Cosyntropin

The biological activity of ACTH resides entirely in its first 24 residues, so cosyntropin is a complete agonist at the adrenal melanocortin-2 receptor while lacking the antigenic C-terminal region of the full 39-residue hormone. A supraphysiologic 250 mcg dose saturates adrenal MC2R and produces the maximal cortisol response a functioning adrenal cortex is capable of. Failure to reach a peak cortisol threshold, conventionally 500 nmol/L or about 18 mcg/dL with older assays and roughly 400 to 450 nmol/L with modern monoclonal assays, indicates adrenal insufficiency. A 1 mcg low-dose variant is sometimes used to catch mild secondary adrenal insufficiency, at the cost of more technical error and less standardisation. A depot tetracosactide formulation is also used therapeutically outside the US in the way corticotropin gel is used within it.

Targets: MC2R, Adrenal cortisol synthesis

• · 250 mcg intravenously or intramuscularly. This is the standard adult and paediatric dose above 2 years.
• · 1 mcg requires careful dilution and immediate saline flush, since drug adsorption to plastic tubing is a real source of false positives.

Work out your exact syringe units →

• uncommonFlushing or mild injection-site reaction
• rareHypersensitivity reaction— Far less common than with the older full-length porcine preparations, but anaphylaxis has been reported, particularly in patients with asthma or atopy.

• Known hypersensitivity to cosyntropin or tetracosactide
• Interpretation is invalid if the patient has taken hydrocortisone within about 12 to 24 hours, since it cross-reacts with the cortisol assay

• redundantcorticotropin — Same receptor; corticotropin gel is the therapeutic long-acting version.

• · Serum cortisol at 0, 30 and 60 minutes
• · Plasma ACTH and renin drawn before the test if primary versus secondary insufficiency is in question

Prescription diagnostic product. Available in the US as Cortrosyn; Synacthen is used across Europe and elsewhere.

• Cortrosyn FDA prescribing information (label)
• Endocrine Society clinical practice guideline on the diagnosis and treatment of primary adrenal insufficiency (guideline)

The pharmacology here is trivially simple and the interpretation is where all the difficulty lives. Residues 1-24 contain everything needed for MC2R binding and activation; the message sequence His6-Phe7-Arg8-Trp9 does the activating and the basic cluster Lys15-Lys16-Arg17-Arg18 does most of the binding. A 250 mcg dose produces plasma ACTH concentrations orders of magnitude above anything physiological, saturating MC2R and extracting the maximum cortisol output the adrenal cortex is capable of. That is the point: the test asks what the gland can do, not what it is doing. The interpretive trap is structural. In primary adrenal insufficiency the adrenal itself is destroyed and the test is definitive. In secondary adrenal insufficiency the adrenal is intact but has been unstimulated, and it only becomes unresponsive once it has atrophied, which takes weeks. So a patient who lost pituitary ACTH last week has a normal short Synacthen test and adrenal insufficiency at the same time, and the test will actively mislead you. That is the single most important thing to know about it. The 1 mcg low-dose variant exists to catch milder or earlier secondary insufficiency by using a submaximal stimulus, at the cost of poorer standardisation and the plastic adsorption problem. Assay drift matters too: the classic 500 nmol/L (18 mcg/dL) cut-off was derived from older polyclonal immunoassays, and modern monoclonal and mass spectrometry assays read lower, so the appropriate threshold is now nearer 400 to 450 nmol/L. Applying an old cut-off to a new assay over-diagnoses adrenal insufficiency, and this is happening in practice.

The single biggest error is trusting a normal test in recent-onset secondary adrenal insufficiency. If the pituitary insult was days or a few weeks ago, the adrenals have not yet atrophied, they respond normally to a supraphysiologic stimulus, and the patient still cannot mount a stress response. In that situation an insulin tolerance test or a glucagon stimulation test is the right investigation, or you simply treat. The second error is applying a 500 nmol/L cut-off to a modern monoclonal assay that reads systematically lower, which manufactures adrenal insufficiency out of healthy people. The third is drawing ACTH after the injection, or drawing it into a warm tube and letting it sit, both of which make the primary-versus-secondary distinction impossible. The fourth is the 1 mcg test done badly: dilution error and plastic adsorption make it far less reliable than its advocates claim. The fifth is testing a patient on hydrocortisone that morning. And a practical point: anaphylaxis, though far rarer than with the old porcine preparations, has been reported, particularly in asthmatic and atopic patients.

