Duk Hee Kim

Transdermal dihydrotestosterone therapy and its effects on patients with microphallus

To investigate the efficacy of transdermal dihydrotestosterone therapy on 22 patients with microphallus, we applied dihydrotestosterone gel for 8 weeks to the external genitalia at daily doses of 12.5 mg. and 25 mg. for ages less than and older than 10 years, respectively. All patients were evaluated for penile and prostatic growth, pituitary-gonadal axis function, serum sex hormone binding globulin, lipid metabolism, hepatotoxicity, bone age and height velocity. All patients demonstrated growth of the penis during treatment. The mean increase rate (153%) in the first 4 weeks of treatment was higher than that (118%) of the second 4 weeks. Of importance is that responses were noted in 4 patients who had failed testosterone therapy for microphallus. The pituitary-gonadal axis was transiently suppressed during treatment, and serum sex hormone binding globulin and lipid metabolism were transiently affected during treatment. Serum alkaline phosphatase increased, mainly due to change of bone isoenzyme but bone ages and mean height velocity were not significantly affected. In conclusion, transdermal dihydrotestosterone therapy is an effective and relatively safe modality in the treatment of microphallus.

Characterization and In Vivo Study of Sustained-Release Formulation of Human Growth Hormone Using Sodium Hyaluronate

AbstractPurpose. Aiming at once-a-week injection, a novel sustained release formulation of recombinant human growth hormone (SR-hGH) using sodium hyaluronate was developed for the treatment of children who have growth failure due to the lack of adequate secretion of endogenous growth hormone. Methods. SR-hGH was produced in the form of solid microparticle using a Niro spray dryer and characterized by Malvern particle size analysis, scanning electron microscopy (SEM), size exclusion chromatography (SEC), reverse phase-high-performance chromatography (RP-HPLC), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). After in vitro release test, pharmacokinetic and pharmacodynamic studies were carried out in beagle dogs. SR-hGH was dispersed in medium-chain triglyceride (MCT) and administered at a dose of 1.0 mg hGH/kg subcutaneously. Results. SR-hGH microparticles were successfully produced with a mean particle size of 5.6 ± 1.0 μm. Physicochemical analysis with SEC, RP-HPLC, and SDS-PAGE showed that hGH extracted from SR-hGH was intact and comparable to that of hGH bulk standard indicating no structural change in hGH during the formulation processes. Monomeric content of hGH recovered from SR-hGH was 97.4% by SEC analysis, and its purity was 96% by RP-HPLC analysis. In vitro release test showed the sustained-release characteristics of SR-hGH up to 48 h with the complete release of hGH loaded. The continuous and monotonous release profile observed in in vitro release test was supported by pharmacokinetic study in beagle dogs. Delayed absorption of hGH was observed with Cmax of 69.5 ± 8.0 ng/ml and Tmax between 10 and 12 h. The administration of SR-hGH induced elevation of serum insulin-like growth factor-I (IGF-I) level for 6 days with a maximum value higher than the predose level by ca. 350 ng/ml. After 6 days, IGF-I level returned to the initial baseline level. Conclusions. Sustained-release formulation of hGH for once-a-week injection was successfully developed using high-molecular-weight sodium hyaluronate. No adverse effect was observed during and after the in vivo test using beagle dogs.

Effects of body composition, leptin, and adiponectin on bone mineral density in prepubertal girls.

Body weight is positively associated with bone mineral density but the relationship between obesity and bone mineral density is unclear. Leptin and adiponectin are potential independent contributors to bone mineral density. We assessed the correlations of body composition, leptin and adiponectin with bone mineral density, and whether leptin, adiponectin and body composition determine bone mineral density independently in prepubertal girls. Forty-eight prepubertal girls were classified into obese and control groups by body mass index. Serum leptin and adiponectin levels were determined by enzyme immunoassay. Bone mineral density was measured using dual energy radiography absorptiometry and body composition was measured using bioelectrical impedance analysis. Lean and fat mass, and leptin were positively correlated with bone mineral density. Lean mass was a positive independent predictor of femoral and L-spine bone mineral density. Serum leptin was a postivie independent predictor of femoral bone mineral density. Fat mass was a negative independent predictor of femoral bone mineral density. In prepubertal girls, lean mass has a favorable effect on bone mineral density. Fat mass seems not to protect the bone structure against osteoporosis, despite increased mechanical loading. Serum leptin may play a biological role in regulating bone metabolism.

Reference values for serum levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in Korean children and adolescents.

