National Cooperative Growth Study Research Articles

Adolescent boys with constitutional delay of growth and puberty grow faster than patients with organic growth hormone deficiency.

Constitutional delay of growth and puberty (CDGP) is a tempo variant with a good prognosis. Healthy late-maturing adolescents grow slower than postulated by age-related references, and therefore, CDGP is frequently confused with growth hormone deficiency (GHD). For differential diagnosis, height velocity references for CDGP are needed. Here, we provide height velocity data for late-maturing boys based on mixed longitudinal and cross-sectional observations in a group of 38 German adolescents with proven CDGP and compare them with cross-sectional observations in a group of 164 adolescents with organic GHD from the National Cooperative Growth Study registry. In the critical age interval from 13.4 to 14.9years, the growth of prepubertal adolescents with CDGP was faster (mean/median height velocity, 5.2/5.4cm/years; quartiles, 4.4-6.2cm/years) than that of prepubertal adolescents with organic GHD (3.5/3.2cm/years; quartiles, 2.0-4.4cm/years) in the cross-sectional analysis (p<.0001). Based on our mixed longitudinal and cross-sectional analysis, the height velocity of adolescent boys with CDGP exceeded previous model calculations on average by 1.0cm. In conclusion, prepubertal adolescents with CDGP grow faster than patients with organic GHD. Previous model estimates underestimated height velocity of boys with CDGP.

National Cooperative Growth Study: 25 Years of Growth Hormone Data, Insights, and Lessons for Future Registries.

The National Cooperative Growth Study (NCGS) data are reviewed from 1985-2010 to report on final demographic, efficacy, and safety findings, and to illustrate the value of long-term, real-world follow-up to physicians and patients. The NCGS was a multicenter, open-label, observational, postmarketing surveillance study of Genentech growth hormone (GH) products for the treatment of children with growth failure in North America. Data from 65,205 patients representing 240,951 patient-years of experience were collected. All etiological groups had clinically meaningful improvements in near-adult height SDS. Females and African Americans were under-represented in the NCGS with little change in accrual over time. The favorable safety profile of GH was validated through the registry. Twenty-five years of monitoring GH use through the NCGS yielded extensive insight into the utility of GH in various underlying etiologies. Demographic disparities were clear and became evident by analyzing data collected through the registry.

Physiological growth hormone replacement and rate of recurrence of craniopharyngioma: the Genentech National Cooperative Growth Study.

OBJECTIVE The object of this study was to establish recurrence rates in patients with craniopharyngioma postoperatively treated with recombinant human growth hormone (rhGH) as a basis for determining the risk of rhGH therapy in the development of recurrent tumor. METHODS The study included 739 pediatric patients with craniopharyngioma who were naïve to GH upon entering the Genentech National Cooperative Growth Study (NCGS) for treatment. Reoperation for tumor recurrence was documented as an adverse event. Cox proportional-hazards regression models were developed for time to recurrence, using age as the outcome and enrollment date as the predictor. Patients without recurrence were treated as censored. Multivariate logistic regression was used to examine the incidence of recurrence with adjustment for the amount of time at risk. RESULTS Fifty recurrences in these 739 surgically treated patients were recorded. The overall craniopharyngioma recurrence rate in the NCGS was 6.8%, with a median follow-up time of 4.3 years (range 0.7-6.4 years.). Age at the time of study enrollment was statistically significant according to both Cox (p = 0.0032) and logistic (p < 0.001) models, with patients under 9 years of age more likely to suffer recurrence (30 patients [11.8%], 0.025 recurrences/yr of observation, p = 0.0097) than those ages 9-13 years (17 patients [6.0%], 0.17 recurrences/yr of observation) and children older than 13 years (3 patients [1.5%], 0.005 recurrences/yr of observation). CONCLUSIONS Physiological doses of GH do not appear to increase the recurrence rate of craniopharyngioma after surgery in children, but long-term follow-up of GH-treated patients is required to establish a true natural history in the GH treatment era.

MANAGEMENT OF ENDOCRINE DISEASE: GH therapy and cancer risk in hypopituitarism: what we know from human studies

It has been difficult to identify factors that affect the risk of cancer, but we know that people are at higher risk as they get older, or if they have a strong family history of cancer. The potential influence of environmental and behavioral factors remains poorly understood. Early population-based and case–control studies suggested that higher serum levels of IGF1 could be associated with increased cancer risk. Since GH therapy increases IGF1 levels, concern has been raised regarding its potential role as a cancer initiation factor. Experimental evidence and some clinical studies showed that when GH/IGF1 secretion or action was inhibited, a decreased incidence and rate of progression of cancers occurred. However, human populations comprise a garden variety of genotypes that respond differently to the same kind of exposures. Human population studies frequently reveal only very small effects to these exposures. So, are GH and cancer guilty by association? After more than 20 years, leukemia, a major safety issue initially believed associated with GH treatment in children with GH deficiency (GHD), has not been confirmed but the risk of second malignancies in patients previously treated with irradiation has been detected or confirmed through the National Cooperative Growth Study. Overall, this large study confirmed the favorable overall safety profile of GH therapy in children with GHD, and also highlighted specific populations at potential risk. The risk of secondary malignancy following radiotherapy is surely related to radiotherapy more than GH therapy that may increase growth but is less likely to start the oncogenic process. In GH-deficient adults treated with GH, observational studies (KIMS, HypoCCS) have shown that when IGF1 levels were targeted within normal age-related reference ranges, the occurrence of malignancies was not higher than in the general population.

Characteristics of children with the best and poorest first- and second-year growth during rhGH therapy: data from 25 years of the Genentech national cooperative growth study (NCGS)

BackgroundModels assessing characteristics contributing to response to recombinant human growth hormone (rhGH) response rarely address growth extremes in both years 1 and 2 or examine how children track from year to year. Using National Cooperative Growth Study (NCGS) data, we determined characteristics contributing to responsiveness to rhGH and the pattern of change from years 1 to 2.Patients and methodsHeight velocity standard deviation score (HV SDS) for 2 years for prepubertal children with idiopathic GH deficiency (IGHD) (n = 1899) and idiopathic short stature (ISS) (n = 1186) treated with similar doses for two years were computed. Group 1 = HV SDS < −1; 2 = HV SDS −1 to +1; 3 = HV SDS > +1.ResultsFor IGHD, mean age was 7.5 years and similar in all groups. Year 1 HV SDS was associated with greater body mass index (BMI) SDS, lower pre-treatment HV, baseline height SDS, greater target height SDS minus height SDS, and lower maximum stimulated GH (P <0.0001). Year 2, 172/271 (73%) in group 1 moved to either group 2 (n = 156) or 3 (n = 16). Year 2 HV SDS was associated with greater year 1 HV SDS (r = 0.045, P <0.0001), greater BMI SDS, taller parents and lower peak GH.For ISS, year 1 HV SDS was associated with greater BMI SDS and lower pre-treatment HV (P ≤0.0001). 109/169 (64%) in group 1 moved to group 2 (n = 90) or group 3 (n = 19). Greater year 2 HV SDS was related to year 1 HV SDS (r = 0.27, P <0.0001).ConclusionFor IGHD, multiple characteristics contributed to best first-year response but for ISS, best first-year HV SDS was associated only with BMI SDS and inversely with pre-treatment HV. For both GHD and ISS, year 1 HV SDS was not a strong enough predictor of year 2 HV SDS to use first-year HV alone to determine GH continuation.

Is there “seasonal” variation in height velocity in children treated with growth hormone? Data from the National Cooperative Growth Study

BackgroundGrowth rate In children is reported to have seasonal variability. There are fewer published data regarding seasonal variability while on growth hormone (GH) therapy, and none analyzing growth rate with respect to number of daylight hours.MethodsWe analyzed 11,587 3-month intervals in 2277 prepubertal children (boys ages 3–14 years, girls ages 3–12 years) with idiopathic GH deficiency from the National Cooperative Growth Study (NCGS) database. All were naive to recombinant human GH (rhGH) therapy. Data were submitted from 31 US study centers. Seasonal variation in height velocity (HV) was assumed to be associated with the average number of daylight hours during the interval of time over which HV was computed. Number of daylight hours was determined from the date of the measurement and the latitude of the study center. Other independent variables evaluated included: height standard deviation score (SDS) at the beginning of the interval, chronologic age at the beginning of the interval, time from the start of rhGH treatment to the middle of the interval, month of the year, body mass index SDS at the beginning of the interval, rhGH dose/kg, mother’s height SDS, father’s height SDS, and log base 10 of the maximum stimulated GH concentration.ResultsAll variables examined, except month of the year, correlated significantly with interval HV. There was significant “seasonal” variability at all latitudes, with summer annualized HV being greater than winter HV. This difference was greatest in the first year of therapy (0.146 cm/yr/daylight hour; P < 0.0001) but persisted in subsequent years (0.121 cm/yr/daylight hr; P < 0.0001). The difference increased with distance from the equator. Growth rate over the year was not different among the latitudes reflected in this North American study.ConclusionsThere is “seasonal” variation in growth of children on rhGH therapy that correlates with number of daylight hours. The effect is modest and is greatest in the first year of therapy. Annual growth rate appears to be equal in children among latitudes covered by the US consistent with exposure to an equal number of daylight hours over the year. The physiologic mechanism behind this seasonal variation is not yet understood.

Growth Hormone and Treatment Controversy; Long-Term Safety of rGH

The availability of recombinant human growth hormone (rGH) for treatment of growth disorders has provided an unlimited supply for replacement in patients with growth hormone insufficiency but also for short stature due to Turner syndrome, renal failure, Prader-Willi syndrome, small for gestational age and idiopathic short stature. Considering the potential for side effects in the use of a growth promoting agent, the community of physicians and pharmaceutical manufacturers developed systematic methods to survey for short and long term effects. Recently published data from the National Cooperative Growth Study (NCGS), managed by Genentech, concluded that GH has a 'favorable profile'. In 2012, results from the European Union's Safety and Appropriateness of GH treatment in Europe (EU SAGhE) study about the long term mortality in GH treated patients were published in two separate manuscripts. This review will examine the issue of safety of rGH in order that practitioners are informed as they consider initiation of therapy with patients.

Intracranial hypertension in pediatric patients treated with recombinant human growth hormone: data from 25 years of the Genentech National Cooperative Growth Study

Intracranial hypertension (IH) is a rare condition in children. However, a relationship between recombinant human growth hormone (rhGH) therapy and IH has been well documented. Risk factors were assessed for 70 rhGH-naive patients enrolled in the National Cooperative Growth Study with reports of IH after treatment initiation. Patients with severe growth hormone deficiency, Turner syndrome, chronic renal insufficiency (CRI), and obesity (particularly in the CRI group) were at highest risk of developing IH during the first year of therapy, suggesting initiation of careful early monitoring. In some patients, factors such as corticosteroid use or other chromosomal abnormalities appear to confer a delayed risk of IH, and these patients should be monitored long-term for signs and symptoms of IH.

First-year response to rhGH therapy in children with CKD: a National Cooperative Growth Study Report

A clear definition of the appropriate growth response during recombinant human growth hormone (rhGH) treatment has never been established in the pediatric chronic kidney disease (CKD) population. We present here data from Genentech's National Cooperative Growth Study (NCGS) on the first-year growth response in prepubertal children with CKD. Using NCGS data, we constructed response curves for the first year of rhGH therapy in 270 (186 males, 84 females) naïve-to-treatment, prepubertal children with CKD prior to transplant or dialysis. Data from both genders were combined because gender was not significantly related to height velocity (p = 0.51). Response to rhGH was expressed as height velocity (HV) in cm/year. Mean, mean + or - 1SD, and mean - 2SD for HV during the first year of rhGH treatment as well as pretreatment HV were plotted versus age. Age-specific HV plots for rhGH-treated children with CKD are presented. At all ages, the first-year mean HV was greater than the mean pretreatment HV. The mean - 2SD for HV in children on rhGH treatment was similar to the mean pretreatment HV. These growth plots will be useful to clinicians for assessing a patient's first-year growth response. We propose that a HV below the mean - 1SD is an inadequate response. These curves may help identify patients with a suboptimal growth response due to confounding medical factors and/or non-compliance.

Growth Hormone Post-Marketing Surveillance: Safety, Sales, and the Unfinished Task Ahead

Twenty-five years ago, the pediatric endocrinology community was stunned by news of Creutzfeldt-Jakob disease transmitted by treatment with pituitary-derived GH (pit-GH). With remarkable serendipity, recombinant DNA-derived human GH (rhGH) became available within months. In an environment fertile with concerns about unexpected adverse effects, postmarketing surveillance studies (PMSSs) were established, managed, and supported by manufacturers of rhGH, of which the Genentech National Cooperative Growth Study (NCGS) has been the largest and most comprehensive in scope. This action appeared prescient when, in the late 1980s, a possible link between GH therapy and new-onset leukemia waspublished(1).Thisassociationwaslaterdisproved(2,3), but a number of possible rhGH-associated adverse effects were subsequently identified, systematically tracked, analyzed,andreported. Inthis issueofJCEM,Belletal. (4)report more than 20 yr of NCGS safety data covering approximately 55,000 patients and nearly 200,000 patient-years of rhGH exposure. The gathering and analysis of this vast amount of drug experience information will likely not be accomplished again, making its value, in some respects, inestimable. It validates for the sponsoring company and participatingphysicians therationale,commitmentofresources, and hopes for the NCGS that marked its inception. The data confirm and extend prior NCGS reports (5, 6), summarized by these general clinical implications for rhGH therapy: 1) certain adverse effects associated with rapid growth (scoliosis progression, slipped epiphyses) and others of unknown mechanism (intracranial hypertension, pancreatitis) occur rarely and merit anticipatory guidance and close monitoring; 2) overt hyperglycemia is rare, but insulin sensitivity is reduced, and a possible increase in risk for type 2 diabetes mellitus (T2DM) may be obscured by its rising general pediatric population incidence; 3) in the rare occurrence when a child already at higher risk for sudden death dies during rhGH therapy, a possible contributing role of rhGH (e.g. reduced cortisol availability in hypopituitary children or airway compromise in children with Prader-Willi syndrome) cannot be excluded; and 4) rhGH does not increase risk for new malignancy in children without risk factors, but may slightly increase or hasten the onset of second malignancies in patients previously treated for cancer. Although the data on the whole are reassuring, caution is warranted when extrapolating these findings to future safety of rhGH. Like any drug, rhGH could cause adverse events that otherwise occur rarely in the reference population (e.g. malignancy) and/or increase the frequency of relatively common events (e.g. T2DM). In addition, adverse events can occur shortlyafter initiationofdruguse,onlywith long-term use, or remotely after the drug has been discontinued (7). This full spectrum of potential rhGH adverse effects is not comprehensively elucidated by PMSSs due to: 1) inherent weaknesses in patient cohort surveillance dependent on physician reports; 2) changes in rhGH dosage and/or recipient characteristics that may alter risk for adverse effects; and 3) failure to capture adverse events that only become manifest after treatment. A separate but important issue unique to rhGH treatment is to define a “tolerable” level of risk for the newest and potentially largest rhGH-treated group in the future—essentially healthy, but short children. As noted by others (8), there are potential pitfalls in relying on data from PMSSs such as the NCGS. Patient enrollment is often incomplete; approximately 75% of eligible rhGH product-treated children are tracked by the

Consensus and Discordance in the Management of Growth Hormone-Treated Patients: Results of a Knowledge, Attitudes, Beliefs, and Practices Survey

Our purpose was to determine pediatric endocrinologists' knowledge, attitudes, beliefs, and practices (KABPs) regarding recombinant human growth hormone (rhGH) treatment, examine care-related attitude consensus or discordance, and identify evidence-based practice gaps. We developed a survey for National Cooperative Growth Study (NCGS) investigators (N = 711) to elicit their KABPs regarding GH stimulation testing as a diagnostic tool, IGF-1 monitoring for safety and dosing guidance, and pubertal dosing. Responses were compared with NCGS data from the last 20 years. Comparison between survey responses and NCGS data revealed potential discrepancies between expressed opinions and actual practice. In conclusion, this KABP survey, combined with NCGS data, suggests changes over time in diagnostic and rhGH-related therapeutic practices. Variability and inconsistency exist between the survey responses and practice trends over time as reflected in the NCGS database. Further study is necessary to provide evidence to guide rhGH treatment decisions.

Long-Term Safety of Recombinant Human Growth Hormone in Children

Between 1985 and 2006, the National Cooperative Growth Study (NCGS) monitored the safety and efficacy of recombinant human growth hormone (rhGH) in 54,996 children. Enrolled patients were followed until rhGH discontinuation. Investigators submitted adverse event reports for targeted events or those potentially rhGH-related. Early concerns about de novo leukemia in patients without risk factors have not been substantiated--three observed vs. 5.6 expected in age-matched general population based on years at risk [standard incidence ratio (SIR), 0.54; 95% confidence interval (CI), 0.11-1.58]. De novo malignancies (intracranial and extracranial) were not significantly increased in patients without risk factors (29 confirmed vs. 26 expected; SIR, 1.12; 95% CI, 0.75-1.61). Second neoplasms occurred in 49 patients, of whom 37 had irradiation for their initial tumors (including five of 16 retinoblastoma patients, three of whom had bilateral retinoblastoma) consistent with an increased risk with rhGH. Thirty-three patients developed type 1 diabetes mellitus (DM) (37 expected; SIR, 0.90; 95% CI, 0.62-1.26). Type 2 DM and nonspecified DM were reported in 20 and eight patients, respectively. Two deaths were reported in patients with Prader-Willi syndrome and five deaths from aortic dissection in patients with Turner syndrome. In patients with organic GH deficiency and idiopathic panhypopituitarism, 11 events of acute adrenal insufficiency occurred, including four deaths, consistent with a reported increased risk for adrenal insufficiency in hypopituitary patients with or