Evolution of glycated haemoglobin in adults on growth hormone replacement therapy

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Datos obtenidos en humanos, ganado ovino, bovino y porcino. Ca2+: calcio; IGF-1: insulin-like growth factor 1; oxLDL: oxidized low-density lipoprotein; SHBG: sex hormone-binding globulin; TNF-α: tumor necrosis factor-alpha; VEGF: vascular endothelial growth factor;. Vasos sanguíneos, ovario, folículos ováricos, y oviducto no están dibujados a escala. 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"email" => array:1 [ 0 => "mayll_c@hotmail.com" ] ] 6 => array:3 [ "nombre" => "Cristina" "apellidos" => "Álvarez-Escolá" "email" => array:1 [ 0 => "escola.cristina@gmail.com" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Endocrinology Department, La Paz University Hospital, Paseo de La Castellana 261, 28046 Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Comportamiento de la hemoglobina glicada en adultos con déficit de GH en tratamiento sustitutivo" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 880 "Ancho" => 2518 "Tamanyo" => 79088 ] ] "descripcion" => array:1 [ "en" => "HbA1c (mean±SD) over time in GH-treated adults that showed dysglycaemia during the period of the study: (a) patients with baseline dysglycaemia; (b) patient with normal glucose metabolism at baseline." ] ] ] "textoCompleto" => "IntroductionGrowth hormone deficiency (GHD) in adults is associated with an adverse metabolic profile, with fat mass gain (especially visceral fat), insulin resistance and type 2 diabetes mellitus (DM2).<a class="elsevierStyleCrossRefs" href="#bib0090">1–3</a> However, GH replacement (GHR) is associated with impaired insulin sensitivity shortly after starting therapy, reflected by increased fasting plasma glucose (FPG) and insulin levels despite reductions in visceral adiposity.<a class="elsevierStyleCrossRefs" href="#bib0105">4,5</a> This impaired insulin sensitivity could be influenced by high doses of GH, especially by its major effects on lipolysis.<a class="elsevierStyleCrossRef" href="#bib0115">6</a> Many of the early GHD studies in adults used weight-based dosing derived from paediatric practice; therefore, hyperglycaemic side effects were more common.Available evidence suggests that concerns regarding glucose intolerance in patients receiving long-term GHR have not been substantiated.<a class="elsevierStyleCrossRef" href="#bib0120">7</a> It has been demonstrated that low-dose GHR over 12 months’ period enhances insulin sensitivity, and that GH standard dose (0.48mg/day) has no effect on glucose metabolism.<a class="elsevierStyleCrossRef" href="#bib0125">8</a> Other studies have suggested that the increase in FPG do not persist after 6 months of GHR therapy, possibly due to a reduction in abdominal visceral fat.<a class="elsevierStyleCrossRefs" href="#bib0105">4,9</a> In addition, several environmental and lifestyle-related factors could influence glucose abnormalities in patients with GHD.Glycated haemoglobin (HbA1c) was included in the diagnosis and diabetes risk prediction in 2010.<a class="elsevierStyleCrossRef" href="#bib0135">10</a> HbA1c range of 5.7–6.4% implies a substantially increased risk of DM. There are few data on the evolution of HbA1c in patients with GHD during GHR therapy,<a class="elsevierStyleCrossRefs" href="#bib0140">11–14</a> and no study has specifically addressed this issue in Spanish patients.We assessed the development of glucose metabolism disorders and the changes in HbA1c during the first 3 years of GHR in a cohort of Spanish patients with GHR therapy, and examined whether these changes were in range of dysglycaemia.Materials and methodsPatient populationData were collected from clinical records of 71 GHD adult Spanish patients who were followed at the Endocrine Department of La Paz University Hospital, in Madrid, Spain, from January 1999 to July 2013. GHD was confirmed through standard stimulation tests like insulin tolerance test or, if it was contraindicated, glucagon stimulation test, or by decreased IGF-I levels for age and sex if multiple pituitary deficiencies were observed. Inclusion criteria for the current study were a confirmed diagnosis of GHD, absence of prior GHR therapy and at least 2 years of follow-up during GHR therapy. Patients who did not complete 2 years of treatment, had an irregular follow-up or had diabetes mellitus (DM) at baseline were excluded.Although the study was retrospective, all patients were followed on the basis of the same standardised protocol that has been applied in our department for several years. All patients, when appropriate, received hormone replacement therapy in the form of l-thyroxine, hydrocortisone, sex steroids and desmopressin. During the study, the adequacy of hormone replacement therapy was assessed periodically.The study was performed in accordance with the Declaration of Helsinki.Outcome and explanatory variablesClinical dataRecorded data included age at diagnosis of GHD, aetiology of GHD, type and number of additional pituitary hormone deficiencies, family history of diabetes as well as weight, BMI and body fat mass (BFM).BMI was calculated as body weight (kg) divided by squared height (m2). Bio-impedance assessment was used to measure total body fat under standard conditions for all measurements. The Tanita BC-420MA high capacity body composition analyser was used in all patients throughout the study. All patients with BMI≥25kg/m2 received behavioural modification recommendations, dietary instruction and advice on regular physical activity.Biochemical dataPatients were evaluated for total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides at baseline and at last visit.Glucose metabolism was assessed by measuring FPG and HbA1c concentrations. These variables were evaluated annually. FPG was measured by the glucose oxidase method. HbA1c was measured by high-performance liquid chromatography in Diamat and Variant autoanalysers (BioRad®, Richmond, California, USA) with exchangeable results calibrated to the Diabetes Control and Complications Trial (DCCT) range of normality. Intra-assay and inter-assay coefficients of variation (CVs) determined using representative blood samples with 5.9 and 10.3% HbA1c were 0.97 and 0.48% respectively.We defined dysglycaemia as an FPG≥100mg/dl and/or an HbA1c≥5.7%. Patients who developed dysglycaemia at any time of the follow up were divided into two groups: those with baseline dysglycaemia and those with normal glucose metabolism at baseline.Statistical analysisDescriptive statistics are presented as mean±SD or range. Student's t-test was used to assess the difference between mean HbA1c values in patients with and without dysglycaemia or Mann–Whitney U test depending on the nature of the data. The χ2 test was employed to compare frequencies of categorical variables. Gender differences and differences between patients receiving or not receiving sex steroid replacement were calculated by ANOVA. Multiple linear regression was used to model the relationship between HbA1c and body composition variables. P values <0.05 were regarded as statistically significant. For statistical evaluation SPSS (v12.0 for Windows; Chicago, Illinois, USA) was used.ResultsOf the 71 subjects with GHD, 41 (21 women and 20 men; mean age 40.1±14 years) met the eligibility criteria for this analysis. One man with DM1 and 29 patients whose follow-up was less than 2 years were excluded. Baseline characteristics of the study subjects are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Mean observation period was 7.5 years (range 4.4–10.7). Only three patients had family history of DM.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The causes of hypopituitarism are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. The majority of hormone-secreting adenomas were prolactinomas (n=5). Twelve patients received radiation therapy.The majority of patients required additional pituitary hormone replacement therapy at baseline. Adrenocorticotropic deficiency was detected in 75.6% of patients (all patients were treated with hydrocortisone), l-thyroxine was used by 73.2% of patients and sex hormones by 82.9%. Antidiuretic hormone deficiency was present in 17.1% of patients. Doses of glucocorticoids and sex steroids remained stable during the first 3 years of GHR therapy in all patients.GH was initiated at a mean dose of 0.26±0.12mg/day, and titrated to a mean of 0.39±0.28mg/day to reach normal IGF-I levels for age and sex. There was no gender difference in terms of GH dose (p=0.543).In the whole study population FPG increased from 88±11mg/dl to 92.3±13.3mg/dl during the first year (p=0.01). This increase was not maintained in the next 2 years. Compared to the baseline, HbA1c increased from 5.4±0.4% to 5.5±0.4% (p=0.05) and 5.5±0.5% (p=0.006), in the first and second year of GHR, returning to baseline during the third year (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Neither gender nor sex steroids therapy influenced the change of HbA1c during GHR (p=0.144 and p=0.48 respectively).