OBJECTIVE Measurements of serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) are utilized in the diagnostic work-up and clinical management of children with growth disorders. We designed this study to establish the reference values of serum IGF-I and IGFBP-3 levels according to age, sex and pubertal stage in Korean children and adolescents. METHODS For the study, 1378 healthy Korean children and adolescents aged 0 to 17 years (722 boys, 656 girls) were randomly selected. Blood samples were collected, and the stored sera were assayed for IGF-I and IGFBP-3 using immunoradiometric assay (IRMA, Immunotech). The R 2.8.1 program (Bell Laboratories) was used to generate reference percentile curves for IGF-I and IGFBP-3 according to age, sex, and pubertal stage RESULTS Serum IGFBP-3 level was higher in girls compared to that in boys of the same ages throughout the pubertal period, whereas IGF-I was only higher for girls younger than 13 years of age. Serum levels of IGF-I and IGFBP-3 increased steadily with age in the prepubertal stage, followed by a progressive decline thereafter. Peak levels of serum IGF-I and IGFBP-3 were observed two years earlier in girls compared to those in boys (13 vs. 15 years of age, respectively). Serum IGF-I and IGFBP-3 concentrations were highest at Tanner stage IV in boys and girls, with a subsequent decline. CONCLUSIONS Our reference value model based on age, sex, and pubertal stage can improve the diagnostic utility of IGF-1 and IGFBP-3 levels in the evaluation and management of Korean children and adolescents with growth disorders.

Spot Urine Albumin to Creatinine Ratio and Serum Cystatin C are Effective for Detection of Diabetic Nephropathy in Childhood Diabetic Patients

Spot urinary albumin to creatinine ratio (ACR) measurement has been suggested as a surrogate to 24-hr urine collection for the assessment of microalbuminuria, and cystatin C (cysC) is known as an advantageous marker for renal function. The aim of this study was to evaluate the clinical values of spot urinary ACR and serum cysC for the assessment of diabetic nephropathy instead of 24-hr urine microalbumin in children and adolescents with diabetes. A total of 113 children and adolescents (age 12-19 yr, M:F = 47:66) with type 1 or 2 diabetes were enrolled. We evaluated the validity of spot urine ACR and serum cysC, and then compared them to 24-hr urine microalbumin and creatinine clearance. Spot urine ACR was correlated with 24-hr urine albumin excretion (R2 = 0.828, P = 0.001) and creatinine clearance (R2 = 0.249, P = 0.017). The ROC curve analysis of serum cysC demonstrated higher diagnostic accuracy than that of serum creatinine (AUC 0.732 vs 0.615). Both the measurements of spot urine ACR and serum cysC might better predict the presence of diabetic nephropathy than 24-hr urine microalbumin in childhood diabetic patients.

Prevalence of microalbuminuria in young patients with type 1 and type 2 diabetes mellitus

This study was designed to determine the prevalence of microalbuminuria and the associated risk factors in patients with childhood-onset diabetes mellitus (DM). One hundred and sixty-three patients (141 with type 1 DM [DM1] and 22 with type 2 DM [DM21), aged 8 to 28 years, were evaluated for albumin excretion rate and HbA(1c). The mean duration of DM was 8.1 +/- 3.4 and 5.5 +/- 3.9 years in DM1 and DM2, respectively. Persistent microalbuminuria and macroalbuminuria were observed in 11.3% and 2.8% of patients with DM1, and 18.2% and 4.5% in patients with DM2, respectively. In DM1, the duration of DM, age of onset, and HbA(1c) levels were significant predictors of microalbuminuria. Our observations suggest that screening for microalbuminuria should be started from early adolescence in patients with DM1 and DM2.

Insulin-Like Growth Factor-Binding Protein-3 Mediates High Glucose-Induced Apoptosis by Increasing Oxidative Stress in Proximal Tubular Epithelial Cells

IGF-binding protein-3 (IGFBP-3) is the major circulating carrier protein for IGF, and also acts as a potent antiproliferative agent in various cell types. Recently, IGFBP-3 was reported to mediate high glucose-induced apoptosis in mesangial cells and podocytes. In this study, we investigated the role of IGFBP-3 in high glucose-induced apoptosis in proximal tubular epithelial cells (PTEC). Expression of IGFBP-3 protein and mRNA in a porcine PTEC line (LLC-PK1 cells) was measured after exposure to either standard (5.5 mM) or high-glucose (30 mM) medium. We quantified apoptosis after treatment with small interfering RNA against IGFBP-3 (siRNA:IGFBP-3) in high-glucose medium or in cells that overexpressed IGFBP-3. Oxidative stress was measured in high-glucose medium, in the presence of siRNA:IGFBP-3, or in IGFBP-3-overexpressing cells. IGFBP-3 protein and mRNA expression in LLC-PK1 cells was higher in high-glucose medium than in standard-glucose medium. Exposure to high-glucose medium increased apoptosis, and high-glucose-induced apoptosis was abolished by siRNA:IGFBP-3. IGFBP-3 overexpression induced apoptosis in LLC-PK1 cells. Both high-glucose medium and IGFBP-3 overexpression increased reactive oxygen species, and siRNA:IGFBP-3 reduced this increase. Antioxidant treatment decreased IGFBP-3 expression and apoptosis, whereas oxidative stress from hydrogen peroxide increased IGFBP-3 expression, suggesting that oxidative stress increases IGFBP-3 expression. Our results suggest that increased IGFBP-3 expression by high glucose mediates high-glucose-induced apoptosis in PTEC. Increased oxidative stress from high glucose enhances IGFBP-3 expression, inducing apoptosis. Increased expression of IGFBP-3 by high glucose induces additional oxidative stress, which may result in amplification of hyperglycemic damage.

