Adrenal Cortex and Cushing's Syndrome

The adrenal cortex produces glucocorticoids such as cortisol which affect metabolic functions including metabolism of carbohydrate, lipid and protein as well as mineralocorticoids in the form of aldosterone. Both are subject to negative feedback. Corticotrophin releasing factor (CRF) from the hypothalamus stimulates ACTH from the pituitary which stimulates cortisol and androgen production by the adrenal cortex. Cortisol is excreted as urinary free cortisol and as various 17-oxogenic steroids (17OGS).

Cushing's syndrome is the result of excessive amounts of circulating steroids and may be due to:

• Excessive autonomous secretion by the adrenals.
• Excessive amounts of ACTH to stimulate the glands.
• Excessive amounts of corticosteroids originating from outside the glands.

In theory there could be a 4th cause, due to excessive production of CRF from the hypothalamus but this is not described. Ectopic production of CRF is very rare.

Most cases of Cushing's syndrome are iatrogenic and caused by exogenous corticosteroids. Of spontaneous cases:

• 70% are caused by Cushing's disease of a pituitary ACTH-producing tumour
• 15% are caused by ectopic ACTH production
• 15% are caused by a primary adrenal tumour

90% of pituitary causes are microadenomas. They are defined as lesions less than 1cm in diameter. MRI detects only around 60%.

The annual incidence of Cushing's disease is around 1 per 100,000 population. It is being sought and found rather more often these days, especially in people who present with obesity or diabetes.¹ Attention to the Cushing's syndrome does seem to improve the control of the diabetes but it is still important to attend to glycaemic control, blood pressure and lipids in the usual way.²

Corticotropin (ACTH) - dependent causes

• Cushing's disease: Adrenal hyperplasia is due to excess ACTH from a pituitary tumour. There is a female preponderance of about 5:1. The peak age is between 30 and 50 years.
• Iatrogenic: ACTH administration or its analogues.
• Ectopic ACTH production: This usually involves malignancy, especially small cell carcinoma of the lung and carcinoid tumours, especially of the lung. Lung cancer is responsible for over half of ectopic ACTH production by malignancies and it affects men 3 times as often as women. Typical features include pigmentation, weight loss, metabolic alkalosis and hyperglycaemia. Classical features of Cushing's syndrome are often absent. As this tends to occur at a later age than Cushing's disease, if the syndrome develops later in life, think of ectopic ACTH production from a carcinoma.
• Ectopic CRF (corticotrophin releasing factor) production is rare whilst autonomous production from the hypothalamus is not reported.

ACTH - independent causes

• Iatrogenic: Pharmacological doses of steroids are the commonest cause in the modern world.
• Adrenal adenoma and carcinoma: Adenoma accounts for about 60% of cases and carcinoma around 40%.² Micronodular or macronodular hyperplasia may occur but are uncommon.
• Carney's syndrome: Cardiac myxoma, freckles and endocrinopathy.
• It can be a feature of multiple endocrine neoplasia, usually MEN1.

Carney complex 1 is an autosomal dominant that is similar to MEN, being a multiple neoplasia syndrome.³ A Carney complex 2 is also described.⁴

These tend to be common to all causes of glucocorticoid excess.⁵ The relative frequency of the common presenting features is taken from several sources but was synthesized for a review.²

Menstrual irregularity includes amenorrhoea. Reduced libido includes erectile dysfunction. There may also be predisposition to infection.
Other findings on examination may include:

• Tissue wasting
• Myopathy
• Purple abdominal striae
• Osteoporosis may be apparent from such features as a dowager's hump
• Water retention
• Buffalo hump on neck
• Supraclavicular fat pad

Muscle weakness is a proximal myopathy affecting especially the pelvic girdle. This leads to difficulty rising from a low chair.

A rapid onset with virilisation in women or feminization in men suggests an adrenal carcinoma.

Skin pigmentation is often a feature of excessive ACTH secretion and is most marked when the source is ectopic production. Look for clubbing of the fingers. The ACTH protein has amino acid sequences in common with melanin. Another condition with high ACTH and pigmentation is Nelson's syndrome.

Other findings

• The pituitary adenomas that produce Cushing's disease are not usually large enough to impinge on the optic chiasma and produce a homonymous hemianopia as in gigantism or acromegaly.
• Rarely there may be galactorrhoea as prolactin is the one hormone that is controlled by an inhibitory rather than a releasing factor.
• Biochemical abnormalities include neutrophilic leucocytosis, hyperglycaemia, hypokalaemia, hypercholesterolaemia and hypercoagulable state.
• There is impaired glucose tolerance with overt diabetes in up to 30%.

A number of conditions may mimic Cushing's syndrome including obesity and polycystic ovary syndrome. The former may even proceed to metabolic syndrome X. Obesity alone will elevate cortisol levels but not to the extent seen in the disease. Carney complex has been mentioned but it is rare. MEN has also been mentioned and Cushing's syndrome may be a part of the multiple endocrine abnormalities.

