Cushing's syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Furqan M M. M.B.B.S[2]

Overview

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 corticotropin (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 corticotrophic 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 mineralcorticoid activity in high concentrations, worsening hypertension and leading to hypokalemia (common in ectopic ACTH secretion).

Pathophysiology

Physiological mechanism of cortisol secretion

Paraventricular nuclei in the hypothalamus releases Corticotrophic releasing hormone (CRH)

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CRH is transferred to anterior pituitary via the portal veins.

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CRH stimulates the activity of corticotrophs; cells that produce proopiomelanocortin (POMC) in the anterior pituitary

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Corticotrophs produce adrenocorticotropic hormone (ACTH) by the post-translational modification of(POMC)

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ACTH is drained into systemic circulation via the pituitary capillaries and stimulates the adrenal cortex to produce cortisol

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Cortisol acts on hypothalamus and pituitary through a feedback mechanism to regulate the secretion of CRH and ACTH

Cushing's syndrome

Cushing's syndrome is basically hypercortisolism which can develop by:

1. Excess pituitary ACTH secretion
2. Excess secretion of cortisol by adrenal glands
3. Ectopic secretion of ACTH

References

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