Review on Alopecia, possible modes and interventions

Seminar:-postgraduate program
By: Awol Mekonnen

August, 30/2010

Table of contents Page

AcronymsII List of figure..III

1. Introduction.1
2. Anatomy and physiology of the human hair..2 2.1. Structure of hair.2 2.2. Hair growth cycle..4 3. Alopecia...6 3.1. Definition and types.6 3.2. Pathophysiology of alopecia...12 4. Models of alopecia..21 5. Treatment of alopecia.23 5.1. Modern drugs..23 5.2. Natural products..27 5.3. Surgery29 5.4. Others..30 6. Future perspective..31 7. References..32

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Acronyms
APCs DEBR DHT DNCB DPCP EGF FGF1 MHC PSA SADBE Antigen presenting cells Dundee experimental bald rat Dihydrotestestrone 1-chloro-2, 4-dinitrobenzene Squaric acid dibutylester Epidermal growth factor Fibroblast growth factor 1 Major histocompatibility complex Prostate specific antigen 2, 3-diphenyclopropenone

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List of figure
Alopecia areata...10 Alopecia areata pathogenesis.17 Anatomy of hair...4 Androgenic alopecia9 Hair growth cycle.5 Hair growth cycle patterns in alopecia areata19 Pathogenesis of androgenetic alopecia..14 Scarring alopecia..7 Traction alopecia11

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1. Introduction
Hair is very complicated thing. The structure of hair includes hair shaft and hair ollicle. Hair follicle is structure of which is located inside the skin. It contains several layers with variety jobs. A hair growth is in cycle manner, which has three cycles. Anagen (growth phase); catagen (regressing phase) and telogen (resting or quiescent phase) are the three phase in hair growth. Each phase has several morphologically and histologically distinguishable subphases. Alopecia is a complete or partial loss of hair, which affect primarily the scalp, which leads one to seek for medical advice so as to find out reason behind and treatment. There are different types of alopecia. Two major forms of alopecia are scarring and non-scarring. In scaring alopecia there is scar formation and the alopecia is irreversible were as in non scaring alopecia there is no scar formation and the alopecia is reversible. Among the different type andrognetic alopecia is most common which affect both man and women. The pathophsiology as well as molecular mechanism of most of the alopecia is not that much understand. The most known causes of baldness include hereditary factors, aging, and diseases affecting the entire body, scalp disorders, ionizing radiation, and reaction to drugs. There are different model for alopecia according to the type of alopecia. Most case mice or rat used to study alopecia. But, other type animal like stump-tailed macaque can be used. Other species can still develop alopecia even if they are not practically used in alopecia. Rodent models used in several ways for testing modes of therapy or disease prevention as well in study pathogenesis of the disease. Several types of alopecia treatment are available. This includes non invasive treatment like modern drug, natural product and different cosmetic aid. The invasive one includes surgery like hair transplantation, scalp reduction. Treating alopecia is essential since alopecia has devastating psychological effect in addition to some type alopecia is progressive unless treated.

2. Anatomy and physiology of human hair

Human hair is morphologically closely analogous to that of other mammals; despite extraordinary specializations the range of hair forms is limited. Other mammals have different forms of hair, such as erectile tactile hairs (under voluntary control and of much physiological interest). Another thing here is that other mammals unlike human homologous with hair growth. But, human hair growth varies depend on sexual and individual difference in regional hair development (Danforth, 1939).

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Hair is very complicated things than it appears. It has many roles for instance; it helps for transmission of sensory information and as same time creates gender identity. It is also the only body structure that is completely renewable without scarring. It is fine filament growing from mammalian skin. Every hair grows from a pit-shaped follicle embedded in the second layer of the skin, the dermis. It consists of dead cells which contain keratin protein (Brannon, 2006). 2.1. Structure of hair The follicle in the skin and the shaft above the skin that we observe are the two main structures of hair. A hair is made up from the corneous cells of the epidermis. At its base it is encircled in a bag like structure called hair sac or follicle, below this there is papilla. The superficial epidermis cells surrounding the papilla harden and form a shaft, which is at last drive out above the surface skin due to new growths from below. As the hair reached its maximum height it dies, but after new papilla and follicle formed for the purpose of growing fresh hair to replace it (Millar, 2002). The shaft of hair is constructed from hard protein called keratin and has three layers. Medulla is the inner layer which may not be present. Next medulla the cortex and finally the outer layer cuticle found. The cortex is one that makes up the main part of hair shaft. The cuticle is formed by tightly packed scales in an overlapping structure. At the cortex and medulla there are pigment cells which give the hair its specific color. Cuticle is the one which is targeted for hair

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Figure 1, Anatomy of hair

2.2. Hair growth cycle

Each head hair lasts 24 years. Hair loss is normally not noticed as new hairs replace the old ones. Baldness results when renewal is unequal to loss. It is a natural process for hair to turn grey with age. Since any change in the color of hair must happen within the follicle and will only show when the changed hairs have grown out, hair cannot become grey overnight. In some families white patches, or premature blanching of the hair, are hereditary (Robert M Hoffman, 2007). Hair grows in cycles of various phases: anagen is the growth phase; catagen is the involuting or regressing phase; and telogen, the resting or quiescent phase. Each phase has several morphologically and histologically distinguishable sub-phases. Prior to the start of cycling there is a phase of follicular morphogenesis (formation of the follicle). There is also a

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shedding phase, or exogen, that is independent of anagen and telogen in which one of several hairs that might arise from a single follicle exits. Normally up to 84% of the hair follicles are in anagen phase while, 1015% are in telogen and 12% in catagen. The cycle's length varies on different parts of the body. For eyebrows, the cycle is completed in around 4 months, while it takes the scalp 24 years to finish; this is the reason eyebrow hairs have a much shorter length limit compared to hairs on the head. Growth cycles are controlled by a chemical signal like epidermal growth factor (Chao-Chun Yang, George Cotsarelis, 2010; Samer Alaiti, 2009). Anagen is the active growth phase of hair follicles. The cells in the root of the hair are dividing rapidly, adding to the hair shaft. During this phase the hair grows about 1 cm every 28 days. Scalp hair stays in this active phase of growth for 24 years. The amount of time the hair follicle stays in the anagen phase is genetically determined. At the end of the anagen phase an unknown signal causes the follicle to go into the catagen phase. The catagen phase is a short transition stage that occurs at the end of the anagen phase. It signals the end of the active growth of a hair. This phase lasts for about 23 weeks while a club hair is formed. The telogen phase is the resting phase of the hair follicle. The final product of a hair follicle in the telogen stage is club hair, and is a dead, fully keratinized hair. Fifty to one-hundred club hairs are shed daily from a normal scalp (Chao-Chun Yang, George Cotsarelis, 2010).

