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  • 1. Albertsson Wikland, K
    et al.
    Alm, F
    Aronsson, S
    Gustafsson, J
    Hagenäs, L
    Häger, A
    Ivarsson, S
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Marcus, C
    Moëll, C
    Nilsson, K O
    Ritzén, M
    Tuvemo, T
    Westgren, U
    Westphal, O
    Aman, J
    Effect of growth hormone (GH) during puberty in GH-deficient children: preliminary results from an ongoing randomized trial with different dose regimens.1999In: Acta Paediatrica. Supplement, ISSN 0803-5326, Vol. 88, no 428, p. 80-4Article in journal (Refereed)
    Abstract [en]

    This paper reports results from an ongoing, randomized, multicentre national trial. The aim is to elucidate whether a dose of growth hormone (GH) of 0.2 IU/kg (0.07 mg/kg), given either as once-daily or twice-daily injections during puberty, is more effective than a once-daily dose of 0.1 IU/kg/day (0.03 mg/kg/day) in improving final height in children with GH deficiency (GHD). The twice-daily regimen comes closer to the spontaneous GH secretion pattern in puberty. Ninety-two children with GHD who had been receiving GH therapy for at least 1 year, and with spontaneous puberty or who were prepubertal and due to be started on replacement therapy to induce puberty, were randomly assigned to receive GH as follows: group A, 0.1 IU/kg/day (0.03 mg/kg/day), administered once daily; group B, 0.2 IU/kg/day (0.07 mg/kg/day), administered once daily; and group C, 0.2 IU/kg/day (0.07 mg/kg/day), divided into two equal injections given at 12-hour intervals. Pubertal height gain was 0.7, 0.7 and 1.3 SDS for groups A, B and C, respectively. The gain in height during puberty was thus most marked in group C. Mean final height, when corrected for parental height, was between 0 and 1 SDS in all treatment groups. All but seven children reached a final height within +/- 2 SD of the general population. There was a wide range of final heights in all three treatment groups. This variation in response suggests the need to individualize treatment in order to achieve an appropriate final height for most individuals.

  • 2. Albertsson-Wikland, Kerstin
    et al.
    Aronson, A Stefan
    Gustafsson, Jan
    Hagenäs, Lars
    Ivarsson, Sten A
    Jonsson, Björn
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Marcus, Claude
    Nilsson, Karl Olof
    Ritzén, E Martin
    Tuvemo, Torsten
    Westphal, Otto
    Aman, Jan
    Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency.2008In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, no 11, p. 4342-50Article in journal (Refereed)
    Abstract [en]

    CONTEXT: The effect of GH therapy in short non-GH-deficient children, especially those with idiopathic short stature (ISS), has not been clearly established owing to the lack of controlled trials continuing until final height (FH). OBJECTIVE: The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children, mainly with ISS, compared with untreated controls. DESIGN AND SETTING: A randomized, controlled, long-term multicenter trial was conducted in Sweden. INTERVENTION: Two doses of GH (Genotropin) were administered, 33 or 67 microg/kg.d; control subjects were untreated. SUBJECTS: A total of 177 subjects with short stature were enrolled. Of these, 151 were included in the intent to treat (AllITT) population, and 108 in the per protocol (AllPP) population. Analysis of ISS subjects included 126 children in the ITT (ISSITT) population and 68 subjects in the PP (ISSPP) population. MAIN OUTCOME MEASURES: We measured FH sd score (SDS), difference in SDS to midparenteral height (diff MPHSDS), and gain in heightSDS. RESULTS: After 5.9+/-1.1 yr on GH therapy, the FHSDS in the AllPP population treated with GH vs. controls was -1.5+/-0.81 (33 microg/kg.d, -1.7+/-0.70; and 67 microg/kg.d, -1.4+/-0.86; P<0.032), vs. -2.4+/-0.85 (P<0.001); the diff MPHSDS was -0.2+/-1.0 vs. -1.0+/-0.74 (P<0.001); and the gain in heightSDS was 1.3+/-0.78 vs. 0.2+/-0.69 (P<0.001). GH therapy was safe and had no impact on time to onset of puberty. A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four populations. CONCLUSION: GH treatment significantly increased FH in ISS children in a dose-dependent manner, with a mean gain of 1.3 SDS (8 cm) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls.

  • 3. Albertsson-Wikland, Kerstin
    et al.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jonsson, Björn
    Hochberg, Zeʼev
    Long-term response to growth hormone (GH) therapy in short children with a delayed infancy childhood transition (DICT)2011In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 69, p. 504-510Article in journal (Refereed)
    Abstract [en]

    Transition of growth from infancy to childhood is associated with activation of the GH-IGF-I axis. Children with a delayed infancy-childhood-transition (ICT) are short as adults. Thus, age at ICT may impact on growth response to GH. The objective was to investigate associations between growth response to GH-treatment and ICT-timing in children with idiopathic short stature (ISS) in a randomized, controlled, multicenter trial, TRN 88-080. 147 pre-pubertal children (mean age, 11.5±1.4 yrs) were randomized to receive GH 33μg/kg/d (GH33, n=43), GH 67μg/kg/d (GH67, n=61) or no treatment (n=43). Data on growth to final height (FH) were analyzed after categorization into those with normal (n=76) or delayed ICT (n=71). Within the GH33 group, significant height gain at FH was only observed in children with a delayed ICT (p<0.001) with each month of delay corresponding to gain of 0.13 standard deviation score (SDS). For the GH67 group, the timing of the onset of the ICT had no impact on growth response. In conclusion, ISS children with a delayed ICT responded to standard-GH-dose (better responsiveness), whereas those with a normal ICT required higher doses to attain a significant height gain to FH.

  • 4. Albertsson-Wikland, Kerstin
    et al.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. berit.kristrom@umu.se.
    Lundberg, Elena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Aronson, A. Stefan
    Gustafsson, Jan
    Hagenäs, Lars
    Ivarsson, Sten-A.
    Jonsson, Bjorn
    Ritzen, Martin
    Tuvemo, Torsten
    Westgren, Ulf
    Westphal, Otto
    Åman, Jan
    Growth Hormone Dose-Dependent Pubertal Growth: A Randomized Trial in Short Children with Low Growth Hormone Secretion2014In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 82, no 3, p. 158-170Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i. e. idiopathic isolated GH deficiency. Methods: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH(33) mu g/kg/day for >= 1 year. They were randomized to receive 67 mu g/kg/day (GH(67)) given as one (GH(67x1); n = 35) or two daily injections (GH(33x2); n = 36), or to remain on a single 33 mu g/kg/day dose (GH(33x1); n = 40). Growth was assessed as height SDS gain for prepubertal, pubertal and total periods, as well as AH SDS versus the population and the midparental height. Results: Pubertal height SDS gain was greater for patients receiving a high dose (GH(67), 0.73) than a low dose (GH(33x1), 0.41, p < 0.05). AH(SDS) was greater on GH(67) (GH(67x1), -0.84; GH(33x2), -0.83) than GH(33) (-1.25, p < 0.05), and height SDS gain was greater on GH(67) than GH(33) (2.04 and 1.56, respectively; p < 0.01). All groups reached their target height SDS. Conclusion: Pubertal height SDS gain and AH SDS were dose dependent, with greater growth being observed for the GH(67) than the GH(33) randomization group; however, there were no differences between the once-and twice-daily GH(67) regimens. (C) 2014 S. Karger AG, Basel.

  • 5. Albertsson-Wikland, Kerstin
    et al.
    Martensson, Anton
    Savendahl, Lars
    Niklasson, Aimon
    Bang, Peter
    Dahlgren, Jovanna
    Gustafsson, Jan
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Norgren, Svante
    Pehrsson, Nils-Gunnar
    Oden, Anders
    Mortality Is Not Increased in Recombinant Human Growth Hormone-treated Patients When Adjusting for Birth Characteristics2016In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 5, p. 2149-2159Article in journal (Refereed)
    Abstract [en]

    Objective: This study aimed to investigate whether reported high mortality in childhood recombinant human GH (rhGH)-treated patients was related to birth-characteristics and/or rhGH treatment.

    Design and Setting: We sought to develop a mortality model of the Swedish general population born between 1973 and 2010, using continuous-hazard functions adjusting for birth characteristics, sex, age intervals, and calendar year to estimate standardized mortality ratio (SMR) and to apply this model to assess expected deaths in Swedish rhGH-treated patients with idiopathic isolated GH deficiency (IGHD), idiopathic short stature (155) or born small for gestational age (SGA).

    Participants: The general population: Swedish Medical Birth Register (1973-2010: 1 880 668 males; 1 781 131 females) and Cause of Death Register (1985-2010).

    Intervention Population: Three thousand eight hundred forty-seven patients starting rhGH treatment between 1985 and 2010 and followed in the National GH Register and/or in rhGH trials diagnosed with IGHD (n = 1890), ISS (n = 975), or SGA (n=982).

    Main Outcome Measures: Death.

    Results: Using conventional models adjusting for age, sex, and calendar-year, the SMR was 1.43 (95% confidence interval, 0.89-2.19), P = .14, observed/expected deaths 21/14.68. The rhGH population differed (P < .001) from the general population regarding birth weight, birth length, and congenital malformations.

    Application of an Advanced Model: When applying the developed mortality model of the general population, the ratio of observed/expected deaths in rhGH-treated patients was 21/21.99; SMR = 0.955 (0.591-1.456)P = .95.

    Model Comparison: Expected number of deaths were 14.68 (14.35-14.96) using the conventional model, and 21.99 (21.24-22.81) using the advanced model, P < .001, which had at all ages a higher gradient of risk per SD of the model, 24% (range, 18-42%; P < .001).

    Conclusions: Compared with the general Swedish population, the ratio of observed/expected deaths (21/21.99) was not increased in childhood rhGH-treated IGHD, ISS, and SGA patients when applying an advanced sex-specific mortality model adjusting for birth characteristics.

