Retinol

Retinol is a natural form of Vitamin A that exerts its significant anti-aging effects through its conversion to tretinoin. Unlike tretinoin however, it is much less irritating to the skin.

Effects


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

A

Wrinkle treatment

Strong

Improves wrinkles on cheek, under the eyes, on the forehead and crow's feet by inducing collagen and GAG synthesis.

A

Skin lightening

Moderate

Brightens skin and lightens brown spots and mottled pigmentation.

A

Increased skin elasticity

Moderate

Increases the elasticity of the skin below the eyes and at the jaw line, as well as the skin's overall firmness.

B

Smoother skin

Moderate

Reduces skin roughness, possibly via the same mechanisms as wrinkle effacement.

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Scientific Research


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Table of contents:

1. Sources

Major sources of natural retinoids are animal fats and fish liver oil, which contain retinyl esters , and yellow and green vegetables, which contain carotenoids. Retinol, a form of Vitamin A, is produced in the human body from the hydrolysis of retinyl esters and from the oxidative cleavage of carotenoids to form retinal, followed by reduction to retinol.[1]

2. Bioavailability

The biological activity of retinol requires its conversion to retinoic acid, the biologically active form of Vitamin A.[2] Topical cosmeceuticals containing retinol are theoreticized to work because once absorbed they are metabolized to retinoic acid, which induces pharmacological activity.[3] Hence, the percutaneous absorption profile of retinol and its metabolism to retinoic acid are equally important to its effectiveness.

2.1 Permeation

In one study, the penetration characteristics of retinol in human skin in vivo was demonstrated by measuring levels of cytochrome P450-dependent retinoic acid 4-hydroxylase (CP450-RAH). 0.025% and greater concentrations of retinol induced the enzyme activity significantly, but not in a linear manner. From this study, the threshold concentration for adequate penetration and metabolism of retinol into retinoic acid appears to be 0.025%.[4]

Raman spectroscopy can be used to monitor the in vivo delivery of retinol into human skin.[5] Using this technique, oleic acid, a skin penetration enhancer, was shown to improve the permeation of retinol into the forearms of human volunteers.[6]

The use of nanoparticle-coated emulsions and microencapsulation[7] also appears to increase both the chemical stability,[8] sustained release and dermal delivery of retinol.[9] In fact, one study found microencapsulated retinol and a blend of active ingredients prepared as a triple nanoemulsion to be therapeutically more effective than tretinoin, a leading commercial product.[10]

In another experiment, between 4-10% of the applied dose of 0.3% retinol using gel and oil-in-water emulsion vehicles penetrated excised human skin, with the emulsion obtaining better penetration. Most of the retinol that permeated was also found to remain in the stratum corneum, though some retinol was located in the viable epidermal and upper dermal layers.[11]

2.2 Metabolism

One experiment studied the metabolism of retinol using in-vitro human skin and dermal fibroblasts. Radiolabelled retinol was applied either topically to skin biopsies or to the culture media of the fibroblast suspension, and the metabolites were identified by HPLC. 60% of the applied retinol remained unmetabolized, with the main metabolites being retinyl esters (18.5%) and only 2% was retinoic acid.[12] Other studies have corroborated these results, concluding that the primary metabolite of topical retinol is retinyl esters,[4] with retinoic acid constituting only a small, sometimes undetectable,[13] proportion of the metabolites formed. Therefore, it stands to reason that retinol-based products must contain a higher concentration of retinol in order to exhibit the same effects as retinoic acid-based formulations. Indeed, one study has shown that 1.1% tri-retinol gradual release cream had the same efficacy and tolerability as 0.025% tretinoin cream.[14]

3. Effects on the skin

3.1 Anti-wrinkle effect

Retinol treatment improves wrinkling in both chronologically aged and photoaged skin. In one randomized, double-blind, vehicle-controlled study on subjects aged 80 years and above, 0.4% topical retinol applied at an average of 1.6 times a week to the upper inner portion of the arms led to significant reductions in fine wrinkling compared to vehicle treatment. The improvements were evident at the beginning of week 4, and continued through the end of the 24 weeks.[15] 1%, 0.5% and 0.1% retinol formulations have also been shown to improve crow's feet as well as lines and wrinkles on the cheek, under the eyes and on the forehead.[16][17] Similarly, a randomized, double-blind, vehicle-controlled study in middle-aged Japanese females found that 0.075% and 0.04% retinol cream resulted in significant improvements in both fine wrinkling and deep wrinkling.[18] Another study on Japanese women evaluating the anti-wrinkle effects of a commercial anti-wrinkle lotion, Retin-OX+, concluded that it led to significant improvements in wrinkles at the corner of the eyes in 34% of subjects, and could be used for treatment.[19]

