Tretinoin

Long a well-established treatment for acne, tretinoin, a form of vitamin A, is also highly effective as an anti-aging ingredient. It improves wrinkles, brightens and smooths the complexion, lightens age spots and tightens sagging skin.

Effects


Grade Level of Evidence
A Multiple double-blind, controlled clinical trials.
B 1 double-blind, controlled clinical trial.
C At least 1 controlled or comparative clinical trial.
D Uncontrolled, observational, animal or in-vitro studies only.
Grade Effect Size of Effect Comments

A

Wrinkle treatment

Strong

Improves fine and coarse wrinkles by restoring dermal collagen and stimulating glycosaminoglycan synthesis.

A

Smoother skin

Strong

Diminishes skin roughness, presumably via a combination of an increase in epidermal thickness, compaction of the stratum corneum and deposition of GAGs.

A

Tighter skin

Strong

Tightens loose and sagging skin, possibly by stimulating the secretion of a basic fibroblast growth factor.

A

Acne treatment

Strong

Reduces comedones, papules and pustules, and is often prescribed for mild to moderate cases of acne vulgaris.

A

Skin lightening

Moderate

Decreases the darkness of brown spots and lentigines by reducing epidermal pigmentation. Also pinkens sallow skin.

B

Increased skin thickness

Mild

Makes the stratum corneum more compact and thickens the epidermal layer.

B

Reduced actinic keratoses

Mild

0.1% tretinoin cream led to fewer actinic keratoses in a double-blind, placebo-controlled trial.

C

Melasma treatment

Moderate

Depigments skin by dispersing keratinocyte pigment granules and interfering with pigment transfer and production.

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Scientific Research


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Table of contents:

1. Sources

Tretinoin, also known as all-trans retinoic acid, is a metabolite of Vitamin A (retinol). It is produced in the body from other retinoids that are ingested, such as retinol, retinyl esters and carotenoids.[1] It is also the main bioactive component of rosehip seed oil, in which its concentration has been found to be at least 0.357 ml/L.[2]

2. Bioavailability

Tretinoin penetrates poorly into the skin. When topically applied, approximately 80% of tretinoin remains on the skin surface, and its penetration through the stratum corneum is vehicle-dependent.[3]

While gel-based formulations of tretinoin tend to trap the molecule, keeping it on the surface of the skin, cream formulations increase penetration to a small extent (less than 5% of the applied amount within 30 minutes).[1] The initial diffusion into the stratum corneum takes place relatively rapidly within a few minutes, but further diffusion into the epidermis and dermis proceeds more slowly.[4]

Nano-lipoidal carriers such as solid lipid nanoparticles and nanostructured lipidic carriers have been shown to enhance the photostability and skin delivery of tretinoin.[5]

3. Effects on the skin

3.1 Anti-wrinkle effect

Tretinoin is the benchmark prescription topical treatment for improving fine facial wrinkles.[6]

In 2 randomized, double-blind, vehicle-controlled clinical trials, a total of 360 subjects with photodamage were treated with once-nightly applications of 0.02% tretinoin cream or a placebo. The results indicated that 0.02% tretinoin cream led to statistically significant improvements in fine wrinkles and coarse wrinkles by the end of 24 weeks.[7] The findings are supported by a separate 24-week study in which wrinkle appearance was significantly improved based on both expert grading and digital image analysis, after application of Renova, a 0.02% tretinoin in an emollient base every evening, along with Neutrogena Healthy Defense Daily Moisturiser, an SPF 30 moisturizing sunscreen.[6] Other studies comparing tretinoin with different wrinkle treatments have also reported that tretinoin complexed with cyclodextrin led to improvements in wrinkle score assessments, wrinkle area measurements and skin elasticity.[8][9]

There is evidence that collagen synthesis is affected in photodamaged skin, and that topical tretinoin use partially restores this reduction of dermal collagen.[10] As treatment is continued beyond 24 months, collagen organization continues to improve.[11] Retinoic acid therapy also increases the capacity of the epidermis to hold water by stimulating the production of hyaluronic acid in the epidermis,[12][13][14] though in the dermis it may have the opposite effect.[15] In addition, tretinoin also inhibits some metalloproteinases responsible for dermal collagen degradation.[16] Specifically, tretinoin has been found to inhibit UVA-induced matrix metalloproteinase-1 (MM1), the only enzyme active at neutral pH that can degrade interstitial collagen,[17] in human skin fibroblasts.[18] These may be the pathways by which tretinoin results in wrinkle effacement at the clinical level.

