Differentially methylated CpGs in response to growth hormone administration in children with idiopathic short stature.

BACKGROUND: Recombinant human growth hormone (rhGH) has shown a great growth-promoting potential in children with idiopathic short stature (ISS). However, the response to rhGH differs across individuals, largely due to genetic and epigenetic heterogeneity. Since epigenetic marks on the methylome can be dynamically influenced by GH, we performed a comprehensive pharmacoepigenomics analysis of DNA methylation changes associated with long-term rhGH administration in children with ISS. RESULTS: We measured DNA methylation profiles before and after GH treatment (with a duration of ~ 18 months in average) on 47 healthy children using customized methylC-seq capture sequencing. Their changes were compared and associated with changes in plasma IGF1 by adjusting sex, age, treatment duration and estimated blood proportions. We observed a considerable inter-individual heterogeneity of DNA methylation changes responding to GH treatment. We identified 267 response-associated differentially methylated cytosines (DMCs) that were enriched in promoter regions, CpG islands and blood cell-type-specific regulatory elements. Furthermore, the genes associated with these DMCs were enriched in the biology process of "cell development," "neuron differentiation" and "developmental growth," and in the TGF-beta signaling pathway, PPAR Alpha pathway, endoderm differentiation pathway, adipocytokine signaling pathway as well as PI3K-Akt signaling pathway, and cAMP signaling pathway. CONCLUSION: Our study provides a first insight in DNA methylation changes associated with rhGH administration, which may help understand mechanisms of epigenetic regulation on GH-responsive genes.

Vitamin D Status in Children With Short Stature: Accurate Determination of Serum Vitamin D Components Using High-Performance Liquid Chromatography-Tandem Mass Spectrometry.

Objective: Vitamin D is critical for calcium and bone metabolism. Vitamin D insufficiency impairs skeletal mineralization and bone growth rate during childhood, thus affecting height and health. Vitamin D status in children with short stature is sparsely reported. The purpose of the current study was to investigate various vitamin D components by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to better explore vitamin D storage of short-stature children in vivo. Methods: Serum circulating levels of 25-hydroxyvitamin D2 [25(OH)D2], 25-hydroxyvitamin D3 [25(OH)D3], and 3-epi-25-hydroxyvitamin D3 [3-epi-25(OH)D3, C3-epi] were accurately computed using the LC-MS/MS method. Total 25(OH)D [t-25(OH)D] and ratios of 25(OH)D2/25(OH)D3 and C3-epi/25(OH)D3 were then respectively calculated. Free 25(OH)D [f-25(OH)D] was also measured. Results: 25(OH)D3 and f-25(OH)D levels in short-stature subgroups 2 (school age: 7~12 years old) and 3 (adolescence: 13~18 years old) were significantly lower compared with those of healthy controls. By contrast, C3-epi levels and C3-epi/25(OH)D3 ratios in all the three short-stature subgroups were markedly higher than the corresponding healthy cases. Based on cutoff values developed by Endocrine Society Recommendation (but not suitable for methods 2 and 3), sufficient storage capacities of vitamin D in short-stature subgroups 1, 2, and 3 were 42.8%, 23.8%, and 9.0% as determined by Method 3 [25(OH)D2/3+25(OH)D3], which were lower than those of 57.1%, 28.6%, and 18.2% as determined by Method 1 [25(OH)D2+25(OH)D3+C3-epi] and 45.7%, 28.5%, and 13.6% as determined by Method 2 [25(OH)D2/3+25(OH)D3+C3-epi]. Levels of 25(OH)D2 were found to be weakly negatively correlated with those of 25(OH)D3, and higher 25(OH)D3 levels were positively correlated with higher levels of C3-epi in both short-stature and healthy control cohorts. Furthermore, f-25(OH)D levels were positively associated with 25(OH)D3 and C3-epi levels in children. Conclusions: The current LC-MS/MS technique can not only separate 25(OH)D2 from 25(OH)D3 but also distinguish C3-epi from 25(OH)D3. Measurement of t-25(OH)D [25(OH)D2+25(OH)D3] alone may overestimate vitamin D storage in children, and short-stature children had lower vitamin D levels compared with healthy subjects. Ratios of C3-epi/25(OH)D3 and 25(OH)D2/25(OH)D3 might be alternative markers for vitamin D catabolism/storage in short-stature children. Further studies are needed to explore the relationships and physiological roles of various vitamin D metabolites.