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3. Alopecia 3.1. Definition and type

Alopecia is a complete or partial loss of hair, which affect primarily the scalp, which leads one to seek for medical advice so as to find out reason behind and treatment. The word hypotrichosis is used when hair loss is incomplete. Hair loss may occur only in certain area (spots) or may spread over the entire head. Physical handicap is not problem of alopecia, but may lead to psychological consequences as result of great cosmetic concern. The most known causes of baldness include hereditary factors, aging, and diseases affecting the entire body, scalp disorders, ionizing radiation, and reaction to drugs (Harrison, 2005; Abdulwahab S. alfouzan et al., 2001).

Hair loss comes in a number of different forms. But, the two major forms of alopecia are scarring and non-scarring. Scarring (cicatricial) alopecia encompasses a group of disorders and is associated with fibrosis, inflammation, and loss of hair follicles. A smooth scalp with a decreased number of follicular openings is usually observed. It is caused primarily due to primary cutaneous disorder, but sometime it may be caused due to systemic disorder. Some of coutanous disorder are; cutaneous lupus, lichen planus, folliculitis decalvans, linear scleroderma (morphea) (Harrison, 2005; Eileen Tan et al., 2004). Cicatricial alopecia occurs due to many type diseases of the scalp. Even though it is usually restricted, sometime it may be widespread. Scarred, sclerosed, or atrophic areas of scalp are represents scaring alopecia. In early stages, the disease is usually diagnosable clinically and histologically, but in late stages, only scarring may be evident. The scarring created due to destruction and fibrosis of hair follicles. It is not always true that disease categorized under the term cicatricial or scarring alopecia have histological evidence of true scar formation that is elastic fibers are destroyed. For instance, scleroderma differs from true scars, in which in scleroderma connective tissue is not destroyed but collagen fibers are thickened and hyalinized. So that under the term scarring/cicatrical alopecia diseases in which there is true scarring and others in which there is no true scar formation are included. It is better that latter could be called permanent alopecia, in which hallmark is mid-dermal hyalinization involving the follicular bulge (David a. whiting, 2001). Scaring alopecia distraction of hair follicle can result from a primary or secondary process. The hair follicle is directly the main target for destruction in primary cicatricial (scaring)

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alopecia. Evidence microscopically elucidated preferential destruction of follicular epithelium and/or its associated adventitial dermis with relative sparing of the inter-follicular reticular dermis. Some examples include discoid lupus erythematosus and folliculitis decalvans. Whereas in secondary cicatricial alopecia follicular destruction occurred indirectly from non-follicular disease. It may be occur due to exogenous and endogenous factors, such as burns and infiltrative and inflammatory diseases (eg, sarcoid, pemphigus vulgaris, tinea capitis) (Elizabeth K. Ross, Eileen Tan and Shapiro., 2005).

Figure 3, Scarring alopecia Non-scarring alopecia the hair follicles are preserved, but the hair shafts are gone, this shows that the reversible nature of non-scarring alopecia. It is caused by cutaneous disorder, some drug & systemic disorder. Some of coutanous disorder are; telogen effluvium, androgenetic alopecia, alopecia areata, tinea capitis, traumatic alopecia & some systemic disorder are; lupus erythematosus, secondary syphilis, hypothryoidism, hyperthyroidism, hypopituitarism, deficiencies of protein, iron, biotin, and zinc (Harrison, 2005). Androgenetic Alopecia is non-scaring alopecia and also known as male pattern baldness. It is commonest cause of hair loss in males, but also affects women. About 50% of adult male populations are affected by androgenic alopecia. It affects both sexes and in all ethnic groups.

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It is thought to be a hereditary form of hair loss. It is the most common form of inherited baldness, which spreads evenly, usually beginning with a partial loss of hair on the upper temples and on the crown of the head. This condition appears most frequently in men over 30 years old, although in some cases it may occur prematurely, even as early as the midteens (Asif Nawaz, Qaiser Alam Khan et al., 2006). In females androgenetic alopecia usually assumes a diffuse pattern but it occurs rarely and starts a decade or so later than in males, but they carry the genes that determine pattern baldness and pass them on to their children. It normally affects menopausal womenthat is, women around the ages of 45 to50 years old, suggesting a link to hormonal changes. Hair loss involve indirectly to physical harm because hair protects against sunburn, cold, mechanical injury, and ultraviolet light. It also has psychologically effect. Even though direct physical harm is not problem of androgenic alopecia, hair loss can end up with in physical harm indirectly since hair protects against sunburn, cold, mechanical injury, and ultraviolet light (Asif Nawaz, Qaiser Alam Khan et al., 2006; Dow Stough, Kurt Stenn et al., 2005). Androgenic alopecia manifestation in men typically in a characteristic pattern, beginning with recession of the frontal hairline and hair loss in the vertex or crown and progressing to complete loss of hair over the frontal and vertex scalp regions. Over long period of time every hair in an affected area may be changed to fine, hardly visible vellus hairs as result of miniaturization process. Besides hair miniaturization the production of pigment stops. It is still a matter of controversy as to whether the total number of hair follicles reduces during androgenic alopecia. However, it can be assumed that hairs are lost in androgenic alopecia definitely, but the majority of hair shafts are still present as tiny vellus hairs. Androgenetic alopecia in men in most severe case, hair only present around temporal, parietal, and occipital regions of the scalp in ring form. But, this is not always the case in all individuals (Dow Stough, Kurt Stenn et al., 2005; R. Hoffmann, 2002)

