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MyDeficiencies

Corticorelin

Also sold as Acthrel.

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Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Corticorelin ovine triflutate (Acthrel) is a single-use diagnostic reagent, not a chronically dosed medication: its entire labeled use is one intravenous bolus of 1 mcg/kg body weight, given once during a CRH stimulation test to distinguish pituitary-dependent Cushing's disease from ectopic ACTH secretion. Its own FDA label describes no hepatic CYP450 metabolism, no enzyme induction or inhibition, and no named catabolic or renal-clearance pathway; corticorelin "does not appear to be bound specifically by a circulating plasma protein," and it clears biphasically with a fast half-life of 11.6 ± 1.5 minutes and a slow half-life of 73 ± 8 minutes (mean volume of distribution 6.2 ± 0.5 L, metabolic clearance rate 95 ± 11 L/m2/day). Because it is injected intravenously rather than swallowed, none of the oral-absorption mechanisms (chelation, gastric pH change, transporter competition, bile-acid sequestration) that drive most drug-nutrient interactions are mechanistically available to it, and the label states no renal or hepatic impairment data, and no food, mineral, or antacid interaction, of any kind. The Step 2 mechanism screen found no present classical-nutrient mechanism for corticorelin: a hormone given once, cleared within roughly two hours, with a pharmacodynamic window (peak ACTH at 15 to 60 minutes, peak cortisol at 30 to 120 minutes) that closes before most nutrient-handling machinery could plausibly be engaged, has essentially no exposure window in which a chronic depletion effect could accumulate. That null result is itself the headline, and it is a tighter, more acute case than most single-course diagnostic hormones reviewed in this series, since corticorelin is normally given exactly once per patient, not even the two-dose regimen used for some comparable agents.

ATC V04CD04 (corticorelin) · also sold as Acthrel (corticorelin ovine triflutate for injection) · reviewed 2026-09-29. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Corticorelin in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe
Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate
At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit.
Yellow — Low
Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction.
Not graded — disclosed evidence gap
Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: Not gradeable under the rules above because nothing has been measured. Published as a documented gap, never as reassurance that there is no effect.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden

Not graded — disclosed evidence gap

See study details

No evidence at any tier connects corticorelin, or CRH/CRH-receptor signaling generally, to direct effects on mitochondrial structure, membrane integrity, electron transport, or biogenesis, and no circulating consumer claim exists to rebut.

Full detail, limits and 1 references

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. UNGRADED

Limits on what this shows

  • Why no grade: Both UNGRADED conditions are met: (1) the one CRH-and-mitochondria source located and opened this session, Asadi & Theoharides, "Corticotropin-releasing hormone and extracellular mitochondria augment IgE-stimulated human mast-cell vascular endothelial growth factor release, which is inhibited by luteolin," J Neuroinflammation 2012;9:85 (DOI 10.1186/1742-2094-9-85, opened via link.springer.com), is an in vitro human mast-cell-line (LAD2) and cord-blood-mast-cell study using supraphysiologic CRH concentrations (0.1 to 10 μmol/l) over 6 to 48 hours. Its mitochondrial angle concerns exogenous, extracellular mitochondria (released by other, separately lysed cells) amplifying mast-cell VEGF release as a distinct damage-associated signal, not CRH damaging or altering the treated cell's own mitochondrial structure or function; on a plain reading it does not meet the category's test (direct effects on mitochondrial structure, membrane integrity, electron transport, or biogenesis) and is not used to ground a graded entry here. A second, titled-only source (Otsuka Y. et al. or similar 1968 rat-liver ACTH/cortisol/oxidative-phosphorylation paper, see the Oxidative stress entry below and Sources) could not be opened. No other Tier B/C source tying corticorelin or CRH-receptor signaling to mitochondrial structure or function was located. (2) No circulating consumer claim naming corticorelin, Acthrel, or CRH stimulation testing and mitochondrial damage was found in the sources checked (see the Fails verification section).

Search channels tried

PubMed search-listing pages (one query returned a zero-result page; a second, differently phrased query was rejected with HTTP 429 mid-session); Crossref API (reachable with a mailto contact parameter, queried with "corticotropin-releasing hormone mitochondria oxidative stress" and again combined with "corticorelin ACTH cortisol oxidative stress hemoglobin iron copper," returning only the in vitro mast-cell paper above, a 1968 rat-liver title that could not be opened, and unrelated general-reference entries); Europe PMC REST API (HTTP 429 on every attempt this session); Semantic Scholar API (HTTP 429); OpenAlex API (HTTP 429 on every attempt, including a final broad query combining all seven categories); WebSearch tool (reported its 200-of-200 session budget already exhausted before this task's first query). This reflects a genuine evidence gap for a single-bolus diagnostic reagent with no clinical rationale for mitochondrial-endpoint study, compounded by a real tooling limitation across most literature-API channels this session.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress, mixed class-level signal

Yellow — Low

See study details

One mechanistic source found that acute CRH-receptor activation increases intracellular oxidative stress and reduces electron-transport capacity in neurons; one human clinical source that directly paired a DEX/CRH-style test with oxidative-stress biomarkers found no group differences at all. Neither source could be confirmed to use the ovine sequence specific to Acthrel, so this is written up as a mixed, class-level signal rather than a corticorelin-specific finding.

