Renata Stawerska

Thyroid function in children with growth hormone (GH) deficiency during the initial phase of GH replacement therapy - clinical implications

BackgroundNormal thyroid hormone secretion or appropriate L-thyroxine (L-T4) substitution is necessary for the optimal effect of the growth hormone (GH) administration on growth rate. The decrease of free thyroxine (FT4) levels at recombinant human GH (rhGH) therapy onset has been reported in several studies. The aim of the present study was to evaluate the effect of rhGH administration on thyrotropin (TSH) and FT4 serum concentrations in children with GH deficiency (GHD) during the 1st year of therapy, as well as to assess potential indications to thyroid hormone supplementation in them.Patients and methodsThe analysis involved data of 75 children (59 boys, 16 girls) with disorders of GH secretion (GHD, neurosecretory dysfunction - NSD) and partial GH inactivity (inactGH), who were treated with rhGH for - at least - one year. In all the children, body height and height velocity (HV) were assessed before and after 1 year of therapy, while TSH, FT4, IGF-I and IGFBP-3 before treatment and after 3-6 months and 1 year of treatment. In the patients, who revealed hypothyroidism (HypoT), an appropriate L-T4 substitution was introduced immediately. The incidence of HypoT, occurring during the initial phase of rhGH therapy, was assessed, as well as its influence on the therapy effectiveness.ResultsBefore rhGH substitution, there were no significant differences in either auxological indices or TSH and FT4 secretion, or IGF-I concentration and its bioavailability among the groups of patients. During the initial 3-6 months of rhGH administration, a significant decrease of FT4 serum concentration, together with a significant increase of IGF-I SDS and IGF-I/IGFBP-3 molar ratio was observed in all the studied groups. In 17 children, HypoT was diagnosed and L-T4 substitution was administered. Despite similar IGF-I secretion increase, the improvement of HV presented significantly lower in children with HypoT than in those who remained euthyroid all the time.ConclusionsThe incidence of HypoT during the initial phase of GH treatment in children with GHD and the negative effect of even transient thyroid hormone deficiency on the growth rate should be taken into account.

Increased melatonin concentrations in children with growth hormone deficiency

Abstract:  A relationship between melatonin and growth hormone (GH) is poorly understood. We compare circadian melatonin rhythms in short children with normal and decreased GH secretion. The analysis included 22 children (20 boys and 2 girls) aged 11.1–16.9 yr (mean ± S.E.M. = 14.1 ± 0.3 yr) with short stature (height SDS below −2.0). Based on the GH peak in stimulation tests patients were divided into two groups: idiopathic short stature (ISS, n = 11; GH peak ≥ 10 ng/mL) and GH deficiency (GHD, n = 11; GH peak < 10 ng/mL). In all patients the circadian melatonin rhythm was assessed on the basis of nine blood samples, collected in 4‐hr intervals during the daytime and 2‐hr intervals at night, with dark period lasting from 22:00 to 06:00 hr. Magnetic resonance imaging examination excluded organic abnormalities in central nervous system in all patients. Melatonin concentration at 24:00, 02:00 and 04:00 hr as well as the area under curve of melatonin concentrations (AUC) were significantly higher in the patients with GHD than in individuals with ISS. Significant correlations between GH secretion and melatonin concentrations at 24:00, 02:00 and 04:00 hr, and AUC were also observed. On the basis of these data it seems that the assessment of nocturnal melatonin secretion might be a valuable diagnostic tool used for the improvement of the difficult diagnosis of short stature in children.

