http://repub.eur.nl/res/aut/2411/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/14103/ 2007-01-01T00:00:00Z CONTEXT: Low birth weight might increase risk of diabetes mellitus type 2 and metabolic syndrome (MS). GH has insulin-antagonistic properties. Therefore, long-term follow-up of GH-treated children born small for gestational age (SGA) is important. OBJECTIVE AND PATIENTS: The objective of the study was to evaluate insulin sensitivity (Si) and disposition index (DI), all components of the MS and IGF-I and IGF binding protein (IGFBP)-3 levels in 37 previously GH-treated young SGA adults in comparison with 25 untreated short SGA controls. RESULTS: GH-treated subjects were 22.3 (1.7) yr old. Mean duration of GH treatment had been 7.3 (1.3) yr. Mean period after discontinuation was 6.5 (1.4) yr. Si and DI were comparable for GH-treated and untreated SGA subjects. Fasting glucose and insulin levels increased during GH treatment but recovered after discontinuation. Body mass index, waist circumference, high-density lipoprotein cholesterol levels, and triglycerides were equivalent. Systolic and diastolic blood pressure and cholesterol were significantly lower in GH-treated subjects. Thirty-two percent of untreated controls vs. none of the GH-treated subjects had an increased blood pressure. GH-induced rises in IGF-I and IGFBP-3 levels had completely recovered after GH stop. CONCLUSION: At 6.5 yr after discontinuation of long-term GH treatment, Si, DI, fasting levels of glucose and insulin, body mass index, waist circumference, and IGF-I and IGFBP-3 levels were equivalent for GH-treated and untreated young SGA adults. Systolic and diastolic blood pressure and serum cholesterol were even lower in GH-treated subjects. These data are reassuring because they suggest that long-term GH treatment does not increase the risk for diabetes mellitus type 2 and MS in young adults. http://repub.eur.nl/res/pub/7552/ 2006-03-08T00:00:00Z The most common clinical characteristic of Turner syndrome (TS) is short stature. Although girls with TS are not growth hormone (GH) deficient, studies show that long-term GH treatment in TS leads to normalisation of height during childhood. In this chapter the results and conclusions are summarised of the multi-centre randomised dose-response growth hormone (GH) trial evaluating the efficacy, safety and psychosocial effect of long-term GH treatment on girls with TS. The TS trial was an open trial consisting of 68 untreated girls, aged between 2 and 11 years, with TS. The girls were randomly assigned to a group using 4 IU GH/m2/day, to a group using 4 IU GH/m2/day in the first year, and 6 IU GH/m2/day in the years thereafter, or to a group using 4 IU GH/m2/day in the first, 6 IU GH/m2/day in the second, and 8 IU GH/m2/day in the years thereafter (~ 0.045, 0.067, or 0.090 mg/kg/day). After at least 4 years of GH treatment, at a minimum age of 12 years, a low dose of micronised oestradiol was given to induce puberty. http://repub.eur.nl/res/pub/13549/ 2004-11-01T00:00:00Z Short stature is not the only problem faced by small for gestational age (SGA) children. Being born SGA has also been associated with lowered intelligence, poor academic performance, low social competence, and behavioral problems. Although GH treatment in short children born SGA can result in a normalization of height during childhood, the effect of GH treatment on intelligence and psychosocial functioning remains to be investigated. We show the longitudinal results of a randomized, double-blind, GH-dose response study initiated in 1991 to follow growth, intelligence quotient (IQ), and psychosocial functioning in SGA children during long-term GH treatment. Patients were assigned to one of two treatment groups (1 or 2 mg GH/m(2) body surface.d, or approximately 0.035 or 0.07 mg/kg.d). Intelligence and psychosocial functioning were evaluated at start of GH treatment (n = 74), after 2 yr of GH treatment (n = 76), and in 2001 (n = 53). IQ was assessed by a short-form Wechsler Intelligence Scale for Children-Revised or Wechsler Adult Intelligence Scale (Block-design and Vocabulary subtests). Behavioral problems were measured by the Achenbach Child Behavior Checklist or Young Adult Behavior Checklist, and self-perception was measured by the Harter Self-Perception Profile. Mean (sem) birth length sd score was -3.6 (0.2), mean age and height at start was 7.4 (0.2) yr and -3.0 (0.1) sd score, respectively, mean duration of GH treatment was 8.0 (0.2) yr, and mean age in 2001 was 16.5 (0.3) yr. After 2 yr of GH treatment, 96% of both GH groups showed a height gain sd score of 1 sd from the start of treatment or more, resulting in a normal height (i.e. height >/= -2.0 sd for age and sex) in 70% of the children. In 2001, 48 (91%) of the 53 children participating in this study had reached a normal height. Block-design s-score and the estimated total IQ significantly increased (P < 0.001 and P < 0.001, respectively) from scores significantly lower than Dutch peers at start (P < 0.001 and P < 0.001, respectively) to comparable scores in 2001. The increase over time for the Vocabulary s-score was not significant. Internalizing Behavior sd scores remained comparable to Dutch peers, whereas Externalizing Behavior sd scores and Total Problem Behavior sd scores improved significantly during GH therapy (P < 0.01 and P < 0.05, respectively) to scores comparable to Dutch peers. Self-perception sd scores improved from start of GH treatment until 2001 (P < 0.001) to scores significantly higher than Dutch peers (P < 0.05). No significant