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ANN ARBOR, Mich., May 21 -- Topical vitamin A (retinol) may improve fine wrinkles, collagen deficiency, and atrophy in the fragile skin of elderly patients.

In a small, randomized, controlled clinical trial, topical retinol improved the clinical appearance of naturally aged skin, said Sewon Kang, M.D., of the University of Michigan here, and colleagues.

It also increased two matrix molecules, procollagen and hydroscopic glycosaminoglycan (hyaluronic acid), they reported in the May issue of the Archives of Dermatology.

As skin ages, even without sun injury, Dr. Kang noted, it becomes thin, lax, and finely wrinkled, as its underlying matrix is depleted. Poor wound healing, a propensity toward non-healing decubitus ulcers, even development of skin cancers are considerable risks, especially in the rapidly expanding U.S. geriatric population.

Safe and effective therapies to reverse the atrophy of natural skin aging do not exist currently, the investigators wrote, possibly because skin aging is poorly understood, and conducting clinical studies in a geriatric population represents a considerable challenge.

The study's original group of 36 included 23 subjects who completed the 24-week study. Their mean age was 87 (range 80 to 96). The subjects were in relatively good health and had no skin diseases on the arms. More than twice as many women were enrolled as men.

At each visit, topical retinol lotion (0.4%) was applied to the upper-inner (sun-protected) portion of one arm and its vehicle lotion (Neutrogena Body Moisturizer) was applied to the other arm. Lotions were applied up to three times a week for 24 weeks.

Clinical assessments of the two arms were made using a semiquantitative scale and biochemical measurements from skin biopsy specimens obtained from treated areas.

The fine wrinkles of intrinsic aging began to efface after four weeks of retinol use, with continued improvement throughout the study, the researchers reported.

After 24 weeks, an intent-to-treat analysis revealed that there were significant differences between retinol-treated (−1.64, 95% CI, −2.06 to −1.22) and vehicle-treated (−0.08 CI, −0.17 to 0.01) skin for changes in fine wrinkling scores, (P<0.001).

As measured in a small subgroup, retinol treatment significantly increased glycosaminoglycan expression in six patients (P=0.02) by about 40% compared with vehicle treatment. Procollagen I immunostaining was also significantly increased in four patients (P=0.049) compared with vehicle.

Significant induction of glycosaminoglycan, which is known to retain water, and increased collagen production are most likely responsible for wrinkle effacement, the researchers said.

Clinically evident atrophy of aged skin correlated histologically with thinner epidermis and dermis, with reduced numbers of keratinocytes and fibroblasts, respectively, the researchers said. In addition, they noted, procollagen synthesis was also reduced, along with a qualitative fragmentation of dermal collagen fibers.

The four-week response in this study was faster than that observed in photoaging studies, the researchers said. Typically, at least two to three months of topical retinoic acid therapy is needed before noting any significant improvement in wrinkles caused by photoaging.

The time difference in wrinkle effacement may reflect differences in the nature of wrinkles caused by photoaging and those caused by intrinsic aging, the researchers said. Or, they noted, it could also be caused by the severity of the matrix deficiency to be overcome by retinoids.

Overall, topical retinol was well tolerated. By week 24, most subjects reported some degree of cutaneous irritation on the retinol-treated arm, including erythema (n=18), peeling (n=16), pruritus (n=12), dryness (n=14), and burning and/or stinging (n=3). But most reactions were rated as mild. In three subjects, cutaneous reactions and/or symptoms were severe enough to withdraw treatment consent.

The improvement was not permanent. The authors wrote that "of the 36 subjects enrolled in our study, 11 were assessed 12 weeks after the therapy was discontinued (week 36). Although the difference in fine wrinkle severity score had lessened between the retinol- and vehicle-treated sides, it remained statistically significant (data not shown). By week 48, 24 weeks after the discontinuation of retinol treatment, no significant differences remained between the 2 sides."

For chronologically aged skin, therapies used to treat collagen deficiency such as ablative CO₂ lasers are not feasible because treatment causes significant wounding and takes time to heal, the researchers noted. Topical retinoic acid, for example, approved for treatment of photoaging, is not suitable in geriatric populations because of consistent irritation at application sites, they said.

Retinol, however, is a precursor of retinoic acid. Once it penetrates skin, it is sequentially oxidized to retinoic acid, causing retinoic acid-like effects, but is notably less irritating, the researchers wrote.

The retinal preparation used in their study was deliberately conservative to maximize retention of the subjects, the researchers said. Treatment was withheld until skin reactions abated or improved, a source of potential bias in such trials.

The gentle treatment in this study, they said, served to at least reduce but not totally eliminate unblinding and bias. In fact, although three treatment sessions a week were planned, patients received a mean of 1.6 treatments weekly. It is possible that a more aggressive regimen might have achieved more robust effects, they said.

Topical retinol is a promising and safe treatment to increase the dermal matrix of aging skin and improve clinical features associated with atrophic wrinkled skin. In this way, the substantial morbidity and poor wound healing and chronic ulcer formation may be reduced, Dr. Kang's team concluded.

Dr. Kang, Gary J. Fisher, Ph.D., James Varani, Ph.D., and John J. Voorhees, M.D., are named inventors on an issued patent application concerning methods of treating skin aging. They will receive royalties under the University of Michigan's Intellectual Property Policy in the event that a commercial license is signed and a product is sold. This article describes research that was part of the basis of the approved application. This study was supported in part by grants from the Babcock Endowment for Dermatologic Research, the Merck-American Federation for Aging Research, Alpha Omega Alpha Student Research Fellowship, and the National Institutes of Health.

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