به نام او كه سبزي و بهارراآفريد

1. به نام او كه سبزي و بهارراآفريد

2. Melasma Dr AnahitaVali Dermatologist & venereologist

3. Spring in Iran is so magical

5. What is melasma? • Melasma, sometimes called chloasma (which means green skin), appears as a symmetrical blotchy, brownish pigmentation on the face. The pigmentation is due to overproduction of melanin by the pigment cells, melanocytes. It can lead to considerable embarrassment and distress.

6. What is melasma? What are signs of melasma? • Melasma is a very common patchy brown, tan, or blue-gray facial skin discoloration, almost entirely seen in women in the reproductive years. It typically appears on the upper cheeks, upper lip, forehead, and chin of women 20-50 years of age. Although possible, it is uncommon in males. Over 90% of those with melasma are women. • primarily related to external sun exposure, external hormones like birth control pills, and internal hormonal changes as seen in pregnancy. Most people with melasma have a history of daily or intermittent sun exposure, although heat is also suspected to be an underlying factor. Melasma is most common among pregnant women, especially those of Latin and Asian descents. People with olive or darker skin, like Hispanic, Asian, and Middle Eastern individuals, have higher incidences of melasma.

7. Melasma facts • Melasma is most common in women 20-50 years of age. • Melasma looks like brown, tan, or blue-gray spots on the face (hyperpigmentation). • Melasma is characterized by three location patterns (central face, cheekbone, and jawline). • Melasma is caused partly by sun, genetic predisposition, and hormonal changes. • The most common treatment is topical creams containing hydroquinone. • Melasmaprevention requires sun avoidance and sun protection with hats and sunscreen.

8. An estimated 6 million women are living in the U.S. with melasma and 45-50 million women worldwide live with melasma. • Prevention is primarily aimed at facial sun protection and sun avoidance. • Treatment requires regular sunscreen application, medications such as 4% hydroquinone and fading creams.

10. What causes melasma? • The exact cause of melasma remains unknown. • triggered by several factors, including pregnancy, birth control pills, hormone replacement therapy(HRT and progesterone), family history of melasma, race, antiseizure medications, and other medications that make the skin more prone to pigmentation after exposure to ultraviolet (UV) light. • Uncontrolled sunlight exposure is considered the leading cause of melasma, especially in individuals with a genetic predisposition. individuals typically develop melasma in the summer months,. In the winter, the hyperpigmentation in melasma tends to be less visible. Heat, such as that experienced in a bakery or factory. • When melasma occurs during pregnancy, it is also called chloasma, or "the mask of pregnancy." Pregnant women experience increased estrogen, progesterone, and melanocyte-stimulating hormone (MSH) levels during the second and third trimesters of pregnancy. Melanocytes are the cells in the skin that deposit pigment. However, it is thought that pregnancy-related melasma is caused by the presence of increased levels of progesterone and not due to estrogen and MSH. postmenopausal women who receive progesterone hormone replacement therapy are more likely to develop melasma. Postmenopausal women receiving estrogen alone seem less likely to develop melasma. • products or treatments that irritate the skin may cause an increase in melanin production and accelerate melasma symptoms. • People with a genetic predisposition or known family history of melasma are at an increased risk of developing melasma. Important prevention methods for these individuals include sun avoidance and application of extra sunblock to avoid stimulating pigment production..

11. What are the types of melasma? • Four types of pigmentation patterns are diagnosed in melasma: epidermal, dermal, mixed, and an unnamed type found in dark-complexioned individuals. The epidermal type is identified by the presence of excess melanin in the superficial layers of skin. Dermal melasma is distinguished by the presence of melanophages (cells that ingest melanin) throughout the dermis. The mixed type includes both the epidermal and dermal type. In the fourth type, excess melanocytes are present in the skin of dark-skinned individuals.

12. Pathology • Occasionally, skin biopsy may be performed to confirm the diagnosis. Histology varies with the type of melasma. But some degree of each of the following features is usually found. • Melanin deposited in basal and suprabasalkeratinocytes • Highly dendritic (branched) deeply pigmented melanocytes • Melanin in the dermis within melanophages • Solar elastosis and elastic fibre fragmentation • The extent and severity of melasma can be described using the Melasma Area and Severity Index (MASI).