Insulin-like growth factor-1 level is a poor diagnostic indicator of growth hormone deficiency.

We evaluated the diagnostic accuracy of insulin-like growth factor-1 (IGF-1) for screening growth hormone deficiency (GHD) to determine the usefulness of IGF-1 as a screening test. Among 298 consecutive children who had short stature or decreased height velocity, we measured IGF-1 levels and performed growth hormone (GH) secretion test using clonidine, arginine, and, in cases with different results of the two tests, L-dopa. Patients with congenital abnormalities were excluded. GHD was defined as peak GH ≤ 6.0 ng/mL in the two tests. We identified 60 and 238 patients with and without GHD, respectively. The mean IGF-1 standard deviation (SD) was not significantly different between the GHD and non-GHD groups (p = 0.23). Receiver operating characteristic curve analysis demonstrated the best diagnostic accuracy at an IGF-1 cutoff of - 1.493 SD, with 0.685 sensitivity, 0.417 specificity, 0.25 positive and 0.823 negative predictive values, and 0.517 area under the curve. Correlation analysis revealed that none of the items of patients' characteristics increased the diagnostic power of IGF-1. IGF-1 level had poor diagnostic accuracy as a screening test for GHD. Therefore, IGF-1 should not be used alone for GHD screening. A predictive biomarker for GHD should be developed in the future.

Growth response to growth hormone (GH) treatment in children with GH deficiency (GHD) and those with idiopathic short stature (ISS) based on their pretreatment insulin-like growth factor 1 (IGFI) levels and at diagnosis and IGFI increment on treatment.

OBJECTIVES: Some idiopathic short stature (ISS) patients may have varying degrees of insulin-like growth factor 1 (IGFI) deficiency. Others with growth hormone deficiency (GHD) (peak GH < 7 ng/dL after provocation) have normal IGFI levels. Do children with ISS or those with GHD with variable pretreatment IGFI standard deviation score (IGFISDS) have different IGFI and growth responses to recombinant human growth hormone (rhGH) therapy? METHODS: We studied the effect of GH therapy (0.035-0.06 mg/kg/day) on linear growth and weight gain per day (WGPD) in children with ISS (n=13) and those with GHD (n=10) who have low pretreatment IGFISDS (IGF SDS < -1.5) and compared them with age-matched prepubertal children with ISS (n=10) and GHD (n=17) who had normal pretreatment IGFISDS. An untreated group of children with ISS (n=12) served as a control group. RESULTS: At presentation, the height standard deviation score (HtSDS) of children with ISS who had low pretreatment IGFISDS was significantly lower compared to the normal IGFI group. The age, body mass index (BMI), BMISDS, peak GH response to clonidine provocation and bone age did not differ between the two study groups. After 1 year of treatment with rhGH (0.035-0.06 mg/kg/day) IGFISDS increased significantly in both groups (p<0.05). Both had significantly increased HtSDS (catch-up growth). The increase in the HtSDS and WGPD were significantly greater in the lower pretreatment IGFISDS group. The IGFSDS, BMISDS, HtSDS and difference between HtSDS and mid-parental HtSDS were significantly greater in the rhGH treated groups vs. the not treated group. In the GHD groups (normal and low IGFISDS), after 1 year of GH therapy (0.03-0.05 mg/kg/day), the HtSDS increased significantly in both, (p<0.01). The WGPD and increment in BMI were significantly greater in children who had low pretreatment IGFISDS. There was a significant increase in the IGFSDS in the two treated groups (p<0.05), however, the WGPD was greater in the pretreatment low IGFISDS. CONCLUSIONS: IGFI deficiency represents a low anabolic state. Correction of IGFI level (through rhGH and/or improved nutrition) in short children (ISS and GHD) was associated with increased linear growth and WGPD denoting significant effect on bone growth and muscle protein accretion.

Treatment of Short Stature with Aromatase Inhibitors: A Systematic Review and Meta-Analysis.

The objective of the study is to determine the risks and benefits of treating idiopathic short stature (ISS) with aromatase inhibitors (AIs). We comprehensively searched PubMed, Embase, and the China National Knowledge Infrastructure between establishment year and January 31, 2020. Mean difference (MD)/Standardized mean differences (SMD) with 95% confidence intervals (CI) of individual studies were pooled using fixed or random effects models. Subgroup and sensitivity analyses were also performed. Publication bias was estimated using funnel plots and Egger tests. Fourteen studies including 388 participants were included. The meta-analysis results showed that AIs significantly increased final height (MD=2.46, 95% CI: 0.8-4.12) and predicted adult height (MD=0.34, 95% CI: 0.11-0.57). Changes in bone age (MD=-0.1, 95% CI: -0.86-0.66) and bone mineral density (MD=-0.05, 95% CI: -0.19-0.1) were not different between intervention and control group. AI significantly increased testosterone level (SMD=2.01, 95% CI: 0.8-3.23) and reduced estradiol level (SMD=-1.13, 95% CI: -1.87 to -0.40); The intervention and control group had no significant differences in the levels of high-density lipoprotein-cholesterol (SMD=-0.31, 95%CI: -0.68-0.06) and IGF-1 (SMD=0.7, 95% CI: -0.66-2.06) levels. Adverse events were more frequent in the intervention group than in the control group (odds ratio=3.12, 95% CI: 1.44-6.73). In conclusion, both AI monotherapy and AI combination therapy can increase predicted adult height and testosterone levels.

Testicular Growth and Pubertal Onset in GH-Deficient Children Treated With Growth Hormone: A Retrospective Study.

The prevalence of idiopathic oligozoospermia has been esteemed as high as 75%. An Italian survey has reported bilateral testicular hypotrophy in 14% of final-year high school students. The search for determinants of testicular growth in childhood is important for the primary prevention of spermatogenic failure. Therefore, this retrospective study aimed to evaluate the testicular growth and pubertal onset in deficient children treated recombinant human growth hormone (rhGH). To accomplish this, the clinical charts of 93 patients with GH deficiency (GHD) were carefully reviewed. Their mean age at the time of diagnosis was 11.2 ± 2.4 years. rhGH was administered for 44.0 ± 22.4 months, and the onset of puberty was recorded after a mean of 25.8 ± 22.4 months from the first rhGH administration. As expected, serum insulin-like growth factor 1 (IGF1) levels increased significantly after treatment. Before rhGH therapy, the Tanner stage was I in 59 out of 70 boys (84.3%), II in 8/70 (11.4%), III in 3/70 (4.3%). No one was on stage IV or V. The mean Tanner stage was 1.19 ± 0.51. At the last visit, the Tanner stage was I in 8/72 boys (11.1%), II in 6/72 (8.3%), III in 6/72 (8.3%), IV in 16/72 (22.2%), and V in 36/72 (50.0%). After a mean of 44.0 ± 22.4 months of rhGH treatment, the mean Tanner stage was 4.05 ± 1.30. Patients treated with rhGH showed a significant testicular volume (TV) growth over time, whereas no growth was observed in age-matched but not yet treated patients, even when the age was compatible with a spontaneous start of puberty. The multivariate regression analysis showed that the duration of treatment and the mean rhGH dose significantly predicted the percentage of TV increase. In contrast, age, serum FSH, and IGF1 levels, and final rhGH dose did not impact TV growth over time. In conclusion, these findings suggest that GH may play a role in testicular growth and pubertal onset, despite the descriptive nature of this study. Further properly designed studies are needed to confirm these findings. This knowledge may be useful to implement the diagnostic-therapeutic algorithm in case of a lack of testicular growth in childhood.

