Sun Protection/Photoaged Skin/Wrinkles

Topical Melatonin: Protective Effects Against UV Radiation

Ultraviolet (UV) radiation is the main etiologic factor for skin cancer. The endogenous hormone melatonin has been proposed to have protective effects against sunlight and topically-applied melatonin has a protective effect against UV-induced erythema. Four human studies and 16 experimental studies evaluated melatonin's protective effect against UVR-induced damage to cellular structures and pathways. Melatonin acts directly as an antioxidant, and indirectly by regulating gene expression and inducing a DNA stabilizing effect. The destructive effects of the UVR are significantly counteracted or modulated by melatonin in the context of a complex intracutaneous melatoninergic anti-oxidative system with UVR-enhanced or UVR-independent melatonin metabolites. Therefore, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin or metabolites would be expected to represent one of the most potent anti-oxidative defense systems against the UV-induced damage to the skin. Treatment of the skin with melatonin 15 minutes before UV irradiation proved to almost completely suppress the development of an UV-induced erythema. In contrast, no significant protective effects of melatonin were observed when it was applied after UV irradiation. Free radical scavenging of UV-generated hydroxyl radicals and interference with the arachidonic acid metabolism are possible mechanisms of the melatonin action.

Following topical application of 0.1% melatonin solution, plasma melatonin levels increased but did not exceed the physiological night peak.

Photodermatol Photoimmunol Photomed. 2014 Aug;30(4):180-8.
Melatonin's protective effect against UV radiation: a systematic review of clinical and experimental studies.

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Int J Mol Sci. 2014 Sep 30;15(10):17705-32.
Local melatoninergic system as the protector of skin integrity.
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Dermatology. 1997;195(3):248-52.
Suppression of UV-induced erythema by topical treatment with melatonin (N-acetyl-5-methoxytryptamine). Influence of the application time point.
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Br J Dermatol. 2004 Feb;150(2):341-5.
Melatonin increases anagen hair rate in women with androgenetic alopecia or diffuse alopecia: results of a pilot randomized controlled trial.
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Cosmeceuticals for Aging Skin

Skin aging includes intrinsic and extrinsic processes, with cell damage caused by metabolic processes, free radicals and cosmic irradiation. Topical and oral administration of antioxidants such as vitamins E and C, coenzyme Q10, alpha-lipoic acid and glutathione enhance anti-aging effects. Other antioxidants such as green tea, dehydroepiandrosterone, melatonin, selenium and resveratrol, have also age management and anti-inflammatory effects. Topical bleaching agents such as hydroquinone, kojic acid and azelaic acid can help reduce signs of aging. Studies confirm the efficacy of these topical agents in combination with superficial and/or medium depth or deep peeling agents for photodamaged skin treatment. Based on individual patient needs, preparations may also contain retinoids, hydroxy acids, bleaching agents, moisturizers, and sunscreens.

Coll Antropol. 2010 Sep;34(3):1145-53.
Modern approach to topical treatment of aging skin.
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Topical Palmitoyl Pentapeptide Provides Improvement in Photoaged Human Facial Skin

Palmitoyl pentapeptide is a synthetic topical agent designed to stimulate collagen production and thus provide a skin anti-wrinkle benefit. To determine if palmitoyl pentapeptide is effective, a clinical study was conducted with 93 Caucasian female subjects, aged 35-55. They participated in a 12-week, double-blind, placebo-controlled, split-face, left-right randomized clinical study assessing two topical products: moisturizer control product vs. the same moisturizer product containing 3 ppm palmitoyl pentapeptide. Palmitoyl pentapeptide was well tolerated by the skin and provided significant improvement vs. placebo control for reduction in wrinkles/fine lines by both quantitative technical and expert grader image analysis. In self-assessments, subjects also reported significant fine line/wrinkle improvements and noted directional effects for other facial improvement parameters.

Int J Cosmet Sci. 2005 Jun;27(3):155-60.
Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin.
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Topically applied antioxidants exert their benefits by offering protection from damaging free radicals produced when skin is exposed to ultraviolet light or allowed to age naturally. Appropriate formulation and use which is supervised by a knowledgeable healthcare professional will maximize the benefits while minimizing any potential side effects of these therapies.

Biofactors 1999;9(2-4):371-8
Coenzyme Q10, a cutaneous antioxidant and energizer.
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Coenzyme Q10 (ubiquinone, CoQ10) is an important antioxidant that is taken to strengthen immune and cardiac function. The processes of aging and photoaging of the skin (due to sunlight) are associated with an increase in cellular oxidation, which may occur as the body’s own levels of CoQ10 decline. A reduction in wrinkle depth was shown following topical application of CoQ10 0.3%, and results indicated that CoQ10 has the efficacy to prevent many of the detrimental effects of photoaging. Wrinkles around the region of the eyes (“crow’s feet”) may be reduced by long-term application of CoQ10.

