Titration of growth hormone dose using insulin-like growth factor-1 measurements: Is it feasible in children?

Abstract

See related article, p 606. For more than 4 decades, growth hormone (GH) has been available to treat growth hormone deficiency (GHD) in children. Until 1985, GH was extracted from human cadaveric pituitary glands, the use of which was eliminated as a result of fatal transmission of the Cruetzfeldt-Jakob virus.1Grumbach MM Bin-Abbas BS Kaplan SL. The growth hormone cascade: progress and long-term results of growth hormone treatment in growth hormone deficiency.Horm Res. 1998; 49: 41-57Crossref Scopus (62) Google Scholar Fortunately, the rapid development of recombinant technology from basic research to clinical testing allowed availability of an “unlimited” commercial source of recombinant human GH (hGH). Refinements in both dosage and frequency of GH administration improved the adult height achieved, even in a range within “genetic” target height (based on parental heights).1Grumbach MM Bin-Abbas BS Kaplan SL. The growth hormone cascade: progress and long-term results of growth hormone treatment in growth hormone deficiency.Horm Res. 1998; 49: 41-57Crossref Scopus (62) Google Scholar, 2Hintz RL. Final height of growth hormone-treated patients with growth hormone deficiency: the North American experience.Acta Paediatr. 1999; 88: 70-71Crossref Google Scholar, 3Cutfield W Lindberg A Albertsson-Wikland K Chatelain P Ranke MB Wilton P. Final height in idiopathic growth hormone deficiency: the KIGS experience. KIGS International Board.Acta Paediatr. 1999; 88: 72-75Crossref PubMed Google Scholar What is yet unresolved is the clinical application of a useful biochemical marker for evaluating the dose of hGH for children. Would it not be ideal to have the ability to titrate the dose of hGH analogous to the titration of thyroid hormone replacement as is readily accomplished in patients with primary hypothyroidism? In this issue of The Journal, Lanes and Jakubowicz4Lanes R Jakubowicz S. Is insulin-like growth factor-1 useful in assessing the response to growth hormone of growth hormone-deficient children.J Pediatr. 2002; 141: 606-610Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar ask the question whether insulin-like growth factor-1 (IGF-1) is useful in monitoring the response to hGH in children with GHD. At first glance, this seems like a rather easy issue to resolve. After all, the somatomedin hypothesis was first proposed almost 45 years ago.5Salmon WD Daughaday WH. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro.J Lab Clin Med. 1957; 49: 825-826PubMed Google Scholar Numerous studies have since substantiated that GH action is mediated through IGF-1 (previously referred to as somatomedin), especially in regard to linear skeletal growth. This hypothesis has gone through major revisions,6LeRoith D Bondy C Yakar S Liu JL Butler A. The somatomedin hypothesis: 2001.Endocr Rev. 2001; 22: 53-74Crossref PubMed Scopus (859) Google Scholar which incorporate paracrine mechanisms of action. Also, as demonstrated by using the somatomedin generation test7Buchway CK Guevara-Aguirre J Pratt KL Burren CP Rosenfeld RG. The IGF-1 generation test revisited: a marker of GH sensitivity.J Clin Endocrinol Metab. 2001; 86: 5176-5183Crossref PubMed Scopus (130) Google Scholar and clinical experience in pediatric endocrine practice, serum IGF-1 concentrations increase acutely and are sustained after chronic hGH treatment. Several studies in adults demonstrate the utility of using serum IGF-1 concentrations to titrate the hGH dose until maintenance levels are achieved8J Clin Endocrinol Metab. 1998; 83: 379-381Crossref PubMed Scopus (707) Google Scholar, 9Bengtsson B-A Johannson G. Treatment of growth hormone deficiency in adults.J Clin Endocrinol Metab. 