  • 6. Albertsson-Wikland, Kerstin
    et al.
    Mårtensson, Anton
    Sävendahl, Lars
    Niklasson, Aimon
    Bang, Peter
    Dahlgren, Jovanna
    Gustafsson, Jan
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Norgren, Svante
    Pehrsson, Nils-Gunnar
    Oden, Anders
    Birth Characteristics Explain One Third of Expected Deaths in rhGH-treated Patients Diagnosed with IGHD, ISS & SGA2016In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 86, p. 49-49Article in journal (Other academic)
  • 7. Andersson, B.
    et al.
    Swolin-Eide, D.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Gelander, L.
    Magnusson, P.
    Albertsson-Wikland, K.
    Seasonal variations in vitamin D in relation to growth in short prepubertal children before and during first year growth hormone treatment2015In: Journal of Endocrinological Investigation, ISSN 0391-4097, E-ISSN 1720-8386, Vol. 38, no 12, p. 1309-1317Article in journal (Refereed)
    Abstract [en]

    Purpose This study investigated the relationship between seasonal variations in 25-hydroxyvitamin D (25(OH) D) levels and growth in prepubertal children during both the pretreatment year and the first year of GH treatment. Methods The study included 249 short prepubertal children with a broad range of GH secretion, GH(max) during a 24 h profile median 23; range 1-127 mU/L, 191 boys (mean age +/- SD, 8.6 +/- 2.6 years), 58 girls (7.5 +/- 1.9 years) receiving GH treatment (mean 43 mu g/kg/day; range 17-99 mu g/kg/day). Serum 25(OH) D was measured using an automated IDS-iSYS immunoassay. Results 25(OH) D levels showed seasonal variation, and decreased significantly during GH treatment. 25(OH) D levels at start and first year reduction in 25(OH) D, correlated (-) with the first year growth response during treatment. The degree of GH secretion capacity within our study population of mainly non-GH deficient children and 25(OH) D sufficient (67 +/- 29 nmol/L) had no influence on 25(OH) D levels. Growth during GH treatment were independent of seasonal variations in 25(OH) D. Multiple regression analysis showed that 25(OH) D levels at treatment start, together with auxological data and IGF-binding protein-3(SDS), explained 61 % of the variation in first year gain in height(SDS). Conclusion 25(OH) D levels were associated with first year growth response to GH and may be a useful contribution to future growth prediction models.

  • 8. Ankarberg-Lindgren, Carina
    et al.
    Gawlik, Aneta
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Mazzanti, Laura
    Ruijgrok, Elisabeth J.
    Sas, Theo C. J.
    Estradiol matrix patches for pubertal induction: stability of cut pieces at different temperatures2019In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 8, no 4, p. 360-366Article in journal (Refereed)
    Abstract [en]

    Objective: Transdermal estradiol patches are primarily designed for adult women. No low-dose patches are licensed for pubertal induction in hypogonadal girls. Low doses can be achieved by cutting a matrix patch into smaller pieces. However, the manufacturers do not guarantee stability or utility of cut estradiol patches. The aim of the study was to assess 1-month stability of cut estradiol patches from four different manufacturers in the laboratory at room temperature (+21 degrees C) and at an elevated temperature (+35 degrees C).

    Design and methods: Estraderm MX 50 mu g, Systen 50 mu g and Oesclim 25 mu g matrix patches were cut into eight pieces while Estradot 50 mu g small patches were cut in half. The cut patches were stored in their respective pouches at +21 degrees C or at +35 degrees C for up to 1 month. The estradiol drug was extracted from the patch by ethyl acetate n-hexane and determined by radioimmunoassay.

    Results: Storage at +21 degrees C or +35 degrees C up to 1 month did not reduce the estradiol concentration in Estraderm MX, Systen and Oesclim patches. However, although the estradiol in Estradot patches was not affected by storage at +21 degrees C, at +35 degrees C, estradiol decreased by 57% (+/- 1%) in cut pieces.

    Conclusions: Unused Estraderm MX, Systen and Oesclim patch pieces may be stored for at least 1 month at <=+35 degrees C. Where estradiol patches for children are not available, cut pieces of these or similar patches can be used for pubertal induction. The Estradot patch was too small to properly cut into low doses and not stable in elevated temperatures.

  • 9. Ankarberg-Lindgren, Carina
    et al.
    Gawlik, Aneta
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Mazzanti, Laura
    Sas, Theo C. J.
    Sustainability of Estradiol Drug Concentrations in Cut Matrix Patches; A Study of Different Brands with Potential Use for Pubertal Induction2018In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, p. 553-553Article in journal (Other academic)
  • 10. Ankarberg-Lindgren, Carina
    et al.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Norjavaara, Ensio
    Physiological Estrogen Replacement Therapy for Puberty Induction in Girls: A Clinical Observational Study2014In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 81, no 4, p. 239-244Article in journal (Refereed)
    Abstract [en]

    Background/Aim: The goal of estrogen replacement therapy (ERT) in girls with hypogonadism is to achieve the endocrine milieu similar to natural puberty, where transdermal administration is the most physiological route. The aim of the study was to evaluate guidelines for the induction of puberty with transdermal estradiol (E-2) patches in a large outpatient setting. Methods: In a retrospective study, serum E-2 levels from 18 clinics were analyzed at the Goteborg Pediatric Growth Research Center laboratory, as part of the initiation of ERT in girls with hypogonadism. Exclusion criteria were pubertas tarda and pubertal arrest. Eighty-eight observations (50 with Turner syndrome, TS) were included. Serum E-2 levels were determined by extraction + radioimmunoassay (detection limit 4 pmol/l) and analyzed in relation to the dose of Evorel (R) (25 mu g/24 h, containing 1.60 mg estradiol hemihydrate; Janssen-Cilag Pharmaceutica N.V., Beerse, Belgium). Results: There was a linear relationship between serum E-2 and the weight-based dose, with r = 0.56, p < 0.0001 for all observations and r = 0.59, p < 0.0001 for the TS study group. Linear regression analysis for doses of 0.05-0.07 mu g/kg resulted in serum levels of 17-23 pmol/l (TS 17-24 pmol/l) and doses of 0.08-0.12 mu g/kg in 26-39 pmol/l (TS 27-39 pmol/l). Conclusions: For the initiation of ERT with nocturnally administered E-2 patches, we recommend reduced starting doses of 0.05-0.07 mu g/kg, with the goal of mimicking E-2 levels during gonadarche. In older girls, when breast development is of high priority, the starting dose can still be 0.08-0.12 mu g/kg. (C) 2014 S. Karger AG, Basel

  • 11.
    Bang, P
    et al.
    Department of Women’s and Children’s Health, Karolinska Institute and University Hospital, Stockholm, Sweden.
    Bjerknes, R
    Department of Clinical Medicine, Section for Pediatrics, University of Bergen, Norway.
    Dahlgren, J
    Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Dunkel, L
    Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland.
    Gustafsson, J
    Department of Women’s and Children’s Health, University of Uppsala, Sweden.
    Juul, A
    Department of Growth and Reproduction, University of Copenhagen, Denmark.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Tapanainen, P
    Department of Pediatrics and Adolescence, University of Oulu, Finland.
    Åberg, V
    Institut Produits Synthèse (IPSEN) AB, Kista, Sweden.
    A comparison of different definitions of growth response in short prepubertal children treated with growth hormone2011In: Hormone research in paediatrics, ISSN 1663-2826, Vol. 75, no 5, p. 335-345Article in journal (Refereed)
    Abstract [en]

    Background: How to define poor growth response in the management of short growth hormone (GH)-treated children is controversial.

    Aim: Assess various criteria of poor response.

    Subjects and Methods: Short GH-treated prepubertal children [n = 456; height (Ht) SD score (SDS) ≤-2] with idiopathic GH deficiency (IGHD, n = 173), idiopathic short stature (ISS, n = 37), small for gestational age (SGA, n = 54), organic GHD (OGHD, n = 40), Turner syndrome (TS, n = 43), skeletal dysplasia (n = 15), other diseases (n = 46) or syndromes (n = 48) were evaluated in this retrospective multicenter study. Median age at GH start was 6.3 years and Ht SDS -3.2.

    Results: Median [25-75 percentile] first-year gain in Ht SDS was 0.65 (0.40-0.90) and height velocity (HtV) 8.67 (7.51-9.90) cm/year. Almost 50% of IGHD children fulfilled at least one criterion for poor responders. In 28% of IGHD children, Ht SDS gain was <0.5 and they had lower increases in median IGF-I SDS than those with Ht SDS >0.5. Only IGHD patients with peak stimulated growth hormone level <3 μg/l responded better than those with ISS. A higher proportion of children with TS, skeletal dysplasia or born SGA had Ht SDS gain <0.5.

    Conclusion: Many children respond poorly to GH therapy. Recommendations defining a criterion may help in managing short stature patients.

  • 12.
    Berglund, Staffan K.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Björn, Matias
    Lindberg, Josefine
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Westrup, Björn
    Norman, Mikael
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Marginally low birth weight increases the risk of underweight and short stature at three and a half years of age2016In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 105, no 6, p. 610-617Article in journal (Refereed)
    Abstract [en]

    AIM: Little is known about the long-term health of marginally low birth weight (LBW) children. This study characterised growth among infants weighing 2,000g-2,500g and explored the prevalence and predictors of sustained growth restriction.

    METHOD: This prospective observational trial followed the weight and height of 281 Swedish marginally LBW children from birth to 3.5 years of age. Children with a standard deviation score (SDS) for body mass index or height below -2 were considered underweight and short respectively.

    RESULTS: The mean SDS for weight and height showed a rapid increase before 12-19 weeks of age. The most rapid weight gain was in infants born small for gestational age. However, at 3.5 years of age, 9.5% of the children remained underweight and 6.5% had short stature. Regression models showed that slow weight gain before 19 weeks of age was the strongest predictor for lasting underweight, while slow height gain before 19 weeks of age and male sex were associated with short stature.

