Farideh Miraki-Moud

Dehydroepiandrosterone (DHEA) replacement reduces growth hormone (GH) dose requirement in female hypopituitary patients on GH replacement.

Objectiveu2002 GH dose requirement is lower in ACTH replete compared with ACTH deficient hypopituitary patients suggesting that adrenal androgens may augment IGF‐I generation for a given GH dose. This study aimed to determine the effect of dehydroepiandrosterone (DHEA) administration on GH dose requirements in hypopituitary adults.

Identification and characterisation of a novel GHR defect disrupting the polypyrimidine tract and resulting in GH insensitivity

Objective GH insensitivity (GHI) is caused in the majority of cases by impaired function of the GH receptor (GHR). All but one known GHR mutation are in the coding sequence or the exon/intron boundaries. We identified and characterised the first intronic defect occurring in the polypyrimidine tract of the GHR in a patient with severe GHI. Design We investigated the effect of the novel defect on mRNA splicing using an in vitro splicing assay and a cell transfection system. Methods GHR was analysed by direct sequencing. To assess the effect of the novel defect, two heterologous minigenes (wild-type and mutant L1-GHR8-L2) were generated by inserting GHR exon 8 and its flanking wild-type or mutant intronic sequences into a well-characterised splicing reporter (Adml-par L1–L2). 32P-labelled pre-mRNA was generated from the two constructs and incubated in HeLa nuclear extracts or HEK293 cells. Results Sequencing of the GHR revealed a novel homozygous defect in the polypyrimidine tract of intron 7 (IVS7-6T>A). This base change does not involve the highly conserved splice site sequences, and is not predicted in silico to affect GHR mRNA splicing. Nevertheless, skipping of exon 8 from the mutant L1-GHR8-L2 mRNA was clearly demonstrated in the in vitro splicing assay and in transfected HEK293 cells. Conclusion Disruption of the GHR polypyrimidine tract causes aberrant mRNA splicing leading to a mutant GHR protein. This is predicted to lack its transmembrane and intracellular domains and, thus, be incapable of transducing a GH signal.

Insulin-like growth factor-I deficiency caused by a partial deletion of the IGF-I gene: Effects of rhIGFmi therapy

Summary Insulin-like growth factor-I (IGF-I) is one of the most important regulator of growth. IGF-I deficiency is associated with prenatal and post-natal growth failure and may arise primarily as a result of GH receptor/post-receptor abnormalities or defects in the synthesis and transport of IGF-I. We have previously reported a 17.2-year-old boy with severe growth retardation and undetectable serum levels of IGF-I caused by a partial deletion of the IGF-I gene. This short review will concentrate on results of a recent study which examined the effects of rhIGF-I therapy on the GH-IGF system of this patient. Similar to healthy individuals, this patient had normal IGFBP-3 but elevated ALS levels. IGF-I treatment has improved linear growth and insulin sensitivity in this patient by restoring IGF-I levels and by normalizing circulating GH, IGFBPs and insulin levels.

Final Height in Patients with Idiopathic Short Stature and High Growth Hormone Responses to Stimulation Tests

Children with idiopathic short stature (ISS) may have normal or increased growth hormone (GH) responses to provocation tests and achieve a final height (FH) below –2.0 standard deviation score (SDS) if untreated. FH of subjects with high stimulated GH levels has not been studied in detail. Aim: It was the aim of this study to analyse FH in ISS patients with high GH peak responses to the provocation test. Patients andMethods: We studied 16 patients (9 pre-pubertal) with ISS and a GH peak ≧40 mU/l to insulin-induced hypoglycaemia. The patients were recalled at age 19.7 ± 2.5 years for measurement of FH when blood samples were obtained for serum insulin-like growth factor (IGF)-I, IGF binding protein 3, acid-labile subunit and GH binding protein measurements. GH bioactivity was determined using the Nb2 bioassay. Results: FH was –3.1 ± 1.0 SDS, being significantly lower than target height (TH). At FH, IGF-I levels were within –1.5 and +1.5 SDS for age and sex in 10 patients and higher than +1.5 SDS in 6 patients. IGF binding protein 3, acid-labile subunit, GH binding protein levels and GH bioactivity values were normal. Summary: These data suggest that patients with ISS and high GH levels during a GH stimulation test may have a more compromised FH. The association of severe ISS with a peak GH >40 mU/l might suggest a degree of insensitivity for the GH-IGF-I axis.