What is the best course of treatment for a patient with suspected adrenal insufficiency, presenting with fatigue and depression, and potentially low adrenocorticotropic hormone (ACTH) levels?

Causes of Low ACTH

Low ACTH with low cortisol is diagnostic of secondary adrenal insufficiency, which results from pituitary or hypothalamic dysfunction rather than primary adrenal gland failure. 1

Primary Etiologies of Low ACTH

Pituitary Disorders

• Pituitary tumors (adenomas, craniopharyngiomas) can compress or destroy ACTH-producing corticotroph cells, leading to secondary adrenal insufficiency 1
• Pituitary hemorrhage (Sheehan syndrome, apoplexy) causes acute destruction of pituitary tissue and ACTH deficiency 2
• Inflammatory or infiltrative conditions including hypophysitis, sarcoidosis, and hemochromatosis can impair ACTH secretion 2
• Pituitary surgery or radiation therapy may damage corticotroph cells and result in permanent ACTH deficiency 2

Hypothalamic Dysfunction

• Hypothalamic lesions that impair corticotropin-releasing hormone (CRH) production cause tertiary adrenal insufficiency with low ACTH 3
• Traumatic brain injury affecting the hypothalamic-pituitary axis can suppress ACTH release 4

Iatrogenic Causes (Most Common)

• Glucocorticoid-induced adrenal insufficiency from supraphysiological doses of exogenous steroids (prednisone ≥20 mg/day for ≥3 weeks) is the most common cause of low ACTH 5, 2
• Opioid medications suppress corticotropin production and can cause secondary adrenal insufficiency 2
• Immune checkpoint inhibitor therapy (used in cancer treatment) can cause hypophysitis leading to ACTH deficiency 1

Diagnostic Approach for Low ACTH

Initial Laboratory Evaluation

• Measure early morning (8 AM) serum cortisol and plasma ACTH simultaneously to establish the diagnosis 5, 1
• Morning cortisol 5-10 µg/dL (140-275 nmol/L) with low or inappropriately normal ACTH indicates secondary adrenal insufficiency 5, 2
• Check basic metabolic panel for hyponatremia (present in 90% of cases), though hyperkalemia is typically absent in secondary AI unlike primary AI 5, 1

Confirmatory Testing

• Cosyntropin stimulation test (0.25 mg IV/IM with cortisol measurements at baseline and 30-60 minutes) confirms adrenal insufficiency when peak cortisol <500 nmol/L (<18 µg/dL) 5, 6
• Important caveat: The Synacthen test can give false-normal results in early secondary adrenal insufficiency, as the adrenal glands may still respond to supraphysiological ACTH doses 7
• If strong clinical suspicion persists despite normal Synacthen test, consider insulin tolerance test (gold standard for secondary AI) or metyrapone test 6, 7

Assess for Other Pituitary Hormone Deficiencies

• Measure TSH, free T4, LH, FSH, and sex hormones (testosterone/estradiol) to identify multiple pituitary hormone deficiencies 1
• Consider MRI of the brain with pituitary/sellar cuts in patients with multiple endocrine abnormalities, new severe headaches, or visual field defects 1

Treatment Algorithm Based on Severity

Mild Symptoms (Fatigue, Depression)

• Initiate hydrocortisone 10-20 mg orally in the morning and 5-10 mg in early afternoon for physiologic replacement 1
• Alternative regimen: prednisone 3-5 mg daily 2
• Do NOT add fludrocortisone in secondary AI, as the renin-angiotensin-aldosterone system remains intact (unlike primary AI) 5, 8

Moderate Symptoms

• Start higher initial dosing: hydrocortisone 20-30 mg morning and 10-20 mg afternoon 1
• Taper to maintenance doses over 5-10 days once symptoms improve 1

Severe Symptoms or Adrenal Crisis

• Administer IV hydrocortisone 100 mg immediately without waiting for diagnostic confirmation 5, 1
• Infuse 0.9% saline at 1 L/hour (at least 2L total) for volume resuscitation 5
• Taper stress-dose corticosteroids to maintenance over 7-14 days after stabilization 1

Critical Management Considerations

When Treating Concurrent Hypothyroidism

• Always start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 5, 1
• Follow free T4 (not TSH) for thyroid dose titration in patients with pituitary disease 1

Patient Education Requirements

• Educate on stress dosing: double or triple doses during illness, fever, surgery, or significant physiological stress 1, 9
• Provide medical alert bracelet indicating adrenal insufficiency 1, 9
• Prescribe emergency injectable hydrocortisone 100 mg IM kit with self-injection training 5, 2
• Arrange endocrine consultation prior to any surgery or procedures for stress-dose planning 1

Common Pitfalls to Avoid

• Never delay treatment of suspected adrenal crisis for diagnostic testing—mortality is high if untreated 5, 6
• Do not attempt diagnostic testing while patients are actively taking exogenous corticosteroids, as this yields false-positive results showing expected HPA suppression 5
• Avoid relying solely on electrolyte abnormalities for diagnosis—hyperkalemia is absent in secondary AI, and 10-20% of patients have normal electrolytes 5
• Do not use dexamethasone for chronic replacement therapy in secondary AI, though it can be used acutely (4 mg IV) when diagnosis is uncertain and you need to preserve the ability to perform cortisol testing 5
• Recognize that psychological stress alone (anxiety, fear from diagnosis) does not require increased glucocorticoid dosing—only physiological stressors warrant dose adjustment 9