    CONCLUSION: Marginally LBW infants were more likely to be underweight and have a short stature at 3.5 years of age and the absence of catch-up growth during the first five months after birth identified those at highest risk.

  • 13. Bjarnason, R
    et al.
    Andersson, B
    Kim, H S
    Olsson, B
    Swolin-Eide, D
    Wickelgren, R
    Kriström, B
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Carlsson, B
    Albertsson-Wikland, K
    Carlsson, L M S
    Cartilage oligomeric matrix protein increases in serum after the start of growth hormone treatment in prepubertal children.2004In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 89, no 10, p. 5156-60Article in journal (Refereed)
    Abstract [en]

    Both GH and IGF-I stimulate bone growth, but the molecular mechanisms mediating their effects on the growth plate are not fully understood. We measured gene expression by microarray analysis in primary cultured human chondrocytes treated with either GH or IGF-I. One of the genes found to be up-regulated by both GH and IGF-I was that encoding cartilage oligomeric matrix protein (COMP). This protein is predominantly found in the extracellular matrix of cartilage. Mutations in the COMP gene have been associated with syndromes of short stature. To verify that COMP is regulated by GH in vivo, we measured COMP levels in serum in short children treated with GH. The study included 113 short prepubertal children (14 girls and 99 boys) with a mean (+/- sd) age of 8.84 +/- 2.76 yr, height sd score of -2.74 +/- 0.67, and IGF-I sd score of -1.21 +/- 1.07 at the start of GH administration. Serum levels of COMP were 1.58 +/- 0.28, 1.83 +/- 0.28 (P < 0.0001), 1.91 +/- 0.28 (P < 0.0001), 1.78 +/- 0.28 (P < 0.001), and 1.70 +/- 0.24 (P < 0.05) microg/ml at baseline and after 1 wk and 1, 3, and 12 months, respectively. In conclusion, we have demonstrated that COMP expression is up-regulated by both GH and IGF-I in primary cultured human chondrocytes. Furthermore, serum levels of COMP increase after the start of GH treatment in short children.

  • 14. Bjarnason, R
    et al.
    Boguszewski, M
    Dahlgren, J
    Gelander, L
    Kriström, B
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Rosberg, S
    Carlsson, B
    Albertsson-Wikland, K
    Carlsson, L M
    Leptin levels are strongly correlated with those of GH-binding protein in prepubertal children.1997In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 137, no 1, p. 68-73Article in journal (Refereed)
    Abstract [en]

    There was a highly significant correlation between serum levels of leptin and those of GHBP, except in children with GHD. The possibility that leptin could mediate the effects of body fat mass on GH sensitivity, therefore, merits further investigation.

  • 15. Carlsson, Goran
    et al.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Nordenskjold, Magnus
    Henter, Jan-Inge
    Fadeel, Bengt
    Ovarian failure in HAX1-deficient patients: is there a gender-specific difference in pubertal development in severe congenital neutropenia or Kostmann disease?2013In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 102, no 1, p. 78-82Article in journal (Refereed)
    Abstract [en]

    Aim Severe congenital neutropenia (SCN) is a rare disorder of myelopoiesis characterized by neutropenia, recurrent bacterial infections and a maturation arrest of the myelopoiesis in the bone marrow. Homozygous mutations in the HAX1 gene were described in patients with autosomal recessive SCN or Kostmann disease. Some of these patients display neurological disease. We noted, during the course of clinical management of patients with Kostmann disease, insufficient pubertal development in female patients, but not in our male patients. The study objective was to provide a detailed account of this phenotype and its possible relation to HAX1 mutations. Methods Detailed clinical histories and laboratory investigations of three patients with Kostmann disease belonging to the original kindred in northern Sweden described by Rolf Kostmann are reported. Results We report one male patient with normal puberty and two female patients with insufficient pubertal development. Elevated levels of LH and FSH were recorded in both patients. All three patients harbour the same p.Glu190X mutation in the HAX1 gene. Conclusions We show for the first time that female patients with Kostmann disease display primary gonadal insufficiency. This suggests a possible role for HAX1 in the development and/or function of the human ovary.

  • 16. Chaplin, John E.
    et al.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jonsson, Bjorn
    Stenlid, Maria Halldin
    Aronson, A. Stefan
    Dahlgren, Jovanna
    Albertsson-Wikland, Kerstin
    When Do Short Children Realize They Are Short?: Prepubertal Short Children's Perception of Height during 24 Months of Catch-Up Growth Hormone Treatment2012In: Hormone Research in Paediatrics, ISSN 1663-2818, Vol. 77, no 4, p. 241-249Article in journal (Refereed)
    Abstract [en]

    Aim: To examine perceived height during the first 24 months of growth hormone (GH) treatment in short prepubertal children. Methods: Ninety-nine 3- to 11-year-old short prepubertal children with either isolated GH deficiency (n = 32) or idiopathic short stature (n = 67) participated in a 24-month randomized trial of individualized or fixed-dose GH treatment. Children's and parents' responses to three perceived height measures: relative height (Silhouette Apperception Test), sense of height (VAS short/tall), and judgment of appropriate height (yes/no) were compared to measured height. Results: Children and parents overestimated height at start (72%, 54%) and at 24 months (52%, 30%). Short children described themselves as tall until 8.2 years (girls) and 9 years (boys). Prior to treatment, 38% of children described their height as appropriate and at 3 months, 63%. Mother's height, parental sense of the child's tallness and age explained more variance in children's sense of tallness (34%) than measured height (0%). Conclusion: Short children and parents overestimate height; a pivotal age exists for comparative height judgments. Even a small gain in height may be enough for the child to feel an appropriate age-related height has been reached and to no longer feel short.

  • 17. Chaplin, John Eric
    et al.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jonsson, Björn
    Hägglöf, Bruno
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry.
    Tuvemo, Torsten
    Aronson, A Stefan
    Dahlgren, Jovanna
    Albertsson-Wikland, Kerstin
    Improvements in behaviour and self-esteem following growth hormone treatment in short prepubertal children2011In: Hormone research in paediatrics, ISSN 1663-2826, Vol. 75, no 4, p. 291-303Article in journal (Refereed)
    Abstract [en]

    Background/Aims: To evaluate effects of growth hormone (GH) treatment on behaviour and psychosocial characteristics in short-stature children.

    Methods: 99 referred prepubertal non-familiar short-stature children (32 GH deficiency; 67 idiopathic short stature) aged 3-11 years, randomized to fixed or individual GH doses and their parents completed questionnaires (Child Behaviour Checklist, Birleson Depression Self-Report Scale, Abbreviated Parent-Teacher Questionnaire, I Think I Am, Well-Being Visual-Analogue Scales for Short-Stature Children) at baseline (BL) and after 3, 12, and 24 months.

    Results: At BL, children showed higher levels of internalizing behaviour (p < 0.001), lower levels of externalizing behaviour (p < 0.006) and self-esteem (p < 0.001) compared to reference values. During GH treatment, behavioural measures (p < 0.001) and depression (p < 0.01) changed towards the mean of the population within the first 3 months and remained improved to 24 months. Self-esteem improved at all time points (p < 0.001), and in all subgroups, as did well-being dimensions stability and mood (p < 0.05). Multiple regression analysis showed that greater improvements were related to lower BL value, height gain, higher maximal GH value, being older, and being male.

    Conclusion: On GH treatment, prepubertal short children significantly improved on behavioural, depression, and psychosocial evaluations over a 2-year period of GH treatment. Most change occurred within the first 3 months, which highlights this short period as important not only for growth and metabolic changes but also for behaviour and psychosocial improvements following GH treatment.

  • 18.
    Chaplin, John Eric
    et al.
    Gothenburg.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jonsson, Björn
    Uppsala.
    Tuvemo, Torsten
    Uppsala.
    Albertsson-Wikland, Kerstin
    Gothenburg .
    Growth Hormone Treatment Improves Cognitive Function in Short Children with Growth Hormone Deficiency2015In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 83, no 6, p. 390-399Article in journal (Refereed)
    Abstract [en]

    Background/Aims: We investigated the association between cognition and growth hormone (GH) status and GH treatment in short prepubertal children with broadly ranging GH secretion. Methods: A total of 99 children (age 3-11 years), 41 with GH deficiency (GHD) and 58 with idiopathic short stature (ISS), were randomized to a fixed dose (43 mu g/kg/day) or a prediction model-guided individualized dose (17-100 mu g/kg/day) and followed up for 24 months. In a longitudinal and mixed within-and between-subjects study, we examined clinical effect size changes, measured by Cohen's d, in full-scale IQ (FSIQ) and secondary IQ indices. Results: Significant increases giving medium effect size in FSIQ (p = 0.001, Cohen's d = 0.63), performance IQ (p = 0.001, Cohen's d = 0.65) and processing speed (p = 0.005, Cohen's d = 0.71) were found in the GH-deficient group. In contrast, perceptual organization only increased in the ISS group (p = 0.001, Cohen's d = 0.53). Baseline IQ was normally distributed with small but significant differences between the groups: GH-deficient children had lower FSIQ (p = 0.042) and lower performance IQ (p = 0.021). Using multiple regression analysis, 40% of the variance in delta processing speed scores (0-24 months) was explained by GH(max) and IGF-I-SDS at baseline. Conclusion: IQ, specifically fluid intelligence, increased in the GH-deficient children. The pretreatment status of the GH/IGF-I axis was significantly predictive for these changes. (C) 2015 S. Karger AG, Basel

  • 19. Dahlgren, Jovanna
    et al.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Niklasson, Aimon
    Nierop, Andreas F M
    Rosberg, Sten
    Albertsson-Wikland, Kerstin
    Models predicting the growth response to growth hormone treatment in short children independent of GH status, birth size and gestational age.2007In: BMC medical informatics and decision making, ISSN 1472-6947, Vol. 7, p. 40-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Mathematical models can be used to predict individual growth responses to growth hormone (GH) therapy. The aim of this study was to construct and validate high-precision models to predict the growth response to GH treatment of short children, independent of their GH status, birth size and gestational age. As the GH doses are included, these models can be used to individualize treatment. METHODS: Growth data from 415 short prepubertal children were used to construct models for predicting the growth response during the first years of GH therapy. The performance of the models was validated with data from a separate cohort of 112 children using the same inclusion criteria. RESULTS: Using only auxological data, the model had a standard error of the residuals (SDres), of 0.23 SDS. The model was improved when endocrine data (GHmax profile, IGF-I and leptin) collected before starting GH treatment were included. Inclusion of these data resulted in a decrease of the SDres to 0.15 SDS (corresponding to 1.1 cm in a 3-year-old child and 1.6 cm in a 7-year old). Validation of these models with a separate cohort, showed similar SDres for both types of models. Preterm children were not included in the Model group, but predictions for this group were within the expected range. CONCLUSION: These prediction models can with high accuracy be used to identify short children who will benefit from GH treatment. They are clinically useful as they are constructed using data from short children with a broad range of GH secretory status, birth size and gestational age.

