NR3C1 and major depressive disorder: Yehuda and LeDoux (2007) propose that chronic release of CRH produces an abnormal response by the pituitary gland. Since the number and sensitivity of lymphocytic glucocorticoid receptors is increased, the negative feedback is also increased, causing an attenuation of the cortisol. This increased negative feedback contrasts with the drop that occurs in depression, in which the chronic release of CRH causes decreased negative feedback leading to hypercortisolism and down-regulation of glucocorticoid receptors (Sherin and Nemeroff, 2011; Pitman et al., 2012). See Figure 4.