Cushing's Syndrome In Remission Research Articles

Evaluation of bone-related mechanical properties in female patients with long-term remission of Cushing's syndrome using quantitative computed tomography-based finite element analysis.

Hypercortisolism in Cushing's syndrome (CS) is associated with bone loss, skeletal fragility, and altered bone quality. No studies evaluated bone geometric and strain-stress values in CS patients after remission thus far. Thirty-two women with CS in remission (mean age [±SD] 51 ± 11; body mass index [BMI], 27 ± 4 kg/m2; mean time of remission, 120 ± 90 months) and 32 age-, BMI-, and gonadal status-matched female controls. Quantitative computed tomography (QCT) was used to assess volumetric bone mineral density (vBMD) and buckling ratio, cross-sectional area, and average cortical thickness at the level of the proximal femur. Finite element (FE) models were generated from QCT to calculate strain and stress values (maximum principal strain [MPE], maximum strain energy density [SED], maximum Von Mises [VM], and maximum principal stress [MPS]). Areal BMD (aBMD) and trabecular bone score (TBS) were assessed by dual-energy X-ray absorptiometry (2D DXA). Trabecular vBMD at total hip and trochanter were lower in CS as compared with controls (P < .05). Average cortical thickness was lower, and buckling ratio was greater in CS vs controls (P < .01). All strain and stress values were higher in CS patients vs controls (P < .05). 2D DXA-derived measures were similar between patients and controls (P > .05). Prior hypercortisolism predicted both VM (β .30, P = .014) and MPS (β .30, P = .015), after adjusting for age, BMI, menopause, delay to diagnosis, and duration of remission. Women with prior hypercortisolism have reduced trabecular vBMD and impaired bone geometrical and mechanical properties, which may contribute to an elevated fracture risk despite long-term remission.

E47 as a novel glucocorticoid-dependent gene mediating lipid metabolism in patients with endogenous glucocorticoid excess.

E47 has been identified as a modulating transcription factor of glucocorticoid receptor target genes, its loss protecting mice from metabolic adverse effects of glucocorticoids. We aimed to analyze the role of E47 in patients with endogenous glucocorticoid excess [Cushing's syndrome (CS)] and its association with disorders of lipid and glucose metabolism. This is a prospective cohort study including 120 female patients with CS (ACTH-dependent = 79; ACTH-independent = 41) and 26 healthy female controls. Morning whole blood samples after an overnight fast were used to determine E47 mRNA expression levels in patients with overt CS before and 6-12 months after curative surgery. Expression levels were correlated with the clinical phenotype of the patients. Control subjects underwent ACTH stimulation tests and dexamethasone suppression tests to analyze short-term regulation of E47. E47 gene expression showed significant differences in patient cohorts with overt CS vs. patients in remission (p = 0.0474) and in direct intraindividual comparisons pre- vs. post-surgery (p = 0.0353). ACTH stimulation of controls resulted in a significant decrease of E47 mRNA expression 30min after i.v. injection compared to baseline measurements. Administration of 1 mg of dexamethasone overnight in controls did not change E47 mRNA expression. E47 gene expression showed a positive correlation with total serum cholesterol (p = 0.0036), low-density lipoprotein cholesterol (p = 0.0157), and waist-arm ratio (p = 0.0138) in patients with CS in remission. E47 is a GC-dependent gene that is upregulated in GC excess potentially aiming at reducing metabolic glucocorticoid side effects such asdyslipidemia.

Altered thalamic volume in patients with mild autonomous cortisol secretion: a structural brain MRI study.