  • 20. Decker, Ralph
    et al.
    Albertsson-Wikland, Kerstin
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Halldin, Maria
    Dahlgren, Jovanna
    Decreased GH dose after the catch-up growth period maintains metabolic outcome in short prepubertal children with and without classic GH deficiency2012In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 77, no 3, p. 407-415Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Few studies have evaluated metabolic outcomes following growth hormone (GH) treatment in short prepubertal children during different periods of growth. Previously, we found that individualized GH dosing in the catch-up period reduced the variation in fasting insulin levels by 34% compared with those receiving a standard GH dose. We hypothesized that the GH dose required to maintain beneficial metabolic effects is lower during the prepubertal growth phase after an earlier catch-up growth period.

    DESIGN: Short prepubertal children with isolated GH deficiency or idiopathic short stature were randomized to individualized GH treatment (range, 17-100 μg/kg/day) or a standard dose in a preceding 2-year study. After achieving near mid-parental height(SDS) (,) children receiving an individualized dose were randomized to either a 50% reduced individualized dose (RID, n=28) or an unchanged individualized dose (UID, n=37) for 2 years. The dose remained unchanged in 33 children initially randomized to receive a standard dose (FIX, 43 μg/kg/day).We evaluated whether the variations in metabolic parameters measured during maintenance growth diminished in RID compared with UID or FIX.

    RESULTS: We observed less variation in fasting insulin levels (-50%), insulin sensitivity as assessed by homeostasis model assessment (-55.1%), lean soft tissue (-27.8%) and bone mineral content (-31.3%) in RID compared with UID (all p<0.05), but no differences compared with FIX.

    CONCLUSIONS: Continued individualized GH treatment after the catch-up growth period is safe and reduces hyperinsulinism. Individualized GH dose can be reduced once the desired height(SDS) is achieved to avoid overtreatment in terms of metabolic outcome.

  • 21. Decker, Ralph
    et al.
    Albertsson-Wikland, Kerstin
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Halldin, Maria
    Gustafsson, Jan
    Nilsson, Nils-Östen
    Dahlgren, Jovanna
    GH Dose Reduction Maintains Normal Prepubertal Height Velocity After Initial Catch-Up Growth in Short Children2019In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 104, no 3, p. 835-844Article in journal (Refereed)
    Abstract [en]

    Context: GH responsiveness guides GH dosing during the catch-up growth (CUG) period; however, little is known regarding GH dosing during the prepubertal maintenance treatment period.

    Objective: To evaluate whether SD score (SDS) channel parallel growth with normal height velocity can be maintained after CUG by reducing the GH dose by 50% in children receiving doses individualized according to estimated GH responsiveness during the catch-up period.

    Design and Settings: Prepubertal children (n = 98; 72 boys) receiving GH during CUG (GH deficient, n = 33; non–GH deficient, n = 65), were randomized after 2 to 3 years to either a 50% reduced individualized dose (GHRID; n = 27; 20 boys) or unchanged individualized dose (GHUID; n = 38; 27 boys). Another 33 children (25 boys) continued a standard weight-based dose [43 µg/kg/d (GHFIX)].

    Main Outcome Measures: The primary endpoint was the proportion of children with ΔheightSDS within ±0.3 at 1 year after GH dose reduction compared with two control groups: GHUIDand GHFIX. The hypothesis was that heightSDS could be maintained within ±0.3 with a reduced individualized GH dose.

    Results: For the intention-to-treat population at 1 year, 85% of the GHRIDgroup maintained ΔheightSDS within ±0.3 vs 41% in the GHUIDgroup (P = 0.0055) and 48% in the GHFIXgroup (P = 0.0047). The ΔIGF-ISDS in the GHRID group was −0.75 ± 1.0 at 3 months (P = 0.003) and −0.72 ± 1.2 at 1 year compared with the GHUID group (0.15 ± 1.2; P = 0.005) and GHFIX group (0.05 ± 1.0; P = 0.02).

    Conclusions: Channel parallel growth (i.e., normal height velocity) and IGF-ISDS levels within ±2 were maintained after completed CUG using a 50% lower individualized dose than that used during the CUG period.

  • 22.
    Decker, Ralph
    et al.
    Department of Pediatrics, Gothenburg Pediatric Growth Research Center (GP-GRC), University of Gothenburg, Institute of Clinical Sciences, The Queen Silvia Children’s Hospital, Gothenburg.
    Albertsson-Wikland, Kerstin
    Department of Pediatrics, Gothenburg Pediatric Growth Research Center (GP-GRC), University of Gothenburg, Institute of Clinical Sciences, The Queen Silvia Children’s Hospital, Gothenburg.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Nierop, Andreas F M
    Muvara bv, Multivariate Analysis of Research Data, Leiderdorp, Netherlands.
    Gustafsson, Jan
    Department of Women’s and Children’s Health, Uppsala University, Uppsala.
    Bosaeus, Ingvar
    Department of Clinical Nutrition, Research Centre for Endocrinology and Metabolism, Sahlgrenska, University Hospital, Gothenburg, Sweden.
    Fors, Hans
    Department of Pediatrics, Gothenburg Pediatric Growth Research Center (GP-GRC), University of Gothenburg, Institute of Clinical Sciences, The Queen Silvia Children’s Hospital, Gothenburg.
    Hochberg, Ze'ev
    Division of Pediatric Endocrinology, Rambam Medical Centre, Haifa, Israel.
    Dahlgren, Jovanna
    Department of Pediatrics, Gothenburg Pediatric Growth Research Center (GP-GRC), University of Gothenburg, Institute of Clinical Sciences, The Queen Silvia Children’s Hospital, Gothenburg.
    Metabolic outcome of GH treatment in prepubertal short children with and without classical GH deficiency2010In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 73, no 3, p. 346-354Article in journal (Refereed)
    Abstract [en]

    Context  Few studies have evaluated the metabolic outcomes of growth hormone (GH) treatment in idiopathic short stature (ISS). Moreover, children with ISS appear to need higher GH doses than children with GH deficiency (GHD) to achieve the same amount of growth and may therefore be at increased risk of adverse events during treatment. The individualized approach using prediction models for estimation of GH responsiveness, on the other hand, has the advantage of narrowing the range of growth response, avoiding too low or high GH doses.

    Design  Short prepubertal children with either isolated GHD (39) or ISS (89) participated in a 2-year randomized trial of either individualized GH treatment with six different GH doses (range, 17–100 μg/kg/day) or a standard dose (43 μg/kg/day).

    Objective  To evaluate if individualized GH treatment reduced the variance of the metabolic measures as shown for growth response and to compare changes in metabolic variables in children with ISS and GHD.

    Hypothesis  Individualized GH dose reduces the range of metabolic outcomes, and metabolic outcomes are similar in children with ISS and GHD.

    Results  We observed a narrower variation for fasting insulin (−34·2%) and for homoeostasis model assessment (HOMA) (−38·9%) after 2 years of individualized GH treatment in comparison with standard GH dose treatment. Similar metabolic changes were seen in ISS and GHD. Delta (Δ) height SDS correlated with Δinsulin-like growth factor I (IGF-I), Δleptin and Δbody composition. Principal component analysis identified an anabolic and a lipolytic component. Anabolic variables [Δlean body mass (LBM) SDS and ΔIGF-I SDS] clustered together and correlated strongly with Δheight SDS and GH dose, whereas lipolytic variables [Δfat mass (FM) SDS and Δleptin] were clustered separately from anabolic variables. Regression analysis showed GH dose dependency in ISS, and to a lesser degree in GHD, for ΔLBM SDS and Δheight SDS, but not for changes in FM.

    Conclusions  Individualized GH dosing during catch-up growth reduces the variance in insulin and HOMA and results in equal metabolic responses irrespective of the diagnosis of GHD or ISS.

