Cushing syndrome

Last updated: January 11, 2022

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Cushing syndrome, or hypercortisolism, is an endocrine disorder that is most often caused iatrogenically by the exogenous administration of glucocorticoids. Less commonly, Cushing syndrome can result from endogenous overproduction of cortisol. Primary hypercortisolism is the result of autonomous overproduction of cortisol by the adrenal gland (e.g., adrenal adenoma, adrenal carcinoma). Secondary hypercortisolism, on the other hand, is the result of increased production of adrenocorticotropic hormone (ACTH), either by pituitary microadenomas (Cushing disease) or by ectopic, paraneoplastic foci (e.g., small cell lung cancer). Typical clinical features include central obesity, thin, easily bruisable skin, abdominal striae, secondary hypertension, hyperglycemia, and proximal muscle weakness. Since serum cortisol levels vary diurnally, 24-hour urine cortisol measurement, midnight saliva cortisol levels, and/or dexamethasone suppression test are used to diagnose hypercortisolism. Serum ACTH levels and CRH stimulation test are used to identify the cause of hypercortisolism, imaging is then employed to localize the tumor. Treatment of endogenous hypercortisolism primarily involves surgical removal of the source of excessive cortisol (e.g., adrenalectomy) or ACTH (e.g., transsphenoidal hypophysectomy). If surgery is contraindicated, drugs that suppress cortisol synthesis (e.g., metyrapone) may be used instead.

Exogenous (iatrogenic) Cushing syndrome

Endogenous Cushing syndrome

Overview of endogenous Cushing syndrome [1][2]
Types Primary hypercortisolism (ACTH-independent Cushing syndrome) Secondary hypercortisolism
Pituitary ACTH production (Cushing disease) Ectopic ACTH production
Relative frequency [3]
  • 5–10%
  • ∼ 75%
  • ∼ 15%

While the term “Cushing syndrome” can be applied to any cause of hypercortisolism, “Cushing disease” refers specifically to secondary hypercortisolism that results from excessive production of ACTH by pituitary adenomas.

Secondary hypercortisolism is also called ACTH-dependent Cushing syndrome because hypercortisolism is the result of increased ACTH levels.

CUSHINGOID” is the acronym for side effects of corticosteroids: Cataracts, Ulcers, Striae/Skin thinning, Hypertension/Hirsutism/Hyperglycemia, Infections, Necrosis (of the femoral head), Glucose elevation, Osteoporosis/Obesity, Immunosuppression, Depression/Diabetes.

Patients with secondary hypercortisolism due to ectopic ACTH production may present with rapid onset of hypertension and hypokalemia without other typical features of Cushing syndrome.Consider a diagnosis of hypercortisolism in patients who present with proximal muscle weakness, central obesity, thinning skin, weight gain, sleep disturbance, and/or depression.

General laboratory findings [4]

Screening for hypercortisolism [7]

Any of the following can be used as a screening test for hypercortisolism :

  • ↑ 24-hour urine cortisol (> 3 times the normal value i.e. > 300 μg/24 h) [2]
  • ↑ Early morning serum cortisol levels (> 50 nmol/L) following a low-dose dexamethasone suppression test [8]
  • ↑ Midnight salivary cortisol (> 4 nmol/L) [9]
  • ↑ Midnight serum cortisol (> 7.5 μg/dL) [10]

A patient with any one of the above findings should be evaluated to identify a possible cause of hypercortisolism. The diagnosis of hypercortisolism is confirmed if at least two of the above-mentioned screening findings are present.

Identifying the cause of hypercortisolism

Hormone analysis

Once glucocorticoid therapy has been ruled out, the following tests are used to identify the cause of hypercortisolism:

  1. Serum ACTH levels
  2. If secondary hypercortisolism is suspected: one of the following tests may be used to differentiate between Cushing disease and ectopic ACTH production
Dexamethasone suppression test [11]
Disorder ACTH levels Low-dose dexamethasone suppression test High-dose dexamethasone suppression test CRH stimulation test
Normal ↔︎ Cortisol Cortisol ACTH, Cortisol
Primary hypercortisolism ↔︎ Cortisol ↔︎ Cortisol ↔︎ ACTH, ↔︎ Cortisol
Cushing disease ↔︎ Cortisol Cortisol ACTH, Cortisol
Ectopic ACTH secretion ↔︎ Cortisol ↔︎ Cortisol ↔︎ ACTH, ↔︎ Cortisol

Only Cushing disease remains (partially) susceptible to suppression (high-dose dexamethasone suppression test) or stimulation (CRH stimulation test) of cortisol secretion.

Imaging to localize the tumor

In the diagnosis of hypercortisolism, hormone analysis always precedes imaging because microadenomas of the pituitary do not always appear upon imaging. Furthermore, imaging can reveal inactive adrenal tumors (incidentalomas) and pituitary tumors in many healthy individuals.

Exogenous Cushing syndrome

Endogenous Cushing syndrome [2]

Following surgical therapy, patients who develop adrenal insufficiency require lifelong glucocorticoid replacement therapy.

Patients who develop severe hypokalemia due to the mineralocorticoid effect of cortisol may be treated with spironolactone (aldosterone antagonist).

Nelson syndrome (post adrenalectomy syndrome)

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