What are the causes of low Adrenocorticotropic hormone (ACTH) levels?

Causes of Low ACTH Levels

Low ACTH (adrenocorticotropic hormone) levels are primarily caused by secondary adrenal insufficiency resulting from hypothalamic-pituitary disease, exogenous glucocorticoid therapy, or isolated ACTH deficiency. 1, 2

Primary Causes of Low ACTH

1. Secondary Adrenal Insufficiency

   • Exogenous glucocorticoid therapy - Most common cause

     • Suppression of the hypothalamic-pituitary-adrenal (HPA) axis due to negative feedback from exogenous steroids 1
     • Can persist for months after discontinuation of glucocorticoids 3

   • Pituitary disorders

     • Pituitary tumors (adenomas)
     • Post-pituitary surgery
     • Pituitary radiation therapy 4
     • Pituitary infarction (Sheehan syndrome)
     • Pituitary apoplexy

   • Hypothalamic disorders

     • Tumors affecting the hypothalamus
     • Radiation damage to hypothalamus 4
     • Infiltrative diseases affecting the hypothalamus

2. Isolated ACTH Deficiency

   • Rare condition characterized by ACTH deficiency with normal secretion of other pituitary hormones 2
   • Can be congenital or acquired
   • Often idiopathic, but may be autoimmune in origin

Diagnostic Considerations

When evaluating low ACTH levels, it's important to differentiate between primary and secondary adrenal insufficiency:

Feature	Primary Adrenal Insufficiency	Secondary Adrenal Insufficiency (Low ACTH)
ACTH Level	High	Low
Cortisol Level	Low	Low
Electrolytes	↓Na, ↑K	Usually normal
Skin pigmentation	Increased	Normal or decreased

1

Testing for Low ACTH

• Morning cortisol samples (8 AM) are preferred for initial assessment 1
• ACTH stimulation test is the standard confirmatory test for adrenal insufficiency
  • Low-dose (1 μg) ACTH stimulation test may be more sensitive for detecting secondary adrenal insufficiency 1, 5
  • A normal response is defined as peak cortisol ≥18 μg/dL and/or increment ≥9 μg/dL from baseline 1

Clinical Pearls and Pitfalls

• Important pitfall: Standard dynamic tests of the HPA axis may occasionally miss ACTH deficiency. Some patients with radiation-induced hypothalamic damage may have normal responses to insulin tolerance or glucagon stimulation tests but still have clinically significant ACTH deficiency 4

• After discontinuation of exogenous glucocorticoids, cortisol secretion may recover more quickly than adrenal androgen production, creating a dissociation in adrenal function 6

• Patients with secondary adrenal insufficiency typically do not have the electrolyte abnormalities (hyperkalemia, hyponatremia) seen in primary adrenal insufficiency 1

• When treating multiple endocrine deficiencies, always start corticosteroids first to prevent precipitating adrenal crisis 1

• Recent etomidate use for intubation can temporarily suppress the HPA axis and cause low ACTH levels 1

Remember that untreated adrenal insufficiency from low ACTH can lead to life-threatening adrenal crisis, particularly during times of stress, illness, or surgery 1.