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Adrenal steroid biosynthesis

Hershel Raff, PhD
Section Editor
Lynnette K Nieman, MD
Deputy Editor
Kathryn A Martin, MD


The primary action of corticotropin (adrenocorticotropin; ACTH) on the adrenal cortex is to increase cortisol secretion by increasing its synthesis; intraadrenal cortisol storage is minimal [1]. The major adrenal steroid hormones are synthesized in different areas of the adrenal cortex: glucocorticoids (particularly cortisol), androgens, and estrogens in the zona fasciculata and reticularis; and aldosterone in the zona glomerulosa. An appreciation of these pathways serves as the basis for understanding the different forms of congenital adrenal hyperplasia (CAH) and isolated hypoaldosteronism in which there are defects in the function of the enzymes involved in adrenal steroid hormone synthesis. It is also critical for understanding the mechanisms of action of new drugs directed at reducing cortisol synthesis in patients with Cushing's syndrome [2]. (See "Medical therapy of hypercortisolism (Cushing's syndrome)".)

The steps involved in the production of adrenal steroids will be reviewed here. The metabolism of adrenal steroids is reviewed in detail separately. (See "Metabolism of adrenal steroids".)


Corticotropin (ACTH) acts by binding to a specific cell-surface receptor, the melanocortin receptor-2 (MC2R) [3]. ACTH upregulates expression of these receptors, thereby increasing the steroidogenic response to further ACTH stimulation [4].

Failure of MC2R to activate in response to ACTH causes familial glucocorticoid deficiency (FGD), a rare autosomal recessive disorder characterized by severe cortisol deficiency with high plasma ACTH concentrations and normal mineralocorticoid levels. MC2R mutations resulting in effective loss of the receptor function are responsible for FGD type 1, which accounts for up to 25 percent of all FGD cases [5]. (See "Causes and clinical manifestations of primary adrenal insufficiency in children", section on 'Familial glucocorticoid deficiency (FGD)'.)

The melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are small, single-pass transmembrane proteins; MRAP is a key accessory factor for the functional expression of the MC2R/ACTH receptor. The clinical observation that 20 percent of FGD cases are due to inactivating MRAP mutations highlights the importance of MRAP in adrenal gland physiology [6].

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Literature review current through: Dec 2017. | This topic last updated: Oct 03, 2017.
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