Reproducibility and utility of an overnight 0.25 mg dexamethasone suppression test as a marker for glucocorticoid sensitivity in children with asthma.

PURPOSE: Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment in children. However, there is considerable inter-individual variation in glucocorticoid sensitivity, leading to over- as well as undertreatment. A simple and fast test to predict glucocorticoid sensitivity would enable more tailored therapy in children with asthma. AIM: To study reproducibility and utility of an overnight 0.25 mg dexamethasone suppression test (DST) with salivary cortisol levels as marker for glucocorticoid sensitivity in asthmatic children. METHODS: 23 children with atopic asthma were recruited for two overnight 0.25 mg DST's, 1 month apart. RESULTS: Baseline cortisol levels correlated well between both tests. However, cortisol levels, change in cortisol levels or fractional suppression of cortisol levels after dexamethasone did not correlate between the two tests. Bland-Altman plots showed that the difference in salivary cortisol levels between test 1 and 2 of an individual patient could go up to 12 nmol/l, which is a clinically relevant difference. ICS dose did not correlate with baseline cortisol levels, height and BMI SDS. CONCLUSION: The low-dose salivary DST test in its current form is not suitable for use in clinical practice in children with asthma, due to low reproducibility. Therefore, studies using the 0.25 mg salivary DST should be interpreted cautiously.

New insights into factors influencing adult height in short SGA children: Results of a large multicentre growth hormone trial.

BACKGROUND: Growth hormone (GH) treatment is effective in improving adult height (AH) in short children born SGA. However, there is a wide variation in height gain, even after adjustment for predictive variables. It is therefore important to investigate new factors which can influence the response to GH. OBJECTIVE: To investigate the efficacy of GH treatment (1 mg/m(2/) day) in short SGA children on AH. To assess the relation between spontaneous catch-up growth after birth and growth during puberty on the total height gain SDS to AH. PATIENTS: Longitudinal GH trial in 170 children. RESULTS: Median age at start of GH was 7·1 years and height -3·0 SDS. AH was -1·8 SDS (TH-corrected AH -1·1 SDS) in boys and -1·9 SDS (TH-corrected AH -1·3 SDS) in girls. Spontaneous catch-up growth after birth was ≥0·5 SDS in 42% of children. In contrast to expectation, spontaneous catch-up growth was negatively correlated with total height gain SDS during GH (P = 0·009). During puberty, height SDS declined (-0·4 SDS in boys and -0·5 SDS in girls) resulting in a lower total height gain SDS than expected. Pubertal height gain was 25·5 cm in boys and 15·3 cm in girls, significantly lower compared to AGA children (P < 0·001). At onset of puberty, BA for boys and girls was moderately advanced (P = 0·02 and P < 0·001, respectively). Growth velocity was comparable to AGA children during the first two years of puberty, but thereafter significantly lower until reaching AH (P < 0·001). CONCLUSION: In contrast to our hypothesis, children with greater spontaneous catch-up growth after birth show a lower total height gain SDS during GH. Height SDS declines from mid-puberty, due to a marked early deceleration of growth velocity.

Thyroid function in short children born small-for-gestational age (SGA) before and during GH treatment.

CONTEXT: Disturbances in thyroid function have been described in small-for-gestational age (SGA) children but the influence of prematurity is unclear. In addition, the effect of GH treatment on thyroid function has not been studied in short SGA children. OBJECTIVES: To determine whether short SGA children have higher TSH levels compared to age-matched controls and evaluate the influence of gestational age. To investigate whether GH treatment alters thyroid function. PATIENTS: A total of 264 short SGA children (116 preterm), prepubertal and non-GH deficient. MEASUREMENTS: Serum FT4 and TSH at baseline and after 6, 12 and 24 months of GH treatment. RESULTS: Baseline mean TSH was higher in preterm short SGA children than in age-matched controls (P < 0.05). Mean FT4 was not significantly different between short SGA children and controls. Baseline FT4 or TSH did not correlate with gestational age, or SDS for birth weight, birth length, height, body mass index, IGF-I or IGFBP-3. Mean FT4 decreased significantly during the first 6 months of GH treatment, but remained within the normal range. TSH did not change during treatment. The change in FT4 did not correlate with the change in height SDS during 24 months of GH treatment. CONCLUSION: Preterm short SGA children have higher, although within the normal range, TSH levels than controls. The level of TSH does not correlate with gestational age, birth weight SDS or birth length SDS. FT4 decreases during GH treatment, but is neither associated with an increase in TSH nor does it affect the response to GH treatment. As these mild alterations in thyroid function do not appear clinically relevant, frequent monitoring of thyroid function during GH therapy is not warranted in short SGA children.

Fat mass and lipid profile in young adults born preterm.

CONTEXT: Associations between small size at birth and abnormal cardiovascular parameters in later life have been reported. It is, however, unknown whether the effect of a small size at birth on cardiovascular risk factors in later life is due to a small size for gestational age or due to prematurity. Due to advances in neonatal care, survival of preterm infants has significantly improved, and nowadays an increasing number of these children reach adulthood. It is, therefore, of increasing importance to assess the long-term effect of prematurity on determinants for cardiovascular disease. OBJECTIVE: The aim of the study was to assess the long-term effects of gestational age and particularly preterm birth on lipid levels and fat mass in early adulthood. DESIGN AND PATIENTS: A cross-sectional study was conducted with 455 healthy subjects, aged 18 to 24 yr; 167 preterm subjects were compared with 288 full-term subjects. OUTCOME MEASURE: Total fat mass, trunk fat mass, and limb fat mass were determined by dual-energy x-ray absorptiometry. Furthermore, fasting lipid levels (total cholesterol, low-density lipoprotein, triglyceride, apolipoprotein B, lipoprotein a, high-density lipoprotein, and apolipoprotein A-I) were measured. RESULTS: Preterm subjects had a significantly higher percentage of total fat mass, trunk fat mass, and limb fat mass than subjects born term. Furthermore, preterm subjects had significantly lower serum lipoprotein a levels and higher apolipoprotein A-I levels than term subjects. Multiple linear regression analyses to assess the association between gestational age and fat mass and lipid levels showed similar results. CONCLUSION: In our cohort of 455 young adults, preterm birth was associated with more total fat mass, trunk fat, and limb fat mass but a relatively favorable lipid profile.

