Cushing syndrome

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.

Cortisol also helps to maintain the blood pressure by increasing the sensitivity of peripheral blood vessels to catecholamines- epinephrine and norepinephrine, and this narrows the blood vessel lumen. Cortisol helps to dampen the inflammatory and immune response by reducing the production and release of inflammatory mediators, like prostaglandins and interleukins, as well as inhibiting the proliferation of T-lymphocytes. Finally, cortisol receptors are present in the brain, where their full effect is still actually unclear but might influence things like mood and memory.

For all this to work properly, though, the levels of free cortisol have to stay within the normal range. To do that, the body uses negative feedback, which means that high levels of cortisol tell the hypothalamus and pituitary gland to decrease their secretion of CRH and ACTH, respectively. Less CRH also tells the pituitary to make less ACTH, so the pituitary ends up having two reasons not to make ACTH. With less ACTH floating around, the zona fasciculata gets less stimulation to make cortisol, and eventually, cortisol levels go back down to the normal range again.  

In Cushing syndrome, cortisol levels are constantly higher than normal, so its effects are exaggerated. Excess cortisol leads to severe muscle, bone and skin breakdown which are the major protein stores of the body. It also leads to elevated blood glucose levels, and that leads to high insulin levels. Insulin, among its many actions, preferentially targets adipocytes or fat cells in the center of the body - around the waist and buttocks. In those cells, the insulin activates lipoprotein lipase, which is an enzyme that helps those adipocytes accumulate more fat molecules. The result is central obesity. 

In addition, to this the high cortisol levels cause hypertension for two reasons. First, they amplify the effect of catecholamines on blood vessels. Second, cortisol starts cross-reacting with mineralocorticoid receptors, which normally only binds a related steroid hormone - mineralocorticoids which are secreted from the zona glomerulosa layer of the adrenal cortex. In other words because the cortisol is structurally similar to mineralocorticoid it can bind to that receptor and it can trigger the mineralocorticoid effect - which is mainly to increase blood pressure by retaining fluid. 

High levels of cortisol also inhibit the secretion of gonadotropin- releasing hormone from the hypothalamus, which messes up normal ovarian and testicular function. Excess cortisol also dampens the inflammatory and immune response, making individuals more susceptible to infections. Finally, high levels of cortisol seem to impair normal brain function but the exact mechanism of that is unclear.

Cushing syndrome can happen because of exogenous cortisol meaning that it comes from “outside” usually in the form of medications, or because of endogenous cortisol - meaning that the excess cortisol is made by the body. The majority of cases of Cushing syndrome occur in individuals using exogenous steroid medications over a long period of time - often to treat autoimmune and inflammatory disorders, like asthma or rheumatoid arthritis. That’s because the molecular structure of exogenous steroid medications is so similar to cortisol that they mimic its actions on various tissues. In fact, exogenous steroid medications can also cause negative feedback on the hypothalamus and the pituitary gland. This causes a decrease in CRH and ACTH, which in turn, shuts down cortisol production from the zona fasciculata.

Over time, this lack of stimulation can cause zona fasciculata to physically shrink or become atrophic. Since that's the widest part of the adrenal cortex, it can have a measurable effect on the overall size of the adrenal gland. Even though this results in less endogenous cortisol production it still doesn’t quite compensate for the huge levels of exogenous cortisol, and that causes Cushing syndrome to develop.

In addition to taking exogenous steroid medications, Cushing syndrome can also result from increased levels of endogenous cortisol. The most common reason for that is excess ACTH. The leading cause of that is a pituitary adenoma, which is a benign tumor of the pituitary gland - and this specific condition is called Cushing disease. The exact reason for the development of this sort of benign tumor isn’t known - but unlike a malignant tumor - the cells don’t invade neighboring tissues or spread to other parts of the body. Instead, the pituitary adenoma simply grows in size and secretes too much ACTH. The excess ACTH overstimulates zona fasciculata of both adrenal glands, which grow larger and secrete excess cortisol.