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Figure 4, Androgenic alopecia Alopecia areata is type of non-scarring recurrent hair loss which can affect any part of body hair-bearing area of hair follicle. It is one of common chronic inflammatory disorder of nail and hair. Even though single gene defect are not important in determining susceptibility and disease severity, genetic factors are important. Like other inflammatory disease alopecia areata environmental factor may have role in disease initiation (Andrew G. Messenger, 1997). It is commonest human autoimmune diseases, with a lifetime risk of 2%. According alopecia foundation, 14.5 million people in United States are affected with it. Both sexes in all ages and in all ethnic groups are affected by alopecia areata. It is illustrated by patchy hair loss on the scalp which may finally lead to alopecia totalis (total hair loss on scalp) or alopecia universalis (total hair loss on the body). It can be recurrent throughout life which has sudden onset and unpredictable progression (Amalia Martinez, Abraham Zlotogorski et al., 2007) Clinically, alopecia areata can manifest many different patterns. It is described by abrupt appearance of round or oval patches of hair loss with spontaneous lessening and worsens. The patches are well restricted, may have a slight peachy hue, sometimes with exclamation point hairs around their margin (broken short hairs that taper at the base). The area of skin

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affected is always is smooth and totally lack hair. Many people with the disease get only a few bare patches. Some people may lose more hair. Rarely, the disease causes total loss of hair on the head or complete loss of hair on the head, face, and body. In alopecia areata another thing is that there is nail changes. The nail changes frequency may vary from 10% to 66%. Changes may be seen in one, several, or all of the nails. Although medically benign, alopecia areata can cause tremendous emotional and psychosocial stress in affected patients and their families (Amos Gilhar, Richard S. Kalish, 2006)

Figure 5, Alopecia areata Traumatic alopecia is occurs as result of excessive pull of hair. The most common causes of traumatic alopecia are traction and trichotillomania alopecia. Trichotillomania alopecia is most seen in children than in adult. In early age female are more affected than male in ratio 2:1, but male more prone when age increase in ratio 3:2. It is used to describe alopecia resulted due to compulsively twists or pulls on hair. It is usually a habit disorder and may be as result of underlying psychologic or emotional factors (Louis Weatherhead, 2001). Traction alopecia is most common & usually seen in women. It is caused as result of excessive pulling or tension on hair shafts for beautifying hair styles. Hair loss depends on the way the hair is being pulled. Prolonged traction alopecia can stop new hair follicles developing and lead to permanent hair loss. Traction with curlers, rubber bands, braiding exposure to heat or chemicals as well mechanical pull leads to traction alopecia (Harrison, 200). Two processes that is hair weakened by chemicals and then may be broken by the application of tension or by friction. In this prolonged tension may produces inflammatory changes in the follicles, leading finally to scarring. Frontal and temporal hair margin, and also in a triangular area in

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front of, and above, the ears most common area of hair loss. Clinically, traction alopecia seen mainly in the African-American population, because of tightly braiding the hair (e.g., cornrow hairstyles) or pulling and chemicals involved in straightening the hair. Another tight hair style like pony tail also may lead to hair loss at the frontal hair margin, due to the traction produced at the hair margins by the pulling on the hair to form the pony tail. In the early stages, the changes of traction alopecia are reversible if the traction event is discontinued. Prolongation of the traction, however, will lead to permanent hair loss, with scarring of the affected follicles (Louis Weatherhead, 2001).

Figure 6, Traction alopecia A range of drug exposure can also cause diffuse hair loss, usually as result of inducing a telogen effluvium. Antimitotic agents exceptionally cause hair loss by managen effluvium such as daunorubicin. Warfarin, heparin, propylthiouracil, carbimazole, vitamin A, isotretinoin, acitretin, lithium, beta blockers, colchicine, and amphetamines have alopecia as side effect. Usually spontaneous regrowth follows discontinuation of the drug (Harrison, 2005). Individuals taking chemotherapy alopecia or hair loss, is a devastating side effect. About 85% patients in the United States, undergoing chemotherapy experience some degree of alopecia. Even if hair regrowth after chemotherapy can take from 3 to 6 months, and a small percentage of patients fail to experience complete recovery. Chemotherapy- induced alopecia is destructive since it is an outward sign of hidden disease, which may lead some patients to refuse systemic chemotherapy (Noboru Sato, Philip L. Leopold, Ronald G. Crystal, 2001).

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Anagen effluvium is hair loss that is caused by the chemotherapy or radiation therapy that is used to treat cancer. Telogen effluvium is described by a general thinning of the hair. Telogen effluvium is a form of hair loss where diffuse shedding of normal hair. Stress causes the normally asynchronous growth cycles of individual hairs to become synchronous; therefore, large numbers of growing (anagen) hairs simultaneously enter the dying (telogen) phase. Unlike some other hair and scalp conditions, it is temporary and the hair growth usually recovers. It follows either major stress (high fever, severe infection) or change in hormones (Harrison, 2005).

3.2. Pathophysiology of alopecia

Pathophysiology varies according to type of alopecia. First in androgenetic alopecia there is no clear understanding about pathology. Growth of hair affected by many type of hormones including thyroid, cortisol and sex hormones. In particular, Androgenetic stimulation will result androgenic alopecia in individuals with genetic predisposition (Asif Nawaz, Qaiser Alam Khan et al., 2006). Androgens are known to up regulate the pubic, axillary and beard hair receptors but down regulate genetically predisposed scalp hair in androgenetic alopecia, there is no clearing thing how this difference appear (Rolf hoffmann, Rudolf happle, 2007). Metabolism and synthesis of androgen has role in androgentic alopecia. Androgenetic alopecia depend on androgens, in particular the androgen dihydrotestosterone (DHT). Steroid sulfatase catalyzes first reaction of production of active androgen like DHT in skin from systemic precursor. Excess of this enzyme is thought to be cause adrogenetic alopecia. Isoenzymes 3 of 17-hydroxysteroid dehydrogenases regulate levels of bioactive androgens and estrogens in a variety of tissues. Some study show greater activity of this enzyme may associate with baldness (Rolf hoffmann, Rudolf happle, 2007). Dihydrotestosterone is synthesized from testosterone by 5_-reductase type 1 and type 2. Type 2 5_-reductase enzymes supposed to be important in androgenic alopecia since it found in hair follicle and androgen dependent tissue like prostate. Person with male partner baldness have type 2 5_- reductase enzyme, so bald male scalp has a greater capacity than non-bald scalp to convert testosterone to dihydrotestosterone. Bald men may have normal level of testosterone, but bioavailability of androgens is high. Higher salivary testosterone and lower sex hormone binding globulins support this idea (Dow Stough, Kurt Stenn et al, 2005).