Influence of preterm birth and small birth size on serum anti-Müllerian hormone levels in young adult women.

BACKGROUND/OBJECTIVES: Preterm birth has been associated with reduced reproduction rates, and controversies remain regarding the effect of being born small for gestational age (SGA) on ovarian function. Recent findings in young men showed no effect of preterm and SGA birth on testis function. We hypothesised that follicle pool size in young adult women is also not affected by preterm and SGA birth. DESIGN/METHODS: In 279 young women of the PROGRAM/PREMS study, aged 18-24 years, the influence of gestational age, birth length and birth weight on serum levels of anti-Müllerian hormone (AMH) was analysed with multiple regression modelling. Additionally, AMH levels were analysed in preterm- versus term-born females and in three subgroups: females born SGA with either short stature or catch-up growth (SGA-CU), and females born term and appropriate for gestational age with normal stature (AGA controls). RESULTS: Preterm and SGA birth did not affect AMH and other hormone levels. Older age at menarche and oral contraceptive pill use (OC-use) were related to lower AMH levels, and maternal smoking during gestation was related to higher AMH levels. After correction for maternal smoking, lower socioeconomic status (SES) was associated with lower AMH levels. In subgroup comparisons, SGA-CU women showed higher AMH levels than AGA controls, also after adjustment for several factors. CONCLUSION: Preterm and SGA birth did not affect AMH levels. Factors associated with serum AMH levels were OC-use, age at menarche, maternal smoking during gestation and SES. We conclude that preterm- and/or SGA-born females are not likely to have a reduced follicle pool size.

Glucocorticoid receptor gene haplotypes are not associated with birth anthropometry, blood pressure, glucose and insulin concentrations, and body composition in subjects born small for gestational age.

OBJECTIVE: Smaller size at birth has been associated with an increased risk of metabolic and cardiovascular disorders in adult life. Fetal programming of the hypothalamic-pituitary-adrenal axis has been suggested as a possible explanation. Fetal glucocorticoid (GC) overexposure has effects that suggest a role of GCs in this programming. The effects of GCs are mediated through the GC receptor (GR or NR3C1). Several functional polymorphisms have been described, which are associated with relative GC resistance or hypersensitivity. Our aim is to compare frequencies of GR haplotypes, characterized by the R23K, N363S, Bcl1, or 9ß polymorphisms, in subjects born small for gestational age (SGA) and associate birth anthropometry data, response to GH treatment, blood pressure, glucose and insulin concentrations, and body composition with these haplotypes. DESIGN: In total, 418 SGA subjects and 697 healthy controls were enrolled in this study. Methods Anthropometry data were obtained, as well as blood samples to determine fasting glucose and insulin concentrations. Dual energy X-ray absorptiometry scans were used to measure the amount of fat and lean mass. RESULTS: No differences were found between GR haplotype frequencies in SGA children compared with healthy controls. No associations were found between GR haplotypes and birth length and birth weight, growth response during GH treatment, blood pressure, glucose and insulin concentrations, and body composition. CONCLUSION: GR haplotypes and their effect on GC sensitivity do not seem to play a significant role in GH-induced catch-up growth and the risk factors of developing metabolic and cardiovascular disorders in adult life of SGA children.

Genetic and epigenetic variability in the gene for IGFBP-3 (IGFBP3): correlation with serum IGFBP-3 levels and growth in short children born small for gestational age.

CONTEXT: IGF-I and IGFBP-3 play a central role in fetal and postnatal growth and levels are low in short SGA children. The -202 A/C and -185 C/T SNPs are located near elements involved in directing IGFBP3 promoter activity and expression. Changes in promoter CpG methylation status affect transcription factor binding and transcriptional activation of IGFBP3 in vitro. OBJECTIVE: To assess the relationship between IGFBP3 promoter SNPs, IGFBP-3 levels, spontaneous growth and growth response to GH treatment in short prepubertal SGA children. To assess promoter methylation status in a subgroup of short SGA subjects and controls. PATIENTS: 292 Short prepubertal SGA children, 39 short young SGA adults and 85 young adults with normal stature. INTERVENTION: Short prepubertal SGA children received GH 1mg/m(2)/day. OUTCOME MEASURES: Fasting levels of IGF-I and IGFBP-3, baseline and delta height SDS. RESULTS: At baseline, IGFBP-3 levels were highest in SGA children with -202 AA genotype and lower in children with 1 or 2 copies of the C-allele (P<0.001). Children with C(-202)/C(-185) haplotype, compared to children with A(-202)/C(-185) haplotype, had lower IGFBP-3 levels (P=0.003) and were shorter (P=0.03). During GH treatment, children with C(-202)/C(-185) haplotype showed a significantly greater increase in IGFBP-3 SDS and in height SDS than children with A(-202)/C(-185) haplotype, resulting in similar IGFBP-3 levels and similar height SDS after 12 months of GH treatment. CpG methylation patterns showed a trend towards more methylation of CpGs involved in transcription factor binding in short young SGA adults compared to controls. CONCLUSION: Polymorphic variation in the IGFBP3 promoter region is correlated with IGFBP-3 levels, spontaneous growth and response to GH treatment in short SGA children.