The Efficacy and Safety of Topical Retinoids for ...

The efficacy and safety of topical retinoids for preventing and reversing the effects of photoageing: a literature review.

Dr. Sarah Tranter MBBS BSc Dermatology in Clinical Practice MSc. University of South Wales.

Word count: 10095

Introduction

Topical retinoids are widely recognised as the gold standard in the medical treatment of the

cutaneous signs of photoageing. They have the largest evidence base regarding their ability to

prevent and reverse the signs of photoageing1. Since their discovery, retinoids have been used as

topical and systemic treatments for acne, disorders of keratinisation, neoplastic disease and

photoageing2. They have gained more traction for their use as an anti-ageing product as consumer

demand grows. Our population is living longer and accumulating sun damage. The desire to reverse

the UV induced photodamage of years gone

by is what is driving further research into

newer formulations for this indication.

Understanding the (photo)ageing process in

the skin and the underlying mechanisms also

gives insight into cutaneous malignancy, given

how strongly associated UV irradiation is with

both ageing and skin cancers2. Novel retinoids

are the current focus of photoageing research,

with the goal of improving retinoid tolerance,

delivery and efficacy3.

The topical retinoids with evidence for their use in photoageing are summarised in table 1. This

review aims to discuss the role of the natural, synthetic and novel retinoids in the management of

photoageing, with specific regards to their efficacy and safety, with the aim of generating a retinoid

hierarchy.

Methods A literature review was conducted using Google Scholar (no date limit) and PubMed (no date limit), to find relevant literature using MeSH keywords including ‘topical retinoid[s]’, tretinoin,

Natural retinoids Synthetic retinoids

• Retinol (vitamin A alcohol) • Tazarotene

• Retinyl-palmitate (vitamin A ester) • Adapalene

• Retinyl-acetate (vitamin A ester) • Seletinoid G

• Retinaldehyde (vitamin A aldehyde)

• Tretinoin (all-trans-retinoic acid) • Novel retinoids

• Isotretinoin (13-cis-retinoic acid)

• Alitretinoin (9-cis-retinoic acid)

Table 1. Summary of the natural and synthetic retinoids with applications in photoageing.


isotretinoin, retinol, retinal, retinaldehyde, adapalene, tazarotene, novel retinoids, receptor selective retinoids, photo-ageing, ultra violet radiation, extrinsic ageing, heliodermatosis.

Exclusion criteria Retinoids taken orally were excluded from the review, and concerning the retinoids that can be applied topically or taken orally, only the literature pertaining to their topical use has been considered. Articles not related to photoageing and topical retinoids were also excluded.

Literature review Our skin and the ageing process The skin - our largest organ - provides essential protection from various daily environmental

exposures. Divided into three layers: the epidermis, the dermis and the subcutaneous tissue, the skin

is a complex organ with many functions in addition to environmental protection. For the purpose of

this review, the protective function of the skin will take precedence. The epidermis is composed

predominantly of differentiating keratinocytes, with melanocytes and Langerhans cells also

featuring prominently. The stratum corneum forms the barrier function of the skin, and is made up

of corneocytes, which interact with proteins such as keratin and fillagrin. Alongside this cornified

involucre, lamellar lipids fill the intercellular spaces. The combination of hydrophilic cells and

proteins, with hydrophobic intercellular material, is what is responsible for the skin barrier. The

epidermis is separated from the dermis below by a basement membrane. The dermis comprises

extracellular matrix (ECM) proteins produced by fibroblasts below. Type I collagen is the most

abundant protein in the skin, and confers structural support, alongside other ECM proteins such as

collagens III, V and VII, elastin and proteoglycans4. The main environmental insult our skin

protects us from is ultraviolet radiation (UVR), along with cigarette smoke, pollution and

occupational exposures.

Skin ageing is a complex process influenced by a number of intrinsic and extrinsic factors. Natural

metabolic processes result in the generation of reactive oxygen species (ROS) which play a crucial

role in cell ageing, and as we age, our cells naturally decline in their ability to perform their normal

function and this is genetically determined. In addition, cumulative damage to our cells, genes and

resulting proteins also results in decreased functionality, and we are dependent on cellular repair

mechanisms to avoid premature ageing and cell death5,6.

Intrinsic ageing is characterised by a general trend towards skin atrophy and decline in normal

processes and cellular functions7. Intrinsically aged skin demonstrates thinning and decreased

growth rate of the epidermis, loss of corneocyte adhesion and flattening of the dermoepidermal

Dr. Sarah Tranter MBBS BSc Professional Project MSc Dermatology in Clinical Practice 2


interface. Melanocyte and Langerhans cell numbers are decreased and there are alterations in

dermal collagen, elastin and glycosaminoglycans. The normal immune and inflammatory responses

are impaired and there is reduced clearance of dermal fluid and foreign materials. The

microvasculature is altered and the physiological functions of thermoregulation, mechanical

protection, sensory perception, sweat and sebum production all decline with increasing age. These

structural, cellular and histological changes correlate clinically with intrinsically aged skin on non-

sun exposed sites that appears finely wrinkled, unblemished and xerotic (figure 1A). There is

impaired wound healing, increased susceptibility to infection and increased incidence of benign and

malignant neoplasms10.

Photoageing describes the constellation of clinical, histological and functional changes in older skin

that has been frequently exposed to ultraviolet radiation. It is these features that have been super-

imposed on intrinsically aged skin, giving rise to a prematurely aged appearance. Photoageing

accounts for 90% of visible skin ageing, particularly in those with less pigmented skin types11. In

contrast to intrinsically aged skin, photodamaged skin exhibits striking alterations in the dermis and

epidermis. Epidermal dysplasia is frequent, even if there are minimal clinical changes. The

photoaged phenotype appears as rough, pigmented, lax, wrinkled and furrowed skin, with solar

elastosis - the clinical and histological hallmark of photoageing (Figure 1B). This elastic

degenerative change results from a change in fibroblasts and collagenolytic activity in the

extracellular matrix (ECM)2. The accumulation of these degenerative changes and imperfect repair

mechanisms results in progressive wrinkling, skin structural changes, vascular and pigmentary

changes12.


A B

Figure 1. A. The clinical appearance of chronologically aged skin on the abdomen of an Indian woman. The skin appears xerotic with loss of elasticity and fine wrinkles. B. The appearance of photo aged skin and solar elastosis. The skin is pigmented, deeply wrinkled, rough and leathery.

A. Reproduced from Durai et al 20128. B. © Professor Raimo Suhonen. Reproduced from ‘Solar elastosis’ via DermNet New Zealand with permission9.


Intrinsically aged skin and photoaged skin have been shown to have some shared mechanisms such

as impaired collagen synthesis, enhanced MMP expression, increased AP-1 expression, increased

oxidative stress13,14. It has been demonstrated that tretinoin is able to improve features of

intrinsically aged skin in a similar way as it does when applied to photoaged skin. The predominant


Figure 2A. Changes seen with staining of elastin in sun-protected and sun-exposed skin from 1st and 8th decades. Facial (a) and abdominal (b) skin in the first decade. Facial skin demonstrating abnormal accumulation of elastin in the 8th decade (c), in comparison to the sun-protected skin in the same age group, which demonstrates a degree of elastin preservation (d).

Figure 2B. Type I collagen staining in facial and abdominal skin taken from 1st and 8th decades. There is loss of type I collagen in the facial skin in the 8th decade (c), collagen appears preserved in the abdominal skin from the 8th decade (d), this is a result of an alteration in the ratio of type I and type III collagen.Reproduced from El-Domyati et al 200217.


mechanism for these improvements is by reducing MMP expression and stimulating collagen

synthesis in the dermis14.

Photoageing in the epidermis and dermis Photoageing can be further considered in terms of the epidermal and dermal changes that occur as

result of exogenous insults. Epidermal photoageing is characterised by initial epidermal hyperplasia

and then epidermal atrophy, acanthosis, cellular atypia and decreased number and function of

Langerhans cells. Slow wound healing, depigmented pseudo scars, greater melanin production in

senescent melanocytes, freckles, lentigines and other pigmentary changes are also typically

seen15,16.