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Twenty-eight patients had dysglycaemia during the follow up, 9 of whom had a baseline disturbed glucose metabolic state before starting GHR. Four of these 28 patients (9.7% of the total group) developed DM, and were all started on oral antidiabetic drug (metformin) during the period of the study. DM was diagnosed in the first year of GHR therapy in two patients, and after 5 years of GH treatment in others two. Three of them had dysglycaemia at baseline. Baseline characteristics of subjects with dysglycaemia are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>When we analysed HbA1c behaviour of patients with baseline dysglycaemia (baseline mean HbA1c 5.8±0.4%), we did not find a significant change (1st year 5.7±0.7%, p=0.27; 2nd year 5.9±0.8% p=0.15 and 3rd year 5.6±0.4% p=0.8) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>a). Nevertheless, FPG was increased in the first year from 98.1±13.3mg/dl to 103±19.4mg/dl (p=0.02). This subgroup of patients had a greater mean BMI than the rest of the population (BMI: 40±22kg/m2).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Those patients who developed de novo dysglycaemia (19 patients) had baseline mean HbA1c values 5.2±0.4% and baseline mean FGP 84±9.0mg/dl). These patients showed a significant increase in both HbA1c (1st year 5.5±0.4%, p<0.050; 2nd year 5.4±0.4% p=.004 and 3rd year 5.4±0.4% p=0.016) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>b) and FPG values (1st year 93±10.3mg/dl, p=.001; 2nd year 92.4±14mg/dl p=.014 and 3rd year 93±12.2mg/dl p=0.004) over 3 years. The mean increment of HbA1c and FPG was 0.23±0.2% and 8.6±11.5mg/dl, respectively.Multivariate regression analyses showed that baseline BFM, BMI and body weight were not associated with the annual increase in HbA1c.Body weight (median weight gain=0.4 [−3.6 to 6.8kg]) and body fat mass (BFM) did not change during the study period in any of the subgroups (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Compared to baseline, triglycerides levels increased after the third year (ΔTg+2.63mg/dl, p=0.008). There were no differences in total cholesterol, LDL-C, HDL-C and glucose behaviour between genders.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Glucocorticoid replacement therapy was not associated with an increase in glucose levels during the follow-up.DiscussionThis study in a Spanish GHD population found that patients with GHR therapy frequently develop an impaired glucose metabolism. A total of 28 of the 41 patients presented dysglycaemia at any time during follow-up, and four patients developed DM during GHR. This increment agrees with the values reported in previous studies,<a class="elsevierStyleCrossRefs" href="#bib0120">7,12,15</a> ranging from 0 to 10.2%; this variability could partly be due to ethnic characteristics, genetic predisposition and baseline dysglycaemia, as well as the remarkable obesity of the recruited patients.Our study revealed a significant increase in FPG in patients treated with GHR therapy, mainly during the first year of treatment. By including HbA1c in the detection of glucose metabolism disorders, we aimed to identifying patients at high risk of DM in the most comprehensive way. We observed a mild increase in HbA1c levels that was not associated with a persistent increase in FPG in the total population. This could be attributed to potential postprandial plasma glucose excursions reflecting insulin resistance as a direct GH effect on carbohydrate metabolism.Regarding patients with baseline prediabetes treated with GHR therapy, HbA1c levels were not modified over a period of 3 years. This observation suggests a low probability of metabolic improvement in patients with previous dysglycaemia and GHR therapy.Two studies of GHR therapy in adults observed a decrease of HbA1c values over 5 and 10 years, respectively.<a class="elsevierStyleCrossRefs" href="#bib0150">13,14</a> This could be explained by the use of higher initial doses of GH (mean baseline dose 0.98mg/day), which were progressively decreased, and the BMI of those populations (27.6 and 27.8kg/m2). It is noteworthy that GH doses in our study were lower, and titrated to obtain serum IGF-I levels in the mid-range of normality according with age. A differential effect of high GH doses on glucose metabolism cannot be ruled out.A study of 5143 GH-deficient patients on GHR reported an increase of 0.7mg/dl/year in plasma glucose concentration and of 0.036%/year in HbA1c value with a mean observation period of 3.9 years. Nonetheless, only 451 patients had annual data of HbA1c values. Patients with baseline glucose intolerance were not identified.<a class="elsevierStyleCrossRef" href="#bib0140">11</a>Woodmansee et al. evaluated the performance of the HbA1c in 572 GH-deficient subjects with and without pre-existing DM receiving GHR during 2.33±1.34 years. In this post hoc analysis, GHR was not associated with an increase of HbA1c levels in subjects without pre-existing diabetes. However, less than half of the subjects had an HbA1c value recorded at any time during the study.<a class="elsevierStyleCrossRef" href="#bib0145">12</a>In our patients, BFM remained similar to the baseline level during the 3 years of GHR, which could possibly be an effect of normal ageing of the patients or an unexpected evolution of body composition during follow-up. Several studies have demonstrated that GHR therapy normalises the alterations in body composition through a reduction in BFM and an increase in lean mass, within the first year of treatment.<a class="elsevierStyleCrossRefs" href="#bib0165">16,17</a> However, BFM gradually returns towards baseline values during prolonged GH replacement.<a class="elsevierStyleCrossRef" href="#bib0155">14</a>The strength of this study was the systematic monitoring of patients, following a standardised protocol in all of the patients, and the availability of HbA1c data. Furthermore, this cohort was representative of the GHD population with GHR therapy because the aetiological spectrum of GHD included the most common diseases related to it.This study had limitations. First, the evidence obtained is limited by the retrospective nature of the study. Second, we recognise that the follow-up time may be insufficient. However, we believe that a significant number of disturbed glucose metabolic states can be detected over a period of 3 years of follow.In conclusion, a mild increase in HbA1c level was observed during a 3-year GHR therapy in overweight/obese Spanish adult patients with GHD. This increase most frequently occurred in patients without baseline dysglycaemia, regardless of BMI. Given that there is a high prevalence of impaired glucose metabolism in GHD adults receiving GHR, these patients should be closely followed regarding carbohydrate metabolism. Based on our results, we think that HbA1c measurements are justified in those with normal baseline FPG values.Conflict of interestNone to declare.FundingThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres490235" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Study design" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec512293" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec512292" "titulo" => "Abbreviations" ] 3 => array:3 [ "identificador" => "xres490234" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Diseño" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec512294" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patient population" ] 1 => array:3 [ "identificador" => "sec0020" "titulo" => "Outcome and explanatory variables" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Clinical data" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Biochemical data" ] ] ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical analysis" ] ] ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Results" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflict of interest" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding" ] 11 => array:2 [ "identificador" => "xack155055" "titulo" => "Acknowledgement" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-10-27" "fechaAceptado" => "2015-01-18" "PalabrasClave" => array:2 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec512293" "palabras" => array:4 [ 0 => "Growth hormone" 1 => "Glycated haemoglobin" 2 => "Diabetes mellitus" 3 => "Dysglycaemia" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec512292" "palabras" => array:6 [ 0 => "BMI" 1 => "DM" 2 => "FPG" 3 => "GHD" 4 => "GHR" 5 => "HbA1c" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec512294" "palabras" => array:4 [ 0 => "hormona de crecimiento" 1 => "hemoglobina glicada" 2 => "diabetes mellitus" 3 => "disglucemia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectivesTo evaluate the effects of GH replacement therapy (GHR) for 3 years on glycated haemoglobin (HbA1c) and on the presence of dysglycaemia at any time during follow-up in Spanish adult patients with growth hormone deficiency (GHD). Study designA retrospective study of 41 patients with GHD was conducted using baseline and long-term data. Changes in HbA1c values during the first 3 years of GHR were studied in both the overall population and patients with or without dysglycaemia during follow-up. Dysglycaemia was defined as FPG≥100mg/dl and/or HbA1c≥5.7%. ResultsMean HbA1c value (5.4±0.4% at baseline) increased during the first and second years of GHR (HbA1c 5.5±0.4%, p=0.05, and 5.5±0.4%, p=0.006 respectively). This increase was not maintained during the third year (HbA1c 5.4±0.3%, p=0.107) of GHR. Twenty-eight patients (68.2%) had dysglycaemia during follow-up, 9 of them since baseline. In the 19 patients without baseline dysglycaemia, HbA1c increased during the first year and remained stable in the next 2 years (mean HbA1c 5.2±0.4% at baseline; 5.5±0.4% at 1 year, p<0.050; 5.4±0.4% at 2 years, p=0.004, and 5.4±0.4% at 3 years, p=0.016). In the 9 patients with baseline dysglycaemia, HbA1c did not significantly change during the 3 years of GHR therapy. ConclusionsHbA1c values increased during the first 2 years of GHR therapy. In patients with no dysglycaemia before treatment, HbA1c steadily increased over the 3 years. However, it did not change in patients with baseline dysglycaemia." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Study design" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivoEvaluar, en una cohorte de pacientes españoles con déficit de GH (GHD), el efecto de 3 años de tratamiento sustitutivo con hormona de crecimiento (GHR) sobre la hemoglobina glicada (HbA1c) y la presencia de disglucemia en cualquier momento del seguimiento. DiseñoEstudio retrospectivo de 41 pacientes con GHD en GHR. Se analizaron los cambios durante los tres primeros años de GHR, en los valores de la HbA1c tanto en la población general como en los subgrupos de pacientes con y sin disglucemia durante el seguimiento. Se definió disglucemia como una glucemia basal≥100mg/dl y/o HbA1c≥5,7%. ResultadosLa HbA1c media (inicialmente 5,4±0,4%) aumentó durante el primer y segundo año de GHR (HbA1c 5,5±0,4%, p=0,05 y 5,5±0,4%, p=0,006, respectivamente); esta tendencia no se mantuvo durante el tercer año (HbA1c 5,4±0,3%, p=0,107). Veintiocho pacientes (68,2%) presentaron disglucemia durante el seguimiento, 9 de ellos desde el inicio del seguimiento. En los 19 pacientes sin disglucemia basal, la HbA1c se incrementó durante el primer año, permaneciendo estable durante los siguientes dos años (HbA1c media basal 5,2±0,4%, 1er año 5,5±0,4%, p<0,050; 2do año 5,4±0,4% p=0,004 y 3er año 5,4±0,4% p=0,016). En los 9 pacientes con disglucemia basal la HbA1c no cambió en forma significativa durante los 3 años de GHR. ConclusionesLos valores de HbA1c aumentaron durante los dos primeros años de GHR. En los pacientes sin disglucemia pre-tratamiento la HbA1c presentó un incremento continuo durante los tres años. Sin embargo, no cambió en aquellos pacientes con disglucemia basal." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Diseño" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 971 "Ancho" => 1646 "Tamanyo" => 57337 ] ] "descripcion" => array:1 [ "en" => "Evolution of HbA1c (mean±SD) in the total population of adults with GHR." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 880 "Ancho" => 2518 "Tamanyo" => 79088 ] ] "descripcion" => array:1 [ "en" => "HbA1c (mean±SD) over time in GH-treated adults that showed dysglycaemia during the period of the study: (a) patients with baseline dysglycaemia; (b) patient with normal glucose metabolism at baseline." ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mean±SD, median(IQ range) or N (%) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Age (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40±14 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Weight (kg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78±19 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">BMI<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> (kg/m2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31±12 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Total body fat (kg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33.5±10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Lean body mass (kg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">27±14 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Family history of diabetes (N) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (7.3%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Fasting plasma glucose (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">88±11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HbA1c (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.4±0.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">IGF-I (ng/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">64 (30–90) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Total cholesterol (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">212±43 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">LDL cholesterol (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">130±33 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HDL cholesterol (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55±14 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Triglycerides (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">106 (60–147) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">GH<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> dose (mg/day) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.2 (0.2–0.4) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Etiology of GHD</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Operated hormone-secreting adenoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Sheehan's syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Operated tumour near the \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">pituitary/hypothalamus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Operated craniopharyngioma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Operated non-functioning pituitary adenoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Adenophypophyseal hypoplasia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Other pituitary pathologies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="char" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Radiation therapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Craniopharyngioma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Acromegaly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Macroprolactinoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Non-functioning pituitary adenoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cushing's disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Cerebral lymphoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Dysgerminoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Meningioma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Medulloblastoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Rathke's cleft cyst \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab779199.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Body mass index." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Growth hormone." ] ] ] "descripcion" => array:1 [ "en" => "Baseline characteristics of a cohort of Spanish adults with GHD." ] ] 3 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dysglycaemia during follow up (N=28) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Baseline dysglycaemia (N=9) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Age (years) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">44±12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53±6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Weight (kg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">81±17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">87±16 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">BMI (kg/m2)<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33±14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40±22 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Total body fat (kg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">36.4±9.