Fundamentally, a hair disorder is any condition where the visible

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1 Biology of the hair follicle and mechanisms of nonscarring and scarring alopecia Thomas W Chu, MD, 1,2 Leopoldo Santos, MD, 1 and Kevin J McElwee, PhD 1,3 n Abstract There are many hair disorders, all of which involve alterations in normal hair biology. Essentially, hair disorders involve changes to hair fiber caliber, density per unit area, and/or the duration of anagen and telogen in the hair growth cycle. Hair disorders may be triggered by inflammation, genetics, the environment, or hormones; the relative contributions of these factors vary for different hair disorder diagnoses. Suitable treatments may either address the underlying causal factors or directly act on hair follicle biology. The objectives are to normalize the hair growth cycle, modulate the size of hair follicles, and potentially regenerate hair follicles to stabilize hair density. The purpose of this manuscript is to review the basic biology of the hair follicle, as well as causal mechanisms for the disordered hair follicle using some selected examples of hair disorders. Semin Cutan Med Surg 34: Frontline Medical Communications Fundamentally, a hair disorder is any condition where the visible hair coverage over the skin falls outside of normal hair growth parameters. The definition of normal hair growth varies with gender, ethnicity, culture, fashion, age, and very often with the particular opinion of the individual concerned. 1 For scalp hair coverage to be normal, there must be a certain density of terminal hair fibers/follicles over the frontal, temporal, auricular, midscalp, vertex, and occipital scalp; though there may be considerable degrees of tolerance in these parameters for any given population. 1 Department of Dermatology and Skin Science, The University of British Columbia, Vancouver, BC, Canada. 2 Department of Dermatology, Far Eastern Memorial Hospital, New Taipei, Taiwan. 3 Vancouver Coastal Health Research Institute, Vancouver, BC, Canada. Funding: Dr Chu: Canadian Dermatology Foundation. Dr Santos: Canadian Dermatology Foundation, and North American Hair Research Society. Dr McElwee: Canadian Institutes of Health Research, Michael Smith Foundation for Health Research, National Alopecia Areata Foundation, Canadian Dermatology Foundation, Replicel Life Sciences. Disclosures: Drs Chu and Santos have nothing to disclose. Dr McElwee is the Chief Scientific Officer and a shareholder of Replicel Life Sciences Inc. Correspondence: Kevin J McElwee, PhD, Department of Dermatology and Skin Science, The University of British Columbia, 835 West Tenth Avenue, Vancouver BC, V5Z 4E8, Canada. kmcelwee@mail.ubc.ca. Hair biology Hair follicle density Outside of experimental induction or injury mediated hair follicle formation (neogenesis), 2,3 embryogenesis determines the total number of hair follicles an individual has, potentially for the duration of life. Extensive research has examined hair follicle embryogenesis and its control, though our understanding of the biological mechanisms involved is still quite limited. 4,5 However, it is clear that very specific signalling through multiple pathways is required for the correct development and geographical distribution of hair follicle formation in the skin. 6 Though very rare and typically due to a genetic modification, perturbations in hair follicle embryogenesis result in hypotrichosis, a deficiency of hair growth from birth. 7 Much more common is an initially normal density of hair follicle formation which is later adversely impacted by an insult subsequently leading to hair loss and alopecia development. Hair fiber size Hair fibers are classed into 3 different groups and size is the key feature that determines their categorization. 4,8 Most of our hair follicles produce short, fine, nonpigmented vellus hairs. In contrast, eyebrow, eyelash, and scalp follicles produce much bigger, slowly cycling, usually pigmented, terminal hairs from birth. Follicles retain a degree of plasticity with respect to the type of hair produced and they can transform from vellus into terminal hair production and vice versa. Hair follicles progressing through a transition in size are defined as producing intermediate hairs. Hair follicle size, and so the size of the hair fiber they produce, potentially has a big impact on hair coverage. A switch of the hair follicle from terminal to vellus (miniaturization) can be seen with the development of androgenetic alopecia or chronic alopecia areata, for example. Conversely, a vellus-to-terminal body hair follicle switch is seen with hirsutism and hypertrichoses. Hair growth cycle Potentially significant changes to normal hair cycling can be part of alopecia development. 