Treatment of Photoaging
http://www.100md.com
《新英格兰医药杂志》
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.
A 45-year-old fair-skinned woman has noted increasing sallowness, roughness, fine wrinkles, and mottled hyperpigmentation on her face. She is bothered by these changes and is worried about the development of nonmelanoma skin cancer. What treatments may minimize skin aging and lower the risk of skin cancer?
The Clinical Problem
Aging and exposure to the environment affect facial appearance. Age-related changes include benign growths and "gravitation," which results from a redistribution of fat, decreased skin elasticity, and bone loss. Exposure to the sun induces clinical and histologic changes to the skin (Figure 1), commonly called photoaging. Clinically, photoaging may be manifested as wrinkles (Figure 2, Figure 3, Figure 4, and Figure 5), skin roughness and dryness (Figure 3), irregular pigmentation (Figure 2, Figure 3, Figure 4, and Figure 5), telangiectasia (Figure 2 and Figure 4), sallowness (Figure 3 and Figure 5), and brown spots (lentigines, Figure 2, Figure 3, and Figure 4).1,2 Other common age-related skin changes include seborrheic keratoses (Figure 3 and Figure 5); actinic keratoses, which are sun-induced, premalignant, aesthetically displeasing, and sometimes symptomatic (burning and tender) growths; and "frown lines," which result from dynamic changes due to muscle hypertonicity.
Figure 1. Photomicrographs of Normal Skin (Panel A) and Photoaged Skin (Panel B) (Hematoxylin and Eosin, x200).
In moderately photoaged skin (Panel B), the epidermis is atrophic with thinning of the spinous layer and loss of the rete ridges. There is condensation of collagen beneath the basement-membrane zone and proliferation of the elastic fibers, which appear thickened, curled, and tangled. Deeper dermal collagen exhibits early basophilic degeneration. Telangiectasia is present in the upper dermis, in the zone of elastosis. Photomicrographs provided courtesy of Dr. Steven Tahan.
Figure 2. A Woman in Early Middle Age with Prominent Telangiectasia, a Few Lentigines, and Fine Wrinkling.
Figure 3. A Middle-Aged Woman with Some Skin Roughness, Mottled Hyperpigmentation, and Fine Telangiectasia.
Evident are discrete, hyperpigmented macules consisting of sun-induced lentigines and age-related seborrheic keratoses.
Figure 4. A Middle-Aged Woman with More Advanced Photoaging.
This woman's skin shows pronounced wrinkling, mottled hyperpigmentation, vascular ectasia, lentigines, and a cherry angioma of the lower eyelid.
Figure 5. A Woman in Late Middle Age with Coarse Wrinkling, Gravitational Changes (Enhanced Nasolabial Fold), Sallowness, Irregular Hyperpigmentation, and Seborrheic Keratoses.
Wrinkles and telangiectasia are associated with increased risks of actinic keratoses and nonmelanoma skin cancer (age-adjusted odds ratio, 2 to 9).3,4,5 The presence of actinic keratoses is strongly associated with an increased risk of squamous-cell cancer.6 Therefore, persons with substantial photoaging should be examined periodically for actinic keratoses and skin cancers.
Cumulative exposure to sunlight and exposure within the past 10 years are strongly associated with the risk of actinic keratoses and therefore squamous-cell cancer in people of any age. They are probably also related to the extent of photoaging, but recent exposure is not associated with the risk of basal-cell cancer.3,6 Risk factors for photoaging and skin cancer include fair skin, difficulty tanning, ease of sunburning, sunburns before the age of 20 years, and advancing age.2,3,4,7,8 Smoking is a moderate independent risk factor for wrinkling, telangiectasia, and squamous-cell cancer.8
Ultraviolet B (UVB) radiation (wavelengths from 290 to 320 nm) is much more important for the induction of nonmelanoma skin cancer and actinic keratoses than ultraviolet A (UVA) radiation (320 to 400 nm).9,10 Both UVA and UVB radiation contribute to changes in pigment, including lentigines and telangiectasia, and wrinkles, but their relative contributions are controversial.11
People who seek therapy for photoaging, benign growths, and frown lines face an extraordinary array of information, much of it misinformation. Thousands of Web sites offer products or procedures that promise to improve facial appearance. In 2002, more than 5 million nonsurgical and 1.5 million surgical cosmetic procedures, costing patients more than $13 billion, were performed.12 Although the procedures are highly profitable, few have been proved effective and few are well regulated.
Strategies and Evidence
Assessment
Most changes that occur as a result of photoaging have similar causes and risk factors, but the extent and consequences of these changes vary greatly among patients. The decision about whether to provide treatment depends on the nature of the changes, their severity, the degree to which they bother the patient, and the patient's willingness to accept the risks and costs of treatment, which most insurance plans do not cover.
Prevention and Therapy
Protection from the Sun
Protection from the sun at any age reduces the risk of actinic keratoses and squamous-cell cancer and the progression of photoaging.13,14,15,16 Reducing the risk of basal-cell cancer depends primarily on reducing sun exposure during childhood.17 In the absence of adequate protection from the sun, other treatments are less effective and may be more hazardous.
Good protection strategies include wearing hats and other clothing and staying out of the sun. Also, many sunscreens that block UVB radiation are available. Sun protection factor (SPF) numbers equal the ratio of doses of ultraviolet radiation (predominantly UVB radiation) that result in erythema (sunburn) with protection to the doses that result in erythema without protection. SPF 2 equals a 50 percent block, SPF 15 equals a 93 percent block, and SPF 45 equals a 98 percent block. The blocking of UVA radiation by nonopaque sunscreens, including those that are claimed to block UVA radiation, cannot be consistently quantified and is generally less than an SPF of 3. Opaque sunscreens, which often contain titanium dioxide, can provide good protection from UVA radiation but may be cosmetically unacceptable.
People typically apply sunscreens less than half as thickly as and less often than recommended, thus compromising their protection substantially.18 If applied as recommended, 170 g (6 oz) of sunscreen would provide only five whole-body applications for an adult. Daily application is essential for good protection. Sweating and swimming necessitate reapplication.
In animals, the use of sunscreens has repaired preexisting damage and prevented further damage caused by exposure to ultraviolet radiation.14,15 In a randomized trial in humans, the use of a sunscreen with an SPF of 29 for two years stabilized histologic changes to the skin, whereas such photoaging increased in the placebo group.16 Although clinical data were not reported, histologic and clinical appearance are generally correlated.16 In controlled studies assessing the daily use of broad-spectrum sunscreens (with an SPF of 15 or higher) for up to 4.5 years, the incidence of actinic keratoses was reduced by about 40 percent, as compared with the incidence with no sunscreen use, and by 24 percent, as compared with discretionary sunscreen use. Daily use of sunscreens with an SPF of 15 or higher reduced the incidence of squamous-cell cancer by 25 percent, but the risk of basal-cell cancer was not reduced.19,20
Although true allergic reactions to the active ingredients in sunscreens are rare, 17 percent of persons using a sunscreen with an SPF of 15 or higher over a seven-month period had irritation reactions, a major barrier to compliance.21 Sunscreens that provide protection against UVB radiation decrease the synthesis of vitamin D and may encourage increased exposure to the sun and to UVA radiation.22 However, the available data suggest that sunscreen use does not increase the risk of melanoma.23
Hydroxy Acids
Many preparations that contain alpha and beta hydroxy acids are both exfoliants and moisturizers. Hydroxy acids in low concentrations (typically 4 to 12 percent) are ubiquitous components of nonprescription creams and lotions that are promoted as being helpful for ameliorating the aging of skin. In high concentrations, these preparations are used as "peels." Their keratolytic and irritant effects depend on the specific acid, the concentration, and the pH. High concentrations of hydroxy acids or lower concentrations in combination with topical retinoids are often irritating. Overall effects on photoaging are limited.