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">38.8±10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Lean body mass (kg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25.4±17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">25±16 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Fasting plasma glucose (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">88±12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">98±12 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HbA1c (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.4±0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.8±0.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">IGF-I (ng/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">71 (36–104) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">76 (48–112) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Total cholesterol (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">215±41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">223±39 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">LDL cholesterol (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">134±31 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">144±31 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HDL cholesterol (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">55±16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">51±11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Triglycerides (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">117 (75–150) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">138 (121–182) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Initial dose GH<a class="elsevierStyleCrossRef" href="#tblfn0020">b</a> (mg/day) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.2 (0.2–0.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.2 (0.2–0.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab779200.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "Body mass index." ] 1 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "b" "nota" => "Growth hormone. Values expressed as mean±SD, median (IQ range) or N (%)." ] ] ] "descripcion" => array:1 [ "en" => "Baseline characteristics of patients with dysglycaemia during the follow up and with baseline dysglycaemia." ] ] 4 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Data are presented as the mean (±SD)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Description \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Baseline \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">1st year \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">2nd year \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">3rd year \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">p-Value \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Body weight (kg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78.28 (18.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">77.41 (18.04) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">79.13 (18.05) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">77.70 (19.94) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.84 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">BFM<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> (kg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33.5 (9.67) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32.73 (8.67) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33.5 (6.56) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33.6 (11.25) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.95 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">HbA1c (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.4 (0.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.5 (0.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.5 (0.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.4 (0.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.006<a class="elsevierStyleCrossRef" href="#tblfn0035">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">FPG<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">88 (11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">92.3 (13.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">91 (15.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">89.5 (11.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.01 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab779198.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "a" "nota" => "Body fat mass." ] 1 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "b" "nota" => "Fasting plasma glucose." ] 2 => array:3 [ "identificador" => "tblfn0035" "etiqueta" => "*" "nota" => "p-Value for comparison of HbA1c after 2 years of GHR therapy with the baseline HbA1c." ] ] ] "descripcion" => array:1 [ "en" => "Effect of GH replacement on body composition, HbA1c and fasting plasma glucose." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0090" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "T. 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Comportamiento de la hemoglobina glicada en adultos con déficit de GH en tratamiento sustitutivo

Paola Andrea Parra R.

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paprch@yahoo.com

Corresponding author.

, Beatriz Barquiel A., Alberto Fernández M., Laura Pérez F., Beatriz Lecumberri S., Mary Gaby Llaro C., Cristina Álvarez-Escolá

Endocrinology Department, La Paz University Hospital, Paseo de La Castellana 261, 28046 Madrid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Growth hormone deficiency &#40;GHD&#41; in adults is associated with an adverse metabolic profile&#44; with fat mass gain &#40;especially visceral fat&#41;&#44; insulin resistance and type 2 diabetes mellitus &#40;DM2&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">1&#8211;3</span></a> However&#44; GH replacement &#40;GHR&#41; is associated with impaired insulin sensitivity shortly after starting therapy&#44; reflected by increased fasting plasma glucose &#40;FPG&#41; and insulin levels despite reductions in visceral adiposity&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">4&#44;5</span></a> This impaired insulin sensitivity could be influenced by high doses of GH&#44; especially by its major effects on lipolysis&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">6</span></a> Many of the early GHD studies in adults used weight-based dosing derived from paediatric practice&#59; therefore&#44; hyperglycaemic side effects were more common&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Available evidence suggests that concerns regarding glucose intolerance in patients receiving long-term GHR have not been substantiated&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">7</span></a> It has been demonstrated that low-dose GHR over 12 months&#8217; period enhances insulin sensitivity&#44; and that GH standard dose &#40;0&#46;48<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; has no effect on glucose metabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">8</span></a> Other studies have suggested that the increase in FPG do not persist after 6 months of GHR therapy&#44; possibly due to a reduction in abdominal visceral fat&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">4&#44;9</span></a> In addition&#44; several environmental and lifestyle-related factors could influence glucose abnormalities in patients with GHD&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Glycated haemoglobin &#40;HbA<span class="elsevierStyleInf">1c</span>&#41; was included in the diagnosis and diabetes risk prediction in 2010&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">10</span></a> HbA<span class="elsevierStyleInf">1c</span> range of 5&#46;7&#8211;6&#46;4&#37; implies a substantially increased risk of DM&#46; There are few data on the evolution of HbA<span class="elsevierStyleInf">1c</span> in patients with GHD during GHR therapy&#44;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">11&#8211;14</span></a> and no study has specifically addressed this issue in Spanish patients&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">We assessed the development of glucose metabolism disorders and the changes in HbA1c during the first 3 years of GHR in a cohort of Spanish patients with GHR therapy&#44; and examined whether these changes were in range of dysglycaemia&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Patient population</span><p id="par0025" class="elsevierStylePara elsevierViewall">Data were collected from clinical records of 71 GHD adult Spanish patients who were followed at the Endocrine Department of La Paz University Hospital&#44; in Madrid&#44; Spain&#44; from January 1999 to July 2013&#46; GHD was confirmed through standard stimulation tests like insulin tolerance test or&#44; if it was contraindicated&#44; glucagon stimulation test&#44; or by decreased IGF-I levels for age and sex if multiple pituitary deficiencies were observed&#46; Inclusion criteria for the current study were a confirmed diagnosis of GHD&#44; absence of prior GHR therapy and at least 2 years of follow-up during GHR therapy&#46; Patients who did not complete 2 years