Now showing items 21-40 of 75

    • Partial Growth Hormone Deficiency is Associated With an Adverse Cardiovascular Risk Profile and Increased Carotid Intima-Medial Thickness.

      Murray, Robert D; Wieringa, Gilbert E; Lawrance, Jeremy A L; Adams, Judith E; Shalet, Stephen M; Department of Endocrinology, Christie Hospital NHS Trust, Manchester, UK. (2009-12-18)
      Abstract. Objective: To quantify the relative prevalence of surrogate markers of vascular risk in adults with partial GHD (GH-insufficiency; GHI) Context: Hypopituitary adults with untreated GHD have an excess vascular mortality and demonstrate clustering of adverse vascular risk factors. The vascular risk profile of GHI adults have yet to be comprehensively studied. Design: A cross-sectional case controlled study. Patients: 30 GHD adults, 24 GHI, and 30 age and sex-matched controls. GHI adults were defined biochemically using two GH stimulation tests (peak GH 3-7mug/l). Measurements: Serum lipids and apolipoproteins, PAI-I, CRP, Lp(a), fibrinogen, blood pressure and carotid IMT. Results: IGF-I levels of GHI adults were lower than controls (373+/-123 vs. 295+/-104mug/l; P<0.001). TC, LDL-C, and TG values were consistently between those of, but not significantly different from, GHD and control subjects. GHI adults showed significantly elevated PAI-I levels (80 [13-98] vs. 50.5 [3-98]ng/ml; P=0.01), though no difference in CRP, Lp(a), and fibrinogen levels compared with control subjects. No differences in systolic or diastolic BP were shown between study groups. In parallel with the increased vascular risk profile of GH-insufficient adults, carotid IMT was significantly increased (0.503+/-0.08 vs. 0.578+/-0.130mm; P=0.02). TC, LDL-C, WHR, truncal FM, and IMT correlated with IGF-I levels and GH status. TG, K(ITT), and PAI-I additionally correlated with GH status, but not IGF-I levels. Conclusion: GHI adults are at elevated vascular risk, reflected by adverse surrogate markers and increased carotid IMT. The surrogate risk marker profile parallels GHD adults, but is less divergent from that observed in healthy individuals. No data are yet available as to whether these anomalies will be reflected in an increased vascular mortality in GHI adults.
    • Corticosteroid-binding globulin regulates cortisol pharmacokinetics.

      Perogamvros, Ilias; Aarons, Leon; Miller, A G; Trainer, Peter J; Ray, David W; Department of Endocrinology, Christie Hospital and Endocrine Sciences Research Group, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK . School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK . Department of Biochemistry, University Hospital of South Manchester, Wythenshawe, UK. (2010-11-05)
      Objective:  Corticosteroid-binding globulin (CBG) is the principal carrier for cortisol in the circulation. Variations in CBG binding capacity are predicted to alter total serum cortisol disposition, but free serum cortisol is believed to be unaffected. Unbound cortisol pharmacokinetics (PK) have not been studied in the context of CBG changes. We aimed to assess the regulation of cortisol PK by CBG. Design and subjects:  Women on oestrogens (OCP), patients homozygous for a non-functioning CBG variant (CBG null) and healthy controls (HV) were studied before and after IV and oral administration of hydrocortisone 20mg. Measurements:  PK parameters were studied for total serum cortisol (SerF), free serum cortisol (FreeF) and cortisone (FreeE), and salivary cortisol (SalF) and cortisone (SalE): area under the curve (AUC), clearance (CL), half-life, and volume of distribution (Vd). Results:  Following IV hydrocortisone, AUC and half-life of SerF were significantly higher in the OCP group and lower in the CBG null. SerF CL and Vd were significantly lower in the OCP group and increased in the CBG null, compared to HV. PK parameters for FreeF and the salivary biomarkers were not different between the CBG null and HV, although OCP patients still had higher AUC compared to HV and prolonged half-life. These findings were confirmed following oral hydrocortisone, but concentration-time profiles were highly heterogeneous and SalF interpretation was problematic due to oral contamination. Conclusions:  We have demonstrated that CBG has a distinct effect on cortisol PK. When CBG binding is disrupted, FreeF retains normal PK characteristics, although CBG null patients lack a CBG-bound pool of readily releasable cortisol. Women on oestrogens may have altered free serum cortisol kinetics and thus may be potentially overexposed to glucocorticoids.
    • Diet-induced obesity, exogenous leptin-, and MADB106 tumor cell challenge affect tissue leukocyte distribution and serum levels of cytokines in F344 rats

