SYSTEMATIC REVIEW article
Front. Endocrinol.
Sec. Cancer Endocrinology
Volume 16 - 2025 | doi: 10.3389/fendo.2025.1636452
This article is part of the Research TopicEndocrine Diseases Related to Immune Checkpoint InhibitorsView all 3 articles
Initial Symptoms and Diagnostic Delay in Immune Checkpoint Inhibitor-Related Adrenal Insufficiency: A Systematic Review and Meta-Ethnography of Case Reports
Provisionally accepted
- 1Kinki Daigaku Byoin, Osakasayama, Japan
- 2Shimane Daigaku Igakubu Igakuka Daigakuin Igakukei Kenkyuka, Izumo, Japan
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Immune checkpoint inhibitors (ICIs) can cause adrenal insufficiency (AI) as an uncommon but potentially life-threatening immune-related adverse event (irAE). Early symptoms are often vague and may overlap with cancer-related fatigue or treatment side effects, contributing to diagnostic delays and underrecognition.We conducted a systematic review and meta-ethnographic synthesis of 64 published case reports (2015-2024) describing ICI-associated AI. Data on demographics, tumor type, ICI regimen, presenting symptoms, diagnostic process, hormonal and imaging findings, treatment, and outcomes were extracted. Narrative data were synthesized to explore contextual barriers to timely diagnosis. Quality assessment was performed using a modified CARE checklist.Fatigue (67.2%), nausea (28.1%), appetite loss (25.0%), and hypotension (21.9%) were the most frequently reported symptoms. Notably, most patients (73.7%) presented with three or more concurrent symptoms, suggesting a pattern of symptom clustering that warrants clinical attention. Despite this, only 40.6% underwent dynamic endocrine testing, and pituitary imaging was frequently normal. Meta-ethnographic analysis revealed five recurrent themes underlying diagnostic delay: nonspecific symptomatology, low clinical suspicion, delayed hormonal testing, misleading imaging, and fragmented specialty care. Hospitalization occurred in 60.9% of cases, and glucocorticoid therapy was initiated in all. Recovery of adrenal function was rare (9.4%).ICI-related adrenal insufficiency often presents with multiple nonspecific symptoms that are easily misattributed, delaying diagnosis. Clinicians should maintain a high index of suspicion, particularly when multiple symptoms co-occur in ICI-treated patients, and initiate prompt endocrine evaluation. Standardized diagnostic pathways and interdisciplinary communication are essential to improve recognition and outcomes of this serious irAE.
Keywords: Immune checkpoint inhibitor, Adrenal Insufficiency, Immune-related adverse event, diagnostic delay, Fatigue, hypophysitis, case report, Systematic review
Received: 27 May 2025; Accepted: 09 Sep 2025.
Copyright: © 2025 Ohta, Ryu, Tanaka, Sano and HAYASHI. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ryuichi Ohta, Kinki Daigaku Byoin, Osakasayama, Japan
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