3.2 Lightening effect

Solar lentigines are benign, hyperpigmented lesions that present in many middle-aged and elderly patients with chronic accumulated sun exposure.[19] Early studies demonstrated that 0.1% tretinoin cream reduced the coloration of brown spots and lentigines in patients,[20] and decreased the number of discrete lentigines.[21] When applied to the face and upper extremities, lesions that disappeared during 10 months of therapy did not return for at least 6 months after therapy is discontinued.[22] 0.05% tretinoin cream (Retin-A) has also been assessed to be effective in improving lentigines in Australian skin.[23]

Combination topical therapy using 2% mequinol and 0.01% tretinoin has been shown to markedly reduce the darkness of solar lentigines lesions on the face and forearm, in a randomized, double-blind study of 216 subjects.[24] In 2 other randomized, controlled, double-blind trials, this combination was also found to be more efficacious than each of its active components and the vehicle in the treatment of solar lentigines, except versus tretinoin on the face.[25] The lightening effect appears to be relatively long-lasting when the solution is applied to the back of the hands, for it is maintained for at least 2 months after stopping treatment.[26] This combination therapy has also been establised as effective and safe in Asian, Latin/Hispanic and African American ethnic groups, and in those with dark skin types.[27]

It has been suggested that 2% mequinol and 0.01% tretinoin therapy can also be considered as maintenance therapy following another treatment, such as ablative therapy with cryotherapy, as the primary therapy.[28]

Histologic analysis has evidenced that tretinoin reduces epidermal pigmentation, which is significantly correlated with the degree of clinical lightening of the lesions.[22]

3.3 Smoothing effect

Computerized image analysis of silicone replicas has been used to show that tretinoin emollient cream improves skin topography and smooths skin surface in subjects treated for 24 weeks.[29] 0.05% tretinoin emollient cream has been found to diminish tactile roughness in 16 weeks,[30] and to further improve roughness features after 44 weeks.[31] Areas where improvements have been noted after 0.05% tretinoin cream application include the face, neck, forearms and hands.[23]

Lower concentrations also appear to be effective. 0.02% tretinoin cream alone, applied daily for 52 weeks, also achieved improvements in tactile roughness of the face at 3, 6, 9 and 12 months.[32] When 0.025% tretinoin cream was applied once daily to the neck and chest along with twice daily application of a proprietary copper zinc malonate lotion and 4% hydroquinone cream (Obagi ELASTIderm Décolletage System), significant improvements in tactile roughness were found from the second week onward.[33] Even at 0.01% concentration, tretinoin emollient cream also reduced roughness when applied to the forearms after 24 and 48 weeks.[34] 0.001% concentration however showed little difference from vehicle.[29]

It has been hypothesized that the effect of tretinoin in skin smoothening results from a combination of epidermal changes including an increase in epidermal thickness, compaction of the stratum corneum and deposition of glycosaminoglycans.[35]

3.4 Tightening effect

Tretinoin is frequently prescribed for its dermal tightening effects.[36] 0.05% tretinoin cream has been shown to ameliorate skin looseness after 6 months of treatment.[37][38] Another randomized, double-blind, vehicle-controlled study supported this finding, showing that significant reductions in skin laxity were observed after 0.05% tretinoin therapy.[39] Efficacy was also shown in photodamaged Australian skin, with significant improvements in laxity noted in a separate multicentre clinical trial.[23] This effect appears to occur soon after starting treatment, with one study noting that patients may observe a tightening of the skin as early as the first month of treatment, and that after 6 months or longer, sagging skin, especially in the area around the eyes, may begin to tighten.[20] A smaller study has also demonstrated that 0.1% tretinoin cream appears to decrease the length, width and severity of stretch marks, as evaluated by physical examinations and analyses of biopsies, when applied daily for 6 months to the affected areas.[40]

In a study on dermal fibroblasts, tretinoin seemed to stimulate the secretion of basic fibroblast growth factor, and this has been postulated as a partial explanation of tretinoin's clinically observed tightening effects.[36]

