María-José Barahona

Verbal and Visual Memory Performance and Hippocampal Volumes, Measured by 3-Tesla Magnetic Resonance Imaging, in Patients with Cushing's Syndrome

CONTEXT Cushings syndrome (CS) affects cognition and memory. OBJECTIVE Our objective was to evaluate memory and hippocampal volumes (HV) on 3-tesla magnetic resonance imaging (3T MRI) in CS patients and controls. PATIENTS AND METHODS Thirty-three CS patients (11 active, 22 cured) and 34 controls matched for age, sex, and education underwent Rey Auditory Verbal Learning Test and Rey-Osterrieth Complex Figure memory tests. Gray matter and HV were calculated on 3T MRI, using FreeSurfer image analyses software. RESULTS No differences in HV were observed between active and cured CS or controls. Memory performance was worse in CS patients than controls (P < 0.04 in active; P < 0.03 in cured CS) but did not differ among CS groups, which were therefore analyzed together; they performed worse for verbal (P = 0.02) and visual memory (P = 0.04) than controls. In 12 CS patients, memory was below normative cutoff values for verbal (n = 6, cured), visual memory (n = 10, six cured) or both (n = 4); these patients with severe memory impairments showed smaller HV compared with their matched controls (P = 0.02 with verbal impairment; P = 0.03 with visual impairment). They were older (P = 0.04), had shorter education (P = 0.02), and showed a trend toward longer duration of hypercortisolism (P = 0.07) than the remaining CS patients. Total (P = 0.004) and cortical (P = 0.03) brain gray matter volumes were decreased in CS compared with controls, indicating brain atrophy, whereas subcortical gray matter (which includes HV) was reduced only in the 12 patients with severe memory impairment. CONCLUSION Verbal and visual memory is worse in CS patients than controls, even after biochemical cure. HV was decreased only in those whose memory scores were below normative cutoff values.

Deleterious effects of glucocorticoid replacement on bone in women after long-term remission of Cushing's syndrome.

Endogenous hypercortisolism and high‐dose and long‐term glucocorticoid (GC) therapy reduce bone mass. Patients in remission after successful treatment of Cushings syndrome (CS) often present hypoadrenalism and require long‐term GC replacement. The aim of our study was to evaluate whether this GC “replacement” had any further effect on bone in women after long‐term remission of CS. Thirty‐seven women (mean age: 50 ± 14 yr; 27 of pituitary and 10 of adrenal origin) with cured CS (mean time of cure: 11 ± 6 yr), 14 with active CS, and 85 sex‐, body mass index (BMI)‐, and age‐matched controls were enrolled. BMD and BMC were measured by DXA scanning. Bone biochemical markers were also measured. Duration and dose of GC replacement and duration of endogenous hypercortisolism were calculated. Cured and active CS patients had less BMC, BMD, and osteocalcin than controls (p < 0.01). These differences were observed in estrogen‐sufficient women but not in those with estrogen deficiency. Duration of GC treatment (mean: 42 mo; range, 2–420 mo) and endogenous hypercortisolism (mean: 70 mo; range, 13–241 mo) negatively correlated with BMC and lumbar spine BMD. After regression analysis, the main predictor of abnormal BMC and BMD was the duration of GC replacement (p < 0.01). Patients treated for CS persistently have less bone mass despite long‐term cure. Both duration of endogenous hypercortisolism and mainly exogenous “replacement” therapy with GC negatively affect bone mass. Thus, the additional deleterious effect of GC for the treatment of adrenal axis suppression should be considered.

Gender dimorphism in body composition abnormalities in acromegaly: males are more affected than females

BACKGROUND Acromegaly changes body composition (BC), but long-term gender differences have not been reported. OBJECTIVE To evaluate BC in active and controlled acromegalic patients. DESIGN AND METHODS Clinical and biochemical variables and BC (by dual-energy X-ray absorptiometry) were evaluated in 60 acromegalic patients (19 active, 41 controlled) and 105 controls, matched for age and gender. RESULTS Acromegalic males (n=24) had more total mass (89+/-13 vs 76.5+/-15.3 kg, P<0.001), lean body mass (LBM; 64.6+/-8.7 vs 56.4+/-5.8 kg, P<0.001), and bone mineral content (BMC; 2.9+/-0.5 vs 2.6+/-0.3 kg, P<0.05) than controls (n=33). Controlled male patients (n=14) had more total mass (89+/-14.7 vs 76.5+/-15.3 kg, P<0.05) and a trend to have more LBM (61.8+/-9.4 vs 56.4+/-5.8 kg, P=0.065) than controls. Only in active disease was a decrease in fat mass (FM) observed, compared with controlled patients and controls (males: 19.5+/-5.3 vs 27+/-6.2 and 25.9+/-4%, P<0.001; females: 30.3+/-6.7 vs 37.1+/-5.8 and 36.5+/-6.6%, P<0.01). In females, no further differences were observed. No differences in BMC were found between eugonadal and hypogonadal acromegalic patients, but in hypogonadal females, acromegaly appeared to prevent the BMC loss seen in hypogonadal postmenopausal controls. GH and IGF1 levels were negatively correlated with FM (males, P<0.05; females, P<0.001), but in the regression analysis GH was a predictor of FM only in women. CONCLUSIONS Control of acromegaly reverts decreased FM in both genders; only in males more total mass and a trend for more LBM persist. The anabolic effect of GH on bone reverted in cured males, but persisted in females and appeared to override the bone loss of menopause.

