Melasma Dr Z. Shahmoradi Associate professor of dermatology

1. In the name of God Melasma Dr Z. Shahmoradi Associate professor of dermatology

2. melanogenesis

4. Melanin is produced in melanocytes and stored in melanosomes within the keratinocytes. 1) The number, 2) melanin content, 3) and location of these melanized cells (along with oxygenated and deoxygenated hemoglobin) help determine the color of the skin.

5. Melanocytes contain tyrosinase, a copper-containing enzyme, that catalyzes the conversion of L-tyrosine to L-dopa and L-dopa to L-dopaquinonein melanin synthesis. Melasma is a dysfunction of this pigmentary system, resulting in an irregular brown or grayish-brown facial hypermelanosis.

8. Causes of acquired hyperpigmentation • Skin disease and conditions: Melasma, erythromelanosis follicularis, poikiloderma of civatte, PIP, Riehl’smelanosis • Exogenous causes: cosmetics, drugs (estrogens, tetracyclines, amiodarone, phenytoin, phenothiazines, sulfonamides, aldacton), photosensitizing agents (bergamot oil, furocoumarins), UV (melasma, freckle, solar lentigo) • Other causes: • Addison, hemochromatosis, liver disease, pituitary tumors, pregnancy, hyperthyroidism

9. Melasma • Acquired, brown hypermelanosis of the face that develops slowly & symmetrically. • Female (90%) , Male (10%) • Etiology: Sunlight, pregnancy, genetic, racial, endocrine (thyroid dysfunction,…) • In men with melasma: higher LH & lower testosterone • Stress: release of MSH can be influenced by stress • 50-70% of pregnant women & 8-30% with OCP

10. ..Melasma • Centrofacial=63% in cheeks, forehead, upper lip, nose, chin • Malar=21% in cheeks & nose • Mendibular=16% in ramous mendibular

11. Centrofacial localization of melasma(63%)

12. Malar localization of melasma(21%)

13. Mandibular localization of melasma(16%)

14. Chloasma: can resolve within a few months after delivery and treatment may not be necessary. However, there are many cases in which the disorder persists indefinitely. Pregnancy-associated melasma may be caused by an increase in placenta, ovarian, and pituitary hormones. Melasma has also been attributed to an elevationof melanocyte-stimulating hormone (MSH), estrogen, and progesterone leading to increased melanogenesis.

15. Pathology • In epidermal type: increased number of melanocyte & melanocyte activity increased melanization transport of melanosomes to epidermal cells • In dermal type: melanophage in dermis (papillary & reticular)

16. ..Melasma • Examination with Wood’s lamp: 1)Epidermal, enhancement of pig. [70%] 2)Dermal, no enhancement 3)Mixed, slightly enhancement 4) a type seen in type 5-6 skin in which the lesions are not discernible under a wood’s light.

17. D.D • Actinic lichen planus • Drug-induced hyperpigmentation • Riehl’smelanosis • Poikiloderma of Civatte • Exogenous ochronosis • Erythema dyschromicumperstans • PIP

18. Treatment of melasma

19. Treatment of Melasma • Eliminate inciting agents: drugs, cosmetics • HQ alone > 3% • Tretinoin 0.05%-0.1% • HQ with retinoic acid, Arbutin, Kojic acid (2-4%) ,Mandelic acid , Azelaic acid 20% , Steroid,... • Broad-spectrum sunscreen • 4-isopropyl catechol (66%) • N-acetyl-4-cysteine 3%

20. …Treatment of melasma • Chemical peeling: glycolic acid 30-70% , • TCA 10-35% , • S.A 20-30% • Dermabrasion, microdermabrasion • Lasers: Erbium:YAG , Q-switched , CO2- laser

21. General management • General management recommendations that assist in the clearing of melasma include discontinuation of birth control pills, scented cosmetic products, and phototoxic drugs, coupled with UV protection with use of broad spectrum (UVA+UVB) sunscreens.Solar exposure exacerbates melasma ,and its avoidance is fundamental for the successful management of the disease.

22. Hydroquinone: • HQ remains one of the most prescribed agents for melasma and is considered the gold standard of therapy, especially for epidermal melasma. The epidermal type generally has a good response to topical therapy, -Whereas skin with mainly dermal deposition of Alternative therapies such as chemical peelingagents or lasertherapy are sometimes also used.

23. Hydroquinone: • Mechanism of action:HQ (1,4-dihydroxybenzene) is a hydroxyphenol, which, in the presence of catalytic amounts of dopa, will compete with tyrosine, the natural substrate of tyrosinase. • This process prevents the enzymatic oxidation of tyrosine to dopa, thus, preventing the synthesis of melanin. This is consistent with the selective mode of action toward cells with active tyrosinase activity.

24. HQ 3-5% concentration was determined to be the optimal strength. • Interestingly, their impression from clinical observations was that many of the side effects experienced may occur from misuse, excessive use, and the application of multiple preparations. It has also been suggested that patients may use unsuitable cleansing agents, carry out vigorousrubbing of the affected areas, and apply excessive amounts of medication.

