Adrenal insufficiency. In primary adrenal insufficiency, the adrenal cortex is typically destroyed (indicated by an X). This relieves the hypothalamus of cortisol negative feedback such that, presumably, corticotrophin-release hormone (CRH) is increased, although sampling portal vein blood is not possible in humans. The loss of negative feedback at the pituitary leads to a large increase in plasma ACTH. In secondary adrenal insufficiency, adequate ACTH secretion is lost (indicated by an X) resulting in suboptimal plasma ACTH and adrenal atrophy.