Skin treated with hydroxy acids admits 20 percent more UVB radiation than untreated skin, making concomitant sunscreen use essential.24 As compared with sunscreens or placebo alone, the use of 5 percent glycolic acid and 8 percent lactic acid creams for three to five months yielded somewhat greater improvement in roughness and mottled pigmentation in two randomized studies, and in sallowness in one study, but no greater improvement in wrinkles or actinic keratoses; unblinding may have occurred as a result of irritation.25,26 There is no evidence that high-cost creams are more effective than low-cost creams.
Topical Retinoids
Although topical retinoids (vitamin A derivatives) were initially controversial, it is now accepted that they reduce the severity of photoaging.27,28 Two topical retinoids, tretinoin and tazarotene, have been approved by the Food and Drug Administration (FDA) for the "palliation" of the fine wrinkles and irregular pigmentation of photoaging.29,30,31 In addition, tretinoin reduces tactile roughness, and tazarotene is approved for the treatment of lentigines.29,30,31 In clinical trials typically lasting six months, some improvement in wrinkling, mottled hyperpigmentation, and roughness was noted in the majority of patients treated with retinoids, at a rate roughly twice that among control subjects who used sunscreen and emollients.27,29,30,31,32 At least one fourth of retinoid users had moderate or greater improvement in fine wrinkling, mottled hyperpigmentation, or skin roughness.27,28,29,30,31,32 However, because the frequency of irritation (and the likelihood of unblinding) increases in direct proportion to the retinoid concentration, it is difficult to determine the true magnitude of improvement attributable to the active agent and the optimal dose. Lower concentrations are probably less beneficial. Continued use seems to be needed to maintain a benefit. Insurance rarely provides coverage for topical retinoids that are prescribed for photoaging. There is no good evidence of the efficacy of other vitamin A derivatives often found in over-the-counter preparations (e.g., night creams and moisturizers), including retinol and retinaldehyde.
The penetration of UVB radiation increases by as much as one third in skin that has been treated with topical retinoids, as compared with untreated skin.33 Therefore, retinoids are unlikely to provide a clinically significant net benefit without concomitant sun protection. The effect of topical retinoids on the incidence of skin cancer and actinic keratoses is unclear.
Fluorouracil Cream
Actinic keratoses appear as discrete, rough, pink spots and are common in people, particularly those over the age of 50 years, who have other signs of photoaging. In sunny locales, about 25 percent of newly identified actinic keratoses will spontaneously regress.34 However, these lesions are premalignant and may evolve into squamous-cell carcinomas. Although evidence is lacking, it is likely that treating actinic keratoses reduces the risk of squamous-cell cancer. Topical application of liquid nitrogen (cryosurgery) clears most lesions and is considered the standard of care.35 Topical 5 percent fluorouracil cream used twice daily for three weeks on body areas with a high density of actinic keratoses reduces the number of keratoses by about 70 percent36 and decreases the epidermal roughness associated with photoaging. The results are similar to those observed with medium-depth chemical peels.37 Substantial irritation occurs during the period when topical fluorouracil cream is being applied and for approximately two weeks afterward. The cream should not be used during pregnancy.
Photodynamic therapy (topical application of aminolevulinic acid, followed about 16 hours later by exposure to blue light) is probably less effective than cryosurgery or the application of fluorouracil cream and is quite uncomfortable.38 Topical diclofenac, approved by the FDA for the treatment of actinic keratoses, is less irritating but far less effective than fluorouracil cream, reducing the number of lesions by about 16 percent.39 Although it has not been approved by the FDA for actinic keratoses, topical 5 percent imiquimod seems to be about as effective and as irritating as fluorouracil cream.40 Laser ablation of the epidermis for resurfacing (Table 1) has little long-term effect on the incidence of actinic keratoses.41
Table 1. Common Nonsurgical Procedures for Photoaging, According to the Primary Indication.
Procedures for Facial Rejuvenation
Dozens of different procedures, ranging from relatively noninvasive approaches to those that are quite invasive, are advocated for facial rejuvenation. Some, including blepharoplasty and face-lifts, have been used for decades for loose, excess, or drooping skin of the eyelids and face. The procedures share the following features: they are expensive for the patient and highly profitable for the provider, and they have not been subjected to well-controlled studies. It has been estimated that about 1.7 million injections of botulinum toxin, 1 million microdermabrasions, 800,000 soft-tissue augmentation procedures, 500,000 chemical peels, and more than 800,000 laser procedures were performed in 2002 in the United States, representing an increase of more than 350 percent since 1997.12 Table 1 summarizes the possible indications for and risks of some common procedures. For most procedures listed in Table 1, the durability of beneficial effects is unknown but is usually measured in months or a few years, and the risks are not well quantified.
Botulinum Toxin
Hypertonicity of muscles creates dynamic changes that are manifested as furrows (lines) of the forehead and glabellar areas. A decrease in muscle tone can reduce these furrows.42 Two antigenically distinct botulinum toxins (type A and type B), which block muscles through their neurotoxic effects, are commercially available. In December 2003, only type A (Botox) was approved for cosmetic indications (treatment of moderate-to-severe glabellar lines).43 Aggressive promotion of Botox has prompted a warning letter from the FDA charging false and misleading promotional activities.44
Since response is subjective, exact quantification is lacking; however, available data suggest that at least moderate improvement is noted in 50 to 75 percent of patients treated for glabellar lines.42,45 Improvement peaks one month after a single injection and is largely gone in four months.43,45 Hence, two or three treatments a year are needed to maintain the effect. Robust long-term data on efficacy and safety are not available, and long-term effects of repeated muscle denervation remain uncertain. Well-designed studies that quantify the efficacy and safety of botulinum toxin for the treatment of other wrinkles of the upper face, including crow's feet, are not available, but the results would probably be similar to those observed for glabellar lines.46 Good technique is essential for optimal results and safety. Therefore, patients should carefully assess the qualifications and experience of the physician.
Skin Fillers
More than 40 filler substances are used for soft-tissue augmentation, which is used for the treatment of coarse (deep) wrinkles and nondynamic furrows.47 In the United States, the most frequently used FDA-approved fillers are injectable bovine collagen preparations, which typically last for three to six months. Recently, the FDA approved a hyaluronic acid filler (Restylane). In one study, hyaluronic acid was associated with a higher incidence of severe bruising (3.6 percent), pain (3.6 percent), and tenderness (2.9 percent) than was a collagen preparation (Zyplast) (0.7 percent, 1.4 percent, and 1.4 percent, respectively); the effects of the two agents on wrinkles were similar at six months.48 The relative safety of approved fillers is not clear. Because of cost and the need for retreatment, few patients find injectable collagen fillers an acceptable form of long-term therapy. Silicone injections are highly profitable for the physician but have not been approved by the FDA, and they should be avoided.
