Abstract
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 µg/kg/day) or a prediction model-guided individualized dose (17-100 µg/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 GHmax and IGF-ISDS 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.
References
1.
van Pareren YK, Duivenvoorden HJ, Slijper FS, Koot HM, Hokken-Koelega AC: Intelligence and psychosocial functioning during long-term growth hormone therapy in children born small for gestational age. J Clin Endocrinol Metab 2004;89:5295-5302.
2.
Siemensma EP, Tummers-de Lind van Wijngaarden RF, Festen DA, Troeman ZC, van Alfen-van der Velden AA, Otten BJ, Rotteveel J, Odink RJ, Bindels-de Heus GC, van Leeuwen M, Haring DA, Oostdijk W, Bocca G, Mieke Houdijk EC, van Trotsenburg AS, Hoorweg-Nijman JJ, van Wieringen H, Vreuls RC, Jira PE, Schroor EJ, van Pinxteren-Nagler E, Willem Pilon J, Lunshof LB, Hokken-Koelega AC: Beneficial effects of growth hormone treatment on cognition in children with prader-willi syndrome: A randomized controlled trial and longitudinal study. J Clin Endocrinol Metab 2012;97:2307-2314.
3.
Webb EA, O'Reilly MA, Clayden JD, Seunarine KK, Chong WK, Dale N, Salt A, Clark CA, Dattani MT: Effect of growth hormone deficiency on brain structure, motor function and cognition. Brain 2012;135:216-227.
4.
Falleti MG, Maruff P, Burman P, Harris A: The effects of growth hormone (GH) deficiency and gh replacement on cognitive performance in adults: a meta-analysis of the current literature. Psychoneuroendocrinology 2006;31:681-691.
5.
Arends NJ, Boonstra VH, Hokken-Koelega AC: Head circumference and body proportions before and during growth hormone treatment in short children who were born small for gestational age. Pediatrics 2004;114:683-690.
6.
Lagrou K, Vanderfaeillie J, Froidecoeur C, Thomas M, Massa G, Tenoutasse S, Craen M, Lebrethon MC, Beckers D, Francois I, Rooman R, Thiry-Counson G, de Beaufort C, De Schepper J: Effect of 2 years of high-dose growth hormone therapy on cognitive and psychosocial development in short children born small for gestational age. Eur J Endocrinol 2007;156:195-201.
7.
Deijen JB, de Boer H, van der Veen EA: Cognitive changes during growth hormone replacement in adult men. Psychoneuroendocrinology 1998;23:45-55.
8.
Sathiavageeswaran M, Burman P, Lawrence D, Harris AG, Falleti MG, Maruff P, Wass J: Effects of GH on cognitive function in elderly patients with adult-onset GH deficiency: a placebo-controlled 12-month study. Eur J Endocrinol 2007;156:439-447.
9.
Arwert LI, Veltman DJ, Deijen JB, van Dam PS, Drent ML: Effects of growth hormone substitution therapy on cognitive functioning in growth hormone deficient patients: a functional mri study. Neuroendocrinology 2006;83:12-19.
10.
Oertel H, Schneider HJ, Stalla GK, Holsboer F, Zihl J: The effect of growth hormone substitution on cognitive performance in adult patients with hypopituitarism. Psychoneuroendocrinology 2004;29:839-850.
11.
Maric NP, Doknic M, Pavlovic D, Pekic S, Stojanovic M, Jasovic-Gasic M, Popovic V: Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy. J Endocrinol Invest 2010;33:770-775.
12.
Vitiello MV, Moe KE, Merriam GR, Mazzoni G, Buchner DH, Schwartz RS: Growth hormone releasing hormone improves the cognition of healthy older adults. Neurobiol Aging 2006;27:318-323.
13.
Johansson JO, Larson G, Andersson M, Elmgren A, Hynsjo L, Lindahl A, Lundberg PA, Isaksson OG, Lindstedt S, Bengtsson BA: Treatment of growth hormone-deficient adults with recombinant human growth hormone increases the concentration of growth hormone in the cerebrospinal fluid and affects neurotransmitters. Neuroendocrinology 1995;61:57-66.
14.
Burman P, Hetta J, Wide L, Mansson JE, Ekman R, Karlsson FA: Growth hormone treatment affects brain neurotransmitters and thyroxine. Clin Endocrinol 1996;44:319-324.
15.
