Endocrine Abstracts

JOINT2280

Background: Pituitary adenomas are common intracranial neoplasms, often presenting with symptoms related to hormone overproduction or mass effect. Cushing’s disease results from adrenocorticotropic hormone (ACTH) secreting pituitary adenomas, typically leading to cortisol overproduction. However, some patients exhibit elevated ACTH levels with normal cortisol and an atypical clinical presentation, complicating the diagnosis. In rare cases, this discrepancy may be due to macro-ACTH, a condition in which pituitary corticotroph cells produce large, biologically inactive ACTH molecules. These molecules have prolonged circulation, leading to falsely elevated ACTH readings without cortisol excess. We present a case of a 34-year-old male with elevated ACTH and normal cortisol levels, raising suspicion for macro-ACTH or a similar rare condition.

Case report: A 34-year-old male was referred by a neurologist with complaints of fatigue, lightheadedness, and mental fog. Neurological examination revealed no meningeal or focal neurological signs. Physical examination was unremarkable, with no signs of hypercortisolism or hypocortisolism. Contrast-enhanced MRI revealed a 15×26×18 mm pituitary macroadenoma with intrasellar, infrasellar, and laterosellar extension, sparing the optic chiasm. Hormonal tests showed elevated ACTH- 215.1 pg/ml (7.2–63.6 pg/ml) but normal morning cortisol levels - 417.3 nmol/l(133–537 nmol/L). Salivary cortisol and 24-hour urinary free cortisol were normal (18.2 nmol/land 42 mg/day, respectively). Levels of the remaining pituitary hormones were within normal limits. Following the low-dose dexamethasone suppression test, cortisol levels were appropriately suppressed, but ACTH remained persistently elevated. The discordance between elevated ACTH and normal cortisol, without clinical signs of cortisol excess, raised suspicion for macro-ACTH secreting adenoma, which releases large, biologically inactive ACTH molecules. However, due to the unavailability of specialized laboratory tests, a definitive diagnosis could not be confirmed. The patient was referred for neurosurgical assessment and management is ongoing.

Discussion: This case highlights the diagnostic challenges in ACTH-secreting pituitary adenomas with atypical presentations. Macro-ACTH, though rare, should be considered when ACTH is elevated despite normal cortisol levels and the absence of clinical signs of cortisol dysregulation.

Conclusions: When laboratory and clinical findings are inconsistent, macrohormone-related interference, such as macro-ACTH, should be considered. Although confirmatory testing was unavailable in this case, recognizing this possibility helped avoid unnecessary treatments. In cases where specialized laboratory tests are unavailable, clinicians should rely on a combination of clinical judgment, biochemical patterns, and response to treatment to guide management. While routine testing for macrohormones is not recommended, awareness of their impact can prevent unnecessary interventions and improve patient outcomes.