Updates in management of aga.pptx

3. Treatment

5. 1- Hormone Antagonists, Hormone Receptor Modulators 2- Wnt/β-catenin Activation 3- Ant-infammatory, Antioxidant and Antimicrobial Agents 4- Stem Cell-Based Therapies 5- Stimulation of ECM components 6- Direct Stimulation of Stem Cells and Dpcs 7- Nutritional and antioxidant therapy 8- Miscellaneous And Emerging Options

7. Therapeutic recommendation for minoxidil • Topical Minoxidil 2–5% solution 1 mL twice daily is recommended to improve AGA in male patients above 18 years with mild to moderate AGA (Hamilton- Norwood IIv-V). • 5% solution or foam for greater efficacy. • NO recommendation for the 5% minoxidil foam instead of the 5% solution at the present time.

8. Therapeutic recommendation for minoxidil • The response to ttt should be assessed at 6 months, if successful, ttt needs to be continued to maintain efficacy. • For greater efficacy: combination of oral finasteride 1 mg, 1/d and topical Minoxidil 2–5% solution, 2/d. • Cannot make a recommendation for combination therapy of topical minoxidil with topical 5a-reductase or azelaic acid and betamethasone valerate at the present time.

9. Therapeutic recommendation for minoxidil • Topical Minoxidil 2% solution 1 mL 2/d or 5% minoxidil topical foam 1/d is recommended to improve AGA in female patients above 18 y. • NO recommendation for the 5% minoxidil foam once daily instead of the 2% solution twice daily at the present time. • The response to ttt assessed at 6 months, if successful, ttt continued. • Cannot make a recommendation for combination therapy of topical minoxidil with red ginseng, azelaic acid and betamethasone or oral nutritional supplements at the present time

10. A- Topical 5 AR Inhibitors B- Oral 5AR inhibition C- Botanical 5AR inhibitors D- Oral anti-androgens and estrogens for FPHL Hormone Antagonists, Hormone Receptor Modulators

11. A- Topical 5 AR Inhibition • Some efficacy as oral formulation + minimal risk of side effects • Topical Finasteride: Efficacy established in increasing hair density • Can be used in maintaining hair density after successful treatment with oral finasteride

12. Topical finastride

15. B- Oral 5AR inhibition Finastride Dutasteride

16. Finasteride • Mechanism of action: – Selective inhibitor of 5 α-reductase type-2. – DHT level lowered but not plasma testosterone level. • Uses: – BPH. – FDA approved for male androgenetic alopecia (1 mg/d). – Hirsutism.

17. Finasteride • Finasteride evaluated in women with FPHL. • No clinical improvement in postmenopausal women receiving finasteride versus placebo (Price et al., 2000). • Oral finasteride, 1.25 mg/d offer improvement in women with hyperandrogenism (Shum et al., 2002). • A small case series show improvement in alopecia in women without hyperandrogenism treated with 2.5-5 mg/d of finasteride (Trueb, 2004).

18. • Unlike dutasteride, finasteride is also a potent inhibitor of type III 5a-reductase (diffusely expressed in the dermis & epidermis) (Azzoni et al., 2012, Boyapati & Sinclair, 2013). • Concomitant use of both finasteride & dutasteride may also be warranted. • Finasteride & dutasteride are considered equally effective and safe for the treatment of AGA in men.

19. • As a potential future treatment option for male AGA, dutasteride 0.5 mg exhibited long-term safety, tolerability and efficacy within this study.  A 35 Korean men with AGA who had not shown significant clinical improvement when treated with finasteride 1 mg/d for at least 6m received dutasteride 0.5 mg/d for 6m.  Dutasteride is suggestive to be an alternative effective safe treatment option to patients with AGA who do not clinically respond to finasteride in 6m.

20. C- Botanical 5AR inhibitors • Owing to the systemic adverse effects associated with FIN and dutasteride, extracts of herbs with 5AR inhibitory effect have been explored as an alternative • Saw Pametto & Berries extracts are the most popular

21. Herbal Extracts Used In Treatment Of AGA (Hormonal Actions) Cimicifuga racemosa: Increase estrogen level Millet seed (contains silicic acid, aminoacids, vitamins and minerals ) Agents acting by inhibition of DHT: (Botanical 5A Reductase inhibitors) Saw palmetto, ß-sitosterol, green tea or polysorbate 60

22. Canadian Willow Herb • Antiproliferative, anti-inflammatory and antioxidant activities • Inhibition of several key enzymes including 5α-reductase and aromatase, caspase 3, metaloproteinases and PGD2 inhibiting activities No trials were found concerning the natural products gingko biloboa, aloe vera, bergamot, hibiscus or sorphora

23. Therapeutic recommendation for 5 alpha reductase inhibitors • Oral Finasteride 1 mg/day is recommended to improve AGA in males above 18 years with mild to moderate AGA (Hamilton-Norwood IIv-V). • The response to ttt assessed at 6 months, although in some men it may occur after 12 months, if successful, treatment needs to be continued . • Cannot make a recommendation for or against ttt with topical finasteride. • For greater efficacy: oral finasteride 1 mg, 1/d + topical Minoxidil 2–5% solution or 5% foam 2/d .