13. How is melasma diagnosed? • Melasma is usually readily diagnosed by recognizing the typical appearance of brown skin patches on the face. Dermatologists are physicians who specialize in skin disorders and often diagnose melasma by visually examining the skin. A black light or Wood's light (340-400 nm) can assist in diagnosing melasma, although is not essential for diagnosis. In most cases, mixed melasma is diagnosed, which means the discoloration is due to pigment in the dermis and epidermis. Rarely, a skin biopsymay be necessary to help exclude other causes of this local skin hyperpigmentation

14. Where is melasma seen on the body? • Melasma is characterized by discoloration or hyperpigmentation primarily on the face. Three types of common facial patterns have been identified in melasma, including • centrofacial (center of the face), • malar (cheekbones), and • mandibular (jawbone). • The centrofacial pattern is the most prevalent form of melasma and includes the forehead, cheeks, upper lip, nose, and chin. The malar pattern includes the upper cheeks. The mandibular pattern is specific to the jaw. • The upper sides of the neck may less commonly be involved in melasma. Rarely, melasma may occur on other body parts like the forearms. One study confirmed the occurrence of melasma on the forearms of people being given progesterone. This was a unique pattern seen in a Native American study.

15. Type of melasma • Clinical features • Epidermal • Well-defined border • Dark brown colour • Appears more obvious under black light • Responds well to treatment • Dermal • The most common type • Ill-defined border • Light brown or bluish in colour • Unchanged under black light • Responds poorly to treatment • Mixed • Combination of bluish, light and dark brown patches • Mixed pattern seen under black light • Partial improvement with treatment

16. DDX • Postinflammatory pigmentation • Solar lentigines and other forms of lentigo • Drug-induced pigmentation, e.g. due to minocycline • Lichen planus • Naevus of Ota.

17. Less common causes of melasma • Scented or deodorant soaps, toiletries and cosmetics may cause a phototoxic reaction triggering melasma that may then persist long-term. • A phototoxic reaction to certain medications may also trigger melasma. • Melasma has been associated with hypothyroidism (low levels of thyroid hormone).

18. COSMETIC- INDUCED MELASMA • Scented or deodorant soaps, toiletries and cosmetics may cause a phototoxic reaction triggering melasma that may then persist long-term.

19. What is the treatment for melasma? • The most common melasma therapies include 2% hydroquinone (HQ) creams like the over-the-counter productsEsoterica and Porcelana and prescription-strength 4% creams like Obagi Clear, Tri-Luma, NeoCutis Blanche, and 4% hydroquinone. Certain sunscreens also contain 4% hydroquinone, such as Glytone Clarifying Skin Bleaching Sunvanish SPF 23 and Obagi'sSunfader sunscreen. Products with HQ concentrations above 2% sometimes require a prescription or are dispensed through physician's practices. Clinical studies show that creams containing 2% HQ can be effective in lightening the skin and are less irritating than higher concentrations of HQ for melasma. These creams are usually applied to the brown patches twice a day. Sunscreen should be applied over the hydroquinone cream every morning. There are treatments for all types of melasma, but the epidermal type responds better to treatment than the others because the pigment is closer to the skin surface.

20. Hydroquinone is the compound most frequently used in skin whitening products. Due to concerns about its side effects, it was almost banned by the FDA in 2006, as there were medical issues of carcinogenicity and reports of disfiguring ochronosis.In the European Union Hydroquinone has been banned in cosmetic creams since 2000.

21. Exogenous ochronosis

22. Symptoms of Exogenous Ochronosis • Symptoms include: • yellow-brown, banana-shaped fibers • caviar-like papules • brown-grey or blue-black hyperpigmentation • The majority of the lesions will be seen on areas of the body that get the most sun.

