ReviewHormones (Athens, Greece)2026
Transient adrenocorticotropic hormone elevation with a disproportionate cortisol response prior to the onset of immune checkpoint inhibitor-related hypophysitis.
Review in Hormones (Athens, Greece), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveImmune checkpoint inhibitors (ICIs) have transformed cancer therapy. However, they are associated with immune-related adverse events (irAEs), including ICI-related hypophysitis (ICI-RH). Secondary adrenal insufficiency, the most common endocrine manifestation, is often life-threatening if left untreated. Transient elevations in adrenocorticotropic hormone (ACTH) levels before the onset of ICI-RH have been reported; however, their clinical significance remains unclear. CASE PRESENTATION: We describe the case of a 76-year-old woman with renal cell carcinoma who underwent nephrectomy followed by pembrolizumab therapy. Initially, the patient had normal baseline adrenal function. However, 12 weeks after the initiation of pembrolizumab, she exhibited transient ACTH elevation without a proportionate increase in cortisol. Fifteen weeks after treatment initiation, the patient developed fatigue and nausea. Laboratory tests revealed hyponatremia with low ACTH and cortisol levels. Hydrocortisone replacement rapidly improved the patient’s symptoms. Stimulation testing confirmed an isolated ACTH deficiency, whereas the other pituitary axes remained intact. Magnetic resonance imaging revealed no pituitary enlargement and tumor pathology revealed weak ACTH expression. DISCUSSION: This case illustrates ICI-related hypophysitis presenting as isolated ACTH deficiency, preceded by a transient ACTH elevation without a corresponding increase in serum cortisol. A literature review indicated a heterogeneous pattern of ACTH and cortisol dynamics, likely reflecting differences in ACTH bioactivity and adrenal responsiveness. Transient ACTH elevation may represent early pituitary damage, which is analogous to transient thyrotoxicosis in thyroid irAEs. Recognition of this phenomenon may enable early ICI-RH detection.
conclusionTransient ACTH elevation, even without a concurrent cortisol increase, may serve as an early marker of ICI-RH.
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