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Tretinoin, tea, and tomato paste
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More promise than proof when it comes to vitamins, photoprotection, and photoaging

More than 20 years after the anti-photoaging benefits of topical tretinoin, a derivative of vitamin A, were extolled in the medical literature, researchers continue to explore the photoprotective and anti-aging properties of oral and topical vitamins and other nutritional substances. Driving the research is a booming market for cosmeceuticals in the United States — estimated to reach $8.2 billion by 2012, according to one industry analyst — coupled with consumer demand for less invasive cosmetic procedures and natural alternatives to chemical ingredients in sunscreens and skin care products.

As patients consider expensive products with extravagant claims to combat aging, dermatologists may be asked for some guidance as to the science behind the marketing. In addition, they may seek prescription-strength alternatives to tretinoin that don’t irritate the skin. While much of the evidence is inconclusive due to a lack of large, well-designed clinical studies, a handful of vitamins and other nutrients show promise, particularly in treating the effects of photoaging.

Photoprotection

Vitamin A occurs in two forms: retinol, also known as preformed vitamin A, and carotenoids, known as provitamin A. Retinol and its natural and synthetic derivatives comprise the retinoids, including tretinoin, tazarotene, acitretin, and bexarotene. “There are a number of studies that show systemic retinoids work quite well in the chemoprevention of non-melanoma skin cancers in high-risk patients,” says Craig A. Elmets, MD, chairman of the department of dermatology and director of the Skin Diseases Research Center at the University of Alabama School of Medicine. “Patients with xeroderma pigmentosa, those who have had extensive PUVA therapy, and organ transplant recipients all can benefit from systemic retinoids. Unfortunately, the results in the general population have been somewhat less impressive.” [pagebreak]

The role of topical use of retinoids in preventing non-melanoma skin cancer in the general population remains uncertain. Investigators conducting the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial sought to evaluate the effectiveness of a 0.1 percent tretinoin cream, applied twice daily to the face and ears, in reducing the risk of basal cell and squamous cell carcinoma. The study population included 1,131 veterans, with a mean age of 71 years; patients with a very high estimated short-term risk of death were excluded. However, the intervention was terminated six months early due to an excessive number of deaths in the tretinoin-treated group (at the time intervention was halted, 112 patients among 566 in the group receiving treatment had died, vs. 78 deaths among 565 patients in the placebo group). In an article examining the relation of topical tretinoin treatment with all-cause mortality in the trial, (published in the January 2009 issue of Archives of Dermatology), the authors noted that topical tretinoin “has been used to treat acne vulgaris (and other indications) and in clinical trials for decades, with no suggestion of an associated mortality risk.” Causes of death in the tretinoin-treated group varied, including neoplasms (16 of 37 were lung cancer), cardiac disorders, respiratory, thoracic and mediastinal disorders, and vascular disorders. The authors considered numerous possible explanations, but ultimately found it “difficult to construct biologically plausible mechanisms that would explain a direct causal link between the intervention in the VATTC Trial and death owing to multiple causes.” An editorial in the same issue of Archives recommended that “practitioners should view the results of the VATTC with discretion” but added that they should also discuss the results of the trial with elderly men using topical tretinoin.

Another vitamin showing some potential as a photoprotective agent is vitamin E, alone and in combination with vitamin C. In a comprehensive review of the scientific data regarding vitamins and photoaging published in the September 2010 issue of the Journal of the American Academy of Dermatology, the authors note that studies in mice have shown topical application of vitamin E to offer protection against the damaging effects of UV irradiation when applied either before or after UV exposure. They cite two studies in humans in which groups receiving oral supplements of vitamins C and E in combination showed a clinically significant increase in minimal erythema dose. One of the studies, which also measured cutaneous blood flow following UV irradiation, found that blood flow changed significantly for most irradiation doses, with decreases in those given vitamins and increases in the placebo group. However, the JAAD review authors warn that no long-term studies of this therapy have been conducted and add that a high intake of vitamin E may be harmful and could interact with the metabolism of other drugs. [pagebreak]