23. Long term use of creams containing this compound may lead to exogenous ochronotic lesions. The duration of the use is directly proportional to the risk of developing the condition with most cases being after years of use.Around 10-15 million skin lightening products are sold annually, with Japan being the major buyer • Exogenous ochronosis can be caused from long term usage of certain ‘’skin lightening products’’, even if the hydroquinone is in amounts as small as 2%. • Skin lightening products are still prevalent in many parts of the world.Reasons for this may be due to aesthetic or social standing reasons, in areas where a lighter skin tone is considered to be a sign of wealth or beauty.As well, skin-lightening creams containing compounds such as hydroquinone are commonly used to help with hyperpigmentation disorders such as melasma

24. Treatment of Exogenous Ochronosis • Hydroquinone-induced exogenous ochronosis is an avoidable dermatosis that is exceedingly difficult to treat. However, some studies show that treatment may be possible with a Q-switched alexandrite (755 nm) laser. • It is recommended that individuals with this disorder stop using hydroquinone containing compounds.It is important to be aware of this as dermatologists may think the symptoms a patient is exhibiting are a melasma, and prescribe a hydroquinone containing cream.

25. There are three clinical stages of exogenous ochronosis: erythema and mild hyperpigmentation hypergimentation and ‘’caviar-like’’ lesions papulo-nodular lesions • Ochronosis is the syndrome caused by the accumulation of homogentisic acid in connective tissues. The phenomenon was first described by Rudolf Virchow in 1865.The condition was named after the yellowish (ocher-like) discoloration of the tissue seen on microscopic examination. However, macroscopically the affected tissues appear bluish grey because of a light scattering phenomenon known as the Tyndall effect. The condition is most often associated with alkaptonuria but can occur from exogenous administration of phenolcomplexes like hydroquinone.

26. Possible side effects of melasma treatments include • temporary skin irritation. People who use HQ treatment in very high concentrations for prolonged periods (usually several months to years) are at risk of developing a side effect called ochronosis. Hydroquinone-induced ochronosis is a permanent skin discoloration that is thought to result from use of hydroquinone concentrations above 4%. Although ochronosis is fairly uncommon in the U.S., it is more common in areas like Africa where hydroquinone concentrations upward of 10%-20% may be used to treat skin discoloration like melasma. • Regardless of the potential side effects, HQ remains the most widely used and successful fading cream for treating melasma worldwide. HQ should be discontinued at the first signs of ochronosis

27. What is the treatment of melasma? • Melasma can be very slow to respond to treatment, so patience is necessary. Start gently, especially if you have sensitive skin. Harsh treatments may result in an irritant contact dermatitis, and this can result in postinflammatory pigmentation. • Generally a combination of the following measures is helpful. • General measures • Discontinue hormonal contraception. • Year-round sun protection. Use broad-spectrum very high protection factor sunscreen of reflectant type and apply it to the whole face every day. Reapply every 2 hours if outdoors during the summer months. Alternatively or as well, use a make-up that contains sunscreen. Wear a broad-brimmed hat. • Use a mild cleanser, and if the skin is dry, a light moisturiser. This may not be suitable for those with acne. • Cosmetic camouflage (make-up) is invaluable to disguise the pigment.

28. Topical therapy • Tyrosinase inhibitors are the mainstay of treatment. The aim is to prevent new pigment formation by inhibiting formation of melanin by the melanocytes. • Hydroquinone 2-4% as cream or lotion, applied accurately to pigmented areas at night for 2 to 4 months. This may cause contact dermatitis (stinging and redness in 25%). It should not be used in higher concentration or for prolonged courses as it has been associated with ochronosis (a bluish grey discolouration). • Azelaic acid cream, lotion or gel can be used longterm, and is safe even in pregnancy. This may also sting. • Kojic acid is often included in formulations as they interact with copper, required by L-DOPA (a cofactor of tyrosinase). Kojic acid can cause irritant contact dermatitis and less commonly, allergic contact dermatitis. • Ascorbic acid (vitamin C) acts through copper to inhibit pigment production. It is well tolerated but highly unstable, so is usually combined with other agents. • New agents under investigation include mequinol, arbutin and deoxyarbutin (from berries), licorice extract, rucinol, resveratrol, 4-hydroxy-anisole, 2,5-dimethyl-4-hydroxy-3(2H)-furanone and/or N-acetyl glucosamine

29. Other active compounds in use include: • Topical corticosteroids such as hydrocortisone, work quickly to fade the colour and reduce the likelihood of a contact dermatitis caused by other agents. • Soybean extract, which is thought to reduce the transfer of pigment from melanocytes to skin cells (keratinocytes) and inhibit receptors. • Tranexamic acid is a lysine analogue that inhibits plasmin (this drug is usually used to stop bleeding) and reduces production of prostaglandins (the precursors of tyrosine). Tranexamic acid has been used experimentally for melasma as a cream or injected into the skin (mesotherapy), showing some benefit. It may cause allergy or irritation.

