Figure 2.

The Hypothalamic–Pituitary–Adrenal (HPA) Axis. Endogenous glucocorticoids (CORT) are vital hormones involved in many physiological processes that are key to homeostasis and survival (e.g., mediating the stress response, anti-inflammatory and immunosuppressive effects, regulation of glucose expenditure). The circulating levels of CORT are controlled by the HPA axis. Corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) stimulate the release of adrenocorticotropic hormone (ACTH) from the pituitary. ACTH in turn stimulates the adrenal glands to synthesise CORT, which further regulates its own synthesis through an intra-adrenal feedback loop. Within the HPA axis, CORT acts to inhibit ACTH in the pituitary as well as CRH and AVP in the hypothalamus, creating a dual negative-feedback loop. Combined mathematical and experimental studies have demonstrated that the tightly coordinated release of ACTH and CORT in ultradian pulses, observed under normal physiological conditions, is governed by this negative feedback [47]. These pulses have been shown to play an important role in the optimal responsiveness of glucocorticoid-sensitive neural processes. However, under pathological conditions (e.g., inflammation, chronic stress, neurological dysfunction) or ageing these pulsatile dynamics are altered and the tight synchrony between ACTH and CORT becomes significantly disrupted [54].