Introduction
Treatment with exogenous growth hormone (GH) has become a well-accepted therapeutic option for children with growth failure. Since the availability of recombinant human GH (rhGH) in 1985, a wide range of conditions associated with decreased growth, including GH deficiency (GHD), Turner syndrome (TS), Noonan syndrome (NS), children born small for gestational age (SGA), Prader-Willi syndrome (PWS), idiopathic short stature (ISS), and SHOX (short stature homeobox) gene haploinsufficiency have been approved by the United States Food and Drug Administration (FDA) for treatment [
1‐
4].
Treatment with GH has been demonstrated to increase both short-term growth and adult height in pediatric patients with a variety of different growth disorders [
5‐
8]. However, considerable variability in response to this treatment has been reported across and within different diagnostic categories [
9‐
11]. Such variability makes decisions about whether to treat with GH, when to begin treatment, and what dosing to use more difficult [
12].
Reports from clinical trials and analyses suggest multiple factors that influence the response to GH treatment. Variables associated with better responses to GH treatment in patients with ISS include first-year growth response, younger age at start of treatment, the difference in height at the start of treatment from target height SD score (HSDS), and GH dose [
13,
14]. Additional factors may include underlying genetic conditions, presence of concomitant illness, and compliance with treatment [
15].
Formal height prediction models have been developed that combine information regarding patient- and treatment-related factors. Such prediction models of response to GH have been developed for patients with isolated or idiopathic GHD [
16‐
20], SGA [
21‐
23], chronic kidney disease [
24], ISS [
25], and TS [
26]. These models have the potential to aid individualized GH treatment planning and the adjustment of therapy based on early responses [
27]. However, even though GH treatment regimens can be based on model-derived predictions of growth response [
28], existing models account for only about one-half of the variability in the response to GH. Addition of genetic, biochemical, and other new variables to existing models may improve their accuracy and clinical utility [
29,
30].
Since 2002, the ANSWER (American Norditropin Studies: Web-enabled Research) Program® registry has collected information on patients receiving Norditropin. Participation within the ANSWER Program is at the discretion of the participating physicians and includes diagnostic categories in which treatment with growth hormone is used. The aim of this paper is to report growth response among different diagnostic categories and to identify factors associated with greater growth response over the first 2 years in children with GHD undergoing treatment with GH.
Discussion
In this longitudinal study of GH treatment in patients with GHD, MPHD, TS, SGA, and ISS, HSDS improved over time. For patients with GHD, several variables were identified that correlated with growth response during the first and second years of GH treatment. HV at 4 months was the most significant predictor of ΔHSDS observed in the first 2 years of GH treatment. This observation that 4-month HV was such a strong predictor is a novel finding, since many studies do not consistently report growth this early in the treatment cycle. Additional factors that were influential in predicting HSDS outcomes were ranked in order of importance: younger baseline age > lower baseline HSDS > higher baseline BMI SDS > lower baseline IGF-I SDS.
For the GHD patient population, age and baseline HSDS were important determinants of the response to GH treatment, as previously demonstrated [
18,
20]. However, other reports have also indicated additional significant factors, such as birth weight SDS and GH dose [
20]. The present results also indicated that higher baseline BMI was positively correlated with the growth response to GH for patients with GHD. Birth weight SDS and weight SDS were shown to be correlated with growth response to GH in the Pharmacia Kabi International Growth Study, suggesting that the heavier the child was, the greater the expected growth response to GH treatment [
20]. The impact of BMI in this study might reflect, at least in part, the importance of nutrition for optimization of outcomes in patients receiving GH [
1,
33].
In general, the results from this analysis are consistent with previously published results for specific patient populations. A prior prediction study in patients with TS indicated that first-year growth response to GH was significantly influenced by weekly GH dose, chronological age, HSDS, body weight SDS, number of GH injections per week, and adjunctive oxandrolone treatment [
26]. Predictors of the growth response over a longer duration of treatment (2-4 years) included HV during previous years, weekly GH dose, weight SDS, age, and oxandrolone treatment [
26]. In SGA patients, results from one study found that first-year growth response to GH treatment was the most important predictor of second-year growth response [
21]. Other variables that were significantly correlated with the growth response to GH included GH dose, weight and age at the start of treatment, and midparental HSDS [
21]. Studies in the ISS patient population have identified additional factors as predictors of longer-term responses to GH, including baseline HSDS, GH dose, weight at the start of treatment, and first-year growth response [
13,
14]. It is important to recognize that this category may be the most heterogenous, with growth failure being a consequence of many different etiologies.
