Human hair is highly responsive to stress, and human scalp hair follicles (HFs) contain a peripheral neuro-endocrine equivalent of the systemic hypothalamic-pituitary-adrenal (HPA) stress axis. Androgenetic alopecia (AGA) is supposed to be aggravated by stress. We used the HPA axis triggering corticotropin-releasing hormone (CRH) to induce a stress response in human ex vivo male AGA HFs. Furthermore, since caffeine is known to reverse testosterone-mediated hair growth inhibition in the same hair organ culture model, we investigated whether caffeine would antagonize CRH-mediated stress in these HFs. HFs from balding vertex area scalp biopsies of AGA-affected men were incubated with CRH (10-7 M) and with/without caffeine (0.001%, 0.005%). Compared to controls, CRH significantly enhanced the expression of catagen-inducing TGF-β2 (p<0.001), CRH receptors 1/2 (p<0.01), ACTH (p<0.001) and melanocortin-receptor-2 (MC-R2) (p<0.001), and additional stress-associated parameters, substance P and p75 neurotrophin receptor. CRH inhibited matrix keratinocyte proliferation and expression of anagen-promoting IGF-1 and pro-proliferative nerve growth factor receptor TrkA. Caffeine significantly counteracted all described stress effects and additionally enhanced IP3 -R, first time detected in human HFs. These findings provide the first evidence in ex vivo human AGA HFs, that the stress mediator CRH induces not only a complex intrafollicular HPA, 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.