In a 33-year-old patient with BMI 26 and a history of Graves’ disease presenting with unexplained dizziness and presyncope, who has elevated DHEA‑S, low ACTH, normal cortisol, normal electrolytes, and hypotension, what is the most likely diagnosis and appropriate management?

Likely Diagnosis: Secondary Adrenal Insufficiency (Isolated ACTH Deficiency)

This patient most likely has secondary adrenal insufficiency, specifically isolated ACTH deficiency (IAD), which is a rare but recognized association with Graves' disease, particularly in younger patients. The combination of low ACTH (6.9 pg/mL), borderline-normal cortisol (11.9 µg/dL), elevated DHEA-S, hypotension (100/70), and symptoms of dizziness/presyncope in a patient with Graves' disease strongly suggests this diagnosis 1, 2.

Diagnostic Reasoning

Why Secondary Adrenal Insufficiency?

• Low ACTH with equivocal cortisol: The ACTH of 6.9 pg/mL is inappropriately low for the cortisol level. In a healthy individual with cortisol around 11.9 µg/dL, ACTH should be higher to stimulate adequate cortisol production 3.

• Graves' disease association: IAD has been documented to occur concomitantly with Graves' disease, though rare. The autoimmune nature of Graves' may predispose to other autoimmune endocrine disorders 1, 2.

• Elevated DHEA-S paradox: The mildly elevated DHEA-S (254-290 µg/dL) may seem contradictory, but in early or partial ACTH deficiency, DHEA-S can remain normal or even elevated initially before declining 4.

• Clinical presentation: Dizziness, presyncope, and relative hypotension (100/70 in a 33-year-old) are classic for adrenal insufficiency, even without frank hypotension 5, 6.

Important Caveat About Graves' Disease

Research shows that thyrotoxicosis itself can attenuate cortisol responses in early Graves' disease without adrenal autoimmunity 7. However, the low ACTH distinguishes true secondary adrenal insufficiency from this phenomenon, where ACTH would be normal or elevated.

Management Algorithm

Immediate Diagnostic Workup

1. Morning cortisol (8-9 AM): Repeat fasting cortisol at 8-9 AM after holding any glucocorticoids for 24 hours

   • <5 µg/dL (138 nmol/L): Very likely adrenal insufficiency 3
   • 5-18 µg/dL (138-500 nmol/L): Proceed to stimulation testing 3

   • 18 µg/dL (500 nmol/L): Adrenal insufficiency unlikely 3

2. ACTH stimulation test (250 µg Synacthen test): If morning cortisol is in the intermediate range

   • Peak cortisol <18 µg/dL (500 nmol/L) at 30 or 60 minutes confirms adrenal insufficiency 3, 8
   • This distinguishes primary from secondary AI and assesses adrenal reserve

3. Additional testing:

   • Repeat ACTH level simultaneously with morning cortisol
   • Check other pituitary hormones (TSH, free T4, LH, FSH, prolactin, IGF-1) to rule out panhypopituitarism 4
   • Pituitary MRI to exclude structural lesions (though IAD typically shows no pituitary abnormalities) 4, 9

Treatment Initiation

Do not wait for test results if the patient is symptomatic with high clinical suspicion 3, 10.

1. Glucocorticoid replacement:

   • Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg morning, 5 mg afternoon, 5 mg evening) 10, 11
   • Alternative: Prednisone 4-6 mg daily (though hydrocortisone is preferred) 12, 11
   • Adjust based on clinical response and morning cortisol levels

2. Mineralocorticoid replacement: NOT needed in secondary adrenal insufficiency, as aldosterone production (regulated by renin-angiotensin system) remains intact 10, 11

3. Patient education on stress dosing:

   • Double or triple dose during illness, fever, or stress
   • Injectable hydrocortisone 100 mg for emergencies (vomiting, severe illness, trauma) 10, 11
   • Medical alert identification

Graves' Disease Management Considerations

• Optimize thyroid treatment: Uncontrolled thyrotoxicosis may worsen cortisol metabolism and adrenal function 7
• Monitor closely during antithyroid therapy: As thyroid function normalizes, reassess adrenal function, as some cases show improvement 1, 7
• Consider that thyrotoxicosis itself increases cortisol clearance, potentially unmasking subclinical adrenal insufficiency

Critical Pitfalls to Avoid

1. Do not dismiss symptoms as anxiety or Graves'-related: Dizziness and presyncope in Graves' disease should prompt adrenal evaluation, especially with borderline cortisol 13, 7

2. Do not use random cortisol levels alone: A single cortisol of 11.9 µg/dL is equivocal and requires proper timing (morning) and/or dynamic testing 3

3. Do not start glucocorticoids before testing if stable: However, if the patient develops hypotension, altered mental status, or severe symptoms, start treatment immediately and confirm diagnosis later 3, 10

4. Do not overlook adrenal crisis risk: Even with "borderline" labs, patients can decompensate rapidly during stress (infection, surgery, trauma) 10, 11

5. Do not add fludrocortisone: This is secondary AI, not primary—mineralocorticoid replacement is unnecessary and potentially harmful 10

Follow-Up Strategy

• Recheck morning cortisol and ACTH after 3-6 months on replacement therapy
• Monitor for recovery of HPA axis (may take months to years, or may be permanent) 12
• Annual reassessment of pituitary function if IAD is confirmed 4
• Coordinate care between endocrinology and primary care for long-term management