Maciej Hilczer

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.

The risk of neoplasm associated with dysgenetic testes in prepubertal and pubertal/adult patients

INTRODUCTION In patients with Y-chromosome in the karyotype, partial gonadal dysgenesis and disorders of male reproductive sex organs development are usually resected in childhood because of the high risk of germ cell tumours (GCT). In patients with Y-chromosome, complete gonadal dysgenesis and female genitalia gonadectomy is performed markedly later. However, due to the relatively low number of adult patients with preserved dysgenetic gonads, the true risk of neoplasm is unknown. The aim of the study was to evaluate the prevalence of neoplasia in dysgenetic gonads of children and adults with Y-chromosome in a retrospective study. MATERIAL AND METHODS A review of medical documentation of 94 patients with disorders of sex development (DSD), Y-chromosome and gonadal dysgenesis (GD), aged 1.2-32 years (47 prepubertal, 1.2-10 years; 47 pubertal/adult, 13-32 years), was conducted. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone were determined. Bilateral gonadectomy was performed in 73.4% of patients, and unilateral gonadectomy with biopsy of the contralateral gonad in 26.4%. All gonadal tissues were subjected to immunohistochemical evaluation with antibodies against PLAP and OCT3/4 (markers of malignant germ cells, but also foetal multipotent germ cells), while gonads of prepubertal patients were examined by c-KIT, as well. RESULTS Streak gonads were identified on both sides (complete GD) in 30.8%, a streak gonad on one side and an underdeveloped testis on the other (asymmetric GD) in 38.3%, and underdeveloped testicular structure on both sides (partial GD) in 30.8% of cases. Germ cell neoplasia was found in 53.2% of patients (51.1% in children, 55.3% in pubertal/adults). Invasive GCT were identified in 11.7% of cases, of which 90.9% were in pubertal/adult patients. Other neoplastic lesions included gonadoblastoma (16% prevalence) and testicular carcinoma in situ (25.5%). In younger patients FSH serum levels were increased in 81% of cases (mean 2.82 ± 2.18 IU/L), while LH in 58% (mean 1.82 ± 1.69 IU/L). Hypergonadotropic hypogonadism was diagnosed in most of the pubertal/ /adult patients (mean FSH 54.2 ± 23.3 IU/L, mean LH 21.7 ± 12.1 IU/L, mean testosterone 5.5 ± 4.5 nmol/L). CONCLUSIONS Dysgenetic gonads in patients with Y chromosome have a high risk of germ cell neoplasia (ca. 50%). If they are preserved until puberty/early adulthood, they may develop overt, invasive GCT. The gonads also have poor hormonal activity (hypergonadotropic hypogonadism) in most of the pubertal/adult patients. Each of these cases must be considered individually and a decision to remove the gonad or not should be based on the comprehensive analysis of the phenotype by a multidisciplinary team of specialists in consultation with the patient and the parents. If dysgenetic gonads are not resected in childhood, these patients need careful ongoing follow-up examination, including biopsy and histopathological evaluation.

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.

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.

Whether the administration of thyroid hormones may play a role in the treatment of short stature

