suggest once or twice daily administration for at least 3 months. Proper and even application is essential, as failure to do so may lead to irregularities in color. 

Regular consultation with a dermatologist throughout the treatment period is important to assess the patient’s response. Adjustments can be made on the prescription depending on the rate of improvement and occurrence of side effects.

Hydroquinone can be continued even after resolution of melasma as maintenance therapy. This usually means scaling down the frequency to once or twice weekly use.  However, you should always be guided by your dermatologist.

What formulations are available?

Formulations for melasma usually contain 2-6% hydroquinone. In some countries, it is possible to buy over-the-counter products at 2% concentration or less. However, in other areas, a prescription is required to purchase hydroquinone-containing products, regardless of concentration.  In Australia, prescribed strengths of hydroquinone 4% and above need to be compounded and a suitable compounding pharmacy.

It can be made as a solution, emulsion, cream, or gel. Some products use hydroquinone as the sole active ingredient, while others use it in combination with other ingredients for added skin benefits (Gupta et al., 2006). These include retinoids such as tretinoin, antioxidants such as ascorbic acid, alpha-hydroxy acids, and other lightening ingredients such as licorice root extract, azelaic acid and tranexamic acid. 

Kligman’s formula is one of the most prescribed products for melasma. It is a combination of hydroquinone, tretinoin, and a corticosteroid. The original formula started as 5.0% hydroquinone, 0.1% tretinoin, 0.1% dexamethasone (Kligman and Willis, 1975). The addition of tretinoin improves penetration, add additional depigmenting power, and improve the texture and appearance of skin. Dexamethasone was included to counter the inflammatory and irritating effects of the other two ingredients. 

Over the years, many modifications to Kligman’s formula have been made.  The concentration of the components may change and corticosteroids other than dexamethasone may be used. Generally, these triple combination creams are very effective at treating melasma, with all three ingredients working together to improve skin appearance (Ferreira Cestari et al., 2007). However, clinical trials are continuously being done to find the best iteration of the triple combination cream, one that is able to deliver the medication in the safest and most effective way possible.

How to maximise the effects of hydroquinone 

Hydroquinone is great at doing its job, but if you want to take full advantage of its benefits and minimise potential adverse side effects, there are a number of things you can do.

Use sun/light protection

Melanin production is triggered by sun exposure, no doubt about it. So if you want to treat melasma, you have to lighten existing marks and stop new ones from popping up. Hydroquinone will also sensitise your skin to UV radiation, so protecting it becomes even more important.

While sunscreen is definitely a pillar of sun protection, take note that it’s only one among many. Using a broad-spectrum, high SPF sunscreen is important, but so is using protective clothing, minimising sun exposure, and seeking shade. 

But note the words in the title of this paragraph “sun/light”.  Yes, you guessed it.  It’s not just UV from the sun that triggers and worsens melasma.  Visible light from the sun is also implicated in melasma.  And it’s not just sun that produces visible light.  The light produces by your phone screen, tablet, laptop and even the LED globes that light up your room can drive those melanocytes into action.  To counter this, using tinted sunscreens with high concentrations of iron oxide pigments can block visible light.  So get that tint on!

Buy from a reputable source

It may be tempting to buy hydroquinone products at a fraction of the cost from overseas or your local ‘friend’, but you might be getting more than you bargained for. Buy from compounding pharmacies who buy their raw ingredients only from accredited and trusted sources.  Cheap is not always good.  Skin Plus Compounding Pharmacy does not buy any raw ingredients from overseas un-trusted sources.

Study your skincare regimen

Hydroquinone is a potent drug that will certainly have an effect on the skin. It does not always take kindly to being used alongside other ingredients. So before making the jump, take a good hard look at the skincare products you have on the shelf, and do research on whether they could react with hydroquinone. 

If you are consulting with a dermatologist, they will likely provide a holistic melasma management plan that contains all the products and advice you need.

Do a patch test

This should be standard protocol whenever trying out a new product on your skin. Apply your hydroquinone formulation in a small patch of skin, and observe for reactions for 24 hours. Red flags include prolonged itching, redness, swelling, heat, or pain. 

Listen to your skin

Everyone’s skin reacts differently, so pay attention to yours. Look for hallmarks of inflammation and irritation, and pay attention to when they occur. Take pictures of your skins’ progress to see if the cream is working. Learning to listen to your skin can help you determine if this skincare regimen is working for you, or if you need something else to treat your melasma.

