Q&A: Primary generalized glucocorticoid resistance

What biological processes underlie this “resistance” to cortisol? Because this resistance includes the hypothalamicpituitary-adrenal (HPA) axis negative feedback regulatory centers in the brain and pituitary gland, this axis is activated to “overcome” or compensate for the glucocorticoid action defect (Figure 1). The production of hypothalamic corticotropin-releasing hormone (CRH), arginine-vasopressin (AVP) and pituitary adrenocorticotropic hormone (ACTH) increase and the adrenal cortices hyperfunction, secreting large amounts of cortisol, adrenal steroid precursors and adrenal androgens. The adrenal steroid precursors include deoxy-corticosterone and corticosterone, both of which, as well as cortisol, have sodium-retaining activity through the mineralocorticoid receptor, which is normal in patients with cortisol resistance. Thus, the patient tissues are exposed to elevated levels of adrenal androgens and mineralocorticoids, which result in manifestations of hyperandrogenism and hypermineralocorticoidism.