30. Superficial or epidermal pigment can be peeled off. Peeling can also allow tyrosinase inhibitors to penetrate more effectively. Agents to achieve this include: • Topical alpha hydroxyacidsincluding glycolic acid and lactic acid, as creams or as repeated superficial chemical peels, not only remove the surface skin but their low pH inhibits the activity of tyrosinase. • Topical retinoids, such as tretinoin are prescription medicines. They can be hard to tolerate and sometimes cause contact dermatitis. Do not use during pregnancy. • Salicylic acid , a common peeling ingredient in skin creams and can also be used for chemical peels but it is not very effective in melasma. • Currently, the most successful formulation has been a combination of hydroquinone, tretinoin, and moderate potency topical steroid, which has been found to result in improvement or clearance in up to 60-80% of those treated. Many other combinations of topical agents are in common use, as they are more effective than any one alone. However, these products are often expensive.

31. In order to treat melasma, combination or specially formulated creams with hydroquinone, a phenolichypopigmenting agent, azelaic acid, and retinoic acid (tretinoin), nonphenolic bleaching agents, and/or kojic acid may be prescribed. For severe cases of melasma, creams with a higher concentration of HQ or combining HQ with other ingredients such as tretinoin, corticosteroids, or glycolic acid may be effective in lightening the skin. • Azelaic acid 15%-20% (Azelex, Finacea) • Retinoic acid 0.025%-0.1% (tretinoin) • Tazarotene 0.5%-0.1% (Tazorac cream or gel) • Adapalene 0.1%-0.3% (Differin gel) • Kojic acid • Lactic acid lotions 12% (Lac-Hydrin or Am-Lactin) • Glycolic acid 10%-20% creams (Citrix cream, NeoStrata) • Glycolic acid peels 10%-70% • Other proprietary ingredients and mixtures of ingredients as in Elure, Lumixyl, and SkinMedica'sLytera products

32. Sunprotection

34.  1) Light, circadian rhythms and melatonin: (1) UV or visible light from the sun is sensed by the retina, which signals the suprachiasmatic nucleus (SCN) region of the brain, enabling entrainment of circadian rhythms throughout the body; • (2) UV light induces skin damage. Both melatonin and Vitamin D3 have protective effects against this damage, through the inhibition of reactive oxygen species (ROS) formation as well as other mechanisms; • (3) UVB light exposure can cause disruption of the circadian rhythms in normal skin, but also has the protective effect of producing Vitamin D3; and • (4) in addition to its protective effects against UVB skin damage, melatonin also plays a role in the regulation of circadian rhythms, through its inhibition of the HDAC SIRT1

35. In addition to its damaging role in contributing to skin cancer, UV exposure also has positive and protective effects, necessitating a balance in the level of UV exposure required to maintain optimal health. • Although UV exposure is detrimental to skin health and key to the carcinogenesis process, it does not explain all skin cancers, including the increase in melanoma incidences of indoor workers. There has been speculation to tie this in with vitamin D production and/or the breakdown of vitamin D stores within the skin which is more common in indoor workers. With all the lifestyle changes we have seen over the past century, there has also been an increase in the incidences of many cancers. Many variables could contribute to the causes of these increases. However, the role that changes in environmental stressors play cannot be ignored. Further understanding of circadian regulations is needed to develop novel strategies towards circadian related conditions and diseases which encompass a wide range from behavioral conditions to cancers.