7 There are 3 main hair follicle growth cycling phases: anagen, when follicles are actively growing hair fiber; hair follicle regression during catagen; and a telogen quiescent resting phase. 4,9 How long each phase takes partly depends on the type of hair follicle involved and its geographic location. On the scalp, about 85% of scalp hair follicles are in anagen and 15% are normally in telogen. 4 Anagen in nonalopecia-affected scalp hair follicles may last 2 to 6 years in duration with about 3 months for telogen and 3 to 4 weeks for catagen. 4 This hair cycle clock can become unbalanced in individuals affected by alopecia. Specific changes in expression of hormones, cytokines, and their respective receptors, as well as transcription factors, enzymes, antagonist binding proteins, and epigenetic events can modify the time duration of anagen and telogen Changes in hair cycle with alopecia development In isolation, increased anagen duration does not alter scalp hair density; it only defines the maximal length to which hair can grow. 50 Seminars in Cutaneous Medicine and Surgery, Vol 34, June /13$-see front matter 2015 Frontline Medical Communications DOI: /j.sder

2 Chu et al A brief anagen phase may only really become apparent if the duration is shortened to a few weeks in scalp hair follicles. However, anagen effluvium and alopecia areata can involve a dystrophic anagen state where the follicle is active, but unable to produce healthy fiber. 12,13 In contrast, prolongation of the telogen phase in scalp hair follicles can be a significant factor in many forms of alopecia development. Hair fibers continue to be shed over time, an event known as exogen. 14,15 Normally, the shedding of old club hair fibers occurs when follicles are in an early anagen phase. A new, actively growing fiber is present to take the place of the shed fiber; and consequently, there is no net loss of hair. However, in prolonged telogen, with the failure of follicles to enter a new anagen phase, new hair fiber is not produced to replace the old, shed fibers. A hair follicle with no hair fiber present is described as being in a state of kenogen. 16 Kenogen can be observed in a few hair follicles in healthy scalp skin, but the frequency and duration of kenogen is significantly greater in individuals with alopecias. 17 Such a situation is classically observed in the early stages of androgenetic alopecia and in telogen effluvium (TE). Noninflammatory hair loss Noninflammatory hair loss most commonly involves a form of TE; essentially, an increased shedding of telogen club hairs. TE may either be the primary diagnosis, observed as part of a larger insult, or the mechanism of TE may be a component of other hair loss diagnoses. This commonality of the telogen shedding mechanism can make it difficult to determine TE as a standalone diagnosis. Clinically, TE is characterized by a diffuse positive hair-pull test and no miniaturization of hair follicles/fibers. Trichoscopy is an important tool to evaluate vellus hair (miniaturization). If the number of vellus hair follicles is increased, the diagnosis is more consistent with pattern hair loss. 18 The most important findings to favor TE are a normal terminal to vellus ratio (no miniaturization) and decrease in the anagen to telogen ratio (increase in telogen hairs). 19 Telogen effluvium Kligman in 1961 was the first to name excessive shedding of normal club hairs as TE. A variety of stress factors can cause TE including; fever, postpartum hormonal changes, psychogenic disorders, chronic systemic diseases, drugs and synchronized shedding in newborns. 20 Headington proposed 5 functional types of TE categorizing them by the nature of the changes made to the hair growth cycle and the exogen event: immediate anagen release; delayed anagen release; short anagen; immediate telogen release; and delayed telogen release. 21 With immediate anagen release, anagen stage follicles prematurely enter telogen, an event that probably characterizes drug-related issues or high fever. Delayed anagen release synchronizes many follicles in the anagen phase which may allow them to shed when changing phase. This is believed to be the mechanism of postpartum hair loss where hair follicle growth cycles are synchronized by elevated hormones during pregnancy and the sudden return to normal hormonal levels releases the synchronized follicles enabling a simultaneous shedding as the follicles enter telogen together. During the short anagen phase, though no clear scientific proof exists, clinical experience shows that persistent TE may involve increased shedding due to idiopathic shortening of anagen duration. Truncated anagen cycling can also be seen in some presentations of