2000; 85: 933-937Crossref PubMed Scopus (42) Google Scholar; this approach is considered standard practice in the treatment of adults with GHD. In adults with GHD, clinical endocrinologists are constrained from using growth as a valuable biologic parameter, but instead depend on serum IGF-1 levels, body composition, treatment emergent adverse events, quality of life and other biochemical markers such as serum and urine measurements of bone formation and resorption. On the other hand, in children these therapeutic response issues are confounded by the controversy as to what constitutes GHD in other than those children who are readily and universally recognized as having “severe” GHD. This latter confounding issue will not be further discussed. In pediatric endocrine practice, GH dose is generally determined by the weight of the patient (0.18-0.30 mg/kg/ week; 0.54-0.9 IU/kg/week) (0.026-0.043 mg/kg/day; 0.08-0.13 IU/kg/day) (3 IU = 1 mg hGH) and the growth rate. Worldwide dosing regimens vary from 25 to 50 μg/kg/day. For obese patients, consideration should be given to hGH dosing based on surface area. As a practical matter, pediatric endocrinologists use growth rate as the key biologic marker of successful hGH treatment, although standard deviation (SD) scores are both useful and readily available by using computer programs and charts. Primarily during the first year, there is a phenomenon of catch-up growth; this exaggerated growth rate is 2 to 4 times greater than the pretreatment growth velocity. In general, by the third and fourth years of hGH therapy, the actual growth velocity in centimeters per year (or expressed as SD height velocity score) in patients receiving hGH therapy more likely approximates the growth rate for age, or in certain circumstances, relative to bone age. IGF-1, IGF binding protein-3 (IGFBP-3), and acid-labile subunit (ALS) IGF protein are all GH-dependent. Serum IGF-1 levels must be interpreted in the absence of other conditions that artifactually lower the serum concentrations; examples include malnutrition, hepatic disease, poorly controlled diabetes mellitus and hypothyroidism. Of these three proteins, serum IGF-1 level has been best validated as a biomarker of GHD, although children with GHD may have IGF-1 levels in the normal range.10Sizonenko PC Clayton PE Cohen P Hintz RL Tanaka T Laron Z. Diagnosis and management of growth hormone deficiency in childhood and adolescence. Part 1: diagnosis of growth hormone deficiency.Growth Horm IGF Res. 2001; 11: 137-165Abstract Full Text PDF PubMed Scopus (135) Google Scholar In this study, Lanes and Jakubowicz4Lanes R Jakubowicz S. Is insulin-like growth factor-1 useful in assessing the response to growth hormone of growth hormone-deficient children.J Pediatr. 2002; 141: 606-610Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar did not find any correlation of hGH dose to serum IGF-1 concentration; however, the design and analysis of the study may not allow the conclusions drawn. There are three larger studies that show positive correlations in height and change of IGF-1 levels in prepubertal GHD children11Cohen P Bright GM Rogol AD Kappelgaard A-M Rosenfeld RG on behalf of the American Norditropin Clinical Trials Group Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety.J Clin Endocrinol Metab. 2002; 87: 90-98Crossref PubMed Scopus (128) Google Scholar, 12An B Bright GM Cohen P Nicar M Rosenfeld R. IGF-based individualized dosing of recombinant human growth hormone (rhGH) hormone children.in: 84th Annual Endocrine Society Meeting [abstract] June 19-22, 2002, San Francisco, California2002: 616Google Scholar, 13Ranke MB Schweizer R Elmlinger MW Weber K Binder G Schwarze CP et al.Relevance of IGF-1, IGF-3, and IGFBP-2 measurements during GH treatment of GH-deficient and non-GH-deficient children and adolescents.Horm Res. 2001; 55: 115-124Crossref PubMed Scopus (41) Google Scholar and non-GHD deficient children.13Ranke MB Schweizer R Elmlinger MW Weber K Binder G Schwarze CP et al.Relevance of IGF-1, IGF-3, and IGFBP-2 measurements during GH treatment of GH-deficient and non-GH-deficient children and adolescents.Horm Res. 2001; 55: 115-124Crossref PubMed Scopus (41) Google Scholar In another study done in a limited number of children with intrauterine growth restriction, De Zegher et al demonstrated a similar relationship in patients receiving a high dose of hGH.14De Zegher F Ong K Van Helvoirt M Mohn A Woods K Dunger D. High-dose growth hormone (GH) in non-GH-deficient children born small of gestational age induces growth responses related to pre-treatment GH secretion and associated with a reversible decrease in insulin sensitivity.J Clin Endocrinol Metab. 