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Topical retinoids in the treatment of photoaging
Christina Stefanaki, Alexander Stratigos & Andreas Katsambas
Department of Dermatology, University of Athens, Andreas Sygros Hospital, Athens, Greece A large number of different substances comprise the family of retinoids, which are tradi-tionally described as vitamin A derivatives. By exerting their action through nuclearand cytoplasmic receptors they may improve photoaging. Tretinoin is the best studiedretinoid in the treatment of photoaging. Others such as isotretinoin, retinaldehyde, andtazarotene, although less well studied, have given promising results.
Keywords: retinaldehyde, retinoids, tazarotene, tretinoin melanocytes, reduction and alteration in collagen, twisted Introduction
and dilated microvasculature, and most of all by deposi- Since human life span has expanded, and people more tion of abnormal elastoid material in the upper dermis and more desire a youthful and attractive appearance, a tremendous public and scientific interest has been The beneficial effects of retinoids on photodamaged skin were first noted by Kligman et al.5 in postadolescent Aging of the skin can be the result of a normal process women treated with tretinoin for persistent acne, as long- that involves a lower rate of metabolic activities and is term use of tretinoin led to improvement of skin wrinkling called chronologic aging.1 Chronologically aged skin remains smooth and demonstrates only subtle changes,such as slight atrophy, loss of elasticity, fine wrinkling, and Retinoids
deepening of expression wrinkles. Those changes arealso evident histopathologically. The epidermis appears Retnoids are traditionally described as vitamin A (all- atrophic and flattened. In the dermis fibroblasts, inflam- trans retinol) derivatives. All-trans retinol is oxidized matory cells and the microvasculature are significantly through retinal to its most active metabolite all-trans reduced and the collagen bundles become thick and retinoic acid (tretinoin), which has two stereoisomers, 13-cis retinoic acid (isotretinoin) and 9-cis retinoic On the contrary, photoaging is the consequence of acid.6 Following application to the skin, 50% of topically chronic sun exposure and manifests clinically with fine applied tretinoin remains in its original form, while the and coarse wrinkling, roughness, dryness, laxity, shallow- remaining is either metabolized to hydroxyretinoic acid ness, pigmentary mottling, telangiectasia, and in some cases with preneoplastic and neoplastic changes.3 Photo- Retinoids bind with specific cytoplasmic receptors and aged skin is typified histopathologically by acanthosis, exert their action through nuclear receptors, which loss of epidermal polarity, a basket weave appearance of belong to the family of steroid-thyroid receptors, thus the epidermis, keratinocyte atypia, irregularly dispersed activating transcription and leading to the production ofretinoid-specific proteins.8 Two families of nuclear receptors have been found, Correspondence: A Katsambas, MD, Department of Dermatology, Andreas RAR and RXR, each consisting of three isotypes, Sygros Skin Hospital, University of Athens, 5 Ionos Dragoumi Street, Athens γ.9 RAR receptors bind both tretinoin and 9-cis retin-oic acid, whereas RXR binds only 9-cis retinoic acid.9 Accepted for publication April 05, 2005 2005 Blackwell Publishing • Journal of Cosmetic Dermatology, 4, 130–134
Topical retinoid treatment • C Stefanaki et al. RXR α is the receptor that is predominately expressed in In the first study assessing the efficacy of tretinoin the epidermis, but RAR γ is also strongly expressed.10 emollient cream on 251 subjects with mild or moderate Tretinoin, when applied to the skin, may either bind to recep- photodamage, it was found that tretinoin 0.05% emol- tors as all-trans retinoic acid or its isomer 9- cis retinoic lient cream applied for 6 months was more effective than acid and alter gene transcription, ultimately affecting cell tretinoin 0.01% in reducing wrinkles, skin roughness, growth and differentiation. Cellular retinoic acid-binding and mottled hyperpigmentation.25 Side effects such as protein (CRABP-II), a binding protein for retinoic acid, is xerosis, mild erythema, peeling, burning, and stinging a very sensitive marker of retinoid activity.11 were also dose dependent. Irritant effects decreased with The beneficial effects of retinoids include: improved ongoing use and when persistent they were effectively fine wrinkling, diminished tactile roughness, improved actinic keratoses, and reduced hyperpigmentation.
