Growth hormone therapy in children with idiopathic short stature – the effect on appetite and appetite-regulating hormones: a pilot study

<p><b>Aim</b>: To investigate the effect of growth hormone (GH) therapy on appetite-regulating hormones and to examine the association between these hormones and the response to GH, body composition, and resting energy expenditure (REE).</p> <p><b>Methods</b>: Nine pre-pubertal children with idiopathic short stature underwent a standard meal test before and 4 months following initiation of GH treatment. Ghrelin, GLP-1, leptin, and insulin levels were measured; area under the curve (AUC) was calculated. Height, weight, body composition, REE, and insulin-like growth factor levels were recorded at baseline and after 4 and 12 months.</p> <p><b>Results</b>: Following 4 months of GH therapy, food intake increased, with increased height-standard deviation score (SDS), weight-SDS, and REE (<i>p </i>< .05). Significant changes in appetite-regulating hormones included a decrease in postprandial AUC ghrelin levels (<i>p </i>= .045) and fasting GLP-1 (<i>p </i>= .038), and an increase in fasting insulin (<i>p </i>= .043). Ghrelin levels before GH treatment were positively correlated with the changes in weight-SDS (fasting: <i>r</i> = .667, <i>p </i>= .05; AUC: <i>r</i> = .788, <i>p </i>= .012) and REE (fasting: <i>r</i> = .866, <i>p </i>= .005; AUC: <i>r</i> = .847, <i>p </i>= .008) following 4 months of GH therapy. Ghrelin AUC at 4 months was positively correlated with the changes in height-SDS (<i>r</i> = .741, <i>p </i>= .022) and fat-free-mass (<i>r</i> = .890, <i>p </i>= .001) at 12 months of GH treatment.</p> <p><b>Conclusions</b>: The reduction in ghrelin and GLP-1 following GH treatment suggests a role for GH in appetite regulation. Fasting and meal-AUC ghrelin levels may serve as biomarkers for predicting short-term (4 months) changes in weight and longer term (12 months) changes in height following GH treatment. The mechanisms linking GH with changes in appetite-regulating hormones remain to be elucidated.</p> <p><b>Abbreviations:</b> SDS: standard deviation score; REE: resting energy expenditure; SMT: standard meal test; AUC: area under the curve; ISS: idiopathic short stature; SGA: small for gestational age; FFM: fat-free-mass; FM: fat mass; EER: estimated energy requirements; DRI: dietary reference intakes; IQR: inter-quartile range</p

DataSheet_1_Children with idiopathic short stature have significantly different gut microbiota than their normal height siblings: a case-control study.docx

ObjectivesTo investigate the role of gut microbiota (GM) in pathogenesis of idiopathic short stature (ISS) by comparing GM of ISS children to their normal-height siblings.MethodsThis case-control study, conducted at the Schneider Children’s Medical Center’s Institute for Endocrinology and Diabetes between 4/2018-11/2020, involved 30 pairs of healthy pre-pubertal siblings aged 3-10 years, each comprising one sibling with ISS and one with normal height. Outcome measures from fecal analysis of both siblings included GM composition analyzed by 16S rRNA sequencing, fecal metabolomics, and monitoring the growth of germ-free (GF) mice after fecal transplantation.ResultsFecal analysis of ISS children identified higher predicted levels of genes encoding enzymes for pyrimidine, purine, flavin, coenzyme B, and thiamine biosynthesis, lower levels of several amino acids, and a significantly higher prevalence of the phylum Euryarchaeota compared to their normal-height siblings (pDiscussionOur findings suggest that different characteristics in the GM may explain variations in linear growth. The varying levels of Methanobrevibacter demonstrated within the ISS group reflect the multifactorial nature of ISS and the potential ability of the GM to partially explain growth variations. The targeting of specific microbiota could provide personalized therapies to improve growth in children with ISS.</p

Table_1_Children with idiopathic short stature have significantly different gut microbiota than their normal height siblings: a case-control study.docx

ObjectivesTo investigate the role of gut microbiota (GM) in pathogenesis of idiopathic short stature (ISS) by comparing GM of ISS children to their normal-height siblings.MethodsThis case-control study, conducted at the Schneider Children’s Medical Center’s Institute for Endocrinology and Diabetes between 4/2018-11/2020, involved 30 pairs of healthy pre-pubertal siblings aged 3-10 years, each comprising one sibling with ISS and one with normal height. Outcome measures from fecal analysis of both siblings included GM composition analyzed by 16S rRNA sequencing, fecal metabolomics, and monitoring the growth of germ-free (GF) mice after fecal transplantation.ResultsFecal analysis of ISS children identified higher predicted levels of genes encoding enzymes for pyrimidine, purine, flavin, coenzyme B, and thiamine biosynthesis, lower levels of several amino acids, and a significantly higher prevalence of the phylum Euryarchaeota compared to their normal-height siblings (pDiscussionOur findings suggest that different characteristics in the GM may explain variations in linear growth. The varying levels of Methanobrevibacter demonstrated within the ISS group reflect the multifactorial nature of ISS and the potential ability of the GM to partially explain growth variations. The targeting of specific microbiota could provide personalized therapies to improve growth in children with ISS.</p

Relation of clinical data to genes expression in the presence or absence of hypoxia.

<p>Average of each parameter in the study groups is shown. p-values determined by the bootstrap are marked by the letter a.</p

Joint distribution of p21 and hif1α in the study population.

<p>No expression (−), Positive (+).</p

Association between hypertension, proteinuria, abnormal fetoplacental Doppler and IUGR with the expressions of the different genes in the maternal plasma.

<p>For p21, hif1α, VEGF and mdm2, logistic regression statistic was used.</p>*<p>For ERCC, Fisher's test was used. Significant results (p<0.05) in bold.</p

Gene's expression in the maternal plasma of twin pregnancies.

<p>Fisher's exact test for the expression of the different genes in hypoxia versus normal twin pregnancies. No expression (−), positive expression (+).</p

Prevalence of mRNA expressions in normal and hypoxic pregnancies.

<p>The number of cases (n) and percentage of cases (%) in each group with no expression (−) and positive expression (+). χ² tests are shown, significant results (p<0.05). NS, not significant.</p