What is the diagnosis and treatment for Cushing's syndrome (Hypercortisolism)?

From the Guidelines

Cushing's syndrome should be diagnosed and treated promptly to prevent morbidity and mortality, with the most recent and highest quality study recommending a combination of surgical intervention and medical therapy, including ketoconazole (400-1200 mg/day) and metyrapone (500-6000 mg/day), to block cortisol production or action 1.

Diagnosis of Cushing's Syndrome

The diagnosis of Cushing's syndrome involves measuring 24-hour urinary free cortisol, late-night salivary cortisol, low-dose dexamethasone suppression test, and determining ACTH levels to identify the source 1.

• 24-hour urinary free cortisol excretion is recommended if cortisol levels are elevated, with a diagnostic cut-off of >193 nmol/24 h (>70 μg/m2) 1.
• Late-night salivary cortisol and low-dose dexamethasone suppression test can also be used to confirm the diagnosis, with a diagnostic cut-off of >=50 nmol/l (>=1.8 μg/dl) 1.
• Determining ACTH levels is crucial to identify the source of Cushing's syndrome, with a cut-off value of >1.1 pmol/l (>5 ng/l) indicating a pituitary source 1.

Treatment of Cushing's Syndrome

The treatment of Cushing's syndrome depends on the underlying cause, with surgical intervention often being the first-line treatment:

• Transsphenoidal surgery for pituitary adenomas,
• Adrenalectomy for adrenal tumors,
• Removal of the ectopic ACTH-producing tumor 1. Medical therapy may include:
• Ketoconazole (400-1200 mg/day)
• Metyrapone (500-6000 mg/day)
• Mifepristone (300-1200 mg/day) to block cortisol production or action 1. Radiation therapy may be used for persistent pituitary tumors.

Medical Management of Hypercortisolism

Medical management of hypercortisolism is achieved with adrenostatic agents, including ketoconazole and mitotane, with ketoconazole being the most commonly used due to its easy availability and relatively tolerable toxicity profile 1.

• Ketoconazole is typically used at doses of 400–1200 mg/d, with response typically seen within a few days 1.
• Metyrapone can also be used, with a typical dose of 250–750 mg every 4 h, but its use is limited due to adverse effects such as hirsutism, dizziness, and hypokalaemia 1.

Importance of Early Diagnosis and Treatment

Early diagnosis and treatment of Cushing's syndrome are crucial to prevent complications like osteoporosis, diabetes, hypertension, and increased susceptibility to infections, with the goal of rapid normalization of cortisol levels to improve morbidity, mortality, and quality of life 1.

From the Research

Diagnosis of Cushing's Syndrome

• Cushing's syndrome is a rare endocrine disorder characterized by sustained pathologic hypercortisolism caused by excessive corticotropin (ACTH) secretion by tumors in the pituitary gland or elsewhere, or by ACTH-independent cortisol secretion from adrenal tumors 2.
• The clinical features of Cushing's syndrome are variable, and no single pattern is seen in all patients. Specific features include abnormal fat distribution, proximal muscle weakness, wide purple striae, and decreased linear growth with continued weight gain in a child 2.
• Patients with characteristics of glucocorticoid excess should be screened with measurements of saliva or urine cortisol or dexamethasone suppression testing 2, 3, 4, 5.
• The diagnosis of Cushing's syndrome should be followed by the measurement of plasma ACTH concentration to determine whether the hypercortisolism is ACTH-independent 2, 3, 5.

Treatment of Cushing's Syndrome

• Surgical resection of tumor is the optimal treatment for all forms of Cushing's syndrome 2, 6, 4.
• Bilateral adrenalectomy, medical treatment, or radiotherapy are sought in inoperable or recurrent cases 2, 6, 4.
• The medical treatment of choice is ketoconazole 2.
• Pharmacological treatment may be used as a preparation for surgery, or in cases where surgery fails or is impossible 6.
• The initiation and adjustment of treatment doses is controversial, with the possibility of titration by gradual dose increase based on biological markers, or a more radical "block and replace" approach 6.

Diagnostic Tests

• Urinary free cortisol measurements, the dexamethasone suppression test, and late-night salivary cortisol or midnight serum cortisol measurements are used to confirm the diagnosis of Cushing's syndrome 3, 4, 5.
• Bilateral inferior petrosal sinus sampling with measurement of ACTH before and after administration of ACTH-releasing hormone is used to distinguish pituitary from ectopic ACTH secretion 2, 3, 5.
• Adrenal imaging provides clues for the aetiology of non-ACTH dependent forms of Cushing's syndrome 3.
• Pituitary MRI imaging, the high dose dexamethasone suppression test, and the CRH test are used to differentiate between the ACTH-dependent forms of Cushing's syndrome 3, 5.