Telomere length analysis in Cushing's syndrome

INTRODUCTION Hypercortisolism in Cushings syndrome (CS) is associated with increased morbidity and mortality. Hypercortisolism also occurs in chronic depressive disorders and stress, where telomere length (TL) is shorter than in controls. We hypothesized that shortening of telomere might occur in CS and contribute to premature aging and morbidity. AIM To investigate TL in CS patients compared with controls. METHODS Seventy-seven CS patients (14 males, 59 pituitary, 17 adrenal, and one ectopic; 21 with active disease) were compared with 77 gender-, age-, and smoking-matched controls. Fifteen CS were evaluated longitudinally, during active disease and after remission of hypercortisolism. Leukocyte TL was measured by telomere restriction fragment-Southern technique. Clinical markers were included in a multiple linear regression analysis to investigate potential predictors of TL. RESULTS Mean TL in CS patients and controls was similar (7667 vs 7483 bp, NS). After adjustment for age, in the longitudinal evaluation, TL was shorter in active disease than after remission (7273 vs 7870, P<0.05). Age and dyslipidemia were negative predictors (P<0.05), and total leukocyte count was a positive predictor for TL (P<0.05). As expected, a negative correlation was found between TL and age (CS, R=-0.400 and controls, R=-0.292; P<0.05). No correlation was found between circulating cortisol, duration of exposure to hypercortisolism or biochemical cure and TL. CONCLUSION Even though in the cross-sectional comparison of CS and controls no difference in TL was found, in the longitudinal evaluation, patients with active CS had shorter TL than after biochemical cure of hypercortisolism. These preliminary results suggest that hypercortisolism might negatively impact telomere maintenance. Larger studies are needed to confirm these findings.

Dyslipidemia and Chronic Inflammation Markers Are Correlated with Telomere Length Shortening in Cushing’s Syndrome

Introduction Cushing’s syndrome (CS) increases cardiovascular risk (CVR) and adipocytokine imbalance, associated with an increased inflammatory state. Telomere length (TL) shortening is a novel CVR marker, associated with inflammation biomarkers. We hypothesized that inflammatory state and higher CVR in CS might be related to TL shortening, as observed in premature aging. Aim To evaluate relationships between TL, CVR and inflammation markers in CS. Methods In a cross-sectional study, 77 patients with CS (14 males, 59 pituitary-, 17 adrenal- and 1 ectopic-origin; 21 active disease) and 77 age-, gender-, smoking-matched controls were included. Total white blood cell TL was measured by TRF-Southern technique. Clinical data and blood samples were collected (lipids, adrenal function, glucose). Adiponectin, interleukin-6 (IL6) and C-reactive protein (CRP) were available in a subgroup of patients (n=32). Correlations between TL and clinical features were examined and multiple linear regression analysis was performed to investigate potential predictors of TL. Results Dyslipidemic CS had shorter TL than non-dyslipidemic subjects (7328±1274 vs 7957±1137 bp, p<0.05). After adjustment for age and body mass index, cured and active CS dyslipidemic patients had shorter TL than non-dyslipidemic CS (cured: 7187±1309 vs 7868±1104; active: 7203±1262 vs 8615±1056, respectively, p<0.05). Total cholesterol and triglycerides negatively correlated with TL (r-0.279 and -0.259, respectively, p<0.05), as well as CRP and IL6 (r-0.412 and -0.441, respectively, p<0.05). No difference in TL according the presence of other individual CVR factors (hypertension, diabetes mellitus, obesity) were observed in CS or in the control group. Additional TL shortening was observed in dyslipidemic obese patients who were also hypertensive, compared to those with two or less CVR factors (6956±1280 vs 7860±1180, respectively, p<0.001). Age and dyslipidemia were independent negative predictors of TL. Conclusion TL is shortened in dyslipidemic CS patients, further worse if hypertension and/or obesity coexist and is negatively correlated with increased inflammation markers. Increased lipids and a “low” grade inflammation may contribute to TL shortening and consequently to premature ageing and increased morbidity in CS.

Long-Term Effects of Prior Cushing’s Syndrome

Cushing’s syndrome, and its most frequent cause pituitary-dependent Cushing’s disease, is a rare disease due to excessive glucocorticoid (GC) secretion. Chronic exposure to GC excess determines a large number of deleterious effects leading to increased morbidity (i.e., cardiovascular complications, psychiatric symptoms, osteoporosis, cognitive impairment, hormonal dysfunctions after surgery) and mortality. Although most of these effects improve after normalization of cortisol, not all are completely reversible after remission of hypercortisolism and negatively impact on health-related quality of life. Therefore, there is a need for both greater diagnostic suspicion and improved diagnostic tools to hasten the delay to diagnosis and effective therapy aimed at improving long-term prognosis. The lack of systematic data analysis and prospective longitudinal studies is due to low prevalence and orphan disease status of CS. Multicenter registries collecting longitudinal data on these patients would contribute to further knowledge on the natural history and long-term outcome data in these patients.