Adrenal gland & paraganglia

Adrenal hyperfunction / hyperplasia

Cushing syndrome

Last author update: 1 February 2013
Last staff update: 3 June 2021

Copyright: 2003-2019,, Inc.

PubMed Search: Cushing syndrome

Nat Pernick, M.D.
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Cite this page: Pernick N. Cushing syndrome. website. Accessed February 6th, 2023.
Definition / general
  • Excess cortisol for any reason
  • Pituitary gland changes: Crooke hyaline change-basophilic cytoplasm of ACTH producing cells changes from granular to homogenous, due to accumulation of intermediate filaments
  • Adrenal gland changes: exogenous cortisol causes low ACTH, which causes atrophy of fasciculata and reticularis, not glomerulosa, in residual or opposite adrenal gland
Pathophysiology / etiology
  • Causes: (a) exogenous glucocorticoids, (b) small ACTH-producing pituitary adenoma or hyperplasia (most common endogenous cause), (c) adrenal adenoma, adrenal carcinoma or bilateral adrenal hyperplasia, (d) ectopic ACTH production by non-adrenal neoplasm, (e) rarely caused by tumors producing cortisol releasing factor

Exogenous glucocorticoids
  • Most cases

Small ACTH-producing pituitary adenoma or hyperplasia
  • Called Cushing disease (Harvey Cushing observed pituitary adenomas associated with hypercortisolism in 1932)
  • Adrenals usually exhibit nodular or diffuse hyperplasia, have increased weight and rounded contours; outer cortical layers are yellow, inner layers tan-brown; nodules are often multiple, associated with hyperplastic cortex
  • Zona glomerulosa is difficult to identify in adults, fasciculata has lipid-depleted cells and reticularis cells are vacuolated
  • Elevated serum ACTH, cortisol and its precursors
  • Can suppress ACTH with high, but not low dose dexamethasone
  • Treatment: surgical resection or radiation of pituitary tumor; surgical or medical (with mitotane) adrenalectomy

Bilateral adrenal hyperplasia, adrenal adenoma or adrenal carcinoma
  • 25% of endogenous cases; also called ACTH-independent Cushing syndrome
  • 80% are women
  • Children have more carcinomas than adenomas, produce more hypercortisolism
  • Adults have similar frequency of adenomas and carcinomas
  • Virilization: in females-male pattern baldness, clitoromegaly and deepening of voice
  • Feminization: in males-loss of libido, testicular atrophy and gynecomastia
  • Large tumors with Cushing syndrome or Cushing syndrome with obvious virilization and marked 17-ketosteroid excretion are usually carcinomas
  • High cortisol levels, low ACTH levels
  • Opposite adrenal gland is atrophic
  • Cannot suppress or lower ACTH with high or low dose dexamethasone

Ectopic ACTH production by non-adrenal neoplasm
  • Tumors secrete ACTH-like substance
  • In adults, usually due to small cell carcinoma of lung or carcinoid tumor of lung or thymus; also medullary thyroid carcinoma, pancreatic endocrine neoplasm, pheochromocytoma or ovarian tumor
  • In children, tumors are usually pheochromocytoma, neuroblastoma, thymic or pancreatic endocrine neoplasm
  • Associated with hypokalemic alkalosis, high urinary excretion of free cortisol, skin pigmentation, edema and severe diabetes mellitus
  • Usually poor prognosis due to malignant disease
  • Treatment: resect or treat tumor; control hypercortisolism with aminoglutethimide or other drugs; bilateral adrenalectomy
  • Gross description: enlarged adrenal glands (total 20-30g) with tan-brown, diffusely hyperplastic cortex
  • Micro description: diffuse hyperplasia and lipid depletion of fasciculata cells; reticularis cells may exhibit atypia; often accompanied by metastatic tumor

Tumors producing cortisol releasing factor
  • Usually men, age 40-59 years
  • Elevated serum ACTH, cannot suppress with high or low dose dexamethasone
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