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Hypercortisolism: Cushing Syndrome

Review literature: (Boscaro et al., 2001).

Definition of Cushing Syndrome and Cushing Disease

Cushing syndrome is a symptom complex caused by an excess of glucocorticoids (hypercortisolism) without refering 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
• Most often women in the 3rd and 4th decade of life

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 adrenocortial carcinoma with production of cortisone
• 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 for ACTH-production (via POMC).

Laboratory Workup in Cushing Syndrome

24-hour urine collection:

Determination of cortisol in a 24-hour urine collection is the test of choice to confirm hypercortisolism. A normal cortisol-concentration in urine, together with a normal dexamethasone suppression test, rules out Cushing syndrome.

Serum cortisol:

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

Dexamethasone Suppression Test:

The administration of 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. 2 mg dexamethasone p.o. are given in the evening. If this leads to a lowering of plasma cortisol concentration the next morning to <3 μg/dl, Cushing syndrome is unlikely. In case of insufficient suppression, the dexamethason suppression test is continued (see below).

Dexamethasone Suppression Test (high dose):

The morning concentration of serum cortisol is determined. 2–4–8 mg dexamethasone p.o. are given in the evening the next three days. If this leads to a lowering of plasma cortisol concentration the next morning to <3 mg/dl, Cushing syndrome is unlikely and the test is stopped.

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.

ACTH in Serum:

ACTH measurement is indicated, if dexamethason suppression test indicates a Cushing syndrome. ACTH concentrations below 5 pg/ml indicate ACTH-independent Cushing syndrome. ACTH concentrations about 50 pg/ml are typical for an ACTH-dependent Cushing syndrome.

Metopiron Test:

The metopiron-test differentiates between ACTH secretion from the pituitary gland or ectopic (paraneoplastic) ACTH production. Metopiron blocks the 11-beta-hydroxylase and thus the completion of cortisol biosynthesis. If the regulation pathway is intact, an intermediate product (17-Hydroxykortikosteroid) 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.) results in an increase of ACTH and cortisol within 30 minutes. ACTH and cortisol are determined before and after CRH injection (15, 30, 60, 90 and 120 minutes).

In ectopic ACTH production, an excessive increase of ACTH and cortisol cannot be observed, since intracellular signaling pathways are downregulated or not intact.

Selective Blood Sampling of ACTH:

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

Imaging in Cushing Syndrome

Cranial CT or MRI:

CT or MRI of pituitary gland is done if Cushing disease is suspected.

CT or MRI of the Abdomen:

Abdominal imaging with CT scan or MRI is done if adrenal adenoma/carcinoma is suspected. In general, adenomas are larger than 2 cm and the adrenal gland of the opposite side is atrophied. Adrenal carcinomas are in general larger than 5 cm, 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

Cushing Disease:

Treatment of choice for Cushing disease is transsphenoidal removal of a pituitary adenoma. The relapse risk is 10%.

In the absence of a surgical option, irradiation of the pituitary gland is feasible, possibly in combination with ketoconazole or Metopiron for blocking the steroid synthesis.

Bilateral adrenalectomy and substitution of glucocorticoids is an alternative to medical inhibition of steroid synthesis. Nelson syndrome is a complication after bilateral adrenalectomy: hypertrophy (and tumor growth) of the pituitary gland may lead to a compression of the optic tract.

Adrenal adenoma/carcinoma:

Removal of the affected adrenal gland [adrenalectomy] is the treatment of choice.

Ectopic ACTH Production:

Identification and resection of the ACTH-producing tumor is the treatment of choice. If localization or resection is not possible, medical inhibition of steroid synthesis or bilateral adrenalectomy is an option.

References

  Deutsche Version: Cushing-Syndrom