Circulating miR-30b levels increase during male puberty.

OBJECTIVE: The role of miRNA as endocrine regulators is emerging, and microRNA mir-30b has been reported to repress Mkrn3. However, the expression of miR-30b during male puberty has not been studied. DESIGN AND METHODS: Circulating relative miR-30b expression was assessed in sera of 26 boys with constitutional delay of growth and puberty (CDGP), treated with low-dose testosterone (T) (n =11) or aromatase inhibitor letrozole (Lz) (n =15) for 6 months and followed up to 12 months (NCT01797718). The associations between the relative expression of miR-30b and hormonal markers of puberty were evaluated. RESULTS: During the 12 months of the study, circulating miR-30b expression increased 2.4 ± 2.5 (s.d.) fold (P = 0.008) in all boys, but this change did not correlate with corresponding changes in LH, testosterone, inhibin B, FSH, or testicular volume (P = 0.25-0.96). Lz-induced activation of the hypothalamic-pituitary-gonadal (HPG) axis was associated with more variable miR-30b responses at 3 months (P < 0.05), whereas those treated with T exhibited significant changes in relative miR-30b levels in the course the study (P < 0.01-0.05). CONCLUSIONS: Circulating miR-30b expression in boys with CDGP increases in the course of puberty, and appears to be related to the activity of the HPG axis.

Nutritional status, hemoglobin level and their associations with soil-transmitted helminth infections between Negritos (indigenous) from the inland jungle village and resettlement at town peripheries.

This study compared the current nutritional status, hemoglobin levels and their associations with soil-transmitted helminth (STH) infections between two categories of Negritos (indigenous): (i) Inland Jungle Villages (IJV) (ii) and Resettlement Plan Scheme (RPS) near town peripheries, decades after redevelopment and demarginalization. A total of 416 Negritos (IJV: 149; RPS: 267) was included for nutritional profiling based on anthropometric analysis. However, only 196 (IJV: 64; RPS: 132) individuals consented to blood taking for the hemoglobin (Hb) measurements. Subsequently, the association of undernutrition and anemia with STH infections were determined based on univariate and multivariate logistic regression analyses. The overall prevalence of stunting, wasting, and underweight amongst children and adolescents (n = 343) were 45.8%, 42.3% and 59.1%, respectively. In adults (n = 73), the prevalence of underweight was low (6.8%) but overweight and obese was prominent (26.0%). For anemia (n = 196), an overall prevalence rate of 68.4% were observed with 80% and 70.4% of children aged 2-6 y/o and aged 7-12 y/o, respectively being anemic. Comparatively, the prevalence of underweight (WAZ) was significantly higher in the RPS versus the IJV (P = 0.03) In the IJV, children aged ≤ 6 y/o and having STH poly-parasitism were associated with underweight (P = 0.01) and moderate-severe T. trichiura infection was associated with anemia. Whilst in the RPS, underweight was highly associated with only T. trichiura infection (P = 0.04). Wasting was significantly associated with young children aged ≤10 in both IJV (P = 0.004) and RPS (P = 0.02). Despite efforts in improving provision of facilities and amenities among the indigenous, this study highlighted a high magnitude of nutritional issues among the Negritos especially those in the RPS and their likely association with STH infections and decades of demarginalization. Joint nutritional intervention strategies with mass anti-helminthic treatment are imperative and urgently needed to reduce the undernutrition problems especially among indigenous children.

Association between triglyceride glucose index and peak growth hormone in children with short stature.

