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For topical application, the form of all-trans retinoic acid (Tretinoin) should be used in a facial cream/lotion containing it in the range of 0.01-0.10%, with the lowest concentration having low side-effects but less efficacy and 0.025-0.05% being the sweet spot. Topical application is once nightly.
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The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects vitamin a has on your body, and how strong these effects are.
|Grade||Level of Evidence|
|Robust research conducted with repeated double-blind clinical trials|
|Multiple studies where at least two are double-blind and placebo controlled|
|Single double-blind study or multiple cohort studies|
|Uncontrolled or observational studies only|
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
|Wrinkles||Notable||Very High See all 3 studies|
|Skin dryness||Minor||Very High See all 3 studies|
|Skin Quality||Low See all 3 studies|
|Skin pigmentation||Low See all 3 studies|
|Collagen Content||Low See study|
|Skin Elasticity||Low See study|
|Skin Thickness||Low See 2 studies|
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1.1. Formulations and Variants
A carboxylic acid ester of retinol known as all-trans retinoic acid (ATRA), also known by names such as Tretinoin, is the most commonly used supplemental and hormonally active form of vitamin A.
In culture, ATRA has been noted to increase the synthesis (anabolism) of collagen.
In regards to the breakdown (catabolism) of collagen, ATRA has been noted to inhibit enzymes responsible for collagen degradation collagenase (EC50 of 0.25-1µM) and gelatinase (EC50 of 3-6µM) which seems to be via reducing the overall amount of enzyme present. The increase in breakdown from corticosteroids and UV radiation are both reduced in the presence of ATRA.
Incubation of the medium with ATRA appears to produce an intermediate which inhibits collagenase despite retinoic acid not having direct inhibitory actions itself, which may be due to production of tissue inhibitor of metalloproteinases (TIMP) mRNA seen with ATRA.
Glycosaminoglycan expression has been noted to be increased with 0.4% ATRA application.
At the molecular level in human skin, ATRA appears to have dual actions in both increasing the rate of collagen synthesis and suppressing the degradation thereof
Photoaging is a term used to refer to the aging of skin which is accelerated under exposure to the sun, resulting in a wrinkling phenotype whereas aging of the skin not related to UV exposure (chronological or 'natural' aging) is characterized by an appearance of finer wrinkles but is thinner and laxer. The former's wrinkling phenotype is known to be associated with less collagen synthesis due to a blocking of TGF-β/Smad signalling suppressing procollagen I synthesis.
Application of 0.4% ATRA lotion can increase expression of procollagen I when applied thrice weekly over 24 weeks and 0.1% over 10-12 months (reaching a 119% increase in immunostaining of fibroblasts, 80% in papillary dermis) while in studies that take skin biopsies it is noted that topical application of ATRA (0.1%) can increase the thickness of skin from the forearm by 273% relative to an 18% increase in placebo; improvements in thickness have been noted on the face as well although to a smaller magnitude (28-30%).
In photoaged skin, topical application of ATRA appears to be able to increase procollagen I expression and subsequently the thickness of the skin secondary to reducing the suppressive effects of sun exposure on collagen synthesis
Application of an 0.4% ATRA lotion thrice weekly for 24 weeks in elderly subjects has been noted to significantly improve the visual appearance of wrinkling relative to placebo lotion within four weeks which is also seen with nightly application of an 0.1% ATRA cream over 16 weeks and 48 weeks.
Topical application of an ATRA cream has been noted in some studies (not measuring this as an end point) to reduce dark spots or sunspots associated with aging and studies that directly investigate this note that 0.1% ATRA over 40 weeks can improve visual scores in 90% of patients and reduce skin pigmentation.
Usage of 0.4% ATRA thrice weekly for 24 weeks in elderly subjects has been noted to be associated with frequent but mild side-effects related to erythema, peeling, dryness, and burning/stinging which has been noted in other studies using nightly applications of lower concentrations of ATRA; the frequency of side-effects, rather than intensity, seems to be reduced with lower concentrations.
One study comparing 0.1% ATRA against 0.025% ATRA noted that both creams exerted similar degrees of improvement on signs of photoaging although the lower concentration was associated with less mild side-effects while elsewhere 0.05% was effective in improving photoaging signs and whlie 0.01% had less symptoms it was also less effective.
Any cream or lotion containing 0.1% ATRA or greater can cause mild side-effects related to dryness, peeling, redness, and warmth while a lower concentration of 0.025-0.05% appears to have less chance of these side-effects while being just as effective on reducing signs of photoaging
- Federspiel SJ1, et al Extracellular matrix biosynthesis by cultured fetal rat lung epithelial cells. IV. Effects of chronic exposure to retinoic acid on growth, differentiation, and collagen biosynthesis . Lab Invest. (1991)
- Bauer EA, Seltzer JL, Eisen AZ Retinoic acid inhibition of collagenase and gelatinase expression in human skin fibroblast cultures. Evidence for a dual mechanism . J Invest Dermatol. (1983)
- Bauer EA, Seltzer JL, Eisen AZ Inhibition of collagen degradative enzymes by retinoic acid in vitro . J Am Acad Dermatol. (1982)
- Schwartz E1, et al In vivo prevention of corticosteroid-induced skin atrophy by tretinoin in the hairless mouse is accompanied by modulation of collagen, glycosaminoglycans, and fibronectin . J Invest Dermatol. (1994)
- Kligman LH1, et al Topical tretinoin prevents corticosteroid-induced atrophy without lessening the anti-inflammatory effect . Curr Probl Dermatol. (1993)
- Clark SD1, Kobayashi DK, Welgus HG Regulation of the expression of tissue inhibitor of metalloproteinases and collagenase by retinoids and glucocorticoids in human fibroblasts . J Clin Invest. (1987)
- Kafi R1, et al Improvement of naturally aged skin with vitamin A (retinol) . Arch Dermatol. (2007)
- Fisher GJ1, et al Pathophysiology of premature skin aging induced by ultraviolet light . N Engl J Med. (1997)
- Fisher GJ1, et al Mechanisms of photoaging and chronological skin aging . Arch Dermatol. (2002)
- Griffiths CE1, et al Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid) . N Engl J Med. (1993)
- Quan T1, et al Solar ultraviolet irradiation reduces collagen in photoaged human skin by blocking transforming growth factor-beta type II receptor/Smad signaling . Am J Pathol. (2004)
- Weiss JS1, et al Topical tretinoin improves photoaged skin. A double-blind vehicle-controlled study . JAMA. (1988)
- Griffiths CE1, et al Two concentrations of topical tretinoin (retinoic acid) cause similar improvement of photoaging but different degrees of irritation. A double-blind, vehicle-controlled comparison of 0.1% and 0.025% tretinoin creams . Arch Dermatol. (1995)
- Griffiths CE1, et al Topical tretinoin (retinoic acid) treatment of hyperpigmented lesions associated with photoaging in Chinese and Japanese patients: a vehicle-controlled trial . J Am Acad Dermatol. (1994)
- Weinstein GD1, et al Topical tretinoin for treatment of photodamaged skin. A multicenter study . Arch Dermatol. (1991)