Relationship between IGF-I Concentration and Metabolic Profile in Children with Growth Hormone Deficiency: The Influence of Children’s Nutritional State as well as the Ghrelin, Leptin, Adiponectin, and Resistin Serum Concentrations

Background Some, however not all, children with growth hormone deficiency (GHD) reveal a tendency towards metabolic disorders. Insulin-like growth factor I (IGF-I) is the main mediator of GH anabolic effects. Objective The aim of the study was to compare ghrelin, adiponectin, leptin, resistin, lipid, glucose, and insulin concentrations in GHD children, depending on the IGF-I bioavailability. Methods The analysis comprised 26 children with GHD, aged 5.7–15.3 yrs. Fasting serum concentrations of IGF-I, IGFBP-3, ghrelin, leptin, adiponectin, resistin, lipids, glucose, and insulin were measured. The GHD children were divided into two subgroups: (1) with lower IGF-I/IGFBP-3 molar ratio and (2) with higher IGF-I/IGFBP-3 molar ratio. The control group consisted of 39 healthy children, aged 5.1–16.6 yrs, of normal height and body mass. Results GHD children with lower IGF-I/IGFBP-3 molar ratio were found to have a significantly lower body mass and insulin and triglyceride concentrations, as well as significantly higher ghrelin and adiponectin concentrations than GHD children with higher IGF-I/IGFBP-3. Conclusions A better metabolic profile characterised GHD children with low IGF-I bioavailability. This phenomenon may be the result of high adiponectin and ghrelin concentrations in those children and their influence on adipose tissue, glucose uptake, and orexigenic axis.

Nutritional Status in Short Stature Children Is Related to Both Ghrelin and Insulin-like Growth Factor I Concentrations

Objectives: Ghrelin plays an important role in the growth processes in children. In addition, it regulates appetite. The aim of the study was to assess ghrelin and insulin-like growth factor type I (IGF-I) concentrations in children with idiopathic short stature, dependent on nutritional status. Methods: The study group included 116 children, ages 10.6 ± 3.5 years (mean ± standard deviation), with idiopathic short stature (height <−2.0 standard deviation scores [SDS], maximal growth hormone [GH] secretion during 2 GH-stimulating tests—>10 ng/mL). In each child, fasting ghrelin, IGF-I, insulin-like growth factor binding protein 3 (IGFBP-3), glucose, insulin, lipids, leptin, adiponectin, and resistin concentrations were assessed. The IGF-I/IGFBP-3 molar ratio was calculated to determine the IGF-I bioavailability. According to body mass index SDS calculated for height age, the children were divided into 3 groups: poorly nourished (thin), normal, and obese. The control group consisted of 19 healthy children, ages 11.0 ± 3.5 years, with normal body weight and height. Results: Ghrelin concentration was significantly higher in short, thin children than in short, obese children (1458.3 ± 798.5 vs 917.2 ± 303.0 pg/mL; P < 0.005). In turn, IGF-I/IGFBP-3 molar ratio was significantly lower in short, thin children than in short, obese children (0.16 ± 0.06 vs 0.28 ± 0.15; P < 0.005). Conclusions: In short, thin children, despite elevated ghrelin production, the low IGF-I concentration is observed, probably due to undernutrition and worse IGF-I formation. In short, normal-weight children and in short, obese ones, ghrelin and IGF-I production is normal, and it seems that mechanisms responsible for their short stature are other than low IGF-I.

Ghrelin, insulin-like growth factor I and adipocytokines concentrations in born small for gestational age prepubertal children after the catch-up growth.

Abstract Background: In children born small for gestational age (SGA) with catch-up growth, a higher risk of insulin resistance (IR) and cardiovascular diseases is noted. Ghrelin stimulates a growth hormone (GH) secretion and regulates lipid and carbohydrate metabolism. We assessed gherlin’s influence on achieving normal height and the occurrence of metabolic complications in SGA children. Methods: Ghrelin, insulin-like growth factor type I (IGF-I), leptin, adiponectin, resistin, glucose, insulin and lipid concentrations were analysed in 134 prepubertal children in four groups: normal-height SGA, short SGA, normal-height born appropriate for gestational age (AGA) and short AGA. Results: Ghrelin and IGF-I concentrations were significantly higher while adiponectin – lower in normal-height SGA comparing to others. Conclusions: The increased production of ghrelin and IGF-I seems to be an adaptive mechanism to achieve normal growth in SGA children. The significance of high ghrelin and low adiponectin concentrations, observed in normal-height prepubertal SGA children, requires elucidation, with reference to the development of metabolic complications.

