Adrenocorticotropic Hormone (ACTH)
Also known as: ACTH, Corticotropin, Cosyntropin, tetracosactide, adrenocorticotropin
Endogenous anterior pituitary peptide hormone (39 amino acids); corticosteroid-stimulating agent; melanocortin receptor agonist; repository corticotropin inject
What it is
People with autoimmune conditions, infantile epilepsy, kidney disease, and acute gout attacks turn to ACTH-based therapies for rapid symptom control when standard treatments fail. As both an endogenous stress hormone and a licensed injectable drug, ACTH regulates cortisol production, calms immune flares, and remains a frontline treatment for infant seizure syndromes.
The scientific side
adrenocorticotropic hormone (ACTH) is a 39-amino-acid peptide produced by the anterior pituitary gland through proteolytic cleavage of the precursor proopiomelanocortin (POMC). As the central hormonal regulator of the hypothalamic-pituitary-adrenal (HPA) axis, ACTH exerts its primary biological effects by binding to the melanocortin 2 receptor (MC2R), a G protein-coupled receptor expressed principally on adrenocortical cells of the adrenal cortex. MC2R trafficking and signaling depend critically on the co-chaperone melanocortin receptor accessory protein (MRAP); mutations in either MC2R or MRAP abolish cortisol production and cause familial glucocorticoid deficiency. Receptor occupancy activates adenylyl cyclase through Gs-protein coupling, elevating intracellular cyclic AMP (cAMP) and activating protein kinase A (PKA). A cardinal downstream response is the acute induction of the Steroidogenic Acute Regulatory protein (StAR), which governs rate-limiting cholesterol transport across the outer to inner mitochondrial membrane — the first and obligatory step in glucocorticoid biosynthesis. PKA-dependent phosphorylation of StAR at serine 194/195 is required for full functional activation, enabling the flux of cholesterol substrate to CYP11A1 (cholesterol side-chain cleavage enzyme) within the mitochondrial matrix. This initiates the steroidogenic cascade producing cortisol in humans and corticosterone in rodents. Chronically elevated ACTH also stimulates aldosterone secretion acutely (while chronic exposure ultimately suppresses it), promotes adrenal cortical cell proliferation and hypertrophy, and regulates expression of multiple steroidogenic enzymes. Beyond adrenal steroidogenesis, ACTH acts through its POMC-derived structure at melanocortin receptors MC1R through MC5R in extra-adrenal tissues. Activation of MC5R on glomerular podocytes has been shown to interrupt the complement amplification loop in membranous nephropathy models, providing a direct anti-proteinuric mechanism independent of cortisol production. In the brain, ACTH and related melanocortin peptides exert neuroendocrine-immunomodulatory effects that appear to contribute to ACTH's efficacy in infantile epileptic spasms syndrome, a mechanism incompletely explained by cortisol elevation alone. Endoplasmic reticulum stress and the unfolded protein response have emerged as additional modulators of ACTH-stimulated glucocorticoid synthesis, potentially influencing inter-individual variation in HPA axis reactivity. ACTH's physiological effects are terminated by rapid proteolytic degradation, giving a plasma half-life of approximately 15 to 25 minutes for the native peptide.
Class: Endogenous anterior pituitary peptide hormone (39 amino acids); corticosteroid-stimulating agent; melanocortin receptor agonist; repository corticotropin injection (RCI) classified as a pituitary hormone / anti-inflammatory biological agent
Administration & storage
- Administration
- Intravenous (IV) injection — standard route for cosyntropin stimulation test (250 µg bolusresults equivalent to IM)Intramuscular (IM) injection — validated route for both diagnostic cosyntropin stimulation and therapeutic ACTH (e.g.1 mg IM for acute gout per PMID 23195793)Subcutaneous (SC) injection — route used for repository corticotropin injection (Acthar Gel) in therapeutic indications including MS relapsenephrotic syndromeand rheumatic diseaseContinuous IV infusion — used for cosyntropin during adrenal vein sampling procedures (50 µg/h per PMID 41202648)Intranasal administration — under investigation for non-invasive diagnostic testing (Nasacthin; STARLIT-3 trialPMID 41644156); not yet approved
- Storage
- Cosyntropin diagnostic vials (lyophilized powder): store at 2–8°C; once reconstituted, use immediately or within 24 hours if refrigerated. Repository corticotropin injection (Acthar Gel): refrigerate at 2–8°C; do not freeze; bring to room temperature before injection. Tetracosactide (Synacthen) multidose vials: refrigerate at 2–8°C after opening; stable for at least 3 weeks under refrigeration based on biological activity testing in dogs (PMID 42854896). Research-grade synthetic ACTH peptides: lyophilized peptides stable at -20°C for extended periods; once in solution, aliquot and freeze at -80°C to avoid repeated freeze-thaw degradation.
- Cautions
- Blood pressure monitoring is mandatory during ACTH treatment; sodium and water retention can cause or worsen hypertension, particularly in the first 1–2 weeks of therapy (PMID 24383115),Adrenal suppression risk on cessation: patients receiving therapeutic ACTH preparations must be tapered — abrupt discontinuation after prolonged use can precipitate adrenal insufficiency (PMID 42464759),ACTH can mask signs of infection and suppress immune defenses; opportunistic infections including Pneumocystis pneumonia and Cushing-related immunosuppression have been reported with therapeutic ACTH use (PMID 26833215),Hyperglycemia and new-onset or worsening diabetes mellitus: cortisol excess from ACTH-stimulated adrenal production impairs insulin sensitivity; glucose monitoring is recommended (PMID 24383115),ACTH administration is contraindicated in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, and in patients with recent surgery per prescribing information,Neonates and infants receiving ACTH for IESS require close monitoring for hypertension, irritability, electrolyte disturbances, and immunosuppression; brain MRI-measurable cerebral shrinkage has been described historically with high-dose ACTH in infants,WADA-prohibited in sport; athletes must obtain a Therapeutic Use Exemption (TUE) for legitimate adrenal function testing with cosyntropin (PMID 25219545),Anaphylaxis and hypersensitivity reactions have been reported with synthetic tetracosactide; allergy testing or cautious first-dose monitoring is recommended for patients with known peptide sensitivities
Legal & regulatory status
Repository corticotropin injection (RCI; H.P. Acthar Gel) holds FDA approval for multiple indications granted originally in 1952, including multiple sclerosis exacerbations, infantile spasms (West syndrome), nephrotic…
Tetracosactide (synthetic ACTH 1-24) and corticotropins are explicitly prohibited in competition and out-of-competition under WADA Prohibited List Section S2 (Peptide Hormones, Growth Factors, Related Substances, and…
Tetracosactide (Synacthen, Cortrosyn) is authorized by Health Canada as a diagnostic agent for adrenal function testing. The short Synacthen stimulation test using 250 µg IV or IM tetracosactide is a…
What it's studied for
- Infantile epileptic spasms syndrome (West syndrome) — spasm cessation and hypsarrhythmia resolution Established / Multiple Retrospective Cohort Studies and RCTs (first-line treatment)
- Multiple sclerosis relapse treatment — acceleration of recovery in patients who failed high-dose corticosteroids Randomized Controlled Trial (small, pilot-scale) / FDA-approved indication
- Nephrotic syndrome — reduction of proteinuria in idiopathic and lupus-related disease Multiple Observational Studies / Small Clinical Trials / FDA-approved indication
- Acute gout attack treatment — pain and inflammation resolution, especially in patients unable to use NSAIDs or colchicine Retrospective Cohort / Systematic Review / Clinical Practice Guideline Reference
- Adrenal function diagnostic testing (cosyntropin stimulation test) — gold standard for adrenal insufficiency diagnosis Established Clinical Standard / Multiple Diagnostic Validation Studies
- Primary aldosteronism subtype differentiation — adrenal vein sampling with cosyntropin stimulation Prospective Multicenter Cohort / Standard Procedural Practice
- Immune-mediated inflammatory and rheumatic diseases (rheumatoid arthritis, psoriatic arthritis, lupus) — anti-inflammatory treatment Observational / Open-label Trials / FDA-approved indications (evidence largely pre-modern RCT era)
Safety signals
- HPA axis suppression and adrenal insufficiency on therapeutic ACTH discontinuation
- Hypertension, sodium retention, and fluid overload with therapeutic ACTH use
- Hyperglycemia and worsening of diabetes mellitus
- Immunosuppression and increased risk of opportunistic infections
- Hypothalamic-pituitary-adrenal axis suppression from exogenous glucocorticoids detected only on cosyntropin testing — 'low-dose, not low-risk'
- Immunotherapy (checkpoint inhibitor)-induced ACTH deficiency — isolated ACTH deficiency (IAD) causing secondary adrenal insufficiency
- Thyroid function test perturbation with high-dose synthetic ACTH
- Iatrogenic Cushing syndrome features with prolonged or high-dose ACTH therapy
All studies (12)
Frequently asked
What is ACTH and why would a doctor prescribe it?