The addition of dihydroxymethylchromone (DMC) and low molecular weight hyaluronic acid to 0.04% retinol also appears to enhance the efficacy of 0.04% retinol in diminishing wrinkles and fine lines, resulting in similar efficacy to 0.1% retinol. There is in-vitro evidence that DMC has an additive effect on retinol-induced gene expression in human keratinocytes.[20]

Biochemically, retinol treatment induces expression of glycosaminoglycan (GAG) and collagen synthesis in both photoaged skin and in naturally aged, sun-protected skin. The tactile smoothening effect of topical retinoic acid is thought to be mediated by induced GAG retaining water in the superficial cutaneous compartment. As a precursor of retinoic acid, the effacement of the fine wrinkles of natural aging brought about by retinol application is hence likely to be due in part to GAG.[15]

3.2 Lightening effect

Several studies have demonstrated the effects of topical retinol on hyperpigmented skin. 1% and 0.5% retinol suspensions (Retriderm ULTRA, Retriderm Serum) were found to reduce hyperpigmentation in female subjects.[17] Separately, a 0.1% retinol facial moisturizer has been demonstrated to prominently reduce mottled pigmentation by 53% after 8 weeks of once-daily applications.[16]

Retinol has also been combined with other active ingredients to treat dyspigmentation. The combination of 0.04% retinol with dihydroxymethylchromone (DMC) and hyaluronic acid has also been found to decrease the intensity of brown spots.[20] Another 16-week study showed that 0.3% retinol with 4% hydroquinone in an emollient cream more effectively diminished dyspigmentation and other signs of photodamage than 0.05% tretinoin cream.[21]

10% retinol gel also improved pigmentation when used as a replacement for 0.1% tretinoin in a 2-phased bleaching protocol together with hydroquinone, lactic acid and ascorbic acid.[22]

3.3 Improvement in skin elasticity

One randomized, double-blind, vehicle-controlled and split-face study on women aged 40-65 found that a 0.1% stabilized retinol formulation improved sub-orbital elasticity, elasticity at the jawline, and overall firmness of the skin, some as early as within 4 weeks of once-daily application.[16] Another formulation of 1% and 0.5% retinol, specifically Retriderm ULTRA and Retriderm Serum respectively, also improved skin laxity within 4 weeks of application.[17]

3.4 Smoothing effect

1% retinol has been shown to improve the roughness of the skin by at least 1 grade following 60-80 days of treatment.[17] 0.4% retinol lotion also reduced tactile roughness in subjects treated for 24 weeks, albeit to a lesser extent.[15]

3.5 Other effects and uses

Cellulite, also called orange peel skin due to its manifestation as an aesthetically disturbing dimpling of the skin, affects 80-90% of all females.[23] Although topical retinol has a reputation for treating cellulite and retinol-containing cosmetic products have demonstrated superiority over placebo in reducing cellulite,[24][25] a randomized, placebo-controlled clinical trial found that treatment with retinol alone did not improve the lumpy-bumpy appearance of the skin in 15 women with mild-to-moderate cellulite after 6 months of treatment.[26]

4. Side Effects

4.1 Mild irritation

Compared to its metabolite retinoic acid, retinol causes much less irritation and is safer to the skin.[17] In one double-blind study, retinol application to buttock skin produced none or only trace erythema not significantly different from vehicle, whereas retinoic acid induced a significant level of erythema.[13] 0.4% retinol was also relatively well-tolerated in elderly subjects, at a mean of 1.6 applications weekly.[15] At a concentration of 0.04%, retinol cream leads to less prominent improvements, but minimal irritation, and may be suitable for daily use in the general population, even for those with sensitive skin.[18]