Association of Trp64Arg Polymorphism of β3-Adrenergic Receptor with Insulin Resistance in Polish Children with Obesity

AIM To establish the influence of the Trp64Arg variant of the beta3-adrenergic receptor (Trp64Arg- beta3AR) on body mass index (BMI) and insulin resistance (IR) in obese children. METHODS BMI, presence of the Trp64Arg mutation, plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT) and IR were determined in 60 obese and 33 normal weight children. RESULTS The frequency of Trp64Arg was similar in normal weight and obese children. BMI, glucose and insulin concentrations during an OGTT in children with Trp64Argbeta3AR were not different from those with Trp64Trpbeta3AR. IR was confirmed in 42.8% of children with Trp64Argbeta3AR and in 45.6% of children with Trp64Trpbeta3AR (NS). CONCLUSIONS 1. The similar frequency of the Trp64Argbeta3AR variant in normal weight and obese children suggests that it is not a susceptibility gene for obesity in Polish children. 2. The presence of the Trp64Argbeta3AR variant does not have an unfavourable influence on BMI, glucose or insulin concentrations during OGTT or on IR frequency in Polish obese children.

Assessment of ghrelin, leptin, orexin A and alpha-MSH serum concentrations and the levels of the autoantibodies against the aforementioned peptides in relation to Helicobacter pylori infections and Candida albicans colonization in children with short stature.

Wstęp. Peptydy produkowane w przewodzie pokarmowym, tkance tłuszczowej i w mózgu odgrywają ważną rolę w wydzielaniu hormonu wzrostu (GH) oraz regulacji przyjmowania posiłków. Zgodnie z hipotezą molekularnego podobieństwa antygeny mikroorganizmów bytujących w przewodzie pokarmowym mogą stać się mechanizmem spustowym dla produkcji przeciwciał, które reagują krzyżowo z peptydami regulatorowymi i modyfikują ich działanie. Celem pracy była ocena stężenia greliny, leptyny, oreksynyA i αMSH oraz poziomu przeciwciał skierowanych przeciwko wymienionym peptydom u dzieci z idiopatycznym niedoborem wzrostu (ISS) i niedoborem GH (GHD) w odniesieniu do infekcji Helicobacter pylori (H.pylori) i zasiedlenia Candida albicans (C.albicans). Materiał i metody. Analiza obejmowała 89 dzieci z niedoborem wzrostu (w wieku 10,24±3,52 lat): 64 z ISS i 25 z GHD oraz 36 dzieci prawidłowego wzrostu (grupa kontrolna) (w wieku 11,41±2,72 lat). U każdego dziecka oceniono w surowicy stężenie greliny, leptyny, oreksynyA i αMSH (alpha-melanocyte-stimulating hormone), poziom przeciwciał IgG skierowanych przeciwko wymienionym peptydom oraz przeciwko H.pylori, zaś obecność C.albicans na podstawie badania próbki kału. Grupa kontrolna została dobrana tak, aby częstość występowania infekcji H.pylori i zasiedlenia C.albicans była podobna do grupy badanej. Wyniki. Poziom przeciwciał IgG przeciwko grelinie i leptynie był znamiennie wyższy w grupie ISS niż w grupie kontrolnej. Stężenie greliny było istotnie wyższe u dzieci z GHD niż w grupie kontrolnej, zaś stężenie leptyny (jak również wskaźnik masy ciała) istotnie niższe w grupie ISS niż w grupach GHD i kontrolnej. Nie wykazano różnic pomiędzy grupami w odniesieniu do stężenia oreksynyA i αMSH ani przeciwciał skierowanych przeciwko nim. Wnioski. Podwyższony poziom przeciwciał skierowanych przeciwko grelinie i leptynie u dzieci z ISS jest związany z upośledzeniem wzrastania i gorszymi przyrostami masy ciała, prawdopodobnie poprzez modyfikację aktywności greliny i leptyny. Możliwe, że te przeciwciała reagują krzyżowo z peptydami na skutek molekularnego podobieństwa między wymienionymi peptydami a H.pylori i C.albicans, jednak potrzebne są dalsze badania wyjaśniające tę kwestię.

