Cushing's Disease

Cushing's syndrome consists of the symptoms and signs associated with prolonged exposure to inappropriately elevated levels of free plasma glucocorticoids due to endogenous (cortisol) and exogenous (e.g., prednisolone, dexamethasone) sources. Iatrogenic Cushing's syndrome is common, occurring to some degree in most patients taking long-term corticosteroid therapy. Endogenous causes of Cushing's syndrome are rare and result in loss of the normal feedback mechanism of the hypothalamic-pituitary-adrenal axis and the normal circadian rhythm of cortisol secretion. The most common endogenous cause is Cushing's disease, when a corticotroph pituitary adenoma secretes excess ACTH. Diagnosis of this challenging condition begins with clinical suspicion of Cushing's syndrome, based on the presence of clinical features more specific to the condition. Biochemical diagnosis is a two-step process wherein endogenous hypercortisolemia is first established, and then a pituitary source confirmed by use of biochemical and imaging modalities that allow differentiation from a nonpituitary source of ACTH. The final diagnosis often requires sophisticated hormonal testing and imaging procedures best performed in specialized referral centers. Transsphenoidal pituitary surgery remains the first-line therapeutic option in patients with Cushing disease, but late recurrences mandate life-long follow-up. Progress has been made in a better understanding of the biology of corticotroph adenomas, raising the possibility of more targeted medical therapies.