ACTH 1-24 (Cosyntropin)

ACTH 1-24 (cosyntropin, tetracosactide) is the synthetic 24-amino acid N-terminal fragment of the 39-amino acid native adrenocorticotropic hormone (ACTH, corticotropin). It retains full biological potency equivalent to the entire ACTH molecule because the full receptor-binding domain and biological activity reside in the first 24 amino acids. The C-terminal residues 25-39 appear to modulate immunogenicity and pharmacokinetics but not bioactivity.

ACTH is normally produced by corticotroph cells of the anterior pituitary gland in response to CRF (corticotropin-releasing factor) from the hypothalamus and is the effector arm of the HPA (hypothalamic-pituitary-adrenal) stress axis.

**Mechanism of action:** ACTH binds to MC2R (melanocortin 2 receptor), a Gs-coupled GPCR expressed primarily on adrenocortical cells (particularly zona fasciculata and zona reticularis). Receptor activation: 1. cAMP → PKA activation 2. Phosphorylation of StAR protein (steroidogenic acute regulatory protein) → cholesterol translocation from outer to inner mitochondrial membrane 3. CYP11A1 (cholesterol side chain cleavage) → pregnenolone 4. Sequential enzymatic steps → cortisol (and, to a lesser extent, DHEA) 5. PKA also activates the transcription of CYP genes needed for sustained cortisol synthesis

The cortisol response to ACTH injection occurs within 5-10 minutes (StAR-mediated) with a peak at 30-60 minutes (new enzyme synthesis).

**Diagnostic gold standard — ACTH stimulation test:** The cosyntropin stimulation test is the most widely used test for adrenal insufficiency. By injecting 250 mcg cosyntropin IV or IM and measuring serum cortisol at 30 and 60 minutes, clinicians can determine whether the adrenal cortex can produce cortisol when maximally stimulated. A cortisol peak <18 mcg/dL suggests adrenal insufficiency (primary, secondary, or tertiary depending on context).

**ACTH therapy for infantile spasms:** The synthetic ACTH depot formulation (Synacthen/tetracosactide depot) is used for infantile spasms (West syndrome), an epilepsy syndrome of infancy. The mechanism here is distinct from cortisol stimulation — ACTH likely acts directly in the brain via MC receptors (including MC3R and MC5R) to suppress the excessive corticotropin-releasing hormone that drives the spasms.