Peptide Schedule
ACTH (Cosyntropin/Cortrosyn)24 residuesSYSMEHFRWGKPVGKKRRPVKVYPEach bubble = one amino acid. Size = residue mass. Color = chemical class.ACTH (Cosyntropin/Cortrosyn)
Benefits
About ACTH (Cosyntropin/Cortrosyn)
Adrenocorticotropic hormone (ACTH) is a critical endocrine peptide synthesized and secreted by corticotroph cells in the anterior pituitary gland. It is cleaved from the larger precursor molecule proopiomelanocortin (POMC), which also gives rise to alpha-MSH and beta-endorphin. ACTH plays a central role in the hypothalamic-pituitary-adrenal (HPA) axis by stimulating the adrenal cortex to produce cortisol and other corticosteroids essential for stress response, immune regulation, and metabolic homeostasis. Cosyntropin (marketed as Cortrosyn) is a synthetic peptide consisting of the first 24 amino acids of the 39-amino-acid native ACTH sequence. This truncated form retains full biological activity at the melanocortin-2 receptor (MC2R) on adrenal cortical cells. A single 0.25 mg dose of cosyntropin provides maximal adrenal stimulation equivalent to 25 units of natural ACTH, making it the gold standard diagnostic tool for the ACTH stimulation test used to evaluate adrenal reserve. Beyond its diagnostic role, ACTH has therapeutic applications through H.P. Acthar Gel (repository corticotropin injection), which is FDA-approved for treating infantile spasms, acute exacerbations of multiple sclerosis, nephrotic syndrome, and over a dozen other inflammatory and autoimmune conditions. Acthar Gel acts through both steroidogenic pathways (stimulating endogenous cortisol production) and direct immunomodulatory effects via melanocortin receptors expressed on immune cells throughout the body. The clinical significance of ACTH extends across endocrinology, neurology, rheumatology, and nephrology. Understanding ACTH physiology is fundamental to diagnosing Cushing's disease, Addison's disease, congenital adrenal hyperplasia, and various forms of adrenal insufficiency. As a peptide hormone, ACTH has a very short plasma half-life of approximately 15 minutes, necessitating careful timing during diagnostic procedures.
Who Should Consider ACTH (Cosyntropin/Cortrosyn)
- Patients undergoing evaluation for adrenal insufficiency
- Infants with infantile spasms (West syndrome)
- Multiple sclerosis patients experiencing acute exacerbations
- Nephrotic syndrome patients refractory to conventional therapy
- Rheumatology patients with acute flares of inflammatory conditions
How ACTH (Cosyntropin/Cortrosyn) Works
ACTH exerts its primary biological effects by binding to the melanocortin-2 receptor (MC2R), a G protein-coupled receptor expressed predominantly on cells of the adrenal cortex zona fasciculata and zona reticularis. MC2R is unique among melanocortin receptors in that ACTH is its only known endogenous agonist, and it requires the melanocortin-2 receptor accessory protein (MRAP1) for proper cell-surface expression and ligand binding. Without MRAP1, MC2R is retained and degraded in the endoplasmic reticulum. Upon ACTH binding, MC2R activates the stimulatory G-protein (Gs), which in turn activates adenylyl cyclase, increasing intracellular cyclic AMP (cAMP) levels. Elevated cAMP activates protein kinase A (PKA), which phosphorylates key enzymes in the steroidogenic pathway, most notably stimulating the rate-limiting conversion of cholesterol to pregnenolone by the steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage enzyme (CYP11A1). This cascade ultimately drives production of cortisol, corticosterone, and adrenal androgens. Beyond steroidogenesis, ACTH and its related melanocortin peptides activate MC1R, MC3R, MC4R, and MC5R on various immune cells including macrophages, lymphocytes, and dendritic cells. This accounts for the direct anti-inflammatory and immunomodulatory effects observed with repository corticotropin therapy, independent of adrenal cortisol production. These non-steroidogenic effects include suppression of NF-kB signaling, reduction of pro-inflammatory cytokine release, and modulation of B-cell antibody production.
What to Expect
Diagnostic: Cortisol begins rising within minutes of cosyntropin injection. Initial adrenal response measurable by 30 minutes post-dose.
Diagnostic: Peak cortisol response typically reached at 30-60 minutes. Normal response is cortisol ≥18-20 mcg/dL confirming adequate adrenal reserve.
Therapeutic (Acthar Gel): Clinical improvement in infantile spasms and MS exacerbations typically observed within the first 1-2 weeks of daily dosing.
Therapeutic: Full treatment effect realized. Begin tapering protocols to prevent adrenal suppression and rebound symptoms.