Z Gerontol Geriatr 1999 Apr;32(2):83-8
Modulation of oxidative stresses in human aging skin
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Vitamin C has been incorporated into a variety of cosmeceuticals designed to protect and rejuvenate photoaged skin. Ascorbyl Palmitate (Vitamin C Ester) is a lipid soluble, neutral pH, non-acidic (thus, non-irritating and non-stinging) form of Vitamin C which can reach cells within the skin rapidly in amounts greater than can be achieved by water soluble Vitamin C (L-Ascorbic Acid).

Dermatol Surg. 2005 Jul;31(7 Pt 2):814-7
Topical vitamin C: a useful agent for treating photoaging and other dermatologic conditions.
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Alpha Lipoic Acid (ALA) is a powerful antioxidant and scavenger with anti-inflammatory properties that promotes optimum efficiency for production of energy and removal of intracellular waste products, essential for cellular healing and elimination of wrinkles and facial scars. Twelve weeks of treatment with a cream containing 5% ALA improves clinical characteristics related to photoaging of facial skin.

Br J Dermatol. 2003 Oct; 149(4): 841-9
Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alpha-lipoic acid related to photoageing of facial skin.
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Topical niacinamide 5% (vitamin B3) reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin.

Int J Cosmet Sci. 2004 Oct;26(5):231-8.
Topical niacinamide reduces yellowing, wrinkling, red blotchiness, and hyperpigmented spots in aging facial skin.
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Topical 2% progesterone increases elasticity and firmness in the skin of peri- and postmenopausal women.

Br J Dermatol. 2005 Sep;153(3):626-34.
Effects and side-effects of 2% progesterone cream on the skin of peri- and postmenopausal women: results from a double-blind, vehicle-controlled, randomized study.
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DMAE (2-dimethylaminoethanol, deanol), when applied topically to the skin, may improve the appearance of sagging skin, boost the effects of other antioxidants, increase smoothness, reduce fine lines and give facial muscles a leaner look. In a randomized clinical study, 3% DMAE facial gel applied daily for 16 weeks has been shown to be safe and efficacious in the mitigation of forehead lines and periorbital fine wrinkles, and in improving lip shape and fullness and the overall appearance of aging skin.

Br J Dermatol. 2007 Mar;156(3):433-9.
The antiwrinkle effect of topical concentrated 2-dimethylaminoethanol involves a vacuolar cytopathology.
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Am J Clin Dermatol. 2005;6(1):39-47.
The role of dimethylaminoethanol in cosmetic dermatology.
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Antioxidants such as vitamins E and C, coenzyme Q10, alpha-lipoic acid, glutathione, and others can help reduce signs of aging.

Acta Dermatovenerol Alp Panonica Adriat. 2008 Jun;17(2):47-54.
Skin aging.
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Alpha-lipoic acid (ALA) 0.5% and proanthocyanidin (PA) 0.3% administered transdermally in a cosmetic formulation supplemented with 2% benzyl alcohol as a penetration enhancer, significantly enhanced collagen synthesis and deposition.

Connect Tissue Res. 2005;46(4-5):251-7.
Transdermal delivery of amino acids and antioxidants enhance collagen synthesis: in vivo and in vitro studies.
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Topical Application of Phytonadione, Retinol and Vitamins C and E to Reduce Infraorbital Dark Circles and Wrinkles of the Lower Eyelids

Infraorbital dark circles and wrinkles of the lower eyelids are cosmetic problems that worsen with age. Fifty-seven healthy adult volunteers with dark under-eye circles and wrinkles were enrolled in an open label study to determine whether a gel containing 2% phytonadione, 0.1% retinol and 0.1% vitamins C and E is effective in reducing dark under-eye circles and wrinkles of the lower eyelids. The gel formulation was applied twice daily to the lower eyelid site for 8 weeks. Hemostasis, pigmentation and wrinkles were evaluated by a physician and by the patients after 4 and 8 weeks of treatment. Topical application of the gel decreased not only hemostasis but also wrinkles after 8 weeks of treatment. Of 57 patients, 27 (47%) had reductions in hemostasis. However, pigmentation was not clearly removed by this gel.

J Cosmet Dermatol. 2004 Apr;3(2):73-5
The effects of topical application of phytonadione, retinol and vitamins C and E on infraorbital dark circles and wrinkles of the lower eyelids.
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Protection and Reversal of Photodamage with Topical Antioxidants

Topical vitamins C and E, as well as topical selenium, protect skin against sunburn, suntan and skin cancer and also reverse the mottled pigmentation and wrinkles of photoaging. However, only certain forms of these antioxidants are stable and active after percutaneous absorption. Benefits of topical application are that the skin attains far higher levels of each antioxidant than can be achieved by taking these vitamins orally and topical application arms the skin with a reservoir of antioxidants that cannot be washed or rubbed off, protecting the skin for several days after application.