of treatment&#44; had an irregular follow-up or had diabetes mellitus &#40;DM&#41; at baseline were excluded&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Although the study was retrospective&#44; all patients were followed on the basis of the same standardised protocol that has been applied in our department for several years&#46; All patients&#44; when appropriate&#44; received hormone replacement therapy in the form of <span class="elsevierStyleSmallCaps">l</span>-thyroxine&#44; hydrocortisone&#44; sex steroids and desmopressin&#46; During the study&#44; the adequacy of hormone replacement therapy was assessed periodically&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The study was performed in accordance with the Declaration of Helsinki&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Outcome and explanatory variables</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Clinical data</span><p id="par0040" class="elsevierStylePara elsevierViewall">Recorded data included age at diagnosis of GHD&#44; aetiology of GHD&#44; type and number of additional pituitary hormone deficiencies&#44; family history of diabetes as well as weight&#44; BMI and body fat mass &#40;BFM&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">BMI was calculated as body weight &#40;kg&#41; divided by squared height &#40;m<span class="elsevierStyleSup">2</span>&#41;&#46; Bio-impedance assessment was used to measure total body fat under standard conditions for all measurements&#46; The <span class="elsevierStyleItalic">Tanita BC-420MA</span> high capacity body composition analyser was used in all patients throughout the study&#46; All patients with BMI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>25<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> received behavioural modification recommendations&#44; dietary instruction and advice on regular physical activity&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Biochemical data</span><p id="par0050" class="elsevierStylePara elsevierViewall">Patients were evaluated for total cholesterol&#44; low-density lipoprotein cholesterol &#40;LDL-C&#41;&#44; high-density lipoprotein cholesterol &#40;HDL-C&#41; and triglycerides at baseline and at last visit&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Glucose metabolism was assessed by measuring FPG and HbA<span class="elsevierStyleInf">1c</span> concentrations&#46; These variables were evaluated annually&#46; FPG was measured by the glucose oxidase method&#46; HbA<span class="elsevierStyleInf">1c</span> was measured by high-performance liquid chromatography in <span class="elsevierStyleItalic">Diamat</span> and <span class="elsevierStyleItalic">Variant</span> autoanalysers &#40;BioRad<span class="elsevierStyleSup">&#174;</span>&#44; Richmond&#44; California&#44; USA&#41; with exchangeable results calibrated to the <span class="elsevierStyleItalic">Diabetes Control and Complications Trial</span> &#40;DCCT&#41; range of normality&#46; Intra-assay and inter-assay coefficients of variation &#40;CVs&#41; determined using representative blood samples with 5&#46;9 and 10&#46;3&#37; HbA<span class="elsevierStyleInf">1c</span> were 0&#46;97 and 0&#46;48&#37; respectively&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">We defined dysglycaemia as an FPG<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mg&#47;dl and&#47;or an HbA1c<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>5&#46;7&#37;&#46; Patients who developed dysglycaemia at any time of the follow up were divided into two groups&#58; those with baseline dysglycaemia and those with normal glucose metabolism at baseline&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical analysis</span><p id="par0065" class="elsevierStylePara elsevierViewall">Descriptive statistics are presented as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD or range&#46; Student&#39;s <span class="elsevierStyleItalic">t</span>-test was used to assess the difference between mean HbA<span class="elsevierStyleInf">1c</span> values in patients with and without dysglycaemia or Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> test depending on the nature of the data&#46; The <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> test was employed to compare frequencies of categorical variables&#46; Gender differences and differences between patients receiving or not receiving sex steroid replacement were calculated by ANOVA&#46; Multiple linear regression was used to model the relationship between HbA<span class="elsevierStyleInf">1c</span> and body composition variables&#46; <span class="elsevierStyleItalic">P</span> values &#60;0&#46;05 were regarded as statistically significant&#46; For statistical evaluation SPSS &#40;v12&#46;0 for Windows&#59; Chicago&#44; Illinois&#44; USA&#41; was used&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><p id="par0070" class="elsevierStylePara elsevierViewall">Of the 71 subjects with GHD&#44; 41 &#40;21 women and 20 men&#59; mean age 40&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14 years&#41; met the eligibility criteria for this analysis&#46; One man with DM1 and 29 patients whose follow-up was less than 2 years were excluded&#46; Baseline characteristics of the study subjects are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Mean observation period was 7&#46;5 years &#40;range 4&#46;4&#8211;10&#46;7&#41;&#46; Only three patients had family history of DM&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">The causes of hypopituitarism are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; The majority of hormone-secreting adenomas were prolactinomas &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41;&#46; Twelve patients received radiation therapy&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The majority of patients required additional pituitary hormone replacement therapy at baseline&#46; Adrenocorticotropic deficiency was detected in 75&#46;6&#37; of patients &#40;all patients were treated with hydrocortisone&#41;&#44; <span class="elsevierStyleSmallCaps">l</span>-thyroxine was used by 73&#46;2&#37; of patients and sex hormones by 82&#46;9&#37;&#46; Antidiuretic hormone deficiency was present in 17&#46;1&#37; of patients&#46; Doses of glucocorticoids and sex steroids remained stable during the first 3 years of GHR therapy in all patients&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">GH was initiated at a mean dose of 0&#46;26<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;12<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; and titrated to a mean of 0&#46;39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;28<span class="elsevierStyleHsp" style=""></span>mg&#47;day to reach normal IGF-I levels for age and sex&#46; There was no gender difference in terms of GH dose &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;543&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In the whole study population FPG increased from 88<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11<span class="elsevierStyleHsp" style=""></span>mg&#47;dl to 92&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#46;3<span class="elsevierStyleHsp" style=""></span>mg&#47;dl during the first year &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; This increase was not maintained in the next 2 years&#46; Compared to the baseline&#44; HbA<span class="elsevierStyleInf">1c</span> increased from 5&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37; to 5&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; and 5&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#41;&#44; in the first and second year of GHR&#44; returning to baseline during the third year &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Neither gender nor sex steroids therapy influenced the change of HbA<span class="elsevierStyleInf">1c</span> during GHR &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;144 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;48 respectively&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Twenty-eight patients had dysglycaemia during the follow up&#44; 9 of whom had a baseline disturbed glucose metabolic state before starting GHR&#46; Four of these 28 patients &#40;9&#46;7&#37; of the total group&#41; developed DM&#44; and were all started on oral antidiabetic drug &#40;metformin&#41; during the period of the study&#46; DM was diagnosed in the first year of GHR therapy in two patients&#44; and after 5 years of GH treatment in others two&#46; Three of them had dysglycaemia at baseline&#46; Baseline characteristics of subjects with dysglycaemia are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">When we analysed HbA<span class="elsevierStyleInf">1c</span> behaviour of patients with baseline dysglycaemia &#40;baseline mean HbA<span class="elsevierStyleInf">1c</span> 