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Still it is not clearly how dihydrotestosterone accomplishes its hair loss effect. Androgen affects hair growth cycle. In normal physiology, anagen has longer duration about 3 years compared to 3 months for telogen, and the usual ratio of anagen to telogen hairs is about 12:1. In androgenetic alopecia, this cycle is affected. Duration of anagen decreases that of the telogen phase either remains the same or gets longer. This results in reducing the anagen to telogen ratio. Maximum length of anagen hair is reduces because the duration of anagen is the main determinant of hair length. Eventually, anagen duration is too short for the growing hair to reach the skin surface and the only thing left is functioning follicle (Dow Stough, Kurt Stenn et al, 2005; Rodney D. sinclair, Rodney P. R. dawber, 2001). Latent component of the telogen phase (period between telogen hair shedding (exogen) and anagen regrowth) becomes progressively longer, which leads to a reduction in the number of hairs present on the scalp. In addition to this the increased telogen hairs, which are more easily plucked than anagen hair, leads to increase shedding usually seen during washing and combing the hair. Generally, shortening of anagen (growth) phase of hair cycle and as result of increase in the proportion of telogen (resting phase) hair cause baldness (Dow Stough, Kurt Stenn et al, 2005; Rodney D. sinclair, Rodney P. R. dawber, 2001). The other thing by which DHT cause alopecia is by initiates a process of follicular miniaturization in prone scalp. Because of follicular miniaturization, hair shaft width is progressively decreased until scalp hair resembles fragile vellus hair or else becomes nonexistent. That is terminal hairs changed into indeterminate hairs and finally to vellus hairs. In androgenetic alopecia there is a reduction in the terminal-to-vellus hair ratio, normally about 4:1 (Rodney D. sinclair, Rodney P. R. dawber, 2001). The papilla, the matrix, and ultimately the hair shaft are main target which affected by follicular miniaturization. The dermal papilla is thought to be target for androgen mediated miniaturization of the follicle as well changes in the hair cycle and it is fundamental to the maintenance of hair growth (Rodney D. sinclair, Rodney P. R. dawber, 2001).

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Figure 7, Pathogenesis of androgenetic alopecia The genetic inheritance of androgenetic alopecia is complex and it follows a polygenic pattern of inheritance. Expected genes are those involved in androgen conversion to DHT, androgen production and activity of the androgen receptor. Even though mode of inheritance is not yet understood, androgenetic alopecia appears to be inherited. Single autosomal dominant gene, a single pair of sexlinked factors, and polygenic inheritance are hypothesized modes of inheritance. On either side of the family a history of androgenetic alopecia may be present, but the absence of such a family history does not exclude the existence of androgenetic alopecia in the offspring (R. Hoffmann, 2002, Rolf hoffmann, Rudolf happle, 2007) Because of limited effectiveness of treatment of androgenetic alopecia with hair growth promoters of androgen metabolism leads to take into account further pathogenic pathways. A recent variety of independent studies show follicular inflammation is involved in the pathogenesis of androgenetic alopecia which is called microinflammation. The word microinflammation given because the process involves a slow, subtle, and indolent course, unlike to the inflammatory and destructive process in the classical inflammatory. Some study pointed out an inflammatory infiltrate of activated T cells and macrophages in the upper part of the hair follicles, associated with an enlargement of the follicular dermal-sheath composed of collagen bundles (perifollicular fibrosis), in regions of actively progressing alopecia. Other

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horizontal section studies of scalp biopsies shows mild perifollicular fibrosis, consisting of loose, concentric layers of collagen (Ralph M. Trueb, 2002). Like that of androgenic alopecia the pathology of alopecia areata is not well understood. It supposed to be an autoimmune disease. Alopecia areata is associated with many disorders in which autoimmunity is suspected or known to be involved. T-cells are appears to be actor of this process which activated by autoantigen. Other than this organ specific or non organ specific auto-antibodies are also detected in alopecia areata. In addition to autoimmunity pathology of hair follicle and hair growth cycle has greater importance (Andrew G. Messenger, 1997). Alopecia areata previously was believed to be infectious or neurotrophic origin. Current study shows that it is occur as result of inflammation and is likely an autoimmune disorder. There is number evidence which support ideas of alopecia areata caused due to an autoimmune mechanism. The existence inflammatory lymphocytes within or around affected hair follicles and association of other autoimmune diseases with alopecia areata has been reported. Besides, it is possible of promoting hair growth by using immunosuppressive agents is consistent with an autoimmune hypothesis (Amos Gilhar, Richard S. Kalish, 2006). It is also found that an infiltration around and within the dystrophic hair follicles of antigen presenting cells such as macrophages and langerhans cells. This is possibly consistent with a response to autoantigens within the hair follicles and attraction of these APCs. Abnormal expression of class I and II major histocompatibility complex antigens in hair follicle epithelia is thought to be the main proinflammatory event in alopecia areata. In addition there is also an increase in proinflammatory markers such as intercellular cell adhesion molecule and endothelial cell selectin in the blood vessels around the hair follicles. The existence of hair follicle specific immunoglobulin G autoantibodies in the peripheral blood of alopecia areata patients strengthen idea of that the development of alopecia areata could be autoimmune related (Andrew J. G. mcdonagh, Andrew G. messenger, 2001; Amos Gilhar, Richard S. Kalish, 2006). Several hypotheses to explain autoimmune disease development have been suggested by immunologists, but majority of these hypotheses have not been considered in the context of alopecia areata. Now day, alopecia areata development hypotheses focus on firstly on hair follicle immune privilege collapse. Immune privilege retains by anagen stage of hair follicles.

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Failer to maintain this immune privilege and exposure of unique hair follicle antigens may result in targeting by the skin immune system. Even if it is attractive due to its simplicity, this hypothesis is highly skin-centric and largely ignores current immunologic dogma (Abdullah Alkhalifah, Adel Alsantali et al., 2009; Amos Gilhar, Richard S. Kalish, 2006). The second alternative hypothesis is inappropriate presentation of antigens to the immune system during normal hair follicle cycling. As it is known hair follicle immune protection is transient, limited to the anagen growth cycle stage. Hair follicle regression in catagen phase involves significant apoptosis and immune cell infiltration. There may be continuously exposure the immune system to low levels of hair follicle derived antigens as result of this normal hair follicle cycling. Some finding shows hair follicle specific autoantibodies found in humans and animal model without alopecia areata may be a result of this constant low level exposure (Abdullah Alkhalifah, Adel Alsantali, 2009)

Figure 8, Alopecia areata pathogenesis.

