Concluses

A Dinmica do Estresse no aparecimento da Queda Capilar

Dr Ademir Jnior International Association of Trichologists - Brasil

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Na Formao do Embrio
Epiderme da Pele e Sistema Nervoso se
mesmo tecido do embrio formam a partir da mesma clula tronco ectodrmica

Folculos Pilosos se formam a partir deste

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Embriologia do Folculo Piloso

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O Folculo Piloso (FP) apresenta peculiaridades:

Estruturas anatmicas bem denidas e clulas com responsabilidades diferentes no processo de crescimento/desenvolvimento do o de cabelo Principais clulas: Queratincitos, Fibroblastos da Papila Drmica, Melancitos At pouco tempo desconhecia-se a complexidade do envolvimento destas clulas com mecanismos neuroendcrinos

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Estudos provam que as clulas dos FPs so alvos e produtoras de substncias qumicas e hormnios que podem favorecer o aparecimento das doenas dos cabelos e couro cabeludo
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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

As clulas dos folculos respondem aos estmulos destes mediadores qumicos e hormonais sendo inibidas ou ativadas por por eles
HAIR-FOLLICLE CYCLING

the precise locations where the hair follicles will form. The protein products of several of these genes are also present at different times during the hair cycle in adults, suggesting that they are important not only for the normal distribution and development of follicles but also for their continued growth.1,18,20 Once the distribution of the follicles has been established, subsequent molecular events in the developing follicle determine the future phenotype of each hair.1,2,13 Morphogens such as sonic hedgehog and wnt, together with intracellular signaling molecules such as b-catenin and lymphoid-enhancer factor 1, influence the maturation of the new hair follicles.15,16,21 Each hair follicle perpetually goes through three stages: growth (anagen), involution (catagen), and rest (telogen) (Table 1 and Fig. 1 and 2). Determining the molecular signals that orchestrate the follicles transit between these stages is one of the key challenges of hair research. Although most of our current knowledge of the substances that modulate hair growth in humans is derived from clinical observations (Table 2), studies in mice have identified some of the molecular events associated with hair-follicle cycling.6,15,16,21,25,26 Numerous growth factors and growth factor receptors are critical for normal hairfollicle development and cycling, but no single growth factor appears to exert ultimate control over these processes.
Anagen Stage

TABLE 2. MODULATORS OF HAIR-FOLLICLE CYCLING IN HUMANS.*

MODULATOR ACTION

Endogenous Androgens

Estrogens Growth hormone Prolactin Thyroxine Exogenous Anabolic steroids

Reconhecer estes mecanismos poder abrir possibilidades para novas teraputicas no tratamento das alopecias

Promote miniaturization of follicles and shorten duration of the anagen stage in androgen-sensitive areas of scalp; enlarge follicles in androgen-dependent areas (e.g., male beard) during adolescence Prolong the anagen stage; postpartum reduction in estrogen secretion causes telogen effluvium Acts synergistically with androgen during virilization in adolescence Can induce hirsutism Low levels cause telogen effluvium; high levels may have a similar effect

Same actions as those of androgens; accelerate androgenetic alopecia and aggravate hirsutism b-Adrenergic antagonists Can cause telogen effluvium Cyclosporine Causes hypertrichosis Estrogens Prolong duration of the anagen stage, counteracting telogen effluvium and androgenic alopecia Finasteride Blocks 5a-reductase type II, inhibits miniaturization, and prolongs the anagen stage in androgen-dependent scalp follicles; converts vellus follicles to terminal follicles Minoxidil Induces and prolongs the anagen stage and converts vellus follicles to terminal follicles Oral contraceptives Cessation may cause telogen effluvium Phenytoin Causes hypertrichosis Retinoids Can cause premature onset of the catagen stage or premature loss of club hair, manifested as telogen effluvium

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The onset of the anagen stage recapitulates hairfollicle development, since the formation of the new Paus R, Cotsarelis G. The Biology of hair Follicles. NEJM. 2006;7(341):491-497 lower hair follicle begins with the proliferation of secondary germ cells in the bulge (Fig. 1A and 2).3,4

*Information is from Orfanos and Hertel,22 Headington,23 Olsen,24 Paus,25 Stenn et al.,26 and Dawber.27