To compare thalamic volume and cognitive functions of patients with mild autonomous cortisol secretion (MACS) with control subjects and patients with overt Cushing's syndrome (CS). In this cross-sectional study, volumes of regions of interest were assessed using 3T magnetic resonance imaging and a voxel-based morphometry approach in 23 patients with MACS, 21 patients with active CS, 27 patients with CS in remission, and 21 control subjects. Cognitive functions were assessed using validated questionnaires. Patients with MACS had smaller left thalamic (F = 3.8, p = 0.023), left posterior thalamic (F = 4.9, p = 0.01), left medial thalamic (F = 4.7, p = 0.028), and right lateral thalamic (F = 4.1, p = 0.025) volumes than control subjects. Patients with active CS also had smaller left thalamic (F = 3.8, p = 0.044), left posterior thalamic (F = 4.9, p = 0.007), left medial thalamic (F = 4.7, p = 0.006), and right lateral thalamic (F = 4.1, p = 0.042) volumes compared to controls. Patients with CS in remission had smaller left medial (F = 4.7, p = 0.030) and right lateral thalamic (F = 4.1, p = 0.028) volumes than controls. Neuropsychological tests showed no difference between the groups. MACS may decrease thalamic volume.

Glucocorticoid receptor polymorphism BclI with increased glucocorticoid sensitivity has a positive influence on quality of life in endogenous Cushing's syndrome in remission.

Patients with endogenous Cushing's syndrome (CS) may suffer from a wide range of neuropsychiatric symptoms leading to impaired quality of life (QoL). Glucocorticoid receptor (GR) polymorphisms are associated with increased (BclI and N363S) or decreased (A3669G and ER22/23EK) GR sensitivity. GR genotypes may modulate and affect QoL and recovery after remission differently via GR sensitivity. 295 patients with endogenous CS (81 active, 214 in remission) from 3 centers of the German Cushing's Registry were included for the cross-sectional analysis. All subjects were assessed with three questionnaires (CushingQoL, Tuebingen CD-25, SF-36). For the longitudinal part, 120 patients of them were analyzed at baseline and after 1.5 ± 0.9 yrs of follow-up. DNA samples were obtained from peripheral blood leukocytes for GR genotyping. Patients in remission scored significantly better than patients with active CS in the CushingQoL questionnaire and in the SF-36 sub-categories physical and social functioning, role-physical, bodily pain, and vitality. In cross-sectional analysis, no differences in QoL between minor allele and wildtype carriers were detected for all polymorphisms in active or cured CS. In longitudinal analysis, however, carriers with BclI minor allele showed significant improvement in SF-36 sub-categories vitality (P = .038) and mental health (P = .013) compared to wildtype carriers (active CS at baseline vs. CS in remission at follow-up). The outcome of the two questionnaires CushingQoL and Tuebingen CD-25 improved significantly in both wildtype and minor allele carriers. BclI minor allele carriers initially had the lowest QoL but recovered better from impaired QoL than wildtype carriers.

Long‐term effects of glucocorticoid excess on the brain

The metabolic and cardiovascular clinical manifestations in patients with Cushing's syndrome (CS) are generally well known. However, recent studies have broadened the perspective of the effects of hypercortisolism, showing that both endogenous and exogenous glucocorticoid excess alter brain functioning on several time scales. Consequently, cognitive deficits and neuropsychological symptoms are highly prevalent during both active CS and CS in remission, as well as during glucocorticoid treatment. In this review, we discuss the effects of endogenous hypercortisolism and exogenously induced glucocorticoid excess on the brain, as well as the prevalence of cognitive and neuropsychological deficits and their course after biochemical remission. Furthermore, we propose possible mechanisms that may underly neuronal changes, based on experimental models and in vitro studies. Finally, we offer recommendations for future studies.

Prevalence of sarcopenia after remission of hypercortisolism and its impact on HRQoL.