5&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37;&#41;&#44; we did not find a significant change &#40;1st year 5&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;7&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;27&#59; 2nd year 5&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;8&#37; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;15 and 3rd year 5&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;8&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>a&#41;&#46; Nevertheless&#44; FPG was increased in the first year from 98&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&#46;3<span class="elsevierStyleHsp" style=""></span>mg&#47;dl to 103<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;dl &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#41;&#46; This subgroup of patients had a greater mean BMI than the rest of the population &#40;BMI&#58; 40<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>22<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Those patients who developed de novo dysglycaemia &#40;19 patients&#41; had baseline mean HbA<span class="elsevierStyleInf">1c</span> values 5&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37; and baseline mean FGP 84<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41;&#46; These patients showed a significant increase in both HbA<span class="elsevierStyleInf">1c</span> &#40;1st year 5&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#59; 2nd year 5&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;004 and 3rd year 5&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;016&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>b&#41; and FPG values &#40;1st year 93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;3<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;001&#59; 2nd year 92&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14<span class="elsevierStyleHsp" style=""></span>mg&#47;dl <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;014 and 3rd year 93<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;dl <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41; over 3 years&#46; The mean increment of HbA<span class="elsevierStyleInf">1c</span> and FPG was 0&#46;23<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;2&#37; and 8&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; respectively&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Multivariate regression analyses showed that baseline BFM&#44; BMI and body weight were not associated with the annual increase in HbA<span class="elsevierStyleInf">1c</span>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Body weight &#40;median weight gain<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;4 &#91;&#8722;3&#46;6 to 6&#46;8<span class="elsevierStyleHsp" style=""></span>kg&#93;&#41; and body fat mass &#40;BFM&#41; did not change during the study period in any of the subgroups &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Compared to baseline&#44; triglycerides levels increased after the third year &#40;&#916;<span class="elsevierStyleItalic">T</span>g<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>2&#46;63<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;008&#41;&#46; There were no differences in total cholesterol&#44; LDL-C&#44; HDL-C and glucose behaviour between genders&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">Glucocorticoid replacement therapy was not associated with an increase in glucose levels during the follow-up&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0125" class="elsevierStylePara elsevierViewall">This study in a Spanish GHD population found that patients with GHR therapy frequently develop an impaired glucose metabolism&#46; A total of 28 of the 41 patients presented dysglycaemia at any time during follow-up&#44; and four patients developed DM during GHR&#46; This increment agrees with the values reported in previous studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">7&#44;12&#44;15</span></a> ranging from 0 to 10&#46;2&#37;&#59; this variability could partly be due to ethnic characteristics&#44; genetic predisposition and baseline dysglycaemia&#44; as well as the remarkable obesity of the recruited patients&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Our study revealed a significant increase in FPG in patients treated with GHR therapy&#44; mainly during the first year of treatment&#46; By including HbA<span class="elsevierStyleInf">1c</span> in the detection of glucose metabolism disorders&#44; we aimed to identifying patients at high risk of DM in the most comprehensive way&#46; We observed a mild increase in HbA<span class="elsevierStyleInf">1c</span> levels that was not associated with a persistent increase in FPG in the total population&#46; This could be attributed to potential postprandial plasma glucose excursions reflecting insulin resistance as a direct GH effect on carbohydrate metabolism&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Regarding patients with baseline prediabetes treated with GHR therapy&#44; HbA<span class="elsevierStyleInf">1c</span> levels were not modified over a period of 3 years&#46; This observation suggests a low probability of metabolic improvement in patients with previous dysglycaemia and GHR therapy&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Two studies of GHR therapy in adults observed a decrease of HbA<span class="elsevierStyleInf">1c</span> values over 5 and 10 years&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">13&#44;14</span></a> This could be explained by the use of higher initial doses of GH &#40;mean baseline dose 0&#46;98<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#44; which were progressively decreased&#44; and the BMI of those populations &#40;27&#46;6 and 27&#46;8<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#46; It is noteworthy that GH doses in our study were lower&#44; and titrated to obtain serum IGF-I levels in the mid-range of normality according with age&#46; A differential effect of high GH doses on glucose metabolism cannot be ruled out&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">A study of 5143 GH-deficient patients on GHR reported an increase of 0&#46;7<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#47;year in plasma glucose concentration and of 0&#46;036&#37;&#47;year in HbA<span class="elsevierStyleInf">1c</span> value with a mean observation period of 3&#46;9 years&#46; Nonetheless&#44; only 451 patients had annual data of HbA<span class="elsevierStyleInf">1c</span> values&#46; Patients with baseline glucose intolerance were not identified&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">11</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Woodmansee et al&#46; evaluated the performance of the HbA<span class="elsevierStyleInf">1c</span> in 572 GH-deficient subjects with and without pre-existing DM receiving GHR during 2&#46;33<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;34 years&#46; In this post hoc analysis&#44; GHR was not associated with an increase of HbA<span class="elsevierStyleInf">1c</span> levels in subjects without pre-existing diabetes&#46; However&#44; less than half of the subjects had an HbA<span class="elsevierStyleInf">1c</span> value recorded at any time during the study&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">12</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">In our patients&#44; BFM remained similar to the baseline level during the 3 years of GHR&#44; which could possibly be an effect of normal ageing of the patients or an unexpected evolution of body composition during follow-up&#46; Several studies have demonstrated that GHR therapy normalises the alterations in body composition through a reduction in BFM and an increase in lean mass&#44; within the first year of treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">16&#44;17</span></a> However&#44; BFM gradually returns towards baseline values during prolonged GH replacement&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">14</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">The strength of this study was the systematic monitoring of patients&#44; following a standardised protocol in all of the patients&#44; and the availability of HbA<span class="elsevierStyleInf">1c</span> data&#46; Furthermore&#44; this cohort was representative of the GHD population with GHR therapy because the aetiological spectrum of GHD included the most common diseases related to it&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">This study had limitations&#46; First&#44; the evidence obtained is limited by the retrospective nature of the study&#46; Second&#44; we recognise that the follow-up time may be insufficient&#46; However&#44; we believe that a significant number of disturbed glucose metabolic states can be detected over a period of 3 years of follow&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">In conclusion&#44; a mild increase in HbA<span class="elsevierStyleInf">1c</span> level was observed during a 3-year GHR therapy in overweight&#47;obese Spanish adult patients with GHD&#46; This increase most frequently occurred in patients without baseline dysglycaemia&#44; regardless of BMI&#46; Given that there is a high prevalence of impaired glucose metabolism in GHD adults receiving GHR&#44; these patients should be closely followed regarding carbohydrate metabolism&#46; Based on our results&#44; we think that HbA<span class="elsevierStyleInf">1c</span> measurements are justified in those with normal baseline FPG values&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflict of interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">None to declare&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Funding</span><p id="par0180" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from any funding agency in the public&#44; commercial or not-for-profit sector&#46;</p></span></span>"