      Behrendt, Patrick; Buchenauer, Tobias; Horn, Rüdiger; Brabant, Georg E; Jacobs, Roland; Bode, Felix; Stephan, Michael; Nave, Heike (2010)
    • The pituitary gland and age-dependent regulation of body composition.

      Van Beek, André P; Wolffenbuttel, Bruce H R; Runge, Evelien; Trainer, Peter J; Jönsson, Peter J; Koltowska-Häggström, Maria; Department of Endocrinology, University Medical Center Groningen, University of Groningen, De Brug 4.069, AA 31, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. a.p.van.beek@int.umcg.nl (2010-08)
      CONTEXT: The prevalence of obesity is increased in hypopituitarism. In the general population, body mass index (BMI) and waist circumference increase with advancing age. It remains uncertain whether age-related changes in pituitary function contribute to the changes in body composition associated with advancing years. OBJECTIVE: Our objective was to study the relationship between pituitary function, body composition, and age in a large cohort of patients with hypopituitarism and a matched reference population. DESIGN, SETTING, AND PARTICIPANTS: A total of 3632 GH-deficient adults with hypopituitarism, adequately replaced with all pituitary hormones except for GH, from the prospective KIMS database (Pfizer International Metabolic Database) were included in present analysis. A random sample of the general population (3427 subjects) was used as reference. Patients and controls were grouped by gender in five age cohorts of 10 yr from 28 yr onward. MAIN OUTCOME MEASURES: Differences in BMI and waist circumference were evaluated. RESULTS: Patients had a significantly higher BMI and waist circumference than controls, with larger differences at younger age. With advancing age, an increase in BMI and waist circumference was seen in controls but was virtually absent in the patients with adult-onset GH deficiency and hypopituitarism. CONCLUSION: Patients with hypopituitarism have more excess body fat than age-matched controls, especially in the youngest age groups. The normal increase in fat mass with advancing age is not seen in adult-onset GH-deficient hypopituitarism, suggesting a potential role for the normal pituitary gland as an age-dependent regulator of body composition in adult life.
    • Doxorubicin fails to eradicate cancer stem cells derived from anaplastic thyroid carcinoma cells: characterization of resistant cells.

      Zheng, Xuqin; Cui, Dai; Xu, Shuhang; Brabant, Georg E; Derwahl, Michael; Division of Endocrinology, Department of Medicine, St Hedwig Hospital and Humboldt University, D-10115 Berlin, Berlin, Germany. (2010-08)
      Current chemotherapy with doxorubicin fails to eradicate anaplastic thyroid cancer or even to stop tumor progress which may be due to the failure of these drugs to effectively target putative cancer stem cells. To test this hypothesis, anaplastic thyroid cell lines were characterized by FACS for their content of cancer stem cells, their in vitro sphere-forming capacity and their expression of multidrug resistance transporters of the ABC gene family which may confer drug resistance to the cells. Cells were treated with doxorubicin in short-term and long-term culture up to 6 months to establish a resistant cell line. The survival of cancer and cancer stem cells and the differential expression of transporters were analyzed. Anaplastic thyroid cancer cell lines that consisted of 0.4-0.8% side population cells, expressed ABCG2 and multi-drug-resistant 1 (MDR1) transporters. Treatment with doxorubicin gradually killed the non-side population of cancer cells derived from anaplastic thyroid carcinoma cells. This conferred a growth advantage to cancer stem cells which in turn overgrew the culture. Resistant cell line consisted of a 70% side population fraction enriched with Oct4-positive cancer stem cells. Inhibition of ABCG2 and/or MDR1 revealed that resistance of cancer stem cells to doxorubicin may be mainly due to the expression of these ABC transporters that were highly up-regulated in the resistant subline. The poor outcome of chemotherapy with doxorubicin in anaplastic thyroid carcinoma may be partly explained by up-regulation of ABCG2 and MDR1 transporters that confers resistance to cancer stem cells. Thus an effective treatment of anaplastic thyroid cancer has not only to destroy cancer cells that represent the bulk of tumor cell population but also cancer stem cells that may drive tumor progression.
    • Factors predicting long-term survival after T-cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid leukemia.