Full detail, limits and 2 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. YELLOW

Limits on what this shows

  • Key null/negative: Two null results temper this entry considerably. Within the Battaglia 2020 model itself, measured ATP output was unchanged despite the oxidative and respiratory-chain stress (see the ATP production entry below), and the authors describe the mitochondrial changes as "strong, but reversible." More directly relevant to corticorelin's actual diagnostic use, the one human study that paired a DEX/CRH-style test with oxidative-stress biomarkers (Rotvig 2024) found no measurable group differences in those markers at all.
  • At-risk subgroups: Cannot be determined for corticorelin specifically. The Battaglia 2020 signal comes from direct, sustained (30 minutes to 2 hours) neuronal CRH exposure or a trauma/chronic-stress model, not a single roughly two-hour-window systemic IV bolus in a Cushing's-workup patient; the Rotvig 2024 population is psychiatric inpatients and outpatients being evaluated for depression or exhaustion disorder, not the Cushing's-syndrome population Acthrel is actually given to.
  • Counter-evidence and drug-identity caveat: Neither source confirms use of the ovine sequence specific to Acthrel: Battaglia 2020 used a Bachem synthetic peptide understood to be human/rat sequence, and Rotvig 2024's CRH product could not be confirmed because its methods section remained blocked on every attempted route. This is graded Tier C class extrapolation, not Tier A/B for corticorelin, for that reason, and the mixed direction, a mechanistic risk signal in one source, a null human clinical finding in the more directly analogous one, is disclosed plainly rather than resolved into a single claim. A source found while researching Copper and Iron, on copper's requirement for endogenous CRH/TRH biosynthesis via peptidylglycine alpha-amidating monooxygenase (see the Copper entry and Sources), runs in the opposite causal direction from this entry and is not used here.

Regulatory status

Not addressed in the Acthrel label; the label does not mention oxidative stress, free radicals, reactive oxygen species, or antioxidant status at all.

Population evidence

Battaglia CR, Cursano S, Calzia E, Catanese A, Boeckers TM. "Corticotropin-releasing hormone (CRH) alters mitochondrial morphology and function by activating the NF-kB-DRP1 axis in hippocampal neurons." Cell Death Dis 2020;11:1004 (DOI 10.1038/s41419-020-03204-3). Opened in full via nature.com (gold open access). In vitro: primary rat hippocampal neurons (embryonic day 17-18, cultured to DIV14) exposed to 100 nM synthetic CRH (Bachem, product H-2435, a human/rat-sequence peptide, chemically identical between those two species and distinct from the 7-residue-different ovine sequence used in corticorelin) for 30 minutes to 2 hours; a parallel in vivo mouse thorax-trauma model was also used. CRH exposure produced significant mitochondrial fragmentation (phospho-DRP1 S616 up about 2.18-fold, the fusion protein OPA1 down to about 0.13-fold, aberrant cristae up to about 76% versus about 5% in vehicle) through an "NF-kB/c-Abl/DRP1 axis," together with reduced oxidative-phosphorylation capacity (0.635-fold of vehicle, p=0.0043), reduced electron-transport-system capacity (0.624-fold, p=0.0049), and reduced Complex IV activity (0.569-fold, p<0.0001); the paper states this was accompanied by increased intracellular oxidative stress, though the text available this session did not surface a separate quantitative reactive-oxygen-species figure. Rotvig DH, Jorgensen A, Jensen JH, et al., full citation in Sources below. Stress 2024;27(1) (DOI 10.1080/10253890.2024.2353781). Confirmed gold open access (CC-BY) and opened at verified abstract level via the DOAJ article registry, the Semantic Scholar API, and the University of Copenhagen research-portal record, all three of which return the same verbatim abstract text; the full PDF itself returned HTTP 403 on both the KU repository file host and the tandfonline.com publisher page, and an Europe PMC lookup for the same DOI was blocked by a proxy-level HTTP 429, so the methods section that would name the CRH product and species could not be read. Thirty inpatients with major depressive disorder (MDD) and 23 outpatients with exhaustion disorder (ED, a work-related-stress diagnosis) underwent a combined dexamethasone-CRH (DEX-CRH) test with plasma cortisol and ACTH sampling, compared against a historical healthy-control (HC) group; urinary 8-oxodG and 8-oxoGuo were collected as "robust markers of oxidative stress." Per the verified abstract: "cortisol concentrations were higher in MDD and ED participants compared to HC, and no differences in AUC cortisol and ACTH were found between ED vs. MDD... No differences in oxidative stress markers or quality of sleep between the groups were found." The combined DEX-CRH test protocol in this line of psychiatric research conventionally uses human-sequence CRH rather than ovine, though this could not be independently confirmed from the blocked methods text.

Mechanism

CRHR1 activation on neurons is described as triggering an NF-kB/c-Abl/DRP1 signaling cascade that drives mitochondrial fission and reduces electron-transport-chain throughput, with the source paper describing this as accompanied by increased intracellular oxidative stress. This is a receptor-mediated signaling effect, not an absorption-mediated one, so corticorelin's intravenous route does not by itself reduce the mechanism's plausibility.

Counter-evidence held on record

This is a mixed, class-level, non-ovine-confirmed signal, not a corticorelin-specific finding. The more clinically analogous of the two sources, a human study built directly around the DEX/CRH test, found no oxidative-stress-marker differences at all. No antioxidant supplement or dosing action follows from this entry, and it should not be read as evidence that a single diagnostic Acthrel dose measurably raises oxidative stress.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Copper

Not graded — disclosed evidence gap

See study details

No evidence at any tier connects corticorelin, or ACTH/cortisol stimulation generally, to copper or ceruloplasmin status, and no circulating consumer claim exists to rebut.