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          "titulo" => "Resumen"
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                  "titulo" => "Clinical data"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2014-10-27"
    "fechaAceptado" => "2015-01-18"
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          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Growth hormone"
            1 => "Glycated haemoglobin"
            2 => "Diabetes mellitus"
            3 => "Dysglycaemia"
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        ]
        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abbreviations"
          "identificador" => "xpalclavsec512292"
          "palabras" => array:6 [
            0 => "BMI"
            1 => "DM"
            2 => "FPG"
            3 => "GHD"
            4 => "GHR"
            5 => "HbA<span class="elsevierStyleInf">1c</span>"
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            0 => "hormona de crecimiento"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To evaluate the effects of GH replacement therapy &#40;GHR&#41; for 3 years on glycated haemoglobin &#40;HbA<span class="elsevierStyleInf">1c</span>&#41; and on the presence of dysglycaemia at any time during follow-up in Spanish adult patients with growth hormone deficiency &#40;GHD&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Study design</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A retrospective study of 41 patients with GHD was conducted using baseline and long-term data&#46; Changes in HbA<span class="elsevierStyleInf">1c</span> values during the first 3 years of GHR were studied in both the overall population and patients with or without dysglycaemia during follow-up&#46; Dysglycaemia was defined as FPG<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mg&#47;dl and&#47;or HbA<span class="elsevierStyleInf">1c</span><span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>5&#46;7&#37;&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Mean HbA<span class="elsevierStyleInf">1c</span> value &#40;5&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37; at baseline&#41; increased during the first and second years of GHR &#40;HbA<span class="elsevierStyleInf">1c</span> 5&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; and 5&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006 respectively&#41;&#46; This increase was not maintained during the third year &#40;HbA<span class="elsevierStyleInf">1c</span> 5&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;3&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;107&#41; of GHR&#46; Twenty-eight patients &#40;68&#46;2&#37;&#41; had dysglycaemia during follow-up&#44; 9 of them since baseline&#46; In the 19 patients without baseline dysglycaemia&#44; HbA<span class="elsevierStyleInf">1c</span> increased during the first year and remained stable in the next 2 years &#40;mean HbA<span class="elsevierStyleInf">1c</span> 5&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37; at baseline&#59; 5&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37; at 1 year&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;050&#59; 5&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37; at 2 years&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#44; and 5&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#37; at 3 years&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;016&#41;&#46; In the 9 patients with baseline dysglycaemia&#44; HbA<span class="elsevierStyleInf">1c</span> did not significantly change during the 3 years of GHR therapy&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">HbA<span class="elsevierStyleInf">1c</span> values increased during the first 2 years of GHR therapy&#46; In patients with no dysglycaemia before treatment&#44; HbA<span class="elsevierStyleInf">1c</span> steadily increased over the 3 years&#46; However&#44; it did not change in patients with baseline dysglycaemia&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Evaluar&#44; en una cohorte de pacientes espa&#241;oles con d&#233;ficit de GH &#40;GHD&#41;&#44; el efecto de 3 a&#241;os de tratamiento sustitutivo con hormona de crecimiento &#40;GHR&#41; sobre la hemoglobina glicada &#40;HbA<span class="elsevierStyleInf">1c</span>&#41; y la presencia de disglucemia en cualquier momento del seguimiento&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Dise&#241;o</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio retrospectivo de 41 pacientes con GHD en GHR&#46; Se analizaron los cambios durante los tres primeros a&#241;os de GHR&#44; en los valores de la HbA<span class="elsevierStyleInf">1c</span> tanto en la poblaci&#243;n general como en los subgrupos de pacientes con y sin disglucemia durante el seguimiento&#46; Se defini&#243; disglucemia como una glucemia basal<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mg&#47;dl y&#47;o HbA<span class="elsevierStyleInf">1c</span><span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>5&#44;7&#37;&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La HbA<span class="elsevierStyleInf">1c</span> media &#40;inicialmente 5&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;4&#37;&#41; aument&#243; durante el primer y segundo a&#241;o de GHR &#40;HbA<span class="elsevierStyleInf">1c</span> 5&#44;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;4&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;05 y 5&#44;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;4&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;006&#44; respectivamente&#41;&#59; esta tendencia no se mantuvo durante el tercer a&#241;o &#40;HbA<span class="elsevierStyleInf">1c</span> 5&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;3&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;107&#41;&#46; Veintiocho pacientes &#40;68&#44;2&#37;&#41; presentaron disglucemia durante el seguimiento&#44; 9 de ellos desde el inicio del seguimiento&#46; En los 19 pacientes sin disglucemia basal&#44; la HbA<span class="elsevierStyleInf">1c</span> se increment&#243; durante el primer a&#241;o&#44; permaneciendo estable durante los siguientes dos a&#241;os &#40;HbA1c media basal 5&#44;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;4&#37;&#44; 1<span class="elsevierStyleSup">er</span> a&#241;o 5&#44;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;4&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;050&#59; 2<span class="elsevierStyleSup">do</span> a&#241;o 5&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;4&#37; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;004 y 3<span class="elsevierStyleSup">er</span> a&#241;o 5&#44;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;4&#37; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;016&#41;&#46; En los 9 pacientes con disglucemia basal la HbA<span class="elsevierStyleInf">1c</span> no cambi&#243; en forma significativa durante los 3 a&#241;os de GHR&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los valores de HbA<span class="elsevierStyleInf">1c</span> aumentaron durante los dos primeros a&#241;os de GHR&#46; En los pacientes sin disglucemia pre-tratamiento la HbA<span class="elsevierStyleInf">1c</span> present&#243; un incremento continuo durante los tres a&#241;os&#46; Sin embargo&#44; no cambi&#243; en aquellos pacientes con disglucemia basal&#46;</p></span>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#44; median&#40;IQ range&#41; or <span class="elsevierStyleItalic">N</span> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Weight &#40;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">78<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">BMI<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">31<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Total