Cushing Syndrome

Article Author:
Hammad Chaudhry
Article Editor:
Gurdeep Singh
1/2/2019 11:26:12 AM
PubMed Link:
Cushing Syndrome


Cushing syndrome is caused by prolonged exposure to high circulating levels of cortisol. The most common cause of cushingoid features is iatrogenic corticosteroid use, while some herbal preparations can also increase circulating corticosteroid levels leading to Cushing syndrome. Cushing syndrome can be interchangeably called hypercortisolism. ACTH-dependent cortisol excess due to a pituitary adenoma is called Cushing disease, and it is responsible for 80% of endogenous Cushing syndrome. [1][2][3]


There are two main etiologies of Cushing syndrome: endogenous hypercortisolism and exogenous hypercortisolism. Exogenous hypercortisolism, the most common cause of Cushing syndrome, is mostly iatrogenic and results from the prolonged use of glucocorticoids. Endogenous Cushing Syndrome results from excessive production of cortisol by adrenal glands and can be ACTH-dependent and ACTH-independent. ACTH-secreting pituitary adenomas (Cushing disease) and ectopic ACTH secretion by neoplasms are responsible for ACTH-dependent Cushing. Adrenal hyperplasia, adenoma, and carcinoma are major causes of ACTH-independent Cushing syndrome.[4][5][6]


Actual incidence and prevalence of Cushing syndrome are not known. The prevalence of the disease is highly variable across different ethnic and cultural groups depending upon the frequency and a spectrum of the medical conditions requiring steroid based therapy. However, of the known cases iatrogenic hypercortisolism outweighs the endogenous causes, of the endogenous causes pituitary mediated ACTH production accounts for up to 80% of cases of hypercortisolism, followed by adrenals, unknown source and ectopic ACTH production secondary to malignancies.[7][8]


Cortisol is a steroid hormone produced by the zona fasciculata of the adrenal cortex. After production the cortisol is carried to different parts of the body by cortisol binding protein, almost 90% of cortisol binds to these (CBG) protein and has a bioavailability of 60% to 100%. Synthetic corticosteroids have varying bioavailability and potency, but all affect similar pathways. It is a catabolic hormone which is released under stressful conditions. The excess of cortisol results in an increased rate of gluconeogenesis, glycogenolysis and increases insulin resistance. Cortisol is a steroid hormone, and it directly affects the transcription and translation of enzyme proteins involved in the metabolism of fats, glycogen, proteins synthesis and Kreb's cycle. It promotes the production of free glucose in the body, elevating glucose levels, while simultaneously increasing insulin resistance. The destruction of protein yields amino acids which are used in gluconeogenesis. The prolonged catabolism of proteins causes purplish striae of the torso, osteoporosis and poor wound healing. All these processes involve collagen which is a three amino based protein. High cortisol levels also cause immune disruptions; this hormone leads to a decrease in lymphocyte levels and increases the neutrophils. It causes detachment of marginating pool of neutrophils in the bloodstream and increases the circulating neutrophil levels although there is no increased production of the neutrophils. This mechanism explains the typical picture of raised TLC where there is decreased lymphocyte number and increased neutrophils. The corticosteroids mediate the downregulation of NF-kappaB, regulation of AMP kinase, glycogen phosphorylase, superoxide dismutase and many other enzymes. Cortisol inhibits production of IL-2, TNF alpha, IFN alpha, and gamma. Decreased IL-2 levels prevent the proliferation of T-lymphocytes.[9]

History and Physical

Patients may have a history of weight gain, fatigue, weakness, delayed wound healing, easy bruising, back pain, bone pain, loss of height, depression, mood swings, emotional reactivity, loss of libido, erectile dysfunction in males, irregular menstrual cycles in females, infertility, hyperhidrosis, hirsutism, biparietal visual loss if there is a large pituitary adenoma, recurrent fungal and bacterial infections due to impaired immunity, and difficulty in combing hair or rising from a sitting position.

Patients may also have a history of hypertension and diabetes.

Physical examination of the patient will reveal increased fat deposits in the upper half of the body leading to "Buffalo torso," characteristic moon facies (earlobes are not visible when viewed from the front), thin arms and legs, acne, hirsutism, proximal muscle weakness of shoulder and hip girdle muscles, paper-thin skin, abdominal pain due to gut perforation in rare cases,  and wide vertical purplish abdominal striae.


