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Verhelst J.,ZNA Middelheim Antwerp | Mattsson A.F.,Pfizer | Luger A.,Medical University of Vienna | Thunander M.,Central Hospital | And 4 more authors.
European Journal of Endocrinology | Year: 2011

Objective: An increased risk of cardiovascular morbidity and mortality in adult GH deficiency (GHD) may be related to hypopituitarism but also to the presence of the metabolic syndrome (MetS). Our objective was to investigate the characteristics and prevalence of MetS as well as its comorbidities in adult GHD. Design: In KIMS (Pfizer International Metabolic Database) 2479 patients with severe adult-onset GHD, naïve to GH replacement, with complete information on all MetS components were found. MetS was defined according to the National Cholesterol Education Program's Adult Treatment Panel III (NCEP) and the International Diabetes Foundation (IDF). Methods: The prevalence of MetS was calculated and compared with previously published data from the normal population. Associations were assessed between background variables, baseline variables, comorbidities, and MetS. Results: MetS was present in 43.1% (NCEP) and in 49.1% (IDF) of patients, clearly higher than data from the normal population (20-30%). MetS prevalence was related to age, GHD duration, and body mass index (BMI), but not to GHD severity, extent of hypopituitarism, or etiology of pituitary disease. Adjusted for age, gender, and BMI, patients with MetS had a higher prevalence ratio for diabetes mellitus: 4.65 (95% confidence interval (CI): 3.29-6.58), for cardiovascular morbidity: 1.91 (95% CI: 1.33-2.75), and for cerebrovascular morbidity: 1.77 (95% CI: 1.09-2.87) than patients without MetS. Conclusions: MetS is highly prevalent in GHD and is associated with a higher prevalence ratio for comorbidities. The presence of MetS in GHD may therefore contribute to the increased risk of cardiovascular morbidity and mortality found in these patients. © 2011 European Society of Endocrinology.

Yuen K.C.J.,Oregon Health And Science University | Koltowska-Haggstrom M.,Pfizer | Cook D.M.,Oregon Health And Science University | Fox J.L.,Pfizer | And 3 more authors.
European Journal of Endocrinology | Year: 2013

Objective: Adults with childhood-onset (CO) craniopharyngioma (COCP) have poor quality of life (QoL) and clinical outcomes, but few studies have compared these patients with adults with other causes of CO hypothalamic-pituitary dysfunction. In this study, we compared baseline clinical characteristics and patient-reported outcomes before starting GH replacement therapy in adults with GH deficiency (GHD) due to COCP with those of adults either with CO idiopathic/congenital hypopituitarism (COH) or with CO extrasellar (COE) tumours, and evaluated the 1- and 5-year effects of GH replacement therapy. Subjects and methods: Retrospective analysis of the data recorded in KIMS (Pfizer International Metabolic Database) was carried out. Patients with COCP, COH and COE tumours were evaluated at baseline, and after 1 and 5 years of therapy. Results: Compared with COH and COE patients, more COCP patients underwent surgery, had greater abnormalities of body composition and higher prevalence of pituitary hormone deficits (all P!0.001), but comparable fasting glucose, HbA1c, total cholesterol and LDL-cholesterol levels, marital status, parenthood, living arrangements, education, employment and annual sick-leave days. After 1 and 5 years of GH replacement therapy, similar changes were evident with regard to body composition, fasting glucose and HbA1c levels, QoL, and the level of and satisfaction with physical activity across the three groups. Conclusions: Adults with untreated COCP with GHD at baseline demonstrated more co-morbidities including greater abnormalities of body composition, pituitary hormone deficits and visual field defects. Overall, adults with COCP, COH and COE tumours responded comparably to short- and long-term GH replacement therapy, suggesting that patients with GHD due to COCP benefited from GH replacement therapy to a similar degree as those with other causes of CO hypothalamic-pituitary dysfunction did. © 2013 European Society of Endocrinology.

Yuen K.C.J.,Oregon Health And Science University | Koltowska-Haggstrom M.,Pfizer | Cook D.M.,Oregon Health And Science University | Fox J.L.,Pfizer | And 3 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Craniopharyngiomas are often associated with significant morbidity due to their location and treatment effects. Little is known of the effects of primary treatment regimen and diabetes insipidus (DI), a clinical surrogate of hypothalamic obesity, on health outcomes in adults with childhood-onset craniopharyngioma (COCP). Objective: The objective of the study was to examine health outcomes of adults with COCP based on primary treatment regimens and the presence of DI. Design: This study included a retrospective KIMS (Pfizer International Metabolic Database) data analysis of 180 adults with COCP according to the primary treatment regimen [one surgery (1Surg) vs complex treatment regimen (CTrR) of more than 1Surg and/or radiotherapy] and the presence of DI. Results: The majority of COCP patients underwent transcranial surgery (77%) without receiving radiotherapy (84%). Compared with the 1Surg group, more CTrR patients developed visual field defects and ophthalmoplegia (all P - .01). Compared with patients without DI, those with DI had higher rates of anterior pituitary hormone deficits, body mass index, and fat mass (all P - .01). By contrast, fasting glucose, hemoglobin A1c, lipid panel, and quality of life were comparable among 1Surg vs CTrR patients, and patients with vs without DI. Regardless of primary treatment received, the presence of DI in either group was associated with higher rates of anterior pituitary hormone deficits and obesity. Conclusion: CTrR and DI predicted health outcomes differently. CTrR predisposed to the development of visual dysfunction, whereas DI was associated with higher rates of anterior pituitary dysfunction and weight gain. Higher body mass index and fat mass in patients with DI further implicate the role of hypothalamic damage as an important causal factor of obesity in these patients. Copyright © 2014 by the Endocrine Society.

