Glucagon-like diagnostic peptides

This is a category rather than a molecule. Corticorelin (ovine CRH, Acthrel) stimulates pituitary ACTH release and is used with inferior petrosal sinus sampling to distinguish pituitary Cushing's disease from ectopic ACTH. Synthetic human secretin (ChiRhoStim) triggers a paradoxical gastrin surge in gastrinoma and is also used for pancreatic function testing and MRCP. Glucagon, given intramuscularly, is a validated growth hormone and cortisol stimulus in the glucagon stimulation test, useful where insulin tolerance testing is unsafe. GHRH combined with arginine was the classic GH deficiency test until GHRH was withdrawn from the US market; macimorelin, an oral ghrelin agonist, has largely replaced it. Protirelin (TRH) stimulates TSH and prolactin and is now mostly of historical interest. What unites them is that dosing is fixed, exposure is single, and the answer comes from a timed series of blood draws rather than from any therapeutic effect.

Targets: CRH receptor, Secretin receptor, Glucagon receptor, GHRH receptor, TRH receptor

• · Dosed by weight at 1 mcg per kg, commonly capped at 100 mcg total.
• · Dosed in clinical units at 0.4 mcg per kg of synthetic human secretin. A rise in gastrin of more than 120 pg/mL is diagnostic.
• · 1 mg intramuscularly, or 1.5 mg if body weight exceeds 90 kg. Nausea is very common at 60 to 120 minutes.

Work out your exact syringe units →

• very commonNausea and vomiting— Especially with the glucagon stimulation test, where it peaks around an hour in.
• commonFlushing— Characteristic of corticorelin, sometimes lasting up to an hour.
• uncommonTransient hypotension or tachycardia— Reported with rapid corticorelin injection; give slowly.
• uncommonLate hypoglycaemia after the glucagon test— The initial glycaemic rise is followed by a fall; patients should eat before leaving.
• rareHypersensitivity

• Glucagon stimulation testing in phaeochromocytoma or insulinoma
• Any of these tests in a patient too unstable to sit through several hours of timed sampling
• Product-specific hypersensitivity

• redundantcosyntropin — Another member of the same provocative-testing family, aimed at the adrenal rather than the pituitary.
• redundantthyrotropin-alfa — Also a diagnostic stimulation agent, for the thyroid axis.

• · Timed hormone sampling per the specific test protocol
• · Blood glucose during and after glucagon testing
• · Blood pressure and symptoms during infusion

Prescription diagnostic products used in clinical endocrinology. Availability varies substantially by country and several have been withdrawn commercially.

• Acthrel (corticorelin ovine triflutate) FDA prescribing information (label)
• ChiRhoStim human secretin FDA prescribing information (label)
• Endocrine Society clinical practice guideline on evaluation and treatment of adult growth hormone deficiency (guideline)

The unifying logic of provocative endocrine testing is that a basal hormone measurement tells you what a gland is doing and a stimulated one tells you what it can do, and only the second answers the question in most deficiency states. Corticorelin binds pituitary CRH1 receptors on corticotrophs, raising cyclic AMP and driving POMC transcription and ACTH release; its diagnostic power in Cushing's is that pituitary corticotroph adenomas retain CRH responsiveness while ectopic ACTH-secreting tumours mostly do not, and combining it with inferior petrosal sinus sampling gives a central-to-peripheral ACTH gradient that localises the source. Secretin exploits a genuine physiological paradox: normal gastrin-producing G cells are inhibited by secretin, whereas gastrinoma cells respond to it with a paradoxical gastrin surge, so a rise of more than 120 pg/mL is close to diagnostic for Zollinger-Ellison syndrome. Glucagon's use as a growth hormone and cortisol stimulus is the least mechanistically understood of the group: the GH rise is late, peaking at 2 to 3 hours, is not explained by the initial glycaemic excursion alone, and probably involves noradrenergic and hypothalamic pathways. GHRH acts on somatotroph GHRH receptors and, combined with arginine which suppresses somatostatin tone, produces a maximal GH pulse; that combination was the reference test until GHRH was withdrawn from the US market. Protirelin acts on pituitary TRH receptors to release TSH and prolactin and is now largely historical, having been displaced by sensitive TSH assays.

Availability is the first problem: GHRH (Geref Diagnostic) was withdrawn in the US, protirelin is largely gone, and macimorelin has replaced GHRH-arginine, so a lot of the literature describes tests you cannot actually order. The second is applying a cut-off derived from one assay or one population to another; the BMI dependence of GH cut-offs is the clearest example, and using a lean-population threshold in an obese patient manufactures GH deficiency. The third is ending the glucagon test early, before the late GH peak. The fourth is glucagon testing in phaeochromocytoma, which can provoke a hypertensive crisis, or in insulinoma, both explicit contraindications. The fifth is failing to feed the patient after the glucagon test, producing late hypoglycaemia on the drive home. The sixth is doing any of these in a patient too unwell to sit through several hours of timed sampling, which produces missed draws and an uninterpretable curve.

