GH levels and insulin sensitivity are differently associated with biomarkers of cardiovascular disease in active acromegaly

Context: Acromegaly is characterized by GH excess and insulin resistance. It is not known which of these disorders is responsible for the increased atherogenic risk in these patients. Objective: To analyse the associations of GH and homoeostasis model assessment (HOMA) with biomarkers of cardiovascular disease and to compare the above-mentioned variables between patients with active acromegaly and controls. Design and setting: This open cross-sectional study was conducted at a University Hospital. Patients: Twenty-two outpatients were compared with sex- and age-matched control subjects. Main outcomes: Included clinical features, hormonal status, markers of insulin resistance, lipoprotein profile and biomarkers of cardiovascular disease. Results: Patients presented higher triglyceride (median [IQR]) (1·2[1·1-1·6] vs 0·9[0·6-1·1] mm, P < 0·05), low-density lipoprotein-cholesterol (LDL-C) (mean ± SD) (3·5 ± 0·9 vs 3·0 ± 0·7mm, P < 0·05), apoB (0·98 ± 0·23 vs 0·77 ± 0·22 g/l, P < 0·05), free fatty acid (0·69 ± 0·2 vs 0·54 ± 0·2 mM, P < 0·05), oxidized-LDL (120 ± 22 vs 85 ± 19 U/l, P < 0·05) and endothelin-1 (0·90 ± 0·23 vs 0·72 ± 0·17 ng/l, P < 0·05) levels, increased cholesteryl ester transfer protein (CETP) activity (179 ± 27 vs 138 ± 30%/ml/h, P < 0·01) and lower C reactive protein (CRP) (0·25[0·1-0·9] vs 0·85[0·4-1·4] mg/l; P < 0·05) levels than control subjects. Vascular cell adhesion molecule (VCAM-1) concentration was not different. By multiple linear regression analyses, HOMA explained the variability of triglycerides (25%), high-density lipoprotein-cholesterol (HDL-C) (30%) and CETP activity (28%), while GH independently predicted LDL-C (18%), oxidized-LDL (40%) and endothelin-1 levels (19%). Conclusions: In patients with active acromegaly, GH excess contributes to the development of insulin resistance, and the interaction between both disturbances would be responsible for the appearance of atherogenic pro-oxidative and pro-inflammatory factors. Insulin resistance would be preferably associated with an atherogenic lipoprotein profile and to high CETP activity, while high GH levels would independently predict the increase in LDL-C, ox-LDL and endothelin-1

Alterations in biomarkers of cardiovascular disease (CVD) in active acromegaly

Objectives: In acromegalic patients, cardiovascular and metabolic comorbidities contribute to enhance mortality. Available data on the lipoprotein profile of these patients are controversial. Our aim was to characterize the lipoprotein profile and emergent biomarkers of cardiovascular disease in active acromegalic patients in comparison with sex- and age-matched healthy controls. Patients: Eighteen patients with active acromegaly and 18 controls were studied. Measurements: Glucose levels, hormonal status, lipoprotein profile and C reactive protein (CRP) were evaluated by standardized methods. Cholesteryl ester transfer protein (CETP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured by radiometric techniques, endothelin-1 and vascular cell adhesion molecule (VCAM)-1 by enzyme-linked immunosorbent assay, and leucocytes CD18, CD49d and CD54 by flow cytometry. Results: After adjusting for body mass index (BMI), acromegalic patients presented a more atherogenic lipoprotein profile, consisting of higher levels of triglycerides and apolipoprotein B and alterations in the ratios which estimate insulin resistance and atherogenic risk. CETP activity was significantly increased in acromegalic patients as compared to controls (168 ± 17 vs. 141 ± 30% per ml h, respectively; P < 0.05). Endothelin-1 levels evidenced an increase in the patients' group (0.9 ± 0.2 vs. 0.7 ± 0.2 ng/l, respectively; P < 0.01) and showed positive and significant correlations with GH, IGF-1 and IGFBP-3 (r = 0.45, 0.42 and 0.44, respectively; P < 0.01 for all of them; with BMI as a fixed variable). Lymphocytes from acromegalic patients showed increased CD49d content (282 ± 59 vs. 246 ± 48 arbitrary units, respectively; P < 0.05). Conclusions: Taken together, the alterations described seem to contribute to constituting a state of higher propensity for the development of atherosclerotic cardiovascular disease, which adds to the presence of specific cardiomyopathy.Fil: Boero, Laura Estela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Manavela, M.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Gomez Rosso, Leonardo Adrián. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Insua, C.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Berardi, V.. No especifíca;Fil: Fornari, M.C.. No especifíca;Fil: Brites, Fernando Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

GH levels and insulin sensitivity are differently associated with biomarkers of cardiovascular disease in active acromegaly.

