Cushing's Syndrome

Cushing's Syndrome Cushing's Syndrome = Elevated levels of cortisol, aka, hypercortisolism. Review cortisol physiology We categorize hypercortisolism as ATCH-dependent (in which elevated cortisol is caused by elevated ACTH) and, ACTH-independent (in which elevated cortisol is not caused by elevated ACTH). Most cases of Cushing's syndrome are due to the use of exogenous glucocorticoids (which is, by definition, ACTH-independent). Exogenous Cushing's syndrome/Iatrogenic Cushing's syndrome. When hypercortisolism is suspected, and glucocorticoid administration is not the cause, we need to rule out physiologic causes and certain medical conditions that raise cortisol levels, which include: pregnancy, alcoholism, anorexia, obesity, depression, and uncontrolled diabetes. Stress is a key trigger for cortisol secretion; chronic physical and/or psychosocial stress and subsequent hypercortisolism can have widespread negative health effects. To screen for hypercortisolism, we can take 24-hour urine samples, midnight salivary samples, or try a dexamethasone suppression test (recall that dexamethasone is a synthetic glucocorticoid that mimics cortisol – thus, it should suppress the HPA axis). If the results of these tests reveal cortisol within the normal range, or suppressed from the dexamethasone, we can exclude Cushing's syndrome. If cortisol levels are elevated and/or not suppressed by the dexamethasone test, then we can say that Cushing's syndrome is likely. Now, we have to figure out what's causing the hypercortisolism – is it due to elevated ACHT, or something else? To determine this, we'll measure plasma ACTH levels. If plasma ACTH levels are low/suppressed, there may be a cortisol-secreting adrenal tumor; we'll want to do imaging tests to investigate this.

• We'd expect to find a tumor in one adrenal gland and atrophy of the other (atrophy is due to lack of stimulation by ACTH, which is inhibited by negative feedback of cortisol on the HPA axis).

Adenomas are more common than carcinomas, and carcinomas are more likely to secrete androgens along with cortisol. Be aware that bilateral macro- and micro-nodular adrenal hyperplasias, though rare, can also cause ACTH-independent Cushing's syndrome. We need to rule out exogenous glucocorticoids and other physiologic and medical causes, as we mentioned in the introduction, as potential sources of ACTH-independent hypercortisolism. If plasma ACTH is elevated/not suppressed, hypercortisolism is ACTH-dependent – the adrenal gland is releasing cortisol in response to excessive stimulation by ACTH. Now, we need to determine the source of the excess ACTH. There are a few ways we can do this; we'll use inferior petrosal sampling in our example. If we find central ACTH levels are higher than peripheral levels, the cause is likely a pituitary tumor secreting ACTH – this is called Cushing's Disease, and typically involves an adenoma.

• This is the most common form of endogenous (non-iatrogenic) Cushing's Syndrome.
• In these patients, the HPA axis is dysfunctional, and is no longer responsive to negative feedback from cortisol.
• Furthermore, the HPA axis is no longer responsive to stressors that would typically stimulate the release of additional ACTH (likely because CRH secretion has been suppressed by chronic hypercortisolism).
• Secretion of thyrotropin, gonadotropin, and growth hormone are also suppressed.
• Treatment involves removal of the pituitary tumor, which can reverse these effects in many, but not all, patients. Some patients may require bilateral adrenalectomy.

• In these cases, be aware of a potential complication called Nelson syndrome (aka, corticotroph tumor progression), in which a pituitary tumor develops, producing headaches, elevated ACTH levels, and hyperpigmentation.

If we find central ACTH levels less than or equal to peripheral levels, the source is likely an ectopic (non-pituitary) tumor.

• Small cell lung cancer and bronchial tumors are often to blame, although tumors in other tissues can also secrete ectopic ACTH.

Diagrams of the HPA axis in these scenarios. Be aware that not all patients will exhibit these signs and symptoms, and they can vary by etiology. "Moon facies" describes the rounded shape of the face and neck that can develop as a result of fat accumulation on the sides of the face. Central, aka, truncal obesity is common, with a so-called "buffalo hump" due to fat redistribution and accumulation between the shoulders in the upper back. As you may have guessed from our earlier discussion on the roles of cortisol, patients with Cushing's syndrome are prone to muscle, bone, and skin atrophy and weakness. Muscle atrophy is particularly apparent in the extremities, so patients' limbs appear disproportionately thin, and their bones may be more prone to fracture. Red or purple striae in the skin, particularly on the abdomen, breasts, thighs, and buttocks; these are the result of increased subcutaneous fat and the loss of collagen and other structural components of the skin. Patients may also bruise more easily. Hypertension is caused via multiple effects, including increased cardiac contractility and increased extracellular fluid volume. Hyperglycemia is common, and may progress to diabetes mellitus, because cortisol increases gluconeogenesis and insulin resistance. Immunosuppression increases vulnerability to infectious diseases that require robust B- and T-cell-mediated immune responses (for example, tuberculosis and fungal infections). Patients may experience emotional or psychiatric disturbances, such as irritability or impaired memory. The excess androgen secretion associated with some forms of Cushing's syndrome (i.e., adrenal tumors) can cause hirsutism and menstrual irregularities. In children, hypercortisolism can impair linear growth via negative effects on bone growth and impaired secretion of growth hormone and thyroid stimulating hormone. The goal of treatment is to reverse the signs and symptoms and prevent complications of hypercortisolism.

• Address underlying causes: tapered discontinuation of medications, surgical removal of tumors, etc.
• Reverse electrolyte imbalances