24. Therapeutic recommendation for 5 alpha reductase inhibitors • Oral Dutasteride 0.5 mg/day can be considered in case of ineffective previous ttt with 1 mg finasteride over 12 months as a second line ttt to improve or to prevent progression of AGA in male patients above 18 years with mild to moderate AGA (Hamilton- Norwood IIIv-V).

25. • Oral finasteride 1 mg daily is not suggested in the treatment of postmenopausal women with female pattern hair loss. • We cannot make a recommendation for or against treatment with oral finasteride 5 mg/day at the present time. Therapeutic recommendation for 5 alpha reductase inhibitors

26. D- Oral Anti-Androgens And Estrogens Estrogen Cyproterone Acetate Spironolactone Flutamide Fluridil Alfatradiol

27. OCPs • Progesterone-only OCPs are not effective in the management of androgen-mediated skin conditions. • Combination OCPs: – Estrogen (ethinyl estradiol in various dosages). – Progestational agent (varies from pill to pill). • The progestins incorporated into OCPs vary in their androgenic capabilities, some concern that they may worsen acne. • When combined with ethinyl estradiol, however, the net effect of a combination pill is antiandrogenic.

30. OCPs • Combined OCP are available as 21-day & 28-day packs. • Start on Day 5 for 21 days.

31. Cyproterone acetate • Direct anti-antiandrogenic action. • Progesterone like – inhibits LH causing antiandrogenic action. • Competes with DHT for intracellular receptor. Uses: • Precocious puberty in Boys. • Prostatic cancer • Inappropriate sexual behaviour in men. • Virilization in women.

32. Cyproterone acetate • Dose: 20-200 mg daily. • CPA 2 mg + ethinyl estradiol, 35 pg, used as an OCP from day 5 of the cycle for 21 days. • CPA, 20-100 mg/day from day 5 of the cycle to day 14. • Side effects: Hepatotoxic, nausea tiredness, depression, weight gain, breast tenderness & loss of libido.

33. Spironolactone • Anti-androgen most used for skin disease in the USA. • Mechanism of action: – K-sparing diuretic. – Blocks the androgen receptor. – Decreases testosterone production in the adrenal gland. – Inhibits the 5a-reductase enzyme. – Displaces estradiol from SHBG, increasing free estrogen levels.

34. Spironolactone • Exposure of a male fetus may cause feminization. • Coadministering with an OCP. • Used effectively to treat AV, FPHL & hirsutism. • It may take 6 or more months to see improvement. • Guidelines for use as anti-androgen: – Start with low dose (25-50 mg) reduces incidence of side effects. – Effective maintenance doses range from 25-200 mg /day.

36. Why we can’t use systemic spironolactone as an anti-androgen in males?? • Exceptional results for many men but at a high cost of side effects. • Severe Gynecomastia is the most common side effect.

38. Flutamide • Non-steroidal anti-androgen. • Active metabolite “2-hydroxyflutamide” causes competitive block Androgen action – Accessory sex organs & Pituitary. • Increased LH secretion by blocking feedback inhibition.

39. Flutamide • Uses: – FDA approved for prostate cancer along with GnRH agonist. – Female hirusitism. – FPHL. – Acne vulgaris. • Side effects: – Gynaecomastia and breast tenderness. – Liver damage. – There is a risk of feminization of the male fetus.

40. Flutamide • In hirsutism: flutamide is more effective than spironolactone. • High cost, hepatotoxic. • Low starting dose (i.e., 125 mg 1-2/d) to minimize side effects. • Depending on the clinical response, the dose can be increased to 125 mg t.i.d. or 250 mg b.i.d.

41. Flutamide • As Flutamide is potent enough to have a feminizing effect in men, its use is limited to females. • Further studies are needed to evaluate the efficacy of Flutamide as a topical agent in treating androgeneic alopecia.

42. • Novel topical non-steroidal antiandrogen that supress androgen receptor. • Numerous studies ascertained the low systemic and topical toxicity. • Authorized in Czech Republic.

