Short Synacthen Test — Adrenal Insufficiency
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The adrenal insufficiency risk assessment calculator evaluates the probability of adrenal insufficiency (AI) using biochemical criteria from the Short Synacthen Test (SST), morning cortisol thresholds, and clinical risk factors. Adrenal insufficiency occurs when the adrenal glands produce insufficient cortisol, which can be life-threatening during physiological stress (surgery, illness, trauma). Primary adrenal insufficiency (Addison disease) results from destruction of the adrenal cortex itself, most commonly by autoimmunity (anti-21-hydroxylase antibodies), infection (tuberculosis, histoplasmosis), or adrenal haemorrhage. Secondary adrenal insufficiency results from ACTH deficiency due to pituitary or hypothalamic disease. Tertiary adrenal insufficiency, the most common form globally, is caused by long-term glucocorticoid therapy suppressing the hypothalamic-pituitary-adrenal (HPA) axis. The Short Synacthen Test (250 mcg synthetic ACTH/Synacthen intramuscular or intravenous) remains the most widely used dynamic test for AI. A peak cortisol below 550 nmol/L at 30 or 60 minutes post-Synacthen is the most widely used threshold for diagnosing AI, though some centres use 500 nmol/L or have lowered the threshold to 450-500 nmol/L following assay changes. Morning cortisol alone (pre-Synacthen or basal) provides useful information: a value above 550 nmol/L makes AI very unlikely, values between 100 and 550 nmol/L are equivocal and require the SST, and a value below 100 nmol/L is highly suggestive of AI. This calculator integrates these thresholds to guide clinical assessment.
Morning cortisol >550 nmol/L = AI unlikely (no further testing needed); 100-550 nmol/L = equivocal (Short Synacthen Test required); <100 nmol/L = AI likely; SST peak cortisol <550 nmol/L at 30-60 min = Adrenal insufficiency confirmed
- 1Collect an early morning (8-9 AM) blood sample for cortisol measurement in the basal, unstressed state.
- 2Interpret basal cortisol: above 550 nmol/L makes significant AI very unlikely in most patients and may avoid the need for SST; below 100 nmol/L is highly suggestive of AI.
- 3For equivocal basal cortisol (100-550 nmol/L), proceed to the Short Synacthen Test: administer 250 mcg synthetic ACTH (tetracosactide/Synacthen) IM or IV.
- 4Measure cortisol at 0 minutes (baseline), 30 minutes, and optionally 60 minutes post-Synacthen.
- 5Interpret peak cortisol: above 550 nmol/L (some labs use 500 nmol/L) = normal response; below threshold = AI confirmed.
- 6Determine the type of AI: primary (elevated ACTH, low aldosterone, electrolyte disturbances) vs secondary/tertiary (low ACTH, preserved aldosterone in most cases).
- 7Identify clinical risk factors: long-term glucocorticoid use (>5 mg prednisolone daily for >4 weeks), pituitary surgery or radiotherapy, autoimmune conditions (type 1 diabetes, autoimmune thyroid disease), known adrenal pathology.
Normal HPA axis function demonstrated
A morning cortisol above 550 nmol/L makes clinically significant adrenal insufficiency very unlikely and can be used to rule out AI without proceeding to SST. This threshold represents a peak cortisol likely achievable during physiological stress.
Cortisol 100-550 nmol/L does not rule in or rule out AI
A morning cortisol of 280 nmol/L in the equivocal range, combined with symptoms of AI (fatigue, postural dizziness) and inhaled corticosteroid use (a potential cause of tertiary AI), requires formal SST for definitive assessment.
Secondary AI post-pituitary surgery — hydrocortisone replacement required
A peak Synacthen-stimulated cortisol of 430 nmol/L below the 550 nmol/L threshold confirms adrenal insufficiency. The context of recent pituitary surgery with low ACTH confirms this as secondary AI. Hydrocortisone replacement (10-15-5 mg daily in divided doses) is required, with sick-day rules education.
Addison disease likely — check anti-21-hydroxylase antibodies, ACTH, aldosterone
A morning cortisol below 100 nmol/L with classic features of primary AI (hyperpigmentation from elevated ACTH/MSH, salt craving, hyponatraemia, hyperkalaemia from mineralocorticoid deficiency) is highly diagnostic of Addison disease. SST is confirmatory; anti-21-hydroxylase antibodies are positive in approximately 80% of autoimmune cases.