36. History • Melatonin was first discovered in connection to the mechanism by which some amphibians and reptiles change the color of their skin. • discovered that feeding extract of the pineal glands of cows lightened tadpole skin by contracting the dark epidermalmelanophores. • dermatology professor Aaron B. Lerner and colleagues at Yale University, in the hope that a substance from the pineal might be useful in treating skin diseases, isolated the hormone from bovine pineal gland extracts and named it melatonin. • production of melatonin exhibits a circadian rhythm in human pineal glands. The discovery that melatonin is an antioxidant was made in 1993.The first patent for its use as a low dose sleep aid was granted to Richard Wurtman at MIT in 1995. • Around the same time, the hormone got a lot of press as a possible treatment for many illnesses.The New England Journal of Medicine editorialized in 2000: "The hype and the claims of the so-called miraculous powers of melatonin several years ago did a great disservice to a scientific field of real importance to human health. With these recent careful and precise observations in blind persons, the true potential of melatonin is becoming evident, and the importance of the timing of treatment is becoming clear. Our 24-hour society, with its chaotic time cues and lack of natural light, may yet reap substantial benefits."

37. Chemically is a hormone found in animals, plants, and microbes. In animals, circulating levels of melatonin vary in a daily cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions. • Many biological effects of melatonin are produced through activation of melatonin receptors, while others are due to its role as a pervasive and powerful antioxidant, with a particular role in the protection of nuclear and mitochondrial DNA. • Melatonin is categorized by the US Food and Drug Administration (FDA) as a dietary supplement and is not regulated as a pharmaceutical drug.

38. hormone of darkness • In mammals, melatonin is biosynthesized in four enzymatic steps from the essential dietary amino acid tryptophan, with serotonin produced at the third step. Melatonin is secreted into the blood by the pineal gland in the brain. Known as the "hormone of darkness," it is secreted in darkness in both day-active (diurnal) and night-active (nocturnal) animals. • It may also be produced by a variety of peripheral cells such as bone marrow cellslymphocytes, and epithelial cells. Usually, the melatonin concentration in these cells is much higher than that found in the blood, but it does not seem to be regulated by the photoperiod.

39. Melatonin in Plants • Melatonin has been identified in many plants including feverfew (Tanacetumparthenium), St John's wort (Hypericumperforatum), rice, corn, tomato and other edible fruits. The physiological roles of melatonin in plants involve regulation of their response to photoperiod, defense against harsh environments, and the function of an antioxidant. Melatonin also regulates plant growth by its ability to slow root formation, while promoting above ground growth. • Melatonin has been reported in foodstuffs includingcherries to about 0.17–13.46 ng/g,bananas and grapes, rice and cereals, herbs, olive oil, wineand beer. • When birds ingest melatonin-rich plant feed, such as rice, the melatonin binds to melatonin receptors in their brains. When humans consume foods rich in melatonin such asbanana, pineapple and orange the blood levels of melatonin significantly increase.

40. Pomegranate Fruit Extract Inhibits UVB-induced Inflammation and Proliferation by Modulating NF-κB and MAPK Signaling Pathways in Mouse Skin  • Solar UV radiation, particularly its UVB component (280–320 nm), causes adverse cellular and molecular events leading to skin cancer. Therefore, additional approaches are needed to define novel agents to prevent skin cancer which results as a consequence of UVB exposure. In this study, we investigated the photochemopreventive effects of pomegranate fruit extract (PFE) after multiple UVB irradiations to the skin of SKH-1 hairless mice. Our data show that PFE consumption afforded protection to mouse skin by inhibiting UVB-induced inflammation and proliferation via modulation of nuclear factor kappa B and mitogen-activated protein kinases pathways. This study suggests the potential efficacy of PFE as a photochemopreventive agent for skin cancer

41. Oral treatment of melasma • Oral medications for melasma are under investigation, including tranexamic acid (a prescription medicine in New Zealand). None can be recommended at this time. • Oral vitc,eantioidants

42. Devices used to treat melasma • Machines can be used to remove epidermal pigmentation but with caution – over-treatment may cause postinflammatory pigmentation. Fractional lasers are preferred and have been approved by the FDA for treating melasma. Patients should be pretreated with a tyrosinase inhibitor . • The ideal treatment for a quick result is just to destroy the pigment, while leaving the cells alone. Intense pulsed light (IPL) appears to be the most effective light therapy investigated so far. The topicals described above should also be used before and after treatment. Pigmentation may recur. Several treatments may be necessary and postinflammatoryhyperpigmentation may complicate recovery. • Conventional carbon dioxide or erbium:YAGresurfacing lasers and pigment lasers (Q-switched ruby and Alexandrite devices) are sometimes used, but they have a high risk of making melasma worse. Dermabrasion and microdermabrasionare not recommended, as they may also cause postinflammatoryhyperpigmentation.