Scientific References


  1. Roos TC, et. al. Retinoid metabolism in the skin. Pharmacol Rev. (1998)
  2. Kurlandsky SB, et. al. Biological activity of all-trans retinol requires metabolic conversion to all-trans retinoic acid and is mediated through activation of nuclear retinoid receptors in human keratinocytes. J Biol Chem. (1994)
  3. Levin J, Momin SB. How much do we really know about our favorite cosmeceutical ingredients? J Clin Aesthet Dermatol. (2010)
  4. Duell EA, et. al. Extraction of human epidermis treated with retinol yields retro-retinoids in addition to free retinol and retinyl esters. J Invest Dermatol. (1996)
  5. Pudney PD, et. al. An in vivo confocal Raman study of the delivery of trans retinol to the skin. Appl Spectrosc. (2007)
  6. Mélot M, et. al. Studying the effectiveness of penetration enhancers to deliver retinol through the stratum cornum by in vivo confocal Raman spectroscopy. J Control Release. (2009)
  7. Cho HK, et. al. Topical delivery of retinol emulsions co-stabilised by PEO-PCL-PEO triblock copolymers: effect of PCL block length. J Microencapsul. (2012)
  8. Eskandar NG, Simovic S, Prestidge CA. Chemical stability and phase distribution of all-trans-retinol in nanoparticle-coated emulsions. Int J Pharm. (2009)
  9. Ghouchi Eskandar N, Simovic S, Prestidge CA. Nanoparticle coated submicron emulsions: sustained in-vitro release and improved dermal delivery of all-trans-retinol. Pharm Res. (2009)
  10. Afornali A, et. al. Triple nanoemulsion potentiates the effects of topical treatments with microencapsulated retinol and modulates biological processes related to skin aging. An Bras Dermatol. (2013)
  11. Yourick JJ, Jung CT, Bronaugh RL. In vitro and in vivo percutaneous absorption of retinol from cosmetic formulations: significance of the skin reservoir and prediction of systemic absorption. Toxicol Appl Pharmacol. (2008)
  12. Bailly J, et. al. In vitro metabolism by human skin and fibroblasts of retinol, retinal and retinoic acid. Exp Dermatol. (1998)
  13. Kang S, et. al. Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable retinoic acid levels or irritation. J Invest Dermatol. (1995)
  14. Ho ET, et. al. A randomized, double-blind, controlled comparative trial of the anti-aging properties of non-prescription tri-retinol 1.1% vs. prescription tretinoin 0.025%. J Drugs Dermatol. (2012)
  15. Kafi R, et. al. Improvement of naturally aged skin with vitamin A (retinol). Arch Dermatol. (2007)
  16. Tucker-Samaras S, et. al. A stabilized 0.1% retinol facial moisturizer improves the appearance of photodamaged skin in an eight-week, double-blind, vehicle-controlled study. J Drugs Dermatol. (2009)
  17. Gold MH, et. al. Treatment of facial photodamage using a novel retinol formulation. J Drugs Dermatol. (2013)
  18. Kikuchi K, et. al. Improvement of photoaged facial skin in middle-aged Japanese females by topical retinol (vitamin A alcohol): a vehicle-controlled, double-blind study. J Dermatolog Treat. (2009)
  19. Kawada A, et. al. Evaluation of anti-wrinkle effects of a novel cosmetic containing retinol using the guideline of the Japan Cosmetic Industry Association. J Dermatol. (2009)
  20. Oddos T, et. al. A Placebo-Controlled Study Demonstrates the Long-Lasting Anti-Aging Benefits of a Cream Containing Retinol, DihydroxyMethylChromone (DMC) and Hyaluronic Acid. JCDSA. (2012)
  21. Draelos ZD. Novel approach to the treatment of hyperpigmented photodamaged skin: 4% hydroquinone/0.3% retinol versus tretinoin 0.05% emollient cream. Dermatol Surg. (2005)
  22. Yoshimura K, et. al. Clinical trial of bleaching treatment with 10% all-trans retinol gel. Dermatol Surg. (2003)
  23. Pavicic T, Borelli C, Korting HC. Cellulite--the greatest skin problem in healthy people? An approach. J Dtsch Dermatol Ges. (2006)
  24. Roure R, et. al. Evaluation of the efficacy of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, forskolin and retinol, In vitro, ex vivo and in vivo studies. Int J Cosmet Sci. (2011)
  25. Bertin C, et. al. A double-blind evaluation of the activity of an anti-cellulite product containing retinol, caffeine, and ruscogenine by a combination of several non-invasive methods. J Cosmet Sci. (2001)
  26. Piérard-Franchimont C, et. al. A randomized, placebo-controlled trial of topical retinol in the treatment of cellulite. Am J Clin Dermatol. (2000)