In a 32‑year‑old woman with early‑morning serum cortisol of 5.6 µg/dL three months ago and 8.8 µg/dL now, and normal thyroid function tests and dehydroepiandrosterone (DHEA) levels, when should glucocorticoid therapy be started and which steroid regimen is appropriate?

When to Start Glucocorticoid Therapy in This Patient

Your patient's cortisol levels (5.6 and 8.8 µg/dL) are in the indeterminate zone and require ACTH stimulation testing before making any treatment decisions—do not start steroids based on these values alone. 1

Understanding the Current Cortisol Values

Your patient's morning cortisol levels fall into a diagnostic gray zone that requires further evaluation:

• Morning cortisol >14 µg/dL effectively rules out adrenal insufficiency 2
• Morning cortisol <5 µg/dL (140 nmol/L) with elevated ACTH strongly suggests primary adrenal insufficiency 1
• Values between 5-14 µg/dL (140-400 nmol/L) are indeterminate and mandate dynamic testing 1

The improvement from 5.6 to 8.8 µg/dL over 3 months actually suggests the HPA axis may be recovering or functioning adequately, not worsening adrenal insufficiency. 3

Required Diagnostic Testing Before Treatment

You must perform a cosyntropin stimulation test to definitively diagnose or exclude adrenal insufficiency before initiating therapy: 1

Standard ACTH Stimulation Test Protocol

• Administer 0.25 mg (250 mcg) cosyntropin IV or IM 1
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes post-administration 1
• Peak cortisol >550 nmol/L (>18-20 µg/dL) excludes adrenal insufficiency 1
• Peak cortisol <500 nmol/L (<18 µg/dL) confirms adrenal insufficiency 1

The test can be performed at any time of day and does not require fasting. 2 The 30-minute cortisol response is constant regardless of basal cortisol level or time of day. 4

Additional Baseline Testing to Obtain

Before or concurrent with the ACTH stimulation test, measure: 1

• Plasma ACTH (to distinguish primary from secondary adrenal insufficiency)
• Basic metabolic panel (sodium, potassium, glucose—hyponatremia present in 90% of new AI cases, but hyperkalemia only in ~50%) 1
• DHEA-S level (you mentioned this is normal, which actually argues against adrenal insufficiency—DHEA-S has excellent diagnostic performance with AUROC 0.81) 5

When to Start Glucocorticoid Therapy

DO NOT Start Steroids If:

The ACTH stimulation test shows peak cortisol >550 nmol/L (>18-20 µg/dL)—this excludes adrenal insufficiency and no treatment is needed. 1

START Steroids Immediately If:

You should bypass testing and treat immediately only in these scenarios: 1

• Acute adrenal crisis (unexplained hypotension, collapse, severe vomiting/diarrhea, altered mental status)
• Vasopressor-resistant hypotension
• Severe symptomatic hypotension with electrolyte disturbances

In these emergencies: Give hydrocortisone 100 mg IV immediately plus 0.9% saline infusion at 1 L/hour—never delay treatment for diagnostic testing. 1

START Steroids After Confirmatory Testing If:

Peak cortisol <500 nmol/L (<18 µg/dL) on ACTH stimulation test confirms adrenal insufficiency and requires lifelong replacement therapy. 1

What Steroid Regimen to Give

For Confirmed Adrenal Insufficiency (After Positive ACTH Stim Test):

Standard maintenance glucocorticoid replacement: 1

• Hydrocortisone 15-25 mg daily in divided doses (preferred regimen)
  • Typical dosing: 10 mg at 7:00 AM, 5 mg at 12:00 PM, 2.5-5 mg at 4:00 PM 6
  • Alternative regimens: 15+5 mg, 10+10 mg, or 10+5+5 mg 1

OR

• Prednisone 4-5 mg once daily upon awakening (alternative) 7
  • Can split as 3 mg morning + 1-2 mg at 2:00 PM 7

For primary adrenal insufficiency (high ACTH, low cortisol), also add: 1

• Fludrocortisone 50-200 µg daily for mineralocorticoid replacement
• Monitor adequacy by assessing salt cravings, orthostatic blood pressure, peripheral edema, and plasma renin activity 1

For Acute Adrenal Crisis (Emergency):

• Hydrocortisone 100 mg IV bolus immediately 1
• 0.9% saline infusion at 1 L/hour (at least 2L total) 1
• Continue hydrocortisone 50-100 mg IV every 6-8 hours until stable 7
• Taper to oral maintenance dose over 5-7 days as patient recovers 7

For Moderate Symptoms (Outpatient):

If confirmed AI with moderate symptoms but not in crisis: 1

• Start hydrocortisone at 2-3 times maintenance dose (30-50 mg total daily)
• OR prednisone 10-15 mg daily initially
• Taper to standard maintenance over 1-2 weeks

Critical Pitfalls to Avoid

• Never start chronic glucocorticoid therapy based solely on morning cortisol values in the 5-10 µg/dL range without confirmatory ACTH stimulation testing 1
• The absence of hyperkalemia does NOT rule out adrenal insufficiency (present in only ~50% of cases) 1
• Normal DHEA-S actually argues against adrenal insufficiency—only 1.3% of patients with baseline cortisol 5-10 µg/dL and DHEA-S ≥60 µg/dL have AI 5
• If you start steroids empirically, you cannot perform accurate diagnostic testing later—exogenous steroids suppress the HPA axis and confound all cortisol measurements 1
• Approximately 10% of patients with primary AI present with normal cortisol concentrations but elevated ACTH—if ACTH is markedly elevated (>300 pg/mL) with cortisol <140 nmol/L, this suggests early primary AI even with "normal" cortisol 8

Patient Education if AI Confirmed

If adrenal insufficiency is diagnosed, mandatory patient education includes: 1

• Stress-dosing instructions: double or triple dose during illness, fever, or physical stress
• Emergency injectable hydrocortisone 100 mg IM kit with self-injection training
• Medical alert bracelet or necklace indicating adrenal insufficiency
• Steroid emergency card to carry at all times
• Annual screening for associated autoimmune conditions (thyroid, diabetes, celiac disease, pernicious anemia) 1