CONTEXT: Acromegaly is characterized by GH excess and insulin resistance. It is not known which of these disorders is responsible for the increased atherogenic risk in these patients. OBJECTIVE: To analyse the associations of GH and homoeostasis model assessment (HOMA) with biomarkers of cardiovascular disease and to compare the above-mentioned variables between patients with active acromegaly and controls. DESIGN AND SETTING: This open cross-sectional study was conducted at a University Hospital. PATIENTS: Twenty-two outpatients were compared with sex- and age-matched control subjects. MAIN OUTCOMES: Included clinical features, hormonal status, markers of insulin resistance, lipoprotein profile and biomarkers of cardiovascular disease. RESULTS: Patients presented higher triglyceride (median [IQR]) (1·2[1·1-1·6] vs 0·9[0·6-1·1] mm, P < 0·05), low-density lipoprotein-cholesterol (LDL-C) (mean ± SD) (3·5 ± 0·9 vs 3·0 ± 0·7mm, P < 0·05), apoB (0·98 ± 0·23 vs 0·77 ± 0·22 g/l, P < 0·05), free fatty acid (0·69 ± 0·2 vs 0·54 ± 0·2 mM, P < 0·05), oxidized-LDL (120 ± 22 vs 85 ± 19 U/l, P < 0·05) and endothelin-1 (0·90 ± 0·23 vs 0·72 ± 0·17 ng/l, P < 0·05) levels, increased cholesteryl ester transfer protein (CETP) activity (179 ± 27 vs 138 ± 30%/ml/h, P < 0·01) and lower C reactive protein (CRP) (0·25[0·1-0·9] vs 0·85[0·4-1·4] mg/l; P < 0·05) levels than control subjects. Vascular cell adhesion molecule (VCAM-1) concentration was not different. By multiple linear regression analyses, HOMA explained the variability of triglycerides (25%), high-density lipoprotein-cholesterol (HDL-C) (30%) and CETP activity (28%), while GH independently predicted LDL-C (18%), oxidized-LDL (40%) and endothelin-1 levels (19%). CONCLUSIONS: In patients with active acromegaly, GH excess contributes to the development of insulin resistance, and the interaction between both disturbances would be responsible for the appearance of atherogenic pro-oxidative and pro-inflammatory factors. Insulin resistance would be preferably associated with an atherogenic lipoprotein profile and to high CETP activity, while high GH levels would independently predict the increase in LDL-C, ox-LDL and endothelin-1.Fil: Boero, Laura Estela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Manavela, M.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas Gral. San Martín. División Endocrinologia; ArgentinaFil: Meroño, Tomás. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Maidana, P.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Gomez Rosso, Leonardo Adrián. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Brites, Fernando Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Condicionantes del aumento del riesgo cardiovascular en pacientes con síndrome de Cushing activo

