From the Guidelines
Secondary adrenal insufficiency should be worked up in patients presenting with symptoms such as fatigue, weakness, weight loss, nausea, vomiting, abdominal pain, hypotension, and hypoglycemia, especially if they have risk factors like recent glucocorticoid therapy, pituitary disease, or surgery, as recommended by the 2021 ASCO guideline update 1.
Initial Evaluation
The initial evaluation should include morning cortisol and ACTH levels, with cortisol <3 μg/dL strongly suggesting adrenal insufficiency and levels >18 μg/dL typically ruling it out, as per the guideline update 1.
- For intermediate values (3-18 μg/dL), an ACTH stimulation test is necessary, where 250 μg of synthetic ACTH (cosyntropin) is administered and cortisol levels are measured at 0,30, and 60 minutes.
- A peak cortisol <18 μg/dL confirms adrenal insufficiency, as stated in the guideline update 1.
Diagnosis and Management
Low ACTH levels with low cortisol indicate secondary adrenal insufficiency, while elevated ACTH suggests primary adrenal insufficiency, as noted in the 2021 ASCO guideline update 1.
- Additional pituitary hormone testing and brain MRI are warranted in secondary cases to identify the underlying cause.
- If adrenal crisis is suspected (severe hypotension, electrolyte abnormalities), immediate treatment with hydrocortisone 100 mg IV should be initiated before completing the diagnostic workup, as delayed treatment can be life-threatening, as recommended by the guideline update 1.
Special Considerations
The 2021 ASCO guideline update also notes that all patients need education on stress dosing for sick days, use of emergency steroid injectables, when to seek medical attention for impending adrenal crisis, and a medical alert bracelet for adrenal insufficiency to trigger stress dose corticosteroids by EMS 1.
- Steroid use for other irAEs can cause isolated central adrenal insufficiency with a low ACTH, and in a patient with adrenal insufficiency, a recent history of treatment with corticosteroids, and no other central hormone deficiencies, the HPA axis should be tested for recovery after 3 months of maintenance therapy with hydrocortisone, as stated in the guideline update 1.
From the FDA Drug Label
PRECAUTIONS General Precautions Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted
The patient should be worked up for secondary adrenal insufficiency in any situation of stress occurring after discontinuation of therapy, as drug-induced secondary adrenocortical insufficiency may persist for months.
- Stress can trigger the need for hormone therapy to be reinstituted.
- The lowest possible dose of corticosteroid should be used to control the condition under treatment. 2
From the Research
Diagnosis of Secondary Adrenal Insufficiency
The diagnosis of secondary adrenal insufficiency can be made based on clinical suspicion and confirmed by biochemical testing.
- A low baseline cortisol level, often <100 nmol/L, can be an indicator of adrenal insufficiency 3.
- The insulin tolerance test is considered the gold standard for diagnosing secondary adrenal insufficiency 3, 4.
- The corticotropin-releasing hormone (CRH) stimulation test is also reliable for diagnosing pituitary or hypothalamic adrenal insufficiency 5.
- Measurement of basal cortisol is an inexpensive and convenient screening test that can include or exclude adrenal insufficiency, but most patients will have intermediate values and will require dynamic testing 4.
When to Work Up a Patient
A patient should be worked up for secondary adrenal insufficiency when they present with non-specific symptoms such as fatigue, malaise, and weight loss, and there is a clinical suspicion of adrenal insufficiency 3, 6.
- The diagnosis should be considered in patients with hypothalamic-pituitary disease or those who have undergone pituitary surgery 7, 5.
- A strategic approach to investigation, including laboratory analysis and imaging, can help identify the underlying cause of adrenal insufficiency 3, 6.
Diagnostic Tests
The following diagnostic tests can be used to evaluate secondary adrenal insufficiency: