Prepubertal Short Small For Gestational Age Research Articles

Metabolites involved in glycolysis and amino acid metabolism are altered in short children born small for gestational age.

BackgroundLater life metabolic dysfunction is a well-recognised consequence of being born Small for Gestational Age (SGA). This study has applied metabolomics to identify whether there are changes in these pathways in pre-pubertal short SGA children and aimed to compare the intracellular and extracellular metabolome in fibroblasts derived from healthy children and SGA children with post-natal growth impairment.MethodsSkin fibroblast cell lines were established from eight SGA children (age 1.8 -10.3 years) with failure of catch-up growth and from three healthy control children. Confluent cells were incubated in serum free media and the spent growth medium (metabolic footprint) and intracellular metabolome (metabolic fingerprint) were analysed by gas-chromatography mass spectrometry.Results19 metabolites were significantly altered between SGA and control cell lines. The greatest fold difference (FD) was seen for alanine (fingerprint FD, SGA: control) 0.3, p=0.01 and footprint FD=0.19, p=0.01), aspartic acid (fingerprint FD=5.21, p=0.01) and cystine (footprint FD=1.66, p=0.02). Network analysis of the differentially expressed metabolites predicted inhibition of insulin and activation of ERK/AKT/PI3K signalling in SGA cells.ConclusionsThis study indicates that changes in cellular metabolism associated with both growth failure and insulin insensitivity are present in pre-pubertal short children born SGA.

Puberty and Pubertal Growth in GH-treated SGA Children: Effects of 2 Years of GnRHa Versus No GnRHa.

Most studies on puberty in children born small for gestational age (SGA) report height and age at onset of puberty. GH-treated SGA children with an adult height (AH) expectation below -2.5 SDS at onset of puberty can benefit from an additional 2 years of GnRH analog (GnRHa) treatment. There are no data on puberty and growth after discontinuation of GnRHa treatment in GH-treated SGA children. This study aimed to investigate the effects on puberty and pubertal growth of 2 years GnRHa vs no GnRHa in GH-treated SGA children. This was a GH trial involving 76 prepubertal short SGA children (36 girls) treated with GH. Thirty-two children received additional GnRHa for 2 years. Pubertal stages were 3-monthly assessed according to Tanner. Age, bone age, and median height at pubertal onset were lower in girls and boys in the GH/GnRHa group compared with the GH group. In girls and boys treated with GH/GnRHa, pubertal duration after stop of GnRHa treatment was shorter than pubertal duration in those with GH only (40.9 vs 46.7 mo; P = .044; 50.8 vs 57.5 months; P = .006; respectively). Height gain from onset of puberty until AH, including height gain during 2 years of GnRHa treatment, was 25.4 cm in girls and 33.0 cm in boys, which was 6.6 cm more than girls and boys treated with GH only. AH was similar in children treated with GH/GnRHa compared with those with GH only. GH-treated SGA children who start puberty with an AH expectation below -2.5 SDS and are treated with 2 years of GnRHa have a shorter pubertal duration after discontinuation of GnRHa compared with pubertal duration in children treated with GH only. Height gain from onset of puberty until AH is, however, more due to adequate growth during 2 years of GnRHa treatment resulting in a similar AH as children treated with GH only.

Insulin Sensitivity Modulates the Growth Response during the First Year of High-Dose Growth Hormone Treatment in Short Prepubertal Children Born Small for Gestational Age

Aim: To study the relationship between insulin sensitivity and growth response in short children born small for gestational age (SGA) treated with growth hormone (GH). Methods: Randomized, open-label, 24-month intervention study in 40 short prepubertal SGA children [age (mean ± SD) 5.3 ± 1.5 years], who either remained untreated (n = 20) or were treated with GH (66 µg/kg/day; n = 20). Changes in fasting glucose, insulin, quantitative insulin sensitivity check index (QUICKI), IGF-1 and leptin after 1 and 2 years were studied. Results: Mean height SDS increased from –3.3 ± 0.7 to –2.3 ± 0.7 after 1 year, and to –1.9 ± 0.7 after 2 years of treatment. QUICKI decreased significantly (p = 0.008) in the first year of GH treatment and stabilized in the second year. Baseline QUICKI was positively associated (r = 0.40; p < 0.05) with the change in height SDS in the first year. Conclusion: Higher insulin sensitivity at the start of GH therapy is associated with greater first-year growth response to GH, and could be a promising parameter in selecting prepubertal short SGA children for GH treatment. However, this finding needs to be confirmed in larger studies.

