Cushing's syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Furqan M M. M.B.B.S[2]


Both the hypothalamus and the pituitary gland are part of the brain. The hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland. Strictly, Cushing's syndrome refers to excess cortisol of any etiology. One of the causes of Cushing's syndrome is a cortisol secreting adenoma in the cortex of the adrenal gland. The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low. Cushing's disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotroph pituitary adenoma. This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because a tumor causes the pituitary to be unresponsive to negative feedback from high cortisol levels. Cortisol can also exhibit mineralocorticoid activity in high concentrations, worsening hypertension and leading to hypokalemia (common in ectopic ACTH secretion).


Mechanism of cortisol secretion

The secretion of cortisol is controlled by hypothalamic-pituitary axis by the following mechanism:[1][2]

Cushing's syndrome

The pathophysiology of Cushing's syndrome is linked to hypercortisolism which can develop by excess ACTH secretion or excess cortisol secretion by adrenal glands. The underlying mechanisms are usually genetic mutations or overexpression of proteins.[1][2][3][4][5]

  1. Excess ACTH secretion
  2. Excess secretion of cortisol by adrenal gland

Associated Conditions

Cushing's syndrome is associated with the following conditions:[6]

  • Carney complex
  • McCune-Albright syndrome
  • Multiple Endocrine Neoplasia Type 1 (MEN 1)


  1. 1.0 1.1 Lacroix A, Feelders RA, Stratakis CA, Nieman LK (2015). "Cushing's syndrome". Lancet. 386 (9996): 913–27. doi:10.1016/S0140-6736(14)61375-1. PMID 26004339.
  2. 2.0 2.1 Raff H, Carroll T (2015). "Cushing's syndrome: from physiological principles to diagnosis and clinical care". J. Physiol. (Lond.). 593 (3): 493–506. doi:10.1113/jphysiol.2014.282871. PMC 4324701. PMID 25480800.
  3. Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, Jolly S, Miller BS, Giordano TJ, Hammer GD (2014). "Adrenocortical carcinoma". Endocr. Rev. 35 (2): 282–326. doi:10.1210/er.2013-1029. PMC 3963263. PMID 24423978.
  4. Vyas S, Gorsi U, Bansali A, Khandelwal N (2012). "Anterior mediastinal mass in a patient with Cushing's syndrome". Ann Thorac Med. 7 (1): 42–3. doi:10.4103/1817-1737.91557. PMC 3277041. PMID 22347350.
  5. "Cushing's Syndrome due to Ectopic ACTH from Bronchial Carcinoid: A Case Report and Review".
  6. Sahdev A, Reznek RH, Evanson J, Grossman AB (2007). "Imaging in Cushing's syndrome". Arq Bras Endocrinol Metabol. 51 (8): 1319–28. PMID 18209870.

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