Injection ACTH (Corticotropin)

What Is It?

Figure: Processing of POMC to ACTH, alpha-MSH, beta-LPH, beta-endorphin, and related peptides (Goodman & Gilman's)

Mechanism of Action

• Acute phase (seconds to minutes): Increased supply of cholesterol substrate to steroidogenic enzymes via mobilization of cholesterol esters and upregulation of StAR (steroid acute regulatory) protein, which translocates cholesterol across mitochondrial membranes - the rate-limiting step.
• Chronic phase (hours to days): Increased transcription of steroidogenic enzymes (CYP11A1, CYP11B1, CYP17A1, CYP21A2, 3β-HSD).

Figure: The three zones of the adrenal cortex. ACTH is the primary regulator of the zona fasciculata (cortisol) and zona reticularis (DHEA). The zona glomerulosa (aldosterone) is primarily regulated by AngII and K+.

Actions on the Adrenal Cortex

• Without ACTH stimulation (e.g., hypopituitarism), the zona fasciculata and reticularis undergo atrophy
• Persistently elevated ACTH causes hypertrophy and hyperplasia of these zones (e.g., congenital adrenal hyperplasia)
• "ACTH escape" phenomenon: with prolonged ACTH excess, aldosterone levels initially rise but then return to normal

Regulation of Secretion (HPA Axis)

1. Diurnal rhythm - ACTH peaks in the early morning; circulating cortisol peaks at ~8 AM
2. Negative feedback - Cortisol inhibits CRH (at hypothalamus) and POMC expression + corticotroph responsiveness to CRH (at pituitary)
3. Stress response - Trauma, hemorrhage, surgery, hypoglycemia, infection, pain, and fear can override negative feedback, sharply raising glucocorticoid levels

• CRH (corticotropin-releasing hormone) from hypothalamus → binds CRH-R on corticotrophs → Gs-cAMP → stimulates both ACTH biosynthesis AND secretion
• Arginine vasopressin (AVP) → binds V1b receptors → Gq-PLC-IP3-Ca²+ → potentiates CRH effects (AVP alone does NOT increase de novo ACTH synthesis)

Pharmaceutical Forms

Therapeutic Uses

1. Infantile Spasms (West Syndrome) - PRIMARY indication

• Repository corticotropin injection gel is the mainstay treatment for this rare epileptic disorder of infancy
• Mechanism in this setting is unknown - may be independent of adrenal steroid release (ACTH can control spasms even in adrenally suppressed patients); proposed CNS suppression of CRH may be involved
• Vigabatrin is an alternative, especially in tuberous sclerosis
• Other options: oral prednisolone, methylprednisolone, dexamethasone, valproate, topiramate, clonazepam
• "The mechanism of action of corticotropin and corticosteroids in the treatment of infantile spasms is unknown" (Katzung's Basic and Clinical Pharmacology, 16e)

2. Other Inflammatory/Autoimmune Conditions

• Repository corticotropin injection has been studied in autoimmune rheumatic conditions and nephrotic syndrome
• Has nonglucocorticoid effects via melanocortin receptors (immune cells express MC1R, MC3R, MC4R) that are not fully understood
• Use is limited by high expense and lack of direct comparative trials vs. glucocorticoids

3. Diagnostic Use - ACTH Stimulation Test

• Cosyntropin 0.25 mg (supraphysiological dose) is given IV/IM
• Cortisol is measured at baseline and 30-60 minutes
• A rise in cortisol to >18-20 μg/dL (using standard assays) indicates a normal response (intact adrenal reserve)
• Used to diagnose primary adrenal insufficiency (Addison's disease) and assess adrenal function
• Also used during adrenal venous sampling to distinguish unilateral vs. bilateral aldosterone excess in primary aldosteronism

4. CRH Testing (related diagnostic use)

• Ovine CRH (corticorelin) is used to differentiate pituitary vs. ectopic ACTH production in Cushing's syndrome (pituitary source responds to CRH; ectopic does not)
• Also used after dexamethasone suppression to distinguish pseudo-Cushing states from true Cushing's syndrome

Why ACTH vs. Corticosteroids?

• ACTH also stimulates mineralocorticoid production (salt/water retention, hypertension)
• Stimulates adrenal androgens (virilization)
• Response is variable depending on adrenal reserve
• Less convenient (requires injection)
• More expensive

• Preserves the adrenal axis (does not suppress HPA)
• Possible non-glucocorticoid immunomodulatory effects via melanocortin receptors
• Essential role in infantile spasms

Adverse Effects (from elevated corticosteroid levels)

• Cushing's syndrome (prolonged heavy dosage)
• Sodium and water retention, hypertension
• Hypokalemia
• Virilization (from adrenal androgen stimulation)
• Immunosuppression, increased infection risk
• In children: significant morbidity with repository formulation (weight gain, irritability, hypertension, infections)

• Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 50 - ACTH, Adrenocortical Steroids, and their Synthetic Analogs
• Katzung's Basic and Clinical Pharmacology, 16th Edition - Medications Effective for Infantile Spasms
• Firestein & Kelley's Textbook of Rheumatology - Repository Corticotropin Injection