Cushing's Syndrome | Hypercortisolism , Causes, Symptoms and Treatment

  • Clinicals
  • Endocrinology
  • 2020-07-27 13:56:08
  • 6 minutes, 37 seconds

Cushing's Syndrome | Hypercortisolism , Causes, Symptoms and Treatment

Cushing's syndrome is a condition where there is an excessive secretion of glucocorticoid cortisol.  T here are a number of reasons why the body may produce too much of the glucocorticoid cortisol.

Causes of cushings syndrome

Causes of Cushing’s syndrome can be allocated to two groups.

ACTH‐dependent disease: excessive ACTH from the pituitary (Cushing’s disease), ectopic ACTH‐producing tumours or excess ACTH administration.

Non‐ACTH‐dependent: adrenal adenomas, adrenal carcinomas, excess glucocorticoid administration. ACTH‐secreting neoplasms cause ACTH‐dependent Cushing’s syndrome. They often are due to an anterior pituitary tumour –classic Cushing’s disease.

Non‐pituitary ectopic sources of ACTH, such as an oat cell carcinoma, small‐cell lung carcinoma or carcinoid tumour, cause the balance of ACTH‐dependent disease.

Ectopic corticotropin‐releasing hormone secretion leading to increased ACTH secretion makes up a very rare group of cases of Cushing’s syndrome

Cushing’s syndrome is caused by prolonged exposure to elevated levels of endogenous glucocorticoids or exogenous glucocorticoids.

Pathophysiology of cushing's syndrome

It is commonly associated with a tumour that either secretes cortisol or stimulates cortisol production through excessive ACTH production.

The tumour may be growing within the pituitary (representing 70–80% of all causes), the adrenal cortex itself or within another tissue not normally associated with the synthesis of these hormones (accounting for about 17% of cases), such as the lungs, thyroid, pancreas or thymus.

Interestingly, ACTH-releasing pituitary tumours appear to be more common in young to middle-aged adults, affecting more women. ACTH-releasing ectopic tumours are more common in older men.

Cushing’s syndrome, another form of hypercortisolism, may also be seen in people during prolonged or high-dose glucocorticoid drug treatments.

A dysfunctional state induced by drug therapy is known as an iatrogenic condition.

Signs and symptoms

The manifestations of Cushing’s syndrome are the result of excessive glucocorticoids.

cushing syndrome

They involve a redistribution of subcutaneous fat, accumulating in three characteristic sites; the face, abdomen (causing truncal obesity) and upper thoracic region of the back.

The lay terms for these distinctive signs involving the face and back are ‘moon face’ and ‘buffalo hump’, respectively.

There may be weight gain, partly associated with sodium and water retention, that is due to the excessive glucocorticoid molecules interacting with aldosterone receptors.

Blood pressure becomes elevated, to a degree due to water retention, and also associated with increased adrenergic receptor numbers on the vasculature, inducing a stronger vasoconstrictive response in response to SNS activation.
Increased gluconeogenesis and glycogenesis lead to the development of insulin resistance.

Glucose intolerance may develop, which can deteriorate into diabetes mellitus in some people.

The rate of protein catabolism is increased in order for more gluconeogenesis to take place.

This can lead to peripheral muscle atrophy. Collagen synthesis is inhibited, leading to thin skin, which is easily bruised and, in combination with the increased protein catabolism, results in paper-thin skin and poor wound healing.

Glucocorticoids stimulate increased loss of calcium ions into the forming urine (hypercalcaemia), which creates the ideal environment for kidney stone formation.

The loss of calcium and protein from bones can induce a state of osteoporosis.

As glucocorticoids have a major modulating influence on immunity, immune suppression is an important consequence of hypercortisolism.

Helper T cells are particularly vulnerable to this suppression, and, as they are keys cells in promoting the immune response, the effect is significant.

Glucocorticoid excess also inhibits pro-inflammatory chemical mediator production. Immune suppression makes the affected person susceptible to microbial infection: bacterial, viral and, in particular, Candida albicans infection.

A focus of health care for these individuals must be to reduce the risk of infection wherever possible.
Glucocorticoids cross the blood-brain barrier and in high concentrations can affect brain function.

Irritability, psychotic behaviour and depression alternating with euphoria can occur.

