Corticorelin and Tetracosactide

Sexual health, hormones & signalling

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Note on this profile. Both compounds are approved prescription medicines used mainly as single-dose diagnostic tests of the adrenal axis in hospitals and clinics. Tetracosactide depot is also a licensed treatment in some countries. They are not research-only compounds and have no self-directed use. This page explains the published science.

Summary

Class: Corticorelin: synthetic 41-amino-acid copy of corticotropin-releasing hormone (ovine sequence in Acthrel; human sequence in Xerecept). Tetracosactide/cosyntropin: synthetic 24-amino-acid N-terminal fragment of ACTH, which carries ACTH's full steroidogenic activity
Mechanism: CRH stimulates pituitary corticotrophs to release ACTH; ACTH(1-24) stimulates the adrenal cortex (MC2 receptor) to release cortisol — each is used to test the next link in the chain
Routes studied: Intravenous (both); intramuscular (cosyntropin, Synacthen Depot); CRH also intrathecal/intraventricular in research
Half-life: Corticorelin ovine: biphasic, ~11 min then ~73 min †; cosyntropin: ~15 minutes, with peak cortisol at 30–60 minutes; Synacthen Depot (zinc complex) acts over ~24–36 hours
Storage: Corticorelin: refrigerated lyophilised vial, use within hours of reconstitution. Cosyntropin: room temperature (lyophilised) or refrigerated (solution). Synacthen Depot: refrigerate
Regulatory status: Cosyntropin/tetracosactide approved in US, EU, UK, AU, ZA; corticorelin approved in the US (availability limited) †

Doses are as reported in studies or by the community — never recommendations.

1What it is

These two peptides are the hormones of the stress axis, made synthetically for diagnosis. CRH is released by the hypothalamus; it tells the pituitary to make ACTH; ACTH tells the adrenal glands to make cortisol. A clinician who suspects the system is failing (adrenal insufficiency) or over-active (Cushing's syndrome) can inject one of these hormones and measure what comes out the other end.

Tetracosactide (called cosyntropin in the US) is the first 24 amino acids of the 39-amino-acid ACTH molecule — the part that does the work, minus the C-terminal portion responsible for most immunogenicity. The 250 µg "short Synacthen test" has been the standard test for adrenal insufficiency since the 1960s. A slow-release zinc-complex depot is also licensed in Europe, the UK and Australia as a treatment, mainly for infantile spasms and some inflammatory conditions, taking the role that natural ACTH gel (Acthar, a different product) plays in the US.

Corticorelin is CRH itself. The sheep sequence (which differs by 7 amino acids and lasts longer in human blood) was approved in the US in 1996 as Acthrel for distinguishing pituitary from ectopic sources of excess ACTH in Cushing's syndrome, often during sampling of blood from the veins draining the pituitary. Human-sequence CRH (Xerecept) has been studied as a treatment for brain-tumour swelling. Supply of Acthrel has been intermittent and some centres now use desmopressin as a substitute stimulus †.

2How it's thought to work

CRH. binds CRH-R1 receptors on pituitary corticotrophs, raising cyclic AMP and releasing stored ACTH within minutes. Pituitary ACTH-secreting tumours usually still respond to CRH; ectopic tumours (e.g. lung carcinoids) usually do not — the logic of the CRH test. In the brain, CRH also drives anxiety and arousal circuits, which is why antagonists were pursued for depression.

ACTH(1-24). binds the MC2 receptor on adrenal cortical cells, stimulating cortisol (and some aldosterone and adrenal androgen) release within minutes. A healthy adrenal roughly doubles cortisol in half an hour; an atrophied or destroyed adrenal cannot. The depot's therapeutic effect in infantile spasms is thought to involve both cortisol and direct central actions of ACTH on melanocortin receptors.