For the past 10 years, Dr. Elmets has investigated the topical application of green tea extracts as a photoprotection agent. “Green tea is produced from the leaves of the plant camillia sinensis, which contains polyphenols that are potent antioxidants,” he explains. “The one which seems to be the most photoprotective is epigallocatechin-3-gallate (EGCG).” Dr. Elmets published a study in the March 2001 issue of JAAD showing that when applied to the skin of normal volunteers 30 minutes before UV exposure, green tea extracts reduced the number of sunburn cells and protected epidermal Langerhans cells from UV damage. He has since applied for a patent on an EGCG-based formulation for photoprotection.

Lycopene, a carotenoid and antioxidant found in red fruits such as tomatoes, grapefruits, and watermelons, was featured in a study published in the September 2010 issue of the British Journal of Dermatology. “Healthy volunteers ate tomato paste [containing 16 mg lycopene daily for 12 weeks] and found that had a mild reduction in sunburn response and also inhibited matrix metalla proteinase 1, which is a biochemical marker of extracellular matrix damage,” Dr. Elmets says. He notes that topical genistein, the most abundant isoflavone of the soy-derived phytoestrogen compounds, has also been found to inhibit UV erythema in humans.

While the data on oral and topical nutrients as a substitute for sunscreen is interesting but preliminary, Dr. Elmets maintains that consumers are seeking natural alternatives for preventing the adverse effects of UV light. “People like food-type ingredients, and they like to have options,” he says. “These substances may provide benefits that act in addition to or synergistically with existing sunscreens.”

Photoaging: Vitamin A unsurpassed

The search for an antidote to photoaging has led researchers to investigate different formulations of vitamin A, as well as a broad range of other vitamins and nutritional substances. The authors of the September 2010 JAAD review, Jamie Zussman, MD, Jennifer Ahdout, MD, and Jenny Kim, MD, cite a study comparing four different concentrations of tazarotene cream (0.1 percent, 0.05 percent, 0.025 percent, and 0.01 percent) with 0.05 percent tretinoin cream. The study found that the highest concentration of tazarotene had significantly greater effects on photoaging than the tretinoin at weeks 12 and 20; 0.05 percent tazarotene had similar efficacy compared with tretinoin; and both 0.025 percent and 0.01 percent tazarotene were less effective than 0.05 percent tretinoin. [pagebreak]

While the effectiveness of prescription formulations of retinoids is well established, Drs. Zussman, Ahdout, and Kim found less clinical evidence to support the use of retinoids in over-the-counter (OTC) preparations. Of the available OTC options, the evidence seemed to point to retinol and one of the retinyl esters as the best choices, according to a co-author of the review. “We found one published study that appeared sound and supported the efficacy of retinol, whereas other products have either not been studied or have failed to show good results,” says Dr. Zussman, a dermatology resident at the David Geffen School of Medicine at the University of California Los Angeles and lead author of the JAAD review. “Retinyl N-formyl aspartamate was the only other OTC retinoid with published positive results.” Dr. Zussman says she has seen no trials comparing different OTC product ingredients, nor has she found any head-to-head trials of prescription versus non-prescription retinoids published in a peer-reviewed journal.

B vitamins, C and E also explored

Among other vitamins tested in topical form for anti-photoaging efficacy, vitamin C emerges as one of the most promising. Also known as ascorbic acid, vitamin C plays a critical role in collagen and elastin synthesis and also acts as an antioxidant in the skin, modulating the effects of UV-induced reactive oxygen species damage. The JAAD review article describes a clinical trial with 19 subjects comparing daily L-ascorbic acid treatment on one side of the face to vehicle treatment on the other side for three months. Using fine wrinkling, tactile roughness, visual dryness, telangiectasia, laxity/tone, pigmentation, and keratoses as the criteria, investigators and the subjects themselves noted improvement on the treatment half of the face in 16 of the 19 subjects. Because ascorbic acid is unstable in formulation, the authors state, it is not clear whether the commercially available OTC forms deliver L-ascorbic acid into the skin.