In the other study conducted by Olsen et al.26 compar- Histopathologically, after treatment with tretinoin the ing different concentrations of tretinoin emollient cream following effects are noted: epidermal hyperplasia, com- (0.05%, 0.01%, and 0.001%) to vehicle, a greater paction of the stratum corneum, thickening of the granu- response was detected in the 0.05% treated group. Over- lar layer, reduced melanocytic hypertrophy, restoration of all improvement was noted in 78% of the subjects using cell porarity, increased angiogenesis, increased new col- the 0.05% cream, whereas only 44% of the subjects in the lagen formation, and normalization of the appearance of vehicle group improved. No significant difference was found between vehicle and tretinoin 0.01% and 0.001%.
The question arises how retinoids improve photodamage.
However, in a study comparing two different concen- Epidermal thickening noted early on after the initi- trations of retinoic acid, 0.025% and 0.1%, no significant ation of therapy and followed after several months by difference was found in clinical efficacy between the two normalization of the epidermal thickness cannot fully concentrations.27 Irritancy was greater with tretinoin 0.1% cream. This study suggested that efficacy is inde- The lightening of mottled hyperpigmentation is prob- pendent to the degree of irritation, in contrast to previous ably the result of increased epidermal turnover, reduced studies that indicated that the effects of tretinoin may be transfer of melanosomes, and inhibition of tyrosinase.16 the result of a nonspecific irritant reaction.28 This issue of It has been found that in retinoic acid-treated skin irritancy and efficacy is not fully resolved. Even a very low there is a significant increase in collagen I synthesis that irritation may be required to produce the desirable clinical is reduced in photoaged skin.12 Anchoring fibrils, consist- ing mainly of collagen VII, are reduced in number in Several studies have been conducted to assess the photoaged skin but increase in number after tretinoin maintenance of the beneficial effects of tretinoin.
treatment.17,18 Furthermore, tretinoin may prevent In one study, 298 photodamaged subjects who com- photodamage by inhibiting UVR-induced matrix metallo- pleted 6 months of once-daily use of tretinoin 0.05% proteinases (e.g., collagenase), which induce collagen or 0.1% emollient cream continued to use the same strength for another 6 months.30 Improvement was Despite those findings, the precise mechanisms of re- maintained and furthered with continuous use. Subjects tinoid actions remain to be elucidated.
receiving the 0.01% formulation improved more duringthe second than the first 6 months of treatment, but stilldid not achieve the level of response of the 0.05% group.
Interestingly, some individuals responded only in the The best-studied retinoid on the treatment of photo- extended 6-month period indicating a slow or delayed damage is tretinoin. Since the first observations by response in certain subjects. Side effects declined with Kligman et al.,5 a great number of studies followed. In the continuous use. It was only after 12 months of treatment earliest controlled trials of topical tretinoin therapy that well-organized collagen fibers and normal-appearing for photodamaged skin, both clinical and histological microfibrils were detected in the majority of subjects, improvements were seen with 0.05% and 0.1% which were detectable in the initial 6-month treatment formulations.15,21–24 However, the formulations used were primarily designed for acne, so an emollient base Subjects on tretinoin 0.05% cream were then ran- for tretinoin was developed and two large 24-week domized into three groups: once weekly therapy, three multicenter, double-blind studies followed.25,26 Both times weekly therapy or no therapy.5 The clinical im- studies concluded that the beneficial effects of retinoic provement was sustained with the three times/weekly acid on photodamaged skin are dose dependent.
application regimen and, to a lesser extent, with the once 2005 Blackwell Publishing • Journal of Cosmetic Dermatology, 4, 130–134
Topical retinoid treatment • C Stefanaki et al.
weekly application regimen.31 Discontinuation of ther- whereas tazarotenic acid selectively binds to RARs β and apy for 6 months resulted in some reversal of the benefi- γ.6 In addition to its RARβ and RARγ binding properties, cial effects seen after 1 year on treatment, while ongoing tazarotenic acid reduces abnormal expression of epidermal treatment further enhanced the reduction of photodam- growth factor and keratinocyte transglutaminase I and down-regulates gene expression dependent on activator These results have been confirmed by other studies.
