Urea: A Clinically Oriented Overview from Bench to Bedside

May 2016 | Volume 15 | Issue 5 | Original Article | 633 | Copyright © 2016

Adam J. Friedman MD FAAD,a Erika C. von Grote PhD,b Matthew H. Meckfessel PhDb

aDepartment of Dermatology, George Washington School of Medicine and Health Sciences, Washington, DC
bGalderma Laboratories, L.P., Fort Worth, TX

Abstract

Urea is an important hygroscopic component of the epidermis, where it participates in the maintenance of skin hydration as part of the skin’s source of natural moisturizing factor (NMF) in the outer most layers. Xerotic skin, which is frequently characterized as NMF-deficient, is a unifying trait of dermatoses such as atopic dermatitis (AD), psoriasis, and ichthyosis vulgaris. The reduced hygroscopic potential of pathologically dry skin leads to unregulated transepidermal water loss (TEWL), epidermal hyperproliferation, and inhibited desquamation; all which clinically translate to hyperkeratotic and possibly pruritic skin. Common underlying etiologies link these dermatoses to aberrant expression of genes encoding epidermal structural and catalytic proteins. Intervention of dry skin pathologies with topical moisturizer formulations is a foundational management strategy. For over a century urea-containing formulations have been used in a concentration-dependent manner to restore skin hydration, thin hyperkeratosis, debride dystrophic nails, and enhance topical drug penetration. Recently, urea’s role in skin hydration and repair has expanded to include regulation of epidermal genes necessary for proper barrier function. Taken together, urea’s versatility in topical formulations and broad range of therapeutic mechanism highlights its utility to clinicians and benefit to patients.

J Drugs Dermatol. 2016;15(5):633-639.

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INTRODUCTION

Urea is a low molecular weight, uncharged polar molecule primarily produced from the digestion of dietary protein in the liver.1 It is maintained as a valuable resource in the human body with a primary function in the reabsorption of water from nephric filtrate in the kidneys.1 Urea is also an important hygroscopic component of the epidermis, where it participates in the maintenance of skin hydration as part of the skin’s source of natural moisturizing factor (NMF) in the outer layers of the stratum corneum (SC) (Figure 1).2-5

Although the SC is a seemingly inactive mantle of anucleated keratinocytes, it is a highly dynamic cell layer and its state of hydration directly affects the activation state of cells throughout the epidermis.6-8 Xerotic skin, which is frequently marked by dry, rough, scaly texture, is also characterized as NMF-deficient. The reduced hygroscopic potential of the SC leaves the epidermal barrier vulnerable to increased transepidermal water loss (TEWL), and inhibits various aspects of proper barrier maturation including cell cornification and desquamation.9-13 Inhibition of desquamation results in SC thickening and loss of flexibility, causing it to yield more easily to cracks and fissures. Common dermatoses, such as atopic dermatitis (AD), psoriasis, and ichthyosis vulgaris are all characterized by an inability of the SC to maintain hydration, and epidermal barrier dysfunction manifested as patches of rough, scaly, or hyperkeratotic skin.14-17

Intervention with topical moisturizer formulations is foundational to managing xerotic skin. The inclusion of select NMF components in topical formulations has been shown to regulate TEWL and restore the SC’s capacity to attract and maintain hydration.18 Routine use of a moisturizer also provides the preventative maintenance necessary to curb the progression of dry skin pathologies involving epidermal hyperproliferation and inflammation.19-21 Urea-containing topical formulations have been used in this manner for over a century.22,23

In addition to its role and benefit in restoring endogenous water-binding capacity, at higher concentrations urea has keratolytic properties and can be used in a more aggressive manner to thin hyperkeratosis, debride dystrophic nails, and facilitate the removal of necrotic eschar associated with wounds or infection.24-26 Urea’s safety, tolerability, and concentration-dependent keratolytic properties further its utility as an facilitator of transepidermal drug penetration.27 More recently, urea’s contribution to hydration has been expanded to include regulation of epidermal genes necessary for proper barrier function.28,29 These findings are significant as they shift the perception of urea’s potential benefit in overall skin health beyond its passive role as a humectant and keratolytic.

Restoring SC barrier integrity and function is a universal goal in the treatment of a multitude of disease states. Despite the continuous discovery of novel skin care ingredients and innovative formulations, urea remains one of the oldest and yet one of the most beneficial ingredients in the clinician’s tool kit. In an effort to renew and reshape the perception of this ingredient and its benefit to patients, this overview highlights urea’s role in

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