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In addition to autoimmunity there is hair growth cycle disruption in alopecia areata (Amos Gilhar, Richard S. Kalish, 2006). Three hair growths cycle phase finely coordinated by the expression of hormones, cytokines, transcription factors, and their corresponding receptors and is carefully regulated through endocrine, paracrine, and autocrine routes. It is known that disruption of these finely tuned pathways can result in the development of hair diseases. Exogen is a hair follicle cycle event that describes the controlled shedding of club hair fibers. Shedding in healthy individuals occurs during the subsequent anagen growth phase as a new hair fiber is produced. Whereas in alopecia exogen occurs in advance of renewed anagen growth, leaving a hair follicle devoid of visible hair fiber which is called kenogen (ChaoChun Yang, George Cotsarelis, 2010; Abdullah Alkhalifah, Adel Alsantali, 2009). In alopecia areata disruption of the hair growth cycle clearly occurs, but different perturbations in hair growth occur depending on the pattern, severity, and duration of alopecia areata. Different type of possible presentations may exist in alopecia areata. Anagen phase of a hair follicle can become inflamed and maintained in a dystrophic anagen state firstly. Dystrophic hair follicle is unable to produce hair fiber of significant size or integrity. Greater intensity of inflammation forces hair follicles into a telogen phase and then cycle go through multiple anagen-telogen phases of short duration. Similarly, inflammatory cell infiltration occurs in early anagen follicles without migration to draining lymph nodes as follicles capitulate and return to telogen. Finally, when alopecia areata is chronic, the hair follicles tend to persist in a prolonged telogen phase without an apparent attempt to return to an anagen growth phase (Abdullah Alkhalifah, Adel Alsantali, 2009).

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Figure 9, Hair growth cycle patterns in alopecia areata. A, Hair follicles held in dystrophic anagen by mild inflammatory insult unable to produce significant hair fiber. B, Anagen growth phases truncated by moderate inflammatory insult resulting in rapid cycling and brief hair fiber growth. C, Hair follicles enter prolonged telogen dormancy with development of chronic alopecia areata. Though the genetic base of alopecia areta is not well known, the major histocompatibility complex (MHC) that is histocompatibility locus antigen on chromosome 6p21 that encodes surface proteins for self-recognition is now recognized as a major contributing factor for

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susceptibility to autoimmune diseases. It is thought that individuals with certain histocompatibility locus antigen on chromosome alleles may be more susceptible to alopecia areata than others. Multi-factorial trait inheritance is now has been suggested for alopecia areata. Researchers have also proposed that this is an autosomal dominant condition with limited penetrance. Both sexes are affected equally. It has also been reported on influence of family history on recurrence risk of alopecia areata and it is wide range reported in family histories (10% to 50%). It also reported about 100% in identical twins (Madeleine duvic, Ashley nelson, Marisa de Andrade, 2001) In spite of the unreliable nature of much of the evidence, it is possible that environmental factors are responsible for triggering alopecia areata in some patients. If this is case, it seems likely that a variety of factors can operate in this way. Even if now a day it be come to be ruled out, the idea of alopecia areata is the result of infection, either directly or as a consequence of a remote focus of infection, has a long history . There are also a few reports of alopecia areata in husband and wife, though this may be coincidence. Number of reports of an apparent association between alopecia areata and drugs, but no single drug or class of drugs predominates, and, once again, these associations may be coincidental. The external factor most frequently implicated in alopecia areata is psychological stress, even if it is difficult to study the association (Andrew J. G. mcdonagh, Andrew G. messenger, 2001). Molecular mechanism of chemotherapeutic alopecia is bit complex. As it is known anticancer drugs impair metabolic and mitotic processes in actively growing cell like hair follicles leading to the thinning of hair shaft, which make the hair fragile and susceptible to fracture with minimal trauma. As time goes on hair follicle in chemotherapy affected skin undergo apoptosis-driven regression (catagen) followed by the resting period (telogen). P53 is an important mediator in chemotherapy induced alopecia. Strong up regulation of P53 was found in cyclophosphamide treated hair follicle in the proximal outer and inner root sheaths and hair matrix, including many apoptotic cells. The exact mechanism of p53-dependent apoptosis in the hair follicle remains unclear. It may involve several p53 responsive genes acting through different mechanisms (Vladimir A. Botchkarev 2003). As it well documented exposure of rapidly divide keratinocytes in hair follicles to cytotoxic drugs is suggested to be the main cause of hair loss. In addition, the association of content of trace elements and of hair loss is well known. Varies study shows role of iron as etiological agent in hair shedding. Again long-term exposure to environmental selenium as well severe

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zinc deficiency causes hair loss. Research indicted also a relationship between trace elements and chemotherapeutic regimens. The concentrations of selenium and zinc decrease, and chromium increases in hair of patients with breast cancer. From this one mechanism of chemotherapy induced alopecia could be its effect on trace elements (Mustafa Buyukavcia, Ali Gurol et al., 2005).