Dermal photoageing is what gives rise to the typical photoaged phenotype and it is the result of

underlying degradation of connective tissue within the dermal extracellular matrix, namely collagen

and elastin. Solar elastosis describes both the clinical appearance, and underlying histological

changes, associated with dermal photoageing. Elastoid material comprising abnormal elastin,

degenerated and homogenised collagen with lack of fibrillary structure is seen in the upper dermis

with a subepidermal grenzzone of sparing. This area represents a subepidermal layer of newly

synthesised collagen seen in photo damaged skin (figure 2A17). It is thought that solar elastosis

occurs as a combination of a process of degradation of ECM proteins whereby there is an initial

phase of collection of normal elastin in the papillary and reticular dermis, followed by a destructive

phase in which elastin becomes coarse and fragmented, leading to elastolysis17. Changes to the

structure and organisation of collagen were seen as early as the 4th decade on histological

assessment of facial skin, and the accumulation of abnormal elastin, occupying areas of lost

collagen, increased with age. There is also a change in the ratio of type I and type III collagen in

intrinsically aged skin (figure 2A and B)17.

In photoaged skin there is also the presence of a chronic perivascular inflammatory infiltrate which

contains high numbers of lymphocytes, macrophages and increased numbers of partially

degranulated mast cells. Their presence causes damage to the ECM proteins by nature of

inflammatory mediated processes - degranulating mast cells in close proximity to fibroblasts

causing collagen and elastin breakdown18. The result is a UV-induced inflammatory state, which is

in contrast to the trend toward senescence and atrophy seen in chronological ageing.



Photoageing and ultraviolet radiationPhotoageing develops gradually after years of chronic UV light exposure, which is in contrast to the

more immediate effects of UVR seen as sunburn and suntan that develop over hours to days

respectively. The main wavelengths of light responsible for photoageing are UVB and UVA. Short-

wave UVB photons (290-315nm) carry higher energy than long-wave UVA photons (315-400nm).

The energy from short-wave UVB photons is mainly dispersed in the epidermis, with less than 10%

reaching the dermis below2. The ability of UVB irradiation to also cause deeper levels of damage

by inducing matrix metalloproteinase (MMP) mRNA, protein and activity within hours of exposure

in human skin was demonstrated to occur at lower doses than required to induce skin erythema.

MMPs are a group of enzymes responsible for the degradation of collagen and elevated levels of

MMPs degrade collagen and elastin within the dermis, which over time result in a ‘solar scar’.

These results highlight the fact that underlying damage to the dermis when exposed to UV

irradiation can occur with minimal external signs on the skin19.

In contrast to UVB, ~ 50% of the energy from long-wave UVA photons reaches the dermis, and so

UVA can be said to have a more damaging effect here2. UVA is also present more consistently

throughout the year, making up a larger percentage of daily UV light (~5% of terrestrial sunlight),

Identification characteristics

Type of ageing Epidermis Dermis Clinical appearance

Chronologically aged skin

(figure 1A)

Epidermal atrophy and reduced cell turnoverReduced corneocyte adhesionFlattening of dermo-epidermal junction, loss of rete pegs

Decreased dermal collagen, elastin and GAGs, irregular arrangement of elastinImpaired immune and inflammatory responsesDecreased melanocyte and Langerhans cellsAltered microvasculature

Laxity, fine wrinklesUnblemishedDevelopment of benign growths eg seborrhoeic keratoses and angiomas

Photoaged skin

(figure 1B)

Thickened stratum corneum Increased melanosomes in basal keratinocytesActinic lentigo - hyperkeratosis and increased basal melanocytes Cellular atypia

Solar elastosis - homogenised, irregular, bunched and degraded elastin, grenz zone Decreased collagen I, III, VII (anchoring fibrils) and fibrillin in papillary dermis

Dilated and tortuous microvasculature

Wrinkles, deep furrows, laxityMottled pigmentation (hypo- or hyperpigmentation, sallownessRough skin, loss of skin tone, dryness*Solar elastosisTelangectasias, actinic purpuraPrecancerous lesions, skin cancer and melanoma

Table 2. A comparison of the clinical features of extrinsic and intrinsic skin ageing. *Note solar elastosis is the hallmark of photoageing, and describes both clinical and histological changes. Chronologically aged skin does not exhibit pigmentary or vascular changes, as seen in photo aged skin.



and it is able penetrate through glass - something UVB is unable to do. These features of UVA mean

that UVA irradiation plays a more significant role in photoageing than it does in the acute effects of

UV exposure (sunburn/tan) or photocarcinogenesis2.

Other exogenous factors in photoageing The role of IR radiation on skin ageing

In addition to UVR, studies have shown the effect of infra-red radiation (IR) on human skin ageing.

IR does not have the photon energy of UVR, but it comprises a much greater percentage of our

cumulative exposure (54% vs 5-7% respectively). IR-A (λ = 760-1440 nm) represents

approximately 30% of total solar energy and penetrates skin deeply compared to UVR, with

approximately 50% reaching the dermis. The mechanisms for IR induced skin damage are similar to

that of UVR, and are a result of induction of MMP-1 and reactive oxygen species (ROS)20.

The role of smoking in skin ageing

Extrinsic ageing can almost be completely attributed to UV irradiation11. However, cigarette

smoking is strongly associated with elastosis in men and women, and telangectasias in men.

Smoking damages the skins microvasculature and reduces capillary blood flow, causing an oxygen

deprived state in the skin. It also induces free radial formation, damages collagen and increases

keratinocyte dysplasia. Studies have shown that smoking can be even more detrimental to the

formation of wrinkles than even UV exposure and found that smoking is an independent risk factor

for premature wrinkle formation even when controlled for age, pigmentation and sun exposure21.

The molecular mechanisms of UV induced photodamage UV radiation (UVR) is a complete carcinogen and can affect the skin in various ways, causing

direct and indirect image to DNA. UVB causes direct damage to DNA through the generation of

photoproducts such as thymidine dimers. UVA primarily causes damage through indirect oxidative

damage of guanine bases and interacts with chromophores to generate ROS. This direct and indirect

damage ultimately leads to mutation of key regulatory genes2. UVA also inhibits DNA repair by

damaging nucleotide excision repair (NER), the mechanism by which this occurs22.

The generation of ROS causes the oxidation and inhibition of protein tyrosine phosphatases, which

have an inhibitory and regulatory function for the pro-inflammatory cytokines; epidermal growth

factor (EGF), tumour necrosis factor (TNF)-α and interleukin-1 (IL-1). Therefore, in UV exposed

skin, there is up regulation of EGF, TNF-α and IL-1 in keratinocytes and fibroblasts23. This is

further compounded by the increase in nuclear factor-κB (NF-κB), releasing further pro-

inflammatory cytokines and increasing ROS24. This switches on mitogen-activated protein (MAP) Dr. Sarah Tranter MBBS BSc Professional Project MSc Dermatology in Clinical Practice 7


kinase pathways that lead to the degradation of extracellular matrix by the induction of transcription

factor AP-1 and subsequent matrix metalloproteinase (MMP) production25. AP-1 is constitutively

composed of c-Fos and JunD proteins (e.g c-Jun). In UV irradiated skin, increased expression of c-

Jun protein occurs within 30 minutes of UV exposure, and continues to be expressed for 24 hours26.

The heterodimer of c-Fos:c-Jun AP-1 complex up-regulates several MMPs that are the mediators of

collagen breakdown - MMP-1 (collagenase 1) degrades type I and III fibrillar collagen, MMP-9

(gelatinase B) further degrades collagen fragments, and MMP-3 (stromelysin 1) which degrades

type IV collagen in the basement membrane and activates proMMP-1. Together, these MMPs have

the capacity to completely degrade mature fibrillar collagen in the skin. Increased collagen

breakdown has been demonstrated to occur within 24 hours of UV exposure in human skin in

vivo4,25. Not only does UV irradiation cause collagen and ECM breakdown, it also impairs new type

I collagen synthesis. It decreases collagen formation19,25 and also impairs the formation of collagen

fibrils27. Type I procollagen gene transcription is negatively regulated by AP-1. Fisher et al 2000

demonstrated the reduction in type I procollagen mRNA within 8 hours of UV exposure in human

skin, and subsequent absence of procollagen mRNA and protein in the upper dermis after 24

hours28. UV irradiation also has the negative effect of impairing TGF-β signalling. This major

profibrotic cytokine regulates multiple cellular functions involving differentiation, proliferation, and

induction of synthesis of ECM proteins, and in human skin, TGF-β inhibits the proliferation of

keratinocytes, stimulates dermal fibroblast growth, and induces the synthesis and secretion of

collagen and elastin within the ECM29,30. It also inhibits MMP-1 and MMP-3. UV irradiation

impairs the TGF-β signalling pathway by reducing expression of it’s receptor protein TβRII and by

increasing the inhibitory signalling protein Smad731. Additionally, TGF-β interacts with CTGF

(connective tissue growth factor; stimulatory effect) and Cyr61 (inhibitory effect) to modulate

procollagen I production. UV irradiation inhibits CTGF gene expression via an unknown

mechanism. This can explain why UV exposure causes reduction of type I collagen production4.

