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Cushing's Syndrome
Essentials
- Cushing's syndrome may be behind the patient's hypertension Secondary Hypertension, metabolic syndrome Metabolic Syndrome or early developing osteoporosis.
- Screening tests for hypercortisolism include a short 1 mg or 1.5 mg dexamethasone test and determination of cortisol concentration in 24-hour urine or late-night saliva. They can be performed in primary care.
- Monitor the devolopment of Cushing symptoms in patients receiving oral glucocorticoids.
Causes and incidence of hypercortisolism
- Iatrogenic hypercortisolism associated with glucocorticoid use is the most common cause of hypercortisolism. See article Pharmacological glucocorticoid treatment Pharmacological Glucocorticoid Treatment.
- Physiological hypercortisolism (pseudo-Cushing's syndrome) is found in association with, for example, obesity, severe depression, severe physical or psychological stress and alcoholism.
- Cushing's syndrome is divided into ACTH-dependent and ACTH-independent forms.
- The ACTH-dependent forms are ACTH-secreting pituitary tumours (65-70%) and extra-pituitary ectopic tumours secreting ACTH or CRH (corticotropin-releasing hormone) (10-15%).
- ACTH-independent forms include adrenocortical tumours (18-20%) and primary pigmented nodular adrenal disease (PPNAD; less than 1%) and bilateral macronodular adrenal hyperplasia (PBMAH; less than 1%).
- The incidence of pituitary Cushing's syndrome in Europe is about 1.2-2.4 per million inhabitants per year. The incidence of Cushing's syndrome caused by glucocorticoid-secreting adrenal adenoma is about 0.6 cases per million inhabitants and adrenal carcinoma 0.2 cases per million inhabitants.
- Cushing's syndrome is more common in women than in men.
Symptoms
- Hypercortisolism may be continuous or cyclic by nature and its intensity varies from subclinical hypercortisolism to rapidly progressing, severe symptom picture. It is particularly significant if several symptoms appear or become worse simultaneously.
- The symptom picture may be modified by the symptoms of a potential tumour and by androgen excess.
- Typical symptoms of Cushing's syndrome
- Moon face, buffalo hump in the neck in almost 100% of the patients
- Truncal obesity in 90%
- Muscular weakness (proximal myopathy) in 90-95%
- Hypertension in 80%
- Hirsutism in 80%
- Menstrual disturbances in 80%
- Osteoporosis in 70-80%
- Bruising tendency in 70%
- Mood disturbances in 70%
- Impaired glucose tolerance or diabetes in 10-15%
- Striae (reddish/bluish-red, more than 1 cm wide)
- Thin skin
- Sleep apnoea
- Decrease in libido
- Fat pads in the supraclavicular area
- Hyperpigmentation
- Venous thromboembolisms before treatment and in association with surgical treatment
Diagnosis
- Cushing's syndrome should be screened if a patient is found to have
- findings inconsistent with age (e.g. osteoporosis or hypertension in an adolescent) or
- multiple findings fitting Cushing's syndrome (e.g. moon face, proximal muscle weakness, striae, bruising tendency, abdominal obesity) or
- adrenal incidentaloma.
- Three different tests can be used for screening:
- a short 1 mg or 1.5 mg dexamethasone test
- a late-night (23-24 o'clock) salivary cortisol measurement or
- 24-hour urine cortisol measurement.
- For both salivary and 24-hour urine cortisol measurements, 2 abnormal test results are required for each test to be interpreted as pathological.
- The 24-hour urine cortisol excretion must be at least 3 times higher than the normal upper limit of the test for the result to be unambiguously pathological.
- False positive results of the dexamethasone test are caused by many drugs (phenytoin, carbamazepine, barbiturates, rifampicin, nifedipine, pioglitazone, oestrogen preparations), and it is not reliable in pregnant women.
- If the dexamethasone test is used, a preceding break of at least 6 weeks in the use of contraceptives is required.
- In adrenal incidentaloma, the short dexamethasone test is primarily recommended.
- The diagnosis of Cushing's syndrome is confirmed if at least 2 first-line screening tests for hypercortisolism are unambiguously positive and physiological hypercortisolism does not explain the condition.
- If a cyclic form of the disease is suspected, it is recommended to repeat the 24-hour urine cortisol test, or the more easily performed late-night salivary cortisol test, as necessary.
Further investigations in specialized care
- Further investigations to confirm the diagnosis and to determine the aetiology of hypercortisolism are carried out in an endocrinological unit.
- The priority is to determine whether the tumour is ACTH-dependent or independent.
- A markedly suppressed blood ACTH concentration strongly suggests an adrenal tumour and an increased ACTH concentration a pituitary or ectopic tumour-induced hypercortisolism.
- A CRH stimulation test and large-dose dexamethasone test are used as confirmatory tests.
- Sinus petrosus catheterization also provides additional information, particularly in the case of small (< 6 mm) pituitary tumours and ectopic tumours.
- Imaging
- CT is preferred for adrenal imaging as it provides an estimate of the potential malignancy of the tumour (density in Hounsfield units [HU]).
- Imaging of the pituitary gland is started with MRI.
- In addition, PET and gamma scans are used in the diagnosis of Cushing's syndrome.
Treatment
- Untreated Cushing's syndrome is associated with increased mortality and significant morbidity (e.g. increase in cardiovascular diseases, immunosuppression, osteoporosis, as well as psychological and cognitive problems).
- The treatment is surgical with the exception of iatrogenic hypercortisolism. Radiotherapy is also used. The aim of treatment is to eliminate hypercortisolism and restore normal hypothalamic-pituitary-adrenal axis function.
- After successful surgical treatment, medication with hydrocortisone is required (often only temporarily) as the pituitary-adrenocortical axis recovers from the depression caused by hypercortisolism. See article on pharmacological glucocorticoid treatment Pharmacological Glucocorticoid Treatment.
- If hypercortisolism is not corrected by surgery or radiotherapy, options for pharmacotherapy include adrenal steroidogenesis inhibitors, dopamine agonists, somatostatin receptor agonists and a glucocorticoid receptor antagonist. It is rarely necessary to remove both adrenal glands.
- Recuperation may take months or years even after successful treatment. Complications, e.g. cardiovascular risk factors and osteoporosis, require follow-up.
References
- Braun LT, Vogel F, Zopp S, et al. Whom Should We Screen for Cushing Syndrome? The Endocrine Society Practice Guideline Recommendations 2008 Revisited. J Clin Endocrinol Metab 2022;107(9):e3723-e3730. [PubMed]