skin roughness, dyspigmentation, and softens fine lines and wrinkles.9,10 Subsequently, a pivotal double-blind, vehiclecontrolled study confirmed the anti-aging effects of tretinoin.11 This study and others that followed ultimately led to tretinoin 0.05% emollient cream being the first prescription topical approved for the treatment for aging skin in 1995.12 In view of the fact that several formulations of tretinoin were already FDA-approved for the treatment of acne, this retinoid remains available today only by prescription.
Despite its anti-aging benefits, the clinical use of tretinoin has been limited by its propensity to cause skin irritation or retinoid dermatitis. Retinoid dermatitis is characterized by redness, peeling, and flaking and is believed to be a result of applying supraphysiologic amounts of retinoic acid to the skin.13 Retinoic acid upregulates heparin-binding epidermal growth factor (HB-EGF) and amphiregulin. These serve as ligands for epidermal growth factor receptor (EGF-R) and cause proliferation of basal keratinocytes, epidermal hyperplasia, and stratum corneum desquamation. Subsequent disruption of the skin barrier by tretinoin causes cytokine release and erythema. Although retinoid dermatitis is viewed as an indicator of efficacy and penetration, it is probably not related to the anti-aging benefits that occur primarily in the dermis. Retinoid dermatitis limits the use of topical tretinoin in many patients so identifying non-irritating alternatives is essential.
Over-the-counter formulations containing vitamin A are now widely available. There are three basic forms of vitamin A used in these cosmetic products including retinyl esters, retinol, and retinaldehyde. The rationale supporting their use comes from our understanding of the metabolism of vitamin A in the skin. (Figure 2).14 When retinyl esters, such as retinyl palmitate, are applied to the skin, they are hydrolyzed to retinol. Retinol is subsequently oxidized to retinaldehyde, which is then irreversibly oxidized to retinoic acid, the active form of vitamin A in the skin. Thus, skin has the inherent capability to utilize a variety of topically applied precursor molecules and convert them to retinoic acid. It is also of interest that when retinol is applied to the skin, only a small amount is converted to retinoic acid while the majority is esterified with fatty acids, such as palmitic acid, stearic acid, and oleic acid.15 These retinyl esters serve as a natural storage form for vitamin A and can be reconstituted back to retinol through hydrolysis. The conversion of retinol to retinoic acid is tightly regulated to maintain relatively low levels of retinoic acid. This helps mitigate irritation with topical retinol and provides cells with retinoic acid only when its needed.
Retinyl esters, retinol, and retinaldehyde differ in their efficacy, potency, and irritation profile (Figure 3). Retinyl esters are the most stable but least potent of all topical retinoids. They are least likely to cause retinoid dermatitis and are favored by some cosmetic chemists due to their stability and safety profile. Retinol and retinaldehyde are more potent than retinyl esters. They are inherently more unstable than retinyl esters although innovations in formulation techniques have allowed their stabilization. Retinol and retinaldehyde are more irritating