Full detail, limits and 1 references

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. UNGRADED

Limits on what this shows

  • Why no grade: Both UNGRADED conditions are met, and a dedicated re-research pass on 2026-09-29 found one genuinely on-topic paper but judged it not to meet the category's test. (1) Dedicated Crossref queries ("ACTH stimulation test copper ceruloplasmin"; "cortisol ceruloplasmin copper"; "corticotropin releasing hormone copper ceruloplasmin"; the combined seven-category query) returned zero on-topic results for a corticorelin/CRH-causes-copper-change direction; a PubMed search-listing query for "corticotropin-releasing hormone AND copper" returned ten results, one of which, Giraud P, Malteseh J-Y, Boudouresque F, et al., "Peptidylglycine alpha-amidating monooxygenase activity and TRH and CRF biosynthesis. Role of copper," Biol Trace Elem Res 1992 (DOI 10.1007/BF02784614), was opened in full via link.springer.com. It reports, using cultured pancreatic and hypothalamic cells, that peptidylglycine alpha-amidating monooxygenase (PAM), the copper-dependent enzyme that carboxy-terminally amidates TRH and CRF into their biologically active forms, requires adequate copper stores, and that manipulating cellular copper alters TRH and CRF immunoreactivity. This runs in the opposite causal direction from a depletion question, copper is shown as a requirement for the body's own endogenous CRF biosynthesis, not as something an already-synthesized, exogenously infused corticorelin bolus consumes or depletes, so on a plain reading it does not meet this category's test and is not used to ground a grade here, consistent with how this dossier treats other found-but-wrong-direction sources (see Mitochondrial burden). Ceruloplasmin is a recognized acute-phase reactant and cortisol is known generally to modulate acute-phase protein synthesis, but no source connecting this specifically to ACTH-stimulation-test-level (single-bolus, roughly two-hour) cortisol exposure, rather than sustained glucocorticoid or inflammatory exposure, was located. (2) No circulating consumer claim naming corticorelin, Acthrel, or CRH/ACTH stimulation testing and copper was found in the sources checked (see Fails verification).

Search channels tried

PubMed search-listing pages (zero-result page for the direct hepcidin-style query in the Iron entry; ten results, one relevant-but-wrong-direction, for the copper query above); Crossref API, four separate queries across both the original and re-research sessions (reachable channel, genuinely searched, zero on-topic results in the corticorelin-depletes-copper direction). Europe PMC REST API, Semantic Scholar API, and OpenAlex API were all re-attempted in this dedicated, solo re-research session specifically to rule out shared-session rate-limiting as the cause, and all three again returned HTTP 429 on every attempt, at both the proxy and target level, confirming the block is not simply shared-session contention; the WebSearch tool again reported its 200-of-200 budget exhausted before category-specific queries could run. The two standard consumer drug-nutrient-depletion compilations (US Pharmacist, chiro.org) were opened directly and searched for corticorelin, Acthrel, CRH, and corticotropin-releasing hormone; neither contains any match. This reflects a genuine evidence gap for a single-bolus diagnostic reagent with essentially no clinical rationale to study trace-mineral status after one injection, compounded by tooling degradation across three of five literature-API channels that persisted even under a dedicated research budget.

Iron

Not graded — disclosed evidence gap

See study details

No evidence at any tier connects corticorelin, or ACTH/cortisol stimulation generally, to iron, ferritin, or hepcidin status, and no circulating consumer claim exists to rebut.

Full detail, limits and 1 references

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. UNGRADED

Limits on what this shows

  • Why no grade: Both UNGRADED conditions are met, and a dedicated re-research pass on 2026-09-29 confirmed the gap rather than closing it. (1) Dedicated Crossref queries ("cortisol hepcidin iron regulation"; "glucocorticoid hepcidin iron"; "CRH ACTH cortisol hepcidin iron"; the combined seven-category query) returned only general hepcidin-biology and iron-homeostasis papers (evolution, cardiomyocyte hepcidin, dietary-iron-absorption reviews) with no ACTH, CRH, or cortisol connection at all; a PubMed search-listing query for "corticotropin-releasing hormone AND hepcidin" returned an explicit zero-result page. A broader PubMed query for "corticotropin-releasing hormone AND iron" returned results on iron's effects on stress-neuropeptide expression (the reverse direction) and one tangential, wrong-population title, Huang KE, Mittelman SD, Coates TD, et al., "A Significant Proportion of Thalassemia Major Patients Have Adrenal Insufficiency Detectable on Provocative Testing," J Pediatr Hematol Oncol 2015 (DOI 10.1097/MPH.0000000000000199), located by title via PubMed and Crossref but not opened in full; on its title alone it concerns iron-overloaded thalassemia patients being tested for adrenal insufficiency, not corticorelin or CRH affecting iron status, and very likely uses standard ACTH (cosyntropin) rather than CRH stimulation, so it is disclosed but not used as evidence. Cortisol and inflammatory cytokines are both known modulators of hepatic hepcidin transcription in the general endocrinology literature, but no source tying this specifically to CRH-receptor stimulation, ACTH-stimulation testing, or corticorelin was located despite genuine search. (2) No circulating consumer claim naming corticorelin, Acthrel, or CRH/ACTH stimulation testing and iron, ferritin, or anemia was found in the same sources checked for Copper. The FDA/DailyMed label was also re-checked specifically for hemoglobin, hematocrit, iron, ferritin, or complete-blood-count language in the adverse-reactions and clinical-pharmacology sections; none appears anywhere in the label.

Search channels tried

Same re-attempted, still-blocked channel set documented under Copper (Europe PMC, Semantic Scholar, and OpenAlex all re-tried in this dedicated session and all still returned HTTP 429; WebSearch budget again exhausted). Crossref API (reachable channel) was queried across both sessions with hepcidin/iron-regulation phrasing and combined-category phrasing; PubMed search-listing pages were reachable for both the hepcidin query (zero results) and the broader iron query (ten-plus results, none on-topic in the corticorelin-affects-iron direction). Disclosed as a genuine evidence gap for a single-bolus diagnostic agent, compounded by the same partial tooling degradation affecting every category in this review, now confirmed to persist under a dedicated re-research budget rather than being a one-off, shared-session artifact.

