In the adrenal stress response, ACTH stimulates cortisol synthesis via multiple intracellular steps. The acute rate-limiting step in cortisol biosynthesis, stimulated within minutes of ACTH signalling, involves:

• A CYP11A1 (P450scc) — the cholesterol side-chain cleavage enzyme in the inner mitochondrial membrane
• B CYP17A1 — 17-alpha hydroxylase in the smooth ER converting pregnenolone to 17-OH pregnenolone
• C StAR (steroidogenic acute regulatory protein) — transporting cholesterol from outer to inner mitochondrial membrane ✓
• D 3-beta-HSD — converting pregnenolone to progesterone in the ER

Explanation

Cholesterol delivery across the aqueous space of the intermembrane gap (outer to inner mitochondrial membrane) is the acute rate-limiting step in steroidogenesis. ACTH → cAMP → PKA → rapid phosphorylation and de novo synthesis of StAR protein accomplishes this within minutes. Once cholesterol reaches the inner membrane, CYP11A1 (P450scc) cleaves the side chain to produce pregnenolone — the committed step — but substrate delivery by StAR is rate-limiting acutely. Congenital lipoid adrenal hyperplasia (the most severe CAH variant) results from StAR mutations.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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Written and medically reviewed by the StethoPrep medical team.