3.5 Improvement of sallow skin

Skin sallowness (yellowing) is a characteristic of photoaging.[41] Topical tretinoin has been demonstrated to induce the pinkening of sallow skin in patients.[42] 0.1% tretinoin microsphere gel[43] and 0.05% tretinoin emollient cream[37][44] have both been shown to improve skin yellowing to a statistically significant extent. 2 randomized, double-blind clinical studies have also indicated that 0.02% tretinoin cream led to statistically significant reductions in skin yellowing at the end of 24 weeks,[7][45] showing that lower concentrations of tretinoin are also effective.

One of the first studies on the use of topical tretinoin to reverse photodamage noted changes in the histologic structure and function of the skin, including an increase in epidermal thickness and a decrease in the atypia of the keratinocytes.[20] This was confirmed in a subsequent double-blind, placebo-controlled trial of 0.1% tretinoin cream, which also found that it reduced the number of actinic keratoses, among other improvements.[46]

3.7 Epidermal melasma treatment

Melasma is a common disorder of hyperpigmentation that generally involves areas of the face and neck. It is characterized by patches of light brown or gray-brown patches on sun-exposed skin.[47] Tretinoin monotherapy has produced a good therapeutic response in clinical trials[48][49] but better results are obtained in combination with other agents.[50]

Multiple studies have investigated the efficacy and tolerability of treating melasma using tretinoin together with other compounds. Triple combination (TC) cream consisting of 0.01% fluocinolone acetonide, 4% hydroquinone and 0.05% tretinoin has been tested extensively in both short and long-term trials for the treatment of melasma. In one 12-month long study, 585 patients were instructed to apply TC cream on a daily basis. 327 patients completed 12 months of treatment, and clinically significant improvements in melasma were reported -- by month 12, 80% of patients had lesions completely or nearly cleared.[51] TC cream has also been demonstrated to be more effective than 4% hydroquinone cream in the treatment of moderate to severe facial melasma,[52] with its superior efficacy confirmed in a separate experiment on Asian patients.[53] Another study combined intense pulsed light (IPL) sessions with TC cream treatment and concluded that the combination led to significant improvements in the reduction of melasma area and severity versus treatment with TC cream alone.[54]

To reduce the side effects of treatment with tretinoin and hydroquinone, one split-face study utilized silicone sheets containing both actives on 24 women and compared the results and tolerability to conventional treatment with tretinoin and hydroquinone. The silicone sheets were found to improve epidermal melanosis to the same extent as conventional treatment, but with fewer occurrences of skin irritation.[55] The tolerability of 0.05% topical tretinoin has also been shown to be improved by the use of a SPF 30 facial moisturizer, specifically Cetaphil Dermacontrol Moisturizer.[56]

Tretinoin's depigmentation ability is due to its ability to disperse keratinocyte pigment granules, interfere with pigment transfer, and accelerate epidermal turnover and therefore, pigment loss.[57] There is also evidence that it inhibits the induction of tyrosinase, the rate-limiting enzyme controlling melanin production.[58]

3.8 Acne vulgaris treatment

Topical tretinoin is a well-established treatment for acne vulgaris.[59] A 2013 study of treatment of preadolescent acne in the United States found topical tretinoin to be a leading medication, prescribed in 12.5% of cases.[60]

Historically, tretinoin has been used as a comedolytic agent to treat mild to moderate cases of acne vulgaris.[61] Micronized 0.05% tretinoin gel and 0.1% tretinoin gel microsphere have both been shown to successfully reduce both inflammatory and non-inflammatory lesions.[62][63][64][65][66]