Nyberg F, Burman P: Growth hormone and its receptors in the central nervous system - location and functional significance. Horm Res 1996;45:18-22.
16.
Nyberg F, Hallberg M: Growth hormone and cognitive function. Nat Rev Endocrinol 2013;9:357-365.
17.
Carson MJ, Behringer RR, Brinster RL, McMorris FA: Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron 1993;10:729-740.
18.
Dentremont KD, Ye P, D'Ercole AJ, O'Kusky JR: Increased insulin-like growth factor-I (IGF-I) expression during early postnatal development differentially increases neuron number and growth in medullary nuclei of the mouse. Brain Res Dev Brain Res 1999;114:135-141.
19.
Le Greves M, Zhou Q, Berg M, Le Greves P, Fholenhag K, Meyerson B, Nyberg F: Growth hormone replacement in hypophysectomized rats affects spatial performance and hippocampal levels of NMDA receptor subunit and PSD-95 gene transcript levels. Exp Brain Res 2006;173:267-273.
20.
Gronbladh A, Johansson J, Nostl A, Nyberg F, Hallberg M: Gh improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats. J Endocrinol 2013;216:31-41.
21.
Araujo DM, Lapchak PA, Collier B, Chabot JG, Quirion R: Insulin-like growth factor-1 (somatomedin-C) receptors in the rat brain: distribution and interaction with the hippocampal cholinergic system. Brain Res 1989;484:130-138.
22.
Lynch CD, Lyons D, Khan A, Bennett SA, Sonntag WE: Insulin-like growth factor-1 selectively increases glucose utilization in brains of aged animals. Endocrinology 2001;142:506-509.
23.
Sonntag WE, Bennett SA, Khan AS, Thornton PL, Xu X, Ingram RL, Brunso-Bechtold JK: Age and insulin-like growth factor-1 modulate N-methyl-D-aspartate receptor subtype expression in rats. Brain Res Bull 2000;51:331-338.
24.
Kristrom B, Aronson AS, Dahlgren J, Gustafsson J, Halldin M, Ivarsson SA, Nilsson NO, Svensson J, Tuvemo T, Albertsson-Wikland K: 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. J Clin Endocrinol Metab 2009;94:483-490.
25.
Nygren A, Sunnegardh J, Teien D, Jonzon A, Bjorkhem G, Lindell S, Albertsson-Wikland K, Kristrom B: Rapid cardiovascular effects of growth hormone treatment in short prepubertal children: impact of treatment duration. Clin Endocrinol 2012;77:877-884.
26.
Decker R, Albertsson-Wikland K, Kriström B, Nierop AF, Gustafsson J, Bosaeus I, Fors H, Hochberg Z, Dahlgren J: Metabolic outcome of GH treatment in prepubertal short children with and without classical GH deficiency. Clin Endocrinol 2010;73:346-354.
27.
Decker R, Nygren A, Kristrom B, Nierop AF, Gustafsson J, Albertsson-Wikland K, Dahlgren J: Different thresholds of tissue-specific dose-responses to growth hormone in short prepubertal children. BMC Endocr Disord 2012;12:26.
28.
Chaplin JE, Kristrom B, Jonsson B, Halldin Stenlid M, Aronson AS, Dahlgren J, Albertsson-Wikland K: When do short children realize they are short? Prepubertal short children's perception of height during 24 months of catch-up growth hormone treatment. Horm Res Paediatr 2012;77:241-249.
29.
Chaplin JE, Kriström B, Jonsson B, Hägglöf B, Tuvemo T, Aronson AS, Dahlgren J, Albertsson-Wikland K: Improvements in behaviour and self-esteem following growth hormone treatment in short prepubertal children. Horm Res Paediatr 2011;75:291-303.
30.
Wikland A-, K., Luo ZC, Niklasson A, Karlberg J: Swedish population-based longitudinal reference values from birth to 18 years of age for height, weight and head circumference. Acta Paediatr 2002;91:739-754.
31.
Karlberg P, Taranger J: The somatic development of children in a Swedish urban community. Acta Paediatr Scand Suppl 1976;258:1-148.
32.
Jansson C, Boguszewski C, Rosberg S, Carlsson L, Albertsson-Wikland K: Growth hormone (GH) assays: Influence of standard preparations, GH isoforms, assay characteristics, and GH-binding protein. Clin Chem 1997;43:950-956.
33.
