Clinical Endocrinology (2009) 70, 192–200 doi: 10.1111/j.1365-2265.2008.03355.x © 2009 The Authors 192 Journal compilation © 2009 Blackwell Publishing Ltd ORIGINAL ARTICLE Blackwell Publishing Ltd A clinical profile of memory impairment in humans due to endogenous glucocorticoid excess José León-Carrión*, Ainara Madrazo Atutxa†, Miguel Angel Mangas‡, Alfonso Soto-Moreno‡, Alfonso Pumar‡, Antonio Leon-Justel§, Juan Francisco Martín-Rodriguez*, Eva Venegas†, Mª Rosario Domínguez-Morales¶ and Alfonso Leal-Cerro‡ *Human Neuropsychology Laboratory, University of Seville, †Division of Endocrinology, ‡Institute of Biomedicine Seville (IBiS), §Division of Chemical Analysis, University Hospital Virgen del Rocío, Sevilla, Spain; and ¶Center for Brain Injury Rehabilitation (CRECER), Sevilla, Spain Summary Objective Glucocorticoid excess is commonly related to neuro- psychiatric and neurological disorders, with memory impairment typically found among these disorders. The objective of this study is to offer a clinical profile of memory deficits resulting from exposure to chronic stress-level elevations of endogenous glucocorticoids in patients with Cushing’s Syndrome (CS). Study subjects Thirty female participants of matching age and education level were studied: 15 had untreated CS (mean age 38 ± 14) and 15 were healthy. In all patients, CS was confirmed by histology of the lesion after surgery. Design Different learning and memory processes were assessed using an adapted version of Luria’s Memory Words-Revised task (LMW-R). Participants’ performances were measured in an imme- diate condition and, 30 min later, in a delayed condition. Attentional and executive functions were also evaluated. Results Our data show that chronic exposure to elevated levels of cortisol is clinically associated with significant working memory deficits, which included less shot-term memory volume, slow learning rate, memory contamination and no accurate perception of own performance. Patients also show impairment in the delayed recall task. No relation was detected between learning and delayed conditions. CS group did not differ significantly from control group in basic attentional and executive functioning. Conclusions Our clinical profile of memory deficits related to CS relates chronic exposure to hypercortisolemia to impaired attentional-dependent working memory and delayed recall process, suggesting that cortisol levels play a critical role in the modulation of learning and memory. Possible damage to hippocampus and extrahippocampal areas is discussed. (Received 21 January 2008; returned for revision 9 April 2008; finally revised 6 June 2008; accepted 15 July 2008) Introduction A substantial number of patients have been diagnosed with hypothalamic-pituitary-adrenal axis (HPA) dysfunction, resulting in elevated levels of cortisol as well as neurological and neuropsychiatric disorders. Studies relating glucocorticoids (GCs) and cognition have shown that these hormones modulate memory functions differently in both animals and humans, 1–5 and that glucocorticoid therapy commonly used in clinical practice to treat neurological disorders affects declarative memory. 6 Among these disorders, spontaneous Cushing’s Syndrome (CS), including the major subtypes of Cushing’s disease (CD), represents a unique human model, which characterizes the relationship between cognitive performance and chronic exposure to elevated levels of GCs. 7 Although memory deficits have consistently been detected in CS patients, a wider range of cognitive impairments have been reported, including attentional deficits, 8 impairment of visuospatial abilities, 8,9 and working memory deficits. 10 Other studies have identified specific memory impairments, whereas other cognitive areas remained preserved. 11 It is well established that the hippocampus is an important receptor for GCs in the human central nervous system. 12 Type I GC receptors are primarily found in this region, whereas type II receptors are present in other brain areas besides the hippocampus. 13 The latter receptors proliferate in the hypothalamus, entorhinal cortices, cerebellum and prefrontal cortex in primates. 14 Hippocampal neurons seem to be particularly vulnerable to chronic exposure to elevated levels of GCs, which provoke neural damage and atrophy. Jameison and Dinan 15 found evidence that HPA axis dysfunction or a state of hypercortisolaemia could be related to dysfunction of the medial temporal lobe declarative memory system. Atrophy of the human hippocampus, a GC target in the brain, has been observed in CS. 16,17 These studies found that changes in hippocampal formation volume are associated with impairment Correspondence: Jose Leon-Carrión, and Alfonso Leal-Cerro, C/Camilo Jose Cela s/n, Human Neuropsychology Laboratory, Facultad de Psicología. University of Seville. 41018 Sevilla, Spain. Tel.: +34 95 4574137; Fax: +34 95 4374558; E-mail: jleoncarrion@us.es