What is the normal 6 am serum cortisol range in a healthy adult and how should low or high values be interpreted and further evaluated?

Normal 6 AM Cortisol Range and Clinical Interpretation

In healthy adults, normal 6 AM serum cortisol ranges from 5–23 μg/dL (138–635 nmol/L), with most values clustering between 10–20 μg/dL (276–552 nmol/L). 1, 2

Diagnostic Thresholds for Low Values

Values That Rule Out Adrenal Insufficiency

• Morning cortisol >14 μg/dL (>386 nmol/L) effectively excludes adrenal insufficiency and requires no further testing. 1, 2
• Values >12.4 μg/dL (>300 nmol/L) provide strong reassurance against ACTH-cortisol insufficiency in most clinical contexts. 2

Values Requiring Dynamic Testing

• Morning cortisol <10 μg/dL (<275 nmol/L) should prompt an ACTH stimulation test, particularly when accompanied by suggestive clinical features (unexplained hypotension, hyperpigmentation, hyponatremia, hyperkalemia, hypoglycemia, or persistent vomiting/diarrhea). 1, 3
• A threshold of <275 nmol/L identifies subnormal adrenal reserve with 96.2% sensitivity. 3

The Equivocal Zone (10–14 μg/dL)

• Values between 275–386 nmol/L (10–14 μg/dL) fall into an indeterminate range where clinical context determines next steps. 1, 3
• Proceed directly to ACTH stimulation testing if clinical suspicion is moderate to high (presence of unexplained collapse, electrolyte abnormalities, or autoimmune thyroid disease). 1
• In low-suspicion scenarios with values >12 μg/dL, observation may be reasonable, though dynamic testing remains the gold standard. 2

ACTH Stimulation Test Protocol

When morning cortisol is equivocal or low:

• Administer 0.25 mg cosyntropin (Synacthen) IV or IM. 1
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-injection. 1
• Peak cortisol <500 nmol/L (<18 μg/dL) confirms primary adrenal insufficiency. 1, 2
• Simultaneously measure plasma ACTH with the baseline cortisol to distinguish primary (ACTH markedly elevated, often >100 pg/mL) from secondary adrenal insufficiency (ACTH low or inappropriately normal). 1

Critical Pitfalls to Avoid

Exogenous Steroid Interference

• Always obtain a comprehensive medication history before interpreting cortisol levels, including oral glucocorticoids, inhaled fluticasone, topical creams, intra-articular/epidural injections, and over-the-counter supplements. 1, 2
• Exogenous steroids suppress endogenous cortisol production and invalidate testing; failure to exclude these sources leads to unnecessary investigations. 1

Age and Sex Considerations

• Morning cortisol reference ranges differ by pubertal status: prepubertal children (Tanner stage 1) rarely exceed 248 nmol/L (9 μg/dL), whereas 90% of healthy adults (Tanner stage 5) exceed this threshold. 4
• Sex differences emerge after puberty, with higher values in post-pubertal individuals. 4
• In children, proceed directly to ACTH stimulation testing rather than relying on morning cortisol screening. 4

Rare Presentation: Normal Cortisol with Primary Adrenal Insufficiency

• Approximately 10% of patients with confirmed primary adrenal insufficiency present with normal or even high basal cortisol concentrations in the presence of markedly elevated ACTH (>300 pg/mL). 5
• When clinical history strongly suggests Addison's disease (progressive fatigue, weight loss, hyperpigmentation, salt craving) and ACTH is clearly elevated, do not dismiss the diagnosis based solely on a "normal" morning cortisol—proceed to ACTH stimulation testing and check 21-hydroxylase antibodies. 5

Diagnostic Thresholds for High Values

Screening for Cushing's Syndrome

• A single elevated morning cortisol (e.g., 19 μg/dL) falls within the normal reference range and does not indicate hypercortisolism. 6
• Morning cortisol is not a screening test for Cushing's syndrome because the circadian rhythm is preserved early in the disease. 6
• Screen for Cushing's syndrome only when multiple progressive clinical features are present (central obesity with striae, proximal myopathy, easy bruising, facial plethora, or unexplained osteoporosis in a young patient). 6

Appropriate Screening Tests for Hypercortisolism

When clinical suspicion warrants screening:

• Overnight 1-mg dexamethasone suppression test (first-line): Give 1 mg dexamethasone at 11 PM–midnight; measure cortisol at 8 AM. Normal suppression is <1.8 μg/dL (<50 nmol/L). 1, 6
• Late-night salivary cortisol (collected 11 PM–midnight on 2–3 separate nights): Abnormal threshold >3.6 nmol/L (>0.1 μg/dL), with sensitivity 92–100% and specificity 93–100%. 1, 6
• 24-hour urinary free cortisol (obtain 2–3 collections): Values >100 μg/24 hours on multiple collections are diagnostic. 1, 6
• At least two abnormal screening tests are required before proceeding to further evaluation, as intra-patient variability is substantial. 1, 6

Emergency Management

Suspected Acute Adrenal Crisis

• In patients with collapse, severe hypotension, or marked electrolyte disturbances, immediately administer 100 mg hydrocortisone IV; draw blood for cortisol and ACTH before the first dose, but never delay treatment for diagnostic procedures. 1
• Cortisol <250 nmol/L with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency; cortisol <400 nmol/L generates strong suspicion. 1