Tretinoin has also been combined with antibacterials to form topical combination treatments for acne.[61] An alcoholic erythromycin/tretinoin solution has been found to effectively reduce comedones, papules and pustules in a multicenter data investigation of 6,500 patients.[67] 1.2% clindamycin phosphate together with 0.025% tretinoin as a gel (CTG) also reduces comedogenesis, inflammation, and aids the healing of acne lesions.[68] This combination therapy appears to be more efficacious than tretinoin monotherapy[69] or clindamycin monotherapy,[70] and is similarly safe and tolerable.[70][71] Other combination therapies include 0.05% tretinoin + 50% aloe vera topical gel, which was found to be superior to tretinoin alone in the treatment of mild-to-moderate acne,[72] and a triple combination therapy with oral minocyline HCl, 1.2% clindamycine phosphate/0.025% tretinoin gel and 6% benzoyl peroxide foaming cloths for the treatment of moderate to severe acne.[73] It should be noted however, that the prolonged use of antibiotics such as clindamycin and erythromycin will promote the development of resistance, unlike a non-antibiotic antibacterial agent such as benzoyl peroxide.[74]

For patients of color, a trial comparing treatment with 1% clindamycin + 5% benzoyl peroxide topical gel in combination with 0.04% tretinoin topical gel, 0.01% tretinoin topical gel, or 0.1% adapalene topical gel, found a trend towards better resolution of hyperpigmentation among subjects receiving the clindamycin + benzoyl peroxide gel together with 0.04% tretinoin microsphere gel.[75] 1.2% clindamycin and 0.025% tretinoin gel has also been assessed to be an effective option for treating mild-to-moderate acne in patients with skin of color.[76] For Mexican patients, 0.05% tretinoin and 0.3% adapalene (separately) were found to be more effective than 0.1% adapalene, but 0.1% adapalene offers a better safety profile.[77]

Tretinoin's comedolytic-related activity has been known for many years.[61] It normalizes the exfoliation of the follicular epithelium within the pilosebaceous unit, inhibits transglutaminase activity that results in cellular adhesion, prevents follicular plugging, leads to drainage and expulsion of excess sebum, and helps create a more aerobic environment that is less conducive to P. acnes.[78][79][80] Tretinoin also appears to plays a role in phagocytosis by modulating macrophage function,[81] inhibiting proteolytic enzyme release,[82] suppressing respiratory burst and degranulation[83] and dampening the activity of nitric acid synthase,[84] all of which may contribute to its anti-acne activity.

3.9 Vitiligo treatment

Vitiligo is an autoimmune disorder characterized by the appearance of lighter patches of skin due to the loss of melanocytes.[85] While repigmentation through approaches such as phototherapy may be feasible in mild cases, if vitiligo involves most of the body, it may be easier to depigment the remaining normal skin.[86] Monobenzone is the most widely used depigmenting agent for this purpose, but a considerable number of vitiligo patients appear to be resistant against the depigmenting effect of monobenzone.[86] It has been found, however, that tretinoin is able to enhance the melanocytotoxic and depigmenting effects of monobenzone.[87]

Interestingly, a separate placebo-controlled, paired comparison, left-right study has also indicated that topical tretinoin + a combination of corticosteroids, may be a possible option for repigmentation in patients with vitiligo.[88]

4. Side Effects

4.1 Dermatitis

Dermatitis, characterized by dry skin, peeling, irritation and erythema, is a common side effect of tretinoin therapy. When the concentration of tretinoin is low, such adverse reactions tend to be of mild severity.[53][89][90] Given that tretinoin can be irritating, the dose must be adjusted to prevent inflammation, which may cause hyperpigmentation.[58] Reducing the concentration of tretinoin used in treatment also lowers the degree of irritation.[91] Further, the development of a tretinoin cyclodextrin complex in which tretinoin is encapsulated by cyclodextrin, has been shown to moderate irritant reactions compared to tretinoin alone, while possessing equal antiwrinkle effects.[8] The combined use of tretinoin and myristyl nicotinate, a lipid derivative of niacin also seems to improve tolerability by mitigating skin barrier impairment and protecting against transepidermal water loss associated with tretinoin therapy.[92]

4.2 Negligible risk of fetal anomalies

Tretinoin has been thoroughly evaluated for its potential as an human developmental toxicant.[93] Unlike isotretinoin, which is known to be teratogenic, studies suggest that the risk of malformations in human fetuses after topical application of tretinoin is negligible. This is due to the poor absorption of tretinoin from the skin, which yields maternal plasma concentrations below the developmentally toxic threshold.[94] One study which followed 106 pregnant women with first-trimester exposure to topical tretinoin found no significant differences in the birth outcomes of these women compared to 389 women with no topical tretinoin exposure, further confirming these results.[95]

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