4. Model for alopecia

Animal model used to study alopecia vary from one type of alopecia to other. There is certain type of animal model to study androgentic alopecia. Even if most of them are impractical several animal species have been reported to develop hair loss resembling human androgenetic alopecia, including bears, lions, red deer and non-human primates. A wellstudied non-human baldness model, however, is the stump-tailed macaque. Alopecia in macaques begins at around 4 years of age, when testosterone levels elevate dramatically in males (Rolf hoffmann, Rudolf happle, 2007; John P. Sundberg, Wesley G. Beamer, et al 1999). Rodent models can also be used in several ways for testing modes of therapy or disease prevention. Hair growth of the dorsal coat male SpraqueDawley rats appears to be androgen-dependent. The hair shafts of castrated rats appeared to be thicker and hair loss was not observed. Supplying androgen to rat cause hair loss. Now a day only one strain of mice, the androchronogenetic mouse has been described that displays androgenetic alopecia like hair loss. This hair loss can be aggravated by infusion of testosterone or DHT. So far, however, no further studies have been performed by use of this model. Transplant human hair follicles from androgen-dependent sites of the scalp (frontal hair) onto testosterone conditioned nude mice and to measure the hair cycles of these hair follicles and to assess the effect of several drugs on growth characteristics of these hairs is another approach (Rolf hoffmann, Rudolf happle, 2007). There are different Animal model for alopecia areata. One of popular of this model is using C3H/HeJ Mouse model. Naturally Alopecia areata occurs in up to 20% of C3H/HeJ females by 18 months of age and to a lesser extent in males. Several other C3H substrains including the C3H/HeN strain also develop alopecia areata. Inbred C3H/HeJ mice and other C3H substrains can be obtained from many of the commercial vendors (Motonobu Nakamura, Junichiro Jo,Yasuhiko Tabata, and Osamu Ishikawa, 2008 )

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The other model is Skin graft at which Alopecia areata can be reproducibly induced in C3H/HeJ mice by transferring full thickness skin grafts from affected C3H/HeJ mice to 10 week old female recipients. These mice develop patchy alopecia within 10 weeks of engraftment with large areas of alopecia areata by 20 weeks after surgery (Jing Sun, Kathleen A. Silva, 2009). Another inbred rodent model is dundee experimental bald rat (DEBR) model. Lesions of alopecia areat covering 50% or more of the skin surface by 18 months were developed in approximately 70% of female dundee experimental bald rat spontaneously. Though the hair loss pattern and extent of alopecia areata in both male and female rats with alopecia areata is similar, the frequency of alopecia areata in males is much less. Female DEBR has unusually high disease phenotype makes the spontaneous model a viable option for pharmacologic research. Because of unusually high disease phenotype induced alopecia areata rat model has not been developed from this strain (Jing Sun, Kathleen A. Silva, 2009; Andrew J. G. mcdonagh, Andrew G. messenger, 2001). Different animal model used for studying chemotherapeutic induced alopecia. The first model for chemotherapeutic induced alopecia is done on new born rat. In this model, administration of different chemotherapeutic agents (cytosine, arabinoside, doxorubicin, cyclophosphamide, etoposide) induced hair loss one week after beginning treatment. It was shown that by local administration of a variety of chemicals (N-acetylcysteine, minoxidil) and growth factors (interleukin-1b, EGF, FGF1) partial protection against cytosine arabinoside induced hair loss was achieved. This model has certain limitation. In first case the result obtained may less relevant to human or mice. In second case absence of rat mutants with constitutive deletion of genes suspected to mediate chemotherapy-induced apoptosis in the hair follicle (Vladimir A. Botchkarev 2003). The other model for chemotherapeutic induced alopecia is using adult mouse. The greatest amount of progress in understanding the pathophysiology of chemotherapy-induced hair loss has been achieved using the C57BL/6 mouse model developed in Ralf Pauss laboratory. In this model, a single intraperitoneal injection of 150 mg/kg cyclophosphamide induces severe alopecia. Cyclophosphamide in a dose-dependent manner induces dystrophic changes in growing hair follicle, or in more severely damaged follicles premature regression leads to hair loss (Vladimir A. Botchkarev 2003).

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5. Treatment of alopecia
Modes of intervention are depending on the type of alopecia. In general management of alopecia include taking a medical history, physical examination, evaluating changes in scalp hair in the according of the age and occupation of the individual, evaluating the importance of hair loss to the patient, and working with the patient to determine the best treatment (Dow Stough, Kurt Stenn et al., 2005).

5.1. Modern drugs

Unless androgenic alopecia treated it is progressive. Pharmacotherapy, doing nothing and accepting the cosmetic outcome (the wait and see approach), hair transplantation, and cosmetic aids are some option of managing androgenic alopecia. Minoxidil and finasteride is drug used for male androgen alopecia. Antiandrogens, hormonal contraception and estrogens (estradiol) which prolong the anagen phase of the hair cycle and thus prevent premature hair loss are for female in addition to minoxidil (Dow Stough, Kurt Stenn et al., 2005). Minoxidil is primarily introduced as a systemic treatment of hypertension. Today it is marketed also as topical 2% and 5% solutions for androgenic alopecia in men and women. Minoxidil is a potassium channel opener. The mechanism of action minoxidil in androgenic alopecia is unknown. Its angiogenic effects reverse miniaturization of hair follicles and it also increase the duration of the anagen phase. Applying minoxidil uniformly to the entire affected area of the scalp maximize its efficacy. It should be administered daily based. Discontinuing the treatment for a few months will reverse scalp to its original appearance. Minoxidil should be applied before any use of hair gel or hair spray and patient should not moisten the scalp for at least 1 hour after minoxidil administration. Generally, it is well tolerated with long-term daily use (Nicole E. Rogers,Marc R. Avram, 2008). Finasteride is primarily introduced in a 5-mg dose for treatment of benign prostatic hyperplasia. Finasteride is now marketed in a 1-mg dose for treatment of androgenic alopecia. Finasteride by selectively inhibits the type 2 5_- reductase isoenzyme responsible for converting testosterone to DHT, reduces serum and scalp DHT concentrations by approximately 60% to 70% (Dow Stough, Kurt Stenn et al., 2005). Be sides finasteride may inhibit or reverse miniaturization of hair follicles. By this it is improvement terminal-tovellus hair ratio in a scalp. Like minoxidil finasteride should be taken for long term daily based, and discontinuation of treatment progress baldness since DHT levels return to

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pretreatment levels. It also reduces total serum prostate specific antigen (PSA). Finasteride generally is well tolerated with long-term daily use (M. Bienova, R. Kuerova et al., 2005; Dow Stough, Kurt Stenn et al., 2005) As known ketoconazole is steroid biosynthesis inhibitor and an imidazole broadspectrum antifungal. High (400 mg three times a day) dose Ketoconazole can blocks both testicular and adrenal androgen biosynthesis. Inhibition of cytochrome P450 and 17, 20-lyase, which are involved in the synthesis and degradation of steroids including the precursors of testosterone is main mechanism of action of high doses of ketoconazole. The androgen lowering potential of high doses of ketoconazole has led to its use in the treatment of advanced prostate cancer as well as in androgenetic alopecia (B.S. Hugo Perez, 2003) Cyproterone acetate is known strong antiandrogens which is an androgen receptor blocker. It is used for treatment of women with hyperandrogenic conditions such as hirsutism, acne and androgenetic alopecia. Dosages of 25100 mg/day for 10 days in the first phase of the menstrual cycle are recommended for androgenetc alopecia (Rodney D. sinclair, Rodney P. R.
dawber, 2001; A. Tostia, F. Camacho- Martinez, R. Dawber, 1999)