alopecia areata. During immediate telogen release, the mechanism in this case occurs due to a shortened telogen phase and initiation of the next anagen phase. Such an event may occur with the start of minoxidil use. As many follicles are pushed into anagen at about the same time under the control of minoxidil, the exogen shedding of club fibers may also occur together in many follicles. The delayed telogen phase occurs at the end of prolonged telogen and at the initiation of anagen. For instance, many mammals shed their winter pelage with the onset of spring. Similarly, Headington suggests that people who travel from low-daylight to high-daylight regions might be exposed to episodes of TE due to this mechanism. 21 Later, Rebora revised and simplified Headington s classification to include 3 groups: premature teloptosis (immediate telogen release), collective teloptosis (delayed anagen and telogen) and premature entry into telogen (immediate anagen release). 22 Clinical telogen effluvium types In the general dermatology clinic, telogen effluvium (TE)is categorized into main 3 subtypes: acute telogen effluvium (ATE) that lasts less than 6 months; chronic diffuse telogen hair loss (CTHL) that last more than 6 months; and chronic telogen effluvium (CTE). ATE and CTHL are associated with triggers such as high fever, surgery, changes in medication, crash diets, postpartum, thyroid disorders, iron deficiency, nutritional and metabolic disturbances, malignancies, and drugs. 23 CTE has been described by Whiting as an idiopathic diffuse hair thinning in middle-aged women. CTE starts abruptly affecting the whole scalp, but most severely in the bitemporal areas, and occurs with a long fluctuating course. 24 There is no increase in miniaturized hairs and no change to the normal anagen to telogen ratio. The main differential diagnosis is female pattern hair loss (FPHL) which is distinguished from CTE due to the presence in FPHL of miniaturization and a decreased anagento-telogen ratio. 24 There is a debate if CTE is an early FPHL stage. However, Sinclair followed up 5 patients with CTE for 7 years; 4 out of 5 patients remained diagnosed with CTE and showed no signs of progression to FPHL. 25 Anagen effluvium Rarely, anagen effluvium can be observed. It is caused by chemotherapeutic agents and radiotherapy. Anagen effluvium occurs 1-2 months after treatment in the absence of a shift in hair follicle cycle from anagen to telogen. The shed hairs are visibly distinct from the shape of telogen club hairs, often exhibiting a tapered root. Chemotherapy drugs blockade rapidly dividing cells in anagen hair follicles cells, essentially placing the follicles into a state of suspended animation. The follicles are no longer capable of maintaining the growth of a coherent hair fiber yet structurally appear to be in anagen. This type of hair loss is usually reversible after treatment, though some individuals can experience permanent alopecia and occasionally changes to hair curl and pigmentation. 26,27 Pattern hair loss While TE may be a distinct diagnosis, TE shedding can be observed in other forms of noninflammatory hair loss, particularly pattern hair loss (androgenetic alopecia). Men can develop pattern hair loss with first onset starting as early as their teenage years. 28 Women can also be affected with a more diffuse patterned hair loss. Up to 70% of men and 40% of women can be affected with Vol 34, June 2015, Seminars in Cutaneous Medicine and Surgery 51

3 n n n Biology of the hair follicle and mechanisms of nonscarring and scarring alopecia some degree of hair loss in mid-adult life, though the frequency varies significantly in different ethnicities. 29 The Norwood-Hamilton classification system is often used in the dermatology clinic to categorize degrees of hair loss in men. The male pattern typically begins with bitemporal recession, followed by vertex baldness and mid-frontal hair loss, though pattern variation has been seen in different ethnic groups. 29,30 For women, either the three-category Ludwig scale, or the more detailed Savin scale, are used to classify degrees of diffuse female pattern hair loss (FPHL). 31 Androgen hormones It is generally accepted that androgen hormone action on hair follicles via androgen receptors provides the driver of androgenetic alopecia (AGA) though there is some debate over the true significance of androgens in FPHL. The effect of androgens on hair follicles in specific scalp regions is likely due to variation in factors such as androgen receptor density and distribution, localized and systemic production of androgens, the local conversion of androgens to dihydrotestosterone (DHT), the local production of androgen antagonists, and the degradation rate of DHT. 32,33 Some small studies have suggested an additional issue with inflammation and scar tissue formation in some men with pattern hair loss. The full significance of fibrosis is unknown, but it has been shown to have an impact on the degree of response to treatment with minoxidil for example. 