La difícil curació de la Síndrome de Cushing

Els pacients amb la síndrome de Cushing (SC) tenen un excés de cortisol a la sang, fet que comporta tota una sèrie d'alteracions tant físiques (obesitat de predomini troncular) com metabòliques (hipertensió, diabetis, dislipèmia), condicionant un increment del risc cardiovascular (CV). Era d'esperar que al normalitzar les xifres de cortisol gràcies al tractament, també donaria lloc a una regulació de totes aquestes alteracions. Un estudi recent, però, ha demostrat la persistència d'algunes alteracions metabòliques després de 5 anys de la curació de la malaltia. No obstant, poc sabem respecte la composició corporal en pacients amb SC curats des de fa molts anys.Los pacientes con el sídrome de Cushing (SC) tienen un exceso de cortisol en la sangre, hecho que conlleva toda una serie de alteraciones tanto físicas (obesidad de predominio troncular) como metabólicas (hipertensión, diabetes, dislipemia), condicionando un incremento del riesgo cardiovascular (CV). Era de esperar que, al normalizar las cifras de cortisol gracias al tratamiento, también daría lugar a una regulación de todas estas alteraciones. Un estudio reciente ha demostrado la persistencia de alguans alteraciones metabólicas después de 5 años de la curación de la enfermedad. No obstante, poco sabemos respecto la composición corporal en pacientes con SC curados desde hace muchos años

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

Telomere length analysis in Cushing's syndrome

Introduction: Hypercortisolism in Cushing's 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

Morbilidad, inflamación de bajo grado y riesgo cardiovascular en pacientes que han sufrido síndrome de Cushing: Estudio observacional de casos y controles

El síndrome de Cushing (SC) endógeno es una entidad muy rara ocasionada por un incremento en las concentraciones sanguíneas de cortisol. Es bien conocido que en la fase activa de la enfermedad existe una composición corporal anómala, con un aumento de la grasa principalmente de distribución central y disminución de la masa ósea, y componentes del llamado síndrome metabólico, como hipertensión arterial, dislipemia, diabetes o intolerancia a la glucosa, componentes todos ellos que se asocian con un incremento del riesgo cardiovascular. En un estudio relativamente reciente se muestra que, a pesar de la curación del hipercorticismo, puede persistir un aumento del riesgo cardiovascular hasta 5 años después de la curación. Pero poco se conoce sobre la composición corporal y el riesgo cardiovascular en pacientes con SC tras curación a largo plazo. Los estudios que conforman esta tesis demuestran que, a pesar de una media de 11 años de curación hormonal, los pacientes con SC persisten con una serie de alteraciones similares a las de la fase activa de la enfermedad: a) Persistencia de una composición corporal anómala, con aumento de la masa grasa principalmente abdominal y disminución de la masa y densidad mineral óseas; b) Persistencia de un patrón anómalo en la secreción de adipoquinas, con un aumento de moléculas con actividad inflamatoria como la IL-6 y el TNF&#945;, y una disminución de la adiponectina, molécula de actividad antiinflamatoria; este perfil desfavorable condicionaría una situación de inflamación crónica de bajo grado, que provocaría daño vascular, aterosclerosis y enfermedad cardiovascular; c) Persistencia de alteraciones metabólicas, como la hipertensión arterial, insulinoresistencia y aumento de los niveles de aproproteína B; d) No sólo el hipercortisolismo endógeno tiene efectos negativos sobre la composición corporal, sino también el tratamiento sustitutivo con glucocorticoides exógenos (en concreto, efectos negativos sobre el hueso), tratamiento que en muchas ocasiones se debe administrar a estos pacientes cuando la cirugía ha sido un éxito. Todos estos hallazgos hacen que tengamos que considerar al SC, aunque curado, como una situación de elevado riesgo cardiovascular.Endogenous Cushing´s síndrome (CS) is a rare endocrine disease due to cortisol hypersecretion. Abnormal body composition (increased total and trunk fat mass and reduced bone mass) is characteristic of active CS, as well as hypertension, dyslipidemia, diabetes and impaired glucose tolerance. All are criteria of the metabolic syndrome which is associated with an increased cardiovascular risk. Persistence of increased cardiovascular risk has been reported in patients with CS after 5 years of cure. However, little is known about body composition and cardiovascular risk after long-term recovery of CS. The studies of this thesis have shown that, despite 11 years of hormonal cure, patients with CS persisted with morbidity, as in the active phase of the disease: a) Persistence of abnormal body composition, favoring central fat accumulation and reducing bone mass and bone mineral density; b) Persistence of an unfavorable adipokine profile, including elevated plasma IL-6 and TNF&#945; and low adiponectin, leading to a state of low-grade inflammation; this "inflammatory state" may determine vascular damage which may contribute to atherosclerosis and cardiovascular disease in patients with long-term cured CS; c) Persistence of hypertension, insulin resistance and elevation of apoprotein B; d) Duration of both endogenous hypercortisolism and exogenous glucocorticoid replacement therapy after successful surgery have been shown to negatively affect bone. In conclusion, having suffered CS, even if hypercortisolism is controlled confers an increase in cardiovascular risk

Morbilidad, inflamación de bajo grado y riesgo cardiovascular en pacientes que han sufrido síndrome de Cushing : estudio observacional de casos y controles /

Descripció del recurs: 26 gener 2011El síndrome de Cushing (SC) endógeno es una entidad muy rara ocasionada por un incremento en las concentraciones sanguíneas de cortisol. Es bien conocido que en la fase activa de la enfermedad existe una composición corporal anómala, con un aumento de la grasa principalmente de distribución central y disminución de la masa ósea, y componentes del llamado síndrome metabólico, como hipertensión arterial, dislipemia, diabetes o intolerancia a la glucosa, componentes todos ellos que se asocian con un incremento del riesgo cardiovascular. En un estudio relativamente reciente se muestra que, a pesar de la curación del hipercorticismo, puede persistir un aumento del riesgo cardiovascular hasta 5 años después de la curación. Pero poco se conoce sobre la composición corporal y el riesgo cardiovascular en pacientes con SC tras curación a largo plazo. Los estudios que conforman esta tesis demuestran que, a pesar de una media de 11 años de curación hormonal, los pacientes con SC persisten con una serie de alteraciones similares a las de la fase activa de la enfermedad: a) Persistencia de una composición corporal anómala, con aumento de la masa grasa principalmente abdominal y disminución de la masa y densidad mineral óseas; b) Persistencia de un patrón anómalo en la secreción de adipoquinas, con un aumento de moléculas con actividad inflamatoria como la IL-6 y el TNFα, y una disminución de la adiponectina, molécula de actividad antiinflamatoria; este perfil desfavorable condicionaría una situación de inflamación crónica de bajo grado, que provocaría daño vascular, aterosclerosis y enfermedad cardiovascular; c) Persistencia de alteraciones metabólicas, como la hipertensión arterial, insulinoresistencia y aumento de los niveles de aproproteína B; d) No sólo el hipercortisolismo endógeno tiene efectos negativos sobre la composición corporal, sino también el tratamiento sustitutivo con glucocorticoides exógenos (en concreto, efectos negativos sobre el hueso), tratamiento que en muchas ocasiones se debe administrar a estos pacientes cuando la cirugía ha sido un éxito. Todos estos hallazgos hacen que tengamos que considerar al SC, aunque curado, como una situación de elevado riesgo cardiovascular.Endogenous Cushing's síndrome (CS) is a rare endocrine disease due to cortisol hypersecretion. Abnormal body composition (increased total and trunk fat mass and reduced bone mass) is characteristic of active CS, as well as hypertension, dyslipidemia, diabetes and impaired glucose tolerance. All are criteria of the metabolic syndrome which is associated with an increased cardiovascular risk. Persistence of increased cardiovascular risk has been reported in patients with CS after 5 years of cure. However, little is known about body composition and cardiovascular risk after long-term recovery of CS. The studies of this thesis have shown that, despite 11 years of hormonal cure, patients with CS persisted with morbidity, as in the active phase of the disease: a) Persistence of abnormal body composition, favoring central fat accumulation and reducing bone mass and bone mineral density; b) Persistence of an unfavorable adipokine profile, including elevated plasma IL-6 and TNFα and low adiponectin, leading to a state of low-grade inflammation; this "inflammatory state" may determine vascular damage which may contribute to atherosclerosis and cardiovascular disease in patients with long-term cured CS; c) Persistence of hypertension, insulin resistance and elevation of apoprotein B; d) Duration of both endogenous hypercortisolism and exogenous glucocorticoid replacement therapy after successful surgery have been shown to negatively affect bone. In conclusion, having suffered CS, even if hypercortisolism is controlled confers an increase in cardiovascular risk

