What is the diagnosis for a patient with low cortisol and low Dehydroepiandrosterone sulfate (DHEAS)?

Diagnosis: Secondary (Central) Adrenal Insufficiency

Low cortisol with low DHEAS indicates secondary (central) adrenal insufficiency, caused by pituitary or hypothalamic dysfunction, rather than primary adrenal disease. 1, 2, 3

Diagnostic Reasoning

Why This Pattern Indicates Secondary AI

• Low ACTH with low cortisol is diagnostic of secondary adrenal insufficiency, distinguishing it from primary adrenal insufficiency where ACTH would be elevated 1, 2, 3
• Low DHEAS supports the diagnosis of central AI because DHEA-S production requires ACTH stimulation—when pituitary ACTH secretion is impaired, both cortisol and DHEA-S fall together 3, 4, 5
• In secondary AI, patients typically have low or intermediate morning cortisol levels (5-10 µg/dL) with low or inappropriately normal ACTH and low DHEAS levels 3
• The combination of low cortisol and low DHEAS has excellent diagnostic performance (AUROC 0.81 for each marker independently), and when both are low, the likelihood of AI is very high 6

Key Diagnostic Distinction

• Primary AI: High ACTH + Low cortisol + Low DHEAS (adrenal glands destroyed) 7, 3
• Secondary AI: Low/normal ACTH + Low cortisol + Low DHEAS (pituitary/hypothalamic dysfunction) 1, 2, 3

Immediate Diagnostic Workup Required

Confirm the Diagnosis

• Measure early morning (8 AM) serum cortisol and plasma ACTH simultaneously to confirm the cortisol-ACTH relationship 7, 3
• If morning cortisol is <5 µg/dL (<140 nmol/L) with low ACTH, this confirms secondary AI 7, 3
• If cortisol is intermediate (5-10 µg/dL), perform ACTH stimulation test with 0.25 mg cosyntropin—peak cortisol <18 µg/dL (500 nmol/L) at 30-60 minutes confirms AI 7, 1, 3

Assess for Other Pituitary Hormone Deficiencies

• Check TSH, free T4, LH, FSH, and sex hormones (testosterone in men, estradiol in women) to identify other pituitary deficiencies 1, 2
• Obtain basic metabolic panel to assess for hyponatremia (present in 90% of AI cases) 7
• Consider MRI of the brain with pituitary/sellar cuts if multiple hormone deficiencies are present or if there are new severe headaches 1, 2

Common Etiologies to Investigate

• Pituitary tumors (adenomas, craniopharyngiomas) causing mass effect 2, 3
• Hypophysitis (autoimmune, IgG4-related, or immune checkpoint inhibitor-induced) 2, 3
• Exogenous glucocorticoid use causing iatrogenic HPA axis suppression 1, 3
• Pituitary surgery or radiation therapy 3
• Infiltrative diseases (sarcoidosis, hemochromatosis, histiocytosis) 3
• Pituitary hemorrhage or infarction (Sheehan syndrome, apoplexy) 3
• Medications that suppress ACTH (opioids, high-dose progestins) 3

Treatment Algorithm

Initiate Glucocorticoid Replacement

• For mild-moderate symptoms: Start hydrocortisone 15-25 mg daily in divided doses (10-20 mg morning, 5-10 mg early afternoon) 1, 2, 3
• For severe symptoms or adrenal crisis: Give IV hydrocortisone 100 mg bolus immediately, plus 0.9% saline infusion at 1 L/hour 7, 2
• Alternative maintenance regimen: Prednisone 3-5 mg daily 3

Critical Pitfall to Avoid

• If concurrent hypothyroidism is present, ALWAYS start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 7, 1, 2
• Starting levothyroxine before glucocorticoids increases metabolic demand and can trigger life-threatening adrenal crisis 7, 2

Replace Other Deficient Hormones

• If TSH is low with low free T4, start levothyroxine only after corticosteroids are established 2
• If hypogonadism is present, consider testosterone or estrogen replacement after addressing adrenal and thyroid issues 2
• Note: Mineralocorticoid replacement (fludrocortisone) is NOT needed in secondary AI because aldosterone secretion is preserved 3

Essential Patient Education and Safety Measures

• Educate on stress dosing: Double or triple glucocorticoid doses during illness, surgery, or significant physical stress 1, 2, 3
• Provide injectable hydrocortisone 100 mg for emergency self-administration to prevent adrenal crisis 3
• Medical alert bracelet stating "adrenal insufficiency" to trigger stress-dose corticosteroids by emergency services 1, 2
• Endocrine consultation prior to any surgery or procedure for stress-dose planning 7, 1, 2

Monitoring and Follow-Up

• Obtain endocrinology consultation for optimization of therapy and long-term management 1, 2
• Periodic re-evaluation of other pituitary hormones if secondary AI is due to pituitary disease 2
• If on thyroid hormone replacement, follow free T4 (not TSH) for dose titration since TSH is unreliable with pituitary disease 2
• Monitor for symptoms of under-replacement (fatigue, nausea, weight loss) or over-replacement (weight gain, insomnia, hypertension) 7

Additional Diagnostic Pearls

• A normal age- and sex-adjusted DHEAS level essentially rules out adrenal insufficiency 4, 6
• Only 1.2% of patients with baseline cortisol ≥10 µg/dL have AI, and among those with cortisol 5-9.9 µg/dL, only 1.3% have AI if DHEAS is ≥60 µg/dL 6
• Conversely, 72.2% of patients with both baseline cortisol <5 µg/dL and DHEAS <25 µg/dL have confirmed AI 6
• Recent glucocorticoid use decreases the diagnostic performance of DHEAS (AUROC 0.72 vs 0.83 without recent use) 6