References:

Bandyopadhyay D. (2009). Topical treatment of melasma. Indian journal of dermatology, 54(4), 303–309. https://doi.org/10.4103/0019-5154.57602

Draelos, Zoe. (2007). Skin lightening preparations and the hydroquinone controversy. Dermatologic therapy. 20. 308-13. 10.1111/j.1529-8019.2007.00144.x. 

Fatma, F. & Baati, Imen & Mseddi, M. & Sallemi, R. & Hamida, Turki & Masmoudi, Jawaher. (2016). The psychological impact of melasma. A report of 30 Tunisian women. European Psychiatry. 33. S327. 10.1016/j.eurpsy.2016.01.1130. 

Ferreira Cestari, T., Hassun, K., Sittart, A., & de Lourdes Viegas, M. (2007). A comparison of triple combination cream and hydroquinone 4% cream for the treatment of moderate to severe facial melasma. Journal of cosmetic dermatology, 6(1), 36–39. https://doi.org/10.1111/j.1473-2165.2007.00288.x

Gupta, A. K., Gover, M. D., Nouri, K., & Taylor, S. (2006). The treatment of melasma: a review of clinical trials. Journal of the American Academy of Dermatology, 55(6), 1048–1065. https://doi.org/10.1016/j.jaad.2006.02.009

Ishack, S., & Lipner, S. R. (2021). Exogenous ochronosis associated with hydroquinone: a systematic review. International journal of dermatology, 10.1111/ijd.15878. Advance online publication. https://doi.org/10.1111/ijd.15878

Jiang, J., Akinseye, O., Tovar-Garza, A., & Pandya, A. G. (2017). The effect of melasma on self-esteem: A pilot study. International journal of women's dermatology, 4(1), 38–42. https://doi.org/10.1016/j.ijwd.2017.11.003

Kooyers, T. J., & Westerhof, W. (2004). Toxicologische aspecten en gezondheidsrisico's van hydrochinon in huidbleekformuleringen [Toxicological aspects and health risks associated with hydroquinone in skin bleaching formula]. Nederlands tijdschrift voor geneeskunde, 148(16), 768–771.

Levitt J. (2007). The safety of hydroquinone: a dermatologist's response to the 2006 Federal Register. Journal of the American Academy of Dermatology, 57(5), 854–872. https://doi.org/10.1016/j.jaad.2007.02.020

McGregor D. (2007). Hydroquinone: an evaluation of the human risks from its carcinogenic and mutagenic properties. Critical reviews in toxicology, 37(10), 887–914. https://doi.org/10.1080/10408440701638970

Kligman, A. M., & Willis, I. (1975). A new formula for depigmenting human skin. Archives of dermatology, 111(1), 40–48.

Majid I. (2010). Mometasone-based triple combination therapy in melasma: is it really safe?. Indian journal of dermatology, 55(4), 359–362. https://doi.org/10.4103/0019-5154.74545

Pichardo, R., Vallejos, Q., Feldman, S. R., Schulz, M. R., Verma, A., Quandt, S. A., & Arcury, T. A. (2009). The prevalence of melasma and its association with quality of life in adult male Latino migrant workers. International journal of dermatology, 48(1), 22–26. https://doi.org/10.1111/j.1365-4632.2009.03778.x 

Schwartz C, Jan A, Zito PM. Hydroquinone. [Updated 2021 Nov 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539693/

Shankar, K., Godse, K., Aurangabadkar, S. et al. Evidence-Based Treatment for Melasma: Expert Opinion and a Review. Dermatol Ther (Heidelb) 4, 165–186 (2014). https://doi.org/10.1007/s13555-014-0064-z

Taylor, S. C., Torok, H., Jones, T., Lowe, N., Rich, P., Tschen, E., Menter, A., Baumann, L., Wieder, J. J., Jarratt, M. M., Pariser, D., Martin, D., Weiss, J., Shavin, J., & Ramirez, N. (2003). Efficacy and safety of a new triple-combination agent for the treatment of facial melasma. Cutis, 72(1), 67–72.

West, T. B., & Alster, T. S. (1999). Effect of pretreatment on the incidence of hyperpigmentation following cutaneous CO2 laser resurfacing. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.], 25(1), 15–17. https://doi.org/10.1046/j.1524-4725.1999.08123.x

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