Is the Adrenocorticotropic Hormone (ACTH) lab test accurate in patients on hormone replacement therapy (HRT)?

ACTH Lab Testing Accuracy in Patients on Hormone Replacement Therapy

ACTH lab testing may be inaccurate in patients on hormone replacement therapy, particularly those on glucocorticoids, which can suppress the hypothalamic-pituitary-adrenal axis and lead to falsely low ACTH levels.

Effects of Different Hormone Replacement Therapies on ACTH Testing

Glucocorticoid Therapy

• Exogenous glucocorticoids directly suppress ACTH production through negative feedback on the hypothalamic-pituitary axis
• ACTH stimulation testing may remain valid within the first 72 hours after initiation of high-dose glucocorticoid therapy 1
• After 72 hours of glucocorticoid therapy, ACTH stimulation tests may show inadequate cortisol response, leading to false positive results for adrenal insufficiency 1

Growth Hormone Replacement

• Growth hormone replacement therapy can affect adrenal androgen secretion and potentially alter ACTH levels
• In ACTH-sufficient patients, GH replacement may increase DHEAS levels, suggesting an interaction between GH and the HPA axis 2
• GH may inhibit 11β-HSD type 1 activity, leading to enhanced cortisol clearance and subsequent activation of the HPA axis 2

Sex Hormone Replacement

• Estrogen therapy increases cortisol-binding globulin (CBG), which can affect total cortisol measurements
• Women on estrogen-containing oral contraceptives may show falsely elevated total cortisol levels during ACTH stimulation testing 3
• This can lead to false negative results when screening for adrenal insufficiency

Diagnostic Considerations for ACTH Testing in Patients on HRT

Preferred Testing Approaches

• The high-dose (250-μg) ACTH stimulation test is recommended over the low-dose (1-μg) test for diagnosing adrenal insufficiency 3
• For patients on hormone replacement, consider:
  • Timing the test appropriately (e.g., before daily glucocorticoid dose)
  • Measuring dexamethasone levels along with cortisol during dexamethasone suppression tests to improve interpretability 3
  • Using salivary cortisol measurements when appropriate, though this may have practical limitations 3

Interpretation Challenges

• Morning serum cortisol and ACTH measurements may be misleading in patients on glucocorticoid therapy 4
• Cortisol response to ACTH stimulation should be evaluated at both 30 and 60 minutes, with 60-minute results being more reliable 1
• A normal response is defined as cortisol exceeding 550 nmol/L at either 30 or 60 minutes post-stimulation 4

Special Considerations for Different Clinical Scenarios

Suspected Cushing's Syndrome

• In patients on hormone replacement being evaluated for Cushing's syndrome:
  • Confirm hypercortisolemia immediately prior to bilateral inferior petrosal sinus sampling (BIPSS) 3
  • Consider that ACTH levels may be affected by exogenous hormone therapy
  • A pituitary source of ACTH excess is confirmed by a ≥2:1 ratio of central-to-peripheral ACTH before CRH or desmopressin and ≥3:1 ratio after stimulation 3

Suspected Adrenal Insufficiency

• For patients on long-term glucocorticoid therapy:
  • The low-dose (1-μg) ACTH test may be more sensitive for detecting mild adrenal insufficiency 5
  • Consider temporarily discontinuing glucocorticoid therapy if clinically safe before testing
  • Interpret results in the context of clinical presentation and pretest probability 6

Pitfalls and Recommendations

Common Pitfalls

• Failure to account for the timing of hormone replacement in relation to ACTH testing
• Not considering the impact of estrogen therapy on cortisol-binding globulin levels
• Misinterpreting ACTH levels in patients on glucocorticoid therapy

Key Recommendations

• Whenever possible, perform ACTH testing before initiating hormone replacement therapy
• If testing must be done while on HRT, document the type, dose, and timing of hormone replacement
• Consider alternative testing methods (e.g., insulin tolerance test) when ACTH testing results are equivocal 6
• Interpret results in the context of the patient's clinical presentation and the specific hormone replacement regimen

By understanding these interactions and following appropriate testing protocols, clinicians can improve the accuracy of ACTH testing in patients on hormone replacement therapy and avoid misdiagnosis of adrenal disorders.