Cosyntropin: FDA-approved adrenal function test (tetracosactide)

What this is

Cosyntropin (also called tetracosactide or tetracosactrin) is a synthetic peptide comprising the first 24 amino acids of adrenocorticotropic hormone (ACTH) — the pituitary hormone that tells the adrenal glands to make cortisol. In clinical medicine it serves almost exclusively as a diagnostic tool: when injected, it triggers a measurable cortisol response, allowing physicians to test whether a patient's adrenal glands are working normally. Two prescription formulations exist in this family: cosyntropin itself, used for diagnostic testing, and repository corticotropin injection (Acthar Gel), a long-acting preparation of the full-length 39-residue porcine ACTH used therapeutically for a narrow set of inflammatory and neurological conditions. The stored sequence here is the full 39-residue ACTH(1-39) backbone; cosyntropin is the 1-24 N-terminal fragment, which retains full biological activity at MC2R because all receptor-binding determinants sit within that region.

History

ACTH was isolated in the early 1950s by groups working on pituitary chemistry, with Choh Hao Li at UC Berkeley among the key contributors who characterized its adrenocorticotropic activity and purified the full sequence. Its clinical career began almost immediately: Philip Hench at the Mayo Clinic had already demonstrated in 1948 that cortisone produced dramatic short-term improvement in rheumatoid arthritis, and ACTH became a companion tool — used either to assess adrenal function or to drive endogenous cortisol release. The synthetic 1-24 fragment, cosyntropin, was developed in the 1960s once the biologically active N-terminus was characterized. It displaced full-length ACTH for diagnostic use because it was cheaper, less immunogenic, and functionally equivalent at the adrenal receptor. The long-acting repository corticotropin injection gained FDA approval for a broad range of conditions during the 1950s under regulatory standards that preceded modern clinical-trial requirements. Its commercial history through the 2000s and 2010s — price escalation that made a single vial among the most expensive drugs in US pharmacy benefits — became a notable case study in legacy-drug pricing. Clinically, the cosyntropin stimulation test has been the reference standard for evaluating adrenal reserve for decades.

What it does

Cosyntropin stimulates the adrenal cortex to release cortisol. When administered as a diagnostic test, it provides a controlled adrenal stimulus and the cortisol response (measured in blood at 30 and 60 minutes) tells clinicians whether the adrenal glands have normal reserve — the basis of the standard cosyntropin stimulation test for primary and secondary adrenal insufficiency. In its therapeutic form (repository corticotropin injection), sustained adrenal stimulation over days is used to drive cortisol release for anti-inflammatory and immunosuppressive effect. Because ACTH shares its first 13 residues with α-melanocyte-stimulating hormone and has some affinity for other melanocortin receptors, a partially separate anti-inflammatory mechanism via MC1R and MC3R on immune cells has been hypothesized — particularly as an argument for why repository corticotropin might differ from giving a synthetic glucocorticoid directly — though the clinical significance of that mechanism at therapeutic doses remains unresolved (Yeo and colleagues 2021).

Evidence

• Human: Strong for the diagnostic use: the cosyntropin stimulation test has been the clinical reference standard for evaluating adrenal reserve for decades, with extensive validation in primary and secondary adrenal insufficiency. For therapeutic use, repository corticotropin injection (Acthar Gel) has randomized controlled trial support for infantile spasms (West syndrome), where ACTH is a recognized first-line treatment. Evidence for other approved indications — acute multiple sclerosis exacerbations, nephrotic syndrome, and several rheumatologic conditions — ranges from historical case series to mixed RCTs.
• Animal: Extensive and largely dated. ACTH physiology was characterized across thousands of animal experiments from the 1950s through the 1980s. More recent preclinical work has focused on MC1R and MC3R anti-inflammatory signaling rather than cortisol-mediated effects.
• In vitro: MC2R pharmacology, cAMP/PKA/StAR steroidogenic signaling, and adrenocortical biochemistry are among the best-characterized pathways in endocrinology (Yeo and colleagues 2021).

Myths and misconceptions

• "ACTH is a biohacker peptide for cortisol support, energy, or anti-aging" — No. Sustained supraphysiologic ACTH raises cortisol, which is catabolic, immunosuppressive, and worsens body composition, glucose tolerance, and sleep. ACTH does not appear on reputable compounded-peptide formularies and has no self-administered wellness use case.

• "Acthar Gel works differently from prednisone because it is 'natural'" — Most of repository corticotropin's clinical effect in inflammatory disease is explained by cortisol release through MC2R activation, pharmacologically similar to giving the equivalent glucocorticoid directly. A hypothesized additional contribution from MC1R/MC3R signaling on leukocytes exists in preclinical work, but whether this produces clinically distinguishable outcomes at therapeutic doses is unresolved, and rigorous head-to-head comparisons with synthetic glucocorticoids are lacking for most approved indications.

• "A normal cosyntropin stimulation test rules out all adrenal insufficiency" — The standard 250 mcg test is sensitive for primary (adrenal) insufficiency but can miss partial secondary (pituitary-origin) insufficiency, because it supplies a supraphysiologic stimulus that can drive a normal cortisol response even when endogenous ACTH secretion is impaired. The low-dose 1 mcg test, insulin tolerance test, or ACTH measurement may be needed to characterize partial central insufficiency. A normal result narrows the differential but does not close it in every clinical context.