34 In the presence of androgens, dermal papilla cells alter their production of hair growth regulatory factors. 35,36 The dermal papilla miniaturization and compromised growth factor signaling yields finer, unpigmented vellus-like hair. Hair biology changes with alopecia development Pattern hair loss is a result of altered hair-growth cycling resulting in reduced anagen to telogen ratios, plus hair follicle miniaturization, and the associated switch to production of shorter, finer hair fibers. 37 Anagen duration in men with pattern hair loss can reduce from 2-6 years to just a few months. The telogen phase may last for the same time, but more typically the telogen phase becomes much longer. 38 This premature curtailment of anagen and the relative prolongation of telogen combine to yield an anagen to telogen ratio reduction from typically 12:1 to as low as 5:1, 34 while the number of telogen stage hair follicles increases from 5%-10% to 15%-20%. 39 The increased duration of telogen combined with the continued shedding of telogen club hairs (exogen), yields a progressive increase in the numbers of empty kenogen hair follicles and a noticeable reduction of scalp hair coverage. Inflammatory hair loss Inflammation and hair loss Hair loss promoted by some form of inflammatory insult is not unusual. The inflammation may be specific for the hair follicle or nonspecific. For example, skin inflammation associated with lupus erythematosus may induce a diffuse alopecia in regions of inflamed skin. 40 In this situation, the inflammatory infiltrate is not specifically targeting hair follicles; but due to the general inflammatory effect, hair follicles in the vicinity are adversely affected. While nonspecific inflammation can promote a hair disorder, inflammatory hair loss disorders involve specific targeting to the affected hair follicles. It is worth noting that the target of interest for the inflammatory cells can be exogenous; the hair canal is a known reservoir of bacteria, fungi, viruses, and even parasitic organisms like demodex folliculorum Where exogenous stimulators are involved, the inflammatory hair loss condition is usually treatable by removing the antigenic challenge. However, usually endogenous hair follicle specific targets are of interest to inflammatory cells, as is probably the case with alopecia areata or scarring alopecias. These conditions have been studied in some detail and for both it has been hypothesized that hair follicle expressed antigens are inappropriately stimulating the immune system. Hair follicles and immune privilege In the same way as for other organs like the testis and the anterior eye chamber, hair follicles exhibit immune privilege (IP), a region of tissue where normal immune cell activity is modulated. 37,48 IP sites are characterized by little or no expression of major histocompatibility complex class I (MHC-I), an increase in cytokines with immunoregulatory potential, and expression of cell surface immunosuppressive factors. 48 Studies from several labs suggest IP is present in at least anagen-stage hair follicles, though catagenand telogen-stage follicles may not be protected. 49,50 Loss of IP function in tissues has been demonstrated in several autoimmune conditions including multiple sclerosis, autoimmune uveitis, and autoimmune hepatitis. 51 In theory, if hair follicles have defective IP function, immune surveillance cells may infiltrate and recognize hair follicle specific self-antigens. 50 Activated immune cells express various inflammatory cytokines and pro-apoptotic factors that could interfere with hair fiber growth and, in turn, this may cause alopecia. Currently, changes to hair follicle IP function underpin several hypotheses of both nonscarring and scarring inflammatory alopecias. Nonscarring inflammatory alopecias Nonscarring inflammatory alopecias involve little or no connective tissue formation. 49 While there may be extensive inflammation with considerable disruption of the hair follicle unit, the damage is usually reversible. Regeneration and reformation of the hair follicle unit is possible in nonscarring alopecia, once the previously hostile milieu becomes more favorable for hair growth. Nonspecific inflammation in response to contact allergens or mild irritants may elicit a reversible alopecia, however, alopecia areata (AA) is the classic example of nonscarring, inflammatory alopecia. 