Cushing’s Syndrome – Signs, Symptoms, Diagnosis, Treatment

Cushing’s Syndrome:

Cushing’s syndrome describes the signs and symptoms associated with prolonged exposure to inappropriately high levels of the hormone cortisol. The most common cause of this is by taking glucocorticoid drugs, or diseases that result in excess cortisol, adrenocorticotropic hormone (ACTH), or CRH levels.
Cushing’s disease refers to a pituitary-dependent cause of Cushing’s syndrome: a tumor (adenoma) in the pituitary gland produces large amounts of ACTH, causing the adrenal glands to produce elevated levels of cortisol. It is the most common non-iatrogenic cause of Cushing’s syndrome, responsible for 70% of cases excluding glucocorticoid related cases.


Cushing’s syndrome is defined as the signs and symptoms associated with long term exposure to inappropriately high levels of Cortisol. The most common causes of Cushing’s syndrome are:

1) Exogenous
2) Endogenous

1) Exogenous causes of Cushing’s syndrome:

— Exogenous (iatrogenic) steroids, such as glucocorticoid drugs are the number one cause of Cushing’s syndrome. Steroid are  which leads to decrease levels of  Corticotropin-releasing hormone (CRH) and Adrenocorticotropic hormone (ACTH) due to negative feedback of cortisol (steroids).

2) Endogenous causes of Cushing’s syndrome:

— Cushing’s disease (70%)—due to ACTH secretion from pituitary adenoma; “Increase ACTH”
— Ectopic ACTH “paraneolplastic tumor” (15%)—from non-pituitary tissue making ACTH (e.g., small cell lung cancer, bronchial carcinoids); “Increase ACTH”
— Adrenal adenoma (15%), carcinoma, nodular adrenal hyperplasia; “Decrease ACTH” due to negative feedback

Signs and Symptoms:

  • Hypertension,
  • Weight gain,
  • Moon facies,
  • Truncal obesity,
  • Buffalo hump,
  • Hyperglycemia (insulin resistance),
  • Skin changes (thinning, striae),
  • Hirsutism
  • Baldness
  • Osteoporosis,
  • Amenorrhea,
  • Diabetes Mellitus Type 2,
  • Immune suppression,
  • Cushing’s syndrome is also a common cause of anovulation.


Dexamethasone (synthetic glucocorticoid) suppression test

Dexamethasone suppression test, is a test that is done to differentiate between different causes of Cushing’s syndrome.

— Healthy: Decrease cortisol after low dose.
— ACTH-producing pituitary tumor: Increase cortisol after low dose; Decrease cortisol after high dose.
— Ectopic ACTH-producing tumor (e.g., small cell carcinoma): Increase cortisol after low and high dose.
— Cortisol-producing tumor: Increase cortisol after low and high dose.


Cushing's syndrome Differentiation

Differentiation of Cushing’s syndrome



— Adrenal zona fasciculata.


1) Maintains Blood pressure (permissive effect with epinephrine, upregulates alpha1 receptors on arterioles)
2) Decrease Bone formation
3) Anti-Inflammatory
4) Decrease Immune function
5) Increase gluconeogenesis, lipolysis, proteolysis


— CRH (hypothalamus) stimulates ACTH release from the pituitary gland, causing cortisol production in adrenal zona fasciculata.
— Excess cortisol –> Decreases CRH, ACTH, and cortisol secretion.


Most Cushing’s syndrome cases are caused exogenous steroid medications (iatrogenic). Consequently, most patients are effectively treated by carefully tapering off (and eventually stopping) the medication.
If the cause is due to adrenal adenoma then it may be removed by surgery. An ACTH-secreting corticotrophic pituitary adenoma should be removed after diagnosis. Regardless of the adenoma’s location, most patients will require steroid replacement postoperatively at least in the interim as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. Clearly, if both adrenals are removed, replacement with hydrocortisone or prednisolone is imperative.
In those patients not suitable for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol synthesis (e.g. ketoconazole, metyrapone) but they are of limited efficacy. Mifepristone is a powerful glucocorticoid receptor antagonist has also rarely been used, but the medication faces considerable controversy due to its use as an abortifacient. In February 2012 the FDA approved mifepristone in order to control high blood sugar level (hyperglycemia) in adult patients who are not candidates for surgery, or who did not respond to prior surgery, with the warning that mifepristone should never be used by pregnant women.
Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol. In some occasions, this removes negative feedback from a previously occult pituitary adenoma, which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson’s syndrome.

Click HERE to view Cushing’s syndrome Mnemonic


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