  • 23.
    Decker, Ralph
    et al.
    Göteborg Pediatric Growth Research Centre (GP-GRC), Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Nygren, Anders
    Göteborg Pediatric Growth Research Centre (GP-GRC), Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Nierop, Andreas F. M.
    Muvara bv, Multivariate Analysis of Research Data, Leiderdorp, Netherlands.
    Gustafsson, Jan
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Albertsson-Wikland, Kerstin
    Göteborg Pediatric Growth Research Centre (GP-GRC), Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Dahlgren, Jovanna
    Göteborg Pediatric Growth Research Centre (GP-GRC), Department of Pediatrics, Institute of Clinical Sciences, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Different thresholds of tissue-specific dose-responses to growth hormone in short prepubertal children2012In: BMC Endocrine Disorders, ISSN 1472-6823, E-ISSN 1472-6823, Vol. 12, p. 26-Article in journal (Refereed)
    Abstract [en]

    Background: In addition to stimulating linear growth in children, growth hormone (GH) influences metabolism and body composition. These effects should be considered when individualizing GH treatment as dose-dependent changes in metabolic markers have been reported. Hypothesis: There are different dose-dependent thresholds for metabolic effects in response to GH treatment. Method: A randomized, prospective, multicentre trial TRN 98-0198-003 was performed for a 2-year catch-up growth period, with two treatment regimens (a) individualized GH dose including six different dose groups ranging from 17-100 mu g/kg/day (n=87) and (b) fixed GH dose of 43 mu g/kg/day (n=41). The individualized GH dose group was used for finding dose-response effects, where the effective GH dose (ED 50%) required to achieve 50% Delta effect was calculated with piecewise linear regressions. Results: Different thresholds for the GH dose were found for the metabolic effects. The GH dose to achieve half of a given effect (ED 50%, with 90% confidence interval) was calculated as 33(+/- 24.4) mu g/kg/day for Delta left ventricular diastolic diameter (cm), 39(+/- 24.5) mu g/kg/day for Delta alkaline phosphatase (mu kat/L), 47(+/- 43.5) mu g/kg/day for Delta lean soft tissue (SDS), 48(+/- 35.7) mu g/kg/day for Delta insulin (mU/L), 51(+/- 47.6) mu g/kg/day for Delta height (SDS), and 57(+/- 52.7) mu g/kg/day for Delta insulin-like growth factor I (IGF-I) SDS. Even though lipolysis was seen in all subjects, there was no dose-response effect for Delta fat mass (SDS) or Delta leptin ng/ml in the dose range studied. None of the metabolic effects presented here were related to the dose selection procedure in the trial. Conclusions: Dose-dependent thresholds were observed for different GH effects, with cardiac tissue being the most responsive and level of IGF-I the least responsive. The level of insulin was more responsive than that of IGF-I, with the threshold effect for height in the interval between.

  • 24. Donaldson, Malcolm
    et al.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Ankarberg-Lindgren, Carina
    Verlinde, Siska
    van Alfen-van der Velden, Janielle
    Gawlik, Aneta
    van Gelder, Marleen M. H. J.
    Sas, Theo
    Agota, Muzsnai
    Akulevich, Natallia
    Albertsson-Wikland, Kerstin
    Bober, Ece
    Buyukgebiz, Atilla
    Carel, Jean-Claude
    Dacou-Voutetakis, Catherine
    Keizer-Schrama, Sabine de Muinck
    Gault, Emma Jane
    Ghizzoni, Lucio
    Kanaka-Gantenbein, Christina
    Kurtev, Alexander
    Malecka-Tendera, Ewa
    Mazzanti, Laura
    Norjavaara, Ensio
    Popovic, Jadranka
    Ranke, Michael
    Sallai, Agnes
    Stagi, Stefano
    Wasniewska, Malgorzata
    Zenaty, Delphine
    Zuckerman-Levin, Nehama
    Optimal Pubertal Induction in Girls with Turner Syndrome Using Either Oral or Transdermal Estradiol: A Proposed Modern Strategy2019In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 91, no 3, p. 153-163Article, review/survey (Refereed)
    Abstract [en]

    Background: Most girls with Turner syndrome (TS) require pubertal induction with estrogen, followed by long term replacement. However, no adequately powered prospective studies comparing transdermal with oral 17β-estradiol administration exist. This reflects the difficulty of securing funding to study a rare condition with relatively low morbidity/mortality when competing against conditions such as cancer and vascular disease. Protocol Consensus: The TS Working Group of the European Society for Paediatric Endocrinology (ESPE) has agreed to both a 3-year oral and a 3-year transdermal regimen for pubertal induction. Prerequisites include suitable 17β-estradiol tablets and matrix patches to allow the delivery of incremental doses based on body weight. Study Proposal: An international prospective cohort study with single centre analysis is proposed in which clinicians and families are invited to choose either of the agreed regimens, usually starting at 11 years. We hypothesise that pubertal induction with transdermal estradiol will result in better outcomes for some key parameters. The primary outcome measure chosen is height gain during the induction period. Analysis: Assessment of the demographics and drop-out rates of patients choosing either oral or transdermal preparations; and appropriate analysis of outcomes including pubertal height gain, final height, liver enzyme and lipid profile, adherence/acceptability, cardiovascular health, including systolic and diastolic blood pressure and aortic root diameter and bone health. Conclusion: The proposed model of prospective data collection according to internationally agreed protocols aims to break the current impasse in obtaining evidence-based management for TS and could be applied to other rare paediatric endocrine conditions.

  • 25. Duchén, Karel
    et al.
    Lindberg, Anders
    Kiplok, Kaire
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Using a spontaneous profile rather than stimulation test makes the KIGS idiopathic growth hormone deficiency model more accessible for clinicians2017In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, no 9, p. 1481-1486Article in journal (Refereed)
    Abstract [en]

    Aim: Children treated with a growth hormone (GH) for idiopathic growth hormone deficiency (IGHD) may be monitored with the first-year prediction model from the Pfizer International Growth Database (KIGS) using auxology, age, GH dose and the maximum GH concentration from a stimulation test (GH(max)stim). We tested the hypothesis that using a 12-hour spontaneous profile (GH(max)12h) would be as accurate. Methods: We studied 98 prepubertal Swedish children (78boys) aged2-12 years enrolled in KIGS. The first-year growth was predicted using the GH(max) from the GHprofile and a stimulation test, and both of these were compared separately with the observed growth response. Results: The increased height observed in the first year was 0.74 standard deviation scores (SDS), and the studentised residuals for the predicted and observed growth with GH(max)stim (-0.16 SDS) and GH(max)12h (-0.22) were similar. Individual predictions calculated with stimulated or spontaneous GH(max) showed a significant correlation (r = 0.80). Conclusion: We validated the KIGS IGHD prediction model and found that the stimulated GH(max) peak can be reliably replaced by the GH(max) 12h with similar accuracy. This makes the model more accessible for clinicians, who can then provide realistic expectations for the growth response during the first year of treatment.

  • 26. Even, Lea
    et al.
    Andersson, Bjorn
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Albertsson-Wikland, Kerstin
    Hochberg, Ze'ev
    Role of growth hormone in enchondroplasia and chondral osteogenesis: evaluation by X-ray of the hand2014In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 76, no 1, p. 109-114Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The process of growth and maturation of long (radius and ulna) and short (metacarpals and phalanges) bones of the hand (enchondroplasia) differs from that of the carpal cuboid bones (chondral osteogenesis). This study aimed to assess the impact of growth hormone (GH) on these two processes of bone maturation. METHODS: Subjects of the study were 95 prepubertal children: 30 children with GH deficiency and 65 children with idiopathic short stature, aged 7.4 +/- 1.9 y (mean +/- SD) (trial registration number 98-0198-033). Bone maturation was assessed by the Greulich and Pyle method from X-rays obtained at the start and at 1 and 2 y of GH treatment, separately for carpals, long bones, and short bones, and was expressed as years of delay relative to chronological age. RESULTS: At GH start, the delay in bone maturation in the GH-deficient group was significantly greater for carpals (3.6 +/- 1.3 y) than for long (3.0 +/- 1.3 y) and short (1.7 +/- 1.1 y) bones. The delay was nonsignificantly greater for carpal bones in GH-deficient subjects than in subjects with idiopathic short stature (3.6 +/- 1.3 vs. 3.1 +/- 1.1 y, respectively) and was normalized after 2 y of GH treatment. CONCLUSION: The dominant effect of GH was on chondral osteogenesis, with milder effect on enchondroplasia. A distinct delay in carpal and long-bone maturation, which normalizes during 2 y of GH treatment, was typical in GH-deficient children. Therefore, separate carpal bone assessment in bone age reading is needed.

  • 27.
    Forsner, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing. Högskolan Dalarna.
    Jansson, Lilian
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Söderberg, Anna
    Being afraid of medical care: a narrative mediated through the symbolic play of one 2 year-old boyIn: Article in journal (Refereed)
  • 28. Ivarsson, S A
    et al.
    Carlsson, A
    Bredberg, A
    Alm, J
    Aronsson, S
    Gustafsson, J
    Hagenäs, L
    Häger, A
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Marcus, C
    Moëll, C
    Nilsson, K O
    Tuvemo, T
    Westphal, O
    Albertsson-Wikland, K
    Aman, J
    Prevalence of coeliac disease in Turner syndrome.1999In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 88, no 9, p. 933-6Article in journal (Refereed)
    Abstract [en]

    This study was undertaken to investigate the prevalence of coeliac disease in children and adolescents with Turner syndrome. Eighty-seven children and adolescents with Turner syndrome were screened for IgA-antiendomysium antibodies (EMA) and IgA-antigliadin antibodies (AGA), 5% (4/87) being found to be EMA-positive, and 15% (13/87) to have AGA levels above normal. Of the 10 patients who were either AGA- or EMA-positive and further investigated with intestinal biopsy, four manifested villous atrophy (i.e. all three of the EMA-positive patients, but only one of the seven AGA-positive patients). The results suggest EMA-positivity to be a good immunological marker for use in screening for coeliac disease, and such screening to be justified in patients with Turner syndrome.