1. 250 mcgStandard short Synacthen test — 250 mcg intravenously or intramuscularly as a single dose, with cortisol at 0, 30 and 60 minutes. This is the adult and paediatric dose above 2 years. Reconstitute the 0.25 mg vial with 1 mL of sterile normal saline immediately before use.
2. 1 mcgLow-dose test for suspected mild secondary adrenal insufficiency — 1 mcg intravenously with cortisol at 0, 20 or 30 minutes. Requires careful serial dilution and an immediate saline flush, because peptide adsorption to plastic tubing is a real source of false positives at this dose.

• MC2R on adrenal zona fasciculata — Full agonist; the 1-24 fragment retains complete biological activity of ACTH(1-39). Numeric affinity not resolved this session.

  Gs-cyclic AMP-PKA signalling, StAR-mediated cholesterol transport and maximal cortisol synthesis within 30 to 60 minutes.

• MC2R on zona glomerulosa — Full agonist

  Acute aldosterone rise, which is why some protocols measure aldosterone alongside cortisol when distinguishing primary from secondary insufficiency.

• MC1R and other melanocortin receptors — Lower than MC2R

  Clinically irrelevant at single diagnostic doses. Relevant only for the depot tetracosactide formulations used therapeutically outside the US.

Cortisol begins rising within about 10 minutes of injection and peaks at 30 to 60 minutes, which is why sampling stops at an hour. The whole test takes about 70 minutes from arrival to the last draw. The 250 mcg test is relatively insensitive to time of day, unlike a basal cortisol, though morning testing remains conventional. Results are typically back within a day or two, and the ACTH and renin drawn alongside it are what turn a positive test into a diagnosis.

This is a single diagnostic dose, so there is no stack in the therapeutic sense, but there is a critical drug-interference list. Hydrocortisone taken within about 12 to 24 hours cross-reacts with the cortisol assay and invalidates the result; dexamethasone does not and is the glucocorticoid to use if a patient must be covered before testing. Prednisolone also cross-reacts. Oestrogen-containing contraceptives and pregnancy raise cortisol-binding globulin and therefore total cortisol, so a patient on the pill can pass a test she should have failed, and the pill should be stopped for around six weeks beforehand or a free cortisol or salivary measurement used. Mitotane lowers cortisol-binding globulin and does the reverse. Recent inhaled or topical steroids in sufficient dose suppress the axis and are a common cause of a genuinely abnormal result nobody expected.

Against the insulin tolerance test: the ITT is the true reference standard because it tests the whole hypothalamic-pituitary-adrenal axis rather than just the adrenal gland, and it is the correct test in recent-onset secondary insufficiency where cosyntropin gives false reassurance. It is also unpleasant, needs supervision, and is contraindicated in ischaemic heart disease, epilepsy and the elderly, which is why cosyntropin dominates in practice. Against the glucagon stimulation test: a safer alternative to the ITT for the same question, with the trade-off of a three to four hour protocol and a lot of nausea. Against the 1 mcg low-dose cosyntropin test: theoretically more sensitive for partial secondary insufficiency, practically more error-prone, and not standardised. Against a simple 8 or 9 am cortisol: a morning cortisol above roughly 400 nmol/L makes adrenal insufficiency very unlikely and below about 100 nmol/L makes it very likely, so the stimulation test is really only needed for the middle band, and a lot of tests are done that a basal cortisol would have settled.

Not applicable. This is a single-use diagnostic vial. US pricing for Cortrosyn has historically been far higher than for Synacthen in Europe, but I did not source figures this session.

• ?The ACTH(1-24) sequence given is the standard published sequence, but the Cortrosyn label renders it as an image and I did not confirm it character by character this session, so verified is false.
• ?The Cortrosyn label contains no pharmacokinetic data at all; the 15 minute half-life and 30 to 60 minute cortisol peak are conventional teaching that I did not resolve against a primary source.
• ?The exact modern assay-specific cortisol cut-offs vary by platform and I have given a range rather than a single number deliberately.
• ?The Endocrine Society guideline is cited as further reading; I did not confirm its identifiers.
• ?No cost figures were sourced.

• CORTROSYN (cosyntropin) for injection - FDA prescribing information Amphastar Pharmaceuticals, DailyMed

  Source of the description as synthetic beta 1-24 corticotropin containing the first 24 of the 39 amino acids of natural ACTH. Worth noting that the label contains no onset, duration or half-life data at all.

• Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline Bornstein SR, et al., Journal of Clinical Endocrinology and Metabolism

  Further reading, not verified this session. The source for the cut-off values, the assay-dependence problem and the recommendation to draw ACTH and renin before the test.