Topical Retinoids

By Dr Sandeep Cliff / 13 Jan 2017

Dr Sandeep Cliff outlines the different forms of topical retinoids and discusses their mechanisms of action

‘Retinoid’ is an umbrella term to describe all forms of vitamin A, including both naturally and synthetically produced derivatives, which have been in regular use in dermatology for more than 70 years.1 Retinoids have been used to treat a variety of cutaneous disorders such as plaque psoriasis, acne, oily skins, epithelial tumours and photoageing with more than 2,500 compounds now available.1 This article will explore the common forms of topical retinoids, how they work and their different functions, as well as how they can be combined with other ingredients.

What are retinoids?

There are three generations of retinoids (Figure 1).2 They are compounds that have biological activity similar to naturally occurring vitamin A (retinol) and cover a huge spectrum of effects, from cosmetic to prescription-only medicine use. It is important to note that vitamin A cannot be synthesised by the body, but needs to be supplied to the body, for example as a topical product, in a ‘ready to use’ form.3 

Figure 1: Chart showing the different generations of retinoids2

Retinoids are known to be irritating to the skin, which limits their use in many patients.3 Retinol and retinaldehyde are commonly used in aesthetic skincare products, as they are gentle yet effective alternatives to retinoic acid (RA).

Topical retinoids have different effects on cell proliferation under different conditions. It has been demonstrated that retinoids can exert both immunomodulatory and anti-inflammatory activity, and in psoriasis have been indicated to reduce proliferation, enhance differentiation, regulate corneocyte desquamation, modulate lymphocyte function and inhibit neutrophil migration.

Retinoid actions

As mentioned previously, retinoids have multiple modes of action, which are outlined below.


Use of both RA and retinol has been indicated to increase epidermal thickness and has demonstrated increases in procollagen I and procollagen III protein expression.5 Topical retinoids can act as UV filters as retinoids absorb UV light; an in vitro study with mice skin exposed to topical retinyl palmitate demonstrated effects in prevention of UVB induced erythema and DNA photodamage, suggesting that epidermal retinyl esters have a biologically relevant filter activity.6 In an eight-week double-blind, split face, vehicle-controlled study with digital photography, researchers demonstrated that the retinol treated side had statistically significant reductions in: lines and wrinkles, mottled pigmentation, and improvements in firmness, elasticity and overall photodamage.

Fine lines and wrinkles and HA production

Topical vitamin A preparations are widely used as a treatment for fine lines and wrinkles.8 Studies have indicated that retinoids increase water content in the dermis by stimulating glycosaminoglycan (GAG) synthesis, particularly hyaluronic acid (HA) and by stimulating both transforming growth factor (TGF-beta) procollagen leading to an increase in dermal Type I collagen.9,10,11 Matrix metalloproteinase production and consequently collagen degradation are prevented when retinoids are applied topically prior to ultraviolet irradiation.8

Skin roughness

Retinoids speed up epidermal cell turnover by modulating the expression of relevant genes, increasing cellular differentiation and proliferation.9,12


RA has been used for hyperpigmentation as it increases cell turnover, which in turn decreases contact time between keratinocytes and melanocytes and reduces pigment through epidermopoiesis, with a reduction of clumping of melanin in basal cells.10 RA suppresses UVB-induced pigmentation by reducing tyrosinase activity. The acid acts at a posttranscriptional level on tyrosinase and tyrosinase-related protein.13,14

Antibacterial and sebum reducing properties 

In patients with acne, topical retinoids have been suggested to increase follicular epithelium turnover, expelling mature comedones and inhibiting formation of microcomedones and creating a negative environment for Propionibacterium acnes.15

Treatment with vitamin A is known to be associated with ‘the retinoid response’, a phrase to describe the typical outcome of pruritus, burning sensation at treatment sites, peeling and erythema

Sebum reduction has been demonstrated in various studies, as well as for the control of formation of comedones, reduced lesion count and increased epithelial desquamation.16,17

Retinoids as antioxidants 

Topical retinoids have been shown to have antioxidant, free-radical scavenging properties in vitro,10 and Draelos suggests their use alongside other topical antioxidants to ensure full antioxidant protection.18

Common types of topical retinoids


Tretinoin in the treatment of photoageing was first demonstrated in 1984. Using an animal model, Kligman et al. observed that 10 weeks of tretinoin treatment on photoaged mice skin resulted in the repair of new collagen in the papillary dermis with a direct correlation to wrinkle effacement.1,19 There are many other studies that support the widespread use of tretinoin in both clinical and aesthetic scenarios.1,3,19,20


Isotretinoin has been used both orally and topically. For topical use, it has been shown to result in a reduction of fine lines and wrinkles as well as pigmentation, sallowness and texture without causing significant irritation.21,22

