Hypercortisolism: Cushing's Syndrome

Review literature: (Boscaro et al, 2001).

Definition of Cushing's Syndrome and Cushing's Disease

Cushing's syndrome is a symptom complex caused by an excess of glucocorticoids (hypercortisolism) without refering to the cause. Cushing's 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's Syndrome

ACTH-dependent Cushing's Syndrome (Overproduction of ACTH):

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

ACTH-independent Cushing's 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's 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 Work-Up in Cushing's 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's 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 mg/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 mg/dl, Cushing's 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's syndrome is unlikely and the test is stopped.

Interpretation of the Dexamethasone Suppression Test

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

ACTH in Serum:

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

Cranial CT or MRI:

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

CT or MRI of the Abdomen:

Abdominal imaging 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's Syndrome

Therapy Principles:

Normalization of cortisol
Removal of life-threatening tumors
Avoid hormone insufficiency
Avoid lifelong dependence on a (hormone)-medication

Cushing's Disease:

Treatment of choice for Cushing's 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's 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.

Catecholamins

Index

Adrenal diseases

Index: 1–9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

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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

Deutsche Version: Cushing-Syndrom

Last update

Dr. med. Dirk Manski
man...@urologielehrbuch.de