      Craddock, Charles; Nagra, Sandeep; Peniket, Andrew; Brookes, Cassandra; Buckley, Laura; Nikolousis, Emmanouil; Duncan, Nick; Tauro, Sudhir; Yin, John A; Liakopoulou, Effie F; et al. (2010-06)
      BACKGROUND: Reduced intensity conditioning regimens permit the delivery of a potentially curative graft-versus-leukemia effect in older patients with acute myeloid leukemia. Although T-cell depletion is increasingly used to reduce the risk of graft-versus-host disease its impact on the graft-versus-leukemia effect and long-term outcome post-transplant is unknown. DESIGN AND METHODS: We have characterized pre- and post-transplant factors determining overall survival in 168 patients with acute myeloid leukemia transplanted using an alemtuzumab based reduced intensity conditioning regimen with a median duration of follow-up of 37 months. RESULTS: The 3-year overall survival for patients transplanted in CR1 or CR2/CR3 was 50% (95% CI, 38% to 62%) and 44% (95% CI, 31% to 56%), respectively compared to 15% (95% CI, 2% to 36%) for patients with relapsed/refractory disease. Multivariate analysis demonstrated that both survival and disease relapse were influenced by status at transplant (P=0.008) and presentation cytogenetics (P=0.01). Increased exposure to cyclosporine A (CsA) in the first 21 days post-transplant was associated with an increased relapse risk (P<0.0001) and decreased overall survival (P<0.0001). CONCLUSIONS: Disease stage, presentation karyotype and post-transplant CsA exposure are important predictors of outcome in patients undergoing a T-cell depleted reduced intensity conditioning allograft for acute myeloid leukemia. These data confirm the presence of a potent graft-versus-leukemia effect after a T-cell depleted reduced intensity conditioning allograft in acute myeloid leukemia and identify CsA exposure as a manipulable determinant of outcome in this setting.
    • Expression of hypoxia-inducible factor 1 alpha in thyroid carcinomas.