Simple Office Procedures
Benign vascular proliferations, including linear telangiectasia, cherry angiomas, and spider angiomas, which often occur with aging and cutaneous photodamage, respond to a variety of procedures, including those involving lasers (Table 1). Cryosurgery and electrosurgery can lighten limited numbers of discrete pigmented lesions (e.g., seborrheic keratoses and lentigines) and can remove actinic keratoses as effectively as and less expensively than lasers.49
Microdermabrasion is very popular and is commonly performed by dermatologists and nonmedical practitioners. The procedure involves the use of a closed-loop, negative-pressure system to deliver to and remove from the skin aluminum oxide or sodium chloride crystals, which mechanically remove (sand off ) the superficial epidermis. Small uncontrolled studies, patients' opinions, and histologic findings suggest that microdermabrasion contributes to small improvements in photoaging, but reliable data are lacking.50
Areas of Uncertainty
Many unregulated and highly profitable products and services are available to reduce signs of aging. Formal training and certification are not required for a physician to offer cosmetic procedures. Separating hype from facts about safety and effectiveness is difficult, and data from randomized trials to support most interventions are lacking.
Many topical or oral products containing vitamins C and E, coenzyme Q10, bioflavonoids, fruit extracts, kinerase (N6-furfuryladenine), beta carotene and other antioxidants, and green-tea extracts have been promoted for the treatment and prevention of photoaging. Data to support these claims are lacking.
Thinning of skin, decreases in collagen, and increases in skin dryness often accompany menopause. Hormone-replacement therapy may be associated with a small increase in collagen and skin thickness and in the mechanical and water-holding properties of skin, with perhaps minor reductions in clinical wrinkling and skin dryness.51,52 However, these benefits, which are modest at best, do not justify the risks associated with hormone-replacement therapy.53
Although beta carotene has been proposed as a systemic chemopreventive agent for nonmelanoma skin cancer, the available data suggest that it is ineffective.17 Data are lacking on the effects of other proposed preventive medications, such as nonsteroidal antiinflammatory drugs and statins, on the risk of nonmelanoma skin cancer.
Guidelines
The American Academy of Dermatology has published guidelines for the care of actinic keratoses and photoaging that emphasize the importance of sun protection but do not recommend particular treatments.35,54 The academy has also published guidelines pertaining to specific therapies.55,56,57,58
Conclusions and Recommendations
Signs of photoaging, including sallowness, roughness, fine wrinkles, and mottled hyperpigmentation, are reduced by photoprotection. I routinely recommend daily use of sunscreen (SPF 15 or higher), which retards and slightly diminishes photoaging and decreases the incidence of actinic keratoses and squamous-cell cancer. I discourage tanning, both artificial and natural.
Given the recognized associations between benign manifestations of photoaging (such as fine wrinkling and telangiectasia) and potentially serious skin lesions, patients with substantial photoaging should be evaluated for actinic keratoses and skin cancers that would warrant treatment. For limited numbers of actinic keratoses, I recommend cryosurgery. If actinic keratoses are numerous and a patient will accept the associated irritation, I prescribe topical fluorouracil cream, used twice daily for two to three weeks — a regimen that reduces the number of actinic keratoses and improves skin texture. When standard therapies are unsuitable, photodynamic therapy and topical imiquimod may be appropriate.
Patients should be reassured about benign lesions, which merit treatment only for cosmetic reasons. For patients who desire treatment for photoaging, topical retinoids, available by prescription, are the most effective topical therapy that can be administered by the patients. Although not usually covered by insurance, they are no more expensive than many cosmetic products for which there are claims of antiaging effects without supporting evidence. Over-the-counter preparations that contain hydroxy acids also have small beneficial effects on roughness, sallowness, and changes in pigment. The benefits of emollients and makeup to smooth and camouflage these changes should not be underestimated. Many cosmetics also contain sunscreens.
Several procedures may improve facial appearance (Table 1). People who are considering these techniques should understand the associated costs, possible risks, and temporary nature of the effects.
I am indebted to Gail A. Howrigan, Ed.D., and Jean C. Lee, B.A., for providing essential editorial assistance.
Source Information
From the Department of Dermatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.
Address reprint requests to Dr. Stern at the Department of Dermatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, or at rstern@bidmc.harvard.edu.
References
Lévêque J-L. Quantitative assessment of skin aging. Clin Geriatr Med 2001;17:673-689.
Holman CDJ, Evans PR, Lumsden GJ, Armstrong BK. The determinants of actinic skin damage: problems of confounding among environmental and constitutional variables. Am J Epidemiol 1984;120:414-422.
Holman CDJ, Armstrong BK, Evans PR, et al. Relationship of solar keratosis and history of skin cancer to objective measures of actinic skin damage. Br J Dermatol 1984;110:129-138.
Memon AA, Tomenson JA, Bothwell J, Friedmann PS. Prevalence of solar damage and actinic keratosis in a Merseyside population. Br J Dermatol 2000;142:1154-1159.
Brooke RC, Newbold SA, Telfer NR, Griffiths CEM. Discordance between facial wrinkling and the presence of basal cell carcinoma. Arch Dermatol 2001;137:751-754.
Foote JA, Harris RB, Giuliano AR, et al. Predictors for cutaneous basal- and squamous-cell carcinoma among actinically damaged adults. Int J Cancer 2001;95:7-11.
Malvy J-MD, Guinot C, Preziosi P, et al. Epidemiologic determinants of skin photoaging: baseline data of the SU.VI.MAX. cohort. J Am Acad Dermatol 2000;42:47-55.
Kennedy C, Bastiaens MT, Bajdik CD, Willemze R, Westendorp RGJ, Bouwes Bavinck JN. Effect of smoking and sun on the aging skin. J Invest Dermatol 2003;120:548-554.
Preston DS, Stern RS. Nonmelanoma cancers of the skin. N Engl J Med 1992;327:1649-1662.
de Gruijl FR, Sterenborg HJ, Forbes PD, et al. Wavelength dependence of skin cancer induction by ultraviolet irradiation of albino hairless mice. Cancer Res 1993;53:53-60.
Kligman LH, Akin FJ, Kligman AM. The contributions of UVA and UVB to connective tissue damage in hairless mice. J Invest Dermatol 1985;84:272-276.
American Society for Aesthetic Plastic Surgery, Cosmetic Surgery National Data Bank. 2002 Statistics. New York: ASAPS Communications, 2003. (Accessed March 15, 2004, at http://www.surgery.org/press/statistics-2002.asp).
Darlington S, Williams G, Neale R, Frost C, Green A. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Arch Dermatol 2003;139:451-455.
Kligman LH, Akin FJ, Kligman AM. Prevention of ultraviolet damage to the dermis of hairless mice by sunscreens. J Invest Dermatol 1982;78:181-189.
Kligman LH, Akin FJ, Kligman AM. Sunscreens promote repair of ultraviolet radiation-induced dermal damage. J Invest Dermatol 1983;81:98-102.
Boyd AS, Naylor M, Cameron GS, Pearse AD, Gaskell SA, Neldner KH. The effects of chronic sunscreen use on the histologic changes of dermatoheliosis. J Am Acad Dermatol 1995;33:941-946.
