Indian Pediatrics 2006; 43:593-599
Growth Pattern and Skeletal Maturation Following Growth Hormone Therapy in Growth Hormone Deficiency: Factors Influencing Outcome
Anurag Bajpai, Madhulika Kabra, *Arun Kumar Gupta and P.S.N. Menon
From the Division of Pediatric Endocrinology, Department of Pediatrics and *Department of Radiodiagnosis , All India Institute of Medical Sciences, New Delhi 110 029, India.
Correspondence to: Professor P.S.N. Menon, Departmnt of Pediatrics Armed Forces Hospital, PO Box No. 5819, Salmiya 22069, Kuwait. E-mail: firstname.lastname@example.org
Table I Comparison of Parameters Following GH Treatment
SDS = standard deviation score, expressed as mean ± standard deviation. * Indicating significance of difference for parameters at initiation and discontinuation of GH treatment.
Factors influencing outcome
Subjects with end height SDS in the target height range had higher initial BA : CA and were treated for longer duration compared to those with height SDS lower than the target height range (Table II). No influence of disease form (idiopathic or organic), pattern of pituitary involvement (IGHD or MPHD), age at treatment, peak GH levels and GH dose on end height SDS was observed (Table III). Duration of treatment, corrected height SDS and initial bone age to chronological age ratio correlated significantly with end height SDS on univariate analysis; the effect for duration of treatment and corrected SDS remained significant on multivariate analysis (Table III). Increase in height SDS correlated positively with duration of treatment, initial corrected SDS and first year growth velocity and negatively with peak GH levels (Table III). The effect of treatment duration, initial corrected height SDS and first year growth velocity was maintained on multivariate analysis (Table III).
Table II Comparison of Individuals with End Height SDS in Target Height Range
SDS = standard deviation score, NS = not significant, expressed as mean ± standard deviation. * Indicating significance of difference for subjects with and without end height SDS in the target height range.
Table III Factors Influencing Response to GH Therapy
HSDS = Height SDS; BA/CA = Bone age to chronological age ratio, GV = Growth velocity, NS = Not significant.
Findings of our study suggest that GH therapy significantly improves auxological outcome in Indian children with GHD. End height SDS was significantly higher than that at initiation and was in the target height range in 52.1% subjects as against 17.7% at the initiation of treatment. The response is however worse compared to developed countries where height SDS similar to target height SDS has been reported(1-5). This may be related to delayed diagnosis with greater height compromise, lower GH dose, shorter duration of treatment, and compromised nutritional status. GH treatment was initiated significantly later in our subjects compared to the studies from the western countries(4,5). Age at initiation of GH treatment has been shown to be negatively correlated to response to therapy emphasizing the need of early diagnosis and treatment of the condition(3,4).
Lower GH dose and shorter duration of treatment in our subjects are linked to self-procuring of GH as against state or insurance funded treatment in most developing countries. The dose of GH in our study (0.07 ± 0.002 IU/kg/day) is definitely lower compared to currently employed dose in developed countries (the dose of GH employed in United States is around 0.14 IU/kg/day). Studies have demonstrated a dose-response relationship of GH in GHD with higher doses (up to 0.3 IU/kg/day) associated with better response (11,12). Normal weight for height and serum albumin levels precludes malnutrition as a major cause of poor response in our subjects. The effect of zinc deficiency, an established cause of growth retardation, can however not be excluded.
Maximum catch-up growth was achieved during the first two years of treatment. Survival analysis suggested that treatment for two years was associated with end height SDS in the target height range. This along with the observation that the first year growth response is an important predictor of increase in height SDS emphasizes the need for careful management during the first two years of therapy. This finding also has implications on the desirable duration of treatment in resource poor settings where treatment till final height is often not feasible. Our study suggests that to achieve optimal catch up growth GH should be continued for a minimum period of two years. Treatment for shorter duration is not expected to result in significant increase in height and may therefore not be cost-effective.
Duration of treatment and initial corrected height SDS emerged as important predictors of end height SDS. Early diagnosis with less growth compromise and prolonging the duration of GH therapy is therefore expected to improve height outcome. This emphasizes the need for increasing the duration of therapy and diagnosis at an early stage with lower growth compromise for improving outcome. Higher end height SDS in individuals with higher initial height SDS has been reported in previous studies on GH therapy in GHD and indicates a trend for target height seeking(3,4). This is reiterated by the observation that individuals with greatest height compromise at initiation had greatest increase in height, a finding that has been observed in other reversible causes of growth retardation following correction of the underlying cause(13). Lack of effect of age at treatment on response may be related to preservation of bone age and therefore growth potential in majority of the subjects.
An important observation of our study was inappropriate skeletal maturation during GH therapy as reflected by an increase in bone age to chronological age ratio and lower increase in height SDS for bone age compared to that for chronological age. This phenomenon has been reported in children with hypothyroidism following thyroid replacement and has the risk of premature epiphyseal fusion and compromised height(14). This observation has led to the use of gonadotropin releasing hormone analog for improving height out-come in children with hypothyroidism(15). Development of highly selective aromatase inhibitors, inhibitors of estrogen synthesis and skeletal maturation, provides a window of opportunity for retarding inadvertent skeletal maturation induced by GH. Preliminary studies have failed to demonstrate increase in predicted height following addition of aromatase inhibitor anastrazole for one year; long-term follow-up is however awaited(8). There is a need of systematic evaluation of the effect of these agents on skeletal maturation and final height in GHD.
Contributors: AB, MK and PSNM were involved in management of patients. AKG reviewed the bone age of all the subjects. AB planned the study, collected data, performed the statistical analysis and drafted the manuscript. MK was involved in planning of the study and reviewed the script. PSNM was involved in planning the study, critically reviewed the manuscript and would act as the guarantor of the study.
Competing interests: None.