Corticotropin

(Adrenocorticotropic Hormone – ACTH)

Overview
Corticotropin is a naturally occurring polypeptide hormone secreted by the anterior pituitary gland. It is also available as a pharmaceutical preparation derived from animal pituitary extracts or produced synthetically. Its primary physiological role is to stimulate the adrenal cortex to produce and release glucocorticoids (mainly cortisol), mineralocorticoids (aldosterone), and adrenal androgens. Therapeutically, corticotropin is used both for diagnostic testing of adrenal function and for the management of certain inflammatory and autoimmune conditions where endogenous corticosteroid production can be leveraged.

Mechanism of Action

• Binds to melanocortin 2 receptors (MC2R) located on adrenal cortical cells.

• Activates adenylate cyclase via G-protein coupling, increasing intracellular cyclic AMP (cAMP).

• cAMP stimulates cholesterol conversion to pregnenolone, the rate-limiting step in corticosteroid biosynthesis.

• Increases secretion of cortisol, corticosterone, aldosterone, and adrenal androgens.

• The anti-inflammatory and immunosuppressive effects result indirectly from the elevated corticosteroid levels.

Therapeutic Uses

1. Diagnostic

   • ACTH stimulation test (short or rapid test) to assess adrenal cortex responsiveness and differentiate primary adrenal insufficiency (Addison’s disease) from secondary adrenal insufficiency (pituitary or hypothalamic dysfunction).

2. Therapeutic

   • Infantile spasms (West syndrome) – particularly in pediatric neurology.

   • Acute exacerbations of multiple sclerosis.

   • Certain rheumatic disorders: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis.

   • Severe allergic and dermatologic conditions refractory to other treatments.

   • Certain ophthalmic inflammatory conditions (e.g., uveitis, iritis).

   • Severe ulcerative colitis flare-ups.

Available Preparations

• Repository corticotropin injection (e.g., Acthar® Gel) – prolonged-release formulation for intramuscular or subcutaneous use.

• Synthetic ACTH analogs (e.g., tetracosactide/cosyntropin) – used mainly for diagnostic purposes.

Dosage and Administration

• Diagnostic use (cosyntropin test): 250 micrograms IV or IM once; measure serum cortisol before and 30–60 minutes after administration.

• Therapeutic use (repository corticotropin): Commonly 40–80 units IM or SC every 24–72 hours for inflammatory disorders; dose and frequency individualized.

• For infantile spasms: Often 75 units/m² once daily IM for 2–3 weeks, followed by taper.

Contraindications

• Systemic fungal infections.

• Uncontrolled hypertension or congestive heart failure (due to sodium/water retention).

• Known hypersensitivity to ACTH or formulation components.

• Peptic ulcer disease (risk of exacerbation).

• Recent surgery with poor wound healing.

Precautions

• Prolonged use can cause symptoms of glucocorticoid excess (Cushing’s syndrome).

• Taper gradually after prolonged therapy to prevent adrenal insufficiency.

• Monitor electrolytes, blood pressure, and glucose during treatment.

• Increased infection risk due to immunosuppression.

• Use caution in patients with osteoporosis, diabetes mellitus, or psychiatric disorders.

Adverse Effects

• Common: Injection site reactions, mood changes, insomnia, fluid retention, increased appetite, weight gain.

• Metabolic: Hyperglycemia, hypokalemia, sodium retention.

• Musculoskeletal: Muscle weakness, osteoporosis.

• Endocrine: Cushingoid features, suppression of hypothalamic-pituitary-adrenal (HPA) axis.

• Gastrointestinal: Peptic ulceration, GI bleeding.

• Neurologic: Seizures (especially in infantile spasms treatment), headache.

Drug Interactions

• Diuretics (especially potassium-depleting): Increased risk of hypokalemia.

• NSAIDs: Increased risk of GI ulceration and bleeding.

• Vaccines: Reduced immune response; avoid live vaccines during therapy.

• Antidiabetic agents: Reduced efficacy due to hyperglycemic effects of ACTH-induced corticosteroids.

• Digitalis glycosides: Increased risk of arrhythmias with hypokalemia.

Monitoring

• For diagnostic use: Cortisol and/or aldosterone levels at specified intervals.

• For therapeutic use: Blood pressure, blood glucose, serum electrolytes, weight, and signs of infection or HPA axis suppression.

omparison: Corticotropin (ACTH) vs. Systemic Corticosteroids

Feature	Corticotropin (ACTH)	Systemic Corticosteroids (e.g., prednisone, hydrocortisone, methylprednisolone, dexamethasone)
Mechanism of action	Indirect: Stimulates adrenal cortex via melanocortin 2 receptors → increases endogenous production of glucocorticoids, mineralocorticoids, and androgens.	Direct: Exogenous supply of glucocorticoids (± mineralocorticoid activity), bypassing the hypothalamic-pituitary-adrenal (HPA) axis.
Onset of action	Delayed relative to IV corticosteroids (depends on adrenal responsiveness); onset typically hours.	Rapid; IV corticosteroids can act within minutes to hours; oral onset within hours.
Dependence on adrenal function	Requires functional adrenal cortex to be effective. Ineffective in primary adrenal insufficiency (Addison’s disease).	Independent of adrenal function; works in both primary and secondary adrenal insufficiency.
Hormonal spectrum	Increases all adrenal cortex hormones: cortisol (glucocorticoid), aldosterone (mineralocorticoid), and adrenal androgens.	Provides only the administered hormone(s); no stimulation of adrenal androgen production.
Physiologic mimicry	More physiologic: promotes pulsatile release and balanced steroid synthesis when adrenal is intact.	Non-physiologic: delivers fixed steroid dose without normal circadian rhythm unless dosing is tailored.
Therapeutic uses	Diagnostic testing of adrenal reserve; treatment of infantile spasms; alternative for some inflammatory/autoimmune conditions when endogenous steroid stimulation preferred or direct steroid therapy is not tolerated.	Broad use for acute and chronic inflammatory, allergic, autoimmune, and endocrine disorders; first-line in adrenal insufficiency.
Formulations	Repository ACTH (prolonged-release IM/SC), synthetic ACTH analogs (cosyntropin – diagnostic).	Multiple oral, IV, IM, intra-articular, and topical preparations.
Tapering	Gradual withdrawal after prolonged use to avoid rebound adrenal insufficiency due to HPA axis suppression.	Gradual withdrawal needed after prolonged high-dose use to avoid adrenal crisis.
Adverse effect profile	Similar to corticosteroids due to increased endogenous glucocorticoid production; may cause more mineralocorticoid-related effects (Na⁺ retention, K⁺ loss, edema) compared to some synthetic corticosteroids.	Similar glucocorticoid-related effects; mineralocorticoid effects depend on specific drug (e.g., dexamethasone minimal; hydrocortisone high).
Metabolic effects	Indirect; cortisol levels fluctuate with adrenal physiology; mineralocorticoid stimulation can be more pronounced.	Direct and dose-dependent; metabolic and fluid balance effects determined by specific drug potency and receptor selectivity.
Use in adrenal insufficiency	Not used for replacement in primary adrenal insufficiency (adrenals unresponsive).	Standard of care for adrenal hormone replacement.
Cost/availability	More expensive; limited availability; mainly specialty use.	Widely available; inexpensive generic formulations.
Clinical preference	Reserved for diagnostic purposes, infantile spasms, and select inflammatory conditions where endogenous stimulation is desired or direct corticosteroids contraindicated.	Preferred for most conditions requiring anti-inflammatory, immunosuppressive, or replacement steroid therapy.