Stern RS, Weinstein MC, Baker SG. Risk reduction for nonmelanoma skin cancer with childhood sunscreen use. Arch Dermatol 1986;122:537-545.
Neale R, Williams G, Green A. Application patterns among participants randomized to daily sunscreen use in a skin cancer prevention trial. Arch Dermatol 2002;138:1319-1325.
Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993;329:1147-1151.
Green A, Williams G, Neale R, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999;354:723-729.
Foley P, Nixon R, Marks R, Frowen K, Thompson S. The frequency of reactions to sunscreens: results of a longitudinal population-based study on the regular use of sunscreens in Australia. Br J Dermatol 1993;128:512-518.
Autier P, Dore JF, Negrier S, et al. Sunscreen use and duration of sun exposure: a double-blind, randomized trial. J Natl Cancer Inst 1999;91:1304-1309.
Huncharek M, Kupelnick B. Use of topical sunscreens and the risk of malignant melanoma: a meta-analysis of 9067 patients from 11 case-control studies. Am J Public Health 2002;92:1173-1177.
Center for Food Safety and Applied Nutrition. AHAs and UV sensitivity: results of new FDA-sponsored studies. Office of Cosmetics and Colors fact sheet. Rockville, Md.: Food and Drug Administration, March 7, 2000.
Stiller MJ, Bartolone J, Stern RS, et al. Topical 8% glycolic acid and 8% L-lactic acid creams for the treatment of photodamaged skin: a double-blind vehicle-controlled clinical trial. Arch Dermatol 1996;132:631-636.
Thibault PK, Wlodarczyk J, Wenck A. A double-blind randomized clinical trial on the effectiveness of a daily glycolic acid 5% formulation in the treatment of photoaging. Dermatol Surg 1998;24:573-578.
Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ. Topical tretinoin improves photoaged skin: a double-blind vehicle-controlled study. JAMA 1988;259:527-532.
Griffiths CEM, Russman AN, Majmudar G, Singer RS, Hamilton TA, Voorhees JJ. Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). N Engl J Med 1993;329:530-535.
Renova (tretinoin cream) 0.05%: prescribing information. Skillman, N.J.: Ortho Dermatological, 1998 (package insert).
Renova (tretinoin cream) 0.02%: prescribing information. Skillman, N.J.: Ortho Dermatological, 2000 (package insert).
Avage (tazarotene) cream, 0.1%: prescribing information. Irvine, Calif.: Allergan, 2002 (package insert).
Kang S, Leyden JJ, Lowe NJ, et al. Tazarotene cream for the treatment of facial photodamage: a multicenter, investigator-masked, randomized, vehicle-controlled, parallel comparison of 0.01%, 0.025%, 0.05%, and 0.1% tazarotene creams with 0.05% tretinoin emollient cream applied once daily for 24 weeks. Arch Dermatol 2001;137:1597-1604.
Hecker D, Worsley J, Yueh G, Kuroda K, Lebwohl M. Interactions between tazarotene and ultraviolet light. J Am Acad Dermatol 1999;41:927-930.
Frost C, Williams G, Green A. High incidence and regression rates of solar keratoses in a Queensland community. J Invest Dermatol 2000;115:273-277.
Drake LA, Ceilley RI, Cornelison RL, et al. Guidelines of care for actinic keratoses: committee on guidelines of care. J Am Acad Dermatol 1995;32:95-98.
Kurwa HA, Yong-Gee SA, Seed PT, Markey AC, Barlow RJ. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses. J Am Acad Dermatol 1999;41:414-418.
Witheiler DD, Lawrence N, Cox SE, Cruz C, Cockerell CJ, Freemen RG. Long-term efficacy and safety of Jessner's solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses. Dermatol Surg 1997;23:191-196.
Food and Drug Administration. Proceedings of the Dermatologic and Ophthalmic Drugs Advisory Committee. Gaithersburg, Md.: Center for Drug Evaluation and Research, November 5, 1999.
Gebauer K, Brown P, Varigos G. Topical diclofenac in hyaluronan gel for the treatment of solar keratoses. Australas J Dermatol 2003;44:40-43.
Stockfleth E, Meyer T, Benninghoff B, et al. A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for treatment of multiple actinic keratoses. Arch Dermatol 2002;138:1498-1502.
Fulton JE, Rahimi AD, Helton P, Dahlberg K, Kelly AG. Disappointing results following resurfacing of facial skin with CO2 lasers for prophylaxis of keratoses and cancers. Dermatol Surg 1999;25:729-732.
Lowe NJ, Maxwell A, Harper H. Botulinum A exotoxin for glabellar folds: a double-blind, placebo-controlled study with an electromyographic injection technique. J Am Acad Dermatol 1996;35:569-572.
Botox cosmetic purified neurotoxin complex (Allergan). In: Physicians' desk reference electronic library. Montvale, N.J.: Thompson PDR, 2003:1-15 (computer disk).
Warning letter to Allergan, Inc. Rockville, Md.: Food and Drug Administration, June 23, 2003. (Accessed March 15, 2004, at http://www.fda.gov/foi/warning_letters/g4093d.htm.)
Carruthers JA, Lowe NJ, Menter MA, et al. A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol 2002;46:840-849.
Matarasso SL. Comparison of botulinum toxin types A and B: a bilateral and double-blind randomized evaluation in the treatment of canthal rhytides. Dermatol Surg 2003;29:7-13.
Klein AW. Skin filling: collagen and other injectables of the skin. Dermatol Clin 2001;19:491-508.
FDA approves new product for facial wrinkles. FDA talk paper T03-85. Rockville, Md.: Food and Drug Administration, December 12, 2003.
Stern RS, Dover JS, Levin JA, Arndt KA. Laser therapy versus cryotherapy of lentigines: a comparative trial. J Am Acad Dermatol 1994;30:985-987.
Hernandez-Perez E, Ibiett EV. Gross and microscopic findings in patients undergoing microdermabrasion for facial rejuvenation. Dermatol Surg 2001;27:637-640.
Maheux R, Naud F, Rioux M, et al. A randomized, double-blind, placebo-controlled study on the effect of conjugated estrogens on skin thickness. Am J Obstet Gynecol 1994;170:642-649.
Dunn LB, Damesyn M, Moore AA, Reuben DB, Greendale GA. Does estrogen prevent skin aging? Results from the First National Health and Nutrition Examination Survey (NHANES I). Arch Dermatol 1997;133:339-342.
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for photoaging/photodamage. J Am Acad Dermatol 1996;35:462-464.
Guidelines of care for cryosurgery. J Am Acad Dermatol 1994;31:648-653.
Guidelines of care for soft tissue augmentation: collagen implants. J Am Acad Dermatol 1996;34:698-702.
Drake LA, Dinehart SM, Goltz RW, et al. Guidelines of care for chemical peeling. J Am Acad Dermatol 1995;33:497-503.
Guidelines of care for dermabrasion. J Am Acad Dermatol 1994;31:654-657.
Related Letters:
Treatment of Photoaging
Rohrich R. J., Decherd M. E., Stern R. S.(Robert S. Stern, M.D.)
