In a patient with hypopituitarism and Cushing's syndrome, where pheochromocytoma (Pheo) has been ruled out, is the cause more likely pituitary or adrenal in origin?

Cushing's Syndrome with Hypopituitarism: Likely Adrenal in Origin

In a patient with hypopituitarism and Cushing's syndrome where pheochromocytoma has been ruled out, the cause is most likely adrenal in origin rather than pituitary. This is because hypopituitarism would result in low ACTH levels, which is characteristic of ACTH-independent (adrenal) Cushing's syndrome, not Cushing's disease (pituitary origin).

Pathophysiology and Diagnostic Classification

• ACTH-dependent Cushing's syndrome is diagnosed when ACTH is detectable in the blood (>5 ng/l or >1.1 pmol/l) in the presence of confirmed hypercortisolism 1
• In ACTH-independent Cushing's syndrome, ACTH is always low and usually undetectable due to autonomous cortisol production from the adrenal glands 1
• Hypopituitarism, by definition, involves decreased function of the pituitary gland, which would lead to decreased ACTH production 2
• When hypopituitarism is present alongside Cushing's syndrome, this strongly suggests an adrenal source of cortisol production that is functioning independently of pituitary control 3

Differential Diagnosis

• Adrenal causes of Cushing's syndrome include:

  • Unilateral adrenal adenoma (most common cause of ACTH-independent Cushing's syndrome) 3
  • Bilateral adrenal hyperplasia 3
  • Adrenal carcinoma (less common) 3

• Pituitary causes (Cushing's disease) account for 75-80% of Cushing's syndrome in children and adolescents but would be inconsistent with hypopituitarism 2

• Ectopic ACTH-producing tumors (like pheochromocytoma) have already been ruled out in this case 4

Diagnostic Approach

• Confirm hypercortisolism with standard tests:

  • 24-hour urinary free cortisol 3
  • Late-night salivary cortisol 3
  • Overnight dexamethasone suppression test 3

• Measure ACTH levels:

  • Low or undetectable ACTH confirms ACTH-independent (adrenal) Cushing's syndrome 1, 3
  • This would be consistent with the patient's hypopituitarism 2

• Adrenal imaging:

  • CT scan with adrenal protocol to identify adrenal adenoma, hyperplasia, or carcinoma 5
  • MRI may be used as an alternative 5

Clinical Implications

• Patients with adrenal Cushing's syndrome may have:

  • Hypertension (present in approximately 78% of cases) 6
  • Hypokalemia (more common in ectopic and adrenal causes than in pituitary Cushing's) 6
  • Classic cushingoid features (moon face, buffalo hump, central obesity) 5

• The presence of hypopituitarism may complicate the clinical picture with additional hormonal deficiencies:

  • Growth hormone deficiency 2
  • Gonadotropin deficiency 2
  • Thyrotropin deficiency 2

Treatment Considerations

• For adrenal causes of Cushing's syndrome:

  • Laparoscopic adrenalectomy is the treatment of choice for unilateral adrenal adenoma 3
  • Bilateral adrenalectomy may be necessary for bilateral disease 3
  • Medical management with adrenostatic agents (ketoconazole) may be considered when surgery is not an option 3

• Postoperative care:

  • Corticosteroid supplementation is required until recovery of the HPA axis 3
  • This is especially important in patients with pre-existing hypopituitarism 3

Important Caveats

• Rare cases of simultaneous pituitary and adrenal adenomas have been reported, but these are extremely uncommon 5
• Physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing's syndrome) should be considered in patients with certain medical conditions (alcoholism, renal failure, poorly controlled diabetes, severe neuropsychiatric disorders) 7
• Careful monitoring of electrolytes, particularly potassium, is essential as hypokalemia can be severe in adrenal Cushing's syndrome 6

In conclusion, the combination of hypopituitarism and Cushing's syndrome, with pheochromocytoma ruled out, strongly points to an adrenal origin of the hypercortisolism rather than a pituitary source.