Hormonal disturbance- Cushings syndrome/disease symptoms

Cushing's syndrome

Cushing's syndrome arises from chronically elevated glucocorticoid levels. It may be iatrogenic (inhaled, oral or topical steroids), due to adrenal disease, ectopic ACTH production or Cushing's disease, which refers to the specific aetiology of Cushing's syndrome due to a pituitary ACTH-secreting adenoma.


The incidence of spontaneous Cushing's syndrome is estimated at 50 per 100 000 per year, with Cushing's disease accounting for approximately 0.2-3 per 100 000 per year. Cushing's disease has a female preponderance and most patients are in their third to fourth decade.


The most common cause of Cushing's syndrome is iatrogenic, due to the side effects of long-term corticosteroid administration. Cushing's syndrome due to adrenal hypersecretion of cortisol is classified as ACTH dependent (80%), which implies that cortisol excess is due to ACTH hypersecretion, or ACTH independent (20%), which implies a primary pathology of the adrenal glands

Causes of Cushing syndrome include;

Iatrogenic - administration of corticosteroid for long term.

ACTH- dependent excess cortisol- Pituitary ACTH producing adenoma ( Cushing disease ) ,ectopic ACTH secretion ( pancreatic tumour, bronchial thymic ) ectopic corticotropin releasing hormone - CRH.

ACTH- independent excess cortisol - Adrenal adenoma, adrenal nodular hyperplasia,adrenal carcinoma.

Pseudo Cushing - Alcoholism, depression.

ACTH-dependent hypercortisolaemia caused by a pituitary adenoma (68%) is defined as Cushing's disease; most of these adenomas are microadenomas. 'Ectopic' ACTH is released by other non-endocrine tumours (12%) such as lung, thymic and pancreatic cancer. ACTH-independent hypercortisolaemia is caused by benign (10%) or malignant (8%) adrenal tumours, or by adrenal nodular hyperplasia (1%).

Alcohol and severe depression can give rise to 'pseudo Cushing's syndrome' (1%). In cyclical Cushing's syndrome, clinical features and biochemical abnormalities may wax and wane, posing difficulties in establishing a diagnosis.

Scope of disease

Excess cortisol affects all aspects of substrate metabolism leading to centripetal fat redistribution, muscle wasting and insulin resistance. Bone resorption is increased (osteoporosis), skin and connective tissues become atrophic, and immune function is impaired. Elevated glucocorticoid levels exert effects at the renal mineralocorticoid receptor leading to salt and water retention. Secondary diabetes can occur. Mental well-being is disturbed in over half of patients.

Clinical features

Diagnostic suspicion is often raised by the typical changes in physical appearance: a rounded, plethoric face, thinning of the scalp hair, acne and hirsutism. Truncal obesity with prominent supraclavicular fat pads is characteristic. The skin bruises easily and heals poorly, purple striae may be present, and with ACTH dependence hyperpigmentation can occur. Proximal muscle weakness and back pain are common: osteoporotic vertebral fractures are demonstrable in up to 20%. There is an increased susceptibility to infections. Signs and symptoms of diabetes may be present and hypertension is frequent. Emotional lability, insomnia, depression and psychosis are the most common psychiatric disturbances.

Effect of disease
Clincal features
Fat redistribution/connective tissue atrophy
Round plethoric face, telangiectasia
Atrophy/androgen excess
Thin skin, easy bruising, poor healing
Melanocyte stimulation by ACTH
Hyperpigmentation, especially of scars
Skin, scalip hairs
Adrenal androgen secretion
Male pattern balding, hirsutism, acne
Trunk and limbs
Centripetal fat redistribution
Abdominal obesity with thin arms and legs, interscapular and supraclavicular fat pads, purple striae
Proximal weakness
Difficulties climbing stairs
Axial skeleton
Back pain, compression fractures
Diabetes mellitus/hypercalciuria
Thirst, polyuria, blurred vision, renal stones
Activation of mineralocorticoid receptor
Hypertension, peripheral oedema
Altered mood and mental function
Depression, agitation, psychosis
Other peripheral glands
Decreased libido, oligo/amenorrhoea
For Cushing disease
Compression of optic chiasm
Bitemporal hemianopia
Raised intracranial pressure/hypertension and diabetes
Papilloedema/hypertensive and diabetic retinopathy/optic atrophy

Apart from identifying the features of Cushing's syndrome, a detailed clinical assessment will also attempt to detect clinical features that may suggest the underlying cause. A drug history will easily identify any exogenous corticosteroids, patients with a pituitary adenoma may also have features of a mass effect such as bitemporal hemianopia from pituitary compression of the optic chiasm, and patients with ectopic ACTH production may have symptoms from underlying causes such as stridor with bronchial obstruction from a tumour.

Initial investigations

Initial tests aim to establish hypercortisolaemia, and further investigations attempt to identify the aetiology. If initial tests are normal, Cushing's syndrome is unlikely or may be intermittent.

