This study uses the KABP process to identify current gaps in the evidence for clinical care in rhGH therapy (Knowledge), determine the opinions of a group of rhGH prescribers (Attitudes and Beliefs), and compare the opinions reflected by that survey to data entered into an rhGH safety and efficacy registry (NCGS) with voluntary data fields (Practice). The goal was to identify specific areas of clinical practice variability that may identify areas of consensus and disagreement where evidence-based data are lacking to provide a basis for future knowledge development which could improve care of children treated with rhGH.
Respondents to the survey, 29% of NCGS investigators, were largely experienced, board-certified endocrinologists who held teaching positions and were members of the LWPES. Although this is a low survey response rate, a similar 2007 survey of LWPES members yielded a similar response rate. In addition, the demographics of our survey were similar to the 2007 LWPES survey except that our study had a slightly higher rate of responders in private practice (37 versus 24%), fewer responders in practice
20 years (43 versus 55%), and more responders in practice
5 years (11% versus 4%). However, regardless of the demographics, due to the low response rate, the responses described may not accurately reflect the opinions of all NCGS investigators or the larger pediatric endocrinology community.
The use of the NCGS database to reflect current and previous practice may not reflect practice in all children receiving rhGH during this period. Estimates based upon the number of children receiving rhGH products eligible for enrollment in the study who have data entered and the market share of these products suggest that NCGS data reflect approximately 30% of nearly 200,000 children treated with rhGH since its approval in 1985. In addition, NCGS data may not be a complete and accurate reflection of practice in those children entered into the database due to the absence of potentially relevant data. However, the NCGS is the largest data repository for rhGH therapy in children in the U S Furthermore, measures of practice may not reflect attitudes, beliefs, and opinions due to insurance requirements.
4.1. Screening Poorly Growing Children and Diagnosis of GHD
The survey consensus was that children should be screened for GHD when height is
2.0 SDS (or
1.5 SDS below midparental height). This consensus is consistent with current practice guidelines [1, 3, 4] and is supported by the characteristics of children enrolled in NCGS (mean height SDS
2.0 SDS). In addition to screening for GHD, the initial evaluation of children with short stature is targeted to identify any chronic illness that could potentially affect growth. Survey responders endorsed the following screening tests most strongly: baseline growth velocity, bone age, thyroxine, TSH, IGF-1, chemistry panel, and karyotyping for girls. In a previous study of pediatric endocrinology practices , these screening tests had a similar rank order of use. However, the actual frequency of these tests on the initial visit was reported to be significantly lower even in children with severe short stature (height SDS
3.0 SDS and/or
1.5 SDS below midparental height). It was also observed that most children never returned for a requested second visit . The latter finding emphasizes the importance of obtaining screening laboratory studies at the initial visit and/or stressing the importance of followup visits to determine the growth velocity .
How or whether to make a diagnosis of GHD prior to initiating therapy remains an area of controversy. Accurate diagnosis of GHD is crucial to the identification of children who are at risk of having or developing other pituitary hormone deficiencies, in particular adrenal insufficiency . Current guidelines include short stature with poor growth velocity, low GH peak following GHST, low serum IGF-1 and IGFBP-3, and delayed bone age as typical features of GHD, with GHST remaining the gold standard [2–5]. The combination of poor height velocity and low IGF-1 has also been shown to correlate well with GHD . However, the use of a combined approach including GHST, IGF-1, and IGFBP-3 levels improves specificity of GHD diagnosis . The use of GHST, and particularly ITT, has declined over time . The reasons for decreased use of GHST may include a lack of reproducibility, lack of personnel to perform the test, confounding influence of pubertal stage and body mass index, expense, and safety risk [15–17].
In our survey, there was general agreement that a low IGF-1 for age, gender, and pubertal status in the absence of malnutrition or chronic illness was equal to or better than GHST. However, nearly a third of respondents felt that GHST should always be performed, and more than half would continue to perform GHST in order to make a diagnosis of GHD even if not required by third-party payers. Despite some evidence impugning the validity of GHST due to a high false-positive rate, this mixture of opinions likely reflects the lack of a definitive alternative for the diagnosis of GHD. Another confounding issue is that interpretation of serum IGF-1 values remains difficult because of the lack of assay standardization and normative data for each current assay for each age and stage of puberty . Currently, there is no single test that can consistently differentiate ISS from idiopathic GHD . This continues to be an area that requires investigation.
Because of the low false-negative rate for GHST, it has been reported that children with a normal response to GHST do not require any further pituitary evaluation . However, following diagnosis of GHD based upon an abnormal GHST, it has been recommended that further functional testing of pituitary function and a brain MRI be performed [2, 4]. Brain MRI with focus on the pituitary has been proposed as an alternative to GHST for diagnosis of GHD . Pituitary MRI has been shown to be more predictive than GHST of need for rhGH replacement in an adult . In our survey, 65% of respondents indicated that an MRI was a necessary test for the diagnosis of GHD if GHST was not required.
4.2. Response to rhGH Therapy
Increased growth rate is the most commonly measured response to rhGH therapy. However, an adequate response, compared with an accurate pretreatment growth velocity, had not been defined at the time of this survey. Published consensus treatment guidelines have provided various metrics that have been adopted. Our survey respondents endorsed the use of an increase of
2 cm/yr over baseline growth velocity. The minimum duration of such a trial or the earliest point at which to judge the clinical response remains unclear. Because of the variability of growth and measurement error, it has been proposed that the minimum interval between growth measurements used to assess the response should be at least 6 months . Recently, in an effort to identify expected growth response to rhGH therapy in the first year of therapy in children diagnosed with GHD, further analysis of NCGS data was performed to establish growth velocity response curves . This paper provides reference data against which to compare a child's first-year growth velocity on treatment and which may be used to assess compliance, accuracy of diagnosis, the need for dose adjustment, consideration of concomitant illness, or discontinuation of therapy. The authors proposed that a response
1 SD below the mean for age and diagnosis should be considered a suboptimal response.
4.3. Monitoring Serum IGF-1 during rhGH Therapy
Although most investigators in our survey support measuring serum IGF-1 during therapy, this test was frequently not entered into the NCGS database. In addition, many investigators did not act upon the IGF-1 values obtained. This finding suggests that once rhGH therapy has been initiated, physicians are reluctant to discontinue it despite a lack of demonstrated response. A recent study demonstrated that adjusting rhGH doses to the target IGF-1 at
2 SDS regardless of growth rate led to improved growth response in the first year of therapy in some children, while others responded as well at lower IGF levels . The authors concluded that some combination of growth rate and IGF targeting might be applicable. In addition, the safety of IGF targeting, which may require very high rhGH doses in some children, remains to be determined and that the use of serum IGF-1 to adjust rhGH doses should be individualized based upon the condition, age, pubertal status, and growth response [25, 26].
4.4. Pubertal Dosing
Mauras et al.  demonstrated significant improvement in growth response in pubertal children with GHD given higher doses of rhGH (0.7 mg/kg/week). Our survey suggests that since the publication and associated U.S. FDA approval of pubertal dosing of Nutropin/Nutropin AQ in GHD patients, many pediatric endocrinologists endorse using higher rhGH doses during puberty, particularly in children not expected to reach expected height. Analysis of the NCGS data documents higher doses used in pubertal patients since the publication and FDA approval of pubertal dosing, but the severity of short stature did not appear to impact this practice. Although these results suggest increased acceptance and use of pubertal dosing, they do not validate it.
4.5. End of Therapy
When determining the right time to stop rhGH therapy, physicians usually consider growth velocity, skeletal maturation, patient comfort with height, severity of GHD, and the presence of other pituitary hormone deficiencies. Survey respondents ranked epiphyseal fusion before patient comfort with height and growth velocity
2 cm/yr, although the NCGS data suggest that most patients were stopped before they had stopped growing. Although the data set is small, it suggests that in practice rhGH therapy is discontinued before cessation of growth and that discontinuation may be due to factors other than satisfaction with height, including the adolescent's desire to end therapy.
In children with multiple pituitary hormone deficiencies who have reached adult height, respondents agreed that no retesting was necessary to continue rhGH. This corresponds with recent publications showing that the incidence of adult GHD increases with the number of other pituitary hormone deficiencies . There was no consensus about the timing or methodology (serum IGF-1, GHST) necessary for reevaluation of individuals diagnosed with isolated GHD after achieving adult height.
4.6. Areas in Need of Evidence-Based Guidelines
The combination of the survey responses and their correlation to NCGS data have helped to outline a number of areas of clinical practice variability that require further investigation.
Identification of the best auxologic, imaging, and biochemical profile to diagnose GHD, predict risk of multiple pituitary hormone deficiency, and predict rhGH therapy response.
Establishment of criteria to determine whether growth response to rhGH therapy beyond the first year is adequate and likely to achieve maximal increase in adult height.
Assessment of the utility of monitoring IGF-1 for long-term safety and efficacy of rhGH therapy.
Identification of the best test and cutoffs for diagnosis of GHD requiring ongoing rhGH therapy after near-adult height is attained.