Androgenetic alopecia: pathogenesis and potential for therapy

Justine A. Ellis, Rodney Sinclair and Stephen B. Harrap

TestosteroneeDHT atuamnosreceptoresda papiladrmica

A c c e s s i o n i n f o r m a ti o n : (0 2 )0 0 5 1 1 - 2 a . p d f ( s h o rt c o d e : t x t 0 0 1 j e m ); 1 9 N o v e m b e r 2 0 0 2 I S S N 1 4 6 2 - 3 9 9 4 2 0 0 2 C a m b ri d g e U n iv e r s it y P r e s s

Testosterone Androgen receptor Transcription

Androgenetic alopecia occurs in men and women, and is characterised by the loss of hair from the scalp in a defined pattern. Determining factors appear to be genetic predisposition coupled with the presence of sufficient circulating androgens. The prevalence of this condition is high (up to 50% of white males are affected by 50 years of age) and, although there are no serious direct health consequences, the loss of scalp hair can be distressing. Knowledge of the pathogenesis of androgenetic alopecia has increased markedly in recent years. Pre-programmed follicles on the scalp undergo a transformation from long growth (anagen) and short rest (telogen) cycles, to long rest and short growth cycles. This process is coupled with progressive miniaturisation of the follicle. These changes are androgen dependent, and require the inheritance of several genes. To date, only one of these genes, which encodes the androgen receptor (AR ), has been identified. Of the many treatments available for androgenetic alopecia, only two (finasteride and minoxidil) have been scientifically shown to be useful in the treatment of hair loss. However, these therapies are variable in their effectiveness. Discovery of the involvement of the AR gene, and the identification of other genes contributing to the condition, might lead to the development of new and more effective therapies that target the condition at a more fundamental level.

DHT 5!-reductase

Ograndemo6vode quedacapilar androgen6ca(CALVCIE GENTICA)soos hormniosTestosteronae DHT Podemcausar miniaturizaodos folculosnaAAG

Cytoplasm

Nucleus

Transcription

Testosterone

Androgen receptor

Transcription

DHT Transcription 5!-reductase 5!-reductase 5!-reductase Finasteride Cytoplasm Nucleus

Justine A. Ellis (corresponding author) Research Fellow, Department of Physiology, The University of Melbourne, Victoria 3010, Australia. Tel: +61 3 8344 0243; Fax: +61 3 9349 4519; E-mail: justine@unimelb.edu.au Rodney Sinclair Senior Lecturer, University of Melbourne Department of Dermatology, St Vincents Hospital, Victoria Parade, Melbourne, Victoria 3065, Australia. Tel: +61 3 9288 3293; Fax: +61 3 9288 3292; E-mail: sinclair@svhm.org.au

Involvement of androgens and the androgen receptor in male-pattern baldness

Expert Reviews in Molecular Medicine C 2002 Cambridge University Press

Stephen B. Harrap Professor and Head, Department of Physiology, The University of Melbourne, Victoria 3010, Figure 3. Involvement of androgens and the androgen receptor in male-pattern baldness. (a) In the nonbalding scalp, testosterone enters the cell and is reduced to 5!-dihydrotestosterone (DHT) by 5!-reductase. Australia. Tel: +61 3 8344 5836; Fax: +61 3 9349 4519; E-mail: s.harrap@unimelb.edu.au

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DHT binds to the androgen receptor, and the complex moves into the nucleus, where transcription control of androgen-dependent genes occurs. (b) In the balding scalp, the concentration of 5!-reductase is increased, 1 A c c e s s i o n i n f o r m a ti o n : (0 2)0 0 5 1 1 - 2 a . p d f ( s h o rt c o d e : t x t 0 0 1 j e m ); 1 9 N o v e m b e r 2 0 0 2 resulting in the increased production of DHT. Because the concentration of the androgen receptor also appears I S S N 1 4 6 2 - 3 9 9 4 2 0 0 2 C a m b ri d g e U n iv e r s it y P r e s s to be increased, more complexes are formed between androgen receptors and DHT, augmenting the regulation of androgen-dependent genes in the nucleus. The androgen-responsive genes that are involved in malejunho de 2011

Androgenetic alopecia: pathogenesis and potential for therapy

j o i n s t h e re c e d i n g f ro n t a l h a i r l i n e . Ultimately, marginal parietal and occipital hair remains, and this might also continue to thin and be lost. Although this pattern is typical of most cases of androgenetic alopecia, the rate of hair loss in the various scalp regions can produce visual