Cushing's syndrome (CS) is associated with skeletal muscle structural and functional impairment which may persist long-term despite surgical removal of the source of cortisol excess. Prevalence of sarcopenia and its impact on Health-Related-Quality of Life (HRQoL) in 'cured' CS is not known. There is a need to identify easy biomarkers to help the clinicians recognise patients at elevated risk of suffering sustained muscle function. We studied 36 women with CS in remission, and 36 controls matched for age, body mass index, menopausal status, and level of physical activity. We analysed the skeletal muscle mass using dual-energy X-ray absorptiometry, muscle fat fraction using two-point Dixon magnetic resonance imaging and muscle performance and strength using the following tests: hand grip strength, gait speed, timed up and go and 30-s chair stand. We assessed HRQoL with the following questionnaires: SarQoL, CushingQoL, SF-36. We calculated the sarcopenia index (SI; serum creatinine/serum cystatin C × 100). Prevalence of sarcopenia, according to the European Working Group on Sarcopenia in Older People (EWGSOP), was greater in CS as compared with controls (19% vs. 3%; p < .05). Patients with sarcopenia had a lower SarQoL score than those without sarcopenia (61 ± 17 vs. 75 ± 14; p < .05), and scored worse on the items pain, easy bruising and worries on physical appearance (p < .05 for all comparisons) of the CushingQoL questionnaire. Patients with sarcopenia had poorer physical functioning on SF-36 than those without sarcopenia (60 ± 23 vs. 85 ± 15; p < .01). SI was lower in patients with sarcopenia than those without (71 ± 3 vs. 77 ± 2; p = .032), and was associated with intramuscular fatty infiltration, worse performance on the 30-s chair stand test, slower gait speed, and worse muscle weakness-related HRQoL, as measured using the SarQoL questionnaire (p < .05). The optimised cut-off value for the SI ratio to diagnose sarcopenia was 72, which yielded a sensitivity of 73% and a specificity of 90%. Sarcopenia is common in patients with CS in long-term remission, and associated with impaired quality of life. The SI is a potential biomarker allowing clinicians to identify patients at high risk of muscle dysfunction.

Thigh Muscle Fat Infiltration Is Associated With Impaired Physical Performance Despite Remission in Cushing's Syndrome.

Muscle weakness is common in patients with Cushing's syndrome (CS) and may persist after the resolution of hypercortisolism. Intramuscular fatty infiltration has been associated with the deterioration of muscle performance in several conditions. To quantify the degree of fatty infiltration in the thigh muscles of "cured" CS patients and evaluate the relationship between intramuscular fatty infiltration and physical performance. This was a cross-sectional study. Tertiary referral center. Thirty-six women with CS in remission, and 36 controls matched for age, BMI, menopausal status, and level of physical activity. We analyzed the percentage fat fraction (FF) of the thigh muscles in the anterior, posterior, and combined anterior and posterior compartments using MRI and 2-point Dixon sequence. We assessed muscle function and strength using the following tests: gait speed (GS), timed up and go (TUG), 30-second chair stand, and hand grip strength. Fat fraction in all the compartments analyzed was increased in patients as compared with controls. The performance on TUG, 30-second chair stand, and GS was more impaired in CS patients versus controls. In patients, greater FF was negatively associated with performance on functional tests. Fat fraction in the combined anterior and posterior compartments predicted performance on TUG (ß 0.626, P < 0.000) and GS (ß -0.461, P = 0.007), after adjusting for age, BMI, menopausal status, and muscle mass. Thigh muscle fatty infiltration is increased in "cured" CS patients and is associated with poorer muscle performance. Future studies are needed to establish therapeutic strategies to improve muscle weakness in these patients.

Translational evidence of prothrombotic and inflammatory endothelial damage in Cushing syndrome after remission.