  • Huang KE, Mittelman SD, Coates TD, Geffner ME, Wood JC. A Significant Proportion of Thalassemia Major Patients Have Adrenal Insufficiency Detectable on Provocative Testing. — J Pediatr Hematol Oncol 2015 (DOI 10.1097/MPH.0000000000000199). Located by title via a PubMed search-listing query for "corticotropin-releasing hormone AND iron" and confirmed via Crossref while re-researching Iron on 2026-09-29; not opened or read this session. On its title alone, concerns iron-overloaded thalassemia-major patients tested for adrenal insufficiency, very likely with standard ACTH (cosyntropin) rather than CRH stimulation; disclosed in the Iron entry as a tangential, wrong-direction, wrong-population find, not used as evidence for any grade.Located by title/metadata only; not opened this session.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk, intestinal-barrier permeability and bacterial-product translocation risk from intravenous CRH-receptor stimulation, mixed direction

Yellow — Low

See study details

Two opened human intravenous-CRH studies measured gut-barrier endpoints with conflicting results: one found a single CRH bolus increased small-intestinal permeability by a mast-cell-dependent mechanism, the other found no consistent worsening of serum bacterial-translocation markers over the same dose. Neither study could be confirmed to have used ovine corticorelin rather than human-sequence CRH, and no study measured gut microbiome composition or diversity directly, so this is written up as a barrier-function and translocation-risk signal, not a microbiome-composition finding, and graded as class-level evidence rather than drug-specific.

Full detail, limits and 2 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. YELLOW

Limits on what this shows

  • Key null/negative: The PLOS ONE 2024 crossover trial is itself the strongest available null/negative finding: four of five serum barrier-integrity and bacterial-translocation markers (I-FABP, syndecan-1, sCD14, LBP:sCD14 ratio) showed no significant CRH-versus-placebo difference, and the one marker that moved (LBP) moved in the direction opposite to what a translocation-risk hypothesis would predict, and lost significance after correction for multiple comparisons.
  • At-risk subgroups: Cannot be determined for corticorelin specifically. If this mechanism is active at all in a diagnostic patient, exposure would be bounded to the roughly two-hour peak-hormone window of a single bolus (per the label's ACTH/cortisol timing), not systemic or chronic; the two source studies used healthy volunteers, not the Cushing's-syndrome population Acthrel is actually given to.
  • Counter-evidence and drug-identity caveat: Neither source study's CRH product was confirmed, from what could be opened this session, to be the ovine sequence specific to Acthrel; the PLOS ONE 2024 study explicitly used Ferring's human-sequence CRH, and the Vanuytsel 2014 study's own methods (species/manufacturer) could not be opened to check. Ovine and human CRH are related but chemically distinct peptides with reportedly different pharmacokinetics (a 1989 comparative study located by title, J Clin Endocrinol Metab 69(1):165, reports the ovine CRH stimulation test as diagnostically superior to the human CRH test for Cushing's disease, consistent with a longer or more sustained hormonal stimulus from the ovine sequence, though this paper could not be opened this session to confirm the mechanism, and is listed in Sources as located-by-title-only). This is disclosed as a genuine cohort-identity gap rather than treated as a minor technicality, and is the reason this entry is graded Tier C class extrapolation rather than Tier A/B for corticorelin itself.

Regulatory status

Not addressed in the Acthrel label; the label does not discuss intestinal permeability, gut barrier function, or microbiome effects at all.

Population evidence

Vanuytsel T, Van Wanrooy S, Vanheel H, et al. "Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism." Gut 2014;63(8):1293-1299 (DOI 10.1136/gutjnl-2013-305690). Human study, two sub-studies (23 and 13 healthy volunteers); in the CRH sub-study, a single intravenous bolus of CRH (100 mcg, per a secondary review's quotation of the paper) increased the urinary lactulose-mannitol permeability ratio (0.042±0.021 vs 0.028±0.009 with placebo/control, p=0.02), an effect blocked by two weeks' pretreatment with the mast-cell stabilizer disodium cromoglycate (800 mg/day). Opened via the journal abstract page, an OpenAlex abstract reconstruction, and a secondary review (Buckinx et al., J Neurogastroenterol Motil 2011, DOI 10.5056/jnm14084, opened directly) that quotes the 100 mcg dose; the primary paper's own methods section, which would name the CRH product's species and manufacturer, could not be independently opened this session (see Sources). Set against this: Michielan A. et al. (title: "Characterisation of biomarkers of intestinal barrier function in response to a high fat/high carbohydrate meal and corticotropin releasing hormone," PLOS ONE 2024;19(1):e0294918, opened in full) gave the same 100 mcg CRH dose, explicitly identified in the methods as "CRH (Ferring, Kiel, Germany)," a human-sequence CRH product, as an intravenous bolus to 10 healthy volunteers in a single-blinded, randomized, placebo-controlled crossover design. Lipopolysaccharide-binding protein (LBP) fell slightly 2 hours post-CRH versus placebo (p=0.05 by Wilcoxon test, not significant after multiple-comparison correction); intestinal fatty-acid-binding protein (I-FABP, p=0.2), syndecan-1 (p=0.8), soluble CD14 (p=0.4), and the LBP:sCD14 ratio (p=0.4) showed no significant acute change over 6 hours. The paper's own stated conclusion, that its data "confirm transient LPS translocation during CRH-induced stress" while "questioning prior reports of I-FABP elevation," is noted here, but the entry records the underlying statistics (a marginal, direction-inconsistent, uncorrected p-value on one of five markers) rather than adopting that framing uncritically.

Mechanism

CRH receptors (CRHR1/CRHR2) are expressed on intestinal mucosal mast cells and enteric neurons; systemic CRH-receptor activation is described as triggering mast-cell mediator release that opens paracellular tight junctions, independent of the oral-absorption mechanisms that do not apply to an intravenously injected drug. This is a receptor-mediated systemic effect, not a gut-lumen exposure effect, so the IV route does not reduce its plausibility the way it does for classical absorption-interference mechanisms.

