Antiaging, antiacne, depigmenting
Important Chemical Components:
Natural retinoids: The major naturally-occurring retinoids are tretinoin (all-trans retinoic acid, also known simply as retinoic acid), the stereoisomers of tretinoin [isotretinoin (13-cis-retinoic acid) and alitretinoin (9-cis-retinoic acid)], retinol, retinaldehyde, and retinol esters (retinyl acetate, retinyl palmitate, retinyl propionate).
Synthetic retinoids: The retinoids that have been designed in the laboratory to increase stability are tazarotene (molecular formula: C21H21NO2S), adapalene (molecular formula: C28H28O3), and retinyl retinoate (an ester of retinoic acid and all-trans retinol).
Retinoids are natural and synthetic derivatives of vitamin A (also known as all-trans retinol). As ingredients in skin therapy, these products are laboratory made.
Personal Care Category:
Recommended for the following Baumann Skin Types:
DRNW, DRPT, DRPW, DSNW, DSPT, DSPW, ORNW, ORPW, ORPT, OSPW, OSNW, and OSPT
Vitamin A is found naturally in the skin and other parts of the body and is obtained through the diet from carotenoid-containing foods, such as sweet potatoes, carrots, dark green leafy vegetables, tomatoes, squash, apricots, cantaloupe, red pepper, and tropical fruits (e.g., mangoes and papayas).1,2 Like β-carotene, lutein, lycopene, and other carotenoids, retinoids are derived from vitamin A (all-trans retinol). The retinoid family includes natural (e.g., tretinoin, isotretinoin, alitretinoin, retinol, and retinaldehyde) and synthetic (e.g., tazarotene, adapalene, and retinyl retinoate) forms. Retinol and retinyl esters represent 99 percent of cutaneous retinoids naturally present in the skin.3 The retinoids used in prescription products and over-the-counter (OTC) skin care formulations are synthesized in laboratories.
Retinoids have demonstrated salutary benefits in the treatment of various cutanous conditions, including acne, psoriasis, ichthyosis, and photoaging. In fact, retinoid efficacy has been reported in more than 125 distinct dermatologic disorders.4 Two prescription retinoids, tretinoin (retinoic acid) and tazarotene, have been approved by the United States Food and Drug Administration (FDA) for use in the treatment of photoaging, although isotretinoin (the 13-cis isomer of tretinoin), and several synthetic retinoids are deployed for therapeutic applications (Table 83-1).3 In addition, retinol, though it has not been approved by the FDA to treat photoaging or included among the FDA monograph ingredients for that purpose, is known to impart antiaging activity. The retinoids used in effective skin care products include retinoic acid (tretinoin), retinol, retinaldehyde, adapalene, or tazarotene. Retinyl esters such as retinyl palmitate (RP) are used in several OTC formulations, but the efficacy is questionable because penetration rates are minimal.
TABLE 83-1Pros and Cons of Retinoids ||Download (.pdf) TABLE 83-1 Pros and Cons of Retinoids
Variety of products
Excellent research on efficacy, with significant evidence from randomized controlled trials
Difficult to formulate
Irritation lessens with time
Many products do not work because of packaging and stability issues
Treats acne and skin pigmentation as well as wrinkles
Causes irritation especially in S2 rosacea types
Protects skin from sun damage
Prevalent myth, actually based on in vitro and animal studies,3 that retinoids make skin more photosensitive
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Should be used at night only
Vitamin A was recognized in 1928 by Green and Mellanby as having anti-infective properties.3,5 The structure of retinol was ascertained just three years later by Karrer et al.6 In 1937, Karrer was a corecipient of the Nobel Prize in Chemistry for this and related work. In 1943, the first study to document the use of vitamin A for the treatment of acne was published.7 Tretinoin was first used in dermatologic therapy in 1959 by Stüttgen.7–9 In 1969, Kligman et al. reported that topically applied tretinoin was efficacious in the treatment of acne vulgaris.8,10
The apparent ameliorative effects of retinoids on aged skin were recognized serendipitously by Kligman et al. in the mid-1980s in examinations of female acne patients who reported that their skin felt smoother and less wrinkled after treatment.11 A small subsequent clinical trial revealed that daily topical application of 0.05 percent tretinoin to the forearm and face diminished ultraviolet (UV)-induced epidermal atrophy, dysplasia, keratosis, and dyspigmentation compared to vehicle control.12 These observations have since been duplicated in numerous studies.