43. Intense pulse light IPL was developed in the late 1990s and involves the use of a xenon-chloride lamp that emits light that is non-coherent not collimated and has a wide spectrum (500–1200 nm). The advantage of IPL lies in the flexibility of parameters. The wavelength, fluence, number, duration, and delay of pulses can be changed for each patient to effectively target chromophore. Hence, it can be used for the treatment of a variety of conditions like vascular lesions, hair removal, and melanocytic lesions. However, there are very few studies on the treatment of melasma with IPL.

45. Rebound hyperpigmentation treated five Chinese patients with melasma with laser toning. There was no significant improvement in melasma and all five patients developed laser-induced depigmentation. Possible pathogenic mechanisms for this depigmentation could be high fluences causing direct phototoxicity and cellular destruction of melanocyte, subthreshold additive effect of multiple doses, intrinsic unevenness of skin pigmentation, and non-uniform laser energy output.Several other side effects mentioned in the literature include rebound hyperpigmentation, physical urticaria, acneiform eruption, petechiae, and herpes simplex reactivation. Rebound hyperpigmentation could be due to the multiple subthreshold exposures that can stimulate melanogenesis in some areas.

46. What is the outcome? • Results take time and the above measures are rarely completely successful. About 30% of patients can achieve complete clearance with a prescription agent that contains a combination of hydroquinone, tretinoin and a topical corticosteroid. • Unfortunately, even in those that get a good result from treatment, pigmentation may reappear on exposure to summer sun and/or because of hormonal factors. New topical and oral agents are being studied and offer hope for effective treatments in the future.

47. Topical alpha hydroxyacidsincluding glycolic acid and lactic acid, as creams or as repeated superficial chemical peels, not only remove the surface skin but their low pH inhibits the activity of tyrosinase.

48. What is Tri-Luma? • Tri-Luma is a combination prescription cream containing fluocinoloneacetonide 0.01%, hydroquinone 4%, and tretinoin 0.05%. • It is used to treat melasma and other skin discoloration. Results may be seen in usually about six to eight weeks from starting treatment. Tri-Luma should not be used for prolonged periods exceeding eight weeks without your doctor's recommendation. It should not be used by pregnant or breastfeeding women unless specifically instructed by your physicianit must also be refrigerated. • Other combination creams include the Kligmanformula which is a triple cream including a retinoid, a hydroquinone, and a topical steroid (for example, fluocinoloneacetonide 0.01%, hydroquinone 8%, and tretinoin 0.1%). These triple combination creams may be compounded in different strengths by specialty pharmacists according to a physician's prescription. Triple creams are highly effective for melasma.

49. It has been suggested that taking an oral proanthocyanidin (a class of flavonols) along with a vitamin regimen may significantly reduce pigmentation. At this time, the mechanism for this treatment method is not fully understood. Significantly more study is necessary before this method of treatment could be deemed effective. One major benefit to this mode, however, is that the use of proanthocyanidin is a natural treatment method, and it is a safe alternative in patients who exhibit a moderate or severe adverse reaction to a topical treatment.[25] • In an attempt to search for a new treatment for melasma, Wu et al studied oral administration of tranexamic acid (TA) in Chinese patients. Tranexamic acid tablets were prescribed to 74 patients at a dosage of 250 mg twice daily for 6 months. At follow-up, more than half of patients (54%) showed good results. This treatment may be effective for some patients, but further study is needed.[26]

50. Communication between the nervous system and epidermal melanocytes has been proven . • The observation that epidermal melanocytes molecularly differ from dermal melanocytes seems to support the hypothesis about double origin of skin melanocytes Thus, melanocytes in the skin either derive directly from NCC populating the skin via a dorsolateral migratory pathway or arise from ventrally migrating precursors forming the myelin around the cutaneous nerves .