Results from 2 years of GH treatment of subjects in the ANSWER Program registry demonstrated increased HSDS from baseline in a large cohort of male and female subjects with ISS, GHD, MPHD, SGA, TS, and NS. Study results did not demonstrate any substantial gender differences for patients with ISS, GHD, MPHD, NS, or SGA. The only difference between male and female subjects that achieved statistical significance was
HSDS at 1 year in those with SGA (male
female), which may or may not be clinically significant.
The general lack of effect of gender on response to GH treatment observed in this registry analysis is consistent with results from a large number of studies that evaluated effects of gender on response to GH. Analysis of results from the Pfizer Kabi International Growth Study (KIGS) database indicated no significant gender-related differences in effects of GH on growth velocity or HSDS over 2 or 3 years of treatment . Analysis of the short- and long-term effects of GH treatment on growth in prepubertal children with chronic renal failure also indicated no significant effects of gender . Evaluation of predictors of response to treatment with GH for up to 7 years in 8,018 patients with ISS indicated no significant effect of gender on first-year growth velocity or change from baseline in HSDS . In contrast, results from a French registry that included 2,852 patients with idiopathic GHD indicated that female gender was a significant positive predictor of adult height gain with GH treatment .
Analyses did show that
HSDS was significantly greater for subjects who started GH treatment at a younger age. While results from the ANSWER Program registry suggest that many patients start GH treatment later than desired, multiple studies suggest better growth outcomes with earlier intervention. For example, the Consensus Statement on the Diagnosis and Treatment of Children with Idiopathic Short Stature indicates that the optimal age for initiation of treatment is 5 years of age to early puberty . The mean age at initiation of therapy for children with ISS in this analysis was 11.2 years and near the upper end of the recommended age range. Similarly, the International Small for Gestational Age Advisory Board Consensus Development Conference Statement indicated that patients who begin therapy at 9-10 years of age will experience lower growth velocity than those who start treatment earlier . The mean age at initiation of treatment for subjects with SGA included in this analysis was 8.4 years. Guidelines for the treatment of childhood GHD do not provide specific guidance on the optimal time for initiation of therapy [1, 2]. However, earlier recommendations from the Growth Hormone Research Society indicate that treatment should be initiated as soon as the diagnosis is made . Current guidelines do not provide a specific recommendation for timing of treatment initiation in patients with TS [1, 21], but one review suggested treatment initiation at 4–6 years of age . The Turner Syndrome Study Consensus Group suggested that treatment with GH should be considered as soon as growth failure is demonstrated and potential risks and benefits of treatment have been discussed with the family . This recommendation is consistent with clinical trial results indicating that initiation of GH as early as 9 months of age in patients with TS is safe and results in significant improvements in length/height SDS . Results from a study of 1,478 females with TS in Japan indicated that the percent of patients with initiation of treatment at
5 years old was 5.11% for the period of 1991 to 1994 but increased to 16.85% for the period from 2000 to 2004, with pretreatment mean HSDS scores of
. Mean ages at initiation of treatment for these 2 periods were 10.95 and 8.78 years, respectively .
Baseline data for subjects included in this analysis of the ANSWER Program registry also indicated lower mean baseline HSDS scores for female subjects compared with male subjects across all diagnostic categories, and these differences were significant for patients with GHD, ISS, and NS. This may be due to a referral bias with earlier recognition of short stature and treatment in male versus female patients. This bias in treatment has been documented in a recent analysis of results from 1,485 Australian children included in the OZGROW database . Results from the United States also indicate that there is almost 2 : 1 male to female ratio for patients referred for GH treatment .
HSDS observed in this study for year 1, ranging from 0.4–0.7, and year 2, ranging from 0.6–1.0 across all diagnostic categories, is consistent with findings from other clinical trials of GH treatment. Results from a meta-analysis of 10 trials with 1-year follow-up data indicated a mean
HSDS of 0.43 for patients with ISS . Within the meta-analysis study, 4 studies had 2-year follow-up data taken from a total of 128 patients, which indicated a
HSDS of about 0.7 . In a registry study of 704 patients with TS, a 1-year gain in HSDS of 0.6 was observed . Data from another registry of patients with isolated idiopathic GHD found a gain in HSDS of 1.0 following 3.6 years of treatment with GH but where the majority of the height was gained during the first 2 years .
The importance of timing of treatment initiation demonstrated by this analysis is also supported by results from other studies of pediatric patients treated with GH. A report by Ranke et. al. validating a mathematical model for predicting the response of pediatric patients with idiopathic GHD to treatment with GH reiterated that chronologic age at start of treatment and maximum baseline GH response were the top two (out of six) parameters predicting first year height velocity. Also, second and third year height velocity were primarily predicted by the growth velocity in the previous year . Although the purpose of the current analysis was not to develop a prediction model, our results are consistent with both younger age at treatment start and baseline peak GH inversely correlating with first year growth response, particularly in GHD and MPHD subjects. In a recent follow-up analysis for predicting two-year growth responses to GH therapy in prepubertal children with either severe GHD, less severe GHD, TS, or SGA, Ranke and Lindberg developed criteria defining an adequate first year
HSDS . For patients with severe GHD (peak GH
g/L), an adequate first year response was defined as
0.4, whereas for less severe GHD (peak GH 5–10
g/L), TS, and SGA, a
0.3 in the first year indicated an adequate response. The growth responses to GH in the current analysis of subjects from the ANSWER Program registry would meet these criteria since the first year mean
HSDS ranged between 0.4 and 0.7 for all diagnostic categories. However, when stratified by age, this did not hold up for all older subjects (males
11 and females
10) in some categories (MPHD, TS, SGA, NS), emphasizing the importance of younger age at treatment start. In this regard, it is important to note that subjects included in our analysis ranged between 0.5 and 18 years of age, whereas the age range in the Ranke analysis model was 1 to12 years .
According to a registry study that included information from 3,007 patients with idiopathic GH deficiency, 1378 with TS, and 65 with NS, the duration of prepubertal, GH treatment correlated significantly with achievement of near-normal adult height . Other registry studies have also suggested that prepubertal initiation of treatment results in greater improvements in HSDS. According to results from the National Registry of Growth Hormone Treatment in the Netherlands that included 342 patients with GHD, initiation of treatment before puberty resulted in a
HSDS of 0.71 versus 0.58 for those who started treatment after pubertal onset . The French registry study of 2,852 patients with idiopathic GHD also demonstrated greater adult height gain with prepubertal initiation of GH treatment . One exception to this general trend toward greater benefit of GH treatment in prepubertal versus pubertal patients involves results from a study of 83 patients with GHD who were treated for 2 to 7 years, that indicated no significant effect with respect to adult height achieved .
In conclusion, in this analysis of data from the ANSWER Program registry, GH treatment resulted in increased HSDS in subjects with idiopathic/isolated GHD, MPHD, TS, NS, and ISS. No consistent gender effect was observed in
HSDS after 2 years of therapy. However, on average, initiation of treatment at a younger age or before the start of puberty (GHD patients) resulted in greater
HSDS. Due to the greater growth response, which was apparent in younger, prepubertal children, the importance of starting growth hormone treatment at a younger age should continue to be emphasized.