Additionally, UVR alters endogenous antioxidants in the skin, and promotes angiogenesis by

increasing expression of vascular-endothelial growth factor (VEGF)23. UVB also acts via a

paracrine pathway between keratinocytes and fibroblasts to increase elastase that degrade elastic

fibres in the dermis32.

UVR also degrades proteoglycans (PG) within the extracellular matrix In photoaged skin, in addition to loss of collagen and elastin, there are changes to the structure and

distribution of glycosaminoglycans (GAGs) and proteoglycans (PGs) within the extracellular

matrix. These molecules have important roles in the assembly and structure of the ECM, and

associate closely with collagen and elastin fibres. In the skin, the most abundant GAG - hyaluronic



acid (HA), forms aggregates of HA and HA-binding PGs which confer structure and stability to the

ECM33. Following exposure of UVR, there is abnormal accumulation of hyaluronic acid (HA), in

addition to the sulphated GAG/PGs versican and chondroitin sulphate (CS), with elastotic material

and reduced decorin within regions of solar elastosis, which is related to chronic sun exposure and

UV induced damage33. In addition, UVB irradiation decreases HA-1 synthase (along with HA-2 and

HA-3) which contributes to the loss of HA from the dermis34. The combined effect of abnormal

accumulation and decreased synthesis of, predominantly, HA compounds the loss of structural

integrity of the dermis, and contributes to the formation of wrinkles. The family of GAGs and PGs

within the ECM are a diverse group of molecules, and Lee et al (2016)33 concluded that further

research into how these changes manifest in ageing phenotypes may give rise to novel therapeutic

targets.

Summary of UVR induced mechanisms of photodamage

UVR causes photo damaged by 1) direct damage to DNA (both mitochondrial and nuclear) - e.g.

UVB causing formation of pyrimidine dimers, 2) indirect damage to DNA by the generation of

ROS - e.g. interaction of UVA with photosensitisers within the skin leading to the formation of

DNA photoproducts (e.g. abnormalities such as base dimers, DNA strand breaks and crosslinks), 3)

by damaging the ability of DNA to repair itself (NER and BER mechanisms impaired) and 4) by

interacting with cell surface receptors on keratinocytes and fibroblasts, triggering signalling

cascades involving AP-1 and NFκB, leading to the breakdown of proteins within the extracellular

matrix of the dermis. This results in a cycle of imperfect repair and ongoing damage, leading to

solar scar formation and ultimately deep wrinkling and furrows in the skin over an extended period

of time as the structural integrity of the skin is gradually broken down. The accumulation of these

repeated exposures and resulting ‘solar scars’ over years is what results in the photoaged phenotype

of prematurely aged rough, lax, skin with mottled pigmentation and leathery appearance19 (figure

1A).

Retinoids in the management of photoageing

Since being shown to improve the signs of mild to moderate photoageing by Kligman and

colleagues in 198463, there have been various large-scale, double-blind, placebo-controlled 6 month

trials that show the beneficial effects of tretinoin (and other topical retinoids) on reducing fine lines

and wrinkles and improving skin roughness. Photoageing leads to the loss of structure support

within the dermal extracellular matrix due to collagenolytic activity and reduced collagen

synthesis25. Tretinoin has been shown to restore extracellular matrix and prevent the loss of



extracellular matrix in chronically photo-damaged skin. Pre-treating the skin with tretinoin also has

the effect of inhibiting UVR induced ECM degradation and it can restore procollagen I levels in

sun-exposed skin to the levels seen in sun-protected skin of the same subject25,35. Retinoids regulate

cell apoptosis, differentiation and proliferation. Anti-wrinkle properties of retinoids promote

keratinocyte proliferation, strengthen the protective function of the epidermis, restrain

transepidermal water loss, protect collagen against degradation and inhibit metalloproteinases

activity36. Retinoids also work by increasing epidermal thickness, increasing granular layer

thickness, compaction of the stratum corneum and decreased melanin content. These changes are

seen after 6 months of regular tretinoin use. These improvements are continued after another 6

months, however at this time point there was also regression of the epidermis. After 12 months of

use new collagen formation was demonstrated in the papillary dermis, along with dermal

reconstruction, improved DEJ adhesion and improved keratinocyte function37. These benefits have

also been observed with lower concentrations of tretinoin, for example 0.02% tretinoin used

regularly demonstrated similar histological changes after 12 months38.

Retinoids and photoageing The retinoid family comprises vitamin A (all-trans-retinol) and its natural derivatives, including

retinaldehyde, retinyl esters and retinoic acid (and its isomers), along with a number of synthetic

and novel compounds (table 1). A ‘retinoid’ can be any molecule that has the capacity to bind and/

or activate retinoid receptors, resulting in the activation of retinoid-sensitive gene transcription

elements within DNA. The stratified structure of the epidermis is organised by retinoid-influenced

cellular processes, and retinoids significantly affect dermal ageing, immune response and wound

healing39. For the purpose of this review, first generation (naturally occurring) retinoids and 3rd/4th

generation (synthetic and novel) retinoids will be considered. The second generation synthetic

retinoids acitretin and etretinate will not be considered in this review as they are approved for the

treatment of psoriasis, and have no role in the management of photoageing40. Third generation

retinoids (synthetic, receptor-specific) include tazarotene and adapalene, which have been employed

against psoriasis and acne respectively, however both show promise and benefit in photoageing40.

Fourth generation novel retinoids, such as seletinoid G, have been developed to help improve the

effects and reduce unwanted side effects, and improve patient compliance41. A prescription is

required to obtain tretinoin, isotretinoin, alitretinoin, tazarotene and adapalene, and they are classed

as drugs. The remaining retinoids, and adapalene sold as Differin, can be purchased and are

cosmeceuticals (medically active cosmetics)42. The most extensively studied, and widely used,

topical retinoid in managing photoageing is tretinoin. Topical retinoids are not the only agents that



can be employed in the management of photodamage, and they can work synergistically with SPF,

alpha hydroxy acids (AHAs) and antioxidants. However, they are the only agents with a significant

evidence base for their use1.

Tretinoin used with SPF has been proven to be one of the most effective regimens for photoageing,

both in prevention and repair of the damage caused. SPF and tretinoin was shown to enhance the

reparative ability of the skin post UV irradiation43. AHAs (especially glycolic and lactic acid)

enhance skin exfoliation and moisturisation. Lactic acid interacts with fibroblasts to induce water

retention in the epidermis and dermis, and glycolic acid has anti-inflammatory and antioxidant

effects, it also penetrates the skin more readily than other AHAs, due to its smaller molecular size44.

AHAs in concentrations of up to 20% can be used comfortably, and AHAs can also be used in

conjunction with retinoids in a synergistic way. Tran et al (20050 demonstrated the efficacy of a

retinaldehye and glycolic acid regime in terms of enhanced bioavailability and delivery of the

retinoid while mitigating the irritant effects45. The use of antioxidants such as vitamin C and

vitamin E have also proven to be effective and complimentary in photoageing20.

Other treatments for photoageing include medium depth chemical peels, dermabrasion and light

chemical peels - but needs repetition, CO2 laser and fractionated laser. There has been some

evidence for the use of fluorouracil (Efudex) and imiquimod (Aldara) in photoageing, however

these treatments remain largely used for preskin cancers, actinic keratoses and non melanoma skin

cancer23,46.

Safety concerns and teratogenicity of topically applied retinoids Tretinoin has long been established as a safe and effective treatment for photoageing. The use of

any of the topically prescribed retinoids, at any strength, does not alter the circulating endogenous

retinoic acid level, or the levels of its metabolites and there is minimal percutaneous absorption of

topically applied tretinoin - the daily dose is approximately 30-fold lower than the lowest

teratogenic dose of isotretinoin. There have been three prospective cohort studies clearly

demonstrating the safety of tretinoin and lack of embryo toxic effects47,48,49. The long term efficacy

and safety of tretinoin has been proven by various studies. They demonstrated no cellular atypia,

with the only adverse effect being a skin irritant dermatitis, characterised by erythema, peeling and

itching. This reaction was self limiting and improved after 3 months of regular tretinoin use37.

