What is the diagnosis and treatment for a patient with a morning cortisol level of 7.8 mcg/dL at 8 am and an Adrenocorticotropic Hormone (ACTH) level of 20 pg/mL?

Diagnosis: Likely Secondary (Central) Adrenal Insufficiency

This patient's morning cortisol of 7.8 mcg/dL (215 nmol/L) with an inappropriately normal ACTH of 20 pg/mL is most consistent with secondary (central) adrenal insufficiency, and requires confirmatory testing with a cosyntropin stimulation test before initiating glucocorticoid replacement therapy. 1

Interpretation of Laboratory Values

Cortisol Assessment

• The morning cortisol of 7.8 mcg/dL (215 nmol/L) falls in the indeterminate range that requires further dynamic testing 2, 3
• A morning cortisol >13 mcg/dL (360 nmol/L) reliably excludes adrenal insufficiency, while <3 mcg/dL (83 nmol/L) confirms it 2
• Values between 3-13 mcg/dL require cosyntropin stimulation testing for definitive diagnosis 2, 3
• This patient's value of 7.8 mcg/dL is below the threshold that predicts adrenal sufficiency (which ranges from 8.5-13.5 mcg/dL depending on the study) 3

ACTH Interpretation

• The critical finding is that ACTH is inappropriately normal (20 pg/mL) in the setting of low cortisol 1
• In primary adrenal insufficiency, ACTH should be markedly elevated (>1.1 pmol/L or >5 ng/L, which equals >22 pg/mL) when cortisol is low 4, 1
• In secondary adrenal insufficiency, both ACTH and cortisol are low or inappropriately normal 1
• An ACTH of 20 pg/mL with cortisol of 7.8 mcg/dL suggests the pituitary is not responding appropriately to the low cortisol signal, indicating central pathology 1

Diagnostic Algorithm

Step 1: Confirm Adrenal Insufficiency with Cosyntropin Stimulation Test

• Administer 250 mcg cosyntropin (synthetic ACTH) intramuscularly or intravenously 2, 3
• Measure cortisol at baseline and 30 minutes post-injection 3
• A 30-minute cortisol >550 nmol/L (>20 mcg/dL) indicates adrenal sufficiency 3
• A subnormal response confirms adrenal insufficiency but does not distinguish primary from secondary 2

Step 2: Distinguish Primary vs Secondary Adrenal Insufficiency

• The baseline ACTH-to-cortisol relationship already suggests secondary insufficiency 1
• In primary adrenal insufficiency: high ACTH (>22 pg/mL) with low cortisol 1
• In secondary adrenal insufficiency: low or inappropriately normal ACTH with low cortisol 1
• This patient's ACTH of 20 pg/mL is inappropriately normal for a cortisol of 7.8 mcg/dL, pointing to secondary insufficiency 1

Step 3: Investigate Underlying Cause of Secondary Insufficiency

• Obtain pituitary MRI to evaluate for pituitary adenoma, empty sella, or other structural lesions 4
• Review medication history for exogenous glucocorticoid use (most common cause of secondary adrenal insufficiency) 1
• Assess other pituitary hormone axes (TSH, LH/FSH, prolactin, IGF-1) to determine if this is isolated ACTH deficiency or panhypopituitarism 4

Treatment Recommendations

Glucocorticoid Replacement

Once adrenal insufficiency is confirmed, initiate hydrocortisone 15-25 mg daily in divided doses 4

Standard Dosing Regimens

• Three-dose regimen (preferred): 10 mg at 07:00,5 mg at 12:00,2.5-5 mg at 16:00 4
• Two-dose regimen: 15 mg at 07:00,5 mg at 12:00 4
• The first dose should be taken upon awakening, with the last dose 4-6 hours before bedtime to avoid insomnia 4

Alternative: Prednisolone

• If hydrocortisone is not tolerated or compliance is problematic, use prednisolone 4-5 mg daily as a single morning dose 5
• Prednisolone is second-line and should only be used when hydrocortisone/cortisone acetate cannot be used 5

Mineralocorticoid Replacement

Fludrocortisone is NOT required in secondary adrenal insufficiency 4

• The renin-angiotensin-aldosterone system remains intact in secondary insufficiency 4
• Fludrocortisone 50-200 mcg daily is only needed in primary adrenal insufficiency 4

Monitoring and Dose Adjustment

• Clinical assessment is the primary monitoring tool, not cortisol or ACTH levels 4
• Signs of under-replacement: lethargy, nausea, poor appetite, weight loss 4
• Signs of over-replacement: weight gain, insomnia, peripheral edema 4
• Medications that increase hydrocortisone requirements: anti-epileptics, barbiturates, rifampin 4
• Substances that decrease requirements: grapefruit juice, licorice 4

Critical Pitfalls to Avoid

Do Not Start Treatment Before Confirmatory Testing

• If clinical suspicion is high and the patient is symptomatic, perform the cosyntropin stimulation test urgently before initiating therapy 2
• Once glucocorticoid replacement is started, dynamic testing becomes unreliable 4

Do Not Add Fludrocortisone in Secondary Insufficiency

• This is a common error that leads to hypertension and fluid retention 4
• Only primary adrenal insufficiency requires mineralocorticoid replacement 4

Do Not Rely on ACTH or Cortisol Levels for Dose Titration

• These values are not useful for adjusting glucocorticoid replacement doses 4
• Clinical symptoms and signs are the gold standard for monitoring 4

Educate on Stress Dosing

• Patients must double or triple their hydrocortisone dose during illness, fever, or significant stress 4
• Provide emergency intramuscular hydrocortisone (100 mg) for severe illness or inability to take oral medication 4
• Patients should wear medical alert identification 4