The human hair follicle has established a fully functional peripheral equivalent of the hypothamalic‐pituitary‐adrenal‐axis (HPA)

After the initial discovery that, in vivo, mammalian skin both transcribes and translates the proopiomelanocortin (POMC) gene, and processes its product into melanocortins (Slominski et al., Experientia 1992), it has become increasingly appreciated that the hair follicle – including the human one – is a prime source and target not only of POMC-derived “pituitary” hormones, e.g. alpha-MSH, ACTH and s-endorphin, but also expresses the most proximal control element of the hypothalamic-pituitary-adrenal (HPA) axis, corticotropin-releasing hormone (CRH) and its receptor (e.g. Roloff et al. FASEB J 1998, Ito et al. J Invest Dermatol 2004). However, while all proximal elements of the HPA are expressed in both murine and human hair follicles (CRH, CHR-R, POMC, ACTH and ACTH-R), it has neither been shown that these are functionally linked (i.e., is CRH actually capable of modulating intrafollicular POMC gene expression and ACTH production?), nor has it been known whether the most distal HPA component – cortisol synthesis – is also present in the hair follicle. Therefore, we have investigated whether the stimulation of microdissected, organ-cultured human hair follicles with CRH or ACTH elicits responses inside this peripheral miniorgan that imitate a functional HPA – in the absence of any systemic or neural connections and under serum-free culture conditions. Here, we show that CRH stimulation of organ-cultured human scalp hair follicles in the anagen VI stage of the hair cycle indeed results in significant upregulation of POMC transcription, and of alpha-MSH, ACTH, MC1, MC2 and glucocorticoid receptor (GR) immunoreactivity in situ (immunofluorescence). ACTH stimulation, in turn, significantly up-regulates the – already constitutively present!– cortisol-immunoreactivity as well as cortisol secretion into the culture medium. This represents the first available evidence that normal human skin (more precisely: the hair follicle) can actually synthesize the “adrenal” steroid hormone cortisol in situ, and that this acticity is regulated by the same “hypothalamic” and “pituitary” hormones that operate as key controls of adrenal cortisol synthesis. Moreover, we show that cortisol stimulation exerts classical feedback responses inside the human anagen hair follicle recognized for the central HPA: cortisol up-regulates GR, while it down-regulates CRH expression. Given that the HPA operates as the major system for coordinating stress-responses of the mammalian organism and for integrating them into changing metabolic demands and neuro-endocrine-immune signaling circuits, it has fascinating implications (e.g. for general skin physiology and dermatological therapy), and raises most intriguing questions, that human hair follicles are utilizing a fully functional peripheral equivalent of the central HPA.