The irritant skin reaction occurs in a predictable dose-related manner, with the retinoids most likely

to cause skin irritation being tretinoin and tazarotene, with adapalene, retinaldehyde, retinol (and

derivatives), and retinyl esters being less likely to cause significant irritation. The closer a form of



retinoid is to retinoic acid the better and faster it works, however there is more potential for skin

irritation.

Retinoid nomenclature Vitamin A (all-trans-retinol) is an essential fat-soluble vitamin, present naturally as retinyl esters

(the main storage form of vitamin A) and beta-carotene. It is vital for many biological processes

involved in embryogenesis, reproduction, growth, vision, inflammation, cell growth and

proliferation, and cell death. The most abundant retinoid forms in the body are retinyl esters and

retinol50. Retinyl esters consumed in the diet are converted to retinaldehyde in the intestine and then

converted back to retinyl esters for storage via the liver. In the circulation retinol is bound to retinol

binding protein (RBP; figure 6), and once in the cell it is strongly associated with cytosolic retinol

binding protein (CRBP; figure 6). These specialised transport proteins allow retinoids to be utilised

in target tissues, given their hydrophobic nature51.

All-trans-retinol is a 20 carbon molecule with a cyclohexenyl ring with a 4 double bond side chain

and an alcohol end group (figure 4A). Retinol is a precursor of the active metabolite all-trans-

retinoic acid (RA), which undergoes a two-step enzymatic activation involving an initial reversible,

and rate limiting step, whereby all-trans-retinol is converted to all-trans-retinaldehyde via oxidation

of the alcohol end group; catalysed by

retinol dehydrogenase (retinol DH, figure

6). The second step is further oxidation by

retinal dehydrogenase (retinal DH) to

irreversibly convert all-trans-retinaldehyde

to all-trans-retinoic acid, or tretinoin (RA),

the active metabolite (figure 4A; figure 6).

Tretinoin has two stereoisomers; 9-cis-

retinoic acid (alitretinoin) and 13-cis-

retinoic acid (isotretinoin) which are formed

via a non-enzymatic process (figure 4B). 13-

cis-retinoic acid is less transcriptionally

active than the all-trans and 9-cis isomers.

The numbering of carbon atoms in all-

trans-retinoic acid, and stereoisomer forms

9-cis-retinoic acid and 13-cis-retinoic acid,


Figure 4. Nomenclature of the natural retinoids.

Reproduced from Fitzpatrick’s Dermatology in General Practice (2003). McGraw-Hill


can be seen in figure 4B. In addition to retinaldehyde and retinyl esters, all-trans-retinol is

metabolised to 4-hydroxy-all-trans-retinoic acid and 4-oxo-retinoic acid (figure 4C) by a

hydroxylation reaction and subsequent oxidation reaction. These hydroxy- and oxo- forms are less

active forms of retinoic acid and are 10-fold less potent at inducing retinoic acid-dependent

responses within the cell, and these forms are likely destined for elimination50,52.

The esterification of retinol with a fatty acyl group generates the storage form of retinol; retinyl

esters (figure 4D). The most abundant esters are those of palmitic, oleic, stearic and linoleic acids50.

The predominant catalyst for this esterification reaction in the skin is Lethicin:retinol

acyltransferase (LRAT; figure 6). Retinyl esters have no known biological activity except to serve as

the storage form of retinol and the substrate for the visual chromophore 11-cis-retinal50. Hydrolysis

of a retinyl ester generates retinol, which then undergoes 2-step oxidation to form RA.

Retinoid metabolism in the skin and mechanism of action When tretinoin is applied topically to human skin, ~50% remains in the active form, the remaining

50% is either isomerised or hydroxylated to 4-hydroxy-all-trans-retinoic acid [DUELL et al 1992].

Topically applied retinoids act via two pathways - the transepidermal pathway and the

transfollicular pathway. The transepidermal pathway gives rise to an epidermal/dermal gradient of

retinoid penetration, which is highly important for disorders of keratinisation. The transfollicular

pathway sees higher association of retinoid to the follicle, linking to its MOA in acne. Spill over to

the systemic compartment from either route is so minimal that circulating levels remain unaltered47.

Once retinoic acid (RA) is generated in the cell, it associates strongly with cytosolic retinoic acid

binding protein (CRABP), of which there are 2 forms, CRABP I and CRABP II, the predominant

form in skin is CRABP II. The expression of CRABP II genes can be used as a marker of retinoid

biological activity53. The RA-CRABP II complex is transported to the nucleus where it binds with

nuclear RA receptors (RARs) and retinoid X receptors (RXRs; figure 6)36,51. The discovery that

these retinoid-specific receptors shared similar features in the DNA binding regions as the thyroid

and vitamin D receptors was first demonstrated in 1987, forming our understanding today that the

RARs function as hormone receptors to activate gene transcription54,55. RA binds RAR and the

isomerisation to 9-cis-retinoic acid allows for binding to the RXR. RAR and RXR form

heterodimers (they are also are capable of forming heterodimers with thyroid and vitamin D

receptors) and they form homodimers that bind RA response elements (RARE) in DNA to change

gene expression through activation and repression of target genes50.



RAR and RXR subtypes are as

follows; RAR-α, RAR-β, RAR-γ,

and RXR-α, RXR-β, RXR-γ. Elder

et al (1992)56 found that human

epidermis expresses RAR-α and 𝛾,

and RXR-α, while RXR-β is

expressed by dermal fibroblasts50.

Roughly 90% of the RAR present in

skin is the RAR-𝛾 subtype and 90%

of the RXR present is RXR-α

subtype58. It has been demonstrated

that normal human epidermis is

regulated by a heterodimer of

RXR-γ and RAR-α , with the RAR-

α portion of the heterodimerbeing

responsible for binding to RARE,

however this would not occur

without the presence of the RXR-𝛾 element56,57. Wang et al (1999) demonstrated that UVR causes a

decrease in the expression of RAR/RXR, and that pre-treatment of the skin prior to UV irradiation

was able to improve this59. In addition to the RAR/RXR subtype, there are also RAR/RXR isomers

and together they form a highly diverse group of retinoid-responsive receptors12,58.

Receptor-selective retinoidsThe discovery of the various retinoid receptor subtypes has lead to the development of synthetic

retinoids that are receptor specific. Adapalene is a third generation, receptor-selective retinoid, with

a napthoic acid base (figure 5). It shows affinity for the RAR β/𝛾 receptors, and does not directly

bind CRABP II but has been shown to have the capacity to induce CRABP II mRNA60.

Tazarotene is the precursor to tazarotenic acid and an analogue of tretinoin (figure 5). It cannot itself

bind directly to RAR/RXR. Tazarotenic acid is the active form and has affinity for the RARs

(RARβ > RARγ > RARα)61.

There is naturally a great variability between the retinoids, in part due to their differing chemical

structure conferring varying degrees of binding and receptor selectivity between them. The retinoids Dr. Sarah Tranter MBBS BSc Professional Project MSc Dermatology in Clinical Practice 14

Fig. 6 Overview of retinoid metabolism (Note: Retinol is oxidised to retinoic acid in two steps: retinol is reversibly oxidised by retinol dehydrogenase to give retinal, then retinal is irreversibly oxidised by retinal dehydrogenase to give retinoic acid). CRABP cytosolic retinoic acid binding protein, CRBP cytosolic retinol binding protein, LRAT lecithin retinol acyltransferase, RA retinoic acid, RAR retinoic acid receptor, RARE retinoic acid response element, RBP retinol-binding protein, Retinal DH retinal dehydrogenase, RXR retinoid X receptor, TTR transthyretin

Reproduced from Riahi 201650


are a diverse group of molecules that modulate the expression of

genes involved in cellular differentiation and proliferation,

resulting in normalising cell keratinisation42.

The topical retinoid family

1. Tretinoin (table 3-1)

Tretinoin was found incidentally to improve the appearance of

fine lines in patients using topical tretinoin for acne62. This

finding generated interest in the potential for tretinoin to be used

in photoageing, and this was further investigated using the

hairless albino mouse model as a surrogate for human skin.