2002; 87: 148-151Crossref PubMed Scopus (101) Google Scholar Although there is variability in the relationship of hGH therapeutic dose and IGF levels in various studies, overall it is helpful to use titration as the approach to determine the specific hGH dose. Are we to assume that children are different from adults or are there other issues to consider before we draw the conclusion suggested by Lanes and Jakubowicz4Lanes R Jakubowicz S. Is insulin-like growth factor-1 useful in assessing the response to growth hormone of growth hormone-deficient children.J Pediatr. 2002; 141: 606-610Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar? Their study design was limited to a small number of children (n = 24) in an investigation involving only one year of therapy. Unlike the previously published studies in adults with only “severe” GHD, these children had varying degrees of GH insufficiency. More discussion about the design and statistics of the current study4Lanes R Jakubowicz S. Is insulin-like growth factor-1 useful in assessing the response to growth hormone of growth hormone-deficient children.J Pediatr. 2002; 141: 606-610Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar is warranted. If the authors intended to test if the height increment in ΔIGF-1 (>1 SDS) was different from ΔIGF-1 group 2 (<1 SDS), then statistical power calculations intended to show the actual difference of 0.8 SD would require at least 100 subjects per group to test at a significance of 0.05 with 80% power in a 2-sided test. Some would argue that IGF-1 SD score should not be used as a dependent or independent variable in either analysis of variance or multiple regression analyses. Unquantifiable bias can be introduced because of difficulties in computing meaningful SD scores, thus IGF-1 concentrations, sex, and age as separate variables are more scientifically sound as measures.11Cohen P Bright GM Rogol AD Kappelgaard A-M Rosenfeld RG on behalf of the American Norditropin Clinical Trials Group Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety.J Clin Endocrinol Metab. 2002; 87: 90-98Crossref PubMed Scopus (128) Google Scholar In fact, the only statistical way to avoid this difficulty is to account for age, sex, bone age, and parental heights. Thus, regression analysis would require measurement of those variables. Moreover, age and bone age may be codependent predictive variables, thus rather than using simple multiple regression anaylsis, a stepwise, forward multiple regression analysis should be used. In adults, Tillman et al15Tillmann V Patel-Cohen P Gill MS Whatmore AJ Price DA Kibirige MS et al.Monitoring serum insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), IGF/IGF-3 molar ratio and leptin during growth hormone treatment for disordered growth.Clin Endocrinol. 2000; 53: 329-336Crossref PubMed Scopus (53) Google Scholar showed increased IGF-1 levels, which were maximized at twelve months. In the study by Lanes and Jakubowicz,4Lanes R Jakubowicz S. Is insulin-like growth factor-1 useful in assessing the response to growth hormone of growth hormone-deficient children.J Pediatr. 2002; 141: 606-610Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar hGH treatment increased IGF-1 and IGFBP-3 levels for the first 6 months, but no further increment occurred after a 40% increase in dose throughout the subsequent 6 months. A third yet higher dose group and significantly larger number of children might have been helpful in the design of the study. Also, an extension of the study to two or more years might have provided a trend as well as additional data points for more in-depth statistical analysis. These results are in contrast to another study in children reported at the 84th Annual Endocrine Society Meeting in June 2002.12An B Bright GM Cohen P Nicar M Rosenfeld R. IGF-based individualized dosing of recombinant human growth hormone (rhGH) hormone children.in: 84th Annual Endocrine Society Meeting [abstract] June 19-22, 2002, San Francisco, California2002: 616Google Scholar Bright et al demonstrated that hGH therapy results in positive correlation of IGF-1 levels to a 2-year adjusted change