Counter-evidence held on record

This is a mixed, class-level, human-sequence-CRH signal about acute gut-barrier permeability and bacterial-product translocation, not a measured change in gut microbiome composition or diversity, and not confirmed to involve the ovine corticorelin specific to Acthrel. The stronger-quality of the two studies (the placebo-controlled crossover) is the null one. No supplement, probiotic, or dietary intervention follows from this entry, and it should not be read as evidence that a single diagnostic Acthrel dose measurably disrupts the gut microbiome.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

ATP production, class-level, non-ovine CRH

Yellow — Low

See study details

The one on-topic mechanistic source directly measured cellular ATP output after CRH-receptor activation and found no significant change, despite the same experiment showing reduced upstream respiratory-chain capacity. This is graded as a class-level context flag rather than a deficiency finding, and it is not confirmed to involve ovine corticorelin.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. YELLOW

Limits on what this shows

  • Key null/negative: This entry's central finding is itself the null result: two independent, purpose-built ATP measurements (the luciferase assay and oxygen-consumption-linked ATP production) in the one on-topic mechanistic source located this session found no significant CRH-versus-control difference in ATP output.
  • At-risk subgroups: Cannot be determined for corticorelin specifically. The source model is direct, sustained (30 minutes to 2 hours) neuronal CRH exposure or a trauma/chronic-stress model, not a single roughly two-hour-window IV bolus in a Cushing's-workup patient, and no human ATP or cellular-energy measurement tied to corticorelin or diagnostic CRH/ACTH stimulation testing was located.
  • Counter-evidence and drug-identity caveat: The source paper used a Bachem synthetic CRH peptide understood to be human/rat sequence, not confirmed ovine; this is graded Tier C class extrapolation for that reason. No consumer "low energy," fatigue, or ATP-depletion claim naming corticorelin or Acthrel exists to rebut (see Fails verification), so this entry is written as a mechanistic context flag rather than a rebuttal of an existing claim.

Regulatory status

Not addressed in the Acthrel label; no ATP, cellular-energy, or fatigue language appears anywhere in the label.

Population evidence

Battaglia CR, Cursano S, Calzia E, Catanese A, Boeckers TM, full citation and model details in the Oxidative stress entry above and in Sources ( Cell Death Dis 2020;11:1004, DOI 10.1038/s41419-020-03204-3, opened in full via nature.com). In the same in vitro rat-hippocampal-neuron model (100 nM Bachem synthetic CRH, human/rat sequence, 30 minutes to 2 hours), the paper directly measured ATP by two independent methods: a luciferase-based ATP assay "showed no significant difference" between CRH-treated and control neurons, and oxygen consumption linked to ATP production (reported as "J-O2-ATP") was likewise unchanged (0.998 ± 0.151-fold of vehicle at 0.5 hours, 0.786 ± 0.146-fold at 2 hours, both p>0.05), despite the same experiment showing significantly reduced oxidative-phosphorylation, electron-transport-system, and Complex IV capacity upstream. The authors' own stated interpretation is that the neurons "maintain a physiological energy metabolism" despite the bioenergetic and morphological stress, which the paper frames as helping the cell avoid apoptosis.

Mechanism

CRHR1-driven mitochondrial fission (the NF-kB/c-Abl/DRP1 axis described in the Oxidative stress entry) reduces respiratory-chain capacity, but the cited paper's own ATP-specific data indicate this reduced capacity did not translate into a measured ATP-output deficit over the exposure window studied, consistent with neurons operating below their maximal respiratory capacity rather than at a bottleneck.

Counter-evidence held on record

This is a reassuring, class-level, non-ovine-confirmed finding, not evidence that corticorelin depletes cellular energy. The one on-topic mechanistic source found ATP output preserved despite upstream mitochondrial stress. No supplement or energy-support recommendation follows from this entry.

Oxygen delivery/utilization

Not graded — disclosed evidence gap

See study details

No evidence at any tier connects corticorelin to hemoglobin, hematocrit, red-cell mass, or tissue oxygen delivery as a direct effect, and no circulating consumer claim exists to rebut. The label's own cardiovascular warnings (transient tachycardia, decreased blood pressure) describe the drug's own intended/associated hemodynamic pharmacology, not a hematologic or oxygen-carrying-capacity finding, and are excluded here under Hard Rule 2.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. UNGRADED

Limits on what this shows

  • Why no grade: Both UNGRADED conditions are met: (1) no Tier B/C evidence links corticorelin, CRH, or ACTH-stimulation testing directly to hemoglobin, hematocrit, red-cell mass, or arterial oxygenation; a dedicated Crossref query for "ACTH cortisol hemoglobin hematocrit erythropoiesis" was rejected with HTTP 429 mid-session, and the combined seven-category query returned only a copper-mediated-oxidative-stress-on-hemoglobin paper unrelated to ACTH or CRH. The label's cardiovascular adverse-reaction language (flushing, transient tachycardia, decreased blood pressure, and at higher doses asystole) is the drug's own labeled, dose-dependent hemodynamic effect, not a directly measured hemoglobin, hematocrit, or red-cell-mass change, so per Hard Rule 2 it is excluded here rather than filed as an oxygen-delivery finding. (2) No circulating consumer claim naming corticorelin, Acthrel, or CRH/ACTH stimulation testing and anemia, hemoglobin, or "oxygen delivery" was found in the sources checked.

Search channels tried

Same blocked-channel set documented under Copper and Iron. The dedicated Crossref hemoglobin/hematocrit/erythropoiesis query returned HTTP 429 on its own first attempt and a non-specific result on retry via the combined query; PubMed, Europe PMC, Semantic Scholar, and OpenAlex were all unavailable across this session as documented above. Disclosed as a genuine evidence gap for a single-bolus diagnostic agent, compounded by the same partial tooling degradation affecting every category in this review.