These mice were irradiated with UVB for a period of 10 weeks, during which time they developed

fine wrinkles and the histological features of solar elastosis63. Tretinoin was then applied for a

further 10 weeks, during which time the authors found there was the generation of a subepidermal

collagen repair zone that correlated clinically with wrinkle effacement63. The same authors were the

first to conduct an in vivo trial of the effect of 0.05% tretinoin in photo aged skin of the face and

forearms of volunteers over 3-10 month period. They found significant improvements in wrinkling

that correlated with the animal model in 1984. The first vehicle-controlled trial looking at the

efficacy of tretinoin in photoageing was in 1988. 0.1% tretinoin emollient cream was applied daily

to the face and forearms for a period of 4 months64. After 4 months there was significant

improvement in the tretinoin treated skin vs. the vehicle treated skin in terms of fine wrinkling,

coarse wrinkles, sallowness, tactile roughness, and actinic lentigines. The authors noted the main

side effect of treatment was the development of a skin irritant reaction, characterised by erythema,

scaling and pruritus, which occurred in approximately 90% of participants64. Within the following

years, the results of 2 large, multi centre trials confirmed that tretinoin was an effective treatment

for photoaged65,66. They enrolled a total of 547 subjects, 393 of which used topical tretinoin in

varying concentrations (0.001% - 0.05%), and their conclusion was that 0.05% tretinoin applied

daily for 6 months was effective at improving fine wrinkling, mottled hyperpigmentation and skin

roughness that result from chronic UV exposure. These clinical improvements correlate with

histological findings of increased stratum corneum compaction, spongiosis, thickened granular

cellular layer, increased basal keratinocyte turnover and increased mucin deposition65,66.

In an attempt to answer the hotly debated question at the time of whether the improvement seen

with topical tretinoin application was a result of the irritant skin reaction that was observed, a study

comparing two different concentrations of retinoic acid 0.025% and 0.1%, was conducted over a


Figure 5. Nomenclature of the receptor-selective retinoids adapalene and tazarotene.Reproduced from Fitzpatrick’s Dermatology in General Practice (2003). McGraw-Hill


period of 48 weeks, and found no significant difference in clinical efficacy between the two

concentrations67. This would imply that the results seen from tretinoin in the skin are independent

of the irritant effect it can cause.

Long term use of tretinoin in photoageing Since the 1980’s there have been many studies that have confirmed the efficacy of tretinoin in

treating the clinical and ultrastructural changes associated with photoageing both in the short and

long term. Kang et al (2005) reported the results of a 2 year vehicle controlled trial of once daily

0.05% tretinoin cream vs vehicle in 204 subjects. Significant improvements in photoageing,

specifically fine wrinkles were demonstrated after 4 months, and continued throughout the 2 year

time frame for the study68. Sustained improvement with topical tretinoin use has been shown after 4

years without detrimental effects on keratinocytes and melanocytes, and with improvements in

epidermal mucin seen at biopsy. In addition to the benefits seen over the short term, long term

therapy decreased dermal elastin content and perivascular inflammation. These changes could

possibly account for the observed continued clinical improvement69,70.

Furthermore, Kligman and Graham (1993) reported that there was markedly reduced density of

melanosomes in the basal layer and they demonstrated the formation of a band of new subepidermal

collagen, evidence of resorption of abnormal and amorphous elastic material, formation of new

reticulin and reduction in GAGs71. This would imply that the long term benefits of tretinoin therapy

can reverse the damage seen with photoageing and encourage normalisation of the epidermis and

dermis.

In addition to the improvements observed with wrinkling, tretinoin also has beneficial effects on

hyperpigmentation that is associated with photoageing. There have been a number of 10 month

studies looking at the efficacy of 0.1% tretinoin in photoageing, that have found significant

improvements in pigmentation. These studies have then been extended, and found that tretinoin

0.1% improved epidermal turnover and thickness and also reduced the number and activity of

melanocytes72,73,74. Another double-blind, vehicle-controlled study examining the effect of 0.1%

tretinoin vs vehicle over 4, 10 and then 22 months found a 71% reduction in discrete lentigines

compared to the number present prior to treatment. An improvement in hyperpigmentation is a

result of dispersion of melanin granules thereby improving the appearance of pigmentation. The

lightening of actinic lentigines and mottled hyperpigmentation correlates with a reduction in

epidermal melanin content maybe resulting from inhibition of tyrosinase activity75,76.

Sorg et al (2005) proposed that retinoids can also improve photoaging due to their chemical

structure and their conjugated double bonds. These structural features allow them to absorb free



radials and oxidative damage, thereby being able to protect DNA, lipid membranes and proteins by

directly preventing photochemical damage or UV-induced oxidative stress77.

The overwhelming evidence for efficacy for tretinoin in photoageing is such that patients should be

advised it is not a cosmetic preparation and there should be appropriate counselling on the

appropriate frequency and method of application for maximal benefits to be obtained. Daily

application of tretinoin for at least 3 months is required to see improvements78.

The beneficial effects of continuing with tretinoin therapy in the long term, but with reduced

frequency of application has also been proven74,79. 126 participants who completed 48 weeks of

daily 0.05% tretinoin use were continued on a three weekly, once weekly or no treatment dosing for

a further 24 weeks. Those who continued on a three weekly and, to a lesser extent, those on a once

weekly dosing schedule maintained and in some cases contained to see improvements. In those

subjects who were assigned to no therapy, the authors found regression in the areas of improvement

obtained from prior treatment79.

1a. Comparison of tretinoin with other retinoids

A randomised trial comparing 0.25%/0.5%/1.0% cosmetic formulations of retinol (with added

agents for optimal irritation control) vs 0.025%, 0.05%, 0.1% tretinoin. Participants were

randomised to receive either 0.025% tretinoin and 0.25% retinol, 0.05% tretinoin and 0.05% retinol,

or 0.1% tretinoin and 1.0% retinol in a split face trial over 12 weeks, with clinical photos at 0, 4, 8,

12 weeks. 65 subjects took part in the trial. After 12 weeks both retinol and tretinoin groups had

statistically significant improvements in the measured parameters of photoageing (fine and coarse

lines/wrinkles, pigmentation, skin tone, brightness, tactile roughness). There were no significant

differences in efficacy between tretinoin and retinol, and retinol produced comparable results to

tretinoin80. Draelos and Peterson (2020) reported results of a step up protocol for increasing dose of

retinol serum vs tretinoin cream in combination with a test moisturiser over 12 weeks. Their aim

was to achieve the rapid benefits of retinisation, but with minimal irritation. At 12 weeks there was

no statistically significant difference between the retinol serum vs tretinoin cream in patient

assessment of improvement in clinical signs of photoageing. Difference in TEWL with the two

products was also not statistically different. However, the retinol serum group showed marked

improvement in skin smoothness at week 4 and highly significant improvement skin dryness with

this group (not seen in tretinoin group). Punch biopsies taken at 12 weeks also demonstrated newly

formed collagen and epidermal thickening in the retinol serum group, compared to tretinoin

group81. Bouloc et al (2015) compared 0.025% tretinoin with a combination product containing

retinal and tetrahydrojasmonic acid (LR2412). LR2412 is a plant-derived hormone from linoleic



acid and is part of a family of compounds that were originally isolated from the jasmine plant.

These compounds have been shown to have beneficial effects in epidermal hyaluronic acid in

human skin83. In this study retinol 0.2% combined with 2% LR2412 was compared to tretinoin

0.025%. Participants used SPF 50 in the morning and either retinol or tretinoin at night. The results

showed no difference between groups in clinical outcome, but retinol/LR2412 was better perceived

and tolerated by participants82. Fu et al (2010) evaluated another cosmetic based preparation with

0.02% tretinoin. A niacinamide⁄peptide⁄retinylpropionate product regimen vs. a prescription 0.02%

tretinoin product regimen was tested over 24 weeks. After 8 weeks those using the cosmetic

preparation reported better improvement wrinkle appearance. This had equalised between the

groups after the full 24 weeks. The cosmetic preparation was better tolerated than the 0.02%

tretinoin throughout all parameters after 8 weeks (erythema, perceived dryness from participants,

TEWL and thinner stratum corneum)84.

2. Retinol (table 3-2)

In photoageing, retinol is used in a cream formulation in concentrations ranging between 0.075% to

1%. It is often considered the “lighter alternative” to tretinoin in patients with sensitive skin42.

However it is regarded as approximately 20-fold less efficacious than tretinoin and a much higher

concentration of retinol required to match the outcomes seen with tretinoin. However, retinol

applied to normal human skin does induce the expression of CRABP-II and CRBP mRNAs and

proteins, similarly to retinoic acid, but without the irritation and erythema85. Retinol is extremely

unstable and easily degraded to biologically inactive forms on exposure to UV light, and there are

few formulations available that offer a stable and appropriate concentration of retinol to be

effective86.