  • 29. Kanumakala, Shankar
    et al.
    Pfaffle, Roland
    Hoybye, Charlotte
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Battelino, Tadej
    Zabransky, Markus
    Zouater, Hichem
    Latest Results from PATRO Children, A Multi-Centre, Non-Interventional Study of the Long-Term Safety and Efficacy of Omnitrope (R) in Children Requiring Growth Hormone Treatment2018In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, p. 124-124Article in journal (Other academic)
  • 30.
    Kriström, Berit
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Aronson, A Stefan
    Dahlgren, Jovanna
    Gustafsson, Jan
    Halldin, Maria
    Ivarsson, Sten A
    Nilsson, Nils-Osten
    Svensson, Johan
    Tuvemo, Torsten
    Albertsson-Wikland, Kerstin
    Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature.2009In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, no 2, p. 483-90Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Weight-based GH dosing results in a wide variation in growth response in children with GH deficiency (GHD) or idiopathic short stature (ISS). OBJECTIVE: The hypothesis tested was whether individualized GH doses, based on variation in GH responsiveness estimated by a prediction model, reduced variability in growth response around a set height target compared with a standardized weight-based dose. SETTING: A total of 153 short prepubertal children diagnosed with isolated GHD or ISS (n = 43) and at least 1 SD score (SDS) below midparental height SDS (MPH(SDS)) were included in this 2-yr multicenter study. INTERVENTION: The children were randomized to either a standard (43 microg/kg.d) or individualized (17-100 microg/kg.d) GH dose. MAIN OUTCOME MEASURE: We measured the deviation of height(SDS) from individual MPH(SDS) (diffMPH(SDS)). The primary endpoint was the difference in the range of diffMPH(SDS) between the two groups. RESULTS: The diffMPH(SDS) range was reduced by 32% in the individualized-dose group relative to the standard-dose group (P < 0.003), whereas the mean diffMPH(SDS) was equal: -0.42 +/- 0.46 and -0.48 +/- 0.67, respectively. Gain in height(SDS) 0-2 yr was equal for the GH-deficient and ISS groups: 1.31 +/- 0.47 and 1.36 +/- 0.47, respectively, when ISS was classified on the basis of maximum GH peak on the arginine-insulin tolerance test or 24-h profile. CONCLUSION: Individualized GH doses during catch-up growth significantly reduce the proportion of unexpectedly good and poor responders around a predefined individual growth target and result in equal growth responses in children with GHD and ISS.

  • 31.
    Kriström, Berit
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Carlsson, B
    Rosberg, S
    Carlsson, L M
    Albertsson-Wikland, K
    Short-term changes in serum leptin levels provide a strong metabolic marker for the growth response to growth hormone treatment in children. Swedish Study Group for Growth Hormone Treatment.1998In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 83, no 8, p. 2735-41Article in journal (Refereed)
    Abstract [en]

    The growth response to GH treatment varies between children. Besides regulating longitudinal growth, GH exerts important metabolic effects, including lipolysis. In this study we examined whether GH-induced changes in serum levels of the adipose tissue-derived hormone leptin can be used as a marker for the long term growth response to GH treatment in short prepubertal children. The study group consisted of 150 children (21 girls and 129 boys), who were 3-15 yr of age at the start of GH treatment and had a maximum GH secretory capacity ranging from very low to high. They were treated with GH (0.1 IU/kg x day) and followed for at least 1 yr. The first year mean increase in height SD score was 0.79 (SD, 0.34), with a broad range (0.08-2.27). Serum leptin concentrations were significantly reduced after 1, 3, and 12 months of GH treatment compared with levels at the start of treatment. The growth response correlated with the serum leptin concentration at the start of treatment (r = 0.49; P < 0.0001) and with the change in serum leptin concentration after both 1 month (r = -0.41; P < 0.01) and 3 months (r = -0.60; P < 0.0001) of treatment. When multiple stepwise regression analysis was applied to the auxological and biochemical variables that correlated (P < 0.10) with the first year growth response to GH treatment, the 3-month change in serum leptin concentration was the single most important variable for explaining the variance in individual growth responses. We conclude that leptin levels at the start of GH treatment as well as short term changes in leptin levels in response to GH treatment are valuable markers of the long term growth response.

  • 32.
    Kriström, Berit
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Dahlgren, Jovanna
    Göteborg Pediatric Growth Research Center, Institute for Clinical Science, The Sahlgrenska Academy at University of Gothenburg, SE-416 85 Gothenburg, Sweden.
    Niklasson, Aimon
    Göteborg Pediatric Growth Research Center, Institute for Clinical Science, The Sahlgrenska Academy at University of Gothenburg, SE-416 85 Gothenburg, Sweden.
    Nierop, Andreas F M
    Muvara, Tijmtuin 8, 2353 PH Leiderdorp, The Netherlands.
    Albertsson-Wikland, Kerstin
    Göteborg Pediatric Growth Research Center, Institute for Clinical Science, The Sahlgrenska Academy at University of Gothenburg, SE-416 85 Gothenburg, Sweden.
    The first-year growth response to growth hormone treatment predicts the long-term prepubertal growth response in children.2009In: BMC medical informatics and decision making, ISSN 1472-6947, Vol. 9, p. 1-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Pretreatment auxological variables, such as birth size and parental heights, are important predictors of the growth response to GH treatment. For children with missing pretreatment data, published prediction models cannot be used. The objective was to construct and validate a prediction model for children with missing background data based on the observed first-year growth response to GH. The accuracy and reliability of the model should be comparable with our previously published prediction model relying on pretreatment data. The design used was mathematical curve fitting on observed growth response data from children treated with a GH dose of 33 microg/kg/d. METHODS: Growth response data from 162 prepubertal children born at term were used to construct the model; the group comprised of 19% girls, 80% GH-deficient and 23% born SGA. For validation, data from 205 other children fulfilling the same inclusion and treatment criteria as the model group were used. The model was also tested on data from children born prematurely, children from other continents and children receiving a GH dose of 67 microg/kg/d. RESULTS: The GH response curve was similar for all children, but with an individual amplitude. The curve SD score depends on an individual factor combining the effect of dose and growth, the 'Response Score', and time on treatment, making prediction possible when the first-year growth response is known. The prediction interval (+/- 2 SD res) was +/- 0.34 SDS for the second treatment year growth response, corresponding to +/- 1.2 cm for a 3-year-old child and +/- 1.8 cm for a 7-year-old child. For the 1-4-year prediction, the SD res was 0.13 SDS/year and for the 1-7-year prediction it was 0.57 SDS (i.e. < 0.1 SDS/year). CONCLUSION: The model based on the observed first-year growth response on GH is valid worldwide for the prediction of up to 7 years of prepubertal growth in children with GHD/ISS, born AGA/SGA and born preterm/term, and can be used as an aid in medical decision making.

  • 33.
    Kriström, Berit
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jansson, C
    Rosberg, S
    Albertsson-Wikland, K
    Growth response to growth hormone (GH) treatment relates to serum insulin-like growth factor I (IGF-I) and IGF-binding protein-3 in short children with various GH secretion capacities. Swedish Study Group for Growth Hormone Treatment.1997In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 82, no 9, p. 2889-98Article in journal (Refereed)
    Abstract [en]

    The purpose of the study was to evaluate the relationship between the 1-yr (n = 193) and 2-yr (n = 128) growth response and the individual serum concentrations of insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) before and during GH treatment. Our study group of prepubertal short children had from very low to high GH secretory capacity, estimated during an arginine-insulin tolerance test, and the ages ranged from 3-15 yr at the start of treatment. Their serum levels of IGF-I and IGFBP-3 were low before treatment compared to those in an age-related reference group of prepubertal children and increased significantly from the start to 1 month of GH treatment. The mean increase in height SD score was 0.80 SD score after 1 yr of GH treatment and 1.26 SD score after 2 yr, with a wide range. In univariate analyses the highest correlation coefficients to the 2-yr growth response were found to be vs. the following variables from the start of treatment: IGF-I SD score (r = -0.49), log maximum GH concentration (log GHmax) during the arginine-insulin tolerance test (r = -0.47), difference between the height SD score of the individual child and the midparental height SD score (diffSD score; r = -0.45), IGFBP-3 SD score (r = -0.39), age (r = -0.30), short term change in IGFBP-3 SD score (r = 0.37), and IGF-I SD score (r = 0.34). In multivariate stepwise regression analysis, 41% of the variation in the 2-yr growth response could be explained by IGF-I SD score or log GHmax together with age at the start of treatment, weight SD score at 1 yr of age, and diffSD score. When both IGF-I SD score and GHmax were included and when the short term changes in IGF-I SD score were added, 46% and 58% of the variation, respectively, could be explained. The regression algorithms using different combinations of variables and their corresponding prediction intervals are also presented.

  • 34.
    Kriström, Berit
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Karlberg, J
    Albertsson-Wikland, K
    Prediction of the growth response of short prepubertal children treated with growth hormone. Swedish Paediatric Study Group for GH treatment.1995In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 84, no 1, p. 51-7Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to identify predictors of the growth response to growth hormone (GH) during the first 2 years of GH treatment, using auxological data and the maximum GH response (GHmax) to provocation tests. The patients were 169 prepubertal short children (27F, 142M), with Gmax values ranging from 0 to 65 mU/l. Their mean age (+/- SD) was 8.3 +/- 2.4 years (range 3-13 years), mean height SDS -3.0 +/- 0.7 (range -1.5 to -6.0 SDS) and mean pretreatment height velocity was normal (+/- 0.0 SDS) (range -1.6 to +0.9 SDS). The increase in height SDS during the first 2 years of GH treatment (0.1 U/kg/day) varied from 0.10 to 3.75 SDS, with younger children having a better growth response. Individual growth responses correlated (p < 0.001) with GHmax (r = -0.37), age (r = -0.35), 1-year pretreatment delta SDS (r = -0.25), mid-parental height SDS (r = 0.34), height SDS at start of treatment (r = -0.22) and difference between height SDS of an individual child at the onset of GH treatment and mid-parental height expressed in SDS (diff SDS) (r = -0.43). In a multiple stepwise linear regression model, diff SDS and log GHmax were found to be the strongest predictors of the magnitude of the growth response. In the short children in this study who exhibited a broad range of GHmax values, 33% of the growth response during the first 2 years of treatment could be predicted.