A 45-year-old fair-skinned woman has noted increasing sallowness, roughness, fine wrinkles, and mottled hyperpigmentation on her face. She is bothered by these changes and is worried about the development of nonmelanoma skin cancer. What treatments may minimize skin aging and lower the risk of skin cancer?
The Clinical Problem
Aging and exposure to the environment affect facial appearance. Age-related changes include benign growths and "gravitation," which results from a redistribution of fat, decreased skin elasticity, and bone loss. Exposure to the sun induces clinical and histologic changes to the skin (Figure 1), commonly called photoaging. Clinically, photoaging may be manifested as wrinkles (Figure 2, Figure 3, Figure 4, and Figure 5), skin roughness and dryness (Figure 3), irregular pigmentation (Figure 2, Figure 3, Figure 4, and Figure 5), telangiectasia (Figure 2 and Figure 4), sallowness (Figure 3 and Figure 5), and brown spots (lentigines, Figure 2, Figure 3, and Figure 4).1,2 Other common age-related skin changes include seborrheic keratoses (Figure 3 and Figure 5); actinic keratoses, which are sun-induced, premalignant, aesthetically displeasing, and sometimes symptomatic (burning and tender) growths; and "frown lines," which result from dynamic changes due to muscle hypertonicity.
Figure 1. Photomicrographs of Normal Skin (Panel A) and Photoaged Skin (Panel B) (Hematoxylin and Eosin, x200).
In moderately photoaged skin (Panel B), the epidermis is atrophic with thinning of the spinous layer and loss of the rete ridges. There is condensation of collagen beneath the basement-membrane zone and proliferation of the elastic fibers, which appear thickened, curled, and tangled. Deeper dermal collagen exhibits early basophilic degeneration. Telangiectasia is present in the upper dermis, in the zone of elastosis. Photomicrographs provided courtesy of Dr. Steven Tahan.
Figure 2. A Woman in Early Middle Age with Prominent Telangiectasia, a Few Lentigines, and Fine Wrinkling.
Figure 3. A Middle-Aged Woman with Some Skin Roughness, Mottled Hyperpigmentation, and Fine Telangiectasia.
Evident are discrete, hyperpigmented macules consisting of sun-induced lentigines and age-related seborrheic keratoses.
Figure 4. A Middle-Aged Woman with More Advanced Photoaging.
This woman's skin shows pronounced wrinkling, mottled hyperpigmentation, vascular ectasia, lentigines, and a cherry angioma of the lower eyelid.
Figure 5. A Woman in Late Middle Age with Coarse Wrinkling, Gravitational Changes (Enhanced Nasolabial Fold), Sallowness, Irregular Hyperpigmentation, and Seborrheic Keratoses.
Wrinkles and telangiectasia are associated with increased risks of actinic keratoses and nonmelanoma skin cancer (age-adjusted odds ratio, 2 to 9).3,4,5 The presence of actinic keratoses is strongly associated with an increased risk of squamous-cell cancer.6 Therefore, persons with substantial photoaging should be examined periodically for actinic keratoses and skin cancers.
Cumulative exposure to sunlight and exposure within the past 10 years are strongly associated with the risk of actinic keratoses and therefore squamous-cell cancer in people of any age. They are probably also related to the extent of photoaging, but recent exposure is not associated with the risk of basal-cell cancer.3,6 Risk factors for photoaging and skin cancer include fair skin, difficulty tanning, ease of sunburning, sunburns before the age of 20 years, and advancing age.2,3,4,7,8 Smoking is a moderate independent risk factor for wrinkling, telangiectasia, and squamous-cell cancer.8
Ultraviolet B (UVB) radiation (wavelengths from 290 to 320 nm) is much more important for the induction of nonmelanoma skin cancer and actinic keratoses than ultraviolet A (UVA) radiation (320 to 400 nm).9,10 Both UVA and UVB radiation contribute to changes in pigment, including lentigines and telangiectasia, and wrinkles, but their relative contributions are controversial.11
People who seek therapy for photoaging, benign growths, and frown lines face an extraordinary array of information, much of it misinformation. Thousands of Web sites offer products or procedures that promise to improve facial appearance. In 2002, more than 5 million nonsurgical and 1.5 million surgical cosmetic procedures, costing patients more than $13 billion, were performed.12 Although the procedures are highly profitable, few have been proved effective and few are well regulated.
Strategies and Evidence
Assessment
Most changes that occur as a result of photoaging have similar causes and risk factors, but the extent and consequences of these changes vary greatly among patients. The decision about whether to provide treatment depends on the nature of the changes, their severity, the degree to which they bother the patient, and the patient's willingness to accept the risks and costs of treatment, which most insurance plans do not cover.
Prevention and Therapy
Protection from the Sun
Protection from the sun at any age reduces the risk of actinic keratoses and squamous-cell cancer and the progression of photoaging.13,14,15,16 Reducing the risk of basal-cell cancer depends primarily on reducing sun exposure during childhood.17 In the absence of adequate protection from the sun, other treatments are less effective and may be more hazardous.
Good protection strategies include wearing hats and other clothing and staying out of the sun. Also, many sunscreens that block UVB radiation are available. Sun protection factor (SPF) numbers equal the ratio of doses of ultraviolet radiation (predominantly UVB radiation) that result in erythema (sunburn) with protection to the doses that result in erythema without protection. SPF 2 equals a 50 percent block, SPF 15 equals a 93 percent block, and SPF 45 equals a 98 percent block. The blocking of UVA radiation by nonopaque sunscreens, including those that are claimed to block UVA radiation, cannot be consistently quantified and is generally less than an SPF of 3. Opaque sunscreens, which often contain titanium dioxide, can provide good protection from UVA radiation but may be cosmetically unacceptable.
People typically apply sunscreens less than half as thickly as and less often than recommended, thus compromising their protection substantially.18 If applied as recommended, 170 g (6 oz) of sunscreen would provide only five whole-body applications for an adult. Daily application is essential for good protection. Sweating and swimming necessitate reapplication.
In animals, the use of sunscreens has repaired preexisting damage and prevented further damage caused by exposure to ultraviolet radiation.14,15 In a randomized trial in humans, the use of a sunscreen with an SPF of 29 for two years stabilized histologic changes to the skin, whereas such photoaging increased in the placebo group.16 Although clinical data were not reported, histologic and clinical appearance are generally correlated.16 In controlled studies assessing the daily use of broad-spectrum sunscreens (with an SPF of 15 or higher) for up to 4.5 years, the incidence of actinic keratoses was reduced by about 40 percent, as compared with the incidence with no sunscreen use, and by 24 percent, as compared with discretionary sunscreen use. Daily use of sunscreens with an SPF of 15 or higher reduced the incidence of squamous-cell cancer by 25 percent, but the risk of basal-cell cancer was not reduced.19,20
Although true allergic reactions to the active ingredients in sunscreens are rare, 17 percent of persons using a sunscreen with an SPF of 15 or higher over a seven-month period had irritation reactions, a major barrier to compliance.21 Sunscreens that provide protection against UVB radiation decrease the synthesis of vitamin D and may encourage increased exposure to the sun and to UVA radiation.22 However, the available data suggest that sunscreen use does not increase the risk of melanoma.23
Hydroxy Acids
Many preparations that contain alpha and beta hydroxy acids are both exfoliants and moisturizers. Hydroxy acids in low concentrations (typically 4 to 12 percent) are ubiquitous components of nonprescription creams and lotions that are promoted as being helpful for ameliorating the aging of skin. In high concentrations, these preparations are used as "peels." Their keratolytic and irritant effects depend on the specific acid, the concentration, and the pH. High concentrations of hydroxy acids or lower concentrations in combination with topical retinoids are often irritating. Overall effects on photoaging are limited.