3. Retinol derivatives e.g. retinyl esters, combinations (table 3-3a)

Developed to combat the inherent instability of retinol, retinol derivatives are now widely used in

cosmetic and OTC products instead of retinol. There has been some evidence of their efficacy in

treating photoageing, with Han and colleagues (2003) developing various retinol derivatives for use

in anti-aging products. An in-vitro study found that N-formyl aspartame derivative has potential due

to good photo stability and its ability to interact well with fibroblasts and suppress collagen

breakdown87. However, not all retinol derivatives are equal, and despite initial promise in in-vitro

studies using animal models (induction of epidermal thickening and collagen formation in UV

irradiated mouse tails), retinyl propionate 0.15% did not translate to a signifiant effect in vivo when



compared to placebo88. Results of a current clinical trial comparing the clinical efficacy and side

effect profile of bakuchiol and retinol in cuteaneous facial photoageing was published in 2019.

Randomised, double-blind trial over 12 weeks in 44 participants. Both agents significantly

decreased surface wrinkles and pigmentation with no statistically significant difference between

them. Retinol was more irritating, with users reporting stinging, erythema and scaling. This trial is

ongoing and is the only currently active clinical trial listed on clinicaltrials.gov looking at retinoids

in the management of photoageing89.

3a. Retinol combinations (table 3-3a)

Retinol combinations can offer significant benefits when combined with the right agent e.g. hydroxy

acids, hydroquinone or ascorbic acid. Evaluation of the efficacy of retinol 0.1% and glycolic acid

8% combination compared with each agent individually on photo damaged forearms, results

showed the combination offered significant improvement than either agent alone90. Retinol 0.3%

plus hydroquinone 4% compared to 0.05% tretinoin in treatment of photoageing - combination

product significantly improved the collective signs of photodamage, including dyspigmentation,

fine wrinkles, tactile roughness within 16 weeks of treatment91.

2 double blind vehicle controlled trials have been conducted to investigate the effect of retinol and

vitamin C combination in 2 different formulations. Study 1 looked at 0.07% retinol and 3.5%

vitamin C applied twice daily over 3 months. Study 2 compared 0.04% retinol and 3% vitamin C

applied twice daily over 6 months. After 3 months results showed thinning of stratum corneum,

increased epidermal thickness and increased interdigitation at the dermo-epidermal junction, and

after 6 months dermal changes were evident including improvement in type III-to-type I

procollagen ratio and an increase in size and frequency of the grenz zone in vitamin C and retinol

treated groups compared to vehicle controls, with the authors concluding that topical application of

preparations containing retinol and vitamin C can reverse, in part, the changes induced by

photoageing92.

A formulation containing an AHA (lactic acid) double conjugated with retinoid cream was

compared to 1.0% retinol and 0.025% tretinoin in a randomised split face trial over 12 weeks.

Retinoid conjugated with lactic acid, formed via double hydrolysis, allows the controlled release of

both agents via the breakdown of the ester bonds that hold the two molecules together. This process

is catalysed by enzymes naturally occurring in the skin. Less irritation was reported compared to

retinol or tretinoin, and significantly improved fine lines/wrinkles, erythema, dyschromia, skin tone

and pore size, with the AHA-retinoid formulation. Improved skin hydration was seen with AHA-


http://clinicaltrials.gov


retnoid cream and not with tretinoin or retinol. AHA-retinoid cream offers increased molecular

stability, reduced irritation, and improved passage through the skin44.

4. Retinaldehyde (table 3-4)

Retinaldehyde, or retinal, is the oxidised form of retinol and the immediate precursor to retinoic

acid. Formulated as a cream or gel in concentrations between 0.015% to 0.1% it has shown promise

in the treatment of photoageing. A pilot clinical tolerance study by Saurat et al (1994) followed 129

patients who applied varying concentrations of retinaldehyde cream (0.05%, 0.1% and 0.5%) over a

1-3 month period. They found that topical application of retinaldehyde induces CRABP II mRNA

and protein, and significantly increases the epidermal thickness in a dose-dependent manner93. The

efficacy of 0.05% retinaldehyde has been compared to 0.05% tretinoin, and retinaldehyde vehicle,

when applied to the face of 125 patients followed over a 44 week period, with follow up at 18

weeks and 44 weeks. Both tretinoin and retinaldehyde reduced roughness and wrinkles after 18

weeks, and these effects were maintained but had plateaued by week 44. Retinaldehyde 0.05% had

efficacy similar to 0.05% tretinoin but was found to be significantly less irritating94,95. Kwon and

colleagues assessed the efficacy of 0.1% and 0.05% retinaldehyde in 40 Korean volunteers who

applied the cream twice daily for 3 months. They found that there was improvement in overall

photoageing with both 0.1% and 0.05%, and both preparations improved skin texture, reduced

TEWL and increased skin hydration, without any statistical significance between groups.

Retinaldehyde 0.1% improved the melanin index by 6.5% (the 0.5% concentration did not affect

this parameter significantly)96.

5. Isotretinoin (table 3-5)

Isotretinoin (13-cis retinoic acid) in topical preparations is available as a 0.05% cream or gel. More

commonly administered as the oral agent Accutane for cystic and severe acne, topical isotretinoin

can also have beneficial effects in treating the signs of photoageing. A double-blind randomised-

control trial involving 776 patients compared the efficacy of the application of vehicle or 0.05%

isotretinoin cream nightly for 12 weeks, followed by application of 0.1% isotretinoin cream for the

next 24 weeks. When compared with vehicle, treatment with 0.05% and then 0.1% isotretinoin

resulted in statistically significant improvement in overall appearance, fine wrinkling, discrete

pigmentation, sallowness, and texture. Isotretinoin cream was well tolerated over the 36 week

period97. There have been no studies directly comparing isotretinoin to tretinoin in terms of efficacy.

6. Alitretinoin (table 3-6)



Alitretinoin (9-cis-retinoic acid) is an approved topical treatment of Kaposi sarcoma. The

theoretical benefit of alitretinoin 0.1% gel for photoageing stems from its ability to bind all subtypes

of RAR and RXR receptors, thus promoting the repair mechanisms within photo damaged skin. An

open label study including 20 participants looked at the use of 0.1% alitretinoin gel in photoageing.

It was well tolerated and participants showed improvements in benign skin lesions (eg seborrhoeic

keratoses) and precancerous lesions such as actinic keratoses. However, larger clinical trials are

needed to further investigate the use of alitretinoin for this indication98. There have been no studies

directly comparing alitretinoin to tretinoin in terms of efficacy, and alitretinoin is not a topical

retinoid that is currently routinely used in the treatment of photoageing.

7. Tazarotene (table 3-7)

Tazarotene is the precursor to tazarotenic acid and an analogue of tretinoin, and is usually available

in 0.05% and 0.1% gel and cream. It binds to RAR-β and RAR-γ subtypes only. Used in acne,

psoriasis and photoageing, it enhances keratinocyte turnover, normalises keratinocyte differentiation

and is anti-inflammatory99. In acne and psoriasis it is usually combined with topical antibiotics and

topical corticosteroids respectively100. There have been a number of large, multi-centre trials

comparing tazarotene in varying concentrations, and tazarotene with tretinoin 0.05% and vehicle. In

2001, Kang et al., conducted a 24 week, multi-centre, randomised control trial with 349 patients

enrolled, comparing the efficacy of tazarotene 0.01%, 0.025%, 0.05%, and 0.1%, with tretinoin

0.05% and vehicle101. All concentrations of tazarotene and 0.05% tretinoin improved the appearance

of wrinkles and pigmentation. 0.1% tazarotene had the biggest improvement at 67%, followed by

0.05% tretinoin (55%), 0.05% tazarotene (52%), 0.025% tazarotene (36%) and 0.01% tazarotene

(41%). There was also increasing chance of skin irritation with increasing strengths of tazarotene

and with tretinoin. However, the reaction was limited to a mild-moderate irritant reaction that was

self limiting101. A further 24 week, vehicle-controlled trial by the same authors concluded that 0.1%

tazarotene was particularly efficacious in relation to the speed in which participants saw

improvements in wrinkles, hyperpigmentation, lentigines, pore size, elastosis, tactile roughness and

overall integrated assessment of photodamage, with some seeing improvement after 2 weeks, and

the majority having reported improvement after week 4. Improvements continued and did not

plateau by week 24102. Lowe et al (2004) further backed up these findings in a study comparing

0.05% tretinoin with 0.1% tazarotene over 24 weeks. The results indicated that tazarotene can offer

a faster improvement in the clinical signs of photoageing103. These impressive clinical results were

supported by Machtinger et al (2004), who reported the histological findings after 24 weeks of 0.1%



tazarotene application to photo damaged skin. There was amelioration in keratinocyte and

melanocyte atypia, increased epidermal thickness and improved epidermal polarity104.

