HAIR SCIENCE MINI-SERIES: Neuroendocrinology of the Human Hair Follicle Episode 2: Scalp Hair Follicles and the Hypothalamic-Pituitary-Adrenal Axis

INTRODUCTION Welcome to Episode 2 of the new HAIR SCIENCE miniseries! In Episode 1, we kicked off this series with a foray into the seemingly outlandish world of hair follicle (HF) neuroendocrinology and covered it in broad strokes by providing key background information, general concepts, and important overarching themes. While this may have exhausted your patience already (yes, once again, there will not be any nice illustrations so as to entice you to check up on the original research papers.), brace yourself: here, we will dive into some of the nitty-gritty details. Probably the best HF neuroendocrinology topic to get started on in Episode 2 is the one that made the field suddenly so fascinating: the discovery that your scalp HFs have a fully functional peripheral equivalent of the central hypothalamic-pituitary-adrenal (HPA) axis, which is the key neuroedocrine system that governs the stress responses of mammalian organisms (Fink 2010, Lechan 2020): In response to various perceived stressors, the hypothalamus generates and secretes corticotropin-releasing hormone (CRH). This up-regulates proopiomelanocortin (POMC) production in CRH receptor-positive cells in the pituitary gland, which enzymatically synthesize key neurohormones such as adrenocorticotropic hormone (ACTH) from the POMC prohormone; ACTH travels via the blood to the adrenal gland, where this stimulates epithelial cells with cognate ACTH receptors (mainly melanocortin receptor 2 [MC-2R] to synthesize the glucocorticoids, namely cortisol, which not only are essential for our survival, but also hormonally coordinate key systemic stress responses of the human body) (Fink 2010, Lechan 2020). In addition, CRH and ACTH themselves unfold many other activities through the mammalian organism, ranging from immunomodulation (e.g., mast cell activation) to pigmentation control (e.g., skin hyperpigmentation and repigmentation of gray/white hair shafts) (Paus et al. 2006, Murphy and Travers 2017, Lechan 2020). When any key element in this central HPA axis is defective or produced in excess, this cannot only have major, potentially life-threatening consequences, but it also can result in striking skin phenotypes well-known to dermatologists, such as alopecia, telogen effluvium, and hypertrichosis (Paus 2016). Even though it had already been known at the time that there were actually many other cells and tissues outside of this central HPA axis, including some cultured human skin cells, that also expressed/produced individual elements of this axis (Slominski et al. 1993, 1993a, 2000; Ito et al. 2004), it was not until 2005 that the first evidence was published that a human (mini-)organ actually mimics the central HPA axis in full and utilizes the locally generated hormones to regulate its own function (Ito et al. 2005). More on that below. Apart from being biologially fascinating and clinically relevant, as we shall see in the following, this discovery also created a dilemma that remains unresolved to-date: Psychologists and stress researchers are now frequently measuring cortisol levels in plucked hair shafts as an instructive indicator of systemic hormonal responses to psychoemotional stress and of monitoring long-term glucocorticoid serum levels (Meyer and Novak 2012). Yet, since the scalp HF itself also produces cortisol, which has now been independently confirmed by multiple studies, how can we distinguish the—chemically identical—cortisol produced in the adrenal gland from that of other so-called “non-classical” sites of cortisol synthesis, namely the HF? (Sergiel et al. 2020, Sharpley et al. 2011) Moreover, it is often forgotten that hair-shaft-producing anagen HFs, especially our largest terminal HFs in scalp and beard skin, are very effective excretory organs that actively take up multiple, potentially noxious compounds from the blood so as to eliminate them from the organism by embedding them into a hair shaft, where they can no longer do harm and eventually get shed into the environment (Carre et al. 2020). This makes it by no means trivial to prove that cortisol found in the hair shaft was actually produced in the HF itself, rather than elsewhere in the body, and was then taken up via the HF’s dense vascular system. Finally, that natural sunlight tends to degrade hair-shaft-embedded glucocorticoids (Wester et al. 2016), and that these levels may be hair growth rate-dependent and may be reduced by frequent shampooing (Xiang et al. 2016) adds other elements of uncertainty. Thus, if you are contemplating offering your patients hair shaft analyses of “stress hormones” so as to assess their level of “chronic stress,” these are considerations and caveats you need to keep in mind. But, in line with our mini-series motto (“back to the future”), let’s have a look at where this neuroendocrinological discovery tour started.