Skin treated with hydroxy acids admits 20 percent more UVB radiation than untreated skin, making concomitant sunscreen use essential.24 As compared with sunscreens or placebo alone, the use of 5 percent glycolic acid and 8 percent lactic acid creams for three to five months yielded somewhat greater improvement in roughness and mottled pigmentation in two randomized studies, and in sallowness in one study, but no greater improvement in wrinkles or actinic keratoses; unblinding may have occurred as a result of irritation.25,26 There is no evidence that high-cost creams are more effective than low-cost creams.
Topical Retinoids
Although topical retinoids (vitamin A derivatives) were initially controversial, it is now accepted that they reduce the severity of photoaging.27,28 Two topical retinoids, tretinoin and tazarotene, have been approved by the Food and Drug Administration (FDA) for the "palliation" of the fine wrinkles and irregular pigmentation of photoaging.29,30,31 In addition, tretinoin reduces tactile roughness, and tazarotene is approved for the treatment of lentigines.29,30,31 In clinical trials typically lasting six months, some improvement in wrinkling, mottled hyperpigmentation, and roughness was noted in the majority of patients treated with retinoids, at a rate roughly twice that among control subjects who used sunscreen and emollients.27,29,30,31,32 At least one fourth of retinoid users had moderate or greater improvement in fine wrinkling, mottled hyperpigmentation, or skin roughness.27,28,29,30,31,32 However, because the frequency of irritation (and the likelihood of unblinding) increases in direct proportion to the retinoid concentration, it is difficult to determine the true magnitude of improvement attributable to the active agent and the optimal dose. Lower concentrations are probably less beneficial. Continued use seems to be needed to maintain a benefit. Insurance rarely provides coverage for topical retinoids that are prescribed for photoaging. There is no good evidence of the efficacy of other vitamin A derivatives often found in over-the-counter preparations (e.g., night creams and moisturizers), including retinol and retinaldehyde.
The penetration of UVB radiation increases by as much as one third in skin that has been treated with topical retinoids, as compared with untreated skin.33 Therefore, retinoids are unlikely to provide a clinically significant net benefit without concomitant sun protection. The effect of topical retinoids on the incidence of skin cancer and actinic keratoses is unclear.
Fluorouracil Cream
Actinic keratoses appear as discrete, rough, pink spots and are common in people, particularly those over the age of 50 years, who have other signs of photoaging. In sunny locales, about 25 percent of newly identified actinic keratoses will spontaneously regress.34 However, these lesions are premalignant and may evolve into squamous-cell carcinomas. Although evidence is lacking, it is likely that treating actinic keratoses reduces the risk of squamous-cell cancer. Topical application of liquid nitrogen (cryosurgery) clears most lesions and is considered the standard of care.35 Topical 5 percent fluorouracil cream used twice daily for three weeks on body areas with a high density of actinic keratoses reduces the number of keratoses by about 70 percent36 and decreases the epidermal roughness associated with photoaging. The results are similar to those observed with medium-depth chemical peels.37 Substantial irritation occurs during the period when topical fluorouracil cream is being applied and for approximately two weeks afterward. The cream should not be used during pregnancy.
Photodynamic therapy (topical application of aminolevulinic acid, followed about 16 hours later by exposure to blue light) is probably less effective than cryosurgery or the application of fluorouracil cream and is quite uncomfortable.38 Topical diclofenac, approved by the FDA for the treatment of actinic keratoses, is less irritating but far less effective than fluorouracil cream, reducing the number of lesions by about 16 percent.39 Although it has not been approved by the FDA for actinic keratoses, topical 5 percent imiquimod seems to be about as effective and as irritating as fluorouracil cream.40 Laser ablation of the epidermis for resurfacing (Table 1) has little long-term effect on the incidence of actinic keratoses.41
Table 1. Common Nonsurgical Procedures for Photoaging, According to the Primary Indication.
Procedures for Facial Rejuvenation
Dozens of different procedures, ranging from relatively noninvasive approaches to those that are quite invasive, are advocated for facial rejuvenation. Some, including blepharoplasty and face-lifts, have been used for decades for loose, excess, or drooping skin of the eyelids and face. The procedures share the following features: they are expensive for the patient and highly profitable for the provider, and they have not been subjected to well-controlled studies. It has been estimated that about 1.7 million injections of botulinum toxin, 1 million microdermabrasions, 800,000 soft-tissue augmentation procedures, 500,000 chemical peels, and more than 800,000 laser procedures were performed in 2002 in the United States, representing an increase of more than 350 percent since 1997.12 Table 1 summarizes the possible indications for and risks of some common procedures. For most procedures listed in Table 1, the durability of beneficial effects is unknown but is usually measured in months or a few years, and the risks are not well quantified.
Botulinum Toxin
Hypertonicity of muscles creates dynamic changes that are manifested as furrows (lines) of the forehead and glabellar areas. A decrease in muscle tone can reduce these furrows.42 Two antigenically distinct botulinum toxins (type A and type B), which block muscles through their neurotoxic effects, are commercially available. In December 2003, only type A (Botox) was approved for cosmetic indications (treatment of moderate-to-severe glabellar lines).43 Aggressive promotion of Botox has prompted a warning letter from the FDA charging false and misleading promotional activities.44
Since response is subjective, exact quantification is lacking; however, available data suggest that at least moderate improvement is noted in 50 to 75 percent of patients treated for glabellar lines.42,45 Improvement peaks one month after a single injection and is largely gone in four months.43,45 Hence, two or three treatments a year are needed to maintain the effect. Robust long-term data on efficacy and safety are not available, and long-term effects of repeated muscle denervation remain uncertain. Well-designed studies that quantify the efficacy and safety of botulinum toxin for the treatment of other wrinkles of the upper face, including crow's feet, are not available, but the results would probably be similar to those observed for glabellar lines.46 Good technique is essential for optimal results and safety. Therefore, patients should carefully assess the qualifications and experience of the physician.
Skin Fillers
More than 40 filler substances are used for soft-tissue augmentation, which is used for the treatment of coarse (deep) wrinkles and nondynamic furrows.47 In the United States, the most frequently used FDA-approved fillers are injectable bovine collagen preparations, which typically last for three to six months. Recently, the FDA approved a hyaluronic acid filler (Restylane). In one study, hyaluronic acid was associated with a higher incidence of severe bruising (3.6 percent), pain (3.6 percent), and tenderness (2.9 percent) than was a collagen preparation (Zyplast) (0.7 percent, 1.4 percent, and 1.4 percent, respectively); the effects of the two agents on wrinkles were similar at six months.48 The relative safety of approved fillers is not clear. Because of cost and the need for retreatment, few patients find injectable collagen fillers an acceptable form of long-term therapy. Silicone injections are highly profitable for the physician but have not been approved by the FDA, and they should be avoided.