52 Alopecia areata The variety of clinical presentations of AA indicates that there are different mechanisms involved in AA pathogenesis, but likely all based on a common principle. 53 Many factors are suggested to be involved in activating the onset of AA such as infectious agents, stress, genetics, diet, hormones, and vaccinations though their specific roles have not been elucidated. 50 Hair follicle specific autoantibodies have been found in peripheral blood and skin lesions of AA patients. 49 However, Gilhar et al were not able to inhibit hair regrowth by injecting serum of AA patients to nude mice grafted with human skin biopsies. 54 Rather, AA is generally believed to be a T-lymphocyte mediated inflammatory alopecia. The collapse of hair follicle IP has been shown in humans and rodent models of AA. 55,56 Classic AA histopathology involves a swarm of bees where a lymphocytic peribulbar infiltrate surrounds anagen hair follicles. Lymphocytes also infiltrate to 52 Seminars in Cutaneous Medicine and Surgery, Vol 34, June 2015

4 Chu et al intrafollicular areas. 57 Several studies now show that the infiltrate is responsible for the initiation of hair loss. 58,59 Notably, Gilhar et al used melanoma associated antigens to stimulate T cells to induce AA in a humanized mouse model. 60 Hair biology changes with AA development In the early phase of AA, follicles often enter a dystrophic anagen state. With time and/or severity of the inflammation, there is a progressive shift from anagen- to telogen-stage follicles. 50,61 Nanogen hairs that result from a miniaturization of hair follicles, can also be observed. The number of nanogen hairs increases as the disease progresses. Interestingly, the intensity of inflammation decreases when the number of telogen hair follicles increases. Therefore, in chronic stages of AA, there may be few lymphocytes, but extensive telogen and/or miniaturized hairs. 61 Despite the intensity of inflammation, scar tissue formation does not occur except perhaps in a few longstanding cases. For most affected individuals, full recovery from AA is possible, even after many years. This is in contrast to people affected by scarring alopecia. 62 Scarring inflammatory alopecias Scarring (cicatricial) alopecia is a general term for a group of relatively rare and complex hair loss disorders involving the permanent destruction of the hair follicle unit. Scarring alopecia implies that the follicular epithelium has been destroyed and replaced by connective tissue. There are primary and secondary scarring alopecias. 63 Primary scarring alopecia involves specific targeting of the hair follicle unit for destruction while secondary scarring alopecia involves the nonspecific destruction of follicles from generalized skin tissue damage such as burns and blistering disorders such as pemphigus vulgaris. The current working classification for primary scarring alopecia is based on the type of principal inflammatory cell (lymphocytic, neutrophilic, mixed, and nonspecific) detected in scalp biopsy specimens from active lesions. 64 Once a histological subgroup has been identified, the specific disease may be further categorized based upon relevant clinical features. Regardless of the causes and classification, the pathologic endgame for all scarring alopecias is the disintegration of the follicular unit and a permanent loss of the ability to produce hair. 65 There are various unifying hypotheses for cicatricial alopecia development that involve inflammatory cell-mediated destruction. Several scarring alopecia diagnoses provide evidence in support of these common hypotheses of development. Lichen planopilaris Lichen planopilaris (LPP), a follicular variant of lichen planus, 66 may present as alopecic patches or diffuse hair thinning accompanied by pruritus, burning, and sensitivity of the scalp that most commonly starts in the parietal region. 67,68 Clinical features may show hyperkeratosis and perifollicular erythema. 66 Exposure to gold, a known nonspecific stimulant of the immune system, as well as atabrine, quinacrine and vaccination, has been linked to the onset of LPP Several reports have documented LPP occurring months or years after hair transplantation. 73,74 Histologic findings noted for the lichenoid interface dermatitis involve the infundibulum and superficial isthmus, with sparing of the lower third of the follicle and interfollicular epithelium. 75 LPP appears as a wedgeshaped scar in the infundibulum with a loss of the elastic fibers in the scar which are preserved in the interfollicular dermis. 76 A recent case series found a decrease or near absence of catagen- and telogen-phase follicles. 77 Discoid lupus erythematosus Discoid lupus erythematosus (DLE) frequently starts at the occipital and parietal scalp 67 and may present as one or more erythematous patches of hair loss. Clinically, follicular hyperkeratosis, hyperpigmentation, depigmentation, and telangiectasia may be found in or around the lesions. 