43. Therapeutic recommendation for hormonal treatment • We do not recommend the use of oral oestrogens or androgenreceptor-antagonists to improve or prevent progression of AGA in males. • We cannot make a recommendation for topical alfatradiol in male patients at the present time. • We suggest that topical fluridil should not be used in male patients with AGA.

44. Therapeutic recommendation for hormonal treatment • We cannot make a recommendation for the use of oral anti- androgens (CPA, spironolactone, flutamide) to improve or prevent progression of AGA in normoandrogenic females at present time. • Oral CPA can be considered to prevent progression of AGA in women with clinical or biochemical evidence of hyperandrogenism. • We cannot make a recommendation for the use of topical alfatradiol, topical natural oestrogens or progesterones & topical fluridil to improve or prevent progression of AGA in females at present time.

46. A- Topical valproic acid • A widely used antiepileptic • Now known to activate the Wnt/ β-catenin pathway, which is associated with hair growth cycle and anagen induction

47. B- Methyl vanillate • Applied topically • Can increase hair count by inducing Wnt10B expression in the scalp

48. C- Hair Stimulating Complex • Bioengineered human cell-derived formulation containing: • Derived from culture of newborn cells grown in an oxygen-deficient embryonic environment Wnt7a protein Epidermal Growth Factors Follistatin

50. A- Ketoconazole • Observed to impede synthesis of steroid at high concentrations • Inhibition of cytochrome P450 and lyase • Inhibitory actions on inflammation and fungal infections in the scalp

51. B- Prostaglandin-Based Therapies Prostaglandin and prostamide analogues: -Drugs that block PGD2 signaling or enhance PGE2 -The prostaglandin F2α analogue latanoprost -Prostamide F2 α analogue bimatoprost

52. C- Melatonin • Secreted from the pineal body • Actions in humans Interaction with specific receptors Inhibits both apoptosis and expression of estrogen receptor Influence androgen and estrogen receptor- mediated downstream processes Free radical scavenging and protective actions

53. D- Cetrizine • H1 receptor blocker that reduce PGD2 release from mast cells • Anti-inflammatory & anti-allergic activities of cetirizine can be useful in AGA patients with scalp irritation and inflammation

55. Stem Cell-Based Therapies • Possibility of creating a functional hair follicle from follicular stem cells, i.e., bioengineering hair for transplant?? • Possibility of creating new hair follicles by injecting autologous dermal and/or epidermal cells??

56. There is many publications were published in recent years & most of these papers elicited the stem cell in treatment of AGA

60. Role of Stem cell 1. Interplay 2. Competitive inhibtor of DHT 3. GF ERK Prolifration ”mitosis” Akt survival

62. Stimulation of ECM components Tetrapeptides: AcSDKP, Angiogenic factor Diguanosine tetraphosphate (GP4G): liposomic solution of Artemia salina extract Stimulation of ECM protein synthesis-----Inhibition of 5 AR activity, and reduction of follicular micro-inflammation

63. 1- Hormone Antagonists, Hormone Receptor Modulators 2- Wnt/β-catenin Activation 3- Anti-infammatory, Antioxidant and Antimicrobial Agents 4- Stem Cell-Based Therapies 5- Stimulation of ECM components 6- Direct Stimulation of Stem Cells and Dpcs 7- Nutritional and antioxidant therapy 8- Miscellaneous And Emerging Options

64. Platelet Rich Plasma Microneedling

67. DHT Wnt X B- Cat TCF/L EF B- Cat X Akt Erk Proliferation Survival

68. Therapeutic recommendation for PRP • There is no standardized technique for performing PRP to permit objective evaluation of its effects on AGA. • We cannot make a recommendation for or against treatment of AGA with PRP at the present time

70. Oxidative Stress • Apoptosis of HF cells followed by early onset of the catagen phase by lipid peroxides that generate free radicals • Balding areas of scalp show increased nuclear expression of markers of oxidative stress and DNA damage including heat shock protein-27, super oxide dismutase, catalase, and p16(INK4a)/pRB Smoking and ultraviolet light induced exacerbation of AGA

72. Non-Minoxidil Miscellaneous Treatment Options Amino Acids (Cysteine)---- increased growth factors Trace elements like copper and zinc ------Improve hair nutrition Iron supplementation in patients with low serum Ferritin Proanthocyanidines like procyanidine B (flavonoid working as an antioxidant) Vitamins especially biotin and niacin ----Improve hair nutrition Caffeine: Prevent progression and induce hair regrowth Prostaglandine analogues like viprostol or latanoprost : Vasodilator effect Aminexil is a vasodilatator chemically similar to minoxidil: Perifollicular Vascularization

