Hypercortisolism

Hypercortisolism refers to prolonged exposure to elevated levels of cortisol, the primary glucocorticoid produced by the adrenal cortex. It can result from endogenous overproduction or from external corticosteroid use. When the excess cortisol causes the characteristic clinical syndrome, it is often referred to as Cushing syndrome.

Causes are broadly categorized as endogenous or exogenous. Endogenous hypercortisolism includes ACTH-dependent forms, such as a pituitary adenoma producing adrenocorticotropic hormone (Cushing disease) or ectopic ACTH secretion from non-pituitary tumors, and ACTH-independent forms, such as adrenal adenomas or carcinomas that autonomously produce cortisol. Exogenous hypercortisolism is most commonly due to chronic administrative or therapeutic use of glucocorticoids.

Pathophysiology and presentation are tied to cortisol’s metabolic and immune effects. Chronic excess promotes central (truncal) obesity, facial fullness, dorsocervical fat pad, and purple abdominal striae, along with proximal muscle weakness, hypertension, glucose intolerance or diabetes, osteoporosis, edema, and skin fragility. Mood changes and menstrual irregularities can occur. In children, growth suppression may be evident.

Diagnosis typically starts with screening tests such as an overnight dexamethasone suppression test, 24-hour urinary free cortisol, or late-night salivary cortisol. If hypercortisolism is confirmed, plasma ACTH helps distinguish ACTH-dependent from ACTH-independent disease. Imaging follows: pituitary MRI for ACTH-dependent cases; adrenal imaging for ACTH-independent disease. In uncertain cases, inferior petrosal sinus sampling may be used.

Treatment targets the underlying cause. It may involve reducing or stopping exogenous steroids, pituitary surgery for Cushing disease, adrenalectomy for adrenal tumors, or resection of ectopic ACTH-secreting tumors. Medical therapies include steroidogenesis inhibitors and glucocorticoid receptor antagonists, alongside management of comorbidities. Prognosis depends on etiology and treatment timeliness.