Figure 2. Pathophysiologic mechanisms and clinical manifestations of primary generalized glucocorticoid resistance syndrome (PGGRS). The HPA axis consists of the brain hypothalamus, the anterior pituitary gland, and the adrenal cortex with their secreting hormones/peptides, CRH/AVP, ACTH and cortisol, respectively. In patients with this syndrome, their HPA axis is re-set to upward with preservation of circadian rhythmicity due to generalized, partial insensitivity to glucocorticoids in entire tissues. Thus, hypothalamic CRH/AVP, pituitary ACTH and adrenal cortisol are all hyper-secreted in order to compensate for the reduced actions of cortisol in both CNS and peripheral tissues. In addition to augmenting production of cortisol in the adrenal glands, elevated ACTH stimulates secretion of mineralocorticoids (e.g., deoxycorticosterone and corticosterone) and androgens (e.g., androstenedione, dehydroepiandrosterone (DHEA) and DHEA-sulfate(S)), which in turn cause a variety of manifestations associated with excess secretion of these hormones. In contrast, manifestations associated with overproduction of cortisol are rare in adult patients but neonates/young children may develop hypoglycemia and associated seizures due to reduced actions of cortisol in the liver. Elevated CRH/AVP in CNS may precipitate anxiety and depression in some patients. Solid lines indicate positive effects, whereas dashed lines show negative effects. Manifestations associated with elevation of the indicated molecules/compounds are shown with red letters. ACTH: adrenocorticotropic hormone; AVP: arginine vasopressin; CNS: central nervous system; CRH: corticotropin-releasing hormone; DHEA: dehydroepiandrosterone; DHEA-S: DHEA-sulfate; PGGRS; primary generalized glucocorticoid resistance syndrome.