In a patient with elevated Adrenocorticotropic hormone (ACTH), would you expect cortisol levels to be elevated as well?

Elevated ACTH and Cortisol Relationship

In a patient with elevated ACTH, you would typically expect cortisol levels to be elevated as well, as this represents ACTH-dependent hypercortisolism (Cushing's syndrome). 1

Physiological Basis

• ACTH directly stimulates cortisol production by the adrenal cortex, so elevated ACTH levels normally drive increased cortisol secretion in ACTH-dependent conditions. 1

• The Endocrine Society confirms that any detectable ACTH level (>5 pg/mL or >1.1 pmol/L) in the setting of confirmed hypercortisolism indicates ACTH-dependent disease, where both ACTH and cortisol are elevated together. 1

• ACTH levels >29 ng/L have 70% sensitivity and 100% specificity for diagnosing Cushing's disease when hypercortisolism is present, demonstrating the strong correlation between elevated ACTH and elevated cortisol. 1

Clinical Scenarios with Elevated ACTH and Cortisol

ACTH-dependent Cushing's syndrome accounts for the majority of cases where both hormones are elevated:

• Cushing's disease (pituitary adenoma) represents 75-80% of ACTH-dependent cases, with both ACTH and cortisol elevated due to autonomous pituitary ACTH secretion. 1

• Ectopic ACTH syndrome from neuroendocrine tumors also produces elevated ACTH driving cortisol hypersecretion, often with very high levels of both hormones. 2, 3

• Research confirms that patients with ectopic ACTH syndrome demonstrate markedly elevated plasma ACTH (ranging from 1340-1520 pg/ml) with correspondingly elevated cortisol levels (51-95 μg/dL). 3

Important Diagnostic Considerations

Morning timing is critical for accurate interpretation:

• ACTH should be measured at 08:00-09:00h when levels are physiologically highest, allowing proper comparison to established diagnostic thresholds. 1

• Cortisol follows the same circadian rhythm with peak morning levels, making simultaneous morning measurement of both hormones the standard approach. 4

Key diagnostic thresholds to remember:

• Morning cortisol <275 nmol/L (<10 μg/dL) warrants investigation for adrenal insufficiency, while levels consistently elevated above normal with elevated ACTH suggest ACTH-dependent hypercortisolism. 4

• Post-dexamethasone cortisol >50 nmol/L (>1.8 μg/dL) with elevated ACTH confirms ACTH-dependent Cushing's syndrome, as normal suppression should reduce cortisol below this threshold. 4, 1

Rare Exception: Dissociation Patterns

While elevated ACTH typically drives elevated cortisol, rare cases demonstrate dissociation:

• Research has documented unusual cases where abnormal steroid metabolism (such as excessive 21-deoxycortisol production) can cause aberrant ACTH and cortisol regulation, though this remains extremely uncommon. 5

• In some ectopic ACTH cases, adrenal androgen responses may be disproportionate to cortisol levels, suggesting ACTH processing variability, but cortisol itself remains elevated. 6, 3

Clinical Algorithm

When you encounter elevated ACTH:

1. Measure simultaneous morning (08:00-09:00h) cortisol to confirm the expected elevation. 1

2. If cortisol is also elevated, proceed with screening tests for Cushing's syndrome (24-hour urinary free cortisol, late-night salivary cortisol, or dexamethasone suppression test). 4, 1

3. If cortisol is unexpectedly normal or low with elevated ACTH, consider primary adrenal insufficiency (Addison's disease) where the adrenal glands cannot respond to ACTH stimulation. 4

4. Confirm ACTH-dependent disease by demonstrating failure of cortisol suppression with dexamethasone (cortisol >50 nmol/L post-suppression). 4, 1

5. Proceed to pituitary MRI to identify potential pituitary adenoma as the source of ACTH excess. 1

6. If MRI is inconclusive or shows lesion <6mm, perform bilateral inferior petrosal sinus sampling (BIPSS) to definitively distinguish pituitary from ectopic ACTH sources. 1

Critical Pitfalls to Avoid

• Do not assume normal cortisol excludes pathology when ACTH is elevated - this pattern suggests primary adrenal insufficiency where the adrenals cannot respond to ACTH. 4

• Ensure patient is not on exogenous steroids, as these suppress both ACTH and endogenous cortisol production, confounding interpretation. 1

• Avoid afternoon ACTH measurements, as physiologically lower levels do not correspond to established diagnostic thresholds and lead to misinterpretation. 1

• Remember that increased cortisol-binding globulin (from oral estrogens, pregnancy, or chronic hepatitis) falsely elevates total serum cortisol, while ACTH remains appropriately regulated. 4