There have been further, interesting studies that seem to indicate that tazarotene may offer another

advantage over tretinoin in terms of treating the photoaged phenotypes in which pigmentation may

feature more prominently. An RCT comparing 0.1% tazarotene vs adapalene 0.3% gel in patients

with post inflammatory hyperpigmentation (PIH) and acne found that tazarotene was more effective

than adapalene at improving the appearance of pigmentation associated with PIH105. Further

evidence for early improvements in mottled hyperpigmentation, as early as 2 weeks, were

demonstrated by Phillips (2004) who looked at 0.1% tazarotene vs vehicle over a 24 week period,

and then continued with an open label extension with 0.1% tazarotene for a further 28 weeks.

Within 4 weeks there were improvements in lentigines and irregular pigmentation, fine wrinkling

improved within 8 weeks, elastosis, roughness and coarse wrinkling had improved by 12 weeks.

These improvements were continued in the 28 week extension period105,106.

8. Adapalene (table 3-8)

A third generation, receptor specific retinoid, with napthoic acid base. Adapalene behaves similarly

to tretinoin but is photochemically and chemically stable. Adapalene is already approved for the

treatment of acne and is highly beneficial in regulating abnormal desquamation of the skin, cellular

differentiation and inflammation107. Adapalene binds more readily to RAR-β, with low affinity for

RAR-α and no cross-reactivity with RXR subtypes. This indicates that adapalene affects the

terminal differentiation pathway of epidermal cells rather than their proliferation107,108. Adapalene

has also been indicated in photoageing. Once daily application of adapalene 0.1% gel for 4 weeks,

followed by twice-daily application for up to 9 months significantly reduced AK and lentigines109.

Adapalene 0.1% gel applied under occlusion for 4 days demonstrated the ability to induce

expression of CRABP-II at 70% of the potency of tretinoin 0.1% under the same circumstances.

Tretinoin induced erythema, epidermal hyperplasia and spongiosis, whereas both vehicles and 0.1%

adapalene did not. CRABP-II gene expression is more useful marker of retinoid biologic activity

than skin erythema or changes in epidermal morphology or differentiation110.

Adapalene comparison studies Adapalene 0.3% gel was shown to be non-inferior to 0.05% tretinoin cream, with a similar safety

profile and effective in global cutaneous photoageing, periorbital wrinkles, ephelides/melanosis,

forehead wrinkles and AK. Can be considered safe and effective treatment for mild or moderate

photoageing111. The cumulative irritation potential of adapalene 0.1% gel and 0.1% cream was



compared with erythromycin (4%)/tretinoin (0.025%) gel, erythromycin (4%)/tretinoin (0.025%)

solution, erythromycin (2%)/isotretinoin (0.05%) gel, and white petroleum as a control. Adapalene

showed itself to be only slightly more irritating than the control (mean cumulative irritation index of

0.25-1), and was significantly less irritating than any of the tretinoin/erythromycin products (P <

0.01). Despite this study looking at the indication of acne, parallels can be drawn when decisions

need to be made on an appropriate retinoid to use in those with acne and photoageing - adapalene

would be beneficial in these cases given its low irritation112. Clinical trials have found that 0.1%

adapalene works faster than 0.025% tretinoin, the most commonly used retinoid, and with less

irritation113.

9. Novel retinoids Various receptor-selective and function-specific retinoids are in experimental stages. Focusing on

selective targets can offer a more narrow therapeutic indication and reduce unwanted side effects.

Current research is focused on “function-specific” retinoids, for example retinoid receptor

antagonists which have implications in the management of mucocutaneous toxicity associated with

retinoids114. With regard to the current research into topical novel retinoids for photoageing, 2 such

agents are discussed below, neither of which are in current clinical use.

9a. Seletinoid G (table 3-9a)

Kim et al (2005) developed a novel synthetic retinoid seletinoid G, using computer-aided molecular

modelling. They applied seletinoid G and tretinoin, under 4-day occlusive dressing, to the buttocks

of 23 subjects and measured skin erythema and cutaneous blood flow (markers of skin irritation),

and also measured the expression of MMP-1 in biopsied taken from the treated areas. The results of

this study showed that seletinoid G did not induce any skin erythema, in contrast to tretinoin which

induces severe erythema. Seletinoid G also induced the expression of procollagen I, tropoelastin

and fibrillin-1, and a reduction in MMP-1115.

Lee et al 2020 demonstrated that seletinoid G promotes the proliferation and migration of

keratinocytes in vitro. They also found that seletinoid G improved wound healing and closure, and

increased dermal collagen in human skin equivalents exposed to UVB irradiation116.

9b. N-retinoyl-D-glucosamine (GRA) (table 3-9b)

A retinoic acid agonist, compared with retinoic acid in photoaged mice. To determine RAR/RXR

activity. Hairless mice irradiated for 10 weeks UVB - then treated with 8 weeks of either RA 0.05%

vs GRA 0.05%, expression of RAR-α and RXR-α. Clinically both agents improved wrinkles caused



by UVB irradiation - promoting wide repair zone and expression of type I collagen. GRA did not

produce erythema or roughness, or TEWL as compared to RA. GRA resulted in a significant, dose-

dependent transcription of RAR 100 time potency of RA, GRA did not induce RXR at all117.

Factors affecting the efficacy of topical retinoid application There are a variety of factors that will affect the efficacy of topical retinoids, including the

formulation and concentration of retinoid, the vehicle used, the frequency and consistency of

application, the degree of baseline photodamage and degree of pigmentation, the patients skin type.

Previous studies with participants lost from the study have indicated that the irritant reaction caused

by the use of topical retinoids has caused issues with patient compliance, and in a significant

number of cases cessation of use. It would follow then that minimising the irritation associated with

topical retinoid use would improve compliance of retinoid use. The factors influencing cutaneous

irritation involve an interplay between patients individual differences in skin sensitivity, the

concentration of the applied retinoid, and vehicle formation. To optimise tolerance both the

concentration and delivery vehicle can be adapted118.

The role of retinoid formulation on efficacy and tolerance Retinoic acid has limitations due to its inherent photo-instability, low aqueous solubility, and

cutaneous irritant effects3. These factors must be mitigated to deliver RA to the skin where it can

exert its effects and increase patient compliance. In order to achieve this, various formulations for

delivery of typical retinoids have been developed; traditional vehicles such as emulsions, gels,

liposomes and polymeric nanoparticles, which in some cases have been modified to target specific

tissues and cells of interest119; compared tretinoin 0.025% was conjugated with polyolprepolymer-2

(PP-2) and compared to standard gel formulation of tretinoin 0.025%. The conjugated formulation

decreased the penetration of tretinoin and enhanced epidermal deposition. It is able to do this by

forming a liquid polymer containing solubilised tretinoin on the epidermis that was shown to

become established in the epidermis 15 minutes after application119.

Further advances and research into topical drug delivery systems; They can roughly be categorised

into 1) phospholipid-based particles, 2) polymeric nanoparticles, and 3) retinoid-conjugated

polymers, in varying sizes (100-400nm) with either neutral (liposomes) or negative charge (SLN,

NLC, polymeric nanoparticles)3. These formulations have demonstrated high retinoid entrapment

efficiency (~65%), a 2-3 fold higher photostability than tretinoin in ethanol, and higher stability

under normal storage conditions3.



