Corticorelin

Synthetic ovine corticotropin-releasing hormone approved in 1996 as Acthrel, a diagnostic injection that distinguishes pituitary from ectopic ACTH secretion in Cushing's syndrome and has been unavailable since its 2020 discontinuation.

Also referenced as: Corticorelin ovine triflutate, Corticorelin ovine, oCRH, oCRF, Acthrel

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What is Corticorelin?

Corticorelin is the nonproprietary name for synthetic corticotropin-releasing hormone (CRH, also called corticotropin-releasing factor or CRF), the 41-amino-acid hypothalamic peptide that drives ACTH release from the anterior pituitary. The FDA-approved product, Acthrel, contains the ovine form, corticorelin ovine triflutate, a trifluoroacetate salt of a synthetic peptide whose amino acid sequence is identical to sheep CRH. The label gives the empirical formula of the free peptide as C205H339N59O63S and a molecular weight of about 4,670 Da. The ovine peptide was the first CRH isolated and sequenced, by Wylie Vale’s group at the Salk Institute, where it stimulated secretion of both corticotropin and beta-endorphin from pituitary cells (Vale et al., Science, 1981;213(4514):1394–1397). The human CRF precursor gene was sequenced two years later, and the human peptide differs from the ovine one at seven of 41 residues (Shibahara et al., EMBO Journal, 1983;2(5):775–779).

The ovine and human peptides are different molecules with different pharmacology, and the name corticorelin without a qualifier can refer to either. Only the ovine form has ever been approved in the US, as a diagnostic agent rather than a treatment: Acthrel is indicated for differentiating pituitary from ectopic production of ACTH in patients with ACTH-dependent Cushing’s syndrome. It is not cosyntropin, the synthetic ACTH fragment used to test the adrenal glands, nor corticotropin, the full-length pituitary hormone; corticorelin acts one level higher, on the pituitary itself.

How it works

• Agonist at the CRF1 receptor on pituitary corticotrophs. CRH acts through CRF1R, a class B G protein-coupled receptor cloned from human tissue by expression cloning in 1993 (Chen et al., Proceedings of the National Academy of Sciences, 1993;90(19):8967–8971). Cryo-electron microscopy structures of CRF1R and CRF2R bound to peptide agonists and the stimulatory G protein show how the ligand is recognized by the extracellular domain and the transmembrane bundle (Ma et al., Molecular Cell, 2020;77(3):669–680.e4). Gs coupling raises cAMP and triggers release of ACTH and of the related pro-opiomelanocortin products beta-lipotropin, gamma-lipotropin and beta-endorphin.
• ACTH rises within minutes and cortisol follows. In healthy subjects, plasma ACTH increases 2 minutes after intravenous doses of 0.3 µg/kg or more and peaks at 10 to 15 minutes; cortisol peaks at 30 to 60 minutes. The Acthrel label’s dose-response series in 29 volunteers put the threshold at 0.03 µg/kg and the maximally effective dose at 3 to 10 µg/kg. Insulin, renin, prolactin and growth hormone are unaffected, and vasopressin synergistically amplifies the ACTH response.
• The sheep peptide outlasts the human one. Ovine corticorelin leaves plasma biexponentially, with half-lives of 11.6 and 73 minutes for the fast and slow components (Schulte et al., Journal of Clinical Endocrinology and Metabolism, 1984;58(1):192–196). In volunteers, human CRF produced brief, pulse-like ACTH and cortisol rises while ovine CRF produced long-lasting stimulation, a difference attributed to the 3- to 4-fold higher metabolic clearance of the human peptide, 7.9 versus 1.9 mL/kg per minute (Schürmeyer et al., Journal of Clinical Endocrinology and Metabolism, 1984;59(6):1103–1108).
• Why the test discriminates. Corticotroph adenomas keep responding to CRH despite high circulating cortisol, whereas ectopic ACTH-secreting tumors do not respond and the normal corticotrophs in those patients are suppressed by hypercortisolism. In the original NIH series, every patient with Cushing’s disease responded to 1 µg/kg of ovine CRF with a further rise in already elevated ACTH and cortisol, no patient with ectopic ACTH syndrome did, and peptide disappearance curves were similar in both groups (Chrousos et al., New England Journal of Medicine, 1984;310(10):622–626).

