Treatment for Idiopathic GH Deficiency and Short Stature
Treatment for Idiopathic GH Deficiency and Short Stature
Objective To investigate response to growth hormone (GH) in the first, second and third years of treatment for all idiopathic GH-deficient (GHD) and idiopathic short stature (ISS) patients in Australia.
Context Eligibility for subsidized GH treatment in Australia is determined on auxological criteria for the indication of Short Stature and Slow Growth (SSSG), which includes ISS (SSSG-ISS). The biochemical GHD (BGHD, peak GH < 10 mU/l) and SSSG indications are treated similarly: starting dose of 4·5 mg/m/week with provision for incremental dosing. Some ISS patients were specifically diagnosed with familial short stature (SSSG-FSS).
Design Responses for each year of treatment for BGHD, SSSG-ISS and SSSG-FSS cohorts were compared in relation to influencing variables and with international benchmarks. The effect of incremental dosing was assessed.
Patients Australian BGHD, SSSG-ISS and SSSG-FSS patients who had completed 1, 2, or 3 years of treatment and were currently receiving GH.
Measurements Growth hormone dose, change in height-standard deviation score (ΔSDS) and growth velocity (GV).
Results First-year response was 2–3 times greater than that in subsequent years: ΔSDS1st year = 0·92, 0·50 and 0·46 for BGHD, SSSG-ISS and SSSG-FSS, respectively. Responses were similar to international reports and inversely related to age at commencement of GH. First-year GV-for-age for BGHD patients was similar to international standards for idiopathic GHD. However, girls had an inferior response to boys when treatment commenced at <6 years of age. First-year GV-for-age for SSSG-ISS/FSS patients was less than ISS standards. Dose increments attenuated the first- to second-year decline in response to BGHD but marginally improved the responses for SSSG-ISS/FSS.
Conclusions The Australian auxology-based GH programme produces comparable responses to international programmes. A lower starting dose is offset by the initiation of treatment at younger ages. Incremental dosing does not appear optimal. A first-year dose of 6·4–6·9 mg/m/week for GHD and 8·9 mg/m/week for ISS with early commencement of GH treatment may be most efficacious.
The growth hormone (GH) treatment programme in Australia is subsidized by the Commonwealth Government's Department of Health and Ageing (DoHA) through the Pharmaceutical Benefits Scheme (PBS) and differs significantly from most other GH prescribing jurisdictions around the world. The most notable differences are the extensive use of auxological assessment, dosing in mg/m rather than in mg/kg, a low, by international comparison, GH starting dose of 4·5 mg/m/week, and the provision to increment the dose at six monthly intervals.
Patients are assessed relative to set eligibility criteria for a number of specified indications. The two most common indications, and the focus of this study, are 'biochemical GH deficiency' (BGHD) and 'short stature and slow growth' (SSSG). BGHD and SSSG eligibility are defined later. Eligibility for GH under the SSSG indication is unique in that it is based solely on auxological criteria: Height less than the first centile with growth velocity (GV) <25th centile for skeletal age and sex. Demographic, treatment and response data for all patients treated through the PBS is stored in the national paediatric GH database, OZGROW.
To compare the efficacy of the Australian system with others, it is necessary to look at specifically recognized international diagnoses. In this study, we concentrate on idiopathic growth hormone deficiency (GHD) and idiopathic short stature (ISS). The Australian indication of BGHD aligns with the internationally recognized diagnosis of idiopathic GHD. SSSG, as might be expected given its auxological definition, contains within it a number of different diagnostic entities. A specific diagnosis for each patient, as determined by their paediatric endocrinologist, is recorded in OZGROW. Patients were diagnosed as ISS by a paediatric endocrinologist form a subgroup within the SSSG indication and are referred to as SSSG-ISS in this study. The consensus statement on the diagnosis of and treatment for children with ISS defines a subcategory of ISS as familial short stature (FSS). Some paediatric endocrinologists have used this subcategorization of ISS as their diagnosis, and this group, SSSG-FSS, has been treated separately in this study.
This study involves a retrospective analysis of an entire national cohort of idiopathic GHD and ISS patients treated with GH. As such it is not a controlled experiment but rather a snapshot of an ongoing programme. In certain circumstances, data that would be desirable is not available for all patients. These cases are noted and appropriate allowances made regarding results.
Response was assessed primarily using change in height standard deviation score, ΔSDS, in the first, second, and third years of treatment. First-year response is known to be highly correlated with adult height in both GHD and ISS. First-year response was compared with international benchmarks and ΔSDS compared with response with respect to the age of treatment commencement graphs published by Bakker et al. GV was also calculated for comparison with the recent comprehensive work on GV response to GH by Bakker et al. Finally, factors influencing response were identified.
For comparison purposes, each patient's dose in terms of mg/m was converted to the equivalent mg/kg dose. It should be noted, however, that there is no simple generic conversion formula as the mg/m dose depends on both the weight and height of the patient at the time of treatment. The efficacy of incremental dosing in a national programme is also addressed and follows other studies that have questioned the practice. Cowell et al. and Werther et al. have previously reported on the Australian programme, and it is timely to update an assessment in an international context.
Abstract and Introduction
Abstract
Objective To investigate response to growth hormone (GH) in the first, second and third years of treatment for all idiopathic GH-deficient (GHD) and idiopathic short stature (ISS) patients in Australia.
Context Eligibility for subsidized GH treatment in Australia is determined on auxological criteria for the indication of Short Stature and Slow Growth (SSSG), which includes ISS (SSSG-ISS). The biochemical GHD (BGHD, peak GH < 10 mU/l) and SSSG indications are treated similarly: starting dose of 4·5 mg/m/week with provision for incremental dosing. Some ISS patients were specifically diagnosed with familial short stature (SSSG-FSS).
Design Responses for each year of treatment for BGHD, SSSG-ISS and SSSG-FSS cohorts were compared in relation to influencing variables and with international benchmarks. The effect of incremental dosing was assessed.
Patients Australian BGHD, SSSG-ISS and SSSG-FSS patients who had completed 1, 2, or 3 years of treatment and were currently receiving GH.
Measurements Growth hormone dose, change in height-standard deviation score (ΔSDS) and growth velocity (GV).
Results First-year response was 2–3 times greater than that in subsequent years: ΔSDS1st year = 0·92, 0·50 and 0·46 for BGHD, SSSG-ISS and SSSG-FSS, respectively. Responses were similar to international reports and inversely related to age at commencement of GH. First-year GV-for-age for BGHD patients was similar to international standards for idiopathic GHD. However, girls had an inferior response to boys when treatment commenced at <6 years of age. First-year GV-for-age for SSSG-ISS/FSS patients was less than ISS standards. Dose increments attenuated the first- to second-year decline in response to BGHD but marginally improved the responses for SSSG-ISS/FSS.
Conclusions The Australian auxology-based GH programme produces comparable responses to international programmes. A lower starting dose is offset by the initiation of treatment at younger ages. Incremental dosing does not appear optimal. A first-year dose of 6·4–6·9 mg/m/week for GHD and 8·9 mg/m/week for ISS with early commencement of GH treatment may be most efficacious.
Introduction
The growth hormone (GH) treatment programme in Australia is subsidized by the Commonwealth Government's Department of Health and Ageing (DoHA) through the Pharmaceutical Benefits Scheme (PBS) and differs significantly from most other GH prescribing jurisdictions around the world. The most notable differences are the extensive use of auxological assessment, dosing in mg/m rather than in mg/kg, a low, by international comparison, GH starting dose of 4·5 mg/m/week, and the provision to increment the dose at six monthly intervals.
Patients are assessed relative to set eligibility criteria for a number of specified indications. The two most common indications, and the focus of this study, are 'biochemical GH deficiency' (BGHD) and 'short stature and slow growth' (SSSG). BGHD and SSSG eligibility are defined later. Eligibility for GH under the SSSG indication is unique in that it is based solely on auxological criteria: Height less than the first centile with growth velocity (GV) <25th centile for skeletal age and sex. Demographic, treatment and response data for all patients treated through the PBS is stored in the national paediatric GH database, OZGROW.
To compare the efficacy of the Australian system with others, it is necessary to look at specifically recognized international diagnoses. In this study, we concentrate on idiopathic growth hormone deficiency (GHD) and idiopathic short stature (ISS). The Australian indication of BGHD aligns with the internationally recognized diagnosis of idiopathic GHD. SSSG, as might be expected given its auxological definition, contains within it a number of different diagnostic entities. A specific diagnosis for each patient, as determined by their paediatric endocrinologist, is recorded in OZGROW. Patients were diagnosed as ISS by a paediatric endocrinologist form a subgroup within the SSSG indication and are referred to as SSSG-ISS in this study. The consensus statement on the diagnosis of and treatment for children with ISS defines a subcategory of ISS as familial short stature (FSS). Some paediatric endocrinologists have used this subcategorization of ISS as their diagnosis, and this group, SSSG-FSS, has been treated separately in this study.
This study involves a retrospective analysis of an entire national cohort of idiopathic GHD and ISS patients treated with GH. As such it is not a controlled experiment but rather a snapshot of an ongoing programme. In certain circumstances, data that would be desirable is not available for all patients. These cases are noted and appropriate allowances made regarding results.
Response was assessed primarily using change in height standard deviation score, ΔSDS, in the first, second, and third years of treatment. First-year response is known to be highly correlated with adult height in both GHD and ISS. First-year response was compared with international benchmarks and ΔSDS compared with response with respect to the age of treatment commencement graphs published by Bakker et al. GV was also calculated for comparison with the recent comprehensive work on GV response to GH by Bakker et al. Finally, factors influencing response were identified.
For comparison purposes, each patient's dose in terms of mg/m was converted to the equivalent mg/kg dose. It should be noted, however, that there is no simple generic conversion formula as the mg/m dose depends on both the weight and height of the patient at the time of treatment. The efficacy of incremental dosing in a national programme is also addressed and follows other studies that have questioned the practice. Cowell et al. and Werther et al. have previously reported on the Australian programme, and it is timely to update an assessment in an international context.