Andrew Whatmore

Serum leptin through childhood and adolescence

Leptin is the protein product of the recently cloned ob gene, that has been implicated in the control of body weight and thermogenesis, but also independently stimulates the reproductive axis. As major changes in body composition and gonadal function occur during human adolescence, we have assessed serum leptin concentration through childhood.

Ghrelin concentrations in healthy children and adolescents

objective  In addition to its regulation by GH releasing hormone (GHRH) and somatostatin, release of GH from the pituitary is modulated by a third factor, ghrelin, which is expressed in high concentration in the stomach and is present in the circulation. Ghrelin has also been shown to cause weight gain by increasing food intake and decreasing fat utilization. Ghrelin is a potential candidate hormone to influence nutrient intake and growth. Its role through normal childhood and adolescence has not been fully defined.

Urinary IGF and IGF binding protein‐3 in children with disordered growth

OBJECTIVE Both IGF‐l and IGFBP‐3 reflect spontaneous GH secretion in healthy individuals. We have evaluated the clinical usefulness of urinary IGF‐I and IGFBP‐3 measurements in the diagnosis of children with disordered growth.

Variability in anterior pituitary size within members of a family with GH deficiency due to a new splice mutation in the GHRH receptor gene

objective  Mutations in the GHRH receptor (GHRHR) gene (GHRHR) cause autosomal recessive isolated GH deficiency (IGHD), and are usually associated with anterior pituitary hypoplasia (APH) (defined as pituitary height more than 2 SDS below normal). We searched for GHRHR mutations and studied pituitary morphology in three prepubertal sibs with severe IGHD, who were born from consanguineous parents.

Growth hormone signalling: sprouting links between pathways, human genetics and therapeutic options

Our molecular understanding of growth hormone-induced signal transduction has improved significantly over the past decades. At the same time, human population genetics and the analysis of genetically engineered animals have led to the discovery of genes that control specific aspects of the overall growth process. Although, currently, growth disorders are still diagnosed and treated on empirical bases, it might soon be possible to stratify patients predominantly by genetic defect, with treatment based on our molecular understanding of the role of the affected gene in the disease.

Human growth is associated with distinct patterns of gene expression in evolutionarily conserved networks

BackgroundA co-ordinated tissue-independent gene expression profile associated with growth is present in rodent models and this is hypothesised to extend to all mammals. Growth in humans has similarities to other mammals but the return to active long bone growth in the pubertal growth spurt is a distinctly human growth event. The aim of this study was to describe gene expression and biological pathways associated with stages of growth in children and to assess tissue-independent expression patterns in relation to human growth.ResultsWe conducted gene expression analysis on a library of datasets from normal children with age annotation, collated from the NCBI Gene Expression Omnibus (GEO) and EBI Arrayexpress databases. A primary data set was generated using cells of lymphoid origin from normal children; the expression of 688 genes (ANOVA false discovery rate modified p-value, q < 0.1) was associated with age, and subsets of these genes formed clusters that correlated with the phases of growth – infancy, childhood, puberty and final height. Network analysis on these clusters identified evolutionarily conserved growth pathways (NOTCH, VEGF, TGFB, WNT and glucocorticoid receptor – Hyper-geometric test, q < 0.05). The greatest degree of network ‘connectivity’ and hence functional significance was present in infancy (Wilcoxon test, p < 0.05), which then decreased through to adulthood. These observations were confirmed in a separate validation data set from lymphoid tissue. Similar biological pathways were observed to be associated with development-related gene expression in other tissues (conjunctival epithelia, temporal lobe brain tissue and bone marrow) suggesting the existence of a tissue-independent genetic program for human growth and maturation.ConclusionsSimilar evolutionarily conserved pathways have been associated with gene expression and child growth in multiple tissues. These expression profiles associate with the developmental phases of growth including the return to active long bone growth in puberty, a distinctly human event. These observations also have direct medical relevance to pathological changes that induce disease in children. Taking into account development-dependent gene expression profiles for normal children will be key to the appropriate selection of genes and pathways as potential biomarkers of disease or as drug targets.

Signal transduction defects in growth hormone insensitivity

Clayton PE, Freeth JS, Whatmore AJ, Ayling RM, Norman MR, Silva CM. Signal transduction defects in growth hormone insensitivity. Acta Pædiatr 1999; Suppl 428: 174–8. Stockholm. ISSN 0803–5326

The Relationship between Nocturnal Urinary Leptin and Gonadotrophins as Children Progress towards Puberty

Background/Aims: Leptin is necessary for normal human pubertal development but its exact role in the period leading up to the onset of puberty has not been defined. This study has assessed the relationship between leptin and gonadotrophin secretion over time as children progress into puberty. Subjects and Methods: Twenty children (13 boys and 7 girls) judged to be close to the initiation of puberty were recruited. Three consecutive first morning urine samples were collected from each subject each month over 6 months. At the end of the study, the children were classified into those who remained physically prepubertal (n = 7) and those that had advanced in puberty (n = 13). Leptin and gonadotrophins were measured by immunoradiometric and immunofluorometric assay, respectively. Results: Total urinary leptin excreted over 6 months was higher in girls than in boys, both prepubertally and in early puberty, and in both sexes, was higher in those advancing into puberty than in those remaining prepubertal (girls 8.0 vs. 3.4 ng/l and boys 3.6 vs. 1.7 ng/l; both p < 0.05). In the whole group, when controlling for gender, there was a significant correlation between both leptin and luteinizing hormone (LH; r = 0.43, p < 0.001) and leptin and follicle-stimulating hormone (FSH; r = 0.32, p = 0.001). The possibility of a lead relationship was explored by pairing leptin values with the gonadotrophin values in the following month. Leptin was significantly correlated with FSH but not LH in both pre- and peripubertal children (prepubertal r = 0.45, p = 0.01; peripubertal r = 0.32, p = 0.01). Conclusions: This study has shown that in children approaching and progressing into puberty, leptin is associated with LH and FSH over the same time frame, and with FSH when leptin is acting as the lead hormone. These data imply that leptin is an important facilitator of the early phases of human puberty.

A pilot study to evaluate gene expression profiles in peripheral blood mononuclear cells (PBMCs) from children with GH deficiency and Turner syndrome in response to GH treatment

Response to GH treatment is variable and dependent on diagnosis and dose. We used a pharmacogenomic approach to assess whether this variability is reflected in patterns of GH‐induced gene expression in peripheral blood mononuclear cells (PBMCs) taken from three children with GH deficiency (GHD) and three girls with Turner syndrome (TS).

The effect of pegvisomant-induced serum IGF-I normalization on serum leptin levels in patients with acromegaly.

background In humans, serum leptin correlates positively with fat mass. GH is lipolytic and patients with active acromegaly have lowered serum leptin compared to age, sex and body mass index (BMI)‐matched controls, but a direct influence of GH on serum leptin remains unclear. In patients with acromegaly, total leptin increases following successful pituitary surgery and during somatostatin (SMS) analogue therapy (despite no change in BMI) but whether this represents changes in soluble leptin receptor, bound or free leptin is unclear. Pegvisomant, a GH receptor antagonist capable of normalizing serum IGF‐I in over 97% of patients, represents a novel treatment strategy in acromegaly and its effect on leptin has not previously been reported.