Pre-operative assessment of patients on long-term corticosteroids to determine whether peri-operative hydrocortisone cover is required, enabling practitioners to make well-informed quantitative decisions based on validated computational methods and industry-standard approaches
Post-pituitary surgery monitoring to detect secondary adrenal insufficiency before hospital discharge, helping analysts produce accurate results that support strategic planning, resource allocation, and performance benchmarking across organizations, where accurate numerical computation is essential for producing reliable outputs that inform planning, evaluation, and continuous improvement processes in both corporate and individual settings
Investigation of unexplained hyponatraemia, weight loss, and fatigue in patients with autoimmune disease history, allowing professionals to quantify outcomes systematically and compare scenarios using reliable mathematical frameworks and established formulas
Monitoring HPA axis recovery in patients tapering long-term corticosteroid therapy, supporting data-driven evaluation processes where numerical precision is essential for compliance, reporting, and optimization objectives, necessitating robust computational methods that deliver consistent and verifiable results suitable for reporting, auditing, and long-term trend analysis in professional environments
Screening patients on immune checkpoint inhibitors for immune-related hypophysitis and secondary adrenal insufficiency, which requires precise quantitative analysis to support evidence-based decisions, strategic resource allocation, and performance optimization across diverse organizational contexts and professional disciplines
Glucocorticoid-induced adrenal suppression
Long-term corticosteroid users are the largest group with AI risk. Risk is proportional to dose, duration, time of day of dosing (morning dosing is less suppressive than evening), route (systemic > intra-articular > inhaled), and potency. Gradual dose tapering over weeks to months allows HPA axis recovery. SST during tapering identifies when adrenal reserve is restored.
Pregnancy and adrenal insufficiency
Cortisol requirements increase substantially in pregnancy due to rising CBG. Women with known AI typically need a 50-100% increase in hydrocortisone dose in the third trimester. During labour, stress-dose hydrocortisone (100 mg IM or IV at onset of labour, continued 6-hourly for 24 hours) is standard. Breastfeeding is safe on physiological hydrocortisone replacement.
Immune checkpoint inhibitor-related AI
Immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA-4) used in cancer immunotherapy cause hypophysitis (pituitary inflammation) in 1-5% of patients, resulting in secondary AI among other hormone deficiencies. Pituitary AI from checkpoint inhibitors often requires lifelong hydrocortisone replacement, as pituitary function rarely recovers even after immunosuppressive treatment.
Bilateral adrenal haemorrhage
Bilateral adrenal haemorrhage is a rare but life-threatening cause of acute AI, occurring in the context of septic shock (Waterhouse-Friderichsen syndrome from meningococcaemia), anticoagulation, antiphospholipid syndrome, or major surgery. It presents as rapid cardiovascular collapse with severe hyponatraemia and hyperkalaemia. Adrenal CT reveals bilateral adrenal haematomas. Immediate IV hydrocortisone is life-saving.
| Morning Cortisol (nmol/L) | Interpretation | Next Step |
|---|---|---|
| > 550 | Normal — AI very unlikely | No further testing required |
| 400 - 550 | Borderline normal | SST if clinical suspicion remains |
| 100 - 400 | Equivocal | Short Synacthen Test required |
| < 100 | AI highly likely | Urgent SST + ACTH + electrolytes |
| SST peak > 550 | Normal adrenal reserve | AI excluded |
| SST peak < 550 | Adrenal insufficiency confirmed | Start hydrocortisone; determine type (1°/2°/3°) |
What is the Short Synacthen Test and how is it performed?
The Short Synacthen Test (SST) administers 250 mcg of synthetic ACTH (tetracosactide, brand name Synacthen) via intramuscular or intravenous injection, then measures cortisol at 30 and optionally 60 minutes. A peak cortisol above 550 nmol/L (some labs use 500 nmol/L) constitutes a normal response. The test assesses adrenocortical reserve and sensitivity — it does not directly assess pituitary ACTH secretion.
Why does the SST threshold differ between labs?