Simple Office Procedures
Benign vascular proliferations, including linear telangiectasia, cherry angiomas, and spider angiomas, which often occur with aging and cutaneous photodamage, respond to a variety of procedures, including those involving lasers (Table 1). Cryosurgery and electrosurgery can lighten limited numbers of discrete pigmented lesions (e.g., seborrheic keratoses and lentigines) and can remove actinic keratoses as effectively as and less expensively than lasers.49
Microdermabrasion is very popular and is commonly performed by dermatologists and nonmedical practitioners. The procedure involves the use of a closed-loop, negative-pressure system to deliver to and remove from the skin aluminum oxide or sodium chloride crystals, which mechanically remove (sand off ) the superficial epidermis. Small uncontrolled studies, patients' opinions, and histologic findings suggest that microdermabrasion contributes to small improvements in photoaging, but reliable data are lacking.50
Areas of Uncertainty
Many unregulated and highly profitable products and services are available to reduce signs of aging. Formal training and certification are not required for a physician to offer cosmetic procedures. Separating hype from facts about safety and effectiveness is difficult, and data from randomized trials to support most interventions are lacking.
Many topical or oral products containing vitamins C and E, coenzyme Q10, bioflavonoids, fruit extracts, kinerase (N6-furfuryladenine), beta carotene and other antioxidants, and green-tea extracts have been promoted for the treatment and prevention of photoaging. Data to support these claims are lacking.
Thinning of skin, decreases in collagen, and increases in skin dryness often accompany menopause. Hormone-replacement therapy may be associated with a small increase in collagen and skin thickness and in the mechanical and water-holding properties of skin, with perhaps minor reductions in clinical wrinkling and skin dryness.51,52 However, these benefits, which are modest at best, do not justify the risks associated with hormone-replacement therapy.53
Although beta carotene has been proposed as a systemic chemopreventive agent for nonmelanoma skin cancer, the available data suggest that it is ineffective.17 Data are lacking on the effects of other proposed preventive medications, such as nonsteroidal antiinflammatory drugs and statins, on the risk of nonmelanoma skin cancer.
Guidelines
The American Academy of Dermatology has published guidelines for the care of actinic keratoses and photoaging that emphasize the importance of sun protection but do not recommend particular treatments.35,54 The academy has also published guidelines pertaining to specific therapies.55,56,57,58
Conclusions and Recommendations
Signs of photoaging, including sallowness, roughness, fine wrinkles, and mottled hyperpigmentation, are reduced by photoprotection. I routinely recommend daily use of sunscreen (SPF 15 or higher), which retards and slightly diminishes photoaging and decreases the incidence of actinic keratoses and squamous-cell cancer. I discourage tanning, both artificial and natural.
Given the recognized associations between benign manifestations of photoaging (such as fine wrinkling and telangiectasia) and potentially serious skin lesions, patients with substantial photoaging should be evaluated for actinic keratoses and skin cancers that would warrant treatment. For limited numbers of actinic keratoses, I recommend cryosurgery. If actinic keratoses are numerous and a patient will accept the associated irritation, I prescribe topical fluorouracil cream, used twice daily for two to three weeks — a regimen that reduces the number of actinic keratoses and improves skin texture. When standard therapies are unsuitable, photodynamic therapy and topical imiquimod may be appropriate.
Patients should be reassured about benign lesions, which merit treatment only for cosmetic reasons. For patients who desire treatment for photoaging, topical retinoids, available by prescription, are the most effective topical therapy that can be administered by the patients. Although not usually covered by insurance, they are no more expensive than many cosmetic products for which there are claims of antiaging effects without supporting evidence. Over-the-counter preparations that contain hydroxy acids also have small beneficial effects on roughness, sallowness, and changes in pigment. The benefits of emollients and makeup to smooth and camouflage these changes should not be underestimated. Many cosmetics also contain sunscreens.
Several procedures may improve facial appearance (Table 1). People who are considering these techniques should understand the associated costs, possible risks, and temporary nature of the effects.
I am indebted to Gail A. Howrigan, Ed.D., and Jean C. Lee, B.A., for providing essential editorial assistance.
Source Information
From the Department of Dermatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.
Address reprint requests to Dr. Stern at the Department of Dermatology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, or at rstern@bidmc.harvard.edu.
References
Lévêque J-L. Quantitative assessment of skin aging. Clin Geriatr Med 2001;17:673-689.
Holman CDJ, Evans PR, Lumsden GJ, Armstrong BK. The determinants of actinic skin damage: problems of confounding among environmental and constitutional variables. Am J Epidemiol 1984;120:414-422.
Holman CDJ, Armstrong BK, Evans PR, et al. Relationship of solar keratosis and history of skin cancer to objective measures of actinic skin damage. Br J Dermatol 1984;110:129-138.
Memon AA, Tomenson JA, Bothwell J, Friedmann PS. Prevalence of solar damage and actinic keratosis in a Merseyside population. Br J Dermatol 2000;142:1154-1159.
Brooke RC, Newbold SA, Telfer NR, Griffiths CEM. Discordance between facial wrinkling and the presence of basal cell carcinoma. Arch Dermatol 2001;137:751-754.
Foote JA, Harris RB, Giuliano AR, et al. Predictors for cutaneous basal- and squamous-cell carcinoma among actinically damaged adults. Int J Cancer 2001;95:7-11.
Malvy J-MD, Guinot C, Preziosi P, et al. Epidemiologic determinants of skin photoaging: baseline data of the SU.VI.MAX. cohort. J Am Acad Dermatol 2000;42:47-55.
Kennedy C, Bastiaens MT, Bajdik CD, Willemze R, Westendorp RGJ, Bouwes Bavinck JN. Effect of smoking and sun on the aging skin. J Invest Dermatol 2003;120:548-554.
Preston DS, Stern RS. Nonmelanoma cancers of the skin. N Engl J Med 1992;327:1649-1662.
de Gruijl FR, Sterenborg HJ, Forbes PD, et al. Wavelength dependence of skin cancer induction by ultraviolet irradiation of albino hairless mice. Cancer Res 1993;53:53-60.
Kligman LH, Akin FJ, Kligman AM. The contributions of UVA and UVB to connective tissue damage in hairless mice. J Invest Dermatol 1985;84:272-276.
American Society for Aesthetic Plastic Surgery, Cosmetic Surgery National Data Bank. 2002 Statistics. New York: ASAPS Communications, 2003. (Accessed March 15, 2004, at http://www.surgery.org/press/statistics-2002.asp).
Darlington S, Williams G, Neale R, Frost C, Green A. A randomized controlled trial to assess sunscreen application and beta carotene supplementation in the prevention of solar keratoses. Arch Dermatol 2003;139:451-455.
Kligman LH, Akin FJ, Kligman AM. Prevention of ultraviolet damage to the dermis of hairless mice by sunscreens. J Invest Dermatol 1982;78:181-189.
Kligman LH, Akin FJ, Kligman AM. Sunscreens promote repair of ultraviolet radiation-induced dermal damage. J Invest Dermatol 1983;81:98-102.
Boyd AS, Naylor M, Cameron GS, Pearse AD, Gaskell SA, Neldner KH. The effects of chronic sunscreen use on the histologic changes of dermatoheliosis. J Am Acad Dermatol 1995;33:941-946.
