Cosyntropin
Hormonal / DiagnosticAlso known as: Cortrosyn, Synacthen, Tetracosactide
Mechanism
A synthetic version of the first 24 amino acids of ACTH (the hormone that tells your adrenal glands to make cortisol). Used primarily as a diagnostic test — inject it and measure cortisol levels 30-60 minutes later to check if the adrenal glands are working properly. In Europe, a depot form (Synacthen Depot) is also used therapeutically for conditions like infantile spasms and multiple sclerosis flares.
Technical detail
Synthetic ACTH(1-24) retaining full biological activity of native ACTH(1-39) — the first 24 residues contain the entire pharmacophore. Binds melanocortin-2 receptor (MC2R) on adrenocortical zona fasciculata cells with MRAP accessory protein. Activates Gs/cAMP/PKA cascade, stimulating cholesterol uptake (via LDLR and SR-BI), StAR protein expression (rate-limiting step), and steroidogenic enzyme transcription (CYP11A1, CYP17A1, CYP21A2, CYP11B1). Cortisol production peaks at 30-60 min post-injection. Standard test: 250 mcg IV/IM; low-dose test: 1 mcg IV. Normal response: cortisol >18-20 mcg/dL at 30-60 min. Synacthen Depot: zinc phosphate complex formulation for sustained release (therapeutic use in infantile spasms at 0.25-0.5 mg IM q48h, MS relapses). Half-life ~15 min (immediate release).
Effects
**Endocrine — HPA Axis (Tier 1 — Human Clinical / Diagnostic):** Cosyntropin is a synthetic 24-amino-acid peptide corresponding to the first 24 residues of endogenous ACTH (39 amino acids). It retains full biological activity at the ACTH receptor (MC2R) on adrenal cortical cells, stimulating cortisol synthesis and release. The cosyntropin stimulation test is the gold standard for diagnosing adrenal insufficiency. **Adrenal Cortex (Tier 1 — Human Clinical / Diagnostic):** Upon IV or IM administration, cosyntropin stimulates the zona fasciculata to produce cortisol. A normal response (cortisol ≥18–20 mcg/dL at 30 or 60 minutes) indicates intact adrenal reserve. A blunted response indicates primary adrenal insufficiency (Addison disease) or prolonged secondary adrenal insufficiency (chronic ACTH suppression leading to adrenal atrophy). **Adrenal Androgens (Tier 2 — Human Clinical):** Cosyntropin also stimulates adrenal androgen production (DHEA, DHEA-S, androstenedione). High-dose cosyntropin stimulation followed by 17-hydroxyprogesterone measurement is used to diagnose non-classic congenital adrenal hyperplasia (21-hydroxylase deficiency). **Mineralocorticoid (Tier 2 — Human Clinical):** Stimulates aldosterone secretion from zona glomerulosa. Used in evaluation of primary aldosteronism and aldosterone biosynthetic defects.
Practitioner Guide
**APPROVED INDICATION:** • Diagnostic agent for adrenal cortical function testing (ACTH stimulation test / cosyntropin stimulation test). **STANDARD-DOSE COSYNTROPIN STIMULATION TEST:** • Dose: 250 mcg IV or IM (standard dose). • Protocol: Draw baseline cortisol → administer cosyntropin → draw cortisol at 30 minutes and 60 minutes. • Normal response: Cortisol ≥18–20 mcg/dL at 30 or 60 minutes (exact cutoff varies by assay; many labs now use 16–18 mcg/dL with newer immunoassays). • Interpretation: - Normal response: Rules out primary adrenal insufficiency and chronic secondary adrenal insufficiency. - Blunted response: Indicates adrenal insufficiency. Cannot distinguish primary from secondary — requires additional testing (ACTH level, imaging). **LOW-DOSE COSYNTROPIN TEST:** • Dose: 1 mcg IV (diluted from 250 mcg vial — requires pharmacy preparation). • Rationale: More sensitive for detecting mild/early secondary adrenal insufficiency (e.g., from recent corticosteroid withdrawal, pituitary surgery). The standard 250 mcg dose may overcome mild adrenal atrophy through supraphysiological ACTH stimulation, giving a false-normal result. • Protocol: Same blood draw timing as standard dose. • Clinical pearl: The low-dose test is technically more challenging (dilution required, IV administration mandatory) but is more sensitive. Many endocrinologists prefer it for suspected secondary AI, particularly post-pituitary surgery or post-steroid taper. **17-OHP STIMULATION TEST (Congenital Adrenal Hyperplasia):** • Dose: 250 mcg IV. • Protocol: Draw baseline 17-hydroxyprogesterone → administer cosyntropin → draw 17-OHP at 30 and 60 minutes. • Stimulated 17-OHP >10 ng/mL (>30 nmol/L) is diagnostic of non-classic CAH (21-hydroxylase deficiency). • Best performed in the early morning (follicular phase in women) to minimize confounding by physiological progesterone. **CLINICAL PEARLS:** • Timing matters: The standard-dose test can be done at any time of day (the supraphysiological ACTH dose overwhelms diurnal variation). The low-dose test should be done in the morning for maximal sensitivity. • Recent exogenous glucocorticoid use: If the patient has been on supraphysiological steroids for >3 weeks, adrenal atrophy may not have developed yet — a normal cosyntropin test does not exclude future adrenal insufficiency after steroid discontinuation. Repeat testing after appropriate washout. • Cosyntropin is NOT a treatment for adrenal insufficiency — it is a diagnostic tool. Treatment for adrenal insufficiency is hydrocortisone or other corticosteroid replacement. • Storage: Refrigerate. Reconstituted solution is stable for 12 hours at room temperature.
Research Summary
**Tier 1 (Human Clinical Evidence):** • The cosyntropin stimulation test is the gold standard diagnostic test for adrenal insufficiency, supported by decades of clinical use and validation studies. • Standard-dose sensitivity/specificity for primary adrenal insufficiency: >95%/>90%. • Low-dose test sensitivity for secondary adrenal insufficiency: 80–90% (superior to standard dose for early/mild disease). • Diagnostic thresholds have been debated as cortisol assay methodology evolves — newer immunoassays give lower values than older RIA methods, prompting some centers to lower cutoffs to 16 mcg/dL. **Tier 2 (Strong Preclinical + Mechanistic):** • MC2R (ACTH receptor) pharmacology is well-characterized. Cosyntropin (ACTH 1–24) has full agonist activity equivalent to full-length ACTH (1–39) at the MC2R. • The structure-activity relationship showing that amino acids 1–24 are sufficient for full biological activity is foundational peptide biochemistry. **Tier 3 (Emerging / Theoretical):** • Investigation of cosyntropin in adrenal function evaluation in critical illness (ICU patients) — the appropriate cortisol response threshold in critically ill patients remains debated. • Potential standardization challenges as cortisol assays transition to LC-MS/MS methodology.