All references used above
  1. ACTHREL (corticorelin ovine triflutate for injection), full prescribing information. — accessdata.fda.gov, FDA label reference ID 020162s010, dated 2015. Opened in full. Source for the pharmacokinetic basis (half-lives, volume of distribution, clearance rate, plasma-protein-binding statement), dosing regimen, mechanism, contraindications, dexamethasone and heparin interactions, adverse-reaction rates, and pregnancy/pediatric notes.
  2. DailyMed - ACTHREL (corticorelin ovine triflutate) injection, powder, lyophilized, for solution. — dailymed.nlm.nih.gov, National Library of Medicine, setid 3c39dcea-d8f7-8594-01e6-24e8d6fa4d2f. Opened in full; corroborates the FDA label's mechanism, pharmacokinetics, contraindications, interactions, and how-supplied/stability data (lyophilized cake containing 100 mcg corticorelin ovine as the trifluoroacetate, 0.88 mg ascorbic acid, 10 mg lactose, 26 mg cysteine hydrochloride monohydrate).
  3. WHO Collaborating Centre for Drug Statistics Methodology, ATC/DDD Index, code V04CD04. — atcddd.fhi.no (redirected from whocc.no). Opened directly; confirms ATC code V04CD04 corresponds to corticorelin, within the V04CD "Tests for pituitary function" subgroup.
  4. Corticorelin. — Wikipedia. Opened; used only for general background (molecular formula, CAS number, the human-sequence Xerecept brand history, general CRH-stimulation-test description), not as evidence for any graded entry. Notes the human and ovine forms are related but distinct preparations. General reference only.
  5. Corticorelin (Xerecept), drug profile. — Drugs in R&D 2004;5(4). Opened via link.springer.com (abstract/summary-level detail). Used only for general background on the human-sequence corticorelin (Xerecept, brain-edema indication, distinct from Acthrel), confirming that human and ovine corticotropin-releasing factor exist as separate development programs; not used as evidence for any graded entry.
  6. Vanuytsel T, Van Wanrooy S, Vanheel H, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. — Gut 2014;63(8):1293-1299 (DOI 10.1136/gutjnl-2013-305690, PMID 24153250). Human study (two sub-studies, 23 and 13 healthy volunteers), Tier A for human-sequence-or-unconfirmed-species CRH, Tier C for corticorelin ovine specifically given the unconfirmed species. Opened via the gut.bmj.com abstract page and an OpenAlex abstract reconstruction; the CRH-arm permeability statistics (lactulose-mannitol ratio 0.042±0.021 vs 0.028±0.009, p=0.02) and the mast-cell-blockade result are sourced from these plus the Buckinx et al. review below. The paper's own methods section, which would state the CRH product's species and manufacturer, returned only a reCAPTCHA interstitial on every attempted route and was not independently opened.Full methods section blocked by a reCAPTCHA interstitial on every attempted route; species/manufacturer of the CRH product used could not be independently confirmed this session.
  7. Buckinx R, Van Nassauw L, Rybarczyk P, et al. Role of Corticotropin-releasing Factor in Gastrointestinal Permeability. — J Neurogastroenterol Motil 2015;21(3):386-394 (DOI 10.5056/jnm14084). Narrative review, Tier C. Opened via jnmjournal.org in full. Source for the 100 mcg IV CRH dose used in the Vanuytsel 2014 study and for the broader table of animal and human CRF-permeability studies (Guilarte 2004, Wallon 2008/2011, Alonso 2008/2012, and others), none of which specify CRF species in what could be extracted from this review; not independently opened for this dossier beyond this review's own text.
  8. Michielan A, et al. Characterisation of biomarkers of intestinal barrier function in response to a high fat/high carbohydrate meal and corticotropin releasing hormone. — PLOS ONE 2024;19(1):e0294918 (DOI 10.1371/journal.pone.0294918). Human study, single-blinded randomized placebo-controlled crossover, n=10 healthy volunteers, Tier B/C (human-sequence CRH, explicitly named as Ferring, Kiel, Germany, not ovine). Opened in full via journals.plos.org. Source for the 100 mcg IV CRH dose, the LBP/I-FABP/syndecan-1/sCD14 statistics, and the study's own stated conclusion, all quoted in the Gut microbiome risk entry above.
  9. The effect of corticotropin-release hormone on duodenal permeability and immune activation in healthy volunteers in a double-blind placebo-controlled study. — Am J Physiol Gastrointest Liver Physiol 2025 (DOI 10.1152/ajpgi.00130.2024). Human placebo-controlled trial, drug-specific to CRH broadly. Located via PubMed/journal search by title; the publisher page returned HTTP 403 on every attempted route and was not opened or read this session. Not used as evidence for any grade; listed for disclosure only, and flagged for a future revision once journals.physiology.org access is available.Publisher page returned HTTP 403 on every attempted route; not opened this session.
  10. Effects of corticotropin-releasing hormone on gastric electrical activity and sensorimotor function in healthy volunteers: a double-blinded crossover study. — Am J Physiol Gastrointest Liver Physiol 2016 (DOI 10.1152/ajpgi.00437.2016). Human crossover study, drug-specific to CRH broadly. Located via web search by title; the publisher PDF route returned HTTP 403 and was not opened or read this session. Not used as evidence for any grade; listed for disclosure only.Publisher route returned HTTP 403; not opened this session.
  11. Landman GW, et al. (title only) The ovine corticotropin-releasing hormone (CRH) stimulation test is superior to the human CRH stimulation test for the diagnosis of Cushing's disease. — J Clin Endocrinol Metab 1989;69(1):165 (PMID 2543689). Located by title via web search only; not opened or read this session. Referenced only as disclosed, unverified context for the headline finding's and Gut microbiome risk entry's discussion of ovine-versus-human CRH pharmacological differences; not used as graded evidence.Located by title/metadata only; not independently opened this session.