  • 35.
    Kriström, Berit
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lundberg, Elena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jonsson, Björn
    Albertsson-Wikland, Kerstin
    IGF-1 and growth response to adult height in a randomized GH treatment trial in short non-GH-deficient children2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 8, p. 2917-2924Article in journal (Refereed)
    Abstract [en]

    Context: GH treatment significantly increased adult height (AH) in a dose-dependent manner in short non-GH-deficient children in a randomized, controlled, clinical trial; the mean gain in height SD score (height(SDS)) was 1.3 (range 0-3), compared with 0.2 in the untreated group. Objective: The objective of the study was to analyze the relationship between IGF-1(SDS), IGF binding protein-3 SDS (IGFBP3(SDS)), and their ratio(SDS) with a gain in the height(SDS) until AH in non-GH-deficient short children. Design and Setting: This was a randomized, controlled, multicenter clinical trial. Intervention: The intervention included GH treatment: 33 or 67 mu g/kg.d plus untreated controls. Subjects: One hundred fifty-one non-GH-deficient short children were included in the intent-to-treat (ITT) population and 108 in the per-protocol (PP) population; 112 children in the ITT and 68 children in the PP populations had idiopathic short stature (ISS). Main Outcome Measures: Increments from baseline to on-treatment study mean IGF-1(SDS) (Delta IGF-1(SDS)), IGFBP3(SDS), and IGF-1 to IGFBP3 ratio(SDS) were assessed in relationship to the gain in height(SDS). Results: Sixty-two percent of the variance in the gain in height(SDS) in children on GH treatment could be explained by four variables: Delta IGF-1(SDS) (explaining 28%), bone age delay, birth length (the taller the better), and GH dose (the higher the better). The lower IGF-1(SDS) was at baseline, the higher was its increment during treatment. For both the All(PP)- and the ISSPP-treated groups, the attained IGF-1(SDS) study level did not correlate with height gain. Conclusion: In short non-GH-deficient children, the GH dose-related increment in IGF-1(SDS) from baseline to mean study level was the most important explanatory variable for long-term growth response from the peripubertal period until AH, when IGF-1(SDS), IGFBP3(SDS), and their ratio(SDS) were compared concurrently.

  • 36.
    Kriström, Berit
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Löfqvist, C
    Rosberg, S
    Albertsson Wikland, K
    Effect of spontaneous GH secretion and the GH sampling period on the accuracy of models for predicting growth responses to GH treatment.2001In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 86, no 10, p. 4963-4Article in journal (Refereed)
  • 37.
    Kriström, Berit
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Wikland, Kerstin Albertsson
    Growth prediction models, concept and use.2002In: Hormone Research, ISSN 0301-0163, E-ISSN 1423-0046, Vol. 57 Suppl 2, p. 66-70Article in journal (Refereed)
    Abstract [en]

    There is a principal and qualitative difference between using regression results on data from groups of children, and using validated prediction models for individual children. Using accurate models, it is now possible to predict the growth response to growth hormone (GH) treatment in a slowly growing child with GH deficiency (GHD) or in a child with idiopathic short stature (ISS). The growth response to the standard dose of GH can be regarded as a bioassay for GH (i.e. the tissue GH responsiveness) and the information on this growth response can be used for different purposes: to decide about treatment or not, for monitoring, and for adjusting the GH dose in order to reach a defined goal for height. This last concept is now used in an ongoing prospective randomized GH dose-finding trial.

  • 38.
    Kriström, Berit
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Zdunek, Anna-Maija
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Rydh, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Sehlin, Petra
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Andersson Escher, Stefan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    A novel mutation in the LIM homeobox 3 gene is responsible for combined pituitary hormone deficiency, hearing impairment, and vertebral malformations.2009In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, no 4, p. 1154-1161Article in journal (Refereed)
    Abstract [en]

    CONTEXT: The LIM homeobox 3 (LHX3) LIM-homeodomain transcription factor gene, found in both man and mouse, is required for development of the pituitary and motor neurons, and is also expressed in the auditory system. OBJECTIVE: The objective of this study was to determine the cause of, and further explore, the phenotype in six patients (aged 6 months to 22 yr) with combined pituitary hormone deficiency (CPHD), restricted neck rotation, scoliosis, and congenital hearing impairment. Three of the patients also have mild autistic-like behavior. DESIGN: Because patients with CPHD and restricted neck rotation have previously been shown to have mutations in the LHX3 gene, a candidate gene approach was applied, and the gene was sequenced. Neck anatomy was explored by computed tomography and magnetic resonance imaging, including three-dimensional reformatting. RESULTS: A novel, recessive, splice-acceptor site mutation was found. The predicted protein encoded by the mutated gene lacks the homeodomain and carboxyl terminus of the normal, functional protein. Genealogical studies revealed a common gene source for all six families dating back to the 17th century. Anatomical abnormalities in the occipito-atlantoaxial joints in combination with a basilar impression of the dens axis were found in all patients assessed. CONCLUSIONS: This study extends both the mutations known to be responsible for LHX3-associated syndromes and their possible phenotypical consequences. Previously reported traits include CPHD and restricted neck rotation; patients examined in the present study also show a severe hearing defect. In addition, the existence of cervical vertebral malformations are revealed, responsible for the rigid neck and the development of scoliosis.

  • 39.
    Lundberg, Elena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Andersson, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Rosberg, Sten
    Albertsson-Wikland, Kerstin
    Are the GH Treatment Doses in Use within Secretion Rates of Healthy Children?2016In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 86, p. 378-378Article in journal (Other academic)
  • 40.
    Lundberg, Elena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Andersson, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Rosberg, Sten
    Albertsson-Wikland, Kerstin
    GH-Pattern with High Trophs are Often Found after Daily sc rhGH-Injection in Children2016In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 86, p. 377-377Article in journal (Other academic)
  • 41.
    Lundberg, Elena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jonsson, Bjorn
    Albertsson-Wikland, Kerstin
    Growth hormone (GH) dose-dependent IGF-I response relates to pubertal height gain2015In: BMC Endocrine Disorders, ISSN 1472-6823, E-ISSN 1472-6823, Vol. 15, article id 84Article in journal (Refereed)
    Abstract [en]

    Background: Responsiveness to GH treatment can be estimated by both growth and Delta IGF-I. The primary aim of the present study was to investigate if mimicking the physiological increase during puberty in GH secretion, by using a higher GH dose could lead to pubertal IGFs in short children with low GH secretion. The secondary aim was to explore the relationship between IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio and gain in height. Methods: A multicentre, randomized, clinical trial (TRN88-177) in 104 children (90 boys), who had received GH 33 mu g/kg/day during at least 1 prepubertal year. They were followed from GH start to adult height (mean, 7.5 years; range, 4.6-10.7). At onset of puberty, children were randomized into three groups, to receive 67 mu g/kg/day (GH(67)) given once (GH(67x1); n = 30) or divided into two daily injection (GH(33x2); n = 36), or to remain on a single 33 mu g/kg/ day dose (GH(33x1); n = 38). The outcome measures were change and obtained mean on-treatment IGF-I-SDS, IGFBP3(SDS) and IGF-I/IGFBP3 ratio(SDS) during prepuberty and puberty. These variables were assessed in relation to prepubertal, pubertal and total gain in height(SDS). Results: Mean prepubertal increases 1 year after GH start were: 2.1 IGF-I-SDS, 0.6 IGFBP3(SDS) and 1.5 IGF-I/IGFBP3ratio(SDS). A significant positive correlation was found between prepubertal Delta IGFs and both prepubertal and total gain in height(SDS). During puberty changes in IGFs were GH dose-dependent: mean pubertal level of IGF-I-SDS was higher in GH67 vs GH(33) (p = 0.031). First year pubertal Delta IGF-I-SDS was significantly higher in the GH(67) vs GH33 group (0.5 vs -0.1, respectively, p = 0.007), as well as Delta IGF-I-SDS to the pubertal mean level (0.2 vs -0.2, p = 0.028). In multivariate analyses, the prepubertal increase in 'Delta IGF-I-SDS from GH start' and the 'GH dose-dependent pubertal Delta IGF-I-SDS' were the most important variables for explaining variation in prepubertal (21 %), pubertal (26 %) and total (28 %) gain in height(SDS). Conclusion: The dose-dependent change in IGFs was related to a dose-dependent pubertal gain in height(SDS). The attempt to mimic normal physiology by giving a higher GH dose during puberty was associated with both an increase in IGF-I and a dose-dependent gain in height(SDS).

  • 42. Nilsson, K O
    et al.
    Albertsson-Wikland, K
    Alm, J
    Aronson, S
    Gustafsson, J
    Hagenäs, L
    Häger, A
    Ivarsson, S A
    Karlberg, J
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Marcus, C
    Moell, C
    Ritzen, M
    Tuvemo, T
    Wattsgård, C
    Westgren, U
    Westphal, O
    Aman, J
    Improved final height in girls with Turner's syndrome treated with growth hormone and oxandrolone.1996In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 81, no 2, p. 635-40Article in journal (Refereed)
    Abstract [en]

    The spontaneous growth process in Turner's syndrome is characterized by a progressive decline in height velocity during childhood and no pubertal growth spurt. Therefore, therapy aimed at improving height during childhood as well as increasing final height is desirable for most girls with Turner's syndrome. Forty-five girls with Turner's syndrome, 9-16 yr of age (mean age, 12.2 yr), were allocated to three study groups. Group 1 (n = 13) was initially treated with oxandrolone alone; after 1 yr of treatment, GH without (group 1a; n = 6) or with (group 1b; n = 7) ethinyl estradiol was added. Group 2 (n = 17) was treated with GH plus oxandrolone. Group 3 (n = 15) was treated with GH, oxandrolone, and ethinyl estradiol. The dosage were: GH, 0.1 IU/kg.day; oxandrolone, 0.05 mg/kg.day; and ethinyl estradiol, 100 ng/kg.day. A height of 150 cm or more was achieved in 61%, 75%, and 60% of the girls in groups 1, 2, and 3, respectively. The most impressive increase in height was seen in group 2. In this group the mean final height was 154.2 cm (SD = 6.6), which is equivalent to a mean net gain of 8.5 cm (SD = 4.6) over the projected final height. In group 3, in which ethinyl estradiol was included from the start of therapy, the initially good height velocity decelerated after 1-2 yr of treatment. Their mean final height was 151.1 (SD = 4.6) cm, equivalent to a mean net gain of 3.0 cm (SD = 3.8). A similar growth-decelerating effect of ethinyl estradiol was seen in group 1b. We conclude that in girls with Turner's syndrome who are older than 9 yr of age, treatment with GH in combination with oxandrolone results in significant growth acceleration, imitating that in normal puberty, leading to a more favorable height during childhood. This mode of treatment also results in a significantly increased final height, permitting a great number of the girls to attain a final height of more than 150 cm. However, early addition of estrogen decelerates the height velocity and reduces the gain in height.

