Challenges and Opportunities
Anat Ben-Shlomo, Michelle Koh, Sarah Kremen, Jeffrey Wertheimer
Endocrine Reviews, First published online September 3, 2025, bnaf029
https://doi.org/10.1210/endrev/bnaf029
Adults with adrenal cortisol insufficiency (ACI) often report cognitive dysfunction, especially in memory processing and executive function. Only a few studies have objectively compared cognitive function as the primary outcome between patients with ACI and controls, and these efforts have yielded inconsistent results. In this review, we examine the challenges facing researchers studying cognitive function in adult patients with ACI. We consider the effect of dysregulated cortisol on cognition in patients with ACI, and the inability of current guideline-recommended glucocorticoid (GC) treatment regimens to accurately reproduce circadian and ultradian cortisol secretion rhythms. Factors that contribute to inter- and intra-individual response to GC are presented; the indirect effects of ACI comorbidities, complications, and symptoms on cognitive dysfunction are reviewed; and obstacles to employing neurocognitive testing are identified. Finally, we outline potential approaches to studying cognition in ACI using well-designed studies that account for the complexities and gaps in ACI research.
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