Cushing Syndrome:

Cushing 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 corticotropin-releasing hormone (CRH) levels.
Cushing disease refers to a pituitary-dependent cause of Cushing 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 syndrome, responsible for 70% of cases excluding glucocorticoid related cases.

Causes of Cushing Syndrome:

Cushing 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 syndrome are:

1) Exogenous
2) Endogenous

1) Exogenous causes of Cushing syndrome:

— Exogenous (iatrogenic) steroids, such as glucocorticoid drugs are the number one cause of Cushing 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 syndrome:

— Cushing 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 of Cushing Syndrome:

– Hypertension,
– Weight gain,
– Moon facies,
– Truncal obesity,
– Buffalo hump,
– Hyperglycemia (insulin resistance),
– Skin changes (thinning, striae),
– Osteoporosis,
– Amenorrhea,
– Immune suppression,
– Cushing syndrome is also a common cause of anovulation.

Diagnostic approach of Cushing Syndrome:

Who should be tested? testing for hypercortisolism in patients in whom a diagnosis is most likely, including the following:

– Unusual findings for their age (osteoporosis or hypertension in young adults)
– Multiple progressive features of Cushing syndrome (CS), particularly those that are predictive of CS such as facial plethora, proximal myopathy, striae (>1 cm wide and red/purple), and easy bruising
– Unexplained severe features (resistant hypertension, osteoporosis) at any age
– Adrenal incidentalomas

Initial testing

The initial diagnostic tests for hypercortisolism should be highly sensitive, even though the diagnosis may be excluded later by more specific tests. The diagnosis of Cushing syndrome is established when at least two different first-line tests are unequivocally abnormal. Once the diagnosis is established, additional evaluation is done to identify the cause of the hypercortisolism. Early diagnosis is an important predictor of improved quality of life after remission is achieved.

Diagnostic approach outlined by the evidence-based 2008 Endocrine Society clinical guidelines:

– For patients with a low index of suspicion, we suggest initial testing with one of the following first-line tests: late-night salivary cortisol (two measurements), 24-hour urinary free cortisol (UFC) excretion (two measurements), or the overnight 1 mg dexamethasone suppression test (DST). For example, a woman with oligomenorrhea and hirsutism might be tested for CS; however, the pre-test probability of the syndrome is low if there are no other associated signs or symptoms.
– For patients with a high index of suspicion, such as those with features suggestive of CS, do two first-line tests.
– To optimize sensitivity, should use the upper limit of the reference range for UFC and salivary cortisol and a serum cortisol concentration <1.8 mcg/dL (50 nmol/L) after dexamethasone as the cutoffs for a normal response.
– If UFC is chosen as the initial screening test, the result should be unequivocally increased (threefold above the upper limit of normal for the assay) or the diagnosis of CS is uncertain and other tests should be performed.
– Some centers use the longer low-dose DST (2 mg/day for 48 hours) as an initial test.
– UFC and late-night salivary cortisol measurements are each obtained at least twice because the hypercortisolism in CS may be variable. Two measurements must be abnormal for the test to be considered abnormal; for patients with mild or fluctuating disease, this may require collecting a number of salivary cortisols or UFCs over weeks.

Normal results — If initial testing is normal in an individual with a low index of suspicion for Cushing syndrome, it is unlikely that the patient has CS unless it is extremely mild or cyclic. No additional evaluation is necessary unless symptoms progress or cyclic CS is suspected. In this case, patient should be referred to an endocrinologist for repeat testing and further evaluation.

On the other hand, if initial testing is normal in someone with a high index of suspicion for Cushing syndrome (clinical features suggestive of CS), patient should be referred to an endocrinologist for additional evaluation to confirm or exclude the diagnosis of Cushing syndrome.

Any abnormal result — In patients with at least one abnormal test result (which could represent true CS or a false positive result), additional evaluation is needed. This includes excluding physiologic hypercortisolism and referral to an endocrinologist. Additional evaluation may include repeating the initial test or other first-line tests.

Exclude physiologic hypercortisolism:

Hypercortisolism can occur in several disorders other than Cushing syndrome. When such patients present with clinical features consistent with Cushing syndrome, they may also be referred to as having physiologic hypercortisolism or pseudo-Cushing syndrome. Clinically, patients with these physiologic forms of hypercortisolism seldom have the cutaneous (ie, easy bruising, thinning, and friability) or muscle (ie, proximal muscle atrophy and weakness) signs of Cushing syndrome. However, these conditions/disorders should be excluded when evaluating patients for Cushing syndrome. Examples of conditions associated with physiologic hypercortisolism that may have some clinical features of CS include:

– Pregnancy
– Patients with severe obesity, especially those with visceral obesity or PCOS
– Patients with psychological stress, especially patients with a severe major depressive disorder and melancholic symptoms
– Poorly controlled diabetes mellitus
– Rarely, chronic alcoholism