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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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.