Adrenal steroid biosynthesis
- Lynnette K Nieman, MD
Lynnette K Nieman, MD
- Section Editor — Adrenal Disease
- Senior Investigator
- Bethesda, MD
The primary action of corticotropin (ACTH) on the adrenal cortex is to increase cortisol secretion by increasing its synthesis; intraadrenal cortisol storage is minimal . 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.
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".)
MECHANISM OF ACTH ACTION
Corticotropin (ACTH) acts by binding to a specific cell-surface receptor, the melanocortin receptor-2 (MC2R) . ACTH up-regulates expression of these receptors, thereby increasing the steroidogenic response to further ACTH stimulation .
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 levels and normal mineralocorticoid levels (see "Unusual causes of adrenal insufficiency", section on 'Familial glucocorticoid deficiency'). 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 . 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 .
ACTH binding to its receptors activates adenylyl cyclase, increasing cyclic AMP (cAMP) production, which in turn stimulates cAMP-dependent protein kinase (protein kinase A) and phosphorylation of a number of proteins.
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- MECHANISM OF ACTH ACTION
- CHOLESTEROL SUBSTRATE
- CORTISOL BIOSYNTHESIS
- Pregnenolone synthesis by CYP11A1
- Conversion of pregnenolone to progesterone
- Progesterone to 17-alpha-hydroxyprogesterone
- 17-alpha-hydroxyprogesterone to 11-deoxycortisol
- Conversion of 11-deoxycortisol to cortisol
- ALDOSTERONE BIOSYNTHESIS
- ADRENAL ANDROGEN BIOSYNTHESIS
- ACUTE AND CHRONIC ACTIONS OF ACTH
- METABOLISM OF ADRENAL STEROIDS
- OVERVIEW OF CAH