ACTH (adrenocorticotropic hormone) is a hormone your pituitary gland naturally produces to signal the adrenal glands to make cortisol, your body's primary stress and anti-inflammatory hormone. As a drug, it is prescribed for specific conditions including infantile seizure syndromes (West syndrome/infantile spasms), multiple sclerosis relapses that did not improve with steroids, kidney disease (nephrotic syndrome), acute gout attacks in patients who cannot take other treatments, and several autoimmune conditions. The injectable form (H.P. Acthar Gel) is FDA-approved in the US. A synthetic version called cosyntropin or tetracosactide is also used as a standard medical test to check whether your adrenal glands are working properly.
Is ACTH the same as a steroid like prednisone?
No — ACTH is not a steroid itself. It is a peptide hormone that signals your adrenal glands to produce your own cortisol (a naturally occurring corticosteroid). Prednisone and similar drugs replace cortisol directly from outside the body. With ACTH, your adrenal glands produce the cortisol in response to the ACTH signal. Additionally, ACTH is thought to have some anti-inflammatory effects in certain tissues (such as kidney podocytes) through separate pathways that do not involve cortisol at all, which may explain some of its effects in nephrotic syndrome.
How is ACTH given — is it a pill?
ACTH medications are not available as pills. The therapeutic form (Acthar Gel) is given by injection under the skin (subcutaneous) or into a muscle. The diagnostic form (cosyntropin/Synacthen) is given as an intravenous or intramuscular injection in a clinical setting. Researchers are studying an intranasal formulation called Nasacthin that would allow non-invasive adrenal testing, but this is not yet approved. ACTH proteins are broken down in the digestive tract and would not survive oral administration.
Can ACTH cause weight gain and other serious side effects?
Yes — because ACTH stimulates cortisol production, extended therapeutic use can cause many of the same side effects as long-term steroid therapy. These include fluid retention, high blood pressure, high blood sugar, increased infection risk, skin changes, and features of Cushing syndrome (weight gain concentrated around the face and abdomen, muscle weakness) with prolonged use. Stopping ACTH suddenly after extended therapy is dangerous because the adrenal glands need time to recover. Monitoring blood pressure, blood sugar, and electrolytes is standard during ACTH treatment. Your doctor will prescribe the lowest effective dose for the shortest necessary duration.
Is the cosyntropin (ACTH stimulation) test safe?
The cosyntropin (Synacthen) stimulation test is generally considered very safe and is the standard medical test for checking adrenal gland function. A single dose of synthetic ACTH (250 µg) is injected and blood cortisol levels are measured over 30–60 minutes. Side effects from this diagnostic test are rare and mild. Occasionally patients experience flushing or mild nausea. Rarely, allergic reactions can occur, particularly in people with known peptide allergies. The test is performed routinely in hospitals and outpatient endocrinology clinics worldwide.
Is ACTH banned in sports?
Yes — tetracosactide (synthetic ACTH) and corticotropins are explicitly prohibited by WADA (World Anti-Doping Agency) both in and out of competition under the prohibited peptide hormones category, because they stimulate adrenal cortisol production which may enhance recovery. A validated ELISA blood test has been developed specifically to detect synthetic ACTH in athletes. Athletes who require an adrenal function test for a legitimate medical reason should apply for a Therapeutic Use Exemption (TUE) through their national anti-doping organization before undergoing the test.