Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty.

OBJECTIVE: Our objective was to assess final height (FH) and adverse effects of combined GH and GnRH agonist (GnRHa) treatment in short adolescents born small for gestational age or with normal birth size (idiopathic short stature). DESIGN AND PATIENTS: Thirty-two adolescents with Tanner stage 2-3, age and bone age (BA) less than 12 yr for girls or less than 13 yr for boys, height sd score (SDS) less than -2.0 SDS or between -1.0 and -2.0 SDS plus a predicted adult height (PAH0) less than -2.0 SDS were randomly allocated to receive GH plus GnRHa (n=17) or no treatment (n=15) for 3 yr. FH was assessed at the age of 18 yr or older in girls or 19 yr or older in boys. RESULTS: FH was not different between treatment and control groups. Treated children had a larger height gain (FH-PAH0) than controls: 4.4 (4.9) and -0.5 (6.4) cm, respectively (P<0.05). FH was higher than PAH0 in 76 and 60% of treated and control subjects, respectively. During follow-up, 50% of the predicted height gain at treatment withdrawal was lost, resulting in a mean gain of 4.9 cm (range, -4.0 to 12.3 cm) compared with controls. Treatment did not affect body mass index or hip bone mineral density. Mean lumbar spine bone mineral density and bone mineral apparent density tended to be lower in treated boys, albeit statistically not significant. CONCLUSION: Given the expensive and intensive treatment regimen, its modest height gain results, and the possible adverse effect on peak bone mineralization in males, GH plus GnRHa cannot be considered routine treatment for children with idiopathic short stature or persistent short stature after being born small for gestational age.

Copy number variants in patients with short stature.

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.

Fetal mesenchymal stromal cells differentiating towards chondrocytes acquire a gene expression profile resembling human growth plate cartilage.

We used human fetal bone marrow-derived mesenchymal stromal cells (hfMSCs) differentiating towards chondrocytes as an alternative model for the human growth plate (GP). Our aims were to study gene expression patterns associated with chondrogenic differentiation to assess whether chondrocytes derived from hfMSCs are a suitable model for studying the development and maturation of the GP. hfMSCs efficiently formed hyaline cartilage in a pellet culture in the presence of TGFß3 and BMP6. Microarray and principal component analysis were applied to study gene expression profiles during chondrogenic differentiation. A set of 232 genes was found to correlate with in vitro cartilage formation. Several identified genes are known to be involved in cartilage formation and validate the robustness of the differentiating hfMSC model. KEGG pathway analysis using the 232 genes revealed 9 significant signaling pathways correlated with cartilage formation. To determine the progression of growth plate cartilage formation, we compared the gene expression profile of differentiating hfMSCs with previously established expression profiles of epiphyseal GP cartilage. As differentiation towards chondrocytes proceeds, hfMSCs gradually obtain a gene expression profile resembling epiphyseal GP cartilage. We visualized the differences in gene expression profiles as protein interaction clusters and identified many protein clusters that are activated during the early chondrogenic differentiation of hfMSCs showing the potential of this system to study GP development.

Impaired body weight and tail length gain and altered bone quality after treatment with the aromatase inhibitor exemestane in male rats.

BACKGROUND: Estrogen deficiency induced by aromatase inhibitors may be a novel treatment modality for growth enhancement in short children, but may have adverse effects on bone, brain and reproduction. AIM: To assess growth effects and potential adverse effects of aromatase inhibition in male rats. METHODS: 26-day-old prepubertal rats received intramuscular injections with placebo or the aromatase inhibitor exemestane at a dose of 10, 30 or 100 mg/kg/week [E10, E30, E100(6)] for 6 weeks, completely covering the sexual maturation phase, or with 3 weeks E100 followed by 3 weeks placebo [E100(3)]. Growth parameters and histology of the testis, seminal vesicle and brain were analyzed. Bone architecture was studied with X-ray microtomography. RESULTS: Exemestane dose-dependently decreased body weight and tail length gain, as well as liver and seminal vesicle weights, but did not affect nose-anus length gain, growth plate width or radial growth. E100(6) decreased trabecular thickness (epiphysis and metaphysis) and number (metaphysis). Normal IGF-I levels and brain, testis and seminal vesicle morphology were observed. E100(3) resulted in decreased tail length gain only. CONCLUSION: Exemestane treatment during sexual maturation did not augment linear growth in male rats, but caused impaired body weight and tail length gain and osteopenia.

Marginal growth increase, altered bone quality and polycystic ovaries in female prepubertal rats after treatment with the aromatase inhibitor exemestane.

BACKGROUND: Aromatase inhibition has been proposed as a potential approach for growth enhancement in children with short stature, but detailed animal studies are lacking. AIM: To assess the effect and potential adverse effects of aromatase inhibition on growth in female rats. METHODS: Prepubertal Wistar rats received intramuscular injections with placebo or the aromatase inhibitor exemestane at a dose of 10, 30 or 100 mg/kg/week (E10, E30, E100) for 3 weeks. A control group was ovariectomized (OVX). Weight and length gain, tibia and femur length, growth plate width, organ weights, insulin-like growth factor I (IGF-I) levels, and histology of the ovaries, uterus and brain were analyzed. X-ray microtomography of femora was performed. RESULTS: E100 significantly increased weight gain and growth plate width, but less prominently than OVX. Trabecular number and thickness were decreased in E100 and OVX in the metaphysis and epiphysis. E100 significantly decreased ovarian weight and multiple cysts were seen upon histological evaluation. No significant effects were found on IGF-I levels and brain morphology in E100. E10 and E30 had no effects on growth. CONCLUSION: A high dose of exemestane marginally increases axial and appendicular growth in female rats, at the expense of osteopenia and polycystic ovaries.