The 550 nmol/L threshold was historically derived from Immunoassay data and validated against clinical outcomes. Different immunoassay platforms measure cortisol differently — the Roche Elecsys platform tends to give lower values than older platforms, leading some centres to adopt thresholds of 450-500 nmol/L. Laboratories must establish their own assay-specific normal response cut-offs.
Can the SST miss secondary adrenal insufficiency?
Yes. The SST is excellent at detecting primary AI (where adrenal atrophy gives a blunted response to Synacthen) but can give a false-normal result in recent-onset secondary AI — because the adrenal glands maintain their responsiveness to exogenous ACTH for several weeks after pituitary ACTH secretion is lost. The insulin tolerance test (ITT) directly assesses the HPA axis response to central stress and is more sensitive for secondary AI of recent onset.
What are sick-day rules for patients with AI?
Patients with confirmed adrenal insufficiency are taught sick-day rules (also called steroid emergency rules): double or triple the usual hydrocortisone dose during any febrile illness (temperature above 37.5°C), significant injury, or before surgery. If vomiting prevents oral medication, the patient must seek emergency care for parenteral hydrocortisone. All AI patients should carry a steroid emergency card and wear medical alert identification.
What causes tertiary adrenal insufficiency?
Tertiary (or iatrogenic) adrenal insufficiency is caused by prolonged exogenous glucocorticoid therapy suppressing hypothalamic CRH and pituitary ACTH secretion, leading to adrenal atrophy. Risk increases with: systemic corticosteroids (prednisolone >5 mg/day for >4 weeks), intra-articular injections, inhaled corticosteroids (high-dose), topical corticosteroids (large area), and rectal preparations. Recovery of the HPA axis typically takes weeks to months after stopping glucocorticoids.
What is an adrenal crisis and how is it treated?
An adrenal crisis is a life-threatening emergency caused by acute cortisol deficiency during physiological stress in a patient with adrenal insufficiency. It presents with hypotension, hyponatraemia, vomiting, severe abdominal pain, and altered consciousness. Treatment is immediate: 100 mg hydrocortisone IV or IM bolus followed by continuous IV hydrocortisone 200 mg/24h or 50 mg IM 6-hourly, along with 1-2L normal saline IV, glucose monitoring, and ICU-level support.
Is the Low-Dose Synacthen Test more sensitive than the Standard Dose (250 mcg)?
The Low-Dose Synacthen Test (1 mcg) achieves near-physiological plasma ACTH levels and has been proposed as more sensitive for detecting partial secondary AI. However, its practical advantages over the standard 250 mcg test are debated, dosing requires careful dilution, and it is more technically demanding. Most international guidelines continue to recommend the standard 250 mcg SST for routine clinical use.
When is the Insulin Tolerance Test preferred over SST?
The insulin tolerance test (ITT) is the gold standard for assessing the entire HPA axis (hypothalamus to pituitary to adrenal) and is preferred when central (secondary/tertiary) AI is suspected — particularly after recent pituitary surgery, in the first 4-6 weeks after pituitary ACTH loss, or when SST results are inconsistent with the clinical picture. It is contraindicated in patients with ischaemic heart disease, epilepsy, or severe hypoadrenalism.
Pro Tip
Any patient who has taken more than 5 mg prednisolone (or equivalent) daily for more than 4 weeks in the past 12 months should be considered at risk of HPA axis suppression. These patients should never have their steroids stopped abruptly and should be tested if undergoing major surgery or presenting with unexplained hypotension or weight loss.
Did you know?
Thomas Addison described primary adrenal insufficiency in 1855 based on eleven patients with 'peculiar anaemia' and bronzed skin — before cortisol had been identified, before the concept of hormones existed, and before the adrenal glands' function was understood. His clinical acumen in recognising this syndrome entirely from bedside observation earns him recognition as one of the founding fathers of endocrinology.
References
- ›Bornstein SR et al. Diagnosis and Treatment of Primary Adrenal Insufficiency (Endocrine Society 2016)
- ›Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003
- ›Society for Endocrinology — Adrenal Insufficiency Emergency Guidance 2020
- ›NICE CG98 — Addison's Disease and Related Conditions 2016
- ›Tomlinson JW et al. Association between premature mortality and hypopituitarism. Lancet 2001