What is the diagnosis and recommended treatment for a patient with low ACTH (adrenocorticotropic hormone) and low cortisol?

Low ACTH and Low Cortisol: Secondary Adrenal Insufficiency

This presentation indicates secondary (central) adrenal insufficiency, and you should initiate glucocorticoid replacement therapy immediately with hydrocortisone 15-25 mg daily (or equivalent) divided into 2-3 doses, mimicking physiologic cortisol secretion 1, 2.

Diagnosis

The combination of low ACTH with low cortisol definitively establishes secondary adrenal insufficiency (SAI), also called central adrenal insufficiency. This reflects impaired ACTH secretion from the pituitary gland, leading to reduced cortisol production by otherwise normal adrenal glands 1.

Key Diagnostic Features:

• Morning serum cortisol <150 nmol/L (5 μg/dL) essentially confirms adrenal insufficiency 3
• Low or inappropriately normal ACTH despite low cortisol distinguishes secondary from primary adrenal insufficiency 4, 5
• Low DHEA-S is typically present and supports the diagnosis 4, 5
• Normal aldosterone and renin - mineralocorticoid production remains intact in SAI 4

When Morning Cortisol is Equivocal (150-300 nmol/L or 5-10 μg/dL):

Dynamic testing becomes necessary. The Short Synacthen Test (SST) is most commonly used, though it has suboptimal diagnostic accuracy in SAI 1. A cortisol peak >500 nmol/L (18 μg/dL) excludes SAI, but understanding the clinical context is essential when interpreting borderline results 1. The CRH stimulation test offers an alternative, with a 30-minute post-CRH cortisol >12.6 μg/dL (347.6 nmol/L) effectively ruling out ACTH deficiency 6.

Common Clinical Pitfalls:

• Nonspecific symptoms (fatigue, weakness, anorexia, weight loss) often delay diagnosis 4, 7, 5
• Hyponatremia may be the presenting feature and can be mistaken for SIADH 4
• Neurological symptoms including gait disturbance can mimic other conditions like normal pressure hydrocephalus 7
• Concurrent glucocorticoid therapy (e.g., for other conditions) can mask SAI symptoms - maintain high suspicion when tapering steroids 8

Identify the Underlying Cause

Work up the etiology systematically:

• MRI of the pituitary/sella turcica to evaluate for tumors, Empty Sella syndrome, or structural abnormalities 4, 8
• Assess other pituitary hormones (TSH, LH, FSH, prolactin, IGH-1) to determine if ACTH deficiency is truly isolated 5, 2
• History of glucocorticoid use - glucocorticoid-induced adrenal insufficiency is the most common cause of SAI 3
• Consider autoimmune hypophysitis, cranial irradiation, surgery, trauma, or infections in appropriate clinical contexts 1, 2

Treatment

Glucocorticoid Replacement:

Initiate short-acting glucocorticoids immediately:

• Hydrocortisone 15-25 mg/day (mean 20 mg or 0.30 mg/kg) divided into 2-3 doses, OR
• Cortisone acetate 25 mg/day (0.35 mg/kg) 1, 2

Dosing strategy:

• Give larger doses in the morning (mimicking circadian rhythm): typically 10 mg upon waking, 5 mg at lunch, 5 mg early afternoon 1
• Use lower doses than historically prescribed to reduce cortisol-related comorbidities 1

Critical Management Points:

• No mineralocorticoid (fludrocortisone) replacement needed - aldosterone production remains intact in SAI 1, 2
• Stress dosing is mandatory during illness, surgery, trauma, or major physiologic stress 3
• For patients with mild, near-asymptomatic disease, glucocorticoid therapy may only be needed during stressful events, though this requires careful individualized assessment 2

Special Considerations for Glucocorticoid-Induced SAI:

If the patient has been on exogenous glucocorticoids, follow the 2024 European/Endocrine Society guidelines 3:

• Do not reduce below physiologic replacement doses (hydrocortisone 15-25 mg or prednisone 4-6 mg daily) until HPA axis recovery is confirmed
• Test for HPA axis recovery with morning cortisol (8-9 AM, 24 hours after last dose):
  • >300 nmol/L (10 μg/dL): Safe to discontinue glucocorticoids
  • 150-300 nmol/L (5-10 μg/dL): Continue physiologic dose, retest in weeks to months
  • <150 nmol/L (5 μg/dL): Continue physiologic dose, retest in several months 3

Emergency Situations:

In acute adrenal crisis (hypotension, severe hyponatremia, hypoglycemia, altered mental status):

• Hydrocortisone sodium succinate (Solu-Cortef) 100 mg IV immediately, then 50-100 mg every 6-8 hours 4
• Aggressive fluid resuscitation with normal saline
• Correct hypoglycemia
• Transition to oral replacement once stabilized