      Burrows, N; Resch, J; Cowen, R L; Von Wasielewski, R; Hoang-Vu, C; West, Catharine M L; Williams, K J; Brabant, Georg E; School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. (2010-03)
      Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is upregulated by hypoxia and oncogenic signalling in many solid tumours. Its regulation and function in thyroid carcinomas are unknown. We evaluated the regulation of HIF-1 alpha and target gene expression in primary thyroid carcinomas and thyroid carcinoma cell lines (BcPAP, WRO, FTC-133 and 8505c). HIF-1 alpha was not detectable in normal tissue but was expressed in thyroid carcinomas. Dedifferentiated anaplastic tumours (ATCs) exhibited high levels of nuclear HIF-1 alpha staining. The HIF-1 target glucose transporter 1 was expressed to a similar level in all tumour types, whereas carbonic anhydrase-9 was significantly elevated in ATCs. In vitro studies revealed a functionally active HIF-1 alpha pathway in thyroid cells with transcriptional activation observed after graded hypoxia (1% O(2), anoxia) or treatment with a hypoxia mimetic cobalt chloride. High basal and hypoxia-induced expression of HIF-1 alpha in FTC-133 cells that harbour a phosphatase and tensin homologue (PTEN) mutation was reduced by introduction of wild-type PTEN. Similarly, pharmacological inhibition of the phosphoinositide 3-kinase (PI3K) pathway using LY294002 inhibited HIF-1 alpha and HIF-1 alpha targets in all cell lines, including those with B-RAF mutations (BcPAP and 8505c). In contrast, the effects of inhibition of the RAF/MEK/extracellular signal-regulated kinase pathway were restricted by environmental condition and B-RAF mutation status. HIF-1 is functionally expressed in thyroid carcinomas and is regulated not only by hypoxia but also via growth factor signalling pathways and, in particular, the PI3K pathway. Given the strong association of HIF-1 alpha with an aggressive disease phenotype and therapeutic resistance, this pathway may be an attractive target for improved therapy in thyroid carcinomas.
    • A consensus on criteria for cure of acromegaly.

      Giustina, A; Chanson, P; Bronstein, M D; Klibanski, A; Lamberts, S; Casanueva, F F; Trainer, Peter J; Ghigo, E; Ho, K; Melmed, S; et al. (2010-07)
      OBJECTIVE: The Acromegaly Consensus Group met in April 2009 to revisit the guidelines on criteria for cure as defined in 2000. PARTICIPANTS: Participants included 74 neurosurgeons and endocrinologists with extensive experience of treating acromegaly. EVIDENCE/CONSENSUS PROCESS: Relevant assays, biochemical measures, clinical outcomes, and definition of disease control were discussed, based on the available published evidence, and the strength of consensus statements was rated. CONCLUSIONS: Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines. Appropriate methods of measuring and achieving disease control were summarized.
    • Simultaneous measurement of cortisol and cortisone in human saliva using liquid chromatography-tandem mass spectrometry: application in basal and stimulated conditions.

      Perogamvros, Ilias; Owen, Laura J; Newell-Price, John; Ray, David W; Trainer, Peter J; Keevil, Brian G; Department of Endocrinology, The Christie, Manchester, UK. ilias.perogamvros@nhs.net (2009-11-01)
      Immunoassays used for the measurement of salivary cortisol are limited by variable interference from cortisone. Salivary cortisone is a consequence of the salivary glands expressing 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) which converts cortisol to cortisone. We report a combined salivary cortisol and cortisone (SalF and SalE respectively) liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to address the cortisone cross-reactivity in cortisol immunoassays and as a tool to study 11beta-HSD2 activity. The method was linear up to 400 nmol/L for SalF and 200 nmol/L for SalE and the lower limits of quantitation were 0.39 nmol/L (SalF) and 0.78 nmol/L (SalE). No evidence of ion suppression was found and precision, accuracy and recovery were within internationally accepted limits. No interference was identified from 13 structurally related steroids. SalF, SalE and SalF/SalE were significantly greater in the morning than at bed-time and following stimulation of the adrenal glands. As serum cortisol increased, an exponential rise was observed in SalF and a linear increase in SalE which reached a plateau at higher SalF concentrations. We have developed a novel, robust LC-MS/MS assay for the combined measurement of SalF and SalE. Our results confirm the 11beta-HSD2 activity of the salivary glands resulting in high SalE concentrations and the enzyme saturation at high substrate concentrations. This method can be used as a simple, non-invasive and highly specific tool to assess the value of salivary cortisol as a surrogate for free serum cortisol and as a potential novel way to assess 11beta-HSD2 activity.
    • Clinical features of GH deficiency and effects of 3 years of GH replacement in adults with controlled Cushing's disease.