Anti-Mullerian hormone in short girls born small for gestational age and the effect of growth hormone treatment

Background Fetal growth restriction is thought to negatively influence reproductive function in later life. Serum anti-Müllerian hormone (AMH) is a marker of the primordial follicle pool. The objectives of this study were to evaluate the effect of being born small for gestational age (SGA) on serum AMH levels and to investigate the effect of growth hormone (GH) treatment on serum AMH levels in short SGA girls. METHODS Serum AMH levels were investigated in 246 prepubertal girls aged 3-10 years: 119 untreated short SGA and 127 healthy controls. Associations between AMH levels and clinical characteristics were analysed using multiple regression analyses. In addition, we investigated the effect of GH treatment on serum AMH levels in short SGA girls. RESULTS Serum AMH levels were similar in short SGA and healthy control girls (P= 0.95). In short SGA girls, AMH levels were not significantly influenced by birth weight standard deviation score (SDS), birth length SDS and gestational age, even after adjustment for age, height SDS and body mass index (BMI) SDS at sampling, socio-economic status and maternal smoking during gestation. Serum AMH levels did not change during 4 years of GH treatment in short SGA girls (P= 0.43). ConclusionS Serum AMH levels in prepubertal short SGA girls are similar to healthy controls, indicating that the follicle pool is not compromised due to SGA birth. GH treatment has no effect on AMH levels in short SGA girls.

Reduced levels of GH during GnRH analogue treatment in pubertal short girls born small for gestational age (SGA)

Several studies showed a decrease in height velocity during GnRH analogue (GnRHa) treatment. No information is available on GH levels during GnRHa treatment in short SGA girls. To study overnight GH profiles and IGF-I and IGFBP-3 levels in girls with Tanner stage 2 and stage 3, before and after 3 months of GnRHa treatment, and to compare levels with those found in prepubertal short SGA girls. Twenty-four pubertal and 16 prepubertal short SGA girls. After baseline overnight GH profiles, pubertal girls received leuprorelide acetate depots of 3.75 mg subcutaneously every 4 weeks. GH, IGF-I and IGFBP-3 levels. At baseline, GH levels were comparable to levels found in prepubertal short SGA girls and IGF-I and IGFBP-3 SDS were significantly below the population mean. After 3 months of GnRHa treatment, AUC(0) (P = 0.02), mean (P = 0.02) and maximum GH levels (P = 0.008) had significantly decreased. Mean GH levels were significantly lower than in prepubertal short SGA girls (P = 0.03). Eight girls with more than 40% decrease in mean GH levels also had a significantly greater decrease in IGF-I and IGFBP-3 levels. Mean and maximum GH levels at baseline correlated significantly with those after 3 months of GnRHa treatment. Short SGA girls lack the normal increase in GH levels seen in puberty and have reduced IGF-I and IGFBP-3 levels, which might explain their reduced pubertal growth spurt. GnRHa treatment led to a significant reduction in GH levels. Therefore, combining GnRHa treatment with GH treatment might improve adult height of short SGA girls.

Testis Function in Prepubertal Boys and Young Men Born Small for Gestational Age

Background/Aims: Some studies reported an impaired gonadal function in males born small for gestational age (SGA). We investigated Sertoli cell function by measuring serum inhibin B and antimullerian hormone (AMH) levels in prepubertal boys and young men born SGA in comparison with age-matched controls born appropriate for gestational age (AGA). Methods: Inhibin B and AMH levels were determined in 73 prepubertal short SGA boys and in 72 age-matched AGA boys. In addition, 25 SGA boys were re-examined after 2 years of growth hormone (GH) treatment. Furthermore, inhibin B, AMH, testosterone, LH and FSH were studied in three groups of young men: 21 SGA men treated with GH, 15 SGA men with spontaneous catch-up growth and 25 young men born AGA. Results: Prepubertal short SGA boys and AGA boys had similar inhibin B (87.3 and 78.2 ng/ml) and AMH levels (75.6 and 63.6 µg/l, respectively). GH treatment did not result in different inhibin B and AMH levels. In young SGA men, inhibin B, testosterone, LH and FSH levels were similar compared to young AGA men. AMH levels were higher in the young SGA men (p = 0.03). Conclusions: Being born SGA does not impair Sertoli cell function. Young men born SGA have a normal hypothalamic-pituitary-testis axis.