El síndrome de Cushing constituye una condición patológica caracterizada por una elevación persistente e inapropiada de los niveles circulantes de glucocorticoides y cuya tasa de mortalidad resulta 4 veces mayor que la esperada en la población general. Los eventos cardiovasculares son, en su mayoría, los responsables de la elevada morbi-mortalidad de los pacientes afectados. El objetivo del estudio fue caracterizar las alteraciones del metabolismo de los hidratos de carbono y de los lípidos, y evaluar la presencia de factores de riesgo aterogénico emergentes y biomarcadores de aterosclerosis en pacientes con síndrome de Cushing activo. Se estudiaron 32 pacientes con síndrome de Cushing activo (23 mujeres) y 32 controles pareados por sexo y edad [34 (27 - 42) vs. 33 (27 - 45) años, pacientes y controles, respectivamente]. Fueron evaluados parámetros antropométricos, niveles plasmáticos de cortisol, marcadores de resistencia insulínica, incluidas las adipocitoquinas adiponectina y resistina, perfil lipoproteico, actividades de enzimas y proteínas asociadas a lipoproteínas, niveles de lipoproteínas de baja densidad oxidadas y de proteína C reactiva ultrasensible, y recuento de leucocitos. El grupo de pacientes con síndrome de Cushing presentó características típicas de la patología como sobrepeso, obesidad central e hipercortisolismo (28 ± 12 vs. 12 ± 5 μg/dl, p < 0.0001, respectivamente). Los pacientes también exhibieron un estado de resistencia insulínica, con elevación de la concentración de resistina [(16 (10 - 22) vs. 6 (5 - 9) ng/ml, p < 0.0001, respectivamente)], un perfil lipoproteico más aterogénico, aumento de los niveles de lipoproteínas de baja densidad oxidadas (100 ± 31 vs. 75 ± 32 U/l, p < 0.05, respectivamente) y un estado proinflamatorio caracterizado por aumento de la concentración de proteína C reactiva ultrasensible [1,2 (0,6 - 3,1) vs. 0,6 (0,3 - 1,1) mg/l, p < 0,05] y mayor recuento de leucocitos (9,5 ± 2,6 vs. 6,5 ± 1,4.103 células/μl, p < 0,0001). En conclusión, la conjunción de las alteraciones metabólicas y la presencia de factores de riesgo y biomarcadores de inflamación y aterosclerosis en los pacientes con síndrome de Cushing activo condicionan un mayor riesgo de enfermedad cardiovascular.Cushing syndrome constitutes a pathological condition characterised by a continuous and inappropriate elevation of circulating glucocorticoids and whose mortality is 4 times higher than in general population. Cardiovascular events are mostly responsible for the elevated morbidity and mortality of affected patients. The aim of the present study was to characterise the alterations in carbohydrate and lípid metabolism, and to evaluate the presence of novel atherogenic risk factors and biomarkers on atherosclerosis in patients with active Cushing syndrome. We studied 32 patients with active Cushing syndrome (23 women) y 32 sex and age-matched controls [34 (27 - 42) vs. 33 (27 - 45) years, patients and controls, respectively]. The following evaluations were carried out: anthropometric parameters, cortisol plasma levels, markers of insulin resistance, including the adipocytokines adiponectin and resistin, lipoprotein profile, activities of lipoprotein-associated enzymes and proteins, oxidized low density lipoprotein and high sensitive C reactive protein levels, and leukocyte count. The group of patients with Cushing syndrome presented typical characteristics of the pathology such as overweight, central obesity and hypercortisolism. (28 ± 12 vs. 12 ± 5 μg/dl, p < 0.0001, respectively). Patients also exhibited an insulin resistant state, with high resistin levels [(16 (10 - 22) vs. 6 (5 - 9) ng/ml, p < 0.0001, respectively)], a more atherogenic lipoprotein profile, high oxidized low density lipoprotein levels (100 ± 31 vs. 75 ± 32 U/l, p < 0.05, respectively) and a proinflammatory state characterised by increased high sensitive C reactive protein levels [1.2 (0.6 – 3.1) vs. 0.6 (0.3 – 1.1) mg/l, p < 0.05] and higher leukocyte count (9.5 ± 2.6 vs. 6.5 ± 1.4.103 cells/ μl, p < 0.0001). In conclusion, the combination of the metabolic alterations observed and the presence of risk factors and biomarkers of inflammation and atherosclerosis in patients with active Cushing syndrome determine an increased risk of cardiovascular disease.Fil: Boero, Laura Estela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Meroño, Tomás. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Manavela, M.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Danilowicz, K.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Maidana, P.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Buttazzoni, M.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Menafra, M.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Gomez Rosso, Leonardo Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Brites, Fernando Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

Temozolomide Therapy for Aggressive Pituitary Tumors: Results in a Small Series of Patients from Argentina

We evaluated results of temozolomide (TMZ) therapy in six patients, aged 34–78 years, presenting aggressive pituitary tumors. In all the patients tested O6-methylguanine-DNA methyltransferase (MGMT) immunoexpression in surgical specimens was absent. Patients received temozolomide 140–320 mg/day for 5 days monthly for at least 3 months. In two patients minimum time for evaluation could not be reached because of death in a 76-year-old man with a malignant prolactinoma and of severe neutro-thrombopenia in a 47-year-old woman with nonfunctioning pituitary adenoma. In two patients (a 34-year-old acromegalic woman and a 39-year-old woman with Nelson’s syndrome) no response was observed after 4 and 6 months, respectively, and the treatment was stopped. Conversely, two 52- and 42-year-old women with Cushing’s disease had long-term total clinical and radiological remissions which persisted after stopping temozolomide. We conclude that TMZ therapy may be of variable efficacy depending on—until now—incompletely understood factors. Cooperative work on a greater number of cases of aggressive pituitary tumors should be crucial to establish the indications, doses, and duration of temozolomide administration