Activation of glucocorticoid secretion is mediated by neuronal signals. The neuroendocrine cascade culminating in corticosteroid release is initiated by stimuli impinging on hypophysiotrophic neurons in the medial parvocellular division of the hypothalamic paraventricular nucleus (PVN). These neurons synthesize ACTH secretagogues [the most prominent of which are corticotropin-releasing hormone (CRH) and arginine vasopression (AVP)] that are released into the hypophysial portal circulation (median eminence) and transported to the anterior pituitary gland. Corticotropes respond to CRH and AVP by releasing ACTH, which is released into the systemic circulation and causes synthesis and release of glucocorticoids at the level of the adrenal gland. Glucocorticoid secretion is self-limited, undergoing end-product feedback inhibition via binding GRs in multiple brain regions as well as the pituitary gland (Keller-Wood and Dallman, 1984; Myers et al., 2012b). The net result is an HPA axis “stress response” that has a rapid onset and more gradual wane, with glucocorticoid secretion generally peaking in 15–30 min and lasting up to several hours, depending on the severity of the stressor (Figure 2). The shape of the response underscores its adaptive value in the short-term, and limits the possible negative effects of a prolonged glucocorticoid response.