73. Main Active ingredients: (in highest concentration 40%) • Grape seed oil (full of Proanthocyanidin) • Omega 3 • Omega 6 • Omega 9 • Vitamin E • Thio-lipisters ( Ecrinal Patency) • 5ml ampoules x 8 = 745 LE • Half amp day after day Ecrinal Ampoules Anti hair loss & hair stimulation Intensive hair treatment Suitable for fine hair (normal to dry hair )

74. Indications : (in highest concentration 40%) • FPHL hair loss, from the very first signs in women, thinning scalp, in cases where hair growth is slowed down, or where it is necessary to assist weakened hair by boosting regrowth. • In certain cases of hair loss with dandruff. • Anemic hair. in cases where the appearance of the scalp and hair requires treatment in order to increase your hair’s vitality. Ecrinal Ampoules Anti hair loss & hair stimulation Intensive hair treatment

75. Main Active ingredients: (spray formula with high compliance conc.20%) • Grape seed oil ( full of Proanthocyanidin) • Omega 3 • Omega 6 • Omega 9 • Vitamin E • Thio-lipisters • Suitable for fine hair (non-greasy & light weight) • 200 ml 289 LE • 6 puffs morning and evening Ecrinal lotion Anti hair loss & hair stimulation Daily treatment

76. Indications : • In mild and moderate cases hair loss (TE) • Maintenance after ampoules course • Suitable for pregnant and lactating women • In children starting from 2 years Anti hair loss Lotion Daily treatment 20%

77. ANP 2+ Complex (exclusive patent) The Thiolipidic complex featuring Thiolipisters and 3 plant origin oils that contributes to & play an important role in boosting the keratin production .. Provitamin B5 , vitamin B3 : It improve your hair’s: Shine ,softness & strength It can also help protect your hair from styling or environmental damage by locking in moisture. Helps to transport blood and oxygen to the scalp and hair follicles.

78. •Inhibit DHT leading to: • Stimulate hair production • Slow down hair loss Grape seed oil (Proanthocyanidin) Enhance keratin synthesis Thio-lipisters Anti-hair loss Stimulate healthy hair growth

79. Thio-lipesters of silk (Patency) • THIO-LIPESTERS® C8SMET 8515 have a stimulating action that boosts hair regrowth in particular thanks to the introduction of L- Cysteine & L-Methionine sulfur amino acids which contributes to the optimization of skin appendage growth and the prevention of hair loss • The very improved results explained by the fact that the sulfur-containing amino acids are present in keratins, particularly in the integuments in high proportion therefore their presence are essential in the synthesis of keratins which increases the growth of hair and improves the strength of regrowth

80. Cysteineas a sulfurated amino acid does it have a role in keratin synthesis and hair growth??

82. • Ensure healthy appearance of hair & scalp • ↑ elasticity  ↓ brittle hair • Sebum regulation  treat dry, dehydrated hair • ↑ Moisture content • Give shiny appearance Great mix of EFA (Omega 3, 6 & 9) Synergism between both potent antioxidants Vitamin E & Proanthocyanidin Stronger & Shiny hair Anti-aging effect

83. Therapeutic recommendation for miscellaneous molecules, substances and interventions • Cannot make a recommendation for or against a treatment with the mentioned molecules, substances and interventions at the present time.

84. New And Emerging Treatment Options

85. Nitric oxide (NO) gel: Promote hair follicle formation through stem cell development, hair regeneration, hair Shaft elongation and increased growth rate in rats Vitamin D3: -The Vitamin D receptor (VDR) is expressed in hair follicle keratinocytes during late anagen and catagen -Vitamin D3 has also been shown to modulate Wnt10b gene expression -VD3 gene knock-out and VD3 supplementation in nude mice has revealed encouraging hair growth

86. Topical roxithromycin: -Inhibition of apoptosis of keratinocytes (via suppressing the production of oxygen reactive species) -Suppression of the AR in human dermal fibroblasts Low-level laser/light therapy (LLLT) : - Modulation of reactive oxygen species (ROS), - Induction of transcription factors Botulinum Toxin Scalp Injection: - A traction component by tension of the musculus occipitofrontalis is discussed, but studies are missing - May act on the inflammatory component of androgenetic alopecia

87. Therapeutic recommendation for Low-level Laser therapy (LLLT) • Suggest using LLLT as ancillary therapy for AGA with devices that use energy levels shown to be effective in randomized controlled clinical trials. • Cannot make a recommendation for or against treatment for more than 6 months with LLLT for AGA at the present time

88. Therapeutic recommendation for hair transplantation • Surgery, especially follicular unit transplantation (FUT) can be considered in males and females with sufficient donor hair. • Suggest FUT to be combined with finasteride 1 mg daily to achieve a better clinical outcome in males.

Updates in management of aga.pptx

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