Muscle Function Improves during Growth Hormone Therapy in Short Children Born Small for Gestational Age: Results of a Peripheral Quantitative Computed Tomography Study on Body Composition

Short small for gestational age (SGA) children can be affected by a lack of muscle mass rather than fat mass. They also face a high risk of the metabolic syndrome developing after childhood. It is not known whether low muscle mass influences muscle function. Our aim was to investigate muscle-fat distribution and muscle function before and during GH treatment in short SGA children. A total of 34 prepubertal short SGA children (11 females, seven with Silver-Russell syndrome) were included in the study. Mean values were: age at GH start 7.3 yr; height sd score (SDS) -3.3; and birth weight SDS -2.7. Investigations over 24 months on GH treatment (57 microg/kg.d) were performed. Body composition, including fat area and muscle area (MA), was assessed through peripheral quantitative computed tomography (XCT 2000; Stratec, Inc., Pforzheim, Germany). Maximal isometric grip force was performed with a Jamar dynamometer (Preston, Jackson, MI). Comparison with height-dependent reference values (SDS(Height)) was calculated. MA SDS(Height) at GH start was -1.8 and increased to -0.8 (P < 0.001) and -0.8, and fat area SDS(Height) decreased from -0.6 to -2.0 (P < 0.001) and -1.5 after 12 and 24 months on GH. Maximal isometric grip force SDS(Height) increased from -0.9 to 0.3 (P < 0.001) and 0.5. MA at start correlated negatively with height velocity (R = -0.54; P < 0.001) and MA SDS at start and Delta-height SDS during the first year of GH treatment (R = -0.40; P < 0.001). Short stature in SGA children is associated with low muscle mass and function. Supraphysiological GH doses led to a concomitant increment in height, muscle mass, and function, whereas fat mass decreased. Furthermore, body composition at GH start gives insight into GH responsiveness and the individual risk of metabolic syndrome.

Concerns, Expectations and Perception Regarding Stature, Physical Appearance and Psychosocial Functioning before and during High-Dose Growth Hormone Treatment of Short Pre-pubertal Children Born Small for Gestational Age

Background/Aims: Few data are available about parental concerns and psychosocial functioning of young children born small for gestational age (SGA) treated with growth hormone (GH). The present study focused on the perception of short stature and the concerns and expectations of the parents regarding GH treatment. Methods: Forty prepubertal short SGA children, randomized into a GH-treated and a GH-untreated group, and their parents were evaluated by a questionnaire and a semi-structured interview at start and after 2 years of follow-up. Results: Before start, 85% of the parents were concerned about short stature, 76% expected an increase in adult height of ≧10 cm and 81% expected a positive impact on well-being. Half of the parents expressed fears regarding GH treatment. After 2 years, more parents of treated children reported obvious growth and physical changes, and fewer parents reported teasing because of short stature. An improvement of well-being was reported by half of the parents of treated and untreated children. Fears about GH treatment disappeared almost completely. Conclusion: The perspective of GH treatment induced major adult height expectations. In treated children, the physical effects of GH treatment became obvious, teasing because of short stature decreased and initial concerns about short stature and GH therapy decreased.

High Serum Levels of Growth Hormone (GH) and Insulin-Like Growth Factor-I (IGF-I) during High-Dose GH Treatment in Short Children Born Small for Gestational Age

Epidemiological studies have indicated that high serum levels of GH and IGF-I are associated with long-term risks. The objective of the study was to evaluate the changes in serum levels of GH during overnight profiles, IGF-I, and IGF binding protein 3 (IGFBP-3) in short small for gestational age (SGA) children during GH treatment with two doses. Thirty-six prepubertal short SGA children were the subjects of this study. Subjects received 1 (group A) or 2 (group B) mg GH/m(2).d. At baseline and after 6 months of GH treatment, overnight GH profiles were performed, and serum IGF-I and IGFBP-3 levels were measured. After 6 months, group B had significantly higher GH levels during the profile (mean, maximum, and area under the curve above zero line) than group A (P < 0.009). In group B, maximum GH levels increased from 43.9-161 mU/liter (P < 0.0002), and in group A, from 57.2-104 mU/liter (P = 0.002). During the profile (i.e. 12 h per day), children of group B had mean GH levels of 64.4 vs. 34.8 mU/liter in group A (P = 0.001). The IGF-I and IGF-I to IGFBP-3 ratio sd scores increased significantly in both groups, but were higher in group B than A [1.5 vs. 0.2 (P = 0.002) and 1.4 vs. 0.3 (P = 0.007), respectively]. In group B, 74% of the children had IGF-I levels in the highest quintile during GH treatment compared with 19% in group A. Our study shows that high-dose GH treatment in short SGA children results in high serum GH and IGF-I levels in most children. We recommend monitoring IGF-I levels during GH therapy to ensure that these remain within the normal range.