Stern RS, Weinstein MC, Baker SG. Risk reduction for nonmelanoma skin cancer with childhood sunscreen use. Arch Dermatol 1986;122:537-545.
Neale R, Williams G, Green A. Application patterns among participants randomized to daily sunscreen use in a skin cancer prevention trial. Arch Dermatol 2002;138:1319-1325.
Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993;329:1147-1151.
Green A, Williams G, Neale R, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999;354:723-729.
Foley P, Nixon R, Marks R, Frowen K, Thompson S. The frequency of reactions to sunscreens: results of a longitudinal population-based study on the regular use of sunscreens in Australia. Br J Dermatol 1993;128:512-518.
Autier P, Dore JF, Negrier S, et al. Sunscreen use and duration of sun exposure: a double-blind, randomized trial. J Natl Cancer Inst 1999;91:1304-1309.
Huncharek M, Kupelnick B. Use of topical sunscreens and the risk of malignant melanoma: a meta-analysis of 9067 patients from 11 case-control studies. Am J Public Health 2002;92:1173-1177.
Center for Food Safety and Applied Nutrition. AHAs and UV sensitivity: results of new FDA-sponsored studies. Office of Cosmetics and Colors fact sheet. Rockville, Md.: Food and Drug Administration, March 7, 2000.
Stiller MJ, Bartolone J, Stern RS, et al. Topical 8% glycolic acid and 8% L-lactic acid creams for the treatment of photodamaged skin: a double-blind vehicle-controlled clinical trial. Arch Dermatol 1996;132:631-636.
Thibault PK, Wlodarczyk J, Wenck A. A double-blind randomized clinical trial on the effectiveness of a daily glycolic acid 5% formulation in the treatment of photoaging. Dermatol Surg 1998;24:573-578.
Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ. Topical tretinoin improves photoaged skin: a double-blind vehicle-controlled study. JAMA 1988;259:527-532.
Griffiths CEM, Russman AN, Majmudar G, Singer RS, Hamilton TA, Voorhees JJ. Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). N Engl J Med 1993;329:530-535.
Renova (tretinoin cream) 0.05%: prescribing information. Skillman, N.J.: Ortho Dermatological, 1998 (package insert).
Renova (tretinoin cream) 0.02%: prescribing information. Skillman, N.J.: Ortho Dermatological, 2000 (package insert).
Avage (tazarotene) cream, 0.1%: prescribing information. Irvine, Calif.: Allergan, 2002 (package insert).
Kang S, Leyden JJ, Lowe NJ, et al. Tazarotene cream for the treatment of facial photodamage: a multicenter, investigator-masked, randomized, vehicle-controlled, parallel comparison of 0.01%, 0.025%, 0.05%, and 0.1% tazarotene creams with 0.05% tretinoin emollient cream applied once daily for 24 weeks. Arch Dermatol 2001;137:1597-1604.
Hecker D, Worsley J, Yueh G, Kuroda K, Lebwohl M. Interactions between tazarotene and ultraviolet light. J Am Acad Dermatol 1999;41:927-930.
Frost C, Williams G, Green A. High incidence and regression rates of solar keratoses in a Queensland community. J Invest Dermatol 2000;115:273-277.
Drake LA, Ceilley RI, Cornelison RL, et al. Guidelines of care for actinic keratoses: committee on guidelines of care. J Am Acad Dermatol 1995;32:95-98.
Kurwa HA, Yong-Gee SA, Seed PT, Markey AC, Barlow RJ. A randomized paired comparison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses. J Am Acad Dermatol 1999;41:414-418.
Witheiler DD, Lawrence N, Cox SE, Cruz C, Cockerell CJ, Freemen RG. Long-term efficacy and safety of Jessner's solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses. Dermatol Surg 1997;23:191-196.
Food and Drug Administration. Proceedings of the Dermatologic and Ophthalmic Drugs Advisory Committee. Gaithersburg, Md.: Center for Drug Evaluation and Research, November 5, 1999.
Gebauer K, Brown P, Varigos G. Topical diclofenac in hyaluronan gel for the treatment of solar keratoses. Australas J Dermatol 2003;44:40-43.
Stockfleth E, Meyer T, Benninghoff B, et al. A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for treatment of multiple actinic keratoses. Arch Dermatol 2002;138:1498-1502.
Fulton JE, Rahimi AD, Helton P, Dahlberg K, Kelly AG. Disappointing results following resurfacing of facial skin with CO2 lasers for prophylaxis of keratoses and cancers. Dermatol Surg 1999;25:729-732.
Lowe NJ, Maxwell A, Harper H. Botulinum A exotoxin for glabellar folds: a double-blind, placebo-controlled study with an electromyographic injection technique. J Am Acad Dermatol 1996;35:569-572.
Botox cosmetic purified neurotoxin complex (Allergan). In: Physicians' desk reference electronic library. Montvale, N.J.: Thompson PDR, 2003:1-15 (computer disk).
Warning letter to Allergan, Inc. Rockville, Md.: Food and Drug Administration, June 23, 2003. (Accessed March 15, 2004, at http://www.fda.gov/foi/warning_letters/g4093d.htm.)
Carruthers JA, Lowe NJ, Menter MA, et al. A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol 2002;46:840-849.
Matarasso SL. Comparison of botulinum toxin types A and B: a bilateral and double-blind randomized evaluation in the treatment of canthal rhytides. Dermatol Surg 2003;29:7-13.
Klein AW. Skin filling: collagen and other injectables of the skin. Dermatol Clin 2001;19:491-508.
FDA approves new product for facial wrinkles. FDA talk paper T03-85. Rockville, Md.: Food and Drug Administration, December 12, 2003.
Stern RS, Dover JS, Levin JA, Arndt KA. Laser therapy versus cryotherapy of lentigines: a comparative trial. J Am Acad Dermatol 1994;30:985-987.
Hernandez-Perez E, Ibiett EV. Gross and microscopic findings in patients undergoing microdermabrasion for facial rejuvenation. Dermatol Surg 2001;27:637-640.
Maheux R, Naud F, Rioux M, et al. A randomized, double-blind, placebo-controlled study on the effect of conjugated estrogens on skin thickness. Am J Obstet Gynecol 1994;170:642-649.
Dunn LB, Damesyn M, Moore AA, Reuben DB, Greendale GA. Does estrogen prevent skin aging? Results from the First National Health and Nutrition Examination Survey (NHANES I). Arch Dermatol 1997;133:339-342.
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
Drake LA, Dinehart SM, Farmer ER, et al. Guidelines of care for photoaging/photodamage. J Am Acad Dermatol 1996;35:462-464.
Guidelines of care for cryosurgery. J Am Acad Dermatol 1994;31:648-653.
Guidelines of care for soft tissue augmentation: collagen implants. J Am Acad Dermatol 1996;34:698-702.
Drake LA, Dinehart SM, Goltz RW, et al. Guidelines of care for chemical peeling. J Am Acad Dermatol 1995;33:497-503.
Guidelines of care for dermabrasion. J Am Acad Dermatol 1994;31:654-657.
Related Letters:
Treatment of Photoaging
Rohrich R. J., Decherd M. E., Stern R. S.(Robert S. Stern, M.D.)