(a) A simplified schematic overview showing the regulation of the hypothalamic–pituitary–adrenal (HPA) axis in a healthy situation. Corticotrophin releasing hormone (CRH), secreted by the hypothalamus, stimulates the production of adrenocorticotropin (ACTH) by the pituitary, resulting in increased secretion of cortisol, mineralocorticoids, and androgens by the adrenal glands. Cortisol controls its own production through a feedback loop to the pituitary, hippocampus (not shown), and hypothalamus. (b) In the syndrome of glucocorticoid resistance this negative feedback mechanism, mediated by the glucocorticoid receptor (GR), is impaired. As a consequence, the HPA axis becomes hyperactivated, resulting in an increased production of the adrenal steroid hormones. Patients suffer from signs and symptoms of overproduction of mineralocorticoids and, of particular importantance in women, androgens. However, no classical signs of glucocorticoid excess are present due to the impaired glucocorticoid signalling.