Can hyperaldosteronism (excessive aldosterone production) lead to low adrenocorticotropic hormone (ACTH) levels in patients with suspected adrenal insufficiency?

Can Hyperaldosteronism Lead to Low ACTH?

No, hyperaldosteronism does not cause low ACTH levels—these are independent hormonal axes that do not directly suppress each other. However, if both conditions coexist in the same patient, they represent separate pathologies occurring simultaneously rather than one causing the other.

Understanding the Hormonal Axes

• Primary aldosteronism involves autonomous aldosterone secretion from the adrenal zona glomerulosa, regulated primarily by the renin-angiotensin system and potassium, not by ACTH 1
• ACTH is produced by the pituitary gland and primarily regulates cortisol production from the adrenal zona fasciculata 2
• In primary adrenal insufficiency, ACTH is characteristically elevated (not low) due to loss of negative feedback from cortisol, while aldosterone is low 2, 3
• In secondary adrenal insufficiency, ACTH is low due to pituitary or hypothalamic dysfunction, resulting in low cortisol but typically normal aldosterone since the renin-angiotensin-aldosterone system remains intact 2, 3

The Exception: Glucocorticoid-Suppressible Aldosteronism

• Glucocorticoid-suppressible aldosteronism (GSA) is a rare genetic form of hyperaldosteronism where aldosterone secretion becomes abnormally ACTH-dependent due to a chimeric gene fusion 4
• In GSA, aldosterone production is driven by ACTH rather than the renin-angiotensin system, and can be suppressed with dexamethasone administration 4
• This represents an abnormal hybrid cell type in the adrenal transitional zone that responds to ACTH but produces aldosterone 4
• Even in GSA, ACTH levels themselves are not low—the aldosterone simply becomes responsive to normal ACTH fluctuations 4, 5

When Both Conditions Coexist

• A documented case report describes a patient with concurrent primary hyperaldosteronism and adrenal insufficiency following prolonged hypotension from a ruptured abdominal aortic aneurysm 6
• This patient demonstrated suppressed plasma renin activity with elevated aldosterone (indicating primary hyperaldosteronism) alongside a blunted cortisol response to cosyntropin stimulation (indicating adrenal insufficiency) 6
• The patient required the unusual combination of prednisone for glucocorticoid replacement and spironolactone for mineralocorticoid receptor blockade 6
• This represents two separate pathological processes affecting different zones of the adrenal gland simultaneously, not one causing the other 6

Diagnostic Approach When Evaluating Both Axes

• Morning measurements of both cortisol and ACTH are essential for evaluating the hypothalamic-pituitary-adrenal axis, with primary adrenal insufficiency showing high ACTH with low cortisol, and secondary adrenal insufficiency showing low ACTH with low cortisol 2
• The aldosterone-to-renin ratio (ARR) is the screening test for primary aldosteronism, with a positive result defined as ARR ≥30 and plasma aldosterone ≥10 ng/dL 1
• The extended ACTH stimulation test can differentiate primary from secondary adrenal insufficiency: in primary adrenal insufficiency, both cortisol and aldosterone fail to rise appropriately, while in secondary adrenal insufficiency, cortisol response is blunted but aldosterone response remains normal 7, 3
• Plasma ACTH, aldosterone, and plasma renin activity measured together provide comprehensive assessment of both axes 3

Critical Clinical Pitfall

• Do not assume that finding one adrenal abnormality excludes the possibility of another—the adrenal cortex has distinct functional zones (zona glomerulosa producing aldosterone, zona fasciculata producing cortisol) that can be affected independently 6, 3
• Hypokalemia is present in only 50% of primary aldosteronism cases, so normal potassium does not exclude the diagnosis 1
• Hyperkalemia is present in only 50% of primary adrenal insufficiency cases, so its absence does not rule out adrenal insufficiency 2