Normal thyroid hormone secretion or optimal substitution of L-thyroxine is necessary for the proper functioning of the hypothalamic-pituitary-IGF-I axis. Over 30 years ago Cacciari et al. [1] indicated a slight risk of inducing an alteration of thyroid function in patients with GH deficiency during hGH therapy and recovery of thyroxine (T4) and trijodthyronine (T3) values to normal limits during follow-up. The rGH therapy might disclose previously unrecognised thyroid insufficiency rather than induce hypothyroidism [2,3]. The phenomenon of unmasking central hypothyroidism after the beginning of rGH therapy in some children with previous diagnosis of isolated GH-deficiency was described. Changes in TSH secretion during initial phase of the rGH therapy are less evident than fluctuations of FT4 concentration. The possibility of a decrease of TSH in terms of rhGH administration has been explained by an increase of somatostatin, a natural TSH inhibitor. The most frequently quoted mechanism of changes in thyroid hormone levels is GH-mediated increase of peripheral T4 to T3 deiodination. The potential role of IGF-I in stimulating that process has been postulated. Chernausek et al. [4] documented that IGF-I concentrations were diminished in hypothyroid patients. The mechanism of this phenomenon remained unclear. Diminished GH secretion or direct effects of hypothyroidism upon IGF-I production were considered. It is well documented that in patients with congenital hypothyroidism and caused by thyroiditis L-T4 replacement led to physiological increase of IGF-I and IGFBP3 secretion. It was proven that in children with neglected congenital hypothyroidism, even after a long period of hypothyroidism, L-T4 replacement improved the growth rate, leading to a partial recovery of the GH-IGF-I axis [5]. In GH-deficient children from the beginning of rhGH therapy - in euthyroid status - has not been recommended the obligatory L-T4 supplementation due a little evidence for the development of clinically significant hypothyroidism in most of previously euthyroid patients and spontaneous recovery to pre-treatment thyroid function in most patients [6]. Maintaining euthyroid status is important for the best effectiveness of rhGH therapy. The incidence of revealing hypothyroidism should be taken into account while starting rhGH therapy, as hypothyroidism may worsen the poor response to the therapy. It seems that assessment of TSH and FT4 concentration after rhGH therapy onset should be performed earlier and more often - for example every 3 months. It seems important to establish, if possible, the threshold values of pre-rhGH treatment TSH and/or FT4 levels for revealing hypothyroidism during rhGH therapy [7].

Screening in specific categories of neonates exposed to congenital hypothyroidism

Zaburzenia czynności tarczycy w okresie płodowym i pourodzeniowym u noworodków przedwcześnie urodzonych prowadzą do zaburzeń dojrzewania tkanki nerwowej, szkieletu i innych tkanek ustroju. Nieprawidłowości wynikające z braku hormonów tarczycy w tym okresie powodują trwałe zmiany, które nie znikają nawet po wyrównaniu czynności tarczycy w późniejszym czasie. W dotychczas istniejącym programie badań przesiewowych u wcześniaków oznaczano TSH w 3–5 dobie życia, a następnie po 3 tygodniu życia. Wartości TSH są wówczas często niskie, gdyż niedojrzały układ podwzgórzowo-przysadkowy wydziela niedostateczne ilości TSH nawet w sytuacji, gdy fT4 i fT3 są obniżone. W związku z potrzebą wczesnego rozpoznawania i leczenia niedoczynności tarczycy pierwotnej i wtórnej u wcześniaków i dzieci z niską masą urodzeniową (small for gestational age, SGA) rekomenduje się oznaczenia TSH i fT4 w 3–5 dobie życia u wcześniaków i dzieci z SGA niezależnie od badania przesiewowego w celu włączenia leczenia l-tyroksyną przed ukończeniem drugiego tygodnia życia wtórnej lub pierwotnej niedoczynności tarczycy.

Changes in circadian rhythm of prolactin in short children are dependent on growth hormone secretion

INTRODUCTION AND OBJECTIVE Taking into consideration the common ontogenic origin of prolactin (Prl) and growth hormone (GH), the Prl circadian pattern was analysed in children with different degrees of GH deficiency (GHD). MATERIALS AND METHODS The analysis comprised 100 short children (31 girls and 69 boys), aged: 10.1±3.51 years. Based on maximal GH secretion (GHmax) during two stimulating tests multiple hormone deficiency (MPHD), severe isolated GHD (SIGHD), partial isolated GHD (PIGHD) or idiopathic short stature (ISS) were diagnosed. Non-inferential chronobiometry (macroscopic analysis) of the circadian Prl rhythm, based on serum Prl measured every 3 hours during 24 hours, was performed. In this analysis, mesor, the area under curve (AUC), peak and trough level, dispersion, mean nocturnal and diurnal concentration, night/day ratio, amplitude and regression index were estimated. RESULTS In the study group, the positive correlations between GHmax and Prl concentrations at 02:00 and at 05:00 were observed, as well as between GHmax and mesor, amplitude, mean nocturnal concentration, night/day ratio and AUC. The nocturnal rise of Prl secretion was blunted in 100% MPHD and 50% SIGHD children, whereas in most children with PIGHD and ISS, the circadian Prl rhythm was normal. CONCLUSIONS 1) In short children, the lower the concentration of GH is, the more blunted nocturnal Prl secretion becomes. 2) In the majority of MPHD and SIGHD children (but not PIGHD), the circadian Prl rhythm was disturbed; namely, reduced nocturnal Prl secretion was noticeable.