body fat &#40;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Lean body mass &#40;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Family history of diabetes &#40;N&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;7&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Fasting plasma glucose &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">88<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">HbA1c &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">IGF-I &#40;ng&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">64 &#40;30&#8211;90&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Total cholesterol &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">212<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">LDL cholesterol &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">130<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">HDL cholesterol &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Triglycerides &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">106 &#40;60&#8211;147&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">GH<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> dose &#40;mg&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;2 &#40;0&#46;2&#8211;0&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Etiology of GHD</span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Operated hormone-secreting adenoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Sheehan&#39;s syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Operated tumour near the&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>pituitary&#47;hypothalamus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Operated craniopharyngioma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Operated non-functioning pituitary adenoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Adenophypophyseal hypoplasia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Other pituitary pathologies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="char" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Radiation therapy</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Craniopharyngioma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Acromegaly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Macroprolactinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Non-functioning pituitary adenoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cushing&#39;s disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cerebral lymphoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dysgerminoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Meningioma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Medulloblastoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rathke&#39;s cleft cyst&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dysglycaemia during follow up &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>28&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Baseline dysglycaemia &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">44<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Weight &#40;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">81<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">87<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">BMI &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#41;<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Total body fat &#40;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">36&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Lean body mass &#40;kg&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Fasting plasma glucose &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">88<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">98<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">HbA1c &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">IGF-I &#40;ng&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">71 &#40;36&#8211;104&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">76 &#40;48&#8211;112&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Total cholesterol &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">215<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">223<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>39&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">LDL cholesterol &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">134<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">144<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>31&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">HDL cholesterol &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">55<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">51<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Triglycerides &#40;mg&#47;dl&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">117 &#40;75&#8211;150&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">138 &#40;121&#8211;182&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Initial dose GH<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a> &#40;mg&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;2 &#40;0&#46;2&#8211;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;2 &#40;0&#46;2&#8211;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Baseline characteristics of patients with dysglycaemia during the follow up and with baseline dysglycaemia&#46;</p>"
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Effect of GH replacement on body composition&#44; HbA<span class="elsevierStyleInf">1c</span> and fasting plasma glucose&#46;</p>"
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                      "titulo" => "Favorable long-term effects of growth hormone replacement therapy on quality of life&#44; bone metabolism&#44; body composition and lipid levels in patients with adult-onset growth hormone deficiency"
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                            3 => "O&#46; Gudmundsen"
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                      "titulo" => "One year of GH replacement therapy with a fixed low-dose regimen improves body composition&#44; bone mineral density and lipid profile of GH-deficient adults"
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                          "etal" => false
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Article information

ISSN: 15750922
Original language: English

DOI:10.1016/j.endonu.2015.01.009

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 October	11	0	11
2024 September	17	9	26
2024 August	24	4	28
2024 July	11	6	17
2024 June	11	5	16
2024 May	13	3	16
2024 April	8	6	14
2024 March	23	3	26
2024 February	17	5	22
2024 January	23	9	32
2023 December	15	15	30
2023 November	14	3	17
2023 October	23	9	32
2023 September	17	7	24
2023 August	9	6	15
2023 July	15	6	21
2023 June	14	10	24
2023 May	8	6	14
2023 April	7	3	10
2023 March	7	6	13
2023 February	10	12	22
2023 January	7	12	19
2022 December	17	10	27
2022 November	14	9	23
2022 October	13	8	21
2022 September	18	13	31
2022 August	19	12	31
2022 July	11	10	21
2022 June	12	17	29
2022 May	18	9	27
2022 April	11	6	17
2022 March	28	9	37
2022 February	7	4	11
2022 January	11	15	26
2021 December	33	11	44
2021 November	12	12	24
2021 October	19	16	35
2021 September	15	13	28
2021 August	15	6	21
2021 July	22	13	35
2021 June	25	6	31
2021 May	20	13	33
2021 April	64	8	72
2021 March	19	17	36
2021 February	18	5	23
2021 January	13	8	21
2020 December	17	13	30
2020 November	13	10	23
2020 October	14	9	23
2020 September	17	15	32
2020 August	14	9	23
2020 July	21	12	33
2020 June	24	22	46
2020 May	16	12	28
2020 April	14	5	19
2020 March	20	12	32
2020 February	26	22	48
2020 January	24	11	35
2019 December	28	15	43
2019 November	12	14	26
2019 October	20	6	26
2019 September	20	4	24
2019 August	18	3	21
2019 July	17	7	24
2019 June	22	31	53
2019 May	65	25	90
2019 April	28	10	38
2019 March	13	9	22
2019 February	13	9	22
2019 January	6	4	10
2018 December	2	6	8
2018 November	14	2	16
2018 October	14	7	21
2018 September	5	2	7
2018 August	5	2	7
2018 July	8	4	12
2018 June	5	2	7
2018 May	8	1	9
2018 April	7	3	10
2018 March	4	0	4
2018 February	5	0	5
2018 January	19	1	20
2017 December	16	1	17
2017 November	16	2	18
2017 October	22	2	24
2017 September	8	5	13
2017 August	28	3	31
2017 July	26	5	31
2017 June	26	6	32
2017 May	37	5	42
2017 April	35	4	39
2017 March	18	23	41
2017 February	12	1	13
2017 January	15	2	17
2016 December	28	8	36
2016 November	48	1	49
2016 October	90	5	95
2016 September	49	9	58
2016 August	27	5	32
2016 July	44	4	48
2016 June	49	8	57
2016 May	42	20	62
2016 April	32	12	44
2016 March	36	21	57
2016 February	40	23	63
2016 January	31	14	45
2015 December	49	17	66
2015 November	49	8	57
2015 October	1	0	1
2015 August	1	1	2
2015 June	2	4	6
2015 May	2	7	9
2015 April	1	0	1

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