Average height gain after 3 years of GH treatment ranges from 1.2 to 2.0 SD for doses of 35-70 µg/kg/day. The growth rate decrease over time in GH therapy25). Annual height velocity was significantly greater among children receiving GH than among untreated children during the first and second years of treatment. Untreated SGA children did not experience an increase in height velocity SDS26). A multicenter, phase III clinical study in Korea reported that height velocity significantly increased from 5.36±1.59 cm/yr at baseline to 10.66±2.03 cm/yr at 6 months within the treated group27).

Factors associated with response to GH over the first 2 to 3 years of therapy included age and height SDS at the start of therapy, midparental height, and GH dose28).

Ranke et al.29) reported that GH dose was the most important response predictor, accounting for 35% of growth response variability. Other predictors of growth response during the first year of treatment were age at the start of treatment, weight SDS, and midparental height SDS. In the second year of GH treatment, the final height outcome could be determined by a child's initial response to GH, which was dose dependent.

In another study, significant differences in final height based on dose were not found, between children treated with 0.033 or 0.067 mg/kg/day of GH. Positive predictors of the growth response to final height in their study were target height SDS, height SDS at the start of treatment and bone age delay at the start of treatment30).

De Zegher et al.31) reported that a GH dose of 0.33 mg/kg/day required 5.5 years to achieve a 2SDS increase in height, but only required 2.5 years with a dose of 0.67 mg/kg/day.

GH treatment for those with very marked growth retardation should be considered at a dose of 35-70 µg/kg/day, as these patients require rapid catch-up growth. The standard GH 'replacement' dose (i.e., the dose used to treat GHD) is insufficient for inducing catch-up growth in many short children born SGA. Age at the start of treatment was also one of the major determinants of growth; the younger the child, the greater his/her growth response to GH therapy.

Previous studies have suggested that GH treatment does not improve final height above that of controls in short children born SGA32,33). Contrary to those findings, Ranke and Lindberg34) found that GH treatment in short older children born SGA can be effective in increasing final height above the predicted height and in achieving the patients' target height. Van Pareren et al.30) reported that an average of 7.8 years of continuous treatment with GH resulted in a normalization of height during childhood and a normalization of adult height (above -2 SDS) in 85% of the patients, whereas 98% reached an adult height within their target height range in 54 short children born SGA.

De Zegher et al.31) reported that a dose of 0.1 mg/kg/day produced a dramatic and rapid increase in height SDS over 2 years of treatment. After treatment ceased, however, height velocity decreased significantly, with a subsequent decrease in height SDS. In contrast, height SDS showed a sustained improvement in patients treated continuously with a GH dose of 0.033 mg/kg/day over 6 years.

Fjellestad-Paulsen et al.35) studied GH therapy given at a dose of 0.47 mg/kg/wk for 3 years, before discontinuation and follow-up for an additional 5 years in 63 patients. GH therapy induced a significant catch-up in height of 2 SDS (P <0.0001) during the 3-year treatment period, but was followed by a decrease in height of 1 SDS 5 years after treatment was discontinued.

GH treatment in short children born SGA also has a positive effect on blood pressure and lipid metabolism in 79 SGA patients36). Before therapy, the mean body mass index (BMI) SDS of the SGA children was significantly lower than zero. During treatment, BMI SDS increased to values not significantly different from zero. This normalization of BMI was not accompanied by changes in body fat percentage.

Pretreatment systolic blood pressure SDS was significantly higher and diastolic blood pressure was significantly lower in children born SGA than in healthy age-matched children. During GH therapy, both systolic and diastolic blood pressure SDS decreased significantly. After 6 years of GH therapy, systolic blood pressure in the SGA children did not differ from those of the controls, and diastolic blood pressure was even lower than those of the controls. After four years of GH therapy, there were significant decreases in total cholesterol, low-density lipoprotein cholesterol, and the atherogenic index, although high-density lipoprotein cholesterol remained unchanged.

Sas et al.37) also reported a positive effect of GH therapy on body proportions in these 79 SGA children. Height, sitting height, hand, foot length, biacromial diameter, and biiliacal diameter were measured before and during GH therapy. At the start of GH therapy, mean SDS values for all measurements were significantly lower than zero, but during 6 years of GH therapy, mean SDS for all measurements increased significantly from baseline and closer zero. There were significant improvements from baseline in the proportions of the hands, feet and biiliacal diameter in relation to height, but the biacromial diameter in relation to height did not change. None of the changes in body proportions differed significantly between the dose groups.

GH treatment also has long-term beneficial effects on muscle and adipose tissue in short children born SGA. Leger et al.38) studied these long-term effects on muscle and adipose tissue in 14 short children born SGA during 3 years of GH therapy and observed an increase in muscle tissue mass. Adipose tissue mass decreased significantly during the first year of therapy, but increased during the second and third years of therapy.

Recombinant human GH has been proven to be relatively safe. High doses of up to 0.067 mg/kg/day for SGA children with growth failure are tolerated well even in young children. Treatment interruption or withdrawal as a result of adverse events is uncommon. A multicenter, phase III clinical study in Korea demonstrated the safety of GH treatment in prepubertal short SGA children27).

GH may induce insulin resistance and hyperglycemia, and may also affect thyroid function. In patients with GHD, slipped epiphyses of the hip may occur. To date, no studies have been conducted to evaluate the interaction of GH with other medications, but no drug-drug interactions have been reported.

The effect of GH on glucose metabolism in short children born SGA is generally mild and transient. Because insulin resistance has been reported in SGA children, fasting insulin and glycosylated hemoglobin or glucose concentrations should be monitored during and after GH treatment in these patients, particularly those with risk factors such as obesity or a family history of diabetes. A French study, Sante Adulte GH Enfant study, reported increased mortality rates among adults treated with recombinant GH as children, particularly in those who had received the highest dose (above 50 µg/kg/day). Specific effects were detected in terms of death due to bone tumors or cerebral hemorrhage but not for all cancers39).