Research status

Foundational NIH studies (1984 to 1993). The CRH stimulation test was developed almost entirely at the National Institutes of Health. After the 1984 proof of concept in 13 patients with Cushing’s disease and 9 with other forms of Cushing’s syndrome, a 41-patient comparison found that 29 of 33 patients with Cushing’s disease and 0 of 8 with ectopic ACTH secretion showed a cortisol response (sensitivity 88%, specificity 100%); requiring negative results on both the CRH test and the dexamethasone suppression test to exclude Cushing’s disease raised sensitivity to 100% and accuracy to 98% (Nieman et al., Annals of Internal Medicine, 1986;105(6):862–867). In 15 patients with Cushing’s disease, human CRH at the same 1 µg/kg dose produced smaller responses than ovine CRH, and 3 patients showed neither an ACTH nor a cortisol response to the human peptide, a finding that favored the ovine analog for diagnostic use (Nieman et al., Journal of Clinical Endocrinology and Metabolism, 1989;69(1):165–169). A retrospective analysis of 118 patients then defined the morning test criteria: a mean ACTH rise of at least 35% at 15 and 30 minutes identified 93 of 100 patients with Cushing’s disease and none of 16 with ectopic secretion (Nieman et al., Journal of Clinical Endocrinology and Metabolism, 1993;77(5):1308–1312).

Inferior petrosal sinus sampling. The largest study of the peptide was a prospective NIH series of 281 patients with Cushing’s syndrome, 262 of whom were sampled before and after ovine CRH. Among 246 surgically confirmed diagnoses, 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, and a peak ratio of 3.0 or more after CRH identified all 203 patients with Cushing’s disease who received it (sensitivity and specificity 100%) (Oldfield et al., New England Journal of Medicine, 1991;325(13):897–905). CRH-stimulated sampling became the reference standard.

The dexamethasone-CRH test. A different use addresses whether Cushing’s syndrome is present at all. In 58 adults with mild hypercortisolism, 39 with surgically confirmed Cushing’s syndrome and 19 with pseudo-Cushing’s states, CRH given 2 hours after low-dose dexamethasone suppression produced a 15-minute plasma cortisol above 38 nmol/L in every case of Cushing’s syndrome and in no pseudo-Cushing’s patient, against accuracies of 71% for the dexamethasone test and 76% for the CRH test alone (Yanovski et al., JAMA, 1993;269(17):2232–2238). The Endocrine Society’s 2008 diagnostic guideline treats the dexamethasone-CRH test as a second-line option for selected patients (Nieman et al., Journal of Clinical Endocrinology and Metabolism, 2008;93(5):1526–1540).

Adrenal insufficiency. In 10 patients with adrenal insufficiency, ACTH response patterns to ovine CRH separated primary from secondary disease and suggested a distinction between pituitary destruction and hypothalamic CRH deficiency (Schulte et al., Journal of Clinical Endocrinology and Metabolism, 1984;58(6):1064–1067); this use never entered the label.