      Höybye, Charlotte; Ragnarsson, Oskar; Jönsson, Peter J; Koltowska-Häggström, Maria; Trainer, Peter J; Feldt-Rasmussen, Ulla; Biller, Beverly M K; Department of Endocrinology, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. charlotte.hoybye@karolinska.se (2010-04)
      OBJECTIVE: Patients in remission from Cushing's disease (CD) have many clinical features that are difficult to distinguish from those of concomitant GH deficiency (GHD). In this study, we evaluated the features of GHD in a large cohort of controlled CD patients, and assessed the effect of GH treatment. DESIGN AND METHODS: Data were obtained from KIMS, the Pfizer International Metabolic Database. A retrospective cross-sectional comparison of background characteristics in unmatched cohorts of patients with CD (n=684, 74% women) and nonfunctioning pituitary adenoma (NFPA; n=2990, 39% women) was conducted. In addition, a longitudinal evaluation of 3 years of GH replacement in a subset of patients with controlled CD (n=322) and NFPA (n=748) matched for age and gender was performed. RESULTS: The cross-sectional study showed a significant delay in GHD diagnosis in the CD group, who had a higher prevalence of hypertension, fractures, and diabetes mellitus. In the longitudinal, matched study, the CD group had a better metabolic profile but a poorer quality of life (QoL) at baseline, which was assessed with the disease-specific questionnaire QoL-assessment of GHD in adults. After 3 years of GH treatment (mean dose at 3 years 0.39 mg/day in CD and 0.37 mg/day in NFPA), total and low-density lipoprotein cholesterol decreased, while glucose and HbAlc increased. Improvement in QoL was observed, which was greater in the CD group (-6 CD group versus -5 NFPA group, P<0.01). CONCLUSION: In untreated GHD, co-morbidities, including impairment of QoL, were more prevalent in controlled CD. Overall, both the groups responded similarly to GH replacement, suggesting that patients with GHD due to CD benefit from GH to the same extent as those with GHD due to NFPA.
    • Association between hepatic steatosis and serum IGF1 and IGFBP-3 levels in a population-based sample.

      Völzke, Henry; Nauck, Matthias; Rettig, Rainer; Dörr, Marcus; Higham, Claire E; Brabant, Georg E; Wallaschofski, Henri; Institute of Community Medicine Institute of Clinical Chemistry and Laboratory Medicine Institute of Physiology Department of Internal Medicine B, University of Greifswald, Greifswald D-17487, Germany. voelzke@uni-greifswald.de (2009-11)
      CONTEXT: It is assumed that hepatic steatosis plays a role in the development and progression of the metabolic syndrome and its cardiovascular sequelae. Low serum IGF1 levels might mediate these associations. OBJECTIVES: The aims of this study were i) to investigate the associations of hepatic steatosis with serum IGF1 and IGF binding protein-3 (IGFBP-3) levels using ultrasound and serum alanine aminotransaminase (ALT) data to define hepatic steatosis, and ii) to analyze the specific role of alcohol consumption in this context. DESIGN: We analyzed data from the population-based Study of Health in Pomerania. METHODS: We used data from 3863 subjects (1971 women) aged 20-79 years who had no history of viral hepatitis, liver cirrhosis, or malignant diseases. Liver hyperechogenicity was diagnosed using ultrasound. Serum IGF1 and IGFBP-3 levels were determined by automated two-site chemiluminescence immunoassays. RESULTS: Hyperechogenic liver pattern was associated with low serum IGF1 levels and low serum IGF1/IGFBP-3 ratios. The lowest serum IGF1 and IGF1/IGFBP-3 values and highest IGFBP-3 levels were present in subjects who had a hyperechogenic liver pattern and increased serum ALT levels. All of these associations were independent of alcohol consumption. CONCLUSIONS: Our data show that hepatic steatosis is associated with low serum IGF1 levels. This association is independent of alcohol consumption.
    • The value of IGF1 estimation in adults with GH deficiency.