Incidence and predictors of persistent growth hormone deficiency (GHD) in patients with isolated, childhood-onset GHD

INTRODUCTION In a considerable proportion of patients with childhood-onset growth hormone (GH) deficiency (GHD), a normalisation of GH secretion at the attainment of final height (FH) is observed. The aim of the present study was to assess the incidence of, and to find out the predictors of, persistent and transient GHD, available in the pre-treatment period, in patients with childhood-onset isolated, non-acquired GHD. MATERIAL AND METHODS The analysis comprised 150 short children (117 boys), with childhood-onset isolated, non-acquired GHD who completed GH therapy and attained FH. Before treatment and at FH (in retesting), auxological parameters were measured, GH peak in stimulation tests and IGF-I concentration were assessed, and pituitary height (PHt) was measured before treatment. RESULTS The incidence of persistent GHD was 12.0%. The patients with persistent GHD had before treatment significantly lower GH and IGF-I secretion, as well as significantly better increase of height SDS (DHSDS) during GH therapy than those with transient GHD. A negative correlation was observed between DHSDS and IGF-I concentration, but not between DHSDS and GH peak. There was no significant difference in the incidence of pituitary hypoplasia between the patients with persistent and transient GHD. CONCLUSIONS The incidence of persistent GHD in patients with childhood-onset, isolated, non-acquired GHD is relatively low. Despite the fact that the predictors of persistent and transient GHD may be identified in childhood, a diagnosis of GHD should be verified in retesting after the attainment of FH in each case.

Frequency of the E23K polymorphism of the KCNJ11 gene in children born small for gestational age and its influence on auxological and metabolic parameters in the prepubertal period.

Abstract Background: The E23K variant of the KCNJ11 gene is possibly responsible for changes in insulin secretion during the fetal life. We tried to assess the influence of the E23K variant on birth weight and metabolic profile in prepubertal children born small for gestational age (SGA). Subjects: One hundred and twenty-three SGA and 132 born appropriate for gestational age (AGA) children were genotyped for the E23K variant. Lipids, glucose, and insulin concentrations during oral glucose tolerance test were assessed in 112 SGA prepubertal children. Results: There were no significant differences between the frequency of the E23K variant in SGA and AGA children. In SGA children with E23K, the mean birth weight was significantly higher than in the E23E group. Body mass index, glucose, insulin, and lipids were not different between the E23K, E23E, and K23K groups. Conclusions: The higher birth weight in SGA children with the E23K variant may be related to higher insulin concentrations in the fetal period. The E23K variant did not affect metabolic disorders in prepubertal SGA children.

Treatment of severe primary IGF-1 deficiency using rhIGF-1 preparation – first three years of Polish experience

INTRODUCTION The objective of this study was to analyse the effects of the first three years of treatment with recombinant human insulinlike growth factor 1 (rhIGF-1) in patients from the Polish population. MATERIAL AND METHODS Twenty-seven children (22 boys and five girls) aged 2.8 to 16.0 years old were qualified for treatment with rhIGF-1 (mecasermin) in different treatment centres, according to Polish criteria: body height below -3.0 SD and IGF-1 concentration below percentile 2.5 with normal growth hormone (GH) levels. Mecasermin initial dose was 40 μg/kg bw twice a day and was subsequently increased to an average of 100 μg/kg bw twice a day. Body height, height velocity, weight, body mass index (BMI), and adverse events were measured. RESULTS Mecasermin treatment resulted in a statistically significant increase in body height (1.45 ± 1.06 SD; p < 0.01) and height velocity in comparison with pre-treatment values. The biggest change in height velocity happened during the first year and diminished during subsequent years. Body weight and BMI also increased significantly after treatment (1.16 ± 0.76 SD and 0.86 ± 0.75 SD, respectively; p < 0.01). Eight patients reported adverse events. These were mild and temporary and did not require treatment modification except in two patients. CONCLUSIONS Treatment with rhIGF-1 was effective and safe in Polish patients with primary IGF-1 deficiency. It had a clear beneficial effect on the height of the patients and significantly accelerated the height velocity, particularly in the first year of treatment.