Dosing Protocol
| Level | Dose / Injection | Frequency |
|---|---|---|
| Beginner | 250mcg | Single dose |
| Moderate | 250mcg | Single dose |
| Aggressive | 250mcg | Single dose |
Note: ACTH (adrenocorticotropic hormone) is a 39-amino-acid peptide produced by the anterior pituitary gland. Cosyntropin is a synthetic analog consisting of the first 24 amino acids of native ACTH, which retains full biological activity at the adrenal cortex. It is FDA-approved exclusively as a diagnostic agent for screening adrenocortical insufficiency (Addison's disease, secondary adrenal insufficiency). The standard diagnostic dose is 0.25 mg (250 mcg) administered IV or IM, with cortisol measured at baseline and 30-60 minutes post-injection. H.P. Acthar Gel, a repository corticotropin preparation, is separately approved for therapeutic use in infantile spasms, MS exacerbations, nephrotic syndrome, and other inflammatory conditions. Cosyntropin vials should be reconstituted with 1 mL normal saline and used immediately per manufacturer labeling.
How to Inject ACTH (Cosyntropin/Cortrosyn)
For diagnostic use (cosyntropin stimulation test): Reconstitute one vial of cosyntropin (0.25 mg) with 1 mL of 0.9% sodium chloride injection. Administer the full 0.25 mg dose via IV push over 2 minutes or as a single IM injection. Draw baseline serum cortisol immediately before injection, then collect follow-up samples at 30 and 60 minutes post-injection. Normal response is cortisol rise to ≥18-20 mcg/dL. Discontinue glucocorticoids and spironolactone on the day of testing. Stop estrogen-containing drugs 4-6 weeks prior to testing as they increase cortisol binding globulin levels. For therapeutic use (Acthar Gel), administer IM or SC per condition-specific dosing: infantile spasms typically 150 U/m²/day divided BID for 2 weeks with 2-week taper; MS exacerbations 80-120 units daily for 2-3 weeks. Rotate injection sites for repeated therapeutic dosing.
Cycling Protocol
Cosyntropin is primarily used as a single diagnostic dose rather than cycled therapy. For therapeutic corticotropin (Acthar Gel), typical protocols are 2-3 weeks for MS exacerbations with gradual taper, or individualized schedules for chronic conditions. Tapering is mandatory after courses exceeding one week to prevent adrenal crisis from HPA axis suppression.
Pharmacokinetics
Source: FDA label and clinical pharmacology references; cosyntropin plasma half-life ~15 minutes
Loading the interactive decay curve.
Side Effects
When used as a single diagnostic dose (cosyntropin 0.25 mg), adverse effects are uncommon but may include hypersensitivity reactions, anaphylaxis (rare), bradycardia, tachycardia, transient hypertension, peripheral edema, and injection-site rash. Chronic therapeutic use of repository corticotropin (Acthar Gel) carries more significant risks similar to exogenous glucocorticoid therapy, including fluid retention, hyperglycemia, weight gain, hypokalemia, increased infection susceptibility, osteoporosis, cataracts, peptic ulceration, adrenal suppression with HPA axis dysfunction, mood disturbances, skin hyperpigmentation from melanocortin receptor activation, and neutralizing antibody formation with prolonged administration. Abrupt discontinuation after chronic use may precipitate adrenal crisis requiring gradual tapering protocols.
Contraindications
- Primary adrenocortical insufficiency (adrenals cannot respond to ACTH stimulation)
- Systemic fungal infections or active untreated infections
- Scleroderma (manufacturer contraindication for corticotropin therapy)
- Hypersensitivity to cosyntropin or any component of the formulation
- Uncontrolled hypertension or congestive heart failure (for therapeutic corticotropin)
- Pregnancy — corticotropin has embryocidal effects in animal studies; use only if potential benefit justifies risk
- Breastfeeding — ACTH-stimulated cortisol elevation may affect nursing infants; use with caution
Drug Interactions
- Glucocorticoids and spironolactone: Falsely elevate cortisol levels during diagnostic testing; discontinue on day of test
- Estrogen-containing drugs: Increase cortisol binding globulin levels; stop 4-6 weeks before cosyntropin testing
- Amphotericin B: Enhanced risk of severe hypokalemia when combined with corticotropin therapy
- Quinolone antibiotics: Increased risk of tendon rupture when co-administered with corticotropin
- Live vaccines: Contraindicated during therapeutic corticotropin use due to immunosuppressive effects
Storage & Stability
Molecular Profile
Related Peptides
References
- Cosyntropin as a diagnostic agent in the screening of patients for adrenocortical insufficiencyReview
- ACTH receptor (MC2R) specificity: what do we know about underlying molecular mechanisms?Review
- Cortrosyn (cosyntropin) FDA Prescribing InformationFDA Label
- Acthar Gel Treatment for Patients with Autoimmune and Inflammatory DiseasesReview