J Cosmet Dermatol. 2004 Jul;3(3):149-55
Photodamage of the skin: protection and reversal with topical antioxidants.
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Topical application of niacinamide (such as in a 2% cream) has a stabilizing effect on epidermal barrier function, seen as a reduction in transepidermal water loss and an improvement in the moisture content of the horny layer, and it may be used as a treatment adjunct in atopic dermatitis. In aging skin, topical application of niacinamide improves the surface structure and pigmentary disorders, smoothes out wrinkles and inhibits photocarcinogenesis.

Cutis 2006 Jan;77(1 Suppl):11-6.
Pharmacologic doses of nicotinamide in the treatment of inflammatory skin conditions: a review.
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Int J Dermatol 2005 Mar;44(3):197-202.
Moisturizing effects of topical nicotinamide on atopic dry skin.
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J Cosmet Dermatol 2004 Apr;3(2):88-93
Nicotinic acid/niacinamide and the skin.
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Niacinamide can be combined with other active ingredients such as DMAE, sodium hyaluronate, benzoyl peroxide, or metronidazole in a customized medication that can be used as anti-wrinkle or age management therapy or to treat acne or rosacea.

Br J Dermatol. 2003 Oct; 149(4): 841-9
Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alpha-lipoic acid related to photoageing of facial skin.
Click here to access the PubMed abstract of this article.


Estrogen Therapy to Prevent or Reverse Skin Aging


Declining estrogen levels are associated with a variety of cutaneous changes, many of which can be reversed or improved by topical or systemic estrogen supplementation. Studies of postmenopausal women indicate that estrogen deprivation is associated with declining dermal collagen content, diminished elasticity and skin strength, loss of moisture in the skin, epidermal thinning, atrophy, fine wrinkling, and impaired wound healing. Keratinocytes, Langerhans' cells, melanocytes, sebaceous glands, collagen content and the synthesis of hyaluronic acid are under hormonal influence. Estrogen may attenuate inflammation in psoriatic lesions. Alone or together with progesterone, estrogen prevents or reverses skin atrophy, dryness and wrinkles associated with chronological or photo-aging. Estrogen and progesterone stimulate proliferation of keratinocytes while estrogen suppresses apoptosis and thus prevents epidermal atrophy. Estrogen maintains skin moisture by increasing acid mucopolysaccharide or hyaluronic acid levels in the dermis, and accelerates cutaneous wound healing.

Low estrogen levels that accompany menopause exacerbate the deleterious effects of both intrinsic and environmental aging. Estrogens clearly have a key role in skin aging homeostasis as evidenced by the accelerated decline in skin appearance seen in the perimenopausal years.

At Yale University School of Medicine, the effects of long-term hormone replacement therapy (HRT) on skin rigidity and wrinkling at 11 facial locations was assessed using the Lemperle scale by a plastic surgeon who was blinded to HRT use. Skin rigidity at the cheek and forehead was measured with a durometer. Demographics including age, race, sun exposure, sunscreen use, tobacco use, and skin type were similar. Rigidity was significantly decreased in HRT users compared to nonusers at both the cheek and forehead. Average wrinkle scores were lower in hormone users than in nonhormone users. The study concluded that long-term postmenopausal HRT users have more elastic skin and less severe wrinkling than women who never used HRT, suggesting that hormone therapy may have cosmetic benefits.

In another study, the dermal collagen of 15 postmenopausal women who had received systemic estrogen replacement was analyzed before and after using a topical 0.01% estrogen treatment. Epithelial and dermal thickness improved after topical estrogen therapy. Facial skin collagen significantly increased after 16 weeks of treatment. Systemic estrogen levels did not significantly increase after topical therapy.


Exp Dermatol. 2004;13 Suppl 4:36-40
Skin aging and sex hormones in women -- clinical perspectives for intervention by hormone replacement therapy.
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Exp Dermatol. 2006 Feb;15(2):83-94
Biology of estrogens in skin: implications for skin aging.
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Eur J Obstet Gynecol Reprod Biol. 2006 Jun 22

J Am Acad Dermatol. 2005 Oct;53(4):555-68; quiz 569-72
Estrogen and skin: the effects of estrogen, menopause, and hormone replacement therapy on the skin.
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Fertil Steril. 2005 Aug;84(2):285-8
Long-term effects of hormone therapy on skin rigidity and wrinkles.
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Am J Clin Dermatol. 2003;4(6):371-8
Skin aging and menopause : implications for treatment.
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Am J Clin Dermatol. 2001;2(3):143-50
Estrogen and skin. An overview.
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J Dermatol Sci. 2005 Apr;38(1):1-7
Regulatory roles of sex hormones in cutaneous biology and immunology.
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A low-dose, topical gel form of diclofenac sodium has been developed in Europe for pain relief and reduction of redness after sunburn.

Eur J Dermatol. 2004 Jul-Aug;14(4):238-46
The efficacy and safety of low-dose diclofenac sodium 0.1% gel for the symptomatic relief of pain and erythema associated with superficial natural sunburn.
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