Abs R.,Antwerp Center for Endocrinology | Mattsson A.F.,Pfizer | Thunander M.,Lund University | Verhelst J.,ZNA Middelheim | And 4 more authors.
European Journal of Endocrinology | Year: 2013

Objective: GH deficiency (GHD) in adults is characterized by a tendency toward obesity and an adverse body composition with visceral fat deposit and may thus predispose to the development of type 2 diabetes mellitus. The aim of this study was to assess the observed prevalence proportion (PP) and observed PP over expected PP ratio (standardized prevalence proportion ratio, SPR) of diabetes according to International Diabetes Federation criteria in a large cohort of GH-untreated adult-onset GHD patients. Design and methods: Associations between baseline variables and diabetes prevalence in 6050 GHD patients from KIMS (Pfizer International Metabolic Database) were studied and robust Poisson-regression analyses were performed. Comparisons between baseline status and HbA1c categories in the nondiabetic patients were done with covariance analysis. P values <0.05 were considered statistically significant. Results: PP was 9.3% compared with the expected 8.2%. SPR was 1.13 (95% confidence intervals (95% CIs), 1.04-1.23), which was significantly increased in females (1.23; 95% CI, 1.09-1.38%) but not in males (SPR 1.04; 95% CI, 0.92-1.17%). PP increased significantly by age, familial diabetes, country selection, BMI, waist circumference, number of pituitary deficiencies, and GHD etiology. SPR decreased significantly by age and increased significantly by BMI, waist circumference, and IGF1 SDS. Multiple regression model showed that the most important impact on SPR was from age and BMI. HbA1c values of 6.0-6.5% were found in 9.5% of nondiabetic patients and were associated with higher BMI and waist circumference. Conclusions: GHD is associated with an increased prevalence of diabetes, largely to be explained by the adverse body composition. These data urge toward early initiation of lifestyle modification measures. © 2013 European Society of Endocrinology.

Luger A.,Medical University of Vienna | Mattsson A.F.,Pfizer | Koltowska-Haggstrom M.,Pfizer | Thunander M.,Vaxjo Central Hospital | And 4 more authors.
Diabetes Care | Year: 2012

OBJECTIVE - Growth hormone (GH) deficiency is associated with insulin resistance and diabetes. The aim of the current study was to determine incidence of diabetes during GH replacement therapy (GHRT) and the effect of GHRT on fasting plasma glucose concentrations and HbA1c in adult patients with GH deficiency. RESEARCH DESIGN AND METHODS - A total of 5,143 GH-deficient patients (male 49.9%; mean age ± SD, 49 ± 13 years; BMI 29.1 ± 5.9 kg/m 2) were analyzed.Mean observation period was 3.9 years (range 0.01-13). Total number of patient-years was 20,106. Observed number of cases (O) was compared with expected number of cases (E). Reference rates were from Sweden, three additional European regions, and one U.S. region. RESULTS - Patients who developed diabetes (n = 523) were older; had higher BMI, waist circumference, triglyceride concentrations, and blood pressure; and had lower HDL-cholesterol concentrations (P< 0.0001) than those who did not develop diabetes. Diabetes incidence was 2.6 per 100 patient-years, equal in both sexes, and significantly increased compared with the Swedish reference (O/E = 6.02; P< 0.0001) as well as with the four other populations (O/E = 2.11-5.22). O/E increased with BMI and decreased with duration of GHRT (P< 0.0001). There was no significant association with GH dose (P = 0.74) or IGF-I SDS (P = 0.47). In subjects not developing diabetes, plasma glucose concentrations increased from 84.4±0.9 mg/dL to 89.5± 0.8 mg/dL (0.70 mg/dL/year) and HbA 1c increased from 4.74 ± 0.04% to 5.09 ± 0.13% (0.036%/year) after 6 years of GHRT. CONCLUSIONS - Diabetes incidence appears to be increased in GH-deficient patients receiving GHRT and exhibiting an adverse risk profile at baseline. Therefore, glucose homeostasis parameters should be monitored carefully in these patients. © 2012 by the American Diabetes Association.

Gaillard R.C.,University of Lausanne | Mattsson A.F.,Pfizer | Akerblad A.-C.,Pfizer | Bengtsson B.-A.,Gothenburg University | And 7 more authors.
European Journal of Endocrinology | Year: 2012

Objective: Hypopituitarism is associated with an increased mortality rate but the reasons underlying this have not been fully elucidated. The purpose of this study was to evaluate mortality and associated factors within a large GH-replaced population of hypopituitary patients. Design: In KIMS (Pfizer International Metabolic Database) 13 983 GH-deficient patients with 69 056 patient-years of follow-up were available. Methods: This study analysed standardised mortality ratios (SMRs) by Poisson regression. IGF1 SDS was used as an indicator of adequacy of GH replacement. Statistical significance was set to P<0.05. Results: All-cause mortality was 13% higher compared with normal population rates (SMR, 1.13; 95% confidence interval, 1.04-1.24). Significant associations were female gender, younger age at follow-up, underlying diagnosis of Cushing's disease, craniopharyngioma and aggressive tumour and presence of diabetes insipidus. After controlling for confounding factors, there were statistically significant negative associations between IGF1 SDS after 1, 2 and 3 years of GH replacement and SMR. For cause-specific mortality there was a negative association between 1-year IGF1 SDS and SMR for deaths from cardiovascular diseases (P=0.017) and malignancies (P=0.044). Conclusions: GH-replaced patients with hypopituitarism demonstrated a modest increase in mortality rate; this appears lower than that previously published in GH-deficient patients. Factors associated with increased mortality included female gender, younger attained age, aetiology and lower IGF1 SDS during therapy. These data indicate that GH replacement in hypopituitary adults with GH deficiency may be considered a safe treatment. © 2012 European Society of Endocrinology.

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