Androgenetic alopecia: pathogenesis and potential for therapy

By 30 years of age, ~30% of white males have androgenetic alopecia; by 50 years of age, 50% are affected (Ref. 1). White males are four times more likely to develop androgenetic alopecia than are males:/of African rtr e vi e w s . o r g / 9). h tt p / w w w . e x p e origin (Ref. Hair loss follows a defined pattern, as described by the HamiltonNorwood scale (Refs 1, 10) (Fig. 1), beginning with bitemporal recession of the frontal hairline. This is followed by diffuse thinning over the vertex (top) of the scalp, eventually leading to complete hair loss in this region. The bald patch progressively enlarges and eventually

Androg

Prevalence and clinical features of androgenetic alopecia

with hair loss from the vertex region of the scalp. Types IVVI show further frontal and vertex loss, culminating in type VII, in which only the occipital scalp region maintains significant amounts of hair. Reproduced from Norwood, O.T. (1973) Hair Transplant Surgery (1st edition), courtesy of Charles C. Thomas, Publisher, Ltd, Springfield, e e s Illinois, USA (fig001jem). x p ie rto r e lvim e wi n e n m le c u ar dic

h tt p :/ / w w w . e x p e rtr e vi e w s . o r g /

e x p e rt r e vi e w s

in m ole c ular m e dicin e

Miniaturizao dos Folculos

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Resultado - Calvcie Androgentica

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AImportnciadainervaodosFPs

FPs so as estruturas que mais apresentam terminaes nervosas Estas produzem fator de crescimento neural e outros neuropeptdeos envolvidos no controle da proliferao de clulas dos FPs

Diversas substncias qumicas produzidas pelo sistema nervoso inibem o crescimento folicular Substncias como a Substncia P, o NGF e a Corticotrona (CRH), podem alterar o ciclo capilar

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EstressePsicoemocionaleCicloCapilar

Peters, Arck e Paus comprovaram a inibio do crescimento capilar por estresse psicoemocional envolvendo mecanismos neuroendcrinos e neuroimunolgicos em ratos Substncia P (SP) e o NGF agiram como inibidores do crescimento folicular em ratos expostos a estresse sonoro. Houve inamao neurognica perifolicular, apoptose de queratincitos dos FPs, inibio da proliferao do epitlio do FP, regresso prematura do FP (induo catgena)

Estes efeitos foram bloqueados por antagonistas de receptores de SP e anticorpos neutralizadores de NGF Tambm foram bloqueados com o uso do minoxidil Comprovou-se com o estudo a existncia de um eixo crebrofolculo piloso

Peters EM, Arck PC, Paus R. Exp Dermatol. 2006;15(1):1-13

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MediadoresdoEstressenosFPs

Concluiu que neuromediadores produzidos no estresse explicam modicaes no ciclo capilar Elucida como o estresse pode desencadear ou agravar o evio telgeno e a alopecia areata
Figure 7. Hypothetical scenario: human hair growth inhibition by substance P. Hypothetical scenario depicting direct and indirect pathways by which substance P may inhibit human hair growth in the context of psychoemotional stress and neurogenic inflammation. On the left an anagen VI hair bulb is depicted. Gray cells with black membrane show location of proliferating Ki-67 cells in the hair matrix that also express weak NK1 and TrkA immuPeters et al. The Am J Pahtol. 2007;171(6):1872-1886 noreactivity. On the right a regressing (mid catagen) hair bulb is depicted. Light gray cells indicate rarified proliferating Ki-67 cells that also express NGF and some of which express p75NTR and show ectopic MHC I expression (gray cells with black membrane). Close by a nerve fiber in contact with

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It the the inhi the ana can cult face biol In indi by the situ high mR flec ana cas sho T imp cial hav ciat

Ciclo Vicioso do Estresse

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Deu no Fantstico da Rede Globo

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FPseumequivalentefuncionalaoeixoHHA

Quem, j ouviu falar em ADRENAL? Folculos pilosos tem uma relao importante com esta glndula Por conta de uma sensibilidade especial o folculo piloso parece responder isoladamente ao estresse

FPs em meios de cultura sintetizam cortisol. Hormnios da ADRENAL aceleram ou reduzem a atividade dos folculos pilosos. Podem fazer os cabelos crescer ou CAIR (caem em situaes de estresse

Ito et al. FASEB J. 2005

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Concluses

O estresse exerce papel importante no desenvolvimento das alopecias por vias neuroendcrinas O estudo destes de hormnios e mediadores qumicos esclarece mecanismos desconhecidos dos problemas capilares
A comprenso dos mecanismos neuroendcrinos poder ajudar no desenvolvimento de novas drogas para o tratamento das alopecias

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Obrigado

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