Human hair follicles display a functional equivalent of the hypothalamic‐pituitary‐adrenal (HPA) axis and synthesize cortisol

The skin and its major appendages are prominent target organs and potent sources of key players along the classical hypothalamic‐pituitary axis, such as corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and α melanocyte stimulating hormone (α‐MSH), and even express key steroidogenic enzymes. Therefore, it may have established local stress response systems that resemble the hypothalamic‐pituitary‐adrenal (HPA) axis. However, functional evidence that this is indeed the case in normal human skin in situ has still been missing. We show that microdissected, organ‐cultured human scalp hair follicles respond to CRH stimulation by up‐regulating proopiomelanocortin (POMC) transcription and immunoreactivity (IR) for ACTH and α‐MSH, which must have been processed from POMC. CRH, α‐MSH, and ACTH also modulate expression of their cognate receptors (CRH‐R1, MC1‐R, MC2‐R). In addition, the strongest stimulus for adrenal cortisol production, ACTH, also up‐regulates cortisol‐IR in the hair follicles. Isolated human hair follicles secrete substantial levels of cortisol into the culture medium, and this activity is further up‐regulated by CRH. CRH also modulates important functional hair growth parameters in vitro (hair shaft elongation, catagen induction, hair keratinocyte proliferation, melanin production). Finally, human hair follicles display HPA axis‐like regulatory feedback systems, since the glucocorticoid receptor agonist hydrocortisone down‐regulates follicular CRH expression. Thus, even in the absence of endocrine, neural, or vascular systemic connections, normal human scalp hair follicles directly respond to CRH stimulation in a strikingly similar manner to what is seen in the classical HPA axis, including synthesis and secretion of cortisol and activation of prototypic neuroendocrine feedback loops.