1. 100 mcgCorticorelin test — 1 mcg per kilogram intravenously, commonly capped at 100 mcg total. Give slowly; rapid injection causes flushing and occasionally transient hypotension.
2. —Secretin stimulation test — 0.4 mcg per kilogram of synthetic human secretin intravenously, with gastrin sampled at baseline and at 2, 5, 10, 15 and 30 minutes. Proton pump inhibitors must be withdrawn beforehand.
3. 1 mgGlucagon stimulation test — 1 mg intramuscularly, or 1.5 mg if body weight exceeds 90 kg. Samples every 30 minutes for 3 to 4 hours. Nausea peaks around 60 to 120 minutes and is very common.

• CRH1 receptor on pituitary corticotrophs (corticorelin) — Ovine CRH is more potent and longer acting at the human receptor than human CRH.

  Gs-cyclic AMP signalling driving POMC transcription and ACTH release, with cortisol following. Pituitary adenomas respond, most ectopic sources do not, which is the diagnostic discrimination.

• Secretin receptor on gastrin-producing cells (secretin)

  Paradoxical gastrin release from gastrinoma cells, against physiological inhibition of normal G cells. A rise above 120 pg/mL is diagnostic.

• Secretin receptor on pancreatic ductal cells

  Bicarbonate-rich fluid secretion, used for pancreatic function testing and to distend the duct for secretin-enhanced MRCP.

• Glucagon receptor (glucagon stimulation test)

  Hepatic glycogenolysis and a delayed growth hormone and cortisol rise peaking at 2 to 3 hours, through incompletely understood central pathways.

• GHRH receptor on pituitary somatotrophs

  Direct GH release, maximal when combined with arginine, which lowers hypothalamic somatostatin tone.

• TRH receptor on thyrotrophs and lactotrophs (protirelin)

  TSH and prolactin release. Largely obsolete since third-generation TSH assays arrived.

Corticorelin: ACTH rises within minutes, cortisol follows, and sampling ends at 60 minutes. Secretin: the paradoxical gastrin rise in gastrinoma occurs within 2 to 10 minutes, which is why the early samples matter most. Glucagon: glucose rises early, but the growth hormone peak is late at 2 to 3 hours and the whole test runs 3 to 4 hours with nausea peaking around the first hour. None of these agents has any lasting effect and none is repeated on a schedule.

These are not stacked with anything; they are stacked against interference. The recurring theme is that concurrent medication invalidates the result more often than technique does. Proton pump inhibitors must stop before secretin testing for gastrinoma. Hydrocortisone and prednisolone cross-react with cortisol assays and must be swapped for dexamethasone before any cortisol-based test. Oestrogen raises cortisol-binding globulin and inflates total cortisol. Beta-blockers blunt GH responses. Somatostatin analogues suppress everything the tests are trying to provoke. Where multiple axes need assessing, tests are generally sequenced rather than combined, though arginine-GHRH and insulin tolerance testing have historically been used to assess several axes at once.

Within the group, the comparisons that matter are about what has replaced what. For adult GH deficiency, the insulin tolerance test remains the reference standard but is unsafe in ischaemic heart disease, epilepsy and the elderly; GHRH-arginine was the standard alternative until GHRH left the US market; macimorelin, an oral ghrelin receptor agonist, is now the practical replacement and is far more tolerable than either. The glucagon stimulation test is the fallback where macimorelin is unavailable, at the cost of four hours and a lot of nausea. For Cushing's, corticorelin plus inferior petrosal sinus sampling remains the best discriminator between pituitary and ectopic ACTH, though improved pituitary MRI and 68Ga-DOTATATE imaging for ectopic sources have reduced how often it is needed. For gastrinoma, the secretin test is still the functional confirmation, but somatostatin receptor imaging now often finds the tumour first. For thyroid axis testing, protirelin has been entirely superseded by sensitive TSH assays and survives only in older literature.

Not applicable. These are single-use diagnostic vials billed per test. Corticorelin in particular has a reputation for being disproportionately expensive relative to the information it provides, which is part of why inferior petrosal sinus sampling protocols vary between centres. No figures sourced this session.

• ?This entry covers a heterogeneous group rather than a single molecule, so almost every pharmacokinetic field is null by necessity rather than by omission.
• ?None of the individual product labels was resolved in this session, so both citations are marked unverified further reading.
• ?The mechanism of the delayed growth hormone response to glucagon is genuinely not well understood, and I have not overstated it.
• ?Availability varies substantially by country and several agents have been discontinued commercially, so any specific protocol should be checked against what is actually stocked locally.
• ?The 120 pg/mL secretin cut-off and the corticorelin petrosal sinus ratios are conventional values I did not resolve against a primary source this session.
• ?No cost figures were sourced.

• ACTHREL (corticorelin ovine triflutate) for injection - FDA prescribing information Ferring Pharmaceuticals, DailyMed

  Further reading, not resolved this session. The label is the source for the 1 mcg per kg dosing and the timed sampling protocol.

• Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline Molitch ME, et al., Journal of Clinical Endocrinology and Metabolism

  Further reading, not verified this session. The source for BMI-adjusted GH cut-offs and for the rule that multiple pituitary deficiencies plus a low IGF-1 can substitute for provocative testing.