|Grade||Level of Evidence|
|A||Multiple double-blind, controlled clinical trials.|
|B||1 double-blind, controlled clinical trial.|
|C||At least 1 controlled or comparative clinical trial.|
|D||Uncontrolled, observational, animal or in-vitro studies only.|
|Grade||Effect||Size of Effect||Comments|
Boosts the thickness of the skin by stimulating epidermal proliferation.
Induces a statistically significant increase in skin elasticity, via altering elastic fibers in the skin.
Has a direct antibacterial activity on P. acnes, and is particularly effective when used in association with glycolic acid.
May efface wrinkles by increasing collagen production and influencing elastic fibres in the skin.
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Table of contents:
Retinal, also known as retinaldehyde, is a precursor of retinoic acid that is produced in the body from ingested retinoids such as carotenoids and retinyl esters. Yellow and green vegetables are rich sources of carotenoids, while fish liver oil and animal fats contain retinyl esters. 
Retinal appears to exert its biological activities only on transformation to retinoic acid. As such, the metabolism of retinal within the skin after its absorption is as important to its efficacy as the ability of retinal to penetrate the skin.
One study uncovered the permeation and metabolism characteristics of retinal by measuring the levels of activity of a tretinoin-specific enzyme. The threshold concentration for adequate penetration and metabolism of retinal to tretinoin seems to be 0.025%, as lower doses failed to cause significant induction in the activity of the enzyme. It is important, therefore, that the concentration of retinal in cosmetic formularies be at least 0.025%. Further, retinal was found to be a better inducer of enzyme activity than retinol at a concentration of 0.025%, but at higher concentrations (0.05% to 1%) retinal and retinol were equally effective.
Unsurprisingly, a 10-fold higher concentration of retinal than all-trans retinoic acid (tretinoin) is required to induce a significant increase in the activity of the enzyme. This is because in the skin, retinal is converted by 2 pathways. One leads to retinol and retinyl esters, which are the major metabolites and function as retinoid stores; the other to retinoic acid. The metabolism occurs in human keratinocytes, with keratinocytes undergoing differentiation oxidising retinal more efficiently.
An experiment in which radiolabelled retinal was applied topically to in-vitro human skin and to the the culture media of dermal fibroblasts discovered that low but significant amounts of retinoic acid were detected in the epidermis, and to a lesser extent, in the dermis after treatment. Another study showed that 0.05% retinal penetrated well into the epidermis of excised human skin, and increased endogenous retinoids in addition to being metabolized to retinoic acid. These findings support the hypothesis that retinal is predominantly converted to storage forms of vitamin A, while delivering relatively small amounts of retinoic acid.
The addition of an alpha-hydroxy acid, such as glycolic acid, seems to result in better bioavailability of retinal, as the epidermal and dermal concentrations of retinal and retinoic acid were higher after treatment with retinal plus glycolic acid, as compared to treatment with retinal alone or glycolic acid alone. This leads to a higher delivery of retinoic acid, which potentiates the biological activities while preventing the side effects usually observed with high concentrations of topical tretinoin.
3. Effects on the skin
3.1 Age-related improvements
Topical retinal is known to alter collagen and elastic fibers as well as upregulate collagen synthesis, both of which are implicated in wrinkle formation. In one randomized controlled trial, 125 patients received treatment with 0.05% retinal cream (Ysthéal), 0.05% retinoic acid cream (Retin-A) or vehicle for 44 weeks. Replicas of the left crow's feet area were taken and analyzed by optical profilometry, and standard wrinkle and roughness features were calculated and statistically analyzed. Treatment with retinal led to significant reductions in wrinkles and roughness over baseline, but the improvements were not statistically significant compared to the vehicle even after 44 weeks.
Another study had 1,462 subjects apply 0.05% retinal and 0.5% hyaluronic acid fragments (Eluage cream; group 1), 0.05% retinal and 1% hyaluronic acid fragments (Eluage antiwrinkle concentrate; group 2) or both products (group 3) daily over 90 days. Groups 2 and 3 experienced significant improvements in wrinkles on the forehead (-19% and -10% respectively), nasolabial folds (-20% and -16%, respectively), crow's feet (-27% in the 2 groups) and wrinkles around the mouth (-34% and -23%, respectively).
2 clinical studies have indicated that topical retinal helps improve the elasticity of aging skin. The first is a 1-year, controlled trial in which 21 subjects applied 0.05% retinal cream on the face while another 19 subjects were treated with an emollient. The treatment with retinal significantly improved cutaneous elasticity compared to the control group, as measured by an echorheometer. The second is a large-scale trial in which 1,462 subjects applied 0.05% retinal and 0.5% hyaluronic acid fragments (Eluage cream; group 1), 0.05% retinal and 1% hyaluronic acid fragments (Eluage antiwrinkle concentrate; group 2) or both products (group 3) daily over 90 days. Patients in groups 1 and 3 had significant improvements in skin elasticity at the end of the 3 months.
