New Insight Into the Pathophysiology of Hair Loss Trigger a Paradigm Shift in the Treatment Approach

identified that androgens also upregulate DPC production of WNT antagonist DKK-1, thus impairing hair follicle stem cell(HFSC) differentiation via dysregulation of WNT signaling, a pathway crucial for anagen entry.¹⁷ Furthermore, once triggered, some other factors can maintain hair loss pathology without the presence of androgens, as seen in men castrated after puberty.^5,42It is likely that the contribution of these downstream effectors to the dysregulation of follicle immune balance triggers a continuous cascade of immune and inflammatory processes that can progress even after androgens are removed. In fact, androgeninduced TGF-b was shown to induce oxidative stress in DPCs, as well as perifollicular fibrosis and inflammation via surrounding fibroblasts, thus playing a role in the chronic process of miniaturization.^38,43 Currently, pharmaceutical formulations only target one aspect of this signaling cascade – androgens. New insight into the mechanism however supports the use of multi-targeted therapeutics that can also target androgen receptors, gene expression, TGF-b, other downstream pro-apoptotic molecules, inflammatory cytokines, and oxidative stress.Environmental vs. Genetic TriggersGenetics play a role in all manifestations of hair loss and the genetic make-up of an individual can predispose them to any hair disorder (AGA, TE, AA).⁸ AA clusters in families, and genetics also determine who will exhibit TE as a result of stress or another insult.⁸ Although the genetics are far from being fully understood, it is now well accepted that, like most multifactorial chronic disorders with a variety of dysregulated signaling pathways, the mode of inheritance in hair loss is polygenic – dependent on multiple genes and interactions with the environment. In the case of FPHL and MPHL, although the androgen receptor was considered a main candidate gene in hair loss susceptibility, recent studies revealed several additional gene loci involving cell proliferation, perturbed neurological pathways, altered immune response, and WNT signaling – supporting androgen-independent mechanisms of predisposition, especially in FPHL.^5,44-46 The hair follicle is a conduit for intensive interactions with the internal and external environment. Although the effects of extrinsic and intrinsic factors are readily recognized in skin photoaging, their influence in hair loss is underappreciated. ⁴⁷Large studies of identical twins with MPHL and FPHL showed that multiple non-genetic exogenous factors including smoking,absence of hat use, chronic stress, excessive alcohol consumption, and extreme exercise contributed significantly to the development and severity of hair loss.^10,48 Studies have shown that exposure to both extrinsic triggers (UV, pollutants, stress, tobacco, bacterial toxins, and antigens), as well as intrinsic factors (aging, poor nutrition) initiate perifollicular inflammatory signaling cascades that enhance pro-inflammatory gene expression and liberate ROS.^5,18,19,49 For example, exposure to UVR has been shown to trigger release of ROS and pro-inflammatory cytokines (eg, IL-1) in follicles and surrounding keratinocytes leading to apoptosis, cycle arrest, and injury of the putative site of follicular stem cells near the infundibulum.^5,9,49 It has been suggested that photoactivation of porphyrins from Propionibacterium spp. in the pilosebaceous duct can also contribute to oxidative tissue injury and follicular micro-inflammation.^9,50 Moreover, preclinical studies have illustrated that antioxidants provide photoprotection against oxidative damage.^1,35,47,51 While genetic predisposition is perhaps largely un-modifiable, genetic research has shown that epigenetic modification through environmental and endogenous factors can regulate gene expression, opening an opportunity to therapeutically intervene to rebalance the environment susceptible to hair loss by targeting inflammation, stress, and oxidative damage.⁶Chronic Psycho-Emotional Stress (Cortisol and Other Stress Mediators)Although clinical observations have provided anecdotal evidence into the brain-skin and brain-follicle axes, the molecular mechanisms underlying these connections have only recently been elucidated. Given the surrounding dense perifollicular meshwork of sensory nerve endings that are closely associated with mast cells and exhibit plasticity during chronic