Specific results from other studies that are consistent with the present analysis, include the lack of gender effect on response to GH treatment. Analysis of results from the Pfizer Kabi International Growth Study database found no significant gender-related differences in effects of GH in HV or HSDS over 2 or 3 years of treatment [
34]. In 8,018 patients with ISS in the National Cooperative Growth Study there was no significant effect of gender on first-year HV or first-year change from baseline in height SDS [
35]. In a recent report, a large cohort of male and female patients with GHD, MPHD, TS, SGA, NS, and ISS from the ANSWER Program registry was used to assess gender-related differences in ΔHSDS following 2 years of GH treatment. Results demonstrated increased ΔHSDS in all patients, however, clinically relevant gender differences were not observed [
36]. The importance of early timing for initiation of treatment from the present analysis is also consistent with previous findings. A National Registry of Growth Hormone Treatment report in the Netherlands that included 342 patients (diagnosis of GHD or a maximal GH response during provocation tests of less than 11 ng/mL) indicated that initiation of treatment before puberty resulted in a change from baseline in HSDS of 0.71 vs 0.58 for those who initiated treatment after puberty [
19]. Results from the French registry of 2,852 patients with idiopathic GHD also indicated that prepubertal initiation of GH treatment was associated with significantly greater adult height gain [
37]. Although in this study it is not known what proportion of patients across the different diagnostic categories may have been in puberty, the mean baseline chronological and bone ages are consistent with the majority of patients being prepubertal, and this likely lessens the impact of puberty on the observed growth responses.
The different correlations between baseline age, HSDS, BMI SDS, and IGF-I SDS, with growth response over 2 years of treatment with GH, carry implications for clinical practice. The correlation of baseline age with ΔHSDS and HV in the patients with GHD further support the initiation of GH at as young an age as possible to promote optimal growth. This concept is supported by results from another study that demonstrated a relationship between baseline age and first-year HV for patients with GHD, MPHD, and TS [
15]. Several consensus statements endorse the use of GH treatment as soon as a diagnosis is made or growth failure is demonstrated for patients from several diagnostic categories [
38‐
41]. The inverse relationship observed between baseline IGF-I and the two-year change in HSDS is consistent with an increased sensitivity to the effects of GH in patients who have a greater degree of GHD. In this non-interventional observational study, serum IGF-I was measured at a number of commercial laboratories reflecting routine clinical practice. IGF-I SDS was calculated using one formula which provided consistency to the analysis. This is also reflected in the finding that mean baseline IGF-I SDS in both the GHD and MPHD populations was lower than that observed in non-GHD patients. The positive correlation observed between baseline BMI SDS and ΔHSDS may emphasize the importance of nutrition in patients with growth failure [
33,
40]. An abnormally low BMI in pediatric patients may be a sign of malnutrition, which can also be associated with growth disturbances. In the end, the role of baseline age, HSDS, BMI SDS, and IGF-I SDS in the response of individual patients to GH therapy should all be considered for optimal management of short stature or growth failure.
Acknowledgements
The authors would like to thank Bob Rhoads, PhD and Jennifer R. Kent, PhD, of MedVal Scientific Information Services, LLC, for providing writing and editorial assistance. Funding to support the preparation of this manuscript was provided by Novo Nordisk, Inc. Data from this paper were presented at the 49th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE) in Prague, Czech Republic, 22-25 September 2010.
Competing interests
PAL is a consultant for Abbott and Novo Nordisk, and has received clinical study support from Abbott, Novo Nordisk, Eli Lilly, Pfizer, and Ipsen. JR is a consultant for Novo Nordisk and Eli Lilly, and has received clinical study support from Novo Nordisk, Eli Lilly, and Pfizer. JG, RG, and NK are employees of Novo Nordisk.
Authors' contributions
All authors contributed equally to this work and were involved in determining the study concept and design as well as providing data analysis and interpretation. RG and JG provided access to the registry data. NK performed the regression analysis. At all stages, the authors discussed the results and implications of the data and commented on the manuscript. All authors read and approved the final manuscript."