MECHANISMS IN ENDOCRINOLOGY: Cushing's syndrome causes irreversible effects on the human brain: a systematic review of structural and functional magnetic resonance imaging studies

Andela, Cornelie D.; Haalen, Femke M van; Ragnarsson, Oskar; Papakokkinou, Eleni; Johannsson, Gudmundur; Santos, Alicia; Webb, Susan M.; Biermasz, Nienke R.; Wee, Nic J.A. van der; Pereira, Alberto M.

doi:10.1530/eje-14-1101

Cited by 150 publications

(149 citation statements)

References 55 publications

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“…The brain volume decreases in CS, especially in active hypercortisolism and in patients diagnosed at an older age, which is thought to be related to less brain plasticity compared to younger subjects, although other factors may also be involved, i.e., longer disease duration and exposure to hypercortisolism (48,55). Interestingly, a positive correlation was found between the right cerebellar cortex volume and the CushingQoL scores.…”

Section: Cushing's Diseasementioning

confidence: 94%

“…It is now evident that this glucocorticoid excess exerts irreversible glucocorticoid toxicity on different brain structures and determines persistent impaired QoL, sustained psychological dysfunction and structural brain abnormalities, despite endocrine remission (48). All causes (adrenal, pituitary or ectopic) affect QoL in a similar way.…”

Section: Cushing's Diseasementioning

confidence: 99%

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MANAGEMENT OF ENDOCRINE DISEASE: Quality of life tools for the management of pituitary disease

Webb

Crespo

Santos

et al. 2017

European Journal of Endocrinology

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Background: In the last few years, quality of life (QoL) has become an outcome measure in patients with pituitary diseases. Objective: To describe the available data on QoL impairment evaluated with questionnaires in patients with pituitary diseases. Design: Critical review of the pertinent literature and pragmatic discussion of available information. Methods: Selection of relevant literature from PubMed and WOK, especially from the last 5 years and comprehensive analysis. Results: QoL is impaired in all pituitary diseases, mostly in acromegaly and Cushing's disease (similar to other causes of Cushing's syndrome), but also in non-functioning pituitary adenomas and prolactinomas, especially in the active phase of the disease. Nevertheless, even after endocrine 'cure', scores tend to be below normative values, indicative of residual morbidity after hormonal control. The presence of hypopituitarism worsens subjective QoL perception, which can improve after optimal substitution therapy, including recombinant human growth hormone, when indicated. Conclusions: To improve the long-term outcome of pituitary patients, helping them to attain the best possible health, it appears desirable to include subjective aspects captured when evaluating QoL, so that the affected dimensions are identified and if relevant treated. Additionally, being aware that treatment outcome may not always mean complete normalisation of physical and mental issues related to QoL can be a first step to adaptation and conforming to this new status.

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Section: Cushing's Diseasementioning

confidence: 94%

Section: Cushing's Diseasementioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Quality of life tools for the management of pituitary disease

Webb

Crespo

Santos

et al. 2017

European Journal of Endocrinology

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“…Psychiatric and neurocognitive disturbances can persistent in some patients after successful treatment. 4,23,37,69,87 Patients with persistent CD after treatment suffer increased morbidity and mortality.…”

Section: Normal Physiologymentioning

confidence: 99%

Cushing's disease: pathobiology, diagnosis, and management

Lonser

Nieman

Oldfield

2017

JNS

150

114

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Cushing's syndrome (CS) is caused by prolonged supraphysiological levels of circulating cortisol. Cushing's disease (CD) is the most common etiology (70%-80% of CS cases) of endogenous CS. It is caused by a pituitary adenoma that secretes adrenocorticotropic hormone (ACTH), which stimulates secretion of cortisol by the adrenal glands. If not effectively treated, CD is associated with hypertension, diabetes, obesity, osteoporosis, vascular disease, and shortened life span. Successful resection of a CD-associated ACTH-secreting pituitary adenoma results in immediate biochemical remission and preservation of pituitary function. Early identification of CD by clinical findings, endocrinological evaluation, and imaging studies is critical for diagnosis and effective surgical management. endocrinological and Clinical Features endocrinological Features Normal PhysiologyInsight into the normal and pathophysiological mechanisms of control of the hypothalamic-anterior pituitaryadrenal axis is critical to understanding the pathologic, diagnostic, and therapeutic features of CD (Fig. 1). 52 Under normal physiological conditions (circadian rhythm, where cortisol levels peak in early morning and nadir late at night), systemic inflammation (cytokine), or stress (physiological or psychological), corticotropin-releasing hormone (CRH; a 41-amino acid peptide) is released from the paraventricular hypothalamic nucleus via the median eminence. From the median eminence, CRH is transported in the hypophyseal portal venous system to the pituitary gland, where it binds to the CRH receptor-1 (CRH-R1) on pituitary corticotroph cells. CRH binding to CRH-R1 receptors activates adenylate cyclase and stimulates proopiomelanocortin (POMC) gene expression in the corticotroph cells.17,66 Proopiomelanocortin preprohormone is processed into ACTH (a 39-amino acid peptide) and b-lipotropin (a 93-amino acid peptide). Products of b-lipotropin include b-endorphin and a-lipotropin. ACTH is secreted into the systemic circulation and binds to receptors in the adrenal cortex, where it stimulates production and secretion of glucocorticoids, including cortisol. 83 Under normal conditions, circulating cortisol provides physiological control of this endocrine axis by its negative feedback inhibition on hypothalamic CRH and pituitary ACTH secretion. Cushing's disease (CD) is the result of excess secretion of adrenocorticotropic hormone (ACTH) by a benign monoclonal pituitary adenoma. The excessive secretion of ACTH stimulates secretion of cortisol by the adrenal glands, resulting in supraphysiological levels of circulating cortisol. The pathophysiological levels of cortisol are associated with hypertension, diabetes, obesity, and early death. Successful resection of the CD-associated ACTH-secreting pituitary adenoma is the treatment of choice and results in immediate biochemical remission with preservation of pituitary function. Accurate and early identification of CD is critical for effective surgical management and optimal prognosis. The authors review the cu...

