What are the implications and treatment options for low Adrenocorticotropic Hormone (ACTH) levels?

Management of Low ACTH Levels

Low ACTH with low cortisol indicates secondary adrenal insufficiency, which requires prompt hormone replacement therapy to prevent life-threatening adrenal crisis and improve quality of life. 1, 2

Diagnostic Approach

• Low ACTH with low cortisol is diagnostic of secondary adrenal insufficiency, distinguishing it from primary adrenal insufficiency (which presents with high ACTH and low cortisol) 1
• Evaluate morning ACTH and cortisol levels, along with basic metabolic panel to check for electrolyte abnormalities 1
• Consider ACTH stimulation test for confirmation, with the 1-μg low-dose test being more sensitive than the conventional 250-μg test for detecting central adrenal insufficiency 3
• Assess for other pituitary hormone deficiencies: TSH, FT4, LH, FSH, testosterone/estradiol 1
• Consider MRI of the brain with pituitary/sellar cuts in patients with multiple endocrine abnormalities or new severe headaches 1

Etiology Assessment

• Consider common causes of secondary adrenal insufficiency:
  • Pituitary disease affecting ACTH production 4
  • Exogenous glucocorticoid therapy (most common cause) 5
  • Immune checkpoint inhibitor therapy causing hypophysitis 1
  • Other causes of hypothalamic-pituitary dysfunction 2

Treatment Algorithm

For Mild Symptoms (able to perform ADLs)

• Initiate hormone replacement with hydrocortisone 10-20 mg orally in the morning and 5-10 mg in early afternoon 1, 6
• Consider endocrine consultation for optimization of therapy 1
• If multiple hormone deficiencies are present, always start corticosteroids several days before thyroid hormone to prevent precipitating adrenal crisis 1

For Moderate Symptoms

• Consider higher initial dosing: hydrocortisone 20-30 mg in the morning and 10-20 mg in the afternoon 1
• Taper stress-dose corticosteroids down to maintenance doses over 5-10 days 1
• Endocrine consultation is recommended 1

For Severe Symptoms/Adrenal Crisis

• Emergency department referral for:
  • IV normal saline (at least 2 L) 1
  • IV stress-dose corticosteroids (hydrocortisone 100 mg or dexamethasone 4 mg if diagnosis not confirmed) 1
• Taper stress-dose corticosteroids down to maintenance doses over 7-14 days after discharge 1
• Hospitalization may be required for monitoring and stabilization 7

Long-term Management

• Maintenance therapy with hydrocortisone 10-20 mg in the morning and 5-10 mg in early afternoon 1, 6
• All patients need education on stress dosing (doubling or tripling doses during illness, surgery, or significant stress) 1
• Provide medical alert bracelet for adrenal insufficiency to trigger stress-dose corticosteroids by emergency services 1
• Endocrine consultation prior to surgery or any procedure for stress-dose planning 1
• Monitor for signs of overtreatment (weight gain, hypertension, glucose intolerance) or undertreatment (fatigue, nausea, hypotension) 4

Special Considerations

• If other pituitary hormone deficiencies are present, replacement therapy should be initiated with corticosteroids first, followed by other hormones 1
• For patients on thyroid hormone replacement, follow FT4 for dose titration as TSH is not accurate 1
• Consider dual-release hydrocortisone formulation which may improve metabolic profile in patients with secondary adrenal insufficiency 4
• Adrenal crisis is a life-threatening emergency with mortality rates of 0.5 per 100 patient-years; prompt recognition and treatment are essential 7

Monitoring and Follow-up

• Regular clinical assessment of symptoms and quality of life 2
• Monitor for signs of inadequate or excessive replacement 4
• Periodic evaluation of other pituitary hormones if secondary adrenal insufficiency is due to pituitary disease 1
• Patients with glucocorticoid-induced adrenal insufficiency may recover axis function over time and should be periodically reassessed 5