stress, the follicles are a target of neuroimmunomodulatory and neuroinflammatory mediators like SP and nerve growth factor (NGF).20,52-54 Studies have shown that psycho-emotional stress triggers systemic and local release of NGF (a catagen inducer) and SP from perifollicular nerve fibers, which leads to activation and degranulation of local mast cells that release a myriad of pro-inflammatory mediators like histamine and TNF-a – inducing neurogenic inflammation, release of ROS, early catagen, and hair growth arrest.8,20,37,53-55 Moreover, SP was also found to up-regulate follicular expression of major histocompatibility complexes (MHC) that are normally down-regulated by hair follicles to maintain an immune privilege. Stress-mediated IP collapse renders the follicle open to activating inflammatory cascades and subsequent hair loss, a biologic imbalance that is implicated as the driving force in AA and scarring alopecias.8,20,22As part of the neuroendocrine stress response, chronically elevated stress levels also lead to the production of excess systemic stress hormones, like cortisol, which are known to cause catagen, inhibit hair growth, and directly correlate with the development and exacerbation of hair loss disorders.56,57 Furthermore, research has identified that the hair follicle is also uniquely equipped to produce its own stress hormones (ACTH, CRH, and cortisol) through an equivalent of the hypothalamic-pituitary-adrenal (HPA) axis, with established regulatory feedback loops.21,22 At times of excess stress, systemic CRH binds to receptors on the follicle and stimulates the internal follicle hormone axis to produce ACTH, cortisol, and CRH locally - leading to further mast cell degranulation, inflammation, and apoptosis.21,22Lending further evidence to the role of stress in dysregulation of follicle immune balance and perifollicular inflammation, a 2017 study of female medical students showed that prolonged life-stress exposure hampered hair growth, accompanied by significant fluctuations in TH1/TH2 cytokine balance compared to control group.58 On a systemic level, chronically elevated cortisol levels (chronic stress) compromise the production and equilibrium of other hormones like TSH and thyroid hormones that are essential for proper hair follicle stem cell function and activation.59 The sustained systemic endocrine disruption from elevated cortisol levels could provide further insight into poorly understood and complex processes like FPHL, and why these can be often precipitated by conditions that induce telogen effluvium. Stress is ubiquitous and the mechanisms through which the follicle is affected by it in one hair disorder apply to all hair disorders. Given the evidence above, managing and reducing stress levels, cortisol, SP, and the downstream mediators (inflammation, oxidative stress, destabilized mast cells, dysregulated immune signaling) should be a part of any hair loss treatment and prevention protocol. Since there are no pharmaceuticals that target stress, it would make sense to employ multi-targeting therapeutics with additional stress-adaptogenic properties.
CONCLUSION
The pathophysiology of hair loss is unequivocally multi-factorial and extremely complex, involving a plethora of factors and signaling pathways. Hormones, the brain-hair axis, and the environment-hair axis influence the hair follicle, chisel against its regulatory circuitry, and in the absence of strategies to counterbalance this attack, can ultimately override the hair follicle’s internal controls. The result is a deleterious self-sustained inflammatory cascade as the new status quo (Figure 1). Restoring hair follicles to a state of homeostasis requires embracing a new outlook in terms of therapeutics. Current pharmaceutical interventions have limited success rate and possible side effects including sexual dysfunction and contact dermatitis. More importantly, these therapies focus on singular targets such as hair follicle testosterone metabolism, without considering the downstream effectors or the underlying pathophysiology of deregulated immune signaling and activated pro-inflammatory and pro-fibrotic cascades.A paradigm shift in hair loss treatment is necessary, from monotargeting to multi-targeting therapeutic approaches that address not only androgens but also inflammation, oxidative stress, aging, elevated stress mediators like cortisol, their downstream signaling mediators, and also stimulate a nutrient-rich microenvironment in the hair follicle niche to promote repair and structural regeneration. Multi-targeted therapies such as platelet-rich plasma, low-level laser light and nutraceuticals are emerging and increasingly recognized for their efficacy as either standalone treatments or in combination with traditional hair loss protocols.60-62 The common thread between these therapies is their multi-modal approach and focus on multiple signaling cascades, cytokines and growth factors that are altered in hair loss. In the next section we will review these novel therapy options, focusing on standardized nutraceuticals with their unique potential for synergistic, multi-targeted action of scientifically studied botanical phytochemicals.
DISCLOSURES
Dr. Sadick is the clinical investigator on the product. Dr. Kircik has received compensation from JDD for his editorial help. Dr. Callendar has no conflicts.