A metabolic precursor to tretinoin, retinol is often incorporated in OTC “antiwrinkle” creams. There is currently no FDA-approved monograph for the use of retinol in cosmetics and personal care products; however, one may be developed in the future.
Vitamin A is found in various forms, with multiple precursors to retinoic acid.
Over the last several decades, myriad synthetic retinoids have been developed, with the vitamin A or “retinoid” family now including retinyl esters (such as RP), retinol, tretinoin (retinoic acid), adapalene, tazarotene, and oral isotretinoin (Accutane) in addition to four carotenoids such as β-carotene.
Retinoids regulate growth and differentiation in epithelial cells and suppress tumor promotion during experimental carcinogenesis, thus hampering malignant cell growth, quelling inflammation, and supporting the immune system.13 This is accomplished at the molecular level through the regulation of gene transcription and influencing cellular differentiation as well as proliferation. Retinoids act directly by initiating transcription from genes with promoter regions containing retinoid response elements or indirectly by precluding the transcription of particular genes.14
The use of topical retinoids has been shown clinically and histologically to be effective in reversing some of the physical alterations and cutaneous manifestations induced in humans by excessive sun exposure. Irritant reactions, such as xerosis, erythema, and scaling, tend to be the worst of any adverse responses to retinoid compounds (i.e., tretinoin, isotretinoin, retinaldehyde, and tazarotene).8 This irritation is dose related and resolves with continued use (tachyphylaxis).
Retinaldehyde, retinol, and retinyl esters, all natural retinoic acid precursors, are the retinoids used in cosmeceuticals.3,15 Retinol is the most efficacious and the most irritating of the forms of retinol available without a prescription. Though less irritating, retinyl esters and retinaldehyde typically have less clinical efficacy, due to decreased penetration. Retinaldehyde, which exhibits slightly more efficacy than retinyl esters, is generally well tolerated, and appears to renew epidermal cells, blunt the effects of photoaging, and limit oxidative stress and bacterial flora on the skin.3
Lipophilic retinoids such as retinol, tretinoin, adapalene, and tazarotene easily penetrate the epidermis.3 Some protocols have suggested short contact time such as 15 minutes with retinoid products to decrease the amount of absorption. This ease of penetration of retinoids is unique among antiaging products; most products cannot penetrate into the skin, greatly reducing their efficacy. (Retinoid esters such as RP are an exception, and do not penetrate well due to their chemical structure.) All retinoids, by definition, bind the retinoic acid receptor and therefore should improve photoaged skin; however, only tretinoin (Renova) and tazarotene (Avage) are approved by the FDA to treat photoaged skin.
Although retinoids have been extensively studied for several years, much remains to be elucidated regarding the mechanisms of action of these compounds. In the 1970s, retinoid-binding proteins were discovered and, in 1987, retinoic acid receptors were identified, leading to the insight that tretinoin functions as a hormone.16–18 The biologic effects of retinoic acid are mediated by binding proteins such as cellular retinoic acid-binding proteins (CRAB) I and II; cellular retinol-binding protein (CRBP); and the nuclear receptors retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both sets of which consist of α, β, and γ isotypes.11,19,20 RARs heterodimerize with RXRs in order to interact with their retinoic acid response elements (RAREs), with RXR-α and RAR-γ heter-odimers serving as the primary cutaneous retinoid receptors in humans.20 (See Chapter 79, Retinol, Retinyl Esters, and Retinoic Acid, for more information on retinoid receptors.)
