Joanna Smyczyńska

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.

Neural modelling of growth hormone therapy for the prediction of therapy results

Abstract In this paper, we presented the problem of predicting response to recombinant human growth hormone (GH) treatment in GH-deficient children. Such a prediction can be done by techniques of mathematical modelling and is important because the therapy consists of daily injections and is expensive; thus, it should be administered only to those patients who will, with high probability, benefit from it. Until now, the leading methodological approach to this problem was multiple regression analysis. Several authors demonstrated that it is possible to derive useful models by this method; however, it has some obvious limitations that can be avoided with the use of the proposed neural network approach.

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.

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.

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.

Influence of neural network structure and data-set size on its performance in the prediction of height of growth hormone-treated patients

Abstract It is well known that the structure of neural network and the amount of available training data influence the accuracy of developed models; however, the exact character of this relation depends on the chosen problem. Thus, it was decided to analyze what impact these parameters have on the solution of the problem on which we work – the prediction of final height of children treated with growth hormone. It was observed that multilayer perceptron with a wide range of numbers of hidden neurons (from 1 to 100) could solve the problem almost equally well. Thus, this task seems to be rather simple, not requiring complex models. Larger networks tended to produce less accurate results and did not generalize well while working with the data not used in training. Repeating the experiment with the training data set reduced to 50% of its original content, as expected, caused a decrease in accuracy.

Does elevated morning prolactin concentration in children always mean the diagnosis of hyperprolactinemia

AIM It has recently been suggested that prolactin (Prl) level above the upper limit of normal range, recorded in a single measurement in serum is enough to diagnose hyperprolactinemia (HPrl). The aim of the study was the analysis of the circadian rhythm of Prl secretion in children with an increased morning Prl concentration in order to establish whether it is a real hyperprolactinemic state or not. MATERIAL AND METHODS The analysis comprised a group of 44 children (32 boys and 12 girls, aged from 4.2 to 14.1 years, mean±SD: 10.4±3.5 years) with either short stature or precocious puberty, with an elevated Prl concentration at 8:00 a.m., suggesting hyperprolactinemic state. In all patients the circadian Prl secretion profile was assessed on the basis of Prl concentrations in 9 blood samples, collected in 3-h intervals. An analysis of the circadian Prl rhythm was performed. Depending on the medical history and the magnetic resonance imaging result, the children were divided into the following groups: A - congenital disorders of hypothalamic-pituitary region (n=10); B - acquired disorders of hypothalamic-pituitary region (other than pituitary adenomas) (n=15), C - pituitary adenomas (n=19). The control group consisted of 14 healthy children (9 boys and 5 girls), aged from 5.2 to 14.3 years, mean±SD: 10.8±3.2 years. RESULTS In only 18 children (41%), apart from a higher morning Prl concentration, an elevated Prl concentration at other time points was observed and the circadian rhythm was disturbed, implying hyperprolactinemic state (2 children from Group A, 8 from Group B and 8 form Group C). In the remaining 26 children (59%), higher morning Prl concentrations were not accompanied by elevated Prl concentrations at other time points of the circadian profile. CONCLUSIONS In children with elevated Prl concentrations in the morning, a circadian Prl secretion profile should be performed in order to avoid overdiagnosing of continuous HPrl. In children with the presence of pituitary adenoma and increased morning Prl concentrations, the diagnosis of Prl-secreting adenoma is not completely obvious.