Cushing's syndrome is a clinical condition resulting from prolonged exposure to excessive glucocorticoids from either endogenous or exogenous sources. The most common cause is the administration of exogenous glucocorticoids. Without treatment, Cushing's syndrome is often fatal because of cardiovascular disease, hypertension, or infectious complications. Early diagnosis and treatment improve clinical outcomes, with most symptoms gradually improving over 2–12 months after successful therapy.

Pathophysiology

Excess glucocorticoids lead to widespread metabolic, cardiovascular, musculoskeletal, immune, and endocrine abnormalities. Cushing's syndrome is classified into:

• ACTH-dependent states

  • Pituitary adenoma (Cushing's disease) (90–95%)

  • Ectopic ACTH syndrome

• ACTH-independent states

  • Adrenal adenoma

  • Adrenal carcinoma

• Exogenous sources

  • Glucocorticoid therapy

• Pseudo-Cushing disorders

  • Depression

  • Alcoholism

• High cortisol secretion without convincing clinical features of Cushing's syndrome

• Pregnancy

Risk factors

• Long-term glucocorticoid therapy (most common)

• Pituitary adenoma (Cushing's disease)

• Adrenal adenoma

• Adrenal carcinoma

• Ectopic ACTH-producing tumors

• Depression

• Alcoholism

• Pregnancy

Signs and symptoms

The symptoms and signs result from chronic exposure to excess glucocorticoids. An important clinical clue is the simultaneous development and progressive worsening of several manifestations.

Common features include:

• Central obesity

• Facial plethora

• Proximal muscle weakness

• Easy bruising

• Purple striae

• Hirsutism

• Glucose intolerance

Diagnostic criteria

The diagnosis is established when at least two first-line screening tests are abnormal.

First-line diagnostic tests

• Low-dose dexamethasone suppression test

• 24-hour urinary free cortisol

• Late-night salivary cortisol

Differential diagnostic testing

To determine the underlying cause:

• Morning serum ACTH

• High-dose dexamethasone suppression test

Investigations

Laboratory investigations

• Low-dose dexamethasone suppression test

• 24-hour urinary cortisol

• Late-night salivary cortisol

• Morning serum ACTH

• High-dose dexamethasone suppression test

Imaging

• Pituitary CT scan (approximately 50% sensitivity for detecting microadenomas)

• Pituitary MRI (sensitivity up to 100%)

• Adrenal ultrasonography or CT scan when an adrenal source is suspected

Management

Non-pharmacological management

Definitive treatment is surgical removal of the underlying source whenever possible.

• Adrenalectomy for adrenal tumors

• Transsphenoidal resection for pituitary adenomas

• Surgical resection of ectopic ACTH-producing tumors

Pharmacological management

Medical therapy may be used when surgery is not immediately possible, as preoperative treatment, or when hypercortisolism persists after surgery.

• Metyrapone (PO) 30 mg/kg, maximum 3,000 mg, administered at midnight, usually with a snack.

Prognosis

Without treatment, Cushing's syndrome carries a high mortality due to cardiovascular disease, hypertension, and severe infections. With appropriate treatment directed at the underlying cause, most patients experience gradual improvement in clinical manifestations over 2–12 months, although recovery varies depending on disease severity and duration.