25. Tri-Luma Cream: HQ 4% +fluocinolone 0.01% + tretinoin 0.05% • Westerhof formula: HQ 2% + N-acetyl cysteine 3% + hydrocortisone 1% . - In 8 weeks: 77% improved the melasma • HQ 4% + tretinoin 0.1% + lactic acid 7% in aqueous gel • Kligman formula: HQ + tretinoin + dexamethasone

26. Ochronosis:

27. Erythema & pigmentation due to HQ

29. Colloid milium

32. Tretinoin: • Mechanism of action (5)Retinoids, such as vitamin A acid and retinoic acid (RA) or tretinoin, were first used in combination with HQ to • 1) enhance the penetration of HQ, but were later recognized to have their own effect on the pigment.2)Tretinoin's ability to depigmentis based on its ability

33. 3)to disperse keratinocyte pigment granules, interfere with pigment transfer, • 4)and accelerate epidermal turnover and, therefore, pigment loss. • 5) In addition, there is also evidence that it can inhibitthe induction of tyrosinase, DOPAchrome conversion factor, and melanogenesis

34. Tretinoin is available in 3 forms: gel, cream, and liquid, at strengths ranging from 0.01% to 0.1% and is approved for the treatment of acne vulgaris and photoaging. As a monotherapy it is not an approved treatment for melasma; however, it is part of a combination HQ, tretinoin, and fluocinolone acetonide cream (Tri-Luma) which is an approved treatment for melasma.

35. Safety and tolerability: • The most common side effects of tretinoin include a retinoid dermatitis characterized byburningor stinging, erythema, scaling, and dry skin. inflammation may cause hyperpigmentation, especially in those with dark skin. Fortunately, most adverse effects (AEs) are reversible on discontinuation of therapy, although the hyperpigmentation/hypopigmentation may persist for many months.

36. Topical tretinoin is not considered mutagenic or carcinogenic, however, animal tests have demonstrated evidence for teratogenicity. • There have not been adequate and well-controlled studies performed in pregnant women.(category C) • In addition, the safety of tretinoin gel has not been established in children younger than 12 years, neither has the safety of the emollient cream in patients younger than 18 years.

37. Corticosteroids: • Mechanism of action(4) Corticosteroids may directly affect the synthesis of melanin, although the mechanism by which the skin is lightened is 1) not completely known. 2) Melanocytes respond to a variety of chemical mediators such as prostaglandins andleukotrienesand, thus, it has been theorized that steroids might alter melanocyte function byinhibition of prostaglandin or cytokine production by various cells of the epidermis.

38. 3) Corticosteroids may suppress secretory metabolic products from melanocytes without causing their destruction, and this could be the reason for their short-lived effect on pigmentation disorders. • 4)Topical steroids also inhibittyrosinase activity & affect endoplasmic reticulum secretory function of melanocytes.

39. Efficacy: • The use of corticosteroids in the treatment of melasma is seen more often in conjunction with other topical therapies (eg, tretinoin and HQ). • As a monotherapy there has been little published research Unfortunately, the study failed to assess whether the improvement caused by steroid treatment was a long-term benefit.

41. Azelaic acid • A.A is a naturally occurring dicarboxilic acid derived from P.ovale. • Itinhibits mitochondrial oxidoreductaseactivation & DNA synthesis, as well as tyrosinase. • Minimal effect on normalpig. and greatest effecton heavily pigmented melanocytes.

42. …Azelaic acid: • Useful in facial lentigomaligna (specificity for abnormal melanocytes), rosacea, solar keratosis, PIP due to herpes or burns. • Effect comparable with HQ, 15-20% twice daily for 3-12 months, effective in dark skin • Side effects: erythema, irritation

43. Azelaic acid: • Mechanism of action:Az.A has anti-inflammatory, antibacterial, and antikeratinizing effects, which make it useful in a variety of dermatologic conditions., acts on hyperactive and abnormal melanocytes by competitively inhibiting tyrosinase.

44. Safety and tolerability: • Topical administration of 20% Az.A has produced pruritus, burning, stinging, and tinglingin 1% to 5% of patients. • Other adverse reactions, such as erythema, dryness, rash, peeling, irritation, dermatitis, and contactdermatitis, have been reported in less than 1% of patients. • Rarely asthma, vitiligo, small depigmented spots, hypertrichosis, development of keratosis pilaris, and exacerbation of recurrent herpes labialismay occur.

45. Kojic acid: • 5-hydroxymethyl-4H-pyrane-4-one is a hydrophylic fungal derivative obtained from Aspergillus & penicilliumspecies. • Some studies indicate kojic acid = HQ in skin-lightening ability. • The activity of kojic acid: prevent tyrosinase activity by binding to copper.

46. Other topical agents Kojic acid is not an approved treatment for melasma. However, because both kojic acid and HQ are tyrosinase inhibitors, the combination should be expected to augment efficacy. Thus, those who do not respond to HQ and GA may benefit from the addition of kojic acid to the treatment regimen

47. Licorice extract (glabridin): • The principal active compound of licorice root extract is glabridin : 10-40% in skin lightening • Depigmenting effect: 16 times greater than HQ • It isfaster acting: after 7 days • 0.4% licorice extract + 0.05% betamethasone + 0.05% retinoic acid = 70% of patient reported excellent effects. • Licorice extracts are used as topical anti-inflammatory agents to decrease skin redness & hyperpig.

48. ..Licorice extracts: • The active agents are known asliquiritin&isoliquiritin, which are glycosides containing flavonoids. Liquiritin induced skin lightening by dispersing melanin.

49. Ascorbic acid • Vit C interrupts the production of melanogenesis by interacting with copper ions to reduce dopaquinone & blocking dihydrochinindol-2-carboxyl acid oxidation. • Vit C, an antioxidant, is rapidly oxidized when exposed to air and is of limited stability. • High concentrations of Vit C must be used with caution, as the low pH can be irritating to the skin. • Cream 10% magnesium L-ascorbic acid-2-phosphate (MAP), a stable derivative of vit C=lighten pig.

50. L-ascorbic-2-phosphate (magnesium-L-ascorbyl-2-phosphate; VC-PMG) is a stable vitamin C derivative that suppresses melanin production. Applying VC-PMG cream 10% twice daily to the skin of 34 patients produced an improvement in 55% of those treated, suggesting that it may be effective in reducing hyperpigmentation