Annemieke J. Lem

Adult Height in Short Children Born SGA Treated with Growth Hormone and Gonadotropin Releasing Hormone Analog: Results of a Randomized, Dose-Response GH Trial

CONTEXT GH treatment is effective in improving height in short children born small for gestational age (SGA). GH is thought to have limited effect when started during adolescence. OBJECTIVE The aim of this study was to investigate GH treatment efficacy in short SGA children when treatment was started during adolescence; to assess whether GH 2 mg/m(2) · d during puberty improves adult height (AH) compared with 1 mg/m(2) · d; and to assess whether an additional 2-yr postponement of puberty by GnRH analog (GnRHa) improves AH in children who are short at the start of puberty (<140 cm), with a poor AH expectation. PATIENTS AND DESIGN In this longitudinal, randomized, dose-response GH trial, we included 121 short SGA children (60 boys) at least 8 yr of age. We performed intention-to-treat analyses on all children and uncensored case analyses on 84 children who reached AH. Besides, we evaluated growth during 2 yr of combined GH/GnRHa and subsequent GH treatment until AH in a subgroup of 40 pubertal children with a height of less than 140 cm at the start. RESULTS Short SGA children started treatment at a median age of 11.2 yr, when 46% had already started puberty. Median height increased from -2.9 at start to -1.7 sd score (SDS) at AH (P < 0.001). Treatment with GH 2 vs. 1 mg/m(2) · d during puberty resulted in significantly better AH (P = 0.001), also after correction for gender, age at start, height SDS at start, treatment years before puberty, and target height SDS. AH was similar in children who started puberty at less than 140 cm and received GH/GnRHa, compared with children who started puberty greater than 140 cm and received GH only (P = 0.795). CONCLUSION When started in adolescence, GH treatment significantly improves AH in short SGA children, particularly with GH 2 mg/m(2) · d during puberty. When SGA children are short at the start of puberty, they can benefit from combined GH/GnRHa treatment.

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 T(4) (FT(4)), TSH, total T(4), T(3), rT(3), and T(4)-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 FT(4) and T(4) levels as the reference population but significantly higher T(3), rT(3), and T(4)-binding globulin levels. During puberty and during GH treatment, FT(4) and rT(3) significantly decreased, whereas T(3) 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 T(3) at the expense of less inactive rT(3), possibly mediated by IGF-I. GH treatment induces altered peripheral thyroid metabolism but does not result in thyroid dysfunction.

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 (BMD(TB)), lumbar spine (BMD(LS)), 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/m(2) · 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 BMD(TB) sd score (SDS) and BMD(LS) SDS were significantly reduced (both P < 0.001), but BMAD(LS) SDS was comparable with zero (P = 0.129). BMD(TB) SDS and BMD(LS) SDS improved (both P < 0.001) from the start until AH, whereas BMAD(LS) SDS remained similar (P = 0.168). At AH, 93% of patients had a normal BMD(TB), 99% a normal BMD(LS), and 98% a normal BMAD(LS) (> -2 and < +2 SDS). From the start until AH, lean body mass SDS(height) 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 BMD(TB) and BMD(LS) but normal bone size-corrected BMAD(LS). During GH treatment, BMD(TB) and BMD(LS) 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.

Health-Related Quality of Life in Short Children Born Small for Gestational Age: Effects of Growth Hormone Treatment and Postponement of Puberty

Aims: To investigate health-related quality of life (HRQoL) in short children born small for gestational age (SGA) during growth hormone (GH) treatment and additional postponement of puberty by gonadotropin-releasing hormone analogue (GnRHa). Methods: HRQoL was studied longitudinally during 2 years of treatment in 97 short SGA children (mean age 11.6 years at start). The children were divided into three groups: prepubertal GH-treated (prep-GH) children, pubertal GH-treated (pub-GH) children, and pubertal GH-treated children with additional GnRHa treatment (pub-GH/GnRHa). HRQoL was measured by generic (TACQOL) and short stature-specific (TACQOL-S) questionnaires. Results: The TACQOL-S showed that prep-GH children experienced significant HRQoL improvement on the subscales ‘contact with adults’, ‘body image’ and ‘vitality’, and pub-GH/GnRHa children on the subscales ‘contact with adults’, ‘contact with peers’ and ‘physical abilities’. Parents of prep-GH and pub-GH/GnRHa children reported significant HRQoL improvement on most TACQOL-S scales, whereas HRQoL improvement in pub-GH children reached significance for ‘future prospects’ only. The HRQoL gain was similar in the three groups, also after correction for confounders. The generic questionnaire TACQOL did not reveal any changes. Conclusions: HRQoL improved in prepubertal and pubertal short SGA children during GH treatment. Additional GnRHa treatment had no adverse effect on the HRQoL gain. Disorder-specific questionnaires were particularly appropriate to evaluate HRQoL in children treated for short stature.

Metabolic Health in Short Children Born Small for Gestational Age Treated With Growth Hormone and Gonadotropin-Releasing Hormone Analog : Results of a Randomized, Dose-Response Trial

CONTEXT Previously we showed that pubertal children born small for gestational age (SGA) with a poor adult height (AH) expectation can benefit from treatment with GH 1 mg/m(2) per day (∼ 0.033 mg/kg/d) in combination with 2 years of GnRH analog (GnRHa) and even more so with a double GH dose. GnRHa treatment is thought to have negative effects on body composition and blood pressure. Long-term effects and GH-dose effects on metabolic health in children treated with combined GH/GnRHa are unknown. OBJECTIVE This study aimed to investigate body composition, blood pressure, and lipid profile during GH treatment, either with or without 2 years of additional GnRHa. To assess whether GH 2 mg/m(2) per day (∼ 0.067 mg/kg/d) results in a similar or even more favorable metabolic health at AH than GH 1 mg/m(2) per day. METHODS This was a longitudinal, randomized, dose-response GH trial involving 107 short SGA children (58 girls) treated with GH until AH (GH randomized 1 or 2 mg/m(2)/d during puberty). Sixty-four children received additional GnRHa. At AH, metabolic parameters were compared between children treated with combined GH/GnRHa and those with only GH. The GH dose effect on metabolic health was evaluated in a subgroup of 47 children who started GH treatment in early puberty (randomized 1 or 2 mg/m(2)/d) with 2 years of GnRHa. RESULTS At AH, fat mass percentage (FM%) SD score (SDS), lean body mass (LBM) SDS, blood pressure SDS, and lipid profile were similar between children treated with combined GH/GnRHa and those with only GH. In the pubertal subgroup, FM% SDS was lower during treatment with GH 2 mg/m(2) per day. There was no GH dose-dependent effect on LBM SDS, blood pressure, and lipid profile. CONCLUSIONS Combined GH/GnRHa treatment has no long-term negative effects on metabolic health compared with only GH. Started in early puberty, a GH dose of 2 mg/m(2) per day results in a similar metabolic health at AH and a more favorable FM% than GH 1 mg/m(2) per day.

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

CONTEXT 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. OBJECTIVE This study aimed to investigate the effects on puberty and pubertal growth of 2 years GnRHa vs no GnRHa in GH-treated SGA children. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Acid-Labile Subunit Levels and the Association with Response to Growth Hormone Treatment in Short Children Born Small for Gestational Age

Aims: To determine acid-labile subunit (ALS) levels in short small for gestational age (SGA) children and to assess the relationship between ALS levels and several clinical and laboratory characteristics. Also, to assess whether adding ALS levels to a growth prediction model might improve the long-term growth prediction. Design/Methods: ALS levels were measured in 312 short SGA children at the start of growth hormone (GH) treatment. Results: Median (interquartile range) ALS of all subjects was -0.5 SDS, significantly below the 0 SDS (p < 0.001). In 34 children (11%), ALS levels were ≤-2 SDS. ALS SDS correlated significantly with height SDS (r = 0.24, p < 0.001), weight SDS (r = 0.30, p < 0.001), BMI SDS (r = 0.20, p = 0.001), IGF-I SDS (r = 0.56, p < 0.001) and IGFBP-3 SDS (r = 0.67, p < 0.001). ALS SDS was also positively correlated with fasting insulin (r = 0.41, p < 0.001) and glucose levels (r = 0.33, p < 0.001), and HOMA-IR (r = 0.35, p < 0.001). Baseline ALS levels contributed to the long-term growth prediction of GH treatment (5%, p < 0.001). Conclusion: Short SGA children tend to have lower ALS levels compared to controls, albeit less reduced than IGF-I and IGFBP-3 levels. Our data suggest that ALS may be involved in glucose homeostasis. Determination of ALS levels before the start of GH treatment in short SGA children contributes moderately to a more accurate prediction of the growth response to GH treatment.

Insulin Sensitivity and β-Cell Function in SGA Children Treated With GH and GnRHa: Results of a Long-Term Trial

CONTEXT Pubertal children born small for gestational age with a poor adult height (AH) expectation can benefit from treatment with GH 1 mg/m(2)/d (∼0.033 mg/kg/d) in combination with 2 years of GnRH analog (GnRHa) and even more so with GH 2 mg/m(2)/d. Because both GH and GnRHa can negatively influence insulin sensitivity, combining these treatments has raised concerns. The long-term GH dose effects on insulin sensitivity in children treated with combined GH/GnRHa are unknown. OBJECTIVE The purpose of this study was to investigate insulin sensitivity and β-cell function by a very precise method during long-term GH treatment, either with or without 2 years of additional GnRHa and to study differences in insulin sensitivity during treatment until AH between GH at 1 or 2 mg/m(2)/d. METHODS This was a randomized, dose-response GH trial involving 110 short small for gestational age children (59 girls) treated with GH until AH (GH randomized to 1 or 2 mg/m(2)/d). Sixty-seven children received additional GnRHa treatment. Frequently sampled intravenous glucose tolerance tests were performed and insulin sensitivity (Si), acute insulin response (AIR), and disposition index (DI) were calculated using Bergmans MINMOD. The GH dose effect was evaluated in a subgroup of 48 children who started GH treatment in early puberty (randomized to 1 or 2 mg/m(2)/d) combined with 2 years of GnRHa. RESULTS At AH, after 5.9 years of GH treatment, Si, AIR, and DI were similar between children treated with combined GH/GnRHa and those treated with GH only. In the subgroup of children who started GH treatment in early puberty (randomized to 1 or 2 mg/m(2)/d) together with 2 years of GnRHa treatment, there were no significant differences in Si, AIR, or DI between the GH dose groups during the treatment. CONCLUSIONS Combined GH/GnRHa treatment has no long-term negative effects on insulin sensitivity and β-cell function compared with GH only. Started in early puberty, a GH dose of 2 mg/m(2)/d results in a similar insulin sensitivity at AH as a GH dose of 1 mg/m(2)/d.

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.

Should short children born small for gestational age with a distance to target height <1 standard deviation score be excluded from growth hormone treatment?

Context  The criteria for starting growth hormone (GH), an approved treatment for short children born small for gestational age (SGA), differ between Europe and the USA. One European requirement for starting GH, a distance to target height (DTH) of ≥1 standard deviation score (SDS), is controversial.