Is an elevated Adrenocorticotropic Hormone (ACTH) level of 161 concerning in a patient with known Adrenal Insufficiency (AI) taking hydrocortisone (cortisol replacement therapy)?

Elevated ACTH in Adrenal Insufficiency on Hydrocortisone Replacement

An ACTH level of 161 pg/mL in a patient with known adrenal insufficiency taking hydrocortisone is NOT concerning and is actually expected—this indicates the patient likely has primary adrenal insufficiency (Addison's disease) where the adrenal glands cannot respond to ACTH, causing compensatory ACTH elevation despite adequate cortisol replacement. 1

Understanding the ACTH-Cortisol Relationship

Primary vs. Secondary Adrenal Insufficiency:

• Primary adrenal insufficiency presents with low cortisol and high ACTH because the pituitary gland attempts to stimulate failing adrenal glands 1
• Secondary adrenal insufficiency presents with low cortisol and low ACTH due to pituitary or hypothalamic dysfunction 1
• Your patient's elevated ACTH of 161 pg/mL confirms primary adrenal insufficiency as the underlying diagnosis 1

Why This ACTH Level is Expected

Physiologic Response in Primary AI:

• In primary adrenal insufficiency, the pituitary gland continues producing ACTH in an attempt to stimulate the non-functioning adrenal glands, even when the patient is receiving adequate hydrocortisone replacement 1
• The ACTH level does not normalize with hydrocortisone therapy in primary AI because the feedback mechanism remains disrupted at the adrenal level 2
• ACTH levels can remain elevated (often >100 pg/mL) despite appropriate glucocorticoid replacement 2

Important Caveats About ACTH Monitoring

Timing of Measurement Matters:

• Morning ACTH levels before the first hydrocortisone dose are typically highest and can be markedly elevated (>300 pg/mL) in adequately treated patients 3
• ACTH measurements should not be used to adjust hydrocortisone dosing in primary adrenal insufficiency 4
• The ACTH level alone does not indicate over- or under-replacement with hydrocortisone 4

What Actually Indicates Adequate Replacement:

• Clinical assessment remains the primary method: evaluate for symptoms of under-replacement (fatigue, hypotension, weight loss) or over-replacement (weight gain, hyperglycemia, hypertension) 5
• Single-point cortisol measurements at 1000h or 1400h (1-2 hours post-dose) correlate best with adequate replacement, with target levels in the physiologic range 4
• The recommended hydrocortisone dose is 15-20 mg daily in divided doses, typically given as 10 mg in morning and 5-10 mg in afternoon 1, 5

When ACTH Levels Should Prompt Concern

Low ACTH in Known AI:

• If a patient with previously diagnosed primary AI develops low ACTH, this suggests either misdiagnosis or development of secondary AI (from steroid use for other conditions, pituitary pathology) 6
• Steroid use for other conditions can cause isolated central adrenal insufficiency with low ACTH, requiring HPA axis testing after 3 months of maintenance therapy 6

Extremely High ACTH (>500-1000 pg/mL):

• While not necessarily indicating inadequate replacement, extremely elevated ACTH may warrant evaluation for pituitary hyperplasia or microadenoma, though this is rare 2

Practical Management Approach

Current Assessment:

• Confirm the patient is taking hydrocortisone 15-20 mg daily in divided doses (typically 10 mg morning, 5-10 mg afternoon) 1, 5
• Assess clinically for signs of under-replacement: fatigue, orthostatic hypotension, weight loss, hyponatremia 7
• Assess for over-replacement: weight gain, hyperglycemia, hypertension, cushingoid features 5

If Adjustment Needed:

• Consider measuring cortisol at 1000h or 1400h (1-2 hours post-dose) rather than ACTH to guide dosing 4
• The optimal daily dose based on pharmacokinetic studies is 6 mg/m² body surface area, typically 10+5+5 mg at 0730h, 1200h, and 1630h 5

Patient Education Essentials:

• Ensure stress dosing education (double or triple dose during illness) 6
• Medical alert bracelet for adrenal insufficiency 6
• Emergency injectable hydrocortisone availability 6