Adapalene and tazarotene bear no structural resemblance to natural retinoids but are categorized as retinoids because they activate retinoic acid receptors and share several functional traits.20 Adapalene is marketed as Differin and EpiDuo. Tazarotene, marketed as Tazorac and Avage, is selective for RAR-β and RAR-γ and is FDA approved to treat psoriasis, acne, and photoaging.21,22
Isotretinoin (Accutane) is used orally to treat acne. Oral retinoids are rarely used for photoaging because of the risk of teratogenicity. One study showed that a dose of 10 to 20 mg three times a week for two months led to improvement of skin aging signs such as wrinkles.23 A discussion of oral retinoid compounds is beyond the scope of this text.
In the author’s opinion, retinoids are the most important ingredients to treat and prevent skin aging. Their use is backed up by multiple studies. Retinoids elicit their effects at the molecular level by regulating gene transcription and affecting activities such as cellular differentiation and proliferation. All-trans retinoic acid (tretinoin) has been shown in various studies to decrease wrinkles and is the most frequently studied retinoid for photoaging treatment.12,20 Much work has been performed to characterize this mechanism.24–27 In general, retinoids treat and prevent photoaging by inhibiting the breakdown and loss of collagen and stimulating skin cells (fibroblasts) to increase collagen synthesis.27–30
The use of retinoids to prevent or treat the cutaneous signs of photoaging has been investigated in several studies. The first clinical trials demonstrating clinical improvement of photoaged skin using tretinoin were published in 1986 and 1988.12,31 The findings by Kligman et al. and Weiss et al. have since been duplicated numerous times. In one randomized, single-center study performed by Griffiths et al. in 1995, 100 subjects were divided into two tretinoin treatment groups (0.1 and 0.025 percent) and a vehicle cream group.32 Statistically significant improvements were seen in both tretinoin groups compared with vehicle.
A cascade of histologic changes have been associated with retinoid use, including the abrogation of cellular atypia, increased compacting of the stratum corneum (SC), diminished clumping of melanin in basal cells, and polarity correction of keratinocytes, with more orderly differentiation as cells move upward. The ultrastructural changes induced by retinoid use include hyperproliferation of keratinocytes (e.g., larger nuclei, increased ribosomes, etc.) and melanosome size reduction. The topical application of tretinoin 0.1 percent to photodamaged skin has been shown to prevent the breakdown of collagen and promote collagen synthesis, partially restoring collagen type I levels and increasing anchoring fibrils (collagen type VII).33
Although tretinoin and tazarotene are FDA approved to treat photoaged skin, which means that the efficacy of these retinoids is proven, retinol has not undergone the FDA approval process. Retinol is considered a cosmetic ingredient. Nevertheless, a number of studies have demonstrated its efficacy in treating aged skin but no company has made the large monetary investment and time commitment required to seek FDA approval. In spite of the lack of FDA approval to treat photoaged skin, several studies support the use of retinol to treat aged skin. Many of these were performed by the same team responsible for the original work on the FDA-approved forms of retinoic acid: John Voorhees, Chair of Dermatology at the University of Michigan, and Sewon Kang, Chair of Dermatology at Johns Hopkins School of Medicine. These studies are published in reputable peer-reviewed journals such as the Journal of Investigative Dermatology.34–38 For this reason, the author believes that using OTC retinol can achieve the same results as using a prescription retinoid.