In 2005 Griffiths et al. conducted a six-month, multicentre, double blind, randomised, parallel-group, vehicle controlled study of 346 subjects with photoaged skin using 0.05% isotretinoin combined with sunscreen. Out of the subjects, 172 received active ingredients and 174 received only the vehicle. Profilometry measurements of replicas of the periorbital region, taken at zero and six months, demonstrated significant reductions in wrinkle depth and improvement in fine lines.23


The mode of action of retinol involves conversion to all-trans-retinoic acid via retinaldehyde within keratinocytes to exert an effect on the epidermis.24 Retinol induces epidermal thickening, enhances the expression of retinol binding protein genes CRABP II and CRBP but produces less erythema and irritation when compared to tretinoin.9 Retinol is also associated with less trans epidermal water loss, erythema and scaling than RA whilst stimulating collagen synthesis and reducing matrix metalloproteinases (MMP) production.9,25

In 2015 Randhawa et al. studied prolonged use of retinol demonstrating that 0.1% retinol significantly improves the signs of photoageing and improvements in photodamage at all time points versus vehicle during the study. Histochemical reports indicated increased expression of procollagen Type I and hyaluronan at 52 weeks.26


Adapalene was the first of the third generation retinoids to be approved by the Food and Drug Administration for acne treatment.27 In one study, Chandararatna demonstrated that adapalene has excellent follicular penetration28 anti-imflammatory29 and comedolytic activity.30 Adapalene is more stable and is associated with less irritation31 than its relative, tretinoin, not breaking down in the presence of light or air.30


Tazarotene gel 0.05% or 0.1% is used for photodamage and is also indicated for plaque psoriasis and acne.32 Tazarotene has the ability to regulate cell proliferation, cell differentiation and inflammation, as well as down regulating keratinocyte expression.33 Results in a comparative study suggested efficacy of adapalene and tazarotene were comparable.34 Lowe et al conducted a further double-blind randomised multi-centre 24 week study of 173 participants that compared tretinoin 0.05% and tazarotene 0.1% daily at night. Results suggested a benefit of tazarotene over tretinoin at 16 weeks for photodamage, coarse wrinkling, fine wrinkling and mottled hyperpigmentation. For tazarotene, patients reported a higher incidence of a burning sensation on the skin in the first week of treatment, but not thereafter.32

Adverse effects of retinoids

Treatment with vitamin A is known to be associated with ‘the retinoid response’, a phrase to describe the typical outcome of pruritus, burning sensation at treatment sites, peeling and erythema.35 The type and dose of retinoid may affect the degree of the retinoid effect,36 conversely, the response to treatment of photoageing does not appear to be dose dependent. In a 99-patient, 48-week study, Griffiths concluded that mechanisms other than irritation dominate tretinoin-induced repair of photoageing in humans.37

To overcome the issue of the retinoid effect, to reduce patient compliance, Bauman advises patients to introduce topical retinoids at the lowest dose – which differs according to the type of retinoid and the delivery system – and acclimatise to the product by increasing frequency of application gradually from once weekly to once nightly, then increasing the dose gradually with a possible aim of moving to a prescription retinoid.2 In my experience, other ways to reduce the retinoid response would be to increase dermal and epidermal hydration, hence the search for ideal ingredients to combine with retinoids. 

Combination with other topical ingredients

Combining topical vitamin A with other ingredients offers two strong possible benefits – synergy for increased treatment effect and a reduction in the retinoid response. There are many combinations now in use, mostly using retinol as this is the cosmetic form that, as above, has indicated good results within studies discussed in terms of efficacy.

Retinol 0.5% in combination with resveratrol, niacinamide and hexylresorcinol was studied in a 10-week, open label study of 25 patients. By week four, hyperpigmentation, skin clarity, skin tone and wrinkles were improved, with mild retinoid dermatitis occurring early in the study. However, by week 10, all tingling, stinging, itching and dryness had resolved.38

As early as 2006, Sayo had demonstrated a synergistic production of HA when combining retinol with NAG.39 In an vitro study looking at stimulation of keratinocyte HA production by N-acetylglucosamine (NAG) and retinol, Sayo demonstrated that retinoids induce expression of HA synthesis (HAS3) mRNA, but NAG does not work through this mechanism indicating that NAG has a complementary mode of action.39 Two forms are available, one at 0.2% retinol and the other at 0.5%. The proof of concept study on the 0.2% preparation demonstrated improvements in all measured ageing symptoms at week four, continuing through to week 12.40 


We now have a selection of cosmetic preparations with retinol and retinoids as well as pharmaceutical preparations of vitamin A to choose from. Cosmetic companies have spent years attempting to create products that get the best out of vitamin A, without creating the retinoid response. This can be achieved by either creating a delivery mechanism that allows gentle, slow release of retinol, or by combining retinol with ingredients that will reduce the potential of the retinoid effect.

Disclosure: Dr Sandeep Cliff is a key opinion leader and consultant for antiageing skincare distributor AestheticSource. 

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