  12. Asadi S, Theoharides TC. Corticotropin-releasing hormone and extracellular mitochondria augment IgE-stimulated human mast-cell vascular endothelial growth factor release, which is inhibited by luteolin. — J Neuroinflammation 2012;9:85 (DOI 10.1186/1742-2094-9-85). In vitro human mast-cell-line (LAD2) and cord-blood-mast-cell study, Tier B mechanistic but judged not to meet the Mitochondrial burden category's test on a plain reading (see that entry). Opened in full via link.springer.com.
  13. Rotvig DH, Jorgensen A, Jensen JH, et al. Can the DEX/CRH test or markers of oxidative stress distinguish work-related stress from major depressive disorder and normal controls? — Stress 2024;27(1) (DOI 10.1080/10253890.2024.2353781). Human study (30 MDD inpatients, 23 exhaustion-disorder outpatients, a historical healthy-control group) directly combining the DEX/CRH stimulation test with urinary oxidative-stress marker measurement (8-oxodG, 8-oxoGuo); confirmed genuinely open-access (CC-BY, gold) via the Unpaywall API. Re-attempted in a dedicated 2026-09-29 re-research session: opened at verified abstract level, with the same verbatim text returned independently by the DOAJ article registry, the Semantic Scholar API, and the University of Copenhagen research-portal record. The full PDF itself (hosted on the KU repository file server) returned HTTP 403, as did the tandfonline.com publisher page directly, and an Europe PMC lookup for the same DOI was blocked by a proxy-level HTTP 429; the paper's methods section, which would name the CRH product and species, was not read. Used as Tier C, class-level evidence for the Oxidative stress entry on the strength of the verified abstract (no group differences in oxidative-stress markers were found); a future revision should still obtain the full PDF to confirm the CRH species and read the discussion in full.Open-access; opened at abstract level via DOAJ, Semantic Scholar, and the KU research portal record; full PDF and publisher page both blocked (HTTP 403), Europe PMC blocked (HTTP 429).
  14. Battaglia CR, Cursano S, Calzia E, Catanese A, Boeckers TM. Corticotropin-releasing hormone (CRH) alters mitochondrial morphology and function by activating the NF-kB-DRP1 axis in hippocampal neurons. — Cell Death Dis 2020;11:1004 (DOI 10.1038/s41419-020-03204-3). In vitro primary rat hippocampal neurons (100 nM Bachem synthetic CRH, product H-2435, human/rat sequence, 30 minutes to 2 hours) and an in vivo mouse thorax-trauma model, Tier B mechanistic, class-level (not corticorelin/ovine-specific). Opened in full via nature.com (gold open access). Located this session (2026-09-29) via a Crossref bibliographic-title search while re-researching ATP production. Source for the mitochondrial-fission (phospho-DRP1, OPA1), reduced oxidative-phosphorylation/electron-transport-system/Complex IV, increased-intracellular-oxidative-stress, and preserved-ATP-output findings cited in the Oxidative stress and ATP production entries above.
  15. Giraud P, Maltese J-Y, Boudouresque F, et al. Peptidylglycine alpha-amidating monooxygenase activity and TRH and CRF biosynthesis. Role of copper. — Biol Trace Elem Res 1992 (DOI 10.1007/BF02784614). Cultured pancreatic and hypothalamic cell study, Tier B/C mechanistic. Opened in full via link.springer.com. Located this session (2026-09-29) via a PubMed search-listing query for "corticotropin-releasing hormone AND copper" while re-researching Copper. Reports that copper is required by the copper-dependent enzyme peptidylglycine alpha-amidating monooxygenase to amidate TRH and CRF into their active forms; runs in the opposite causal direction from a depletion question (copper needed to synthesize endogenous CRF, not corticorelin consuming copper) and is disclosed in the Copper entry but not used to ground a grade.
  16. Huang KE, Mittelman SD, Coates TD, Geffner ME, Wood JC. A Significant Proportion of Thalassemia Major Patients Have Adrenal Insufficiency Detectable on Provocative Testing. — J Pediatr Hematol Oncol 2015 (DOI 10.1097/MPH.0000000000000199). Located by title via a PubMed search-listing query for "corticotropin-releasing hormone AND iron" and confirmed via Crossref while re-researching Iron on 2026-09-29; not opened or read this session. On its title alone, concerns iron-overloaded thalassemia-major patients tested for adrenal insufficiency, very likely with standard ACTH (cosyntropin) rather than CRH stimulation; disclosed in the Iron entry as a tangential, wrong-direction, wrong-population find, not used as evidence for any grade.Located by title/metadata only; not opened this session.
  17. Effect of ACTH, Cortisol and Insulin on Several NADPH-Generating, Oxidizing Systems and Oxidative Phosphorylation in Rat Liver. — Folia Endocrinologica Japonica 1968;44(1):19 (DOI 10.1507/endocrine1927.44.1_19). Animal (rat liver) study of ACTH and cortisol, not CRH/corticorelin directly; would be once-removed, Tier C evidence at best even if opened. J-STAGE article page returned HTTP 500; PDF route disallowed by robots.txt. Not opened or read this session; not used as evidence for any grade, listed for disclosure only.HTTP 500 on the article page; PDF route disallowed by robots.txt. Not opened this session.
  18. Drug-Induced Nutrient Depletions: What Pharmacists Need to Know. — US Pharmacist (consumer/professional circulating-claims source). Opened and searched for corticorelin, Acthrel, CRH, and corticotropin-releasing hormone; no matches found. Used as negative evidence in the circulating-claim audit.
  19. Drug-Nutrient Depletion and Interaction Charts. — Chiro.org compilation (consumer/practitioner circulating-claims source). Opened and searched for corticorelin, Acthrel, CRH, and corticotropin-releasing hormone; no matches found. Used as negative evidence in the circulating-claim audit.
  20. Acthrel side effects. — Drugs.com consumer/professional drug-information page. Opened in full; confirms labeled adverse-reaction content (flushing, allergic reaction, cardiovascular and neurological warnings) and used as negative evidence in the circulating-claim audit; no mineral, vitamin, or "detox" content found.