Pseudo-cushing's syndrome

Patients with depression, alcoholism or therapy for HIV can show some features of Cushing's syndrome,⁶ but cortisol hypersecretion in most cases is minimal. Blood levels of cortisol can be high when oestrogen levels are high as it elevates cortisol-binding globulin.

People with pseudo-cushing's syndrome do not develop the progressive effects of Cushing's syndrome, such as muscle weakness, fractures and thinning of the skin. This was originally described in people who were depressed or drank excess alcohol, but it is now known to be more common.¹ Pseudo-cushing's syndrome does not require endocrine treatment but the underlying cause such as depression or alcoholism must be addressed.

The aim of investigations is first to confirm the diagnosis and then to locate the source. The probable site of pathology should be elucidated before imaging as misleading masses called "incidentalomas" occur in both the adrenals and pituitary. Abdominal CT is preferred if an adrenal source is suspected and pituitary MRI with possible petrosal sinus sampling, if a pituitary source is suspected.

Confirming the diagnosis

There are 3 basic screening tests. All tests, whether to establish the disease or its cause, have limitations and so it is common to perform more than one. Furthermore, some tumours causing Cushing's syndrome are cyclical in action and sampling may occur during inactivity.¹

1. The low dose dexamethasone suppression test is the best screening test.

Give dexamethasone 1mg by mouth at midnight. Check serum cortisol before and at 8am.
If the level suppresses to <50nmol/l then it is probably not Cushing's syndrome. The false negative rate is <2% but the false positive rate is 12.5%.

2. 24 hours urinary free cortisol is an alternative. Normal is <280nmol/24hr but note the reference range for your own laboratory. Three tests are often done to minimise errors in urine collection. Values of less than 3 or 4 times normal are inconclusive. The test is invalid in chronic renal failure with a GFR < 30ml/min. Some drugs can interfere with assays and so drugs must be named on the request form.

3. Other screening tests include midnight plasma cortisol. Cushing's syndrome can almost be excluded if the midnight level is <50nm/l. An alternative is salivary cortisol that correlates well with plasma cortisol but as levels are lower, it requires more sensitive assays.

Normal circadian rhythm of cortisol is lowest at midnight and highest early in the morning but this is lost in Cushing's syndrome. Illness and stress, including venepuncture may interfere with the normal rhythm, making interpretation difficult.

Establishing the cause

Having confirmed the diagnosis of Cushing's syndrome, the next step is to determine if the primary pathology is in the adrenals, the pituitary or an ectopic source. In a smoker over the age of 50, a chest x-ray may be indicated at an early stage.

Measure plasma ACTH. If it is undetectable, an adrenal tumour is likely. The next step is a CT scan of the adrenals. Although "incidentalomas" occur in the adrenals, it is said that an adenoma or carcinoma will always be visible on CT.⁷

The high dose dexamethasone suppression test can help to distinguish between excess production of ACTH due to pituitary adenomas from those with ectopic ACTH-producing tumours. Dexamethasone is given orally at 1mg every 6 hours for 48 hours or as a single dose of 8mg. The day before the test and on each day of the test, 24 hour urine collections are made. The normal response after taking dexamethasone is a drop in blood and urine cortisol levels. Production from a pituitary adenoma is more readily suppressed than from an ectopic ACTH-producing tumour.

False positive results with failure of suppression can occur with depression, alcohol abuse, high oestrogen levels, acute illness, and stress. Enzyme-inducing drugs may cause failure to respond to dexamethasone suppression as the dexamethasone is more rapidly metabolised.

Suppression of cortisol production will occur in 80% of patients with a pituitary adenoma. This is unimpressive, considering that 90% of women with Cushing's disease will have an adenoma and 10% of the normal population have pituitary "incidentalomas".²

If the suggestion is a pituitary source, then CT or MRI of the pituitary is the next investigation but sensitivity is not high. Plasma sampling from the inferior petrosal sinus may help to distinguish Cushing's disease from ectopic ACTH production and in lateralising a pituitary adenoma.⁸ Sampling from the jugular vein may be a more acceptable alternative⁹ but it is said to be less reliable. Imaging fails to show a pituitary adenoma in nearly half of those who eventually need surgery.

The CRH test can also be used to distinguish pituitary causes from ectopic ACTH production.

• Give 100 μg ovine CRH IV .
• Follow cortisol for 120 minutes.
• Cortisol rises with pituitary disease but not with ectopic ACTH production.

Patients with pituitary adenomas usually have a rise in blood levels of ACTH and cortisol. This response is rarely seen in patients with ectopic ACTH syndrome and almost never in patients with cortisol-secreting adrenal tumours.

Pseudo-cushing's syndrome

The desmopressin test can also be used to differentiate pseudo-cushing's syndrome from even mild true disease. Desmopressin will usually raise cortisol levels in the true disease but not in normal people or in pseudo-cushing's syndrome.¹⁰ This may gain popularity as a first line test.