Spironolactone is the one which directly inhibits the interaction of androgen receptor and androgen. Again, it also reduces the levels of the cytochrome P450- dependent enzymes 17_hydroxylase and desmolase, both of which are required for androgen synthesis. It is recommended that spironolactone be given at a dosage of 200 mg/day for women with androgenetc alopecia (A.Tostia, F. Camacho-Martinez, R. Dawber, 1999). Estrogens act indirectly as antiandrogenic agents by increasing the circulating levels of sex hormone binding globulin which in turn reduces circulating free testosterone, and in addition by inhibiting the release of LH-releasing hormone which results in an overall decrease in gonadal androgen synthesis (Rodney D. sinclair, Rodney P. R. dawber, 2001; A. Tostia, F. Camacho-Martinez, R. Dawber, 1999). Dutasteride and Latanoprost are drugs which undergone development. Dutasteride is a dual type I and type II 5_-reductase inhibitor. It is approximately 3 times as potent as finasteride at inhibiting type II enzyme action, and 100 times as potent at inhibiting type I enzyme action. It is has an ability of reducing serum DHT by up to 90%, about a 20% greater reduction compared to finasteride. Even though type II 5_-reductase is the predominant 5_-reductase enzyme expressed in scalp, expression of the type I enzyme occurs in scalp also. This dual

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inhibitor has recently been tested for improved efficacy over finasteride in promoting hair growth (Justine A. Ellis, Rodney D. Sinclair, 2008). Latanoprost is a prostaglandin analogue which was first introduced as a treatment for glaucoma (ocular hypertension) to reduce intraocular pressure. Soon after, it was known the stimulatory effects of this compound on eyelash and eyebrow hair growth and pigmentation in high numbers of patients were reported. Due to this potential for the use of latanoprost as a hair growth stimulant was highly attract researchers. The expression of prostaglandin receptors was examined in mouse skin hair follicles, and mRNA was identified in dermal papilla and outer root sheath follicular structures during anagen (Justine A. Ellis, Rodney D. Sinclair, 2008). Even though several treatments can induce hair growth in alopecia areata, none has been shown to alter the course of the disease. Again also high rate of spontaneous remission makes it difficult to assess efficacy, particularly in mild forms of the disease. Not treating alopecia areata is a legitimate option for many patients. In <1 years spontaneous remission occurs in up to 80% of patients with limited patchy hair loss of short duration (S.P.Macdonald hull, M.L.Wood, et al., 2003). Corticosteroids are drug which has capability of reducing inflammation and allergic reactions, prevention of graft rejection. Topical corticosteroids, intralesional corticosteroids, and systemic corticosteroids are used for the treatment of alopecia areata (Abdullah Alkhalifah, Adel Alsantali et al., 2009). Like andogenetic alopecia in alopecia areata minoxidil used for treatment. 5% minoxidil is mainly used as adjuvant treatment to conventional therapy. Topical minoxidil show efficacy in treatment of alopecia totalis and alopecia unversalis (S.P.Macdonald hull, M.L.Wood, et al., 2003). Contact immunotherapy the other possible treatment for alopecia areata and was introduced by Rosenberg and Drake in 1976. 1-chloro-2, 4-dinitrobenzene (DNCB), squaric acid dibutylester (SADBE) and 2, 3 diphenylcyclopropenone (DPCP) are contact allergens used for treatment for alopecia areata (S.P.Macdonald hull, M.L.Wood, et al., 2003; Abdullah Alkhalifah, Adel Alsantali et al., 2009). The protocol for contact immunotherapy in patient is sensitized using a 2% solution of DPCP applied to a small area of the scalp. Two weeks later the scalp is painted with a weak solution of DPCP, starting at 0.001%, and this is repeated at weekly intervals. The concentration is

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increased at each treatment until a mild dermatitis reaction is obtained (S.P.Macdonald hull, M.L.Wood, et al., 2003). DNCB is not generally used today because it has been shown to be mutagenic in the Ames test. DPCP is the topical sensitizer of choice because SADBE is not stable in acetone (Abdullah Alkhalifah, Adel Alsantali et al., 2009). Photochemotherapy is used in treatment of alopecia areata with limited success. Systemic and topical psoralen plus ultraviolet a light phototherapy has been used with limited success. Long-term safety, side effects, and a high relapse rate have curtailed the use of psoralen plus ultraviolet a light phototherapy (Abdullah Alkhalifah, Adel Alsantali et al., 2009; S.P.Macdonald hull, M.L.Wood, et al., 2003). Cyclosporine is an immunosuppressant agent that inhibits helper T-cell activation and suppresses interferon gamma production. Success rates with oral cyclosporine range from 25% in some trials to 76.7% in others if combined with methyl prednisolone. Cyclosporine has been used alone or in conjunction with corticosteroids with a success rate up to 76.6%. Cyclosporine use is limited by its side effects and high relapse rate (Abdullah Alkhalifah, Adel Alsantali et al., 2009). There is difficulty in treatment alopecia areata sub type that alopecia unversalis and alopecia totalis. Accourding to Ursula Kaelin et al. study efalizumab, which is a humanized monoclonal anti-CD11a antibody that inhibits T-cell activation and migration, is effective in the treatment of such type (Ursula Kaelin., 2006)

5.2. Natural product

Study shows Help Hair Shake which contains whey protein concentrate, not whey protein isolate is used to improve hair as well nail change. Natural whey which was produced from cow has been used for millennium, both internally and externally, to enhance hair growth, strength and shine. Whey provides calcium, as well as protein necessary for proper hair growth (Lawrence Shapiro, 2010). Artocarpin is a naturally occurring compound isolated from a diethyl ether extract of heartwood of Artocarpus incisus. Artocarpin is capable of inhibiting 5-reductase. It acts on androgen receptors which are found in both preputial skin and nongenital skin. So, it might be useful in selective treatment of androgendependent disorders such as male pattern alopecia and achne. The penetration of Artocarpin into the deeper layers of the skin where androgen receptors are present is limited. To avoid this problem it prepared as microparticles (U.B. Jagtap, V.A. Bapat, 2009).