  21. PubMed search-listing pages (pubmed.ncbi.nlm.nih.gov). — Attempted for corticorelin/CRH plus gut permeability, oxidative stress, mitochondria, copper, ceruloplasmin, hemoglobin, and ATP terms, across multiple phrasings. Reachable for some queries (one returned a genuine zero-result page; one returned a usable results table used for the Gut microbiome risk entry), but rejected by an HTTP 429 proxy response or a reCAPTCHA interstitial on several others. Disclosed as an intermittent, partial tooling-access limitation rather than a total block.Intermittently blocked (HTTP 429 and reCAPTCHA interstitials) across this session.
  22. Unpaywall API. — Queried directly by DOI for the Rotvig 2024 paper in the dedicated 2026-09-29 re-research session. Returned a working JSON response confirming gold open-access (CC-BY) status and three OA locations (the publisher page, a DOAJ article record, and a University of Copenhagen research-portal record), which led to the DOAJ and KU pages that were then opened directly for the verified abstract text used in the Oxidative stress entry. None of the three OA locations exposed a direct machine-readable PDF URL in Unpaywall's own metadata.
  23. Europe PMC REST API. — Attempted for corticorelin/CRH plus mitochondria, oxidative stress, gut permeability, copper, iron, and the Rotvig 2024 DOI lookup specifically. Returned HTTP 429 on every attempt across the original session. Re-attempted in a dedicated, solo 2026-09-29 re-research session with its own tool budget, specifically to test whether the block was shared-session rate-limiting; it again returned HTTP 429 (or a proxy-level rejection carrying the same status) on every attempt, indicating the limitation is not resolved by a dedicated budget alone. Not used as an evidence source; disclosed as a genuine, persistent tooling-access limitation.HTTP 429 on every attempt, both in the original session and in a dedicated 2026-09-29 re-attempt.
  24. Semantic Scholar API and web frontend. — Attempted for corticorelin/CRH plus the Rotvig 2024 DOI, copper, iron, and general category terms. API returned HTTP 429; the web frontend search page returned a robots.txt disallowance. Re-attempted in the dedicated 2026-09-29 re-research session (copper- and iron-specific queries) and again returned HTTP 429 on every attempt. Not used as an evidence source; disclosed as a genuine, persistent tooling-access limitation.HTTP 429 (API) and robots.txt disallowance (web frontend), both in the original session and in a dedicated 2026-09-29 re-attempt.
  25. OpenAlex API. — Attempted for the AJP-GI 2016 DOI and a combined query across all seven required categories. Returned HTTP 429 on every attempt in the original session. Re-attempted in the dedicated 2026-09-29 re-research session (copper- and iron-specific queries, with and without a mailto contact parameter for the polite pool) and again returned HTTP 429 on every attempt. Not used as an evidence source; disclosed as a genuine, persistent tooling-access limitation.HTTP 429 on every attempt, both in the original session and in a dedicated 2026-09-29 re-attempt.
  26. WebSearch tool. — Used for the initial label-location and background queries early in the original session, then reported "this session has used its web search budget (200 of 200 WebSearch calls)" partway through the review, before several planned category-specific queries (including a targeted search for the Rotvig 2024 abstract) could run. Re-attempted once in the dedicated 2026-09-29 re-research session; it again reported the 200-of-200 budget exhausted, indicating this limit is tracked at the account level rather than reset per session. Disclosed as a genuine, persistent tooling-access limitation; all research relied on WebFetch against specific URLs (PubMed, Crossref, Europe PMC, DOAJ, Semantic Scholar, OpenAlex, Unpaywall, publisher and repository pages) instead.WebSearch budget exhausted (200/200) in the original session and confirmed still exhausted on a 2026-09-29 re-attempt.
  27. ClinicalTrials.gov, NCT05071781 (Effect of CRH on Duodenal Markers and Gastric Sensorimotor Function). — Attempted to confirm the CRH product/manufacturer used in the related AJP-GI 2025 trial. The fetched page returned only site metadata and navigation elements, no intervention or arm details. Not used as an evidence source; disclosed as an inconclusive attempt.Page returned metadata/navigation only; intervention details not retrievable this session.
  28. Crossref API. — The one literature-search channel that remained genuinely usable across both the original session and the dedicated 2026-09-29 re-research session, once a mailto contact parameter was added, though it too returned HTTP 429 on several individual attempts requiring a pause and retry. Queried roughly fifteen times in the original session and a further nine times in the re-research pass, across all seven required categories plus classical-mechanism and circulating-claim terms; supplied the majority of the sources listed above, including the bibliographic lookups that identified the Battaglia 2020 and Giraud 1992 papers by title, and confirmed, by its absence of on-topic results, the evidence gaps still disclosed in the Mitochondrial burden, Copper, Iron, and Oxygen delivery/utilization entries.
  29. DOAJ (Directory of Open Access Journals) article registry and API. — Reached for the Rotvig 2024 DOI in the dedicated 2026-09-29 re-research session, following the OA-location URL returned by Unpaywall. Both the article's registry page and its API endpoint returned the same full, verbatim CC-BY abstract, used as Tier C evidence in the Oxidative stress entry.
  30. University of Copenhagen Research Portal record for the Rotvig 2024 paper. — Reached in the dedicated 2026-09-29 re-research session, following the OA-location URL returned by Unpaywall. The record page returned the same verbatim CC-BY abstract as DOAJ and named a direct PDF-download link on the KU repository file server; that PDF link itself returned HTTP 403 when fetched.