      Mukherjee, Annice; Shalet, Stephen M; Department of Endocrinology, Salford Royal NHS Foundation Trust, UK. annice.mukherjee@srft.nhs.uk (2009-11)
      The GH/IGF1 system, like other endocrine systems, is dynamic and its activity changes with age and sexual maturation, and is influenced by body composition and other factors. A normal level of IGF1 does not exclude a diagnosis of GH deficiency (GHD) in adults, and the usefulness of IGF1 in the diagnosis of adult GHD has historically been confusing and contentious. The regulation of IGF1 secretion in adults is complex, and is not solely dependent on GH status with factors recognized to influence IGF1 status in patients with GHD including age, gender, exogenous estrogen therapy, prolactin status, and severity of GHD. The usefulness of IGF1 for monitoring treatment of GH disorders in adulthood is now widely accepted, especially as GH-dosing regimens for GHD have evolved from weight-based dosing (associated with overtreatment and side effects) to individualized dose-titration strategies, which maintain IGF1 within target limits. Sub-optimal replacement therapy may be associated with morbidity and mortality risk from a continuing state of functional GHD. Conversely, avoiding iatrogenic biochemical acromegaly is clearly important and other potential safety issues may be associated with a persistently high IGF1. Analysis and interpretation of IGF1 status therefore represent a useful diagnostic tool especially in the younger adult patients with severe GHD and an essential measurement for monitoring GH replacement in all adults with GHD. High-quality, method-specific reference ranges for IGF1 and a high degree of methodological consistency in the assay are essential for reliable comparison of results.
    • Assessment of quality of life in adult patients with GH deficiency: KIMS contribution to clinical practice and pharmacoeconomic evaluations.

      Koltowska-Häggström, Maria; Mattsson, Anders F; Shalet, Stephen M; KIMS Medical Outcomes, Pfizer Health AB, Endocrine Care, Sollentuna, Sweden. maria.koltowska-haggstrom@pfizer.com (2009-11)
      Quality of life (QoL) has emerged as an important construct that has found numerous applications across healthcare-related fields, ranging from research and clinical evaluation of treatment effects to pharmacoeconomic evaluations and global healthcare policy. Impairment of QoL is one of the key clinical characteristics in adult GHD and has been extensively studied in the Pfizer International Metabolic Database (KIMS). We provide summarized evidence on GH treatment effects for both clinical and health economic applications based on the KIMS data. The primary focus is on those aspects of QoL research that cannot be investigated in the traditional clinical trial setting, such as specific patient subgroups, cross-country comparisons and long-term follow-up. First, the impact of age, gender, disease onset, primary aetiology, extent of hypopituitarism, previous radiotherapy and obesity on QoL before and during long-term GH replacement is discussed. Secondly, the studies on QoL in relation to country-specific normative values are reviewed. Finally, health economic data derived from KIMS including both burden of disease and utility assessment are evaluated. We conclude that the wide spectrum of analyses performed on the KIMS data allows for practical application of the results not only to research and clinical practice but also to health policy and global medical decision making.
    • Diet-induced obesity alters behavior as well as serum levels of corticosterone in F344 rats.

      Buchenauer, T; Behrendt, P; Bode, F J; Horn, R; Brabant, Georg E; Stephan, M; Nave, H; Institute for Functional and Applied Anatomy, Hannover Medical School, 30625 Hannover, Germany. (2009-12-07)
      Obesity is an increasing socio-economic health problem. Diet-induced obese (DIO) rodents are widely used as a model of obesity in humans. However, there is no comprehensive data about the behavioral phenotype of DIO rodents. Therefore, the aim of the present study was to determine whether a high-fat-diet changes behavioral patterns of DIO Fischer 344 (F344) rats in comparison with lean littermates. The behavioral tests (homecage, holeboard, social interaction, and hotplate) were performed in 28 normal-weight and 28 male DIO F344 rats (mean age: 16 weeks) and revealed a significantly higher level of anxiety- and aggression-related parameters in obese rats, whereas their pain threshold was significantly lower. Fitting to a different behavioral response, basal corticosterone levels (measured by RIA) of obese animals were significantly elevated (16.0ng/ml vs. 12.5ng/ml; p<0.01). We conclude that obese rats differ in various aspects from their lean littermates. The altered behavioral characteristics displayed by DIO F344 rats have to be considered in further experiments involving DIO rodents.
    • Altered phenotype of NK cells from obses rats can be normalized by transfer into lean animals.

