MON-482 - Spectrum of Adrenal Dysfunction Associated with Immune Checkpoint Inhibitors: Dual Case Reports of Ipilimumab-Nivolumab-Associated Primary Adrenal Insufficiency and Pembrolizumab-Induced Secondary Adrenal Insufficiency

Introduction
Immune checkpoint inhibitors (ICIs) are associated with a spectrum of immune-related endocrinopathies, with adrenal insufficiency (AI) occurring in approximately 1–10% of treated patients. The majority represent secondary (central) AI due to hypophysitis or isolated ACTH deficiency, while primary adrenal insufficiency (PAI) from autoimmune adrenalitis is rare but potentially life-threatening. Distinguishing primary from secondary AI is critical, as management differs with respect to mineralocorticoid replacement and long-term monitoring. We report two contrasting cases illustrating the spectrum of ICI-associated adrenal dysfunction.
Case Presentation
We describe two women receiving immune checkpoint inhibitor (ICI) therapy who presented with presyncope, orthostatic hypotension, hypoglycemia, and gastrointestinal symptoms attributable to adrenal insufficiency.
The first case involved a 63-year-old woman with metastatic endometrial carcinoma on maintenance pembrolizumab who presented with presyncope, orthostatic hypotension, hypoglycemia, and dizziness. Evaluation revealed a profoundly low morning cortisol level (0.5 µg/dL) with suppressed ACTH (1.5 ng/L) in the absence of exogenous glucocorticoid exposure, consistent with secondary adrenal insufficiency. She improved rapidly with stress-dose hydrocortisone followed by transition to physiologic replacement.
The second case involved a 78-year-old woman with pleural mesothelioma treated with combination ipilimumab–nivolumab who presented with progressive weakness, nausea, anorexia, recurrent falls, and metabolic acidosis. Her cortisol was 4.7 µg/dL with elevated ACTH level of 200 ng/L. Normal pituitary imaging and subsequent evidence of mineralocorticoid deficiency, including elevated renin and low aldosterone levels, confirmed primary adrenal insufficiency. She required both glucocorticoid and mineralocorticoid replacement, with subsequent clinical stabilization.
Discussion
These cases highlight the heterogeneity of ICI-associated adrenal dysfunction and emphasize the importance of biochemical evaluation with paired cortisol and ACTH levels to distinguish primary from secondary AI. Secondary AI accounts for approximately 95% of ICI-related cases and is most often associated with PD-1 inhibitors and hypophysitis or isolated ACTH deficiency, whereas PAI remains rare but is more frequently reported with combination CTLA-4/PD-1 therapy and carries higher morbidity. Early recognition is essential, as most cases are irreversible and require lifelong hormone replacement. Clinicians should maintain a high index of suspicion when patients on ICIs present with fatigue, hypotension, hypoglycemia, or electrolyte abnormalities, as prompt diagnosis and appropriate steroid replacement can be lifesaving and allow continuation of effective cancer immunotherapy.

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