Ultraviolet (UV) exposure is implicated in skin aging. UV radiation induces structural and cellular changes in all skin compartments, one of which is the depletion of epidermal vitamin A (retinol and retinyl esters). Experiments on hairless mouse skin show that both UVA and UVB exposure led to an immediate reduction in vitamin A content in the skin. Prevention of this may be relevant in counteracting the long-term side effects of UV radiation.
Topical treatment with retinal prior to UVB exposure appears to accelerate the reconstitution of epidermal retinol and retinyl esters after their depletion by UVB. Moreover, 0.05% retinal cream has been demonstrated to repair UVA-induced elastic fiber and collagen damage in ex vivo human skin. In this study, human skin explants were subjected to UVA exposure to simulate skin photoaging, and retinal cream was then applied for 2 weeks. UVA exposure was found to induce significant alterations of collagen and elastic fibers, and to induce a decrease in collagen synthesis. Subsequent treatment with retinal however reversed these effects, with levels of collagen synthesis similar to that of unexposed skin, and with collagen and elastic fibers restored to the levels of unexposed skin.
Retinal associated with pretocopheryl, an antioxidant, enhances these benefits. A controlled study found that a cream containing 0.05% retinal plus pretocopheryl significantly decreased UV-generated free radicals, and also repaired laminins, elastic fiber and the collagen network to a greater extent than a control cream containing just 0.05% retinal.
3.2 Improved skin thickness
The thickness of the skin appears to decrease with age. In a study on upper inner arm skin biopsies, epidermal thickness was found to decline 7.2% per decade in men and 5.7% per decade in women, while dermal thickness decreased by 6% per decade in both men and women. The thinning of the skin may be attributed to lower epidermal cell turnover, the flattening of the dermal-epidermal junction and dermal and subcutaneous atrophy.
Retinal seems to alleviate some of these changes in aging skin. Retinal has been demonstrated to increase epidermal proliferation and hence epidermal thickness. Several studies also indicate that retinal boosts the thickness of the dermis. Ultrasound scanning showed that 0.05% retinal cream applied topically to the face induced a significant increase in epidermal thickness of the temple in one such study. In another study, ultrasound imaging showed that concomitant daily topical application of 0.05% retinal led to a greater increase in dermal thickness in the forehead among patients receiving non-ablative laser remodeling treatment compared to the control group which applied an excipient.
3.3 Acne vulgaris treatment
Retinal combined with an antibiotic also appears to improve acne to a greater extent than the antibiotic alone. For instance, topically applied 0.1% retinal gel in combination with a topical 4% erythromycin lotion not only significantly reduced papules and pustules to the same extent as erythromycin alone, but also improved comedones and microcysts, which were not observed in the treatment with just erythromycin.
A multitude of clinical studies have also shown that 0.1% retinal and 6% glycolic acid in a single formulation (Diacneal) is an effective topical acne treatment. In one, patients with mild to moderate acne vulgaris had significantly reduced numbers of papules, pustules and comedones from after 1 month of treatment with Diacneal, compared to treatment with vehicle. Apart from its antibacterial activity, retinal also modulates the differentiation and proliferation of keratinocytes, which is of interest in retentional acne lesions, while glycolic acid increases the exfoliation of corneocytes, explaining its mild activity on retentional lesions. Hence, their association has complementary activities, leading to a synergistic effect.
The combination of retinal with glycolic acid is also able to reduce post-acne sequelae such as postinflammatory hyperpigmentation (PIH) and acne scarring. Retinal has been shown to decrease melanin content in human skin, and glycolic acid decreases excess pigment by a wounding and re-epithelization process. In a double-blind, vehicle-controlled trial conducted on 145 patients, application of Diacneal every evening for 3 months was found to improve scarring more efficiently than vehicle cream, in addition to reducing the number of inflammatory lesions and comedones.
2 large-scale clinical studies have also demonstrated that Diacneal may be used in association with other topical anti-acne treatments including benzoyl peroxide and topical antibiotics, with excellent tolerance.
4. Side Effects
It is well-established that topical retinal is well-tolerated on human skin and less irritant than topical tretinoin. In one study, 229 patients received topical retinal at different concentrations; the 1% preparation was tolerated by up to 70% of the patients; tolerance of the 0.5% preparation was slightly better, and both the 0.1% and 0.05% preparations applied to facial skin allowed prolonged use of up to 3 years. Furthermore, none of 45 patients developed toxic allergic reactions or photosensitivity after long-term use of retinal with a median of 48.6 months.
2 studies utilizing 0.1% retinal and 6% glycolic acid in acne patients also demonstrated very good tolerance, with few complaints about side effects. In one of the studies 3 out of 71 patients in the treatment group experienced cutaneous adverse effects, but it is not clear whether this was related to the presence of retinal or some of the other ingredients, such as glycolic acid, or a combination.
Keratinocytes in the skin predominantly channel retinal into storage forms such as retinyl esters, with only a small proportion converted to tretinoin. Moreover, the metabolism of retinal to retinoic acid appears to take place at a defined stage of keratinocyte differentiation, leading to a more controlled release of active retinoic acid. This explains the low irritancy and weaker adverse effects of topical retinal compared to topical tretinoin.
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