24-Hour urinary free cortisol

24-Hour urinary free cortisol measurements serve as a screening test to establish cortisol excess. They should be repeated as the false-negative rate is 5-10%

Low-dose dexamethasone suppression test

The low-dose overnight dexamethasone suppression test can be performed in the outpatient setting or as an inpatient. The loss of circadian rhythm in cortisol secretion can be demonstrated in the hospital by a detectable midnight cortisol (>50 nmol/L) taken whilst asleep. Failure to suppress indicates autonomous cortisol secretion.

Further investigations

Once excess cortisol is established, further investigations are performed to determine the cause.

Basal ACTH levels

Low or undetectable ACTH levels imply an adrenocortical tumour as the underlying cause or iatrogenic corticosteroid administration. Detectable ACTH levels may arise from a pituitary adenoma or from ectopic sources.

High-dose dexamethasone suppression test

Suppression of cortisol secretion (less than 50% of the baseline value) with high-dose dexamethasone implies a pituitary adenoma or occult ACTH-producing tumour. Failure of suppression with high-dose dexamethasone occurs with adrenocortical tumours, but can also occur with ACTH-secreting tumours that produce a large amount of ACTH.

Urea and electrolytes

Severe hypokalaemic (<3.2 mmol/L) alkalosis in the absence of diuretic therapy occurs with most ectopic ACTH secretion but in less than 10% of those with pituitary-dependent disease.

CT or MRI of the abdomen

Imaging of the adrenal glands is usually performed to screen for tumours in patients with excess serum cortisol and low basal ACTH levels with failure of cortisol suppression on the high-dose dexamethasone suppression test. An adrenal tumour may be identified. Adrenal tumours larger than 6 cm, the presence of irregularities and local invasion are features suggestive of malignancy. Bilateral adrenal enlargement suggests nodular hyperplasia.

CT or MRI of the head

Imaging of the pituitary is performed to screen for adenomas in patients with excess serum cortisol, high basal ACTH levels and evidence of cortisol suppression on the high-dose dexamethasone suppression test.

Corticotropin-releasing hormone (CRH) stimulation tests

CRH administration causes a >50% rise in ACTH and a >20% rise in cortisol levels in 95% of patients with an ACTH-secreting pituitary adenoma, but occasionally a similar response is seen in ectopic disease. Bilateral inferior petrosal sinus sampling with CRH stimulation is reserved for patients in whom there is continuing diagnostic ambiguity between a hypothalamic or pituitary aetiology. It compares ACTH concentrations obtained in the venous drainage of both sides of the pituitary with peripheral samples.

Further specific imaging

Specific imaging may be required to screen for ectopic ACTH-producing tumours, such as chest X-ray or CT for bronchial tumours.

Initial management

Address any underlying cause

Where possible, substitution of a steroid-sparing immunomodulation agent should be undertaken for patients with Cushing's syndrome due to exogenous steroid administration for concomitant chronic disease.

Medical management

Metyrapone or ketoconazole

Correction of the glucocorticoid excess is the initial aim of medical therapy irrespective of its aetiology, in particular to reduce subsequent operative risk. Metyrapone or ketoconazole is used, with the dose titrated according to cortisol levels on a day curve (e.g. 9 a.m., 12 p.m., 3 p.m. and 6 p.m. samples) .

Surgical management

Surgical management is directed to the underlying diseased organ, which is usually the adrenal or the pituitary gland.


Unilateral adrenalectomy is indicated for Cushing's syndrome due to adrenal adenoma or carcinoma. Bilateral adrenalectomy is usually undertaken for patients with adrenal nodular hyperplasia or as a last resort for patients with refractory ACTH secretion (pituitary or exogenous ACTH secretion).

Prolonged glucocorticoid replacement therapy is required postoperatively until functional recovery of the contralateral gland in patients with unilateral adrenalectomy, and life-long treatment is required when bilateral adrenalectomy is performed. If bilateral, Nelson's syndrome may occur in up to 30% of cases.

Adrenal carcinomas have often metastasized at the time of diagnosis. Surgical resection to reduce tumour mass is usually accompanied by postoperative administration of mitotane, an adrenolytic drug used to reduce cortisol production and possibly improve survival.

Transsphenoidal surgery

Transsphenoidal surgery is performed for patients with an ACTH-secreting pituitary adenoma, possibly followed by external radiotherapy if cortisol levels fail to fall below50 nmol/L. Until radiotherapy takes full effect, concurrent medical therapy may be required.

Other tumours

ACTH-secreting tumours should be removed and treated according to their aetiology. Medical therapy or adrenalectomy may be indicated if this fails to control cortisol levels.


Untreated Cushing's syndrome has a high mortality due to cardiovascular complications and infections (30-50% at 5 years). Even following successful therapy the initial effects on atherosclerosis persist whilst hypertension and diabetes often resolve. Osteoporosis may require specific therapy.

Recurrence rates for Cushing's disease are low (<20%) if postoperative cortisol levels were undetectable. In ectopic disease the prognosis is dependent on the underlying tumour characteristics. Adrenal adenomas can be cured by adrenalectomy whereas adrenal carcinomas have a poor prognosis.

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