Two probes of one axis, entering it a step apart. Corticorelin is CRH and acts on the pituitary to release ACTH; tetracosactide is the first 24 amino acids of ACTH and acts directly on the adrenal cortex. Comparing the cortisol response to each shows where in the axis a failure sits.Schematic — not to scale

3What the research shows

Graded A (diagnostic accuracy)

Short cosyntropin test for adrenal insufficiency

A systematic review and meta-analysis of 30 studies found the 250 µg test has good accuracy for primary adrenal insufficiency and moderate accuracy for secondary (pituitary) insufficiency, where a recently failed pituitary can leave the adrenal still responsive (Ospina 2016, J Clin Endocrinol Metab). The traditional cut-off of a 30- or 60-minute cortisol ≥18 µg/dL (500 nmol/L) is being revised downward (to roughly 14–15 µg/dL) for newer, more specific immunoassays and mass spectrometry (Javorsky 2021, J Endocr Soc †). The 1 µg low-dose test is more sensitive for mild secondary insufficiency in some studies but technically fiddly (dilution errors) and not clearly superior in meta-analysis. [1]

Graded A (diagnostic accuracy)

CRH test and inferior petrosal sinus sampling in Cushing's syndrome

Sampling ACTH from the petrosal sinuses before and after CRH gave a sensitivity and specificity approaching 100% for pituitary Cushing's disease in the NIH series of 281 patients (Oldfield 1991, NEJM). The peripheral CRH test alone (ACTH rise ≥35–50% or cortisol rise ≥20%) distinguishes pituitary from ectopic sources with sensitivity around 85–90% and high specificity (Nieman 1993, Ann Intern Med; Newell-Price 2002, Clin Endocrinol). The dexamethasone-suppressed CRH test was proposed to separate Cushing's from pseudo-Cushing's states, with later studies showing lower accuracy than first reported. [2][3]

Tetracosactide depot in infantile spasms

UK trials (UKISS) randomised infants to hormonal treatment (tetracosactide depot or prednisolone) versus vigabatrin: spasm cessation at 14 days was higher with hormonal treatment (73% vs 54%) (Lux 2004, Lancet). The ICISS trial found adding vigabatrin to hormonal treatment improved short-term spasm control without changing developmental outcome (O'Callaghan 2017, Lancet Neurol). Hormonal therapy (ACTH or prednisolone) is first-line in most guidelines; which steroid route is best remains debated. [4][5]

Tetracosactide depot in multiple sclerosis relapse, nephrotic syndrome, gout

Older trials support ACTH preparations in MS relapse, roughly equivalent to high-dose methylprednisolone; small series in membranous nephropathy and refractory gout. Largely superseded by corticosteroids.

Graded A/B

Human CRH (Xerecept) for peritumoural brain oedema

Phase 2–3 trials in patients with brain tumours tested whether CRH could reduce dexamethasone requirements with fewer steroid side effects; results were mixed and the programme has not led to approval †.

4Reported side effects and interactions

Literature-reported

Literature — corticorelin. transient facial flushing (the most common, in up to ~20%), a metallic taste, brief drop in blood pressure and tachycardia at higher doses or rapid injection, shortness of breath; rare anaphylactoid reactions. Cosyntropin/tetracosactide (single dose): very well tolerated; rare hypersensitivity (more common with natural ACTH than with the 1-24 fragment), flushing, nausea; cortisol rise can transiently raise glucose. Synacthen Depot (therapeutic courses): all the effects of corticosteroid excess — hypertension, hyperglycaemia, irritability, infection risk, hypokalaemia, weight gain, adrenal suppression on withdrawal, in infants hypertrophic cardiomyopathy and growth slowing; hypersensitivity reactions are more frequent than with single diagnostic doses.

Community-reported

essentially none documented.

Theoretical. CRH given repeatedly could in principle drive anxiety-like effects; not relevant to single diagnostic doses.

Interactions. glucocorticoids (including hydrocortisone, prednisolone and inhaled or topical steroids) blunt or confound both tests and must be timed or paused per protocol — the main practical interaction; oestrogens raise cortisol-binding globulin and total cortisol, which can give falsely reassuring results; spironolactone cross-reacts in some cortisol assays †.