Newer nanostructured formulations, such as solid lipid nanoparticles (SLNs) and nanostructure

lipid carriers (NLCs), have been found to further enhance retinoid delivery and have become the

target of the cosmeceutical industry in the quest for formulations that are efficacious and well

tolerated by consumers. The nanoencapsulation of tretinoin in a lipid core polymeric nanocapsule

improved the photo stability and reduced the skin permeation of tretinoin. It does this by retaining

the drug on the surface of the skin for longer, prolonging the half life of tretinoin by 7 times and

reducing the degradation of tretinoin by UVA120. Further support of the nanoparticle method of

delivery has been demonstrated by Puglia and Bonina (2012)121. They demonstrated that solid lipid

nanoparticles (SLNs) and nanostructure lipid carriers (NLCs) increased the efficacy and delivery of

cosmeceutical and dermal pharmaceutical drugs to the epidermis. Furthermore, they were

completely biodegraded and were felt to offer greater efficacy when compared to emulsions,

liposomes and polymeric nanoparticles delivery systems121.

Most recently, Raminelli et al 2018 have found that tretinoin in small unilamellar vesicles promoted

greater cutaneous delivery and retention in the skin of RA, even more so when the lipid carried a

negative charge122. Rahimpour and Hamishehkar (2012) found that liposomes enhance the topical

delivery of tretinoin and improve skin moisturisation when used. They allow for better penetration

into the dermis due to their structure being similar to biological cell123. In a pilot trial involving

acne patients, retinoic acid in liposomal delivery system enhanced the penetration of RA into the

stratum corneum124. Tretinoin complexed with cyclodextrin (Cyd; an oligosaccharide) was found to

be less irritating and less inflammation-inducing than tretinoin in a double-blind trial involving 12

participants. They found that the RA-Cyd complex had an equal effect to RA in improving wrinkle

scores, skin elasticity and wrinkle area, and both agents induced epidermal hyperplasia125.

Formulations enhancing target area of action of retinoid Sardana et al 2003 reported the ability of a tretinoin gel microsphere formulation (10-20μm) to

target the follicle in acne patients. The gel microsphere formulation was found to accumulate

preferentially at the follicle and so can be targeted towards this site, particularly useful in acne, a

disorder of the follicular unit126.

Discussion

Can we make conclusions about a hierarchy of retinoids?

The overwhelming evidence for the efficacy of topical retinoids in preventing and reversing the

clinical and histological features of photoageing has been demonstrated by various groups and in

various patient populations. Tretinoin is the oldest, and most commonly used retinoid for this Dr. Sarah Tranter MBBS BSc Professional Project MSc Dermatology in Clinical Practice 25


indication, and it is effective when used appropriately. However, the irritant reaction it can cause

may not be tolerated in those with sensitive skin or other concurrent skin disease. It is not often you

come across a patient who simply needs an agent that will address one problem; the skin and the

patient is unique, and so treatment must be tailored to that. Younger patients with skin types I and

II, who have mild early signs of photoageing may also suffer with acne. In contrast, a more mature

patient with pigmentation and melasma, may have more significant photodamage. Treatment choice

in terms of type of retinoid, formulation, delivery system and method of application (i.e. patient

compliance, frequency of use, baseline skin sensitivity and type) will all contribute to treatment

success. The variety of preparations and formulations mean that a tailored treatment regime can be

determined for almost all patients.

The evidence presented in this review supports a recommendation for the use of tazarotene in those

for whom a more rapid response may be required, and whose skin can tolerate the potential for

irritation. In addition, the use of adapalene in those patient wishing to treat both acne and

photoageing can be recommended. In those patients with sensitive skin, a retinol combination

product, with a focus on skin barrier repair and hydration, may be the most appropriate choice, and

the evidence suggests that a similar improvement in comparison to that seen with tretinoin can be

gained with these products.

Ultimately, the evidence supports the use of tretinoin, tazarotene, adapalene, retinaldehyde and

retinol in combination with complimentary agents such as AHAs, hydroxyquinone and anti-

oxidants for the management of photoageing. However patient assessment and education on the

appropriate way to use topical retinoids is key to ensuring the most successful outcome.

Conclusion Topical retinoids are an efficacious and well tolerated medical treatment for the clinical and

histological signs of cutaneous photoageing. The variety of preparations mean that treatment can be

tailored to specific patient characteristics and requirements, and almost all patients can benefit from

the addition of a topical retinoid to their skin care regime.



Word count: 10095


Table 3. The topical retinoids and their applications in preventing and reversing photoageing - a summary of their key characteristics, actions and evidence

Observations with treatment

RetinoidRAR affinity Prep

Histological and ultrastructural changes Clinical

Adverse effects Ref.

1. Tretinoin All-trans-retinoic acid

Natural1st generation

Directly activates all RARs, indirectly RXR

0.1%

0.05%

0.02%0.025%

Compaction of stratum corneum, increased GAGsStimulates epidermal proliferation

Compaction of stratum corneum, disappearance of atypia and dysplasia

Similar to effects seen with 0.05 and 0.1% however to lesser degree

Additional effects:Accelerates elimination of sebum and reduces inflammation of sebaceous glands, inhibits keratosis

Improvement in fine and coarse wrinkles, tactile roughness and sallownessHyperpigmentation/mottled hyperpigmentation (>6 months)

Improvement in fine wrinkles (after 3 months)

Similar to effects seen with 0.05 and 0.1% however to lesser degree

Improvement in inflammatory conditions, acne, psoriasis, keratosis pilaris

Mild-moderate irritant reaction, characterised by erythema, skin peeling, irritation.

Self limiting with continued use.

Dose dependent and improves on cessation of product.

[64], [65], [66], [68], [69], [70], [71], [75], [76]

2. Retinol All-trans-retinolRetinoic acid precursor



0.1%

0.5%

0.25%

Inhibits collagenase and MMP expression; stimulates collagen type 1 and GAGs synthesis

Less efficacious in improving fine lines and wrinkle, pigmentation. Approx 20-fold less effective than tretinoin.

Well tolerated

[42], [85], [86]

3. Retinol derivatives

Esters/ Combination products


RARs Varied Stimulates epidermal proliferationRegulates sebum

Improvement in fine lines and wrinkles

Well tolerated

[44], [87], [88], [91], [92]

4. Retinaldehyde

Retinoic acid and retinol precursor



0.05% Stimulates epidermal proliferationReduced TEWL

Reduction in skin roughness and wrinkles (after 44 weeks).Improved skin hydration

Well tolerated

[93], [94], [95]

5. Isotretinoin

13-cis-retinoic acid


Low affinity for RAR and RXR. May be converted intracellularly to active metabolites.

0.1% cream

Not reported Improvement in fine wrinkles, roughness, discrete pigmentation and sallowness over 36 weeks

Well tolerated

[97]

6. Alitretinoin

9-cis-retinoic acid


RXRs 0.1% Not reported Improvement in actinic and seborrhoeic keratoses

Well tolerated

[98]

Retinoid


7. Tazarotene

Precursor of tazarotenic acid

Synthetic3rd generation

RAR β/γ 0.1%

0.05%

0.025%

Regulates keratinocyte proliferation, differentiation and inflammationIncreases epidermal thickness, improved epidermal polarity

Improvement in wrinkles, pigmentation*, pore size, elastosis, tactile roughness

*possibly more efficacious than retinoic acid for this indication

Increasing irritant reaction with increasing concentration

[99], [100], [101], [102], [103], [104], [105], [106]

8. Adapalene

Napthoic acid base

Synthetic3rd generation

RAR β/γ 0.3% and 0.1% gel

Improved cellular atypia

Reduced epidermal melanin content

Potent modulator of follicular keratinisation, increases keratinocyte proliferation, keratolytic

Lightening of solar lentigines

Improvement in wrinkles, pigmentation

Improvement in acne, inflammation, excessive keratosis

Well tolerated

[108], [109], [110], [111]

9. Novel retinoids

9a. Seletinoid G

9b. N-retinoyl-D-glucosamine

Varied

Pyranone based

Synthetic4th generation

Retinoic acid agonist

Synthetic4th generation

RAR

RAR 0.05%

Induces procollagen I, tropoelastin and fibrillin-1Reduces expression of MMP-1Promotes proliferation /migration of keratinocytes (in vitro)Increases dermal collagen in human skin equivalents

Promotes wide repair zone and expression of collagen IInduces RAR transcription 100 times the potency of RA

Improved wound healing and closure

Improvement of wrinkles (in in UVB irradiated animal model)

Does not induce erythema

Does not induce erythema, roughness. Reduced TEWL

[115], [116]

[117]

Observations with treatment

RetinoidRAR affinity Prep

Histological and ultrastructural changes Clinical

Adverse effects Ref.Retinoid


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https://pubmed.ncbi.nlm.nih.gov/?term=Voorhees+JJ&cauthor_id=8396608

https://doi.org/10.3109/09546639309080547


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