Growth hormone (GH) secretion is related to many factors, such as weight and puberty, and the reproducibility of GH provocation tests is very poor. This study aimed to evaluate whether the triglyceride (TyG) index was associated with peak GH in children with short stature. This study included 1095 children with short stature divided into two groups based on peak GH level in GH provocation tests [GH deficiency (GHD) group = 733 children; non-GHD group = 362 children]. We found that the TyG index was significantly higher in the GHD group than in the non-GHD group (P < 0.001). A nonlinear relationship was detected between the TyG index and peak GH, whose point was 7.8. A significant negative association between the TyG index and peak GH was observed when the TyG index was greater than 7.8 (ß - 2.61, 95% CI - 3.98, - 1.24; P < 0.001), whereas, the relationship between the TyG index and peak GH was not significant when the TyG index was lower than 7.8 (ß 0.25, 95% CI - 1.68, 2.17; P = 0.799). There is a nonlinear relationship between the TyG index and peak GH, and a higher TyG index is associated with decreased peak GH in children with short stature.

High-methionine diet in skeletal muscle remodeling: epigenetic mechanism of homocysteine-mediated growth retardation.

Epigenetic DNA methylation (1-carbon metabolism) is crucial for gene imprinting/off-printing that ensures epigenetic memory but also generates a copious amount of homocysteine (Hcy), unequivocally. That is why during pregnancy, expectant mothers are recommended "folic acid" preemptively to avoid birth defects in the young ones because of elevated Hcy levels (i.e., hyperhomocysteinemia (HHcy)). As we know, children born with HHcy have several musculoskeletal abnormalities, including growth retardation. Here, we focus on the gut-dysbiotic microbiome implication(s) that we believe instigates the "1-carbon metabolism" and HHcy causing growth retardation along with skeletal muscle abnormalities. We test our hypothesis whether high-methionine diet (HMD) (an amino acid that is high in red meat), a substrate for Hcy, can cause skeletal muscle and growth retardation, and treatment with probiotics (PB) to mitigate skeletal muscle dysfunction. To test this, we employed cystathionine ß-synthase, CBS deficient mouse (CBS+/-) fed with/without HMD and with/without a probiotic (Lactobacillus rhamnosus) in drinking water for 16 weeks. Matrix metalloproteinase (MMP) activity, a hallmark of remodeling, was measured by zymography. Muscle functions were scored via electric stimulation. Our results suggest that compared to the wild-type, CBS+/- mice exhibited reduced growth phenotype. MMP-2 activity was robust in CBS+/- and HMD effects were successfully attenuated by PB intervention. Electrical stimulation magnitude was decreased in CBS+/- and CBS+/- treated with HMD. Interestingly; PB mitigated skeletal muscle growth retardation and atrophy. Collectively, results imply that individuals with mild/moderate HHcy seem more prone to skeletal muscle injury and its dysfunction.

Novel missense variants in PCK1 gene cause cytosolic PEPCK deficiency with growth failure from inadequate caloric intake.

Cytosolic PEPCK deficiency (PCKDC) is a rare autosomal recessive inborn error of metabolism, which can present with hypoglycemia, lactic acidosis, and liver failure. It is caused by biallelic pathogenic variants in the PCK1 gene. Only four PCK1 variants have been previously reported in seven patients with PCKDC, and their clinical course of this condition has not been well characterized. Here, we report a Hispanic male with novel biallelic PCK1 variants, p.(Gly430Asp) and p.(His496Gln), who had a unique clinical presentation. He presented with a new onset of growth failure, elevated blood lactate, transaminitis, and abnormal urine metabolites profile, but he has not had documented hypoglycemia. Growth restriction happened due to insufficient caloric intake, and it was improved with nutritional intervention. PCKDC is a manageable disorder and therefore appropriate nutritional and clinical suspicion from typical lab abnormalities which lead to molecular confirmation tests are essential to prevent poor clinical outcomes.

Optimal Monitoring of Weekly IGF-I Levels During Growth Hormone Therapy With Once-Weekly Somapacitan.