Sustained evidence from observational studies indicates that after remission of Cushing syndrome (CS) a cardiovascular risk phenotype persists. Here, we performed a translational study in active CS and CS in remission (RCS) to evaluate the subclinical cardiometabolic burden and to explore the direct pro-inflammatory and prothrombotic potential of their sera on the endothelium in an in vitro translational atherothrombotic cell model. Cross sectional study. The groups were (n=9/group): I. RCS; II. Active CS (ACS) and III. Controls (CTR), all matched for age, body mass index, sex, without other hormonal deficits. We evaluated in vivo: cardiometabolic profile; endothelial markers (sVCAM-1, NO); endothelial dysfunction (FMD); intima-media thickness and body composition (DEXA). In vitro endothelial cells (EC) were exposed to sera taken from the different subjects to evaluate inflammatory EC response (tisVCAM) and thrombogenicity of the generated extracellular matrix (ECM): von Willebrand factor (VWF) and platelet reactivity. Three of the 9 RCS subjects were on glucocorticoid replacement therapy (GC-RT). Patients on GC-RT had a shorter period of time in stable remission. In vivo analysis ACS showed typically metabolic features, while cardiometabolic markers reached statistical significance for RCS only for Hs-CRP (P<.01). In vitro:EC exposed to ACS and RCS sera displayed increased tisVCAM-1 (P<.01 for ACS and P<.05 for RCS vs CTR), VWF (P<.01 for ACS and P<.05 for RCS vs CTR) and platelet adhesion on ECM (P<.01 for ACC and P<.05 for RCS vs CTR). No statistically significant differences were observed between GC-RT RSC and RCS without GC-RT. The sera of premenopausal women with CS in remission, without atherothrombotic disease, contain circulatory endothelial deleterious factors with a direct thrombogenic and pro-inflammatory endothelial effect that could increase cardiovascular risk.

Body composition and bone mineral density in women with Cushing's syndrome in remission and the association with common genetic variants influencing glucocorticoid sensitivity.

Adverse body compositional features and low bone mineral density (BMD) are the characteristic of patients with active Cushing's syndrome (CS). The aim of this study was to evaluate body composition and BMD in women with CS in long-term remission and the influence of polymorphisms in genes affecting glucocorticoid (GC) sensitivity on these end-points. This was a cross-sectional, case-controlled study, including 50 women previously treated for CS and 50 age and gender-matched controls. Median (interquartile range) remission time was 13 (5-19) years. Body composition and BMD were measured with dual-energy X-ray absorptiometry. Five polymorphisms in four genes associated with GC sensitivity were analysed using TaqMan or Sequenom single-nucleotide polymorphism genotyping. Patients with CS in remission had increased abdominal fat mass (P<0.01), whereas BMD was not significantly different at any site between patients and controls. In patients, the NR3C1 Bcl1 polymorphism was associated with reduced total (P<0.05) and femur neck BMD (P<0.05). The polymorphism rs1045642 in the ABCB1 gene was associated with increased abdominal fat mass (P<0.05) and decreased appendicular skeletal muscle mass (P<0.05). GC replacement was associated with reduced total BMD (P<0.01), BMD at lumbar spine (P<0.05) and increased abdominal fat (P<0.01). Ongoing GC replacement therapy together with polymorphisms in two genes related with GC sensitivity is associated with abdominal obesity and adverse skeletal health in patients with CS in long-term remission.

Common genetic variants in the glucocorticoid receptor and the 11β-hydroxysteroid dehydrogenase type 1 genes influence long-term cognitive impairments in patients with Cushing's syndrome in remission.

Cognitive function is impaired in patients with Cushing's syndrome (CS) in remission. The objective of the investigation was to study the effects of polymorphisms in genes associated with glucocorticoid (GC) sensitivity on cognitive function in patients with CS in long-term remission. This was a cross-sectional, case-controlled, single-center study. Fifty-three patients with CS in remission and 53 controls matched for age, gender, and educational level participated in the study. Cognitive function, studied using standardized neuropsychological testing, and polymorphisms in the GC receptor (NR3C1; Bcl1 and A3669G), mineralocorticoid receptor (NR3C2; I180V), 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1; rs11119328), and ATP binding cassette B1 (ABCB1; rs1045642) genes were measured. The association between cognitive function and polymorphisms were analyzed using linear regression with adjustments for age and educational level. The mean age in patients and controls was 53 ± 14 years. The median (interquartile range) duration of remission was 13 (5-18) years. In patients, the single-nucleotide polymorphism rs11119328 was associated with impairments in processing speed, auditory attention, auditory working memory, and reading speed. This association was not seen in matched controls. The Bcl1 polymorphism was associated with fatigue and worse visual attention and working memory. The remaining single-nucleotide polymorphisms were not associated with cognitive performance. In this study, polymorphisms in the 11βHSD1 and NR3C1 genes were associated with impaired cognitive function, indicating that GC sensitivity and prereceptor regulation of GC action may play a role in the long-term consequences of CS. The study provides a novel insight into the etiology of cognitive dysfunction in patients with CS in remission.