  • 43. Nygren, Anders
    et al.
    Sunnegårdh, Jan
    Teien, Dag
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jonzon, Anders
    Björkhem, Gudrun
    Lindell, Sven
    Albertsson-Wikland, Kerstin
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Rapid cardiovascular effects of growth hormone treatment in short prepubertal children: impact of treatment duration2012In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 77, no 6, p. 877-884Article in journal (Refereed)
    Abstract [en]

    Objective Previous studies show that growth hormone (GH) treatment increases cardiac dimensions in short children with GH deficiency (GHD) and has diverse cardiac effects in children with idiopathic short stature (ISS). This study was performed to assess the effect of GH on the cardiovascular system in short children with a broad range of GH secretion and GH sensitivity/responsiveness.

    Design and patients In this prospective, multicentre study, short prepubertal children diagnosed with isolated GHD (89) or ISS (38) were followed during 2 years of GH treatment. They were randomized to receive either a standard (43 mu g/kg/day) or an individualized GH dose (range 17100 mu g/kg/day) based on GH responsiveness estimated by a prediction model and distance to target height. Echocardiography, blood pressure and electrocardiography were performed at baseline, 3, 12 and 24 months.

    Results Left ventricular mass (LVM) indexed to body surface area increased significantly during 2 years of GH treatment in both GHD and ISS irrespective of randomized dose. This change was already apparent at 3 months, when standard deviation scores (SDS) of wall thickness and diameter were increased. At 24 months, left ventricular diameter SDS remained increased, whereas myocardial thickness SDS returned to baseline values. There was no impairment of systolic or diastolic function. There was no correlation with treatment dose and LVM SDS at 24 months.

    Conclusions Irrespective of GH status, there was a rapid increase in LVM during GH treatment in short children. At 3 months, wall thickness and diameter were increased, whereas only diameter remained increased at 24 months.

  • 44. Pfäffle, Roland
    et al.
    Kanumakala, Shankar
    Höybye, Charlotte
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Zabransky, Markus
    Battelino, Tadej
    Colle, Michel
    Four-Year Results from PATRO Children, a Multi-Centre, Non-Interventional Study of the Long-Term Safety and Efficacy of Omnitrope (R) in Children Requiring Growth Hormone Treatment2016In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 86, p. 379-379Article in journal (Other academic)
  • 45. Schrier, Lenneke
    et al.
    de Kam, Marieke L.
    McKinnon, Rachel
    Bakri, Amalina Che
    Oostdijk, Wilma
    Sas, Theo C. J.
    Menke, Leonie A.
    Otten, Barto J.
    Keizer-Schrama, Sabine M. P. F. de Muinck
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Ankarberg-Lindgren, Carina
    Burggraaf, Jacobus
    Albertsson-Wikland, Kerstin
    Wit, Jan M.
    Comparison of Body Surface Area versus Weight-Based Growth Hormone Dosing for Girls with Turner Syndrome2014In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 81, no 5, p. 319-330Article in journal (Refereed)
    Abstract [en]

    Background/Aims: Growth Hormone (GH) dosage in childhood is adjusted for body size, but there is no consensus whether body weight (BW) or body surface area (BSA) should be used. We aimed at comparing the biological effect and cost-effectiveness of GH treatment dosed per m(2) BSA in comparison with dosing per kg BW in girls with Turner syndrome (TS). Methods: Serum IGF-I, GH dose, and adult height gain (AHG) from girls participating in two Dutch and five Swedish studies on the efficacy of GH were analyzed, and the cumulative GH dose and costs were calculated for both dose adjustment methods. Additional medication included estrogens (if no spontaneous puberty occurred) and oxandrolone in some studies. Results: At each GH dose, the serum IGF-I standard deviation score remained stable over time after an initial increase after the start of treatment. On a high dose (at 1 m(2) equivalent to 0.056-0.067 mg/kg/day), AHG was at least equal on GH dosed per m(2) BSA compared with dosing per kg BW. The cumulative dose and cost were significantly lower if the GH dose was adjusted for m(2) BSA. Conclusion: Dosing GH per m(2) BSA is at least as efficacious as dosing per kg BW, and is more cost-effective. (C) 2014 S. Karger AG, Basel

  • 46. Tuvemo, T
    et al.
    Jonsson, B
    Gustafsson, J
    Albertsson-Wikland, K
    Aronson, A S
    Häger, A
    Ivarson, S
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Marcus, C
    Nilsson, K O
    Westgren, U
    Westphal, O
    Aman, J
    Proos, L A
    Final height after combined growth hormone and GnRH analogue treatment in adopted girls with early puberty2004In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 93, no 11, p. 1456-62Article in journal (Refereed)
    Abstract [en]

    Background: Girls adopted from developing countries often have early or precocious puberty, requiring treatment with gonadotrophin-releasing hormone (GnRH) analogues. During such treatment, decreased growth velocity is frequent. Aim: To study whether the addition of growth hormone (GH) to GnRH analogue treatment improves final height in girls with early or precocious puberty. Methods: Forty-six girls with early or precocious puberty (age ± 9.5y) adopted from developing countries were randomized for treatment for 2–4 y with GnRH analogue, or with a combination of GH and GnRH analogue. Results: During treatment, the mean growth velocity in the GH/GnRH analogue group was significantly higher compared to the control group. Combined GH/GnRH analogue treatment resulted in a higher final height: 158.9 cm compared to 155.8 cm in the GnRH analogue-treated group. Three out of 24 girls (13%) in the combined group and nine of the 22 girls (41%) treated with GnRH analogue alone attained a final height below –2 standard deviation scores (SDS).

    Conclusion: The difference between the two groups is statistically significant, and possibly of clinical importance. A future challenge is to identify a subgroup with clinically significant advantage of GH addition to GnRH analogue treatment. Being very short on arrival in Sweden and being short and young at start of treatment are possible indicators.

  • 47.
    Wikland, Kerstin Albertsson
    et al.
    International Pediatric Growth Research Center, Department of Pediatrics University of Göteborg, SE-41685 Göteborg.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Rosberg, Sten
    International Pediatric Growth Research Center, Department of Pediatrics University of Göteborg, SE-41685 Göteborg.
    Svensson, Birgitta
    International Pediatric Growth Research Center, Department of Pediatrics University of Göteborg, SE-41685 Göteborg.
    Nierop, Andreas F. M.
    Muvara bv, Tijmtuin 8, 2353 PH Leiderdorp, the Netherlands.
    Validated multivariate models predicting the growth response to GH treatment in individual short children with a broad range in GH secretion capacities.2000In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 48, no 4, p. 475-484Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to develop and validate models that could predict the growth responses to GH therapy of individual children. Models for prediction of the initial one and 2-y growth response were constructed from a cohort of 269 prepubertal children (Model group) with isolated GH deficiency or idiopathic short stature, using a nonlinear multivariate data fitting technique. Five sets of clinical information were used. The "Basic model" was created using auxological data from the year before the start of GH treatment and parental heights. In addition to Basic model data, the other four models included growth data from the first 2 y of life, or IGF-I, or GH secretion estimated during a provocation test (AITT) or a spontaneous GH secretion profile. The performance of the models was validated by calculating the differences between predicted and observed growth responses in 149 new GH treated children (Validation group) who fulfilled the inclusion criteria used in the original cohort. The SD of these differences (SD(res)) in the validation group was compared with the SD(res) for the model group. For the 1st y, the SD(res) for the Basic model was 0.28 SDscores. The lowest SD(res) (0.19 SDscores), giving the most narrow prediction interval, was achieved adding the 24h GH profile and data on growth from the first 2 y of life to the Basic model. The models presented permit estimation of GH responsiveness in children over a broad range in GH secretion, and with an accuracy of the models substantially better than when using maximal GH response during an provocation test. The predicted individual growth response, calculated using a computer program, can serve as a guide for evidence-based decisions when selecting children to GH treatment.

  • 48. Wit, J. M.
    et al.
    Ranke, M. B.
    Albertsson-Wikland, K.
    Carrascosa, A.
    Rosenfeld, R. G.
    Van Buuren, S.
    Kriström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Schoenau, E.
    Audi, L.
    Hokken-Koelega, A. C. S.
    Bang, P.
    Jung, H.
    Blum, W. F.
    Silverman, L. A.
    Cohen, P.
    Cianfarani, S.
    Deal, C.
    Clayton, P. E.
    de Graaff, L.
    Dahlgren, J.
    Kleintjens, J.
    Roelants, M.
    Personalized Approach to Growth Hormone Treatment: Clinical Use of Growth Prediction Models2013In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 79, no 5, p. 257-270Article, review/survey (Refereed)
    Abstract [en]

    The goal of growth hormone (GH) treatment in a short child is to attain a fast catch-up growth toward the target height (TH) standard deviation score (SDS), followed by a maintenance phase, a proper pubertal height gain, and an adult height close to TH. The short-term response variable of GH treatment, first-year height velocity (HV) (cm/year or change in height SDS), can either be compared with GH response charts for diagnosis, age and gender, or with predicted HV based on prediction models. Three types of prediction models have been described: the Kabi International Growth Hormone Study models, the Gothenburg models and the Cologne model. With these models, 50-80% of the variance could be explained. When used prospectively, individualized dosing reduces the variation in growth response in comparison with a fixed dose per body weight. Insulin-like growth factor-I-based dose titration also led to a decrease in the variation. It is uncertain whether adding biochemical, genetic or proteomic markers may improve the accuracy of the prediction. Prediction models may lead to a more evidence-based approach to determine the GH dose regimen and may reduce the drug costs for GH treatment. There is a need for user-friendly software programs to make prediction models easily available in the clinic.

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