CONTEXT: Somapacitan is a long-acting growth hormone (GH) in development for once-weekly treatment of GH deficiency (GHD). Optimal monitoring of insulin-like growth factor-I (IGF-I) levels must account for weekly IGF-I fluctuations following somapacitan administration. OBJECTIVE: To develop and assess the reliability of linear models for predicting mean and peak IGF-I levels from samples taken on different days after dosing. DESIGN: A pharmacokinetic/pharmacodynamic model was used to simulate IGF-I data in adults and children following weekly somapacitan treatment of GHD. SETTING AND PATIENTS: 39 200 IGF-I profiles were simulated with reference to data from 26 adults and 23 children with GHD. INTERVENTION(S): The simulated dose range was 0.02 to 0.12 mg/kg for adults and 0.02 to 0.16 mg/kg for children. Simulated data with >4 average standard deviation score were excluded. MAIN OUTCOME MEASURE(S): Linear models for predicting mean and peak IGF-I levels based on IGF-I samples from different days after somapacitan dose. RESULTS: Robust linear relationships were found between IGF-I sampled on any day after somapacitan dose and the weekly mean (R2 > 0.94) and peak (R2 > 0.84). Prediction uncertainties were generally low when predicting mean from samples taken on any day (residual standard deviation [RSD] ≤ 0.36) and peak from samples taken on day 1 to 4 (RSD ≤ 0.34). IGF-I monitoring on day 4 and day 2 after dose provided the most accurate estimate of IGF-I mean (RSD < 0.2) and peak (RSD < 0.1), respectively. CONCLUSIONS: Linear models provided a simple and reliable tool to aid optimal monitoring of IGF-I by predicting mean and peak IGF-I levels based on an IGF-I sample following dosing of somapacitan. A short visual summary of our work is available (1).

Reference Ranges of Serum Insulin-Like Growth Factor-I and Insulin-Like Growth Factor Binding Protein-3: Results from a Multicenter Study in Healthy Korean Adults.

Insulin-like growth factor-I (IGF-I) plays a pivotal role in the diagnosis and treatment of growth hormone (GH) excess or deficiency. The GH study group of the Korean Endocrine Society aims to establish the Korean reference ranges of serum IGF-I and insulin-like growth factor binding protein-3 (IGFBP-3) and assess the relationship between IGF-I and IGFBP-3 and clinical parameters. Fasting serum was collected from healthy Korean adults at health promotion centers of five hospitals nationwide. Serum IGF-I and IGFBP-3 were measured via an immunoradiometric assay using a DSL kit (Diagnostic Systems Laboratories). Serum samples from 354 subjects (180 male, 174 female) were analyzed based on sex at 10-year intervals from 21 to 70 years. IGF-I levels were inversely correlated with age. After adjustment of age, the IGF-I/IGFBP-3 ratio was significantly negatively associated with blood pressure and free thyroxine and positively associated with weight, hemoglobin, creatinine, alanine transferase, fasting glucose, and thyroid stimulating hormone. Therefore, age- and sex-specific reference ranges of serum IGF-I and IGFBP-3 can be efficient in evaluating GH excess or deficiency in Korean population.

Discordance Between Stimulated and Spontaneous Growth Hormone Levels in Short Children Is Dependent on Cut-Off Level and Partly Explained by Refractoriness.

Background: A growth hormone (GH) stimulation test is the recommended method for evaluating GH levels in children with possible GH deficiency (GHD). However, serial measurements of nocturnal spontaneous GH secretion are also performed. Divergent results from these tests have been reported, but with variable frequencies. Objectives: To investigate whether performing one or two GH tests is associated with the probability to diagnose a child with GHD; the frequency of divergent results in the arginine-insulin tolerance test (AITT) and the nocturnal spontaneous test using different cut-off levels, and whether refractoriness may explain some of the discordance. Methods: In a population-based setting, the medical records of all short children evaluated for possible GHD during January 1993-February 2017 were reviewed. Twenty-one patients had been evaluated with one GH test only and 102 children had been evaluated with a spontaneous nocturnal GH test followed immediately by a complete AITT. Divergent results were defined as having a pathological response on only one of the tests when using 3, 5, 7, and 10 µg/L as cut-offs for peak GH on both tests, 1.1 and 3.3 µg/L for mean nocturnal values and receiver operating characteristic curves-derived cut-offs for nocturnal values. Results: Children evaluated with one test only were more often diagnosed with GHD compared with children evaluated with both tests (48 vs. 19%, p = 0.019). Divergent results were found in 6-42% of the patients, with higher frequencies seen when higher cut-offs were applied. A higher proportion of patients with stimulated peak values ≤ 7 and ≤ 5 µg/L had a spontaneous peak within 2 h before the start of the AITT compared with patients with higher stimulated peak values (68 vs. 45%, p = 0.026, and 77 vs. 48%, p = 0.033, respectively). Conclusions: Divergent results between AITT and nocturnal spontaneous secretion are common in short children, dependent on the cut-offs applied and partly due to refractoriness. Performing both tests decreases the risk of over diagnosing GHD in short children.

Plasma Kynurenine to Tryptophan Ratio Is Negatively Associated with Linear Growth of Children Living in a Slum of Bangladesh: Results from a Community-Based Intervention Study.

Chronic exposure to infectious agents results in environmental enteric dysfunction-a significant contributor to childhood stunting. Low plasma tryptophan (TRP), increased kynurenine (KYN), and KYN-TRP (KT) ratio are associated with infections and chronic immune activation. We postulated that both these conditions are interlinked, and therefore aimed to identify the association between KT ratio and the linear growth of Bangladeshi children. A total of 480 stunted and at risk of being stunted children aged 12-18 months were enrolled and provided nutrition intervention for 90 days. Plasma samples were assessed using liquid chromatography tandem mass spectrometry to measure TRP and KYN concentrations. Multivariable linear regression with generalized estimating equations was applied to analyze association between the KT ratio and linear growth. Tryptophan, KYN, and KT ratio were significantly higher in stunted children than in children at risk of being stunted both at baseline and at the end of nutrition intervention. Following intervention, the median (interquartile range [IQR]) KYN concentration was significantly reduced from 4.6 (3.6, 5.4) µmol/L to 3.9 (0.3, 7.6) µmol/L, and median (IQR) KT ratio decreased from 104 (80.9, 131) to 92.8 (6.6, 247) in stunted children. We also found KT ratio to be negatively associated (coefficient = -0.7; 95% CI = -1.13, -0.26; P-value = 0.002) with linear growth. In addition, KYN and KT ratio were positively correlated with fecal neopterin and plasma C-reactive protein, whereas TRP was negatively correlated with both of these biomarkers and alpha-1-acid glycoprotein. Our findings imply that KT ratio is associated in the pathophysiology of stunting as well as with biomarkers of inflammation in Bangladeshi children.

Establishment of Reference Intervals for Serum Insulin-Like Growth Factor I in Korean Adult Population.

Appropriate reference intervals of serum insulin-like growth factor I (IGF-I) is important for diagnosing and monitoring patients with growth hormone-related diseases. To establish reference intervals, adult individuals (n=1,334, 680 men and 654 women) were divided into six age groups (20-29, 30-39, 40-49, 50-59, 60-69, ≥70). Serum IGF-I was measured by chemiluminescence immunoassay (Liaison). Concordance of patient classification based on reference intervals, manufacturer's intervals, and standard deviation score (SDS) was evaluated. New reference intervals had higher upper and lower limits than those specified by the manufacturer. The agreement between classification using new reference interval and the manufacturer's reference interval, and that using new reference interval and SDS was 75.0% (weighted kappa, 0.17), 91.9% (weighted kappa, 0.51) in men and 91.0% (weighted kappa, 0.41), 92.5% (weighted kappa, 0.53) in women, respectively. Reference intervals should be established not only based on age and sex, but also on ethnicity and assay method.

Childhood growth hormone deficiency, a diagnosis in evolution: The intersection of growth hormone history and ethics.

In 1958 the first recorded case of a patient treated with human growth hormone for growth hormone deficiency was published. Since that time, the source and availability of human growth hormone have changed. With the increased availability of growth hormone, there has been an uptrend in the level below which childhood growth hormone deficiency is diagnosed based on provocative GH stimulation testing. This increase is despite better specificity of growth hormone assays in addition to a lack of supportive evidence regarding appropriate normal values. With these trends the diagnosis of childhood growth hormone deficiency is evolving, and clinicians should be aware that this may have potential ethical implications.

A common deletion in the growth hormone receptor gene (d3-GHR) in the offspring is related to maternal placental GH levels during pregnancy.

BACKGROUND: A common growth hormone receptor polymorphism with deletion of exon 3 (d3-GHR) has previously been linked to increased postnatal growth on the one hand and decreased fetal growth on the other. Regulation of fetal growth is positively dependent on secretion of placental GH (hGH-V). OBJECTIVE: We explored the effect of the fetal d3-GHR genotype on maternal serum levels of hGH-V and fetal growth. The cellular localization of hGH-V synthesis and the GH receptors were determined in normal placentas. METHODS: 43 healthy mother-child pairs were examined during pregnancy with measurements of hGH-V during third trimester, and serial ultrasound measurements determined fetal growth rate. Birth anthropometrics were obtained. The GHR genotype of the child was analysed postnatally. Immunohistochemical (IHC) analysis was conducted on four placentas. RESULTS: The presence of the d3-GHR genotype was associated with a markedly reduced concentration of hGH-V in maternal serum (ß -0.52, SE 0.24, p = 0.04) compared to those who had a fl/fl genotype. Accordingly, a tendency towards reduced fetal growth rate during third trimester (ß -25.8, SE 12.7, p = 0.05) and a lower birth weight were found among carriers of the d3-GHR allele, but these associations did not reach statistical significance (p = 0.08). IHC analysis showed expression of placental GH and GHR in the villous syncytiotrophoblast, the extravillous trophoblast, and the decidual cells and smooth muscle cells in chorionic vessels. CONCLUSIONS: The presence of the d3-GHR polymorphism in the fetus was associated with lower maternal serum levels of hGH-V, decreased fetal growth rate in third trimester and lower birth weight compared to the wildtype.

The inter - Test variability of growth hormone stimulation tests and factors affecting this variability.

OBJECTIVE: To evaluate the variability of growth hormone stimulation tests results and factors affecting it in short children suspected of having growth hormone deficiency. DESIGN: The cohort included patients with short stature suspected of having growth hormone deficiency, and who underwent a second stimulation test, after the first stimulation test was positive. Testing was done at a single center from May 2014 to October 2017. Patients' weight, height, age, sex, stimulating agents and test results were recorded. RESULTS: The study population comprised 200 patients, 108 males and 92 females, average age 9.2 years (2.2-16.6 years). The average peak growth hormone was 5.2 µg/L and 7.8 µg/L in the first and second tests respectively and the concordance rate was 56.5%. The probability of a second positive test was increased if the peak growth hormone level in the first test was below 5 µg/L. In the second test, Clonidine and Glucagon led to higher peak growth levels than Arginine with averages of 9.02, 9.97 and 6.88 µg/L respectively. Younger children and children with higher BMI SDS only had lower peaks of growth hormone in the second test. The effect of height SDS on peak growth hormone levels was equivocal. CONCLUSION: The reproducibility rate of GH simulation tests in our study was low. A few factors may affect the peak levels of growth hormone in the second test, the most prominent being the peak of growth hormone in the first test.