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Hypercortisolism: Symptoms and Treatment of Cushing Syndrome

Definition of Cushing Syndrome and Cushing Disease

Cushing syndrome is a symptom complex caused by an excess of glucocorticoids (hypercortisolism) without referring to the cause. Cushing disease is a specific cause of hypercortisolism, an ACTH-producing tumor of the pituitary gland.

Epidemiology

• Prevalence 5–6/100.000
• The female:male ratio is 3:1, usually adults 30–50 years old.

Causes (Etiology) of Cushing Syndrome

ACTH-dependent Cushing Syndrome (Overproduction of ACTH):

• Pituitary adenoma (Cushing disease)
• Paraneoplastic ACTH production: in lung cancer, pancreatic cancer and carcinoid.
• Paraneoplastic CRH production (rare)

ACTH-independent Cushing Syndrome:

• Adrenal adenoma or adrenocortical carcinoma with cortisone secretion
• Iatrogenic steroid medication
• Micronodular hyperplasia of the adrenals
• Paraneoplastic cortisol production (rare)

Signs and Symptoms of Cushing Syndrome

• Truncal obesity, moon face
• Arterial hypertension
• Diabetes mellitus
• Muscle weakness, muscle atrophy
• Menstrual disorders
• Striae rubrae, acne, edema
• Mental changes, headache
• Hyperpigmentation of the skin is a sign of ACTH production (via POMC).

Laboratory Workup in Cushing Syndrome

Late-night salivary cortisol:

The method of choice for confirming hypercortisolism is the late-night salivary cortisol (LNSC) test, which determines cortisone and cortisol in saliva between 11 pm and midnight. At least two or three LNSC tests are recommended. The saliva test is simpler and more reliable than measuring cortisol in a 24-hour urine collection.

24-hour urine collection:

Determining cortisol in a 24-hour urine collection is the test of choice to confirm hypercortisolism. A normal cortisol concentration in urine and dexamethasone suppression test rule out Cushing syndrome.

Serum cortisol:

The serum concentration of cortisol is determined in the morning and evening. The normal range at 8 o'clock in the morning is 4–22 μg/dl, the concentration in the evening should be lower.

ACTH in Serum:

ACTH concentrations below 5 pg/ml indicate an ACTH-independent Cushing syndrome, while concentrations about 50 pg/ml are typical for an ACTH-dependent Cushing syndrome.

Dexamethasone Suppression Test:

Dexamethasone leads to a reduction in morning serum cortisol if the regulation pathway between hypothalamus-pituitary gland-adrenals is intact.

Dexamethasone Suppression Test (low dose):

The morning concentration of serum cortisol is determined, and 1 mg dexamethasone p.o. is given in the evening. Cushing syndrome is unlikely if this leads to a lowering of plasma cortisol concentration the next morning to <1.8 μg/dl. In case of insufficient suppression, the dexamethasone suppression test is continued with a higher dose (see below).

Dexamethasone Suppression Test (high dose):

The morning concentration of serum cortisol is determined, and 8 mg dexamethasone p.o. is given in the evening. The serum cortisol concentration is measured the next morning.

Interpretation of the Dexamethasone Suppression Test

• No suppression and low ACTH: primary adrenal Cushing syndrome.
• No suppression and normal/high ACTH: ectopic ACTH-production or Cushing disease
• If only the highest dosage leads to a suppression of cortisone and normal/high ACTH: Cushing disease still has to be considered.
• Sufficient suppression: Cushing syndrome is unlikely.

Metyrapone Test:

The metyrapone test differentiates ACTH secretion from the pituitary gland and ectopic (paraneoplastic) ACTH production. Metyrapone blocks the 11-beta-hydroxylase and, thus, the completion of cortisol biosynthesis. If the regulation pathway is intact, an intermediate product (17-hydroxycorticosteroid) can be detected increasingly in the urine, since (with intact feedback via the pituitary) ACTH and intermediate products increase due to the defective cortisol biosynthesis. Ectopic ACTH-producing tumors do not have this feedback; the intermediate products in the urine do not increase.

CRH Test:

The administration of CRH (1 mg/kg i.v.) increases ACTH and cortisol within 30 minutes. ACTH and cortisol are determined before and after CRH injection (15, 30, 60, 90, and 120 minutes).

• Cushing disease: increased basal ACTH and cortisol. The CRH test significantly increases ACTH and cortisol.
• Adrenal hypercortisolism: suppressed basal ACTH and increased basal cortisol. There is no excessive increase in ACTH or cortisol in the CRH test.
• Ectopic ACTH production: increased basal ACTH and cortisol. There is no excessive increase in ACTH or cortisol in the CRH test.

Selective Blood Sampling of ACTH:

Blood sampling is done from the right and left inferior petrosal sinus to localize a pituitary adenoma. Petrosal blood sampling is done before and after stimulation with CRH.

Imaging in Cushing Syndrome

Cranial CT or MRI:

To diagnose pituitary adenoma if Cushing disease is suspected.

CT or MRI of the Abdomen:

Abdominal imaging with CT scan or MRI is done if adrenal adenoma or carcinoma is suspected. Adenomas with hormone production are usually larger than 2 cm and the adrenal gland of the opposite side is atrophied. Adrenal carcinomas are often larger than 5 cm and show calcification or irregularities.

Treatment of Cushing Syndrome

Therapy Principles:

1. Normalization of cortisol
2. Removal of life-threatening tumors
3. Avoid hormone insufficiency
4. Avoid lifelong dependence on a (hormone)-medication

Treatment of Cushing Disease:

The best treatment for Cushing disease is transsphenoidal removal of a pituitary adenoma. The relapse risk is 10%. In the event of recurrence or if surgery is not possible, pituitary irradiation is feasible, possibly in combination with drug therapy: options include pasireotide (somatostatin analog), (levo)ketoconazole, osilodrostat or metapyron (blocking of steroid synthesis) or mifepristone (glucocorticoid receptor antagonist).

Bilateral adrenalectomy and lifelong substitution of glucocorticoids is an option if the above-mentioned treatment options fail. Nelson syndrome is a complication after bilateral adrenalectomy: the ACTH-producing pituitary tumor proliferates and causes hyperpigmentation, compression of the optic tract, and headaches.

Adrenal adenoma or carcinoma:

Removal of the affected adrenal gland [adrenalectomy] is the treatment of choice. In metastatic adrenal carcinoma, therapy with mitotane (a derivative of a pesticide) is an option for blocking hormone production.

Ectopic ACTH Production:

Identification and resection of the ACTH-producing tumor is the treatment of choice. If localization or resection is not possible, medical treatment or bilateral adrenalectomy is an option (see above).

References

Boscaro u.a. 2001 BOSCARO, M. ; BARZON, L. ; FALLO, F. ; SONINO, N.: Cushing’s syndrome.
In: Lancet
357 (2001), Nr. 9258, S. 783–91

Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847-875. doi: 10.1016/S2213-8587(21)00235-7.

  Deutsche Version: Cushing-Syndrom