61 Exposure to ultra violet (UV) light has been associated with DLE onset and it is thought that, as a sequalae of UV light exposure, keratinocyte apoptosis and a reactive T-cell or immune complex-mediated response occurs, leading to onset of an inflammatory cell-mediated alopecia. 78 Key histological findings are vacuolar interface alterations of the follicular and interfollicular epithelium with epidermal atrophy. 75 Also seen are basement membrane thickening, follicular plugging, superficial and deep perivascular and perieccrine lymphoplasmacytic infiltrates, deep dermal mucin, and loss of sebaceous glands. 75 DLE is known to occur in areas of excoriation and, in a mouse model, superficial wounding induces keratinocyte trauma with features similar to those seen in DLE Though the evidence is circumstantial, it is consistent with activation of the immune system through inappropriate antigen exposure and/or presentation. Central centrifugal cicatricial alopecia Central centrifugal cicatricial alopecia (CCCA) refers to central scarring hair loss seen predominantly in women of African descent. 64 Although hair care practices such as traction and chemical processing with relaxers were thought to play a role, current evidence does not support a strong association. 81 CCCA is characterized by an alopecic patch on the central scalp that slowly progresses in a centrifugal and symmetrical manner. 67 Although histologic features of late-stage CCCA are nonspecific and seen in other scarring alopecias, the most important histologic finding of CCCA is premature desquamation of the inner root sheath (PDIRS). 75 It is thought that the loss of physical barrier provided by the inner root sheath (IRS) enables the entry of bacteria or chemicals to initiate inflammation. 75 Folliculitis decalvans While LPP, DLE, and CCCA potentially suggest autoimmune mediation of alopecia, folliculitis decalvans (FD) may be more strongly associated with exogenous agent stimulation of the immune system. FD, also known as tufted hair folliculitis, is a scarring alopecia associated with neutrophilic inflammatory cell infiltration. It occurs mostly in young and middle-aged adults with a slight male predominance. 82 It presents as erythematous patches, follicular pustules and follicular hyperkeratosis. 67 Staphylococcus aureus is commonly cultured from the primary lesions of FD patients. Factors thought to contribute to FD include a local or systemic immune deficit that predisposes one to S. aureus infection and properties related to S. aureus strains, 83,84 with some believing that the immune deficit a likely causative factor in scarring alopecia onset. 85,86 Several acquired and inherited immune disturbances have been associated with FD. 85,87 However, the majority of affected patients have no overt systemic or lesional immune abnormality. Recently, there was evidence that bacterial biofilm could be found in the anaerobic part of affected hair follicles. 88 Vol 34, June 2015, Seminars in Cutaneous Medicine and Surgery 53

5 n n n Biology of the hair follicle and mechanisms of nonscarring and scarring alopecia Immunoreglulation and scarring alopecia Some suggest an autoimmune-mediated mechanism is common to many forms of cicatricial alopecia where a clear exogenous target cannot be identified. Autoimmunity either involves inappropriate presentation of self-antigens by antigen-presenting cells (APC) to the adaptive immune system with either activation of self-reactive lymphocytes and targeting of self-antigens, or alternatively, a response to danger signals by activated lymphocytes The specific lymphocytic infiltration in scarring alopecia implies an autoimmune mechanism whereby the self-reactive lymphocytes are activated against hair follicle antigens located in the permanent hair follicle region. Immune complex deposition is a feature of DLE and variably LPP, but the specific nature of the antibodies has not been investigated. 92 Also not known is the nature of the folliculocentric inflammation, the specific cell clones involved, and ultimately what epitopes the lymphocyte clones are targeting. As part of the existing mechanism for immunoregulation, a resident population of Langerhans cells in the permanent follicular region are presumably involved in the surveillance of the follicular canal for the potential invasion of pathogens. 