Surgical remission of Cushing's syndrome reduces cardiovascular risk.

Recent studies have questioned the reversibility of complications of Cushing's syndrome (CS) after successful surgical treatment. The aim of this study was to assess the outcome of patients with CS who achieved disease remission compared with those patients with persistent hypercortisolism and matched controls. A retrospective study of 75 patients with CS followed at an academic center. Cardiovascular risk profile was evaluated in 51 patients with CS in remission (group 1) and 24 patients with persistent disease (group 2) and compared with 60 controls. Mortality of patients with CS was compared with the background population. In group 1, the frequency of cardiovascular risk factors dropped after disease remission even if it remained higher at the last follow-up than in the control group. In group 2, the frequency of cardiovascular risk factors remained unchanged during follow-up. The rate of cardiovascular and thromboembolic events was higher in group 2 than in group 1, as was the mortality rate (two deaths in group 1 and nine in group 2; ratio of two SMRs, 0.11; 95% CI, 0.011-0.512). Survival was significantly longer in group 1 than in group 2 (87 months, 80-98 vs 48 months, 38-62; P<0.0001). Successful surgical treatment of hypercortisolism significantly improves cardiovascular risk and may reduce the mortality rate. Patients with persistent disease have increased morbidity and mortality when compared with patients in remission.

MANAGEMENT OF ENDOCRINE DISEASE: Cushing's syndrome: a structured short- and long-term management plan for patients in remission

One hundred years have passed since Harvey Williams Cushing presented the first patient with the syndrome that bears his name. In patients with Cushing's syndrome (CS), body composition and lipid, carbohydrate and protein metabolism are dramatically affected and psychopathology and cognitive dysfunction are frequently observed. Untreated patients with CS have a grave prognosis with an estimated 5-year survival of only 50%. Remission can be achieved by surgery, radiotherapy and sometimes with medical therapy. Recent data indicate that the adverse metabolic consequences of CS are present for years after successful treatment.In addition, recent studies have demonstrated that health-related quality of life and cognitive function are impaired in patients with CS in long-term remission. The focus of specialised care should therefore be not only on the diagnostic work-up and the early postoperative management but also on the long-term follow-up. In this paper, we review the long-term consequences in patients with CS in remission with focus on the neuropsychological effects and discuss the importance of these findings for long-term management. We also discuss three different phases in the postoperative management of surgically-treated patients with CS, each phase distinguished by specific challenges: the immediate postoperative phase, the glucocorticoid dose tapering phase and the long-term management. The focus of the long-term specialised care should be to identify cognitive impairments and psychiatric disorders, evaluate cardiovascular risk, follow pituitary function and detect possible recurrence of CS.

Neurodegenerative and inflammatory biomarkers in cerebrospinal fluid in patients with Cushing's syndrome in remission