differences between the two GH dosage groups were found. Improvement in Externalizing and Total Problem Behavior sd scores over time was significantly related to change in height sd score (P < 0.05 and P < 0.01, respectively), whereas scores over time for Vocabulary, Block-design, Internalizing, or total Harter Self-Perception score were not related to change in height sd scores.In conclusion, parallel to a GH-induced catch-up growth in adolescents born SGA, IQ, behavior, and self-perception showed a significant improvement over time from scores below average to scores comparable to Dutch peers. In addition, children whose height over time became closer to that of their peers showed less problem behavior. http://repub.eur.nl/res/pub/10108/ 2003-01-01T00:00:00Z Although GH treatment for short stature in Turner syndrome is an accepted treatment in many countries, which GH dosage to use and which age to start puberty induction are issues of debate. This study shows final height (FH) in 60 girls with Turner syndrome treated in a randomized dose-response trial, combining GH treatment with low dose estrogens at a relatively young age. Girls were randomly assigned to group A (4 IU/m(2).d; approximately 0.045 mg/kg/d), group B (first year, 4 IU/m(2).d; thereafter 6 IU/m(2).d), or group C (first year, 4 IU/m(2).d; second year, 6 IU/m(2).d; thereafter, 8 IU/m(2).d). After a minimum of 4 yr of GH treatment, at a mean age of 12.7 +/- 0.7 yr, low dose micronized 17beta-estradiol was given orally. After a mean duration of GH treatment of 8.6 +/- 1.9 yr, FH was reached at a mean age of 15.8 +/- 0.9 yr. FH, expressed in centimeters or SD score, was 157.6 +/- 6.5 or -1.6 +/- 1.0 in group A, 162.9 +/- 6.1 or -0.7 +/- 1.0 in group B, and 163.6 +/- 6.0 or -0.6 +/- 1.0 in group C. The difference in FH in centimeters, corrected for height SD score and age at start of treatment, was significant between groups A and B [regression coefficient, 4.1; 95% confidence interval (CI), 1.4, 6.9; P < 0.01], and groups A and C (coefficient, 5.0; 95% CI, 2.3, 7.7; P < 0.001), but not between groups B and C (coefficient, 0.9; 95% CI, -1.8, 3.6). Fifty of the 60 girls (83%) had reached a normal FH (FH SD score, more than -2). After starting estrogen treatment, the decrease in height velocity (HV) changed significantly to a stable HV, without affecting bone maturation (change in bone age/change in chronological age). The following variables contributed significantly to predicting FH SD score: GH dose, height SD score (ref. normal girls), chronological age at start of treatment, and HV in the first year of GH treatment. GH treatment was well tolerated. In conclusion, GH treatment leads to a normalization of FH in most girls, even when puberty is induced at a normal pubertal age. The optimal GH dosage depends on height and age at the start of treatment and first year HV. http://repub.eur.nl/res/pub/10028/ 2002-01-01T00:00:00Z GH treatment increases insulin levels in girls with Turner syndrome (TS), who are already predisposed to develop diabetes mellitus and other risk factors for developing cardiovascular disease. Therefore, in the present study, we investigated carbohydrate metabolism and several other risk factors that may predict development of cardiovascular disease in girls with TS after discontinuation of long-term GH treatment. Fifty-six girls, participating in a randomized dose-response study, were examined before, during, and 6 months after discontinuing long-term GH treatment with doses of 4 IU/m(2).d ( approximately 0.045 mg/kg.d), 6 IU/m(2).d, or 8 IU/m(2).d. After a minimum of 4 yr of GH treatment, low-dose micronized 17beta-estradiol was given orally. Mean (SD) age at 6 months after discontinuation of GH treatment was 15.8 (0.9) yr. Mean duration of GH treatment was 8.8 (1.7) yr. Six months after discontinuation of GH treatment, fasting glucose levels decreased and returned to pretreatment levels. The area under the curve for glucose decreased to levels even lower than pretreatment level (P < 0.001). Fasting insulin levels and the area under the curve for insulin decreased to levels just above pretreatment level (P < 0.001 for both), although being not significantly different from the control group. No dose-dependent differences among GH dosage groups were found. At 6 months after discontinuation, impaired glucose tolerance was present in 1 of 53 girls (2%), and none of the girls developed diabetes mellitus type 1 or 2. Compared with pretreatment, the body mass index SD-score had increased (P < 0.001), and the systolic and diastolic blood pressure SD-score had decreased significantly at 6 months after discontinuation of GH treatment (P < 0.001 for both) although remaining above zero (P < 0.001, P < 0.05, and P < 0.005, respectively). Compared with pretreatment, total cholesterol (TC) did not change after discontinuation of GH treatment, whereas the atherogenic index [AI = TC/high-density lipoprotein cholesterol (TC/HDL-c)] and low-density lipoprotein cholesterol (LDL-c) had decreased; and both HDL-c and triglyceride levels increased (P < 0.001 for AI, LDL-c, and HDL-c; P < 0.05 for triglyceride). Compared with the control group, AI, serum TC, and LDL-c levels were significantly lower (P < 0.001 for all), whereas HDL-c levels were significantly higher (P < 0.05). In conclusion, after discontinuation of long-term GH treatment in girls with TS, the GH-induced insulin resistance disappeared, blood pressure decreased but remained higher than in the normal population, and lipid levels and the AI changed to more cardio-protective values.