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“…Additionally, the effects of chronic hypercortisolism, still present in active patients, may affect brain volume and cognitive function more than cardiovascular risk. Hypercortisolism itself causes cognitive dysfunctions and reduces brain volume (10,11,12,13,14,15,16,17). Possibly in the active population, hypercortisolism plays a more important role than cardiovascular risk on both cognitive function and brain volume.…”

Section: Discussionmentioning

confidence: 99%

“…This can impair adult neurogenesis, lead to region-specific alterations in dendrite and spine morphology (i.e., reducing dendritic length and branching morphology), impair hippocampal long-term potentiation and synaptic plasticity and also imply inappropriate functional responses after a brief stress exposure (9,10). Reduced brain volume, both general and specifically in the cerebellum or the hippocampus, has been described in CS (11,12,13,14,15). Patients also present neuropsychological alterations, mainly involving memory.…”

mentioning

confidence: 99%

Cardiovascular risk and white matter lesions after endocrine control of Cushing's syndrome

Santos

Resmini

Gómez‐Anson

et al. 2015

European Journal of Endocrinology

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Objective: Cushing's syndrome (CS) is associated with high cardiovascular risk. White matter lesions (WML) are common on brain magnetic resonance imaging (MRI) in patients with increased cardiovascular risk. Aim: To investigate the relationship between cardiovascular risk, WML, neuropsychological performance and brain volume in CS. Design/methods: Thirty-eight patients with CS (23 in remission, 15 active) and 38 controls sex-, age-and education-level matched underwent a neuropsychological and clinical evaluation, blood and urine tests and 3Tesla brain MRI. WML were analysed with the Scheltens scale. Ten-year cardiovascular risk (10CVR) and vascular age (VA) were calculated according to an algorithm based on the Framingham heart study. Results: Patients in remission had a higher degree of WML than controls and active patients (P!0.001 and PZ0.008 respectively), which did not correlate with cognitive performance in any group. WML severity positively correlated with diastolic blood pressure (rZ0.659, PZ0.001) and duration of hypertension (rZ0.478, PZ0.021) in patients in remission. Both patient groups (active and in remission) had higher 10CVR (PZ0.030, PZ0.041) and VA than controls (PZ0.013, PZ0.039). Neither the 10CVR nor the VA correlated with WML, although both negatively correlated with cognitive function and brain volume in patients in remission (P!0.05). Total brain volume and grey matter volume in both CS patient groups were reduced compared to controls (total volume: active PZ0.006, in remission PZ0.012; grey matter: active PZ0.001, in remission PZ0.003), with no differences in white matter volume between groups. Conclusions: Patients in remission of Cushing's syndrome (but not active patients) have more severe white matter lesions than controls, positively correlated with diastolic pressure and duration of hypertension. Ten-year cardiovascular risk and vascular age appear to be negatively correlated with the cognitive function and brain volume in patients in remission of Cushing's syndrome.

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MECHANISMS IN ENDOCRINOLOGY: Cushing's syndrome causes irreversible effects on the human brain: a systematic review of structural and functional magnetic resonance imaging studies

Cited by 150 publications

References 55 publications

MANAGEMENT OF ENDOCRINE DISEASE: Quality of life tools for the management of pituitary disease

MANAGEMENT OF ENDOCRINE DISEASE: Quality of life tools for the management of pituitary disease

Cushing's disease: pathobiology, diagnosis, and management

Cardiovascular risk and white matter lesions after endocrine control of Cushing's syndrome

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