The 2023 reappraisal and the supply gap. A review of 323 patients with confirmed ACTH-dependent Cushing’s syndrome tested at the NIH between 1986 and 2019, 78 with ectopic ACTH secretion, found the CRH test more accurate than the 8 mg dexamethasone suppression test (diagnostic accuracy 91% versus 75%). The optimal criterion was a 40% or greater rise in ACTH and/or cortisol, concordant positive results on both tests carried 93% sensitivity and 98% specificity, and the authors proposed an algorithm that would spare 64% of patients with Cushing’s disease from petrosal sinus sampling while describing the peptide’s “current worldwide unavailability” as an obstacle to care (Elenius et al., Journal of Clinical Endocrinology and Metabolism, 2023;109(1):e182–e189). The same authors reported that ovine CRH had not been available since July 2020 and that human CRH became unavailable to them in 2023; the FDA drug shortage database lists corticorelin ovine triflutate injection as a discontinuation by Ferring, the sole supplier. In Europe, a Swiss series of 40 patients found that petrosal sinus sampling without CRH lost sensitivity (85% versus 97%) and specificity (57% versus 71%) (Andereggen et al., Acta Neurochirurgica, 2024;166(1):167). The main substitute is desmopressin: a meta-analysis of 11 studies and 612 patients found pooled sensitivity of 96% for desmopressin-stimulated sampling versus 98% for CRH-stimulated sampling, each with specificity of 100% (Valizadeh et al., Reviews in Endocrine and Metabolic Disorders, 2022;23(5):881–892).

Human corticorelin abroad. The human-sequence peptide, corticorelin human triflutate, is a separate product line. CRH Ferring 100 µg, a pituitary function diagnostic from Ferring GmbH, holds a German authorization, and in Japan a human-sequence hCRH injection is approved under the generic name corticorelin (human) as a hypothalamic-pituitary-adrenal function test agent. Celtic Pharma developed the human peptide as Xerecept for peritumoral brain edema; a 200-patient phase 3 trial completed in March 2008 (NCT00088166) without any approval. As of November 2026, no corticorelin trial aimed at a new US approval is registered and no return of Acthrel has been announced.

Safety. The label describes adverse effects as dose-dependent and uncommon at the labeled dose, with facial flushing the typical reaction and hypersensitivity reactions including urticaria and angioedema reported. At 200 µg bolus doses given to 60 subjects, 4 had drops in blood pressure, one with asystole requiring resuscitation, and 3 had brief absence-like loss of consciousness.

Common dosage forms

• Acthrel for injection. A sterile lyophilized powder in a single-dose vial containing 100 µg of corticorelin ovine (as the trifluoroacetate), for intravenous diagnostic use only, administered by clinicians. No presentation has been available since 2020.
• No other approved presentation. No intramuscular, subcutaneous, nasal or oral form of ovine corticorelin was ever approved in the US.

Key considerations

• Regulatory status. The FDA Approved status reflects the May 23, 1996 approval of Acthrel (corticorelin ovine triflutate) for injection under application 020162, a former NDA that Drugs@FDA has listed as BLA 020162 since it was deemed a biologics license application on March 23, 2020. Ferring discontinued the product in 2020 and has not resumed supply; the FDA drug shortage database records the discontinuation, and as of November 2026 Drugs@FDA still listed the marketing status as Prescription rather than Discontinued, so the approval stands while no vials exist.
• A diagnostic, not a therapy. The only approved use is to help separate pituitary from ectopic ACTH secretion once ACTH-dependent Cushing’s syndrome has been established and adrenal causes excluded. The dexamethasone-CRH test and the adrenal-insufficiency patterns are investigator-developed uses that never entered the label.
• Supply dictates practice. With the ovine peptide unavailable, centers have substituted desmopressin during petrosal sinus sampling at a cost of a few points of sensitivity, while unstimulated sampling performs markedly worse.
• Dose-related hemodynamic effects. The serious reactions on record (hypotension, loss of consciousness, asystole) occurred at roughly twice the labeled dose, which is why the product was never given outside monitored settings; at the labeled dose flushing is the expected reaction and hypersensitivity the main residual risk.
• Naming. Corticorelin ovine triflutate, oCRH, oCRF and Acthrel denote the sheep peptide; corticorelin human triflutate, CRH Ferring, hCRH and Xerecept denote the human peptide, which differs at seven residues and is cleared 3 to 4 times faster. Cosyntropin (ACTH 1-24) has been mistakenly substituted for Acthrel during petrosal sinus sampling, producing an artifactual fall in measured ACTH because the fragment interferes with sandwich immunoassays (Carroll et al., Endocrine Practice, 2014;20(7):646–649).