Telomeres and endocrine dysfunction of the adrenal and GH/IGF-1 axes

Telomeres, located at the end of linear chromosomes, are essential to maintain genomic stability. Telomere biology has recently emerged as an important player in the fields of ageing and disease. To maintain telomere length (TL) and reduce its degradation after mitosis, the telomerase enzyme complex is produced. Genetic, epigenetic, hormonal and environmental factors can regulate telomerase function. These include stress hormones such as cortisol and growth factors. The hypothalamic-pituitary-adrenal (HPA) axis has been evaluated in psychiatric diseases where hypercortisolism and oxidative stress are often present. Some researches have linked TL shortening to increases in stress-related cortisol, but others have not. The effects of cortisol on the telomere system are complex and may depend on the intensity and duration of exposure. On the other hand, low levels of IGF-1 are associated with inflammation and ageing-related diseases (ischaemic heart disease, congestive heart failure). Both IGF-1 and TL diminish with age and are positively and strongly correlated with each other. It is not clear whether this positive correlation reflects a single association or a cause-effect relationship. Further research will ideally investigate longitudinal changes in telomeres and both these hormonal axes. To our knowledge, TL dysfunction has not been described in either endogenous hypercortisolism (Cushing's syndrome) or acromegaly where excessive amounts of GH and consequently IGF-1 are produced. This review focuses on the possible relationships between telomere dysfunction and the hypothalamic-pituitary-adrenal (HPA) axis and GH-IGF-1 system

Telomeres and endocrine dysfunction of the adrenal and GH/IGF-1 axes

Telomeres, located at the end of linear chromosomes, are essential to maintain genomic stability. Telomere biology has recently emerged as an important player in the fields of ageing and disease. To maintain telomere length (TL) and reduce its degradation after mitosis, the telomerase enzyme complex is produced. Genetic, epigenetic, hormonal and environmental factors can regulate telomerase function. These include stress hormones such as cortisol and growth factors. The hypothalamic-pituitary-adrenal (HPA) axis has been evaluated in psychiatric diseases where hypercortisolism and oxidative stress are often present. Some researches have linked TL shortening to increases in stress-related cortisol, but others have not. The effects of cortisol on the telomere system are complex and may depend on the intensity and duration of exposure. On the other hand, low levels of IGF-1 are associated with inflammation and ageing-related diseases (ischaemic heart disease, congestive heart failure). Both IGF-1 and TL diminish with age and are positively and strongly correlated with each other. It is not clear whether this positive correlation reflects a single association or a cause-effect relationship. Further research will ideally investigate longitudinal changes in telomeres and both these hormonal axes. To our knowledge, TL dysfunction has not been described in either endogenous hypercortisolism (Cushing's syndrome) or acromegaly where excessive amounts of GH and consequently IGF-1 are produced. This review focuses on the possible relationships between telomere dysfunction and the hypothalamic-pituitary-adrenal (HPA) axis and GH-IGF-1 system

Telomere length analysis in Cushing's syndrome

Introduction: Hypercortisolism in Cushing's 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