Retinol has been shown to penetrate skin better than retinoic acid.37 One study demonstrated that retinol improves the appearance of wrinkles in sun-protected areas.39 Biopsies of treated skin show that retinol does induce cellular and molecular changes similar to those observed with the application of 0.025 percent retinoic acid.37 A separate study showed that 1.6 percent retinol induced significant epidermal thickening and other skin changes similar to those produced by retinoic acid but without measurable irritation.38 An elegant and frequently quoted randomized, double-blind, vehicle-controlled, left and right arm comparison study by Kafi et al. in 2007 showed that skin treated with 0.4 percent retinol showed increased glycosaminoglycans and collagen in biopsies as compared to those treated with vehicle.39 Visual scales also showed improvement of skin wrinkling in the retinol-treated group. Another study by Tucker-Samaras et el. showed that 0.1 percent stabilized retinol improved photoaged skin as compared to vehicle.40
Retinol and RP are the two most frequently used retinoids in OTC products. They are typically listed as excipient or “inactive” ingredients based on their status as “cosmetic” ingredients according to the FDA. Retinol is now well known for its photoinstability, but using it at night, along with the addition of an antioxidant to the regimen or formulation, circumvents this problem. Significantly, retinol is now recognized for exerting similar effects on the retinoic acid receptor as tretinoin.
RP, a storage and ester form of retinol and the main type of vitamin A present naturally in the skin,41 has steadily gained popularity over the last two decades and is incorporated into more than 600 skin care products, including cosmetics, sunscreens, as well as FDA-approved OTC and prescription drugs.42 However, Xia et al., who had earlier demonstrated that irradiation of RP with UVA yields photodecomposition products, synthesis of reactive oxygen species, and lipid peroxidation induction, obtained similar findings identifying RP as a photosensitizer after irradiation with UVB.43 Four years later, the Environmental Working Group (EWG) issued a consumer warning about the potential photocarcinogenicity of RP-containing sunscreens. The EWG’s methodology and conclusions, which the organization stood by, were roundly criticized in a debate that wound up in the pages of the Journal of the American Academy of Dermatology.44 While current evidence is inconclusive, the weight of extant evidence and clinical experience suggests that RP does not easily penetrate into the skin. Retinol rather than RP, even though it is easier to formulate,22 is thus the recommended choice.
In 2011, Kim et al. conducted a 12-week, randomized, double-blind, controlled trial to investigate the efficacy of retinyl retinoate, a new synthetic hybrid of retinoic acid and retinol, in treating the periorbital wrinkles of 11 Korean women over the age of 30. The researchers observed a statistically significant reduction in facial wrinkles in all 11 participants. Compared to 0.075 percent retinol cream, 0.06 percent retinyl retinoate treatment over three months resulted in diminished wrinkle depth and size. In addition, the test cream outperformed retinol by 22 percent in terms of visual wrinkle improvement and the maximum roughness improvement rate. The authors concluded that retinyl retinoate reduced facial wrinkles while exhibiting greater photostability and provoking less irritation than earlier generations of retinoids.45
A year earlier, several of the same team performed two similar clinical studies, with a total of 46 Korean women with periorbital wrinkles. Twenty-four subjects applied 0.06 percent retinyl retinoate to one side of the face twice daily and a placebo ointment to the other side for 12 weeks in the first study. Twenty-two patients in the second study, conducted over eight weeks, applied 0.06 percent retinyl retinoate twice daily to one side of the face and 0.075 percent retinol to the other side. Assessments by investigators and subjects indicated greater improvements in wrinkles on skin treated with retinyl retinoate compared to placebo or retinol, with no reported side effects. In addition, average roughness was significantly diminished by retinyl retinoate based on skin replica analysis. The investigators concluded that twice-daily application of retinyl retinoate was significantly more effective in treating periorbital wrinkles than placebo or retinol.46
Erythema, skin irritation, and desquamation are the most common adverse side effects of topical retinoids. The type and dose of retinoid influences such reactions, which typically occur within two to four days of beginning topical treatment.47 When retinoid products were first commercialized, many believed that the redness and inflammation were a prerequisite for improvement of aged skin. It has now been established that benefits can be derived from using retinoids without incurring irritation. Indeed, the attenuating effects on photoaging can be separated from the irritation reliably produced by retinoids. Griffiths et al. showed this in 1995 in their double-blind, vehicle-controlled experiment with two different strengths of tretinoin (0.1 and 0.025 percent) used to treat photoaging. Although the formulations were equally efficacious, the degree of irritation varied substantially between the two treatment groups, with the 0.1 percent tretinoin-treated group displaying almost a threefold greater incidence of irritation than those treated with the 0.025 percent preparation.32 New ingredients are being investigated to block the irritation of retinoids without affecting the efficacy.