protein 1, a transcription factor associated with cell Ellis et al.15 noted a sustained clinical and histological improvement in the severity of photodamage with con- Preliminary data from a small pilot study in 10 tinuous treatment with tretinoin 0.1% and 0.05% over a patients showed that tazarotene 0.1% gel applied to phodamaged skin for 12 weeks results in a statisticallysignificant increase in epidermal thickness and a signi-ficant decrease in skin roughness.36 Isotretinoin
Tazarotene was evaluated further against photo- Although isotretinoin is less well studied than retinoic damage in two subsequent studies. The first was a double- acid, it has given promising results. Prompted by animal blind, randomized, dose-ranging study involving 349 studies that have demonstrated isotretinoin efficacy in patients.37 Tazarotene 0.1% performed better than lower reversing photoaging, Sendagorta et al.32 conducted a concentrations in reducing fine wrinkling, mottled double-blind controlled trial to assess the efficacy of the hyperpigmentation, lentigines, and elastosis. In the formulation in 776 subjects with mild to moderate second 24-week multicenter, double-blind, randomized, photodamage. Isotretinoin 0.05% applied at night for vehicle-controlled trial enrolling 563 patients, tazaro- 3 months followed by 0.1% cream for 6 months im- tene 0.1% applied once daily achieved greater than 50% proved photoaging without causing any significant global improvement and at least 1 grade improvement of fine wrinkles, mottled hyperpigmentation, lentigines,elastosis, pore size, irregular depigmentation, tactileroughness, and coarse wrinkling.38 Actinic keratoses Retinaldehyde
and telangiectasia were not significantly improved after Human keratinocytes transform retinol into retinal- 24 weeks of treatment. After the first 24 weeks, an open- dehyde and then into retinoic acid — a two-step label extension of tazarotene 0.1% cream followed for enzymatic process involving dehydrogenase. The use of another 28 weeks. Additional clinical improvement was retinaldehyde seemed appealing for two reasons. First, noted, which did not plateau after 52 weeks on treat- it would bypass the first step of retinol oxidation.
ment. Irritation was generally mild or moderate and Furthermore, because only well-differentiated epidermal declined with ongoing treatment, whereas plasma tazaro- cells are capable of oxidizing retinaldehyde to retinoic acid, tenic acid concentration did not exceed the plasma levels a controlled delivery of retinoic acid and a better tolerance would be achieved with retinaldehyde, compared to To assess the efficacy of four different concentrations retinoic acid and its synthetic analogues.33,34 of tazarotene in the treatment of facial photodamage, A study enrolling 125 photodamaged individuals dem- a multicenter, randomized, vehicle-controlled study was onstrated a significant reduction of wrinkles and skin conducted.37 Three hundred forty-nine subjects were roughness after 44 weeks of treatment in both tretinoin randomized to use either tazarotene in various formula- 0.05% and retinaldehyde-treated patients.35 Retinalde- tions (0.1%, 0.05%, 0.025%, 0.01%) or tretinoin 0.05%, hyde was shown to be well tolerated, in contrast to retinoic or vehicle. Tazarotene 0.1% had the best overall efficacy, acid, which caused more local irritation, affecting com- with significant improvement of mottled hyperpigmenta- tion occurring as early as week 8 and of fine wrinkling atweek 12.38 Increased epidermal thickness and reducedmelanin content were the only histopathological features Tazarotene
that changed significantly. Tazarotene 0.1% and tre- Tazarotene is a synthetic retinoid that has been used tinoin 0.05% cream achieved a similar degree of improve- primarily for psoriasis. Tazarotenic acid, the active ment of fine wrinkling and mottled hyperpigmentation, metabolite of tazarotene, appears not to be convertible although a trend toward a quicker response was noted to other potentially active retinoid forms.6 Tazarotene with tazarotene 0.1%. The irritation observed was gener- and tretinoin display different receptor selectivities.
ally of mild and moderate severity and was greater with Tretinoin activates directly the RARs α, β, and γ, the higher tazarotene concentrations.
2005 Blackwell Publishing • Journal of Cosmetic Dermatology, 4, 130–134
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