hair loss (FPHL) where the duration of anagen is progressively shortened, while dormancy is increased - the compromise of intrinsic cycle controls and dysregulation of local follicle immune balance is inevitable.5,8The immune system and inflammation are the body’s primary defenses against noxious stimuli, as well as key mechanisms in healing. However, whereas acute inflammation can stimulate healing and in the case of follicles even lead to anagen induction, non-specific and chronic inflammation is a prolonged dysregulated cascade that suspends the body’s normal responses, causing progressive damage. The prevalence of an inflammatory component in hair loss is underscored by the fact that it’s observed in both traditionally ‘inflammatory’ and ‘non-inflammatory’ alopecias. Numerous histochemical, ultrastructural, and immunohistochemical studies have demonstrated perifollicular micro-inflammation in MPHL and FPHL presenting as lymphocytic infiltrates, mast cell degranulation, fibroblast activation, and immunoglobulin (IGM) deposits.3,6,11,13,15,16 The term “micro-inflammation” was coined to allude to the indolent sub-clinical process of dysregulated chronic inflammation rather than the classic inflammatory attack seen on pathology in alopecia areata (AA), lupus, etc.9 The basis for this phenomenon and its role in the pathogenesis of hair loss has been the subject of much research. In the instance of chronic processes like MPHL and FPHL, the micro-inflammatory component is localized to the vicinity of the bulge stem cell niche. The inflammatory processes, the release of ROS, and inflammatory mediators (eg, TNF-a, IL-1, histamine) alter the follicle immune milieu – and although not immediately destructive to the follicle, can over time dysregulate normal cycling dynamics and stem cell renewal.5,9,11 In fact, studies show that biopsies from areas of clinically uninvolved scalp with high density scores in subjects with early AGA already demonstrate the presence of inflammatory infiltrates and fibrosis, indicating that micro-inflammation is not a secondary phenomenon but an active participant in pathogenesis.3,8,15,16 A recent study also found a correlation between inflammatory infiltrates and apoptosis in miniaturized follicles, suggesting that inflammation can play a role in the pathogenesis of follicle miniaturization via activation of the extrinsic apoptotic pathway.34 Further, sustained inflammatory processes also contribute to progressive perifollicular fibrosis.9An important question is why the follicle becomes a target for an inflammatory reaction, whether it’s micro-inflammation in AGA or an immune attack against self-antigens in AA. There are no definitive answers, but it is worth noting that inflammation is a multi-step process that may start from a primary event or a group of events, later perpetuated through a cyclic continuous cascade. In AGA for example, the localization of infiltrates to the upper follicle suggests the contribution of environmental factors in the inflammatory process. Colonization with normal microbial inhabitants or actual microbial toxins have been implicated.8,9,11 Additionally keratinocytes have been shown to respond to irritants like UV irradiation, pollutants, and chemical or mechanical stresses by producing inflammatory cytokines and ROS.5,9 Damage from free radicals triggers the release of inflammatory mediators, which thereby generate more ROS in a cyclic cascade. Oxidative stress overrides innate antioxidant defense mechanisms in aging cells and leads to apoptosis. In the case of the scalp, there is evidence it plays a pivotal role in hair greying and hair loss, where affected hair follicles were shown to be particularly vulnerable to ROS from environmental stressors.23,35,36 Further, androgen signaling, TGF-b1, and mediators of stress have all been shown to be mediated via generation of ROS in the follicle – leading to growth arrest.37,38 Aging hair exhibits up-regulation of oxidative stress and inflammatory response genes, predisposing follicles further.35,36 And the compromise of regulatory mechanisms by psycho-emotional stress can also make follicles more susceptible to inflammatory attack, as in the case of AA.8,20,22The presence and role of inflammation and oxidative stress cannot be ignored in the pathophysiology of hair loss and in the development of therapeutics. Adding anti-inflammatory therapies to treatment protocols of both AGA and trichotillomania with micro-inflammation lead to improved treatment outcomes.11,39 Similarly, administration of anti-oxidants reversed the effects of oxidative stress on hair follicles in vitro and resulted in hair growth clinically.37,38,40 This data supports the case for multi-targeted therapeutics for hair loss that can address the inflammatory and oxidative stress cascade, as well as the factors that precipitate it.Consequences of Androgen HormonesThe fact that androgens influence hair growth has been known for ages. Androgen metabolism as well as androgen receptor (AR) levels and sensitivity are enhanced in balding scalp follicles in a spatial pattern in individuals with MPHL; and to a much lesser degree in FPHL, where the contribution of androgens is unclear, and stress, environment, and other hormones likely play a greater role.34,41 Although the impact of androgens in the pathophysiology of hair disorders is the most elucidated of all hair loss triggers, ongoing research continuously reveals new molecular mechanisms behind androgen action. It is accepted now that the main target of androgens in hair follicles is the dermal papilla (DP), through which they induce secretion of autocrine and paracrine factors, dysregulating intrinsic signaling cascades that mediate hair growth.17 Several factors induced from DP by androgens have been identified, with many more still to be discovered. It has been shown that androgens stimulate the DPCs to overproduce TGF-b, which is normally secreted to signal catagen and regression; and accordingly studies confirmed that androgen-induced TGF-b leads to catagen and suppression of follicular keratinocyte growth.5,6,8,14,31 New research has
