Short Adolescents Born Small for Gestational Age : Gonadal and thyroid function, bone mineral density, quality of life and adult height: The effects of growth hormone and additional postponement of puberty

From 1991, our research group and others have been investigating children with short stature who were born small for gestational age (SGA), both before and during treatment with biosynthetic growth hormone (GH). In 2005, GH treatment was licensed for short SGA children in the Netherlands. Many questions though remained unanswered, especially about the efficacy of GH treatment when started at an older age, just before or during puberty. This doctoral thesis describes studies evaluating short adolescents born SGA who were treated with GH, and additionally with postponement of puberty by gonadotropin-releasing hormone analogue (GnRHa)

Methylphenidate and the Response to Growth Hormone Treatment in Short Children Born Small for Gestational Age

Background: Growth hormone (GH) treatment has become a frequently applied growth promoting therapy in short children born small for gestational age (SGA). Children born SGA have a higher risk of developing attention deficit hyperactivity disorder (ADHD). Treatment of ADHD with methylphenidate (MP) has greatly increased in recent years, therefore more children are being treated with GH and MP simultaneously. Some studies have found an association between MP treatment and growth deceleration, but data are contradictory. Objective: To explore the effects of MP treatment on growth in GH-treated short SGA children Methods: Anthropometric measurements were performed in 78 GH-treated short SGA children (mean age 10.6 yr), 39 of whom were also treated with MP (SGA-GH/MP). The SGA-GH/MP group was compared to 39 SGA-GH treated subjects. They were matched for sex, age and height at start of GH, height SDS at start of MP treatment and target height SDS. Serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) levels were yearly determined. Growth, serum IGF-I and IGFBP-3 levels during the first three years of treatment were analyzed using repeated measures regression analysis. Results: The SGA-GH/MP group had a lower height gain during the first 3 years than the SGA-GH subjects, only significant between 6 and 12 months of MP treatment. After 3 years of MP treatment, the height gain was 0.2 SDS (±0.1 SD) lower in the SGA-GH/MP group (P = 0.17). Adult height was not significantly different between the SGA-GH/MP and SGA-GH group (-1.9 SDS and -1.9 SDS respectively, P = 0.46). Moreover, during the first 3 years of MP treatment IGF-I and IGFBP-3 measurements were similar in both groups. Conclusion: MP has some negative effect on growth during the first years in short SGA children treated with GH, but adult height is not affected

Bone mineral density and body composition in short children born SGA during growth hormone and gonadotropin releasing hormone analog treatment

Context: Postponement of puberty by GnRH analog (GnRHa) in addition to GH treatment might increase adult height (AH) in short adolescents born small for gestational age (SGA). GnRHa treatment is thought to have negative effects on bone mineral density (BMD) and body composition. Objective: The objective of the study was to assess the BMD of total body (BMDTB), lumbar spine (BMDLS), bone mineral apparent density lumbar spine (BMAD LS), lean body mass, fat mass, and fat distribution during GH treatment, with or without an additional 2 yr of GnRHa. Patients and Design: This was a prospective GH trial involving short SGA adolescents (≥8 yr). Eighty-eight children (50 girls) were treated until AH (GH randomized 1 or 2 mg/m2·d during puberty); 52 of these children received additional GnRHa. BMD and body composition were longitudinally assessed by dual-energy X-ray absorptiometry. Results: Baseline BMDTB SD score (SDS) and BMDLS SDS were significantly reduced (both P-2 and <+2 SDS). From the start until AH, lean body mass SDSheight and fat mass SDS increased significantly toward zero (both P < 0.001). Multiple regression analyses showed that additional GnRHa treatment had no adverse effect on the changes in BMD and body composition during GH treatment, also after correction for influencing variables. Conclusion: Untreated short SGA adolescents had reduced BMDTB and BMDLS but normal bone size-corrected BMADLS. During GH treatment, BMDTB and BMDLS increased significantly, leading to a normal adult BMD in almost all patients. Two years of GnRHa in addition to GH treatment had no adverse effect on BMD or body composition. Copyrigh

Serum thyroid hormone levels in healthy children from birth to adulthood and in short children born small for gestational age

Context: Age-appropriate reference ranges for thyroid hormones are required for detecting pediatric thyroid dysfunction. Data on thyroid hormones and peripheral thyroid metabolism in short children born small for gestational age (SGA) before and during GH treatment are lacking. Objectives: Our objectives were to obtain pediatric thyroid hormone reference ranges; to investigate thyroid hormones in short SGA children before puberty, during puberty, and during postponement of puberty by GnRH analog; and to evaluate thyroid hormones during GH treatment. Patients and Design: In 512 healthy children (225 females; 0-18 yr), free T4 (FT4), TSH, total T4, T3, rT3, and T4-binding globulin were determined. Reference ranges were calculated using the linearity, median, and skewness method. In 125 short SGA children (62 females; mean age 11.3 yr), thyroid hormones were analyzed before and after 2 yr of GH treatment and additional GnRH analog. Results: Thyroid references showed wide ranges postnatally and age-specific patterns thereafter, similar in boys and girls. Untreated short SGA children had similar FT4 and T4 levels as the reference population but significantly higher T3, rT3, and T4-binding globulin levels. During puberty and during GH treatment, FT4 and rT3 significantly decreased, whereas T3 significantly increased. Conclusion: Age-specific thyroid reference ranges are presented. Puberty and GH treatment both induce changes in peripheral thyroid metabolism, resulting in more biologically active T3 at the expense of less inactive rT3, possibly mediated by IGF-I. GH treatment induces altered peripheral thyroid metabolism but does not result in thyroid dysfunction. Copyrigh