Cushing syndrome, named after the famous neurosurgeon, Harvey Cushing who first described it, is an endocrine disorder with elevated cortisol levels in the blood. In some cases, Cushing syndrome results from a pituitary adenoma making excess ACTH, and in those situations it’s called Cushing disease.
Normally, the hypothalamus, which is located at the base of the brain, secretes corticotropin-releasing hormone, known as CRH, which stimulates the pituitary gland to secrete adrenocorticotropic hormone, known as ACTH. ACTH, then, travels to the pair of adrenal glands, on top of each kidney, where it specifically targets cells in the adrenal cortex.
The adrenal cortex is the outer part of the adrenal gland and is subdivided into three layers- the zona glomerulosa, the zona fasciculata, and the zona reticularis. Zona fasciculata is the middle zone and also the widest zone and it takes up the majority of the volume of the whole adrenal gland.
The ACTH specifically stimulates cells in this zone to secrete cortisol, which belongs to a class of steroids, or lipid-soluble hormones, called glucocorticoids. Glucocorticoids are not soluble in water, so most cortisol in the blood is bound to a special carrier protein, called cortisol-binding globulin, and only about 5% is unbound or free. In fact, only this small fraction of free cortisol is biologically active, and its levels are carefully controlled. Excess free cortisol is filtered in kidneys and dumped into the urine.
Free cortisol in the blood is involved in a number of things and it’s part of the circadian rhythm. Cortisol levels peak in the morning, when the body knows we need to “get up and go” and then drop in the evening, when we’re preparing for sleep. In times of stress, the body needs to have plenty of energy substrates around, so cortisol increases gluconeogenesis, which is the synthesis of new glucose molecules, proteolysis, which is the breakdown of protein and lipolysis, which is the breakdown of fat.