Cushing’s syndrome is caused by prolonged exposure to an excess of glucocorticoids.
Clinical features depend on the duration of disease and degree of cortisol excess but include weight gain, skin changes, menstrual irregularities, glucose intolerance and mood disturbance.
The cause may be endogenous or exogenous:
Cushing's syndrome is defined based upon its aetiology - whether the cortisol excess is ACTH dependent or independent:
Cortisol secretion is controlled by the hypothalamus-pituitary-adrenal axis.
Corticotropin-releasing hormone (CRH) is released by the paraventricular nucleus of the hypothalamus. It is transported via the hypophyseal portal system to the anterior pituitary where it stimulates the release of adrenocorticotropic hormone (ACTH).
ACTH, released from the corticotrophs of the anterior pituitary, stimulates the release of cortisol.
The precursor of ACTH is POMC, this is also the precursor of beta-melanocyte-stimulating hormone. In addition, ACTH may be cleaved to form alpha-melanocyte-stimulating hormone. As a result ACTH excess results in hyperpigmentation (resulting from melanocyte stimulation), particularly affecting the oral mucosa and palmar creases.
ACTH excess is a feature of both Addison's disease (primary adrenocortical insufficiency) and ACTH dependent Cushing's syndrome.
Cortisol is released from the adrenal cortex in response to ACTH. It exerts negative feedback on the release of both ACTH and CRH.
Cortisol exhibits diurnal variation, that is to say, the plasma concentration of cortisol levels vary during a 24 hour period.
It reaches a zenith (highest point) at around 8 am and a nadir (lowest point) at around midnight to 1 am.
The causes of Cushing’s may be divided into those that are ACTH dependent and those that are ACTH independent.
ACTH dependent Cushing's occurs due to the excess production of ACTH. When exogenous causes are excluded, ACTH dependent causes are responsible for 80% of all Cushing's syndrome.
There are a number of causes:
The pituitary adenoma seen in Cushing's disease is less responsive to glucocorticoid negative feedback but will respond at high levels - as such a high dose dexamethasone suppression test (see 'Identifying a cause' below) can be used to distinguish a pituitary adenoma from ectopic ACTH sources.
ACTH independent Cushing's occurs in the presence of normal ACTH production. There are a number of causes:
The clinical features asssociated with Cushing's syndrome are related to the effects of excess cortisol.
* NOTE: The precursor of ACTH is POMC, this is also the precursor of beta-melanocyte-stimulating hormone. In addition, ACTH may be cleaved to form alpha-melanocyte-stimulating hormone. As a result ACTH excess results in hyperpigmentation due to melanocyte stimulation). This is particularly noted on the oral mucosa and palmar creases.
The work-up for Cushing's syndrome follows two stages, establishing a diagnosis and establishing a cause.
There are a number of diagnostic tests that can be arranged that either aim to demonstrate excess cortisol production or abnormal hypothalamus-pituitary-adrenal axis function. Of course the below tests are for endogenous causes - in exogenous disease there should be a clear history of prolonged glucocorticoid use.
A 24-hour urinary cortisol is often the initial test in a patient with suspected Cushing's syndrome. Three or more collections are usually needed. Levels 3-4x normal are highly suggestive of Cushing's syndrome.
Importantly, creatinine levels also need to be measured as the variation in levels between samples (>10 %) indicates that the test needs to be repeated.
Taking midnight cortisol levels helps to demonstrate a loss of the normal circadian pattern.
Cortisol levels can be salivary or blood based. If blood, samples should ideally be taken from an indwelling cannula, which helps minimise stress.
The low-dose dexamethasone suppression test is aimed at demonstrating the loss of normal negative feedback on the pituitary gland and hypothalamus.
1 mg of dexamethasone is given at 11pm and serum cortisol is then measured at 8am. In a normal individual, the administration of dexamethasone should suppress the morning rise in serum cortisol. However, in patients' with Cushing's syndrome, there is a lack of suppression, which warrants further investigation.
This test is less commonly used, dexamethasone is given for a period, followed by the administration of CRH. Serum cortisol (and ACTH) levels can then be measured. It may help distinguish between Cushing's and hypothalamus-pituitary-adrenal axis dysregulation seen in severe depression.
After diagnosing cortisol excess we must identify the underlying aetiology.
Plasma ACTH is the first test conducted when attempting to establish the cause of Cushing's syndrome:
Once a decision has been made as to whether the disease is or isn't ACTH dependent further investigations can be ordered.
The vast majority of non-exogenous ACTH independent Cushing's is caused by adrenal pathology. As such in patients with suspected ACTH independent Cushing's syndrome a CT of the adrenal glands is normally the first line investigation. Further tests may include MRI adrenal glands and PET/CT.
The high-dose dexamethasone suppression test helps to determine, in ACTH dependent causes:
Other tests may then be arranged to identify the pituitary adenoma or look a malignancy responsible for ectopic production - this will typically involve CTs and MRIs.
Petrosal sinus sampling is an invasive test that may be used to help identify a microscopic pituitary adenoma. A catheter is passed into the petrosal sinuses that surrounds the pituitary gland and the level of ACTH (+/- CRH stimulation) can be assessed. This can be compared to levels from a peripheral vein. Petrosal sinus sampling may be used to identify the side of the tumour.
The management of exogenous Cushing's is the withdrawal of the glucocorticoid.
Patients who have developed Cushing's from exogenous steroid use should not abruptly stop. They will likely have developed suppression of their normal endogenous glucocorticoid production - as such stopping could result in an addisonian crisis.
Instead the patient should have a gradual tapering regimen with close safety netting and monitoring.
Transsphenoidal surgery is the gold-standard for treatment of Cushing's disease.
Cushing’s disease is typically treated with transsphenoidal surgery, with either:
Medical therapy is most commonly used as a bridge to definitive surgical management or in the case that surgery is not possible or fails.
Metyrapone can be used, an inhibitor of 11β-hydroxylase, that leads to a reduction in cortisol synthesis.
This may be used in children and young people or those in whom surgical techniques have failed. Effects are not immediate and takes around 6-12 months to have maximal effect.
In those in who all other therapies have failed bilateral adrenalectomy may be used. This mandates lifelong glucocorticoid and mineralocorticoid replacement.
Adrenal lesions may be treated with surgical resection.
Unilateral adrenalectomy offers curative therapy. Where available the laparoscopic approach is generally preferred to open surgery. Following surgery patients will need a tapering course of exogenous steroids for a period of time as their endogenous CRH and ACTH will be suppressed.
In patients with overt Cushing's bilateral adrenalectomy may be offered. Following this patients require replacement of glucocorticoids and mineralocorticoids.
Following appropriate staging resection is the mainstay of management. Adjuvant chemotherapy, radiotherapy or mitotane may be given.
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