93 As such, it is possible that scarring alopecia is the result of Langerhans cells being inappropriately activated by a variety of stimuli that could include ultraviolet light in those with scalp DLE, certain medications in LPP, and Staphylococcus aureus infection in FD. The migration of activated antigen-presenting cells to the lymph nodes and the presentation of hair follicle located antigens may then elicit an immune response. Alternatively, Asebia mice have hypoplastic sebaceous glands and a defect in an enzyme that affects the fatty acid content of sebum The change in sebum composition may cause a delayed desquamation of the inner root sheath such that the adherent sheath prevents the hair shaft from moving forward. Instead, the hair shaft is either forced downwards, or remains in place; during catagen regression, the retained shaft may perforate the hair bulb, leading to inflammation. 95 A genetic defect of keratin may be involved, as with follicularis spinulosa decalvans (KFSD). 97 Similar patterns of scarring alopecia independent of sebaceous gland defects have been described in transgenic mice expressing mutant keratin genes. 97,98 The question remains whether these findings are applicable to human cicatricial alopecias. 99 A deficiency of peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor that regulates peroxisome and lipid metabolism, has been identified in LPP. Deletion of PPARγ in mutant mice results in alopecia associated with significant focal inflammation and lipid deposition in the dermis. The therapeutic response to pioglitazone, a PPARγ agonist, further suggests that PPARγ-regulated pathways could be involved in the onset of cicatricial alopecia Bulge stem cell destruction in scarring alopecia The ability for a telogen follicle to cycle back to anagen involves stem cells residing in the bulge region, the so-called permanent, noncycling region in the upper pilosebaceous follicular unit. This permanent upper region, where the inflammatory infiltrate of scarring alopecia is predominantly located, is distinguished from the lower, transient cycling region and hair follicle bulb that is targeted by inflammatory infiltrates in AA. 61 Potentially, destruction of the bulge stem cell region, whether by autoimmune inflammation or otherwise, may permanently destroy the hair follicle. Multiple hypotheses have been put forward to explain the phenomena of cicatricial alopecia. 72 Each hypothesis is not necessarily exclusive of another and it is possible that different hypotheses will eventually be respectively linked to different scarring alopecia presentations. Hair disorder treatment development Development of treatments for hair loss either targets the underlying cause or focuses on the aberrant changes in hair biology. The overall objective is to return hair follicle growth cycles to normal and/or improve the density and size of the affected follicles. Treatment of the underlying cause for hair loss depends on the nature of the condition. Noninflammatory, nonscarring hair loss due to an exogenous source can be remedied by removing the factor or avoiding further contact, though it can be challenging to confidently identify the insult. With pattern hair loss, the primary role of local and systemic androgen hormone action makes targeting the underlying problem difficult. However, the type 2 5α- reductase inhibitor, finasteride, reduces the conversion of testosterone to DHT which improves terminal hair density and prolongs the anagen growth phases. 103,104 For inflammatory alopecias, there have been many investigations of anti-inflammatory drugs as treatment candidates. 105 Targeting a disorder-initiating event does not directly act on hair follicles, but follicles have regenerative ability and can improve if the nonscarring alopecia-inducing mechanism is blocked. The alternative treatment approach is to directly modify anagen and telogen duration in the hair growth cycle, improve the ratio of terminal-to-vellus hair follicles, and increase terminal follicle density. Minoxidil is a clear example with its ability to directly stimulate hair growth through prolonging anagen and increasing hair fiber size. 52, Where follicles have been permanently destroyed, as with late-stage male AGA or scarring alopecias, new treatments are under development that may potentially promote follicle formation and increase hair density. 2,111 Acknowledgements This work was supported by grants from the North American Hair Research Society (NAHRS) and the Canadian Dermatology Foundation (CDF). Dr McElwee is a recipient of the Canadian Institutes of Health Research (MSH-95328) and Michael Smith Foundation for Health Research [CI-SCH-00480(06-1)] investigator awards. References 1. Breitkopf T, Leung G, Yu M, Wang E, McElwee KJ. The basic science of hair biology: what are the causal mechanisms for the disordered hair follicle? Dermatol Clin. 2013;31(1): McElwee KJ, Kissling S, Wenzel E, Huth A, Hoffmann R. 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