ACTH to Cortisol Ratio in Secondary Adrenal Insufficiency
In secondary adrenal insufficiency, the ACTH to cortisol ratio is typically low, with low or low-normal ACTH levels and low or intermediate cortisol levels (5-10 µg/dL). This pattern of low ACTH with low cortisol distinguishes secondary adrenal insufficiency from primary adrenal insufficiency, which presents with high ACTH and low cortisol levels. 1
Diagnostic Patterns in Secondary Adrenal Insufficiency
- Secondary adrenal insufficiency is characterized by low or low-normal ACTH levels with low or intermediate cortisol levels, reflecting the underlying pituitary or hypothalamic disorder 2, 1
- Morning cortisol levels are typically in the range of 5-10 µg/dL, but a single measurement is insufficient for definitive diagnosis 2, 1
- Unlike primary adrenal insufficiency (where ACTH is elevated), secondary adrenal insufficiency shows inadequate ACTH production leading to cortisol deficiency 3, 1
- The 250-μg ACTH stimulation test is the recommended diagnostic test for evaluating adrenal insufficiency in patients with suspected hypopituitarism 2, 3
Laboratory Findings in Secondary vs. Primary Adrenal Insufficiency
In secondary adrenal insufficiency:
- ACTH levels: Low or low-normal
- Cortisol levels: Low or intermediate (5-10 µg/dL)
- DHEAS levels: Low or low-normal 1
In primary adrenal insufficiency:
- ACTH levels: High (compensatory increase)
- Cortisol levels: Very low (<5 µg/dL)
- DHEAS levels: Low 1
ACTH Stimulation Testing
- The high-dose (250-μg) ACTH stimulation test is recommended over the low-dose (1-μg) test due to comparable diagnostic accuracy and easier practical administration 3
- In secondary adrenal insufficiency, the cortisol secretion rate (CSR) in response to ACTH is significantly reduced compared to healthy controls 4
- Maximal cortisol secretion rate (CSRmax) is approximately 0.17 ± 0.09 nM/s in secondary adrenal insufficiency versus 0.46 ± 0.14 nM/s in healthy controls 4
- The ACTH stimulation test helps differentiate between primary and secondary adrenal insufficiency, as patients with secondary adrenal insufficiency typically have normal aldosterone responses but subnormal cortisol responses 5
Clinical Implications
- Basal cortisol levels can be useful in predicting adrenal insufficiency:
- Cortisol ≥450 nmol/L has a 98.7% negative predictive value to rule out adrenal insufficiency
- Cortisol ≤100 nmol/L has a 93.2% positive predictive value to rule in adrenal insufficiency 6
- Patients with secondary adrenal insufficiency continue to secrete aldosterone in response to renin, unlike those with primary adrenal insufficiency who are deficient in both cortisol and aldosterone 3
- Secondary adrenal insufficiency carries significant mortality risk, with risk ratios of 2.19 for men and 2.86 for women 3
Management Considerations
- Treatment involves supplemental glucocorticoids (e.g., hydrocortisone 15-25 mg daily or prednisone 3-5 mg daily) 1
- Unlike primary adrenal insufficiency, mineralocorticoid replacement (fludrocortisone) is not required in secondary adrenal insufficiency since aldosterone secretion remains intact 3, 1
- Patients should be educated about stress dosing during illness or surgery to prevent adrenal crisis 7
- Perioperative management requires increased glucocorticoid dosing based on the severity of surgical stress 3
Pitfalls and Caveats
- A single morning cortisol measurement is insufficient for diagnosis; ACTH stimulation testing is required for confirmation 2, 8
- When starting both glucocorticoid and thyroid replacement in hypopituitarism, always start glucocorticoids first to prevent precipitating adrenal crisis 7
- Adrenal crisis is a life-threatening emergency that can occur in patients with adrenal insufficiency who have inadequate glucocorticoid therapy during acute illness or physical stress 1, 8
- Inhaled corticosteroid therapy can cause suppression of the hypothalamo-pituitary-adrenal axis, potentially leading to secondary adrenal insufficiency 3