Corticorelin
Corticorelin ovine triflutate, Ovine corticotropin-releasing hormone, oCRH, Ovine CRF-41, Corticorelin human (hCRH), Corticotropin-releasing factor
Corticorelin is synthetic corticotropin-releasing hormone, the hypothalamic peptide that sits at the top of the stress axis and drives ACTH release from the pituitary. It is not a treatment for anything. It is a diagnostic agent, licensed in the United States since 1996 to distinguish pituitary Cushing's disease from ectopic ACTH secretion, and it is a central component of inferior petrosal sinus sampling.
Mechanism
Corticotropin-releasing hormone is a 41-residue peptide synthesised in the paraventricular nucleus of the hypothalamus and delivered to the anterior pituitary through the hypophyseal portal circulation. It binds the CRF1 receptor, a class B G-protein-coupled receptor on corticotroph cells, coupling through Gs to activate adenylyl cyclase, raise cyclic AMP and activate protein kinase A. This drives both the immediate exocytotic release of stored adrenocorticotropic hormone and, over a longer timescale, transcription of the pro-opiomelanocortin gene from which ACTH is cleaved. Released ACTH acts at the melanocortin-2 receptor on the adrenal cortex to stimulate steroidogenesis and cortisol output. A second receptor, CRF2, has a different distribution and different endogenous ligands (the urocortins) and mediates largely distinct autonomic and cardiovascular effects; corticorelin's diagnostic action is CRF1-mediated.
The diagnostic logic exploits a difference in feedback biology. Corticotroph adenomas in Cushing's disease retain functional CRF1 receptors and remain responsive to CRH, even though they have escaped normal glucocorticoid negative feedback. Ectopic ACTH-secreting tumours, typically bronchial carcinoids or small-cell lung cancers, generally do not respond. Administering corticorelin to a patient with confirmed ACTH-dependent hypercortisolism separates the two: the US approved labelling reports a mean peak ACTH rise of about 227% in Cushing's disease against roughly 15% for ectopic sources. Ovine CRH is preferred over the human sequence for this purpose because it is cleared more slowly, producing a more prolonged and more clearly interpretable ACTH response. Corticorelin is also given during inferior petrosal sinus sampling, where it amplifies the central-to-peripheral ACTH gradient and makes the distinction between pituitary and ectopic sources essentially perfect in expert hands. One claim in the draft has been corrected here: CRH does not greatly improve lateralisation within the pituitary. In the landmark 1991 series the intersinus gradient predicted the side of the microadenoma in 68% of patients basally and 71% after CRH, so CRH transforms the diagnosis of source but barely changes side-of-lesion prediction.
What the research shows
Corticorelin's evidence base is unusual for a peptide in that it consists almost entirely of diagnostic accuracy studies rather than treatment trials. The strongest single dataset remains the National Institutes of Health petrosal sinus sampling series of 281 patients, where adding CRH stimulation lifted sensitivity for Cushing's disease from 95% on basal sampling to 100%, at unchanged perfect specificity. What CRH does not do is localise the adenoma within the gland: intersinus gradients predicted the side correctly in only 68-71% of cases either way. The peripheral CRH stimulation test performs less impressively than the invasive procedure but is clinically useful, and the 2023 series of 323 patients gives a modern estimate of 91% diagnostic accuracy for the CRH test against 75% for high-dose dexamethasone suppression.
Attempts to find therapeutic applications for CRH pharmacology have not succeeded, and this deserves stating plainly. CRF1 receptor antagonists were pursued extensively for major depression, anxiety and irritable bowel syndrome on the rationale that CRH hyperactivity underlies stress-related disorders; large randomised trials of several such compounds failed to demonstrate efficacy, and the programmes were largely abandoned. Corticorelin itself was examined in peritumoural brain oedema without a convincing benefit emerging over corticosteroid treatment. There is no evidence supporting corticorelin as a performance, recovery or wellbeing agent, and WADA prohibits it outright, which reflects a theoretical concern about manipulating endogenous corticosteroid production rather than any demonstrated ergogenic effect. The practical constraint now dominating the field is supply: CRH has become largely unavailable worldwide, and endocrinologists have said so in print.
Evidence assessment
High-quality evidence
This tier refers to diagnostic performance, which is the only claim made for the compound. Corticorelin has held FDA-approved labelling since 1996, and its diagnostic accuracy has been characterised in large prospective and retrospective series: a 281-patient National Institutes of Health study of petrosal sinus sampling with and without CRH, a 41-patient prospective comparison against dexamethasone suppression, and a 323-patient retrospective series from the same centre spanning 1986 to 2019. There is no therapeutic claim for corticorelin, and none is being graded here.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome Preclinical only
A basal inferior petrosal sinus to peripheral ACTH ratio of 2.0 or more identified 205 of 215 patients with Cushing's disease (sensitivity 95%) with no false positives (specificity 100%). After CRH, a peak ratio of 3.0 or more identified all 203 patients with Cushing's disease who received CRH (sensitivity 100%, specificity 100%). Lateralisation was much weaker: an intersinus gradient of 1.4-fold or more predicted microadenoma location in 68% of 104 patients basally and 71% of 105 after CRH. This is the study that made CRH-stimulated petrosal sinus sampling the reference standard for identifying the source of ACTH excess.