Albertsson-Wikland K, Rosberg S: Methods of evaluating spontaneous growth hormone secretion; in Ranke M (ed): Functional Endocrinologic Diagnostics in Children and Adolescents. Mannheim, J&J Verlag, 2010, pp 129-159.
34.
Lofqvist C, Andersson E, Gelander L, Rosberg S, Blum WF, Albertsson Wikland K: Reference values for IGF-I throughout childhood and adolescence: a model that accounts simultaneously for the effect of gender, age, and puberty. J Clin Endocrinol Metab 2001;86:5870-5876.
35.
Lofqvist C, Andersson E, Gelander L, Rosberg S, Hulthen L, Blum WF, Wikland KA: Reference values for insulin-like growth factor-binding protein-3 (IGFBP-3) and the ratio of insulin-like growth factor-I to IGFBP-3 throughout childhood and adolescence. J Clin Endocrinol Metab 2005;90:1420-1427.
36.
Wechsler D: Wechsler Preschool and Primary Scale of Intelligence - Revised Manual. San Antonio, , The Psychological Corporation, 1989.
37.
Wechsler D: The Wechsler Intelligence Scale for Children - Third Edition. San Antonio, The Psychological Corporation, 1991.
38.
Canivez GLW: Long-term stability of the Wechsler intelligence scale for children-third edition among demographic subgroups: gender, race/ethnicity, and age. J Psychoeduc Assess 1999;17:13.
39.
Cattell RB: The theory of fluid and crystallized general intelligence checked at the 5-6 year-old level. Br J Educ Psychol 1967;37:209-224.
40.
Hale JB, Fiorello CA, Kavanagh JA, Hoeppner JA, Gaither RA: WISC-III predictors of academic achievement for children with learning disabilities: are global and factor scores comparable? Sch Psychol Q 2001;16:24.
41.
Barnett AG, van der Pols JC, Dobson AJ: Regression to the mean: what it is and how to deal with it. Int J Epidemiol 2005;34:215-220.
42.
Goodman SN: Discussion: an estimate of the science-wise false discovery rate and application to the top medical literature. Biostatistics 2014;15:23-27, discussion 39-45.
43.
Wuensch KL: Using SPSS to obtain a confidence interval for Cohen's d. 2012. http://core.ecu.edu/psyc/wuenschk/SPSS/CI-d-SPSS.pdf.
44.
Cohen J: Statistical Power Analysis for the Behavioral Sciences, ed 2. Hillsdale, Lawrence Erlbaum, 1988.
45.
Cohen J: A power primer. Psychol Bull 1992;112:155-159.
46.
Glass G: Primary, secondary and meta-analysis of research. Educ Res 1976 5:3-8.
47.
Aleman A, de Vries WR, Koppeschaar HP, Osman-Dualeh M, Verhaar HJ, Samson MM, Bol E, de Haan EH: Relationship between circulating levels of sex hormones and insulin-like growth factor-1 and fluid intelligence in older men. Exp Aging Res 2001;27:283-291.
48.
Fry AF, Hale S: Relationships among processing speed, working memory, and fluid intelligence in children. Biol Psychol 2000;54:1-34.
49.
Gray JR, Chabris CF, Braver TS: Neural mechanisms of general fluid intelligence. Nat Neurosci 2003;6:316-322.
50.
Aleman A, Verhaar HJ, De Haan EH, De Vries WR, Samson MM, Drent ML, Van der Veen EA, Koppeschaar HP: Insulin-like growth factor-I and cognitive function in healthy older men. J Clin Endocrinol Metab 1999;84:471-475.
51.
Deijen JB, Arwert LI, Drent ML: The GH/IGF-I axis and cognitive changes across a 4-year period in healthy adults. ISRN Endocrinology 2011;2011:249421.
52.
Beglinger LJ, Gaydos B, Tangphao-Daniels O, Duff K, Kareken DA, Crawford J, Fastenau PS, Siemers ER: Practice effects and the use of alternate forms in serial neuropsychological testing. Arch Clin Neuropsychol 2005;20:517-529.
53.
McCaffrey RJ, Ortega A, Haase RF: Effects of repeated neuropsychological assessments. Arch Clin Neuropsychol 1993;8:519-524.
54.
Noeker M: Neurocognitive development in children experiencing intrauterine growth retardation and born small for gestational age: pathological, constitutional and therapeutic pathways. Horm Res 2005;64(suppl 3):83-88.
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