Cushing's syndrome pathophysiology

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).

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

• Paraventricular nuclei in the hypothalamus release corticotropin releasing hormone (CRH).
• CRH is transferred to anterior pituitary via the portal veins.
• CRH stimulates the activity of corticotrophs; cells that produce proopiomelanocortin (POMC) in the anterior pituitary.
• Corticotrophs produce adrenocorticotropic hormone (ACTH) by the post-translational modification of POMC.
• ACTH is drained into systemic circulation via the pituitary capillaries and stimulates the adrenal cortex (zona fasciculata) to produce cortisol.
• Cortisol acts on hypothalamus and pituitary through a feedback mechanism to regulate the secretion of CRH and ACTH.

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
   • The excess ACTH secretion can be due to the pituitary adenoma or ectopic (non-pituitary) ACTH secretion. ACTH stimulates the adrenal cortex to release cortisol and is not regulated by the feedback mechanism.
     1. Pituitary adenoma: Various gene mutations are involved in the development of pituitary adenoma commonly USP8, MEN1, CDKIs, and CDKN1B/p27Kip1. Many proteins are also overexpressed like Brg1, HDAC2, TR4, PTTG, and EGFR. It is the most important cause of ACTH-dependent cushing’s syndrome and is also called cushing’s disease. It is considered that the corticotroph tumors are resistant to glucocorticoid negative feedback inhibition which results in the pathological adrenal cortisol secretion.
     2. Ectopic ACTH secretion: The molecular defects in the neuroendocrine tumors leading to ectopic ACTH secretion from gastroenteropancreatic tumors are largely unknown. Germline menin mutations or RET oncogene mutations in multiple endocrine neoplasias (MEN) may be responsible. Ectopic secretion of ACTH can be seen as a manifestation of the paraneoplastic syndrome in small cell lung carcinoma and carcinoid tumors(bronchial and thymus).
2. Excess secretion of cortisol by adrenal gland
   • Excess secretion of the cortisol by the adrenal gland is due to the adrenal causes independent of ACTH secretion.
     1. Benign Adrenocortical adenoma: Common defects leading to adrenocortical adenoma are mutations or activation of the cAMP-dependent or β-catenin signaling pathways and aberrant expression and function of various G-protein-coupled receptors (GPCR).
     2. Adrenal cortical carcinoma It is associated with germline TP53 mutations and MEN syndrome.
     3. Bilateral adrenal hyperplasia: It is associated with MEN1, familial adenomatous polyposis, and fumarate hydratase gene mutations. Several inactivating mutations of armadillo repeat containing 5 genes (ARMC5, chromosome 16p11.2) are also identified.

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

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

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