in height SD scores.16Bright G An B Cohen P Rosenfeld R. Prediction of height change with recombinant human growth hormone.in: 84th Annual Endocrine Society Meeting [abstract] June 19-22, 2002, San Francisco, California2002: 616Google Scholar The number of evaluable subjects in that study was greater (n = 71) and three groups were studied, each receiving one dose (either 0.175, 0.35, or 0.7 mg/kg/week). Moreover, there are two reports where IGF-1 is considered a useful marker of hGH efficacy but the issue of titrating the dose by using IGF-1 levels was not addressed.11Cohen P Bright GM Rogol AD Kappelgaard A-M Rosenfeld RG on behalf of the American Norditropin Clinical Trials Group Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety.J Clin Endocrinol Metab. 2002; 87: 90-98Crossref PubMed Scopus (128) Google Scholar, 17Mandel SH Moreland E Rosenfeld RG Gargosky SE. The effects of GH therapy on the immunoreactive forms and distribution of IGFBP-3, IGF-1, the acid-labile subunit, and growth rate in GH-deficient children.Endocrine. 1997; 7: 351-360Crossref PubMed Google Scholar For purpose of discussion in this current study, only prepubertal gender issues are addressed here because it is notable that pubertal and adult females require higher doses of hGH to normalize IGF-1 levels. Variation in IGF-1 levels by as much as 30% with diurnal fluctuations of 14% to 17%18Oscarsson J Johannsson G Johansson J-O Lundberg P-A Linstedt G Bengtsson B-A. Diurnal variation in serum insulin-like growth factor (IGF)-1 and IGF binding protein-3 concentrations during daily subcutaneous injections of recombinant human growth hormone in GH-deficient adults.Clin Endocrinol. 1997; 46: 63-68Crossref PubMed Scopus (50) Google Scholar and monthly intra-individual differences of 14%19Gelander L Blum WF Larsson L Rosberg S Albertsson-Wikland K. Monthly measurements of insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 in healthy prepubertal children: characterization and relationship with growth: the 1-year growth study.Pediatr Res. 1999; 45: 377-383Crossref PubMed Scopus (47) Google Scholar contribute to the difficulty of demonstrating clinically relevant as well statistically significant differences. This suggests that a larger study is necessary to address the issue about titration of hGH dose by using IGF-1 concentrations. Nevertheless, there may ultimately be a useful correlation for groups of patients, but for individual patients, all biomarkers must be interpreted in the clinical context, most significantly growth velocity. Even if the issue of dose titration is not resolved at this time, IGF-1 can still play an important role in assessing compliance and aid in the avoidance of side effects as a result of overtreatment.20Wetterau L Cohen P. Role of insulin-like growth factor monitoring in optimizing growth hormone therapy.J Pediatr Endocrinol Metab. 2000; 13: 1371-1376PubMed Google Scholar At this point with limited data, the use of titration of hGH dose to maintain age-specific IGF-1 and IGFBP-3 might be considered. However, more studies are indicated before IGF-1 can be heralded as a clinically useful biomarker for titration of hGH treatment in children. The current investigation by Lanes and Jakubowicz4Lanes R Jakubowicz S. Is insulin-like growth factor-1 useful in assessing the response to growth hormone of growth hormone-deficient children.J Pediatr. 2002; 141: 606-610Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar is an early attempt to address the question. Is insulin-like growth factor-1 monitoring useful in assessing the response to growth hormone of growth hormone-deficient children?The Journal of PediatricsVol. 141Issue 5PreviewObjective: To assess the relationship between insulin-like growth factor-1 (IGF-1), the growth hormone (GH) dose utilized to treat GH-deficient children and the changes noticed in height-standard deviation score (H-SDS) and height velocity (HV). Study design: We studied 24 prepubertal GH-deficient patients with a mean age of 10.5 ± 1.8 years and a mean bone age (BA) of 8.4 ± 2.1 years. H-SDS for chronologic age (CA) and BA before therapy were −2.6 ± 0.8 and −1.2 ± 0.8, whereas height velocity (HV)-SDS was −1.1 ± 1.5. Full-Text PDF