Patients with Cushing's syndrome (CS) in long-term remission have impaired cognitive function. Cerebrospinal fluid (CSF) biomarkers are important diagnostic tools in the work-up of patients with cognitive impairment. The aim of this study was to analyze neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission. A cross-sectional, single-center study. Twelve women previously treated for CS and six healthy subjects. Neurodegenerative CSF markers: total tau, hyperphosphorylated tau, amyloid beta peptides, soluble amyloid precursor protein alpha and beta, neurofilament light proteins, glial fibrillary acidic protein, and monocyte chemoattractant protein 1; and inflammatory CSF markers: interferon gamma, interleukin (IL) 1B, IL2, IL4, IL5, IL8, IL10, IL12p70, IL13, and tumor necrosis factor alpha. The mean age (mean±S.D.) was similar in patients with CS in remission (44.9±14 years) and healthy subjects (42.3±15.7 years; P=0.726). No differences were observed in the concentrations of any neurodegenerative biomarkers between the patients and healthy subjects. Nor were the concentrations of inflammatory biomarkers different between the groups. The pattern of neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission does not differ from that of the healthy subjects. The underlying mechanisms of the cognitive deficits in patients with CS in remission are different from those observed in patients with neurodegenerative disorders and remain to be explained.

Long-Term Cognitive Impairments and Attentional Deficits in Patients with Cushing's Disease and Cortisol-Producing Adrenal Adenoma in Remission

Cognitive function is impaired in patients with active Cushing's syndrome (CS). The aim was to study cognitive function in patients with CS in long-term remission. We conducted a cross-sectional, case-controlled, single center study. Fifty-five patients previously treated for Cushing's disease (n = 43) and cortisol-producing adrenal adenoma (n = 12) and 55 controls matched for age, gender, and educational level participated in the study. Working memory, attention, information-processing speed, verbal fluency, and reading speed were studied using standardized neuropsychological testing and alerting, orienting, and executive control using the Attentional Network Test. Fatigue impact scale and the comprehensive psychopathological rating scale were used to evaluate fatigue and affective disorder. Median (interquartile range) duration of remission was 13 (5-19) yr and the mean ± SD age at follow-up was 54 ± 14 yr. Compared to controls, patients had a higher score on the fatigue impact scale, indicating greater burdens of fatigue, and a higher score on the comprehensive psychopathological rating scale subscales for depression and anxiety. In a multivariate analysis, attention, spatial orienting, alerting, working memory, verbal fluency, and reading speed were all diminished in comparison to controls, independent of scores for affective disorder and fatigue. No overall difference in outcome was seen between patients in long-term remission for Cushing's disease and cortisol-producing adrenal adenoma. Patients with CS in remission have impaired cognitive function that cannot be explained by the coexistence of affective disorder or chronic fatigue. The pattern of cognitive and attentional deficits suggests a more global involvement of the brain function than has previously been suggested.

Persistent Body Fat Mass and Inflammatory Marker Increases after Long-Term Cure of Cushing’s Syndrome

Although increased central fat mass is characteristic of active Cushing's syndrome (CS), little is known about body composition and secretion of adipokines after long-term recovery of CS. The aim of this study was to evaluate central fat mass and its correlation with adipokines and cardiovascular risk factors in patients after long-term remission of CS. Thirty-seven women with CS in remission (27 of pituitary and 10 of adrenal origin; mean age, 50 +/- 14 yr; mean time of hormonal cure, 11 +/- 6 yr) were enrolled and compared to 14 women with active CS and 85 gender-, age-, and body mass index-matched healthy controls. Total and trunk fat mass were measured by dual-energy x-ray absorptiometry scanning. Laboratory parameters and adipokine levels [including adiponectin, visfatin, soluble TNFalpha-receptor 1 (sTNF-R1), sTNF-R2, and IL-6] were measured. Cured CS patients had more total and trunk fat mass than controls. Cured and active CS had higher levels of sTNF-R1 and IL-6 and lower adiponectin levels than controls. Higher insulin levels and blood pressure in both groups of CS patients and higher apolipoprotein B in cured CS were observed compared to controls. sTNF-R1 correlated positively with percentage of trunk fat mass and remained significant after adjusting for anthropometric parameters. Despite long-term cure, patients who have suffered CS exhibit persistent accumulation of central fat, as in active hypercortisolemia, with the consequent unfavorable adipokine profile, leading to a state of low-grade inflammation. This situation determines a persistent and increased cardiovascular risk in these patients.