The best initial test for diagnosis of Cushing syndrome is 24-hour urinary cortisol estimation. If the level of cortisol is four times the normal limit, and clinical appearance is suggestive, a diagnosis of Cushing syndrome is established. Alternatively, midnight serum or salivary cortisol levels (at 11 pm) or a low-dose dexamethasone suppression test (1 mg dexamethasone given orally at 11 pm and plasma cortisol level measured at 8 am the next day with normal cortisol level less than 2 micrograms per deciliter) can be used to confirm hypercortisolism, random cortisol levels are not useful in the diagnosis. In patients with milder urinary elevation of cortisol a low-dose dexamethasone suppression test shall be performed (0.5 mg dexamethasone by mouth every 6 hours for 48 hours is given starting at 8 am, urine cortisol is measured over the last 24 hours, and plasma cortisol is measured in the last 6 hours) if there is no adequate suppression in the levels or urinary cortisol the diagnosis is made. If the patient is taking enzymes inducing drugs like phenytoin dexamethasone suppression test shall not be performed, as they accelerate the dexamethasone metabolism, similarly testing should be avoided in depression and severe illness as these conditions may lead to false-positive results. Serum ACTH levels are obtained to differentiate ACTH-dependent (high ACTH) from ACTH-independent (low ACTH levels) Cushing syndrome. In patients with ACTH-dependent Cushing, high-dose dexamethasone suppression test is ordered to differentiate pituitary from an ectopic source. Cortisol secretion will decrease with a high dose of dexamethasone in the case of a pituitary adenoma and will not be suppressed if there is an ectopic source of ACTH. MRI pituitary gland, unenhanced CT scan of adrenals, and chest x-ray and CT are also obtained to localize the pathology.[10][11]

Treatment / Management

The best therapy in iatrogenic Cushing syndrome is to taper off steroids slowly. Cushing disease is best treated with transsphenoidal surgical resection of pituitary adenoma. Adrenal adenomas, adrenal carcinomas, and ACTH-secreting ectopic sources are surgically resected. Post-operative mitotane is given in the case of adrenal carcinoma. Ketoconazole, metyrapone, and mifepristone are given in selected cases. [12][13]

Differential Diagnosis

  • Obesity
  • Alcoholism
  • Bulimia
  • Depression




Pearls and Other Issues

Cushing syndrome caused by exogenous drugs is a fairly preventable malady. Controlled use of corticosteroids in the clinical settings with regular health follow up may reduce the burden of disease significantly. If the patient with ACTH-dependent Cushing syndrome undergoes a curative surgery, special attention should be paid to prevent adrenal crises and subsequent mortality and morbidity.

Enhancing Healthcare Team Outcomes

All patients diagnosed with Cushing syndrome need to be educated about the side effects of these hormones. At the time of discharge, the patient should have a dietary consult and how to prevent osteoporosis. The pharmacist should educate the patient on the prevention of peptic ulcer disease, diabetes, and weight gain. The nurse should educate the patient on the risk of infections and when to follow up with the healthcare provider. All patients diagnosed with Cushing syndrome need long-term follow up until the syndrome has been cured or eradicated. [14][15](Level V)


Prolonged exposure to corticosteroids is not a benign event and associated with high morbidity and mortality. Individuals diagnosed with Cushing syndrome are a higher risk of death compared to the general population. The mortality and morbidity is primarily due to the secondary effects of the drugs like diabetes, hypertension, heart disease, obesity, fractures, osteoporosis and so on. In patients in whom the cause is long-term therapy, the prognosis can be improved by the discontinuation of the hormone. But the prognosis is worse if the patient has an unresectable tumor secreting the hormones. More important, the high doses of endogenous glucocorticoids may mask some abdominal signs and symptoms leading to a missed bowel perforation. Finally, it is important to be aware that sudden removal of glucocorticoids can also precipitate adrenal crises, hence the withdrawal has to be tapered over a few weeks or months. [4][16](Level V)

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      Contributed by Muhammad Zaman Khan Assir