The ovine corticotropin-releasing hormone stimulation test and the dexamethasone suppression test in the differential diagnosis of Cushing's syndrome Preclinical only
Twenty-nine of 33 patients with Cushing's disease and none of 8 with ectopic ACTH responded to ovine CRH with a rise in cortisol, giving sensitivity 88%, specificity 100% and accuracy 90%. A combined strategy requiring negative results from both tests to exclude Cushing's disease gave sensitivity 100% and accuracy 98%. The two tests provide complementary rather than redundant information, which is the basis of the combined testing strategy still used.
A simplified morning ovine corticotropin-releasing hormone stimulation test for the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome Preclinical only
Demonstrated that a shortened morning testing protocol retained adequate discriminatory performance, making the test practical outside highly specialised research settings. Most current clinical protocols descend from this simplification.
Ovine CRH Stimulation and 8 mg Dexamethasone Suppression Tests in 323 Patients With ACTH-Dependent Cushing's Syndrome Preclinical only
The CRH stimulation test outperformed high-dose dexamethasone suppression: diagnostic accuracy 91% (95% CI 87-94) versus 75% (69-79). Optimal criteria were a rise of 40% or more in ACTH and/or cortisol during the CRH test, and 69% or more cortisol suppression on dexamethasone. A 40% cortisol rise was the most specific single measure (positive predictive value 99%). Concordant positive results on both tests, seen in 74% of subjects, gave sensitivity 93%, specificity 98% and accuracy 95%. The authors' own conclusion is notably positive about CRH and laments its worldwide unavailability.
Safety
At the 1 microgram per kilogram intravenous dose used diagnostically, corticorelin is generally well tolerated, but transient facial flushing is common and expected. Higher doses cause dose-dependent cardiovascular effects: tachycardia, hypotension and dyspnoea, and asystole has been reported rarely. The US labelling therefore warns against exceeding the diagnostic dose. Because ACTH and cortisol both rise sharply, patients with unstable hypercortisolism should be assessed carefully before testing.
Hypersensitivity reactions are described, presenting with flushing of the face, neck and upper chest, dyspnoea, wheezing, urticaria and angioedema, and require immediate treatment. Injection should be slow, as rapid administration increases the frequency of flushing and haemodynamic effects. Corticorelin is a hospital diagnostic agent given under direct medical supervision with resuscitation facilities available. There is no context in which self-administration would be appropriate, and none in which it would be legal in the United Kingdom, where the product is unlicensed. Athletes should note that its use requires a therapeutic use exemption, since it is prohibited at all times under WADA S2.4.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Not licensed by the MHRA. Corticorelin has been obtained as an unlicensed medicinal product (a 'special') or imported for use in specialist endocrine centres, in the CRH stimulation test and during inferior petrosal sinus sampling. Use is confined to tertiary pituitary services, and availability is now the binding constraint: the 2023 National Institutes of Health series states plainly that the current worldwide unavailability of CRH impedes optimal management of these patients. |
| United States | Corticorelin ovine triflutate was approved by the FDA in 1996 for use as a diagnostic agent in the differential diagnosis of pituitary and ectopic ACTH production in patients with ACTH-dependent Cushing's syndrome. It holds orphan designation. Prescription-only, administered under specialist supervision. Supply has been intermittent. |
| WADA (sport) | Prohibited at all times, in and out of competition. WADA category S2.4 covers corticotrophins and their releasing factors and names corticorelin explicitly. The prohibition applies to both the ovine and human sequences. A therapeutic use exemption would be required for any legitimate diagnostic use in a tested athlete. |
Questions
A test. It has never been approved as a treatment for anything. Its only licensed use is diagnostic, given as a single intravenous injection to distinguish pituitary Cushing's disease from ectopic ACTH production, and as an adjunct during inferior petrosal sinus sampling. Attempts to develop CRH pathway drugs as therapeutics, mainly CRF1 antagonists for depression and anxiety, failed in large randomised trials.
Ovine corticotropin-releasing hormone differs from the human peptide at seven of 41 positions and is cleared more slowly. The result is a longer and more clearly interpretable ACTH response, which improves the discrimination between pituitary and ectopic disease. Human-sequence CRH has also been used diagnostically, particularly in European centres, but ovine CRH is the FDA-approved product.
Not reliably, and this is a common misconception. CRH-stimulated petrosal sinus sampling is close to perfect at answering whether the ACTH is coming from the pituitary at all. Predicting which half of the gland contains the microadenoma is a different question, and in the landmark 281-patient study the intersinus gradient got it right in 68% of cases basally and 71% after CRH. Surgeons treat lateralisation data as a hint, not an instruction.
Yes, at all times, in and out of competition. WADA category S2.4 covers corticotrophins and their releasing factors and names corticorelin explicitly. Any athlete needing it for genuine diagnostic purposes would require a therapeutic use exemption in advance.