What does it mean if Adrenocorticotrophic Hormone (ACTH) levels are low?

What Low ACTH Levels Mean

Low ACTH levels in the context of low cortisol indicate secondary adrenal insufficiency, a condition where the pituitary gland fails to produce adequate ACTH to stimulate cortisol production by the adrenal glands. 1, 2

Distinguishing Primary from Secondary Adrenal Insufficiency

The relationship between ACTH and cortisol is critical for diagnosis:

• Secondary adrenal insufficiency: Low ACTH with low cortisol 2, 3
• Primary adrenal insufficiency: High ACTH with low cortisol (the adrenal glands themselves have failed) 1, 3

In secondary adrenal insufficiency, patients are deficient in cortisol but continue to secrete aldosterone normally because the renin-angiotensin system remains intact. 1 This distinguishes it from primary adrenal insufficiency where both cortisol and aldosterone are typically deficient. 1

Common Causes of Low ACTH

The most common cause of secondary adrenal insufficiency is exogenous glucocorticoid therapy, which suppresses the hypothalamic-pituitary-adrenal axis through negative feedback. 1, 4 This includes:

• Oral corticosteroids (affecting 7 in 1,000 people on long-term therapy) 1
• Inhaled corticosteroids (even at commonly prescribed doses, causing dose-dependent suppression) 1
• Topical, intranasal, and intra-articular routes 1

Other causes include:

• Pituitary or hypothalamic disorders (tumors, radiation, surgery) 1, 4
• Immune checkpoint inhibitor therapy causing hypophysitis 1, 2
• Idiopathic isolated ACTH deficiency (rare) 5

Clinical Significance and Mortality Risk

Secondary adrenal insufficiency carries significant mortality risk if untreated. In Swedish cohorts, the risk ratio for all-cause mortality was 2.19 for men and 2.86 for women, with excess deaths from cardiovascular, malignant, and infectious diseases. 1 Adrenal crises occur 6-8 times per 100 patient-years and can be fatal. 1

Diagnostic Approach

When low ACTH is suspected:

• Measure morning (8 AM) cortisol and ACTH simultaneously 2, 3
• Obtain basic metabolic panel (hyponatremia may be present, but hyperkalemia is typically absent in secondary adrenal insufficiency) 1, 3
• Assess for other pituitary hormone deficiencies: TSH, free T4, LH, FSH, testosterone/estradiol 2
• Consider MRI of the pituitary/sella in patients with multiple endocrine abnormalities or severe headaches 2

Morning cortisol <250 nmol/L (<9 μg/dL) with low or inappropriately normal ACTH strongly suggests secondary adrenal insufficiency. 3 If results are indeterminate, ACTH stimulation testing (cosyntropin test) is required, with peak cortisol <500 nmol/L being diagnostic. 3

Critical Management Principles

If adrenal crisis is suspected, never delay treatment for diagnostic testing. 1, 3 Administer IV hydrocortisone 100 mg immediately plus 0.9% saline infusion. 1

For confirmed secondary adrenal insufficiency:

• Initiate hydrocortisone 10-20 mg in the morning and 5-10 mg in early afternoon 2, 6
• Always start corticosteroids before thyroid hormone replacement if both deficiencies exist, as thyroid hormone accelerates cortisol clearance and can precipitate adrenal crisis 1, 2, 6
• Mineralocorticoid replacement (fludrocortisone) is NOT needed in secondary adrenal insufficiency 1

Recovery from Steroid-Induced Suppression

The hypothalamic-pituitary-adrenal axis typically recovers 6-12 months after cessation of exogenous glucocorticoids, though timing is variable. 4 In patients with isolated central adrenal insufficiency from prior steroid use and no other pituitary deficiencies, test for HPA axis recovery after 3 months of maintenance hydrocortisone therapy. 1

Essential Patient Education

All patients with secondary adrenal insufficiency require:

• Education on stress dosing (doubling or tripling doses during illness, surgery, or significant stress) 1, 2
• Medical alert bracelet to trigger emergency stress-dose corticosteroids 1, 2
• Emergency injectable hydrocortisone with instructions 2, 6
• Endocrine consultation before any surgical procedure for stress-dose planning 2

Common Pitfalls

• Do not rely on electrolyte abnormalities alone: Hyponatremia occurs in 90% of adrenal insufficiency cases, but hyperkalemia is present in only ~50% and is often absent in secondary adrenal insufficiency 1, 3
• ACTH stimulation testing can give false-negative results early in hypophysitis as adrenal reserve declines slowly after pituitary stimulation is lost 1
• Avoid inappropriately high glucocorticoid replacement doses, as they contribute to cardiovascular and metabolic complications including hypertension, insulin resistance, weight gain, and dyslipidemia 7, 8