Erythema, flushing, and facial stinging – common side effects of topical retinoids – can be reduced by applying the retinoid on top of a moisturizer to limit penetration and by decreasing the amount and frequency of application until the retinoid can be tolerated as tachyphylaxis occurs. Care should be taken when designing the skin care regimen to include anti-inflammatory ingredients and reduce ingredients that increase skin penetration when retinoid treatments are being initiated.
It is well established that teratogenicity is a significant risk associated with the use of oral retinoids. Long debated is the advisability of topical retinoid use by women of childbearing age due to the potential risk of systemic absorption. As a general rule, great care should be taken when prescribing retinoids (even OTC retinol) to women of childbearing age, although no studies have convincingly demonstrated harm from use during pregnancy. A 1993 study by Jick et al. demonstrated no significant rise in the fetal malformation rate in 215 women treated with topical tretinoin during the first trimester of pregnancy, as compared with 430 age-matched nonexposed women.48
The topical application of tretinoin has been thought by many to augment photosensitivity because its daily use engenders thinning of the SC, rendering it more compact. Such concern arose partly as a result of admonitions to early tretinoin users to apply the product only at night. This warning was based solely on the poor stability of tretinoin upon UV light exposure. Retinoids are now known not to have photosensitizing or phototoxic properties, and may actually protect the skin from the deleterious sequelae of UV exposure.27
There is no environmental impact of commercial topical retinoid formulation manufacture known by the author.
It is important to understand that not all retinol-containing products are equal. Retinol is very unstable and loses biologic activity on exposure to UV light, air, heat, water, and lipid peroxidation.46 When it is formulated and packaged retinol must remain in an airless system with no exposure to light. Proper packaging of retinol is in an aluminum tube with a small mouth or an airless pump. Retinol must be manufactured, formulated, and packaged properly to avoid oxidation and loss of potency. Also, the amount of retinol in the product must be high enough to be effective. New stabilized forms of retinol have been shown to exhibit greatly increased efficacy in aging skin.49 Nanoparticles have displayed potential in enhancing the efficacy, stability, and tolerability of retinoid agents, particularly those more prone to elicit irritant reactions such as tretinoin and tazarotene.50
In 2011, Ourique et al. showed that nanoencapsulation of tretinoin with lipid-core polymeric nanocapsules yielded improved photostability, with hydrogels containing nanoencapsulated tretinoin manifesting a half-life seven times longer than the nonencapsulated tretinoin after eight hours of UVA irradiation. Their experiments also revealed that nanoencapsulation led to extended retention of the drug on the skin surface and decreased skin permeation.51
The side effects commonly seen in patients on retinoid therapy can usually be alleviated by directing the patient to apply small amounts of the retinoid at less frequent intervals. The lowest available dose should be started initially. For individuals with sensitive skin, topical retinol can be used every third night for the first two weeks. If no redness or irritation results, the retinoid can be increased to every other night for two weeks. Eventually most patients can tolerate nightly use. Once the patient is consistently applying the retinol nightly, the strength of the retinol can be increased. Once the maximal retinol strength is reached, the patient can be seamlessly switched to a prescription retinoid if desired.