Dr. Zussman notes that the small sample size of many of the studies her team reviewed limits the strength of the evidence. “Topical vitamin C looks very promising from the studies that we have, but these studies typically have low numbers such as 20 in the placebo arm and 20 in the treated arm,” she said. “Still, the majority have had positive results, so that is definitely a treatment that should be explored further. It has minimal side effects, it produces less irritation than the retinoids, and it can be used during the day.” Dr. Zussman says she uses an OTC vitamin C formulation herself “because there’s really no drawback — it’s unlikely to hurt you — and what we do have looks so promising.” [pagebreak]

Vitamin C also works synergistically with vitamin E, or tocopherol. “Vitamin E is the main antioxidant present in the skin, but it’s very difficult to consume large quantities,” says Zoe Diana Draelos, MD, consulting professor in the department of dermatology at the Duke University School of Medicine. “Once vitamin E has donated its electron to reactive oxygen species, it can’t work anymore. So the human body was designed to have vitamin C donate its electron to vitamin E. Instead of using up your vitamin E, you use up your vitamin C, which can be easily consumed.”

Dr. Draelos, who has worked with vitamin C-deficient individuals, says some researchers believe that depletion of vitamin C can lead to premature photoaging. But, she adds, that doesn’t necessarily mean that large doses of the vitamin convey any benefit. “That is the problem with the nutritional literature as it now stands for dermatology,” she says. “We know the minimum dose but we don’t know the optimum dose, and we don’t know the age-adjusted dose for essential vitamins. So if you look at people in their 70s and 80s whose skin doesn’t look good, you think maybe if they had taken more vitamin C when they were younger their skin might look better. But when you’re looking at prevention of damage going forward, you need a lot of longitudinal case studies, and those are difficult to do.”

While the literature does not indicate that topical vitamin D has been tested in humans as a protective agent against photoaging, Dr. Draelos emphasizes the critical role of systemic vitamin D in preserving the facial bones. In an article exploring nutrition and the enhancement of youthful-appearing skin, published in Vol. 28, issue four of Clinics in Dermatology, she notes that bone loss in the gingival bones leads to wrinkling of the skin around the mouth and inward turning of the lips. For this reason, she recommends that dermatologists consider obtaining levels of 1,25-dihydroxy vitamin D for all female patients older than 50 to look for deficiency.

Regarding topical treatment of photoaged skin with vitamins, Dr. Draelos maintains that only the application of tretinoin is clearly supported by a wealth of scientific literature. “We don’t know of any other receptors present on the cell besides the retinoid receptors that can have a dramatic effect” on photoaged skin, she says. “The vitamins now used in formulations are there to help the skin hold water, because most vitamins are humectants.” [pagebreak]

Vitamin B3 (niacin and niacinamide) has been found to increase collagen production in human fibroblast cell culture. The JAAD review article states that trials of topical vitamin B3 have begun only recently and are characterized by small sample sizes, but early results are promising. Two studies of Japanese women with a variety of hyperpigmentation disorders found that topical niacinamide lightened pigmented areas. In the sole clinical trial conducted in Caucasian women, topical 5 percent niacinamide effected reduction in the appearance of hyperpigmented spots, skin redness, wrinkles, and yellowing, as well as improving skin elasticity. While the results did not equal those of retinoid treatment, the subjects using niacinamide did not experience the side effects of skin irritation, dryness, peeling, or burning.

Dermatologists may be reluctant to recommend OTC products for which there is a lack of definitive clinical data to support their effectiveness. But nutrition, including vitamins, and overall health have a clear role in skin maintenance, Dr. Zussman argues. “Vitamin deficiencies often manifest in the skin, and I think we need to emphasize to our patients that if they want healthy-looking skin, they have to be healthy,” she says. “If their skin’s not looking good, ask about their diet and their lifestyle.” Dr. Draelos says she tells her patients to eat something of every color every day “because all the vitamins and essential nutrients have a color associated with them. And since we really don’t have a lot of good data on what you need and don’t need, it’s better to take in a little of everything to avoid deficiencies.”