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Vinegar, garlic and sometime castor oil used in Arabic world for alopecia. Friction is applied to the area of alopecia with a piece of cloth until bleeding occurs, followed by an application of garlic or vinegar (Oumeish Youssef Oumeish, 1999). According to Seok-Seon RhoA et al study a radix has hair growth effect. A radix is a traditional herb medicine that is used in Korea and China to treat various diseases, such as aphthous stomatitis, local pain, toothache, and gingivitis. A. radix extract has outstanding hair growth promoting effects in rodent models (Seok-Seon Rho, 2005). According to Lipi Purwal et al study hair formulation which consists of Emblica officinalis (Euphorbiaceae), Bacopa, monnieri (Scrophulariaceae), Trigonella foenumgraecum (Leguminosae), Murraya koenigii (Rutaceae) in various concentrations in the form of herbal oil has hair growth activity (lipi purwal, 2008). Cuscuta reflexa is a holoparasitic vine that attacks the aerial parts of many shrubs, trees, and is used immensely in the Indian system of medicine. The petroleum ether extract of Cuscuta reflexa and its isolate is useful in treatment of androgeninduced alopecia by inhibiting the enzyme 5_-reductase (Salim Khan et al., 2010) Different parts of several types of plant in India used for their hair growth effect. Hbiscus rosa-sinensis Linn (Malvaceae), Cuscuta reflexa Roxb (Convolvulaceae), Asiasari radix (Aristolochiaceae), Ocimum gratissum Linn (Lamiaceae) and many other used for their hair growth effect (V.M. Jadhav, 2009).

5.3. Surgery
A range of surgical procedures is available, which include hair transplants, scalp reduction, rotation flaps, punch grafting, and single follicle transplantation. Transplants are currently the most popular form of procedure, and together with scalp reduction and rotation flaps can give good results if performed by an experienced surgeon (A. Tostia, F. Camacho-Martinez, R. Dawber, 1999). Nearly for half a century surgical techniques especially hair transplantation have been used to manage androgenic alopecia. Hair transplantation is the main treatment option for those who do not success with other therapy. This technique takes advantage of the fact that hair in the posterior scalp grows for much longer than other areas of the scalp. Elliptical strips harvested from this donor region, and divide the strip into individual hair follicles. Area to be transplanted was numbed and hundreds of nicks were created where the transplanted hairs will be placed. Then hair will be moved efficiently into the new sites. The

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grafts heal in overnight, and over the next 6 to 8 months these new hairs will grow (Nicole E. Rogers, Marc R. Avram, 2008). In the past 20 years hair restoration surgical technology and techniques show great advancement. Pervious techniques are not that much effective, because unnatural results remain in patients who underwent procedures performed with older techniques. While in present technique the result from hair restoration appears to be much more pleasing and natural than the previous one because of advance in surgical technique (Dow Stough, Kurt Stenn et al., 2005). Scalp reduction another possible surgical intervention in which areas of balding scalp are take off to bring areas of hair containing scalp closer to one another. Scalp reduction has draw back since repeated scalp reduction need because of progressive nature of hair loss beside there is potential possibility widening of scars over time. But, it has beneficial effect in selected androgenic alopecia patient (Dow Stough, Kurt Stenn et al., 2005).

5.4. Others
Cosmetic aids give other possibility in management of androgenic alopecia. Cosmetic aids like wigs (false hair) and hairpieces used for hiding hair loss. They can be used lonely or in conjunction with surgical or pharmacotherapy. One thing here is that they do not treat underlying condition. At present wigs and hair systems appears much more natural than the pervious. Pigmented powders, lotions, and hair sprays can be used to assist in hiding hair loss since they increased density or decreasing the color contrast between the hair and the underlying scalp loss by adhering to existing hair. As whole managing patient perception play an important role for the effectiveness of the treatment (M. Bienova, R. Kuerova et al., 2005; Dow Stough, Kurt Stenn et al., 2005) For many female patients with extensive alopecia areata a wig or hairpiece is the most effective solution. Some men also request a wig although male wigs rarely appear as natural. Acrylic wigs are much cheaper than real hair wigs and are easier to look after (S.P.Macdonald hull, M.L.Wood, et al., 2003). Camouflage is the cheapest, easiest as well the simplest way of dealing with mild androgenetic alopecia. Balding is noticeable when the scalp seen through the hair. Treatment with camouflage dye of the scalp gives the scalp the same color as the hair, and gives the illusion of thicker hair. Numerous brands are available in pressurized spray cans in a number of different colors, and they are often combined with a

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holding hair spray (and sunscreen). The hair is dried and styled before the dye that matches the patients hair color is sprayed onto the base of the hair. Although many of the newer agents are water resistant, problems may still arise if the hair gets wet and the dye runs. In addition, patients should avoid touching their hair, as the dye will color their hands (Rodney D. sinclair, Rodney P. R. dawber, 2001).

6. Future perspective
So far the predisposing genes for most of alopecia like androgentic alopecia, alopecia areata as well for others are not well known and again the molecular steps involved in alopecia is not well understand. Near future by cloning the entire human gene there may chance of getting new tools to explore the pathogenesis most of alopecia type in detail. Knowing the pathogenesis will help in developing new treatment strategies, since most the treatment which exist now day are not that much effective. In addition of developing new pharmacological treatment, it also helps in upgrading the non pharmacological treatment. In general the future is bright but it is not because of any reflections from bald spots. Rather, it is due to new technologies and research which discover new methods for treating hair loss. Even though there are several treatments which used clinically their effectiveness is not that much. And again the progress of searching new treatment option for alopecia is seems to be slower than expected. In the future treatment options like such as gene therapy, hair multiplication and other new drugs will eventually become available. Which thought to be effective as well reduce the duration of treatment.

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Ursula Kaelin, Akmhal Said Hassan, Lasser Roger Braathen, Nikil Yawalkar (2006), Treatment of alopecia areata partim universalis with efalizumab, p 529532

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