A 1997 study by Olsen et al. suggested that after a 48-week regimen of once-daily 0.05 percent tretinoin emollient cream, the benefits of tretinoin could be sustained by at least three applications each week for an additional 24 weeks. The investigators found that once-weekly treatment was insufficient for maintaining the previously seen clinical improvement. In addition, they noted that discontinuation of therapy for 24 weeks led to the abrogation of the earlier benefits derived from the tretinoin regimen.52
Although tretinoin has long been approved for the treatment of photoaging, evidence suggests that it also plays a role in the prevention of cutaneous aging. The inhibitory effects of retinoids on harmful matrix metalloproteinases (MMPs) are thought to be responsible for this potential benefit. UVB exposure dramatically upregulates MMP synthesis. Activation of the genes of these collagen-degrading enzymes leads to the production of collagenase, gelatinase, and stromelysin, all of which have been shown to fully degrade cutaneous collagen.53 Fisher et al. showed in 1996 that topical tretinoin application suppresses the induction of all three of these detrimental MMPs.27
In addition to elevating MMP levels, UV exposure has also been demonstrated to reduce collagen production. In 2000, Fisher et al. showed that expression of collagen types I and III was markedly diminished within 24 hours after one UV exposure. They found that pretreating the skin with tretinoin mitigated such a decline in procollagen production.54 Consequently, the consistent pretreatment of skin with topical retinoids is thought to likely contribute to the prevention as well as treatment of photodamage.55
Significantly, the use of topical retinoids (especially tretinoin, isotretinoin, and tazarotene) is the only therapeutic option established through randomized clinical trials to improve the clinical appearance of photoaged skin. In addition, to elaborate on the above, topically applied retinoids show indications of being able to prevent photoaging and possibly altering the course, and blunting the effects, of intrinsically aging skin.56 It is important to note that, to date, the cogent evidence in support of topical retinoids for photoaging correlates to mild-to-moderate photodamage.20
Stabilized, Low-irritancy Retinol
Tucker-Samaras et al. conducted an eight-week, double-blind, split-face, randomized clinical study in 2009 to evaluate the effects of once-daily application of stabilized 0.1 percent retinol-containing moisturizer in 36 subjects with moderate facial photodamage. The vehicle was used in 28 control subjects. With some improvement evident and significant at week 4, after eight weeks, the retinol moisturizers were found to be significantly more efficacious than the vehicle in reducing overall signs of photodamage, specifically improving elasticity and firmness and diminishing lines and wrinkles. The investigators concluded that a stabilized retinol formulation was safe and effective in enhancing the appearance of photoaged facial skin.40
Also that year, Kikuchi et al. conducted a randomized, blinded, vehicle-controlled study to assess the efficacy of once-nightly applied 0.075 percent retinol cream in treating mild photoaging in 57 middle-aged Japanese females. Fifty-four of 57 participants completed the 26-week study, with three withdrawing due to irritation. Signs of photoaging (fine and deep wrinkling) were significantly reduced on the retinol-treated side of the face versus control [27 on retinol (50 percent) vs. 13 (24 percent) for fine wrinkling and, for deep wrinkling, 15 (28 percent) vs. 1 (2 percent)].
The investigators also led a 13-week study using a 0.04 percent retinol cream, with less salient improvements in fine wrinkling revealed but minimal irritation elicited. They concluded that retinol creams, particularly the 0.04 percent formulation, are appropriate for daily use, even by those with sensitive skin, because of low irritancy.57
In a 2010 literature review of combination treatments for photoaging, Tierney and Hanke identified 10 studies documenting histologic evidence that several combination approaches, including the use of topical retinoids, yielded cutaneous repair of photodamaged skin.58 Retinoids should be combined with daily sunscreen, antioxidants, and other treatment solutions depending on the patient’s skin type.
Retinoid therapy is appropriate for all patients that are wrinkle-prone types within the BSTS. OTC retinol appears to be just as effective as prescription retinoids in conferring improvement to photoaged skin, but with less irritation. The author recommends combining retinol with an antioxidant and a daily sunscreen for optimal benefit. Patients should be carefully instructed on the use of retinoids and taught to slowly increase the frequency, amount used, and strength to avoid excessive irritation. They should be educated that retinoids do not increase sun sensitivity and can help protect them from the ravages of UV exposure. Care should be taken to recommend a retinol that has a stable formulation and proper packaging. The product should be discarded after six months because retinol loses its activity, especially after being opened. RP is less effective than other retinoids and its safety is a controversial issue; for this reason the author recommends avoiding retinyl palmitate and other retinyl esters.
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