• "Cosyntropin is a different drug from ACTH" — Cosyntropin is the first 24 amino acids of ACTH. It binds the same receptor (MC2R) and triggers the same adrenal response. The truncation removes the C-terminal region, which is the more immunogenic portion, while retaining the N-terminal sequence responsible for MC2R binding and adrenal stimulation.

• "ACTH is safe for long-term use because it is an endogenous hormone" — Chronic supraphysiologic ACTH exposure produces the full Cushingoid side-effect profile — central weight gain, skin thinning, osteoporosis, hyperglycemia, hypertension, mood disturbance, and adrenal suppression on withdrawal. Endogenous origin does not equal favorable chronic-exposure biology; it is the sustained cortisol elevation that drives toxicity, and that dose-response relationship is the same whether the driver is exogenous ACTH or a synthetic glucocorticoid.

Known effects

• Adrenal cortisol stimulation (diagnostic use) — FDA-approved; the cosyntropin stimulation test is the clinical standard for adrenal reserve assessment
• Infantile spasms (West syndrome) treatment — Strong evidence; ACTH is a recognized first-line therapy with RCT support
• Acute multiple sclerosis relapses — Moderate evidence; FDA-approved for repository corticotropin; comparisons with high-dose synthetic glucocorticoids are incomplete
• Nephrotic syndrome and steroid-responsive inflammatory conditions — Moderate evidence; approved for repository corticotropin; head-to-head data vs. synthetic steroids are limited

Safety signals

Safety signals for cosyntropin in single-dose diagnostic use are minimal — the brief adrenal stimulus carries little toxicity risk beyond rare hypersensitivity. For therapeutic repository corticotropin (multi-day or multi-week courses), the safety profile mirrors that of systemic glucocorticoid therapy, because the mechanism is cortisol-mediated: fluid retention, hyperglycemia, hypertension, hypokalemia, Cushingoid features with prolonged use, mood changes, and injection-site reactions have been documented. Hypersensitivity reactions including anaphylaxis have been reported, particularly with the animal-derived Acthar Gel formulation. Risk of HPA-axis suppression is present after prolonged courses, analogous to withdrawal from systemic glucocorticoids, though uncommon after short therapeutic courses.

Regulatory status

• US: Cosyntropin (Cortrosyn) and repository corticotropin injection (Acthar Gel) are FDA-approved prescription medications. Cosyntropin is approved for diagnostic use in suspected adrenal insufficiency. Acthar Gel holds FDA approval for a range of conditions including infantile spasms, acute MS exacerbations, nephrotic syndrome, and several rheumatologic conditions; most of these approvals date to the 1950s.
• International: Cosyntropin is available internationally under the names Synacthen and tetracosactide and is an approved prescription agent across the EU, UK, Canada, Australia, Japan, and most major markets. Prescription-only status is universal in developed markets.
• WADA: Corticotropins are prohibited under WADA's prohibited list. Tetracosactide (cosyntropin) is named specifically in WADA technical documents. Therapeutic use exemptions are required for athletes with documented medical need.

Mechanism

Cosyntropin binds the melanocortin-2 receptor (MC2R), a Gs-coupled GPCR expressed predominantly on cells of the adrenal cortex zona fasciculata. MC2R is uniquely selective for ACTH among the five melanocortin receptors; it does not respond to the MSH peptides that activate MC1R, MC3R, MC4R, and MC5R (Yeo and colleagues 2021). Receptor activation raises intracellular cAMP, which activates protein kinase A; PKA phosphorylates and activates StAR (steroidogenic acute regulatory protein), the rate-limiting transporter that shuttles cholesterol into the mitochondria to initiate steroidogenesis. Downstream, this drives synthesis and release of cortisol from the zona fasciculata and, to a lesser extent, aldosterone (zona glomerulosa) and adrenal androgens (zona reticularis). Chronic ACTH stimulation produces adrenocortical hyperplasia. Because ACTH shares its N-terminal 13-residue core sequence with α-melanocyte-stimulating hormone, it retains modest affinity for MC1R, MC3R, and MC5R, which are expressed on immune cells and elsewhere; this has fueled the hypothesis that repository corticotropin may carry an anti-inflammatory effect partially independent of cortisol. The full 39-residue ACTH sequence is shown here; cosyntropin encompasses only residues 1-24 of that sequence but retains full MC2R binding efficacy.

Open questions

• Whether therapeutic repository corticotropin's hypothesized melanocortin-receptor-mediated anti-inflammatory effect produces clinically meaningful benefit beyond equivalent glucocorticoid exposure — the central unresolved question for most non-infantile-spasms indications
• Optimal cortisol cut-off thresholds for the cosyntropin stimulation test on modern immunoassay and LC-MS/MS platforms, where historical thresholds derived from older polyclonal assays may require recalibration
• Comparative effectiveness of ACTH versus high-dose oral prednisolone in infantile spasms — both have individual RCT support, but head-to-head long-term developmental-outcome data remain incomplete
• Long-term endocrine and developmental consequences of early-life high-dose ACTH exposure in infantile-spasms cohorts
• Whether selective MC1R/MC3R agonists could capture any anti-inflammatory benefit of repository corticotropin while avoiding the glucocorticoid-mediated toxicity profile

Related peptides

• α-MSH — the 13-residue N-terminal ACTH fragment (Ac-SYSMEHFRWGKPV-NH₂) that activates MC1R for pigmentation and anti-inflammatory effects; shares the N-terminal core sequence with cosyntropin but diverges in receptor selectivity
• See also: oxytocin, gonadorelin — other anterior pituitary–related peptides used in clinical medicine