Excess glucocorticoid levels can induce androgen-like effects, leading to increased body hair, acne and oligomenorrhoea.


An initial 24-hour screening test to measure urinary free cortisol is the first test to be performed but as it has a 5–10% false-negative rate, it is usually combined with other tests, such as an overnight dexamethasone suppression test.

If both of these tests are within the normal range, Cushing’s syndrome is unlikely.

Dexamethasone suppression test

An overnight dexamethasone suppression test is performed to differentiate between pituitary-dependent and adrenal Cushing’s disease.

Dexamethasone is a longa acting glucocorticoid medication, which suppresses ACTH secretion but does not cross the blood-brain barrier; this enables the affected part of the HPA axis to be identified.

Normally, cortisol levels are suppressed. If the HPA axis is functioning normally, cortisol production will be suppressed.
The test results need to be interpreted in light of a thorough history and assessment because obesity, depression, stress and some medicines, such as anti-epileptic (anticonvulsant) medicines and oestrogen, can lead to elevated cortisol levels.

Once the diagnosis is established, high- or low-dose dexamethasone suppression testing may be needed to distinguish pituitary tumours from ectopic causes.

These tests are similar to the overnight suppression test but the dexamethasone dose and the sample collection times are different.

Other tests A low-dose dexamethasone suppression test can also be used where the drug is given every 6 hours for 48 hours (9 am, 3 pm, 9 pm, 3 am), which should suppress cortisol levels.

Serum cortisol is measured at baseline and on day 2.

Midnight cortisol levels can be used to determine loss of circadian rhythm, which is usually the case in Cushing’s syndrome.

The patient must be asleep. Midnight is the normal cortisol nadir and the level is usually low. Patients with pseudo Cushing's syndrome also lose the normal cortisol diurnal rhythm, so an ITT might be performed.

Other hormones are usually measured as a part of this diagnostic phase, including thyroid hormone, growth hormone, thyroid-stimulating hormone, gonadotropins and androgens. CT, ultrasound or MRI scans of the adrenal glands and/or pituitary gland can be used in combination with the administration of the ferrometallic metal element, gadolinium, to localise the tumour.

Treatment of Cushing's syndrome

Management depends on the cause.

In the case of pituitary-dependent Cushing’sdisease, surgical removal of the tumour by transsphenoidal surgery is usual and results in a successful cure in 90% of cases.

Hydrocortisone is usually administered pre-operatively on the assumption that the patient will become cortisol deficient postoperatively. The dose is gradually reduced postoperatively and cortisol levels monitored.
Radiation therapy of the pituitary gland can be undertaken but it takes longer than surgery to control the symptoms.

Sometimes medicines and/or radiation are used to shrink pituitary tumours prior to surgery or following unsuccessful surgery, but it takes a long time to control the dysfunction.

Radiotherapy also reduces the possibility of Nelson’s syndrome occurring following adrenalectomy.

Nelson’s syndrome is where a pituitary tumour enlarges rapidly after adrenalectomy.

Adrenalectomy is the treatment of choice in patients with adrenal hyperplasia.

Symptoms of adrenal insufficiency occur after surgery when the ACTH and cortisol levels drop, usually within 12–48 hours.

Hydrocortisone replacement therapy may be required for several months until the normal adrenal function returns. However, replacement therapy will be required permanently if both adrenal glands were removed.

If surgery is contraindicated, adrenal enzyme inhibitors, such as metyrapone, aminoglutethimide or ketoconazole, can be used to treat ectopic ACTH or cortisol-producing tumours if they cannot be treated in any other way (surgery or chemotherapy).

These medicines can lead to adrenal insufficiency; therefore, the patient must be closely monitored.
Treatment of Cushing’s syndrome consists of reducing the dose gradually, if possible, so as to avoid the development of adrenal insufficiency.

If not, alternate-day dosing reduces the symptoms and allows the adrenal glands to recover and respond normally to ACTH.


Daniel Ogera

Medical educator, passionate about simplifying difficult medical concepts for easier understanding and mastery by nursing and medical students.

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About this article:
  • Topic:Clinicals
  • Duration:6 minutes, 37 seconds
  • Subtopic:Endocrinology

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