The dexamethasone-CRH test was developed to distinguish between the true and false conditions, so that Cushing's patients can receive prompt treatment. This test combines the dexamethasone suppression and the CRH stimulation tests. Elevation of cortisol in response to CRH after dexamethasone suggests Cushing's syndrome.¹¹

This will depend upon the cause.

Iatrogenic

If the cause is iatrogenic, the prescription needs to be reviewed. There will be a medical need for the steroids but it may be possible to use "steroid sparing" drugs to reduce the dose. This may include antimetabolites such as azathioprine. Usually, help will be required from consultant colleagues to manage the condition effectively. Remember to reduce the dose of steroids slowly to prevent an Addisonian crisis.

Pituitary adenoma

Transphenoidal adenectomy is the most commonly used approach for pituitary tumours. Selective microadenectomy is the preferred operation if possible. The success rate is well over 80% in the hands of an experienced surgeon. If surgery fails, or produces only temporary relief, it can be repeated, often with good results. Post operation, ACTH levels fall below normal. This is temporary, but hydrocortisone or prednisolone must be given. Most patients can stop this replacement therapy in less than a year.

Where transphenoidal surgery has failed or in patients who are unsuitable candidates for surgery, radiotherapy is another possible treatment. Radiation to the pituitary gland gives improvement in 40 to 50% of adults and up to 80% of children. It may take several months or years before there is symptomatic improvement. However, the combination of radiation and the drug mitotane can speed recovery. Mitotane suppresses cortisol production.

Adrenal tumours

Surgery for adrenal adenomas is usually curative but carcinomas have a much worse prognosis. Adrenal adenomas are usually removed at laparoscopy.

Micronodular or macronodular hyperplasia is usually treated by bilateral total adrenalectomy as leaving any gland will often lead to recurrence.

If the source cannot be identified, bilateral adrenalectomy may be employed, but this may be complicated by Nelson's syndrome with development of an enlarging pituitary tumour and hyperpigmentation. Radiotherapy is used in children and to prevent Nelson's syndrome.

Ectopic ACTH production

This may be treated by surgery if the tumour can be located and has not spread. Medical treatment may be required.

There are a number of drugs that can be used alone or in combination to control the production of excess cortisol. They include mitotane, aminoglutethimide, metyrapone, trilostane and ketoconazole. Each has its own side effects. Treatment with mitotane alone can be successful in 30 to 40% of patients.

Metyrapone and ketoconazole tend to suffer "escape" from control and lose effectiveness. Mitotane does not suffer "escape" but is slower to take effect. In ectopic ACTH production, octreotide or lanreotide may be used, possibly in combination with high dose cabergoline.

Complications of Cushing's syndrome may simply be a list of the clinical features.

• Perhaps 2% of poorly controlled diabetics have Cushing's syndrome.¹
• Pressure symptoms may cause other endocrine problems from tumour of the pituitary. Polyuria without glycosuria may represent diabetes insipidus.
• A person with suppression of the hypothalamic-pituitary-adrenal axis is unable to respond to the stress of illness and so a relative deficiency of cortisol may induce an Addisonian crisis.

• Untreated, 50% are dead within 5 years. With treatment the results are very good unless there is underlying malignancy.
• Poorly controlled Cushing's syndrome is associated with 5 times the normal mortality rate.¹²
• Transphenoidal surgery fails in 5% and there is recurrence in 5%.
• Even with treatment, of those with an adrenal carcinoma, the 5 years survival rate is around 30%.
• The prognosis for lung cancer is very poor.

The only effective approach to the prevention of Cushing's syndrome is a cautious approach to the prescription of steroid drugs. Their prescription, as with any other prescription, is a matter of balancing risks and benefits. If high doses and prolonged courses are needed, consider steroid sparing agents.

Harvey Cushing was born in Cleveland Ohio in 1869 and died in New Haven, Connecticut in 1939. He graduated from Yale and later spent some time working in London. Back in Massachusetts General Hospital, Boston, he worked on the clinical use of x-rays that Roentgen had only recently discovered. He also devised "The Ether Chart" to make anaesthetics safer.

He spent 1900 and 1901 in Europe but returned to the John Hopkins in 1902. His first operation for pituitary disease was in 1901, when he carried out a decompression of a girl aged 14 who had complained of headaches and visual failure. She was fat and sexually immature. In March 1909 he carried out his first operation for acromegaly. The patient was a 38-year old farmer referred by Charles Mayo. The approach to the pituitary was via a frontal flap opening the frontal sinuses. The patient made a remarkable recovery and lived until 1930. Between 1909 and 1911, Cushing collected 46 patients with lesions involving the pituitary and operated on most.

One of his patients with gigantism had been a successful boxer, being of great stature, but as the tumour developed, so did the homonymous hemianopia. He became vulnerable to hooks that he could not see coming and became punch drunk. He ended his days as a wrestler in circus booths.

Harvey Cushing is known best for publications about ACTH producing tumours in 1912¹³ and again in 1932¹⁴ and the disease bears his name. Harvey Cushing was held in very high regard and is often praised as the greatest of the neurosurgeons.¹⁵