Markers researchers commonly monitor

These compounds are the test; the markers are the readout:

Marker	Why it's watched
Serum cortisol at 0, 30 and 60 minutes	the short Synacthen test result; interpret against assay-specific cut-offs.
Plasma ACTH at baseline	distinguishes primary (high ACTH) from secondary (low/normal ACTH) adrenal insufficiency alongside the cosyntropin test.
ACTH and cortisol at timed intervals after CRH	percentage rise defines a positive CRH test; central-to-peripheral ACTH ratio in petrosal sinus sampling.
Renin, aldosterone, electrolytes	mineralocorticoid axis in suspected primary adrenal failure.
Blood pressure, glucose, potassium, growth and echocardiography (infants)	during therapeutic depot courses.
Morning cortisol after stopping depot courses	adrenal suppression on withdrawal.

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5Reconstitution and handling

Corticorelin: 100 µg vial with the supplied 2 mL and given IV over 30 seconds, with timed blood samples (typically −5, 0, 15, 30, 45, 60 minutes). Cosyntropin: 250 µg vial, reconstituted with 1 mL saline (or supplied as solution), IV bolus or IM, with cortisol at 0, 30 and (often) 60 minutes. Synacthen Depot: 1 mg/mL suspension, shake before deep IM injection. All are clinician-administered; the calculator is not applicable.

6Commonly studied alongside

Dexamethasone (suppression tests, combined dexamethasone-CRH test), desmopressin (#107 — used as an alternative corticotroph stimulus when CRH is unavailable), metyrapone and insulin (alternative stress-axis tests), hydrocortisone replacement, prednisolone and vigabatrin (infantile spasms), ACTH gel (natural ACTH 1-39).

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Cosyntropin (Cortrosyn and generics) FDA-approved as a diagnostic for adrenocortical insufficiency. Corticorelin ovine triflutate (Acthrel) FDA-approved 1996 for differentiating pituitary and ectopic ACTH-dependent Cushing's syndrome; supply intermittent †. Human CRH (Xerecept) investigational, orphan designation
European Union	Tetracosactide (Synacthen) and Synacthen Depot nationally authorised in many states for diagnosis and, for the depot, selected therapeutic indications; corticorelin (human) authorised in some countries as a diagnostic (e.g. Germany, CRH Ferring) †
United Kingdom	Synacthen 250 µg (diagnostic) and Synacthen Depot 1 mg (therapeutic: infantile spasms off-label but standard; licensed inflammatory indications) MHRA-licensed; corticorelin available only as an unlicensed import
Australia	Synacthen and Synacthen Depot TGA-registered (supply disruptions reported in recent years †); corticorelin not registered
South Africa	Synacthen registered with SAHPRA †; corticorelin not registered
Sport (WADA)	Prohibited under S2: corticotrophins and their releasing factors are named (e.g. corticorelin, tetracosactide); diagnostic use requires a Therapeutic Use Exemption

8Open questions

What the correct cortisol cut-off is for modern assays, and whether the 1 µg test should replace the 250 µg test for secondary insufficiency.
Whether CRH testing retains a role now that desmopressin stimulation and high-resolution pituitary imaging are widely used.
The optimal hormonal regimen (ACTH depot versus oral prednisolone, dose and duration) in infantile spasms.

9References

1Ospina NS et al. (2016). ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. PubMed · DOI
2Oldfield EH et al. (1991). Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome. NEJM. PubMed · DOI
3Nieman LK et al. (1993). A simplified morning ovine corticotropin-releasing hormone stimulation test for the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab. [verify journal] PubMed · DOI
4Lux AL et al. (2004). The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet. PubMed · DOI
5O'Callaghan FJK et al. (2017). Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial. Lancet Neurol. PubMed
6Bornstein SR et al. (2016). Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. PubMed · DOI
7Acthrel (corticorelin ovine triflutate) and Cortrosyn (cosyntropin) US prescribing information; Synacthen Depot UK Summary of Product Characteristics (current). PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

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11Page history

31 Oct 2026Profile published — awaiting medical review

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