      Lautenbach, Anne; Wrann, Christiane D; Jacob, Roland; Muller, Guenter; Brabant, Georg E; Nave, Heike; Institute for Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany. (2009)
    • ACTROSTUDY: the first 5 years

      Trainer, Peter J; Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, UK (2009)
    • Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency.

      Alatzoglou, Kyriaki S; Turton, James P; Kelberman, Daniel; Clayton, Peter E; Mehta, Ameeta; Buchanan, Charles; Aylwin, Simon; Crowne, Elizabeth C; Christesen, Henrik T; Hertel, Niels T; et al. (2009-09)
      CONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.
    • Human growth hormone-related iatrogenic Creutzfeldt-Jakob disease--being aware of diagnostic features 25 years later.

      Dixit, Kashinath C S; Kreitschmann-Andermahr, Ilonka; Basu, Ambar; Dick, Jeremy P R; Manoharan, Prakash; Shalet, Stephen M; Brabant, Georg E; Department of Endocrinology, The Christie, Manchester, United Kingdom. kashinath.dixit@yahoo.com (2009-08)
    • Mortality and serum insulin-like growth factor (IGF)-I and IGF binding protein 3 concentrations.

      Friedrich, Nele; Haring, Robin; Nauck, Matthias; Lüdemann, Jan; Rosskopf, Dieter; Spilcke-Liss, Elisabeth; Felix, Stephan B; Dörr, Marcus; Brabant, Georg E; Völzke, Henry; et al. (2009-05)
      BACKGROUND: Previous studies provided conflicting results regarding the association of serum IGF-I or IGF-binding protein-3 (IGFBP-3) and mortality. The aim of this study was to assess the relation of IGF-I and IGFBP-3 levels with mortality from all causes, cardiovascular disease (CVD), and cancer in a prospective population-based study. METHODS: From the Study of Health in Pomerania (SHIP) 1988 men and 2069 women aged 20-79 yr were followed up on average 8.5 yr. Causes of deaths were coded according to the International Classification of Diseases, 10th revision. Serum IGF-I and IGFBP-3 levels were determined by chemiluminescence immunoassays and categorized into three groups (low, normal, high) according to the sex- and age-specific 10th and 90th percentiles. RESULTS: Adjusted analyses revealed that men with low but not high IGF-I levels had an almost 2-fold higher risk of all-cause mortality [hazard ratio (HR) 1.92 (95% confidence interval [CI] 1.35; 2.73)], CVD mortality [HR 1.92 (95% CI 1.00; 3.71)], and cancer mortality [HR 1.85 (95% CI 1.00; 3.45)] compared with men with normal IGF-I levels. In women, no association between IGF-I and mortality was found. Moreover, low IGFBP-3 levels were associated with higher all-cause mortality in men [HR 1.87 (95% CI 1.31; 2.64)] and women [HR 1.63 (95% CI 0.96; 2.76)]. CONCLUSIONS: The present study found inverse associations between IGF-I or IGFBP-3 levels and mortality from all causes, CVD, or cancer in men and between IGFBP-3 and all-cause mortality in women.
    • Etiology, baseline characteristics, and biochemical diagnosis of GH deficiency in the adult: are there regional variations?

      Brabant, Georg E; Poll, E M; Jonsson, P; Polydorou, D; Kreitschmann-Andermahr, Ilonka; Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX. (2009)