Background: Human hair is highly responsive to stress, and human scalp hair follicles (HFs) contain a peripheral neuroendocrine equivalent of the systemic hypothalamic–pituitary–adrenal (HPA) stress axis. Androgenetic alopecia (AGA) is supposed to be aggravated by stress. We used corticotropin-releasing hormone (CRH), which triggers the HPA axis, to induce a stress response in human ex vivo male AGA HFs. Caffeine is known to reverse testosterone-mediated hair growth inhibition in the same hair organ culture model. Objectives: To investigate whether caffeine would antagonize CRH-mediated stress in these HFs. Methods: HFs from balding vertex area scalp biopsies of men affected by AGA were incubated with CRH (10−7 mol L−1) with or without caffeine (0·001% or 0·005%). Results: Compared to controls, CRH significantly enhanced the expression of catagen-inducing transforming growth factor-β2 (TGF-β2) (P < 0·001), CRH receptors 1 and 2 (CRH-R1/2) (P < 0·01), adrenocorticotropic hormone (ACTH) (P < 0·001) and melanocortin receptor 2 (MC-R2) (P < 0·001), and additional stress-associated parameters, substance P and p75 neurotrophin receptor (p75NTR). CRH inhibited matrix keratinocyte proliferation and expression of anagen-promoting insulin-like growth factor-1 (IGF-1) and the pro-proliferative nerve growth factor receptor NGF-tyrosine kinase receptor A (TrkA). Caffeine significantly counteracted all described stress effects and additionally enhanced inositol trisphosphate receptor (IP3-R), for the first time detected in human HFs. Conclusions: These findings provide the first evidence in ex vivo human AGA HFs that the stress mediator CRH induces not only a complex intrafollicular HPA response, but also a non-HPA-related stress response. Moreover, we show that these effects can be effectively antagonized by caffeine. Thus, these data strongly support the hypothesis that stress can impair human hair physiology and induce hair loss, and that caffeine may effectively counteract stress-induced hair damage and possibly prevent stress-induced hair loss. What is already known about this topic?. Caffeine stimulates hair growth in male and female human hair follicles (HFs) in vitro. What does this study add?. For the first time, corticotropin-releasing hormone induction of the hypothalamic–pituitary–adrenal (HPA) stress axis is documented in male human HFs from biopsies (balding vertex area) of men with androgenetic alopecia. First time, the non-HPA neurogenic stress axis is shown in the same male human HFs. Caffeine counteracts both stress axes. Inositol trisphosphate receptor was newly identified in human HFs. What is the translational message?. Stress can impair human hair physiology and induce hair loss. Caffeine may effectively counteract stress-induced hair damage and possibly prevent stress-induced hair loss.
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