Relationship between serum 25-hydroxyvitamin D concentration and risks of metabolic syndrome in children and adolescents from Korean National Health and Nutrition Examination survey 2008-2010

Purpose Previous studies have revealed many inconsistent results regarding the relationship between vitamin D and metabolic syndrome. The purpose of our study was to investigate the association between serum 25-hydroxyvitamin D (25(OH)D) concentration and factors that characterize metabolic syndrome in Korean children and adolescents. Methods We analyzed data from 2,880 children and adolescents aged 10-18 years collected from the 2008-2010 Korean National Health and Nutrition Examination Survey. We investigated the data according to quartiles of 25(OH)D concentrations. Results Systolic blood pressure and diastolic blood pressure with adjustment for sex and age differed significantly between the serum 25(OH)D groups and exhibited negative trend as 25(OH)D concentrations increased. The number of subjects with metabolic syndrome was greater in the low 25(OH)D groups (I, II, and III quartile) than in the high 25(OH)D group (IV quartile) (P=0.029). BMI and waist circumference were lower in the high 25(OH)D group. Serum 25(OH)D concentration correlated negatively with homeostasis model assessment estimate of insulin resistance (ρ=-0.073, P<0.001) and correlated positively with quantitative insulin sensitivity check index (ρ=0.095, P<0.001). Conclusion Low serum 25(OH)D level is associated with an increase of insulin resistance and metabolic syndrome in children and adolescents.

Longitudinal Standards for Height and Height Velocity in Korean Children and Adolescents: the Kangwha Cohort Study

Longitudinal standards for height and height velocity are essential to monitor for appropriate linear growth. We aimed to construct standards in Korean children and adolescents through the population-based longitudinal Kangwha study. Our study was a part of a community-based prospective cohort study from 1986 to 1999 with 800 school children. Height and height velocity were recorded annually from age 6 until final height. Results were compared with cross-sectional data from the 2007 Korean National Growth Charts. Final height was 173.5 cm in boys and 160.5 cm in girls. Although final height was similar between longitudinal and cross-sectional standards, the mean height for age was higher in the longitudinal standard by 1-4 cm from age 6 until the completion of puberty. Using the longitudinal standard, age at peak height velocity (PHV) was 12 in boys and 10 in girls; height velocity at PHV was 8.62 cm/yr in boys and 7.07 cm/yr in girls. The mean height velocity was less than 1 cm/yr at age 17 in boys and 15 in girls. Thus, we have presented the first report of longitudinal standards for height and height velocity in Korean children and adolescents by analyzing longitudinal data from the Kangwha cohort.

Clinical manifestations of testicular adrenal rest tumor in males with congenital adrenal hyperplasia.

Purpose In male patients with congenital adrenal hyperplasia (CAH), the presence of testicular adrenal rest tumors (TARTs) have been reported, however their prevalence and clinical manifestations are not well known. Untreated TARTs may lead to testicular structural damage and infertility. This study was conducted to investigate the prevalence of TARTs in male patients with CAH, and characterize the manifestations to identify contributing factors to TART. Methods Among 102 CAH patients aged 0-30 years, 24 male patients have been regularly followed up in our outpatient clinic at Severance Childrens Hospital from January 2000 to December 2014. In order to reveiw the characteristics of TART patients, we calculated the mean levels of hormones during the 5 years before the time of investigation. Five patients underwent follow-up scrotal ultrasonography (US) after adjusting the dosage of glucocorticoids. Results TARTs were detected in 8 of the 13 patients (61.5%). The median age of TARTs diagnosis was 20.2 years with the youngest case being 15.5 years old. The mean serum level of adrenocorticotropic hormone (ACTH) was higher in the TARTs patient group compared to the non-TARTs group (P<0.05). The tumor size decreased in 3 cases, slightly increased in 1 case, and had no change in another case. Conclusion The serum ACTH level might be associated with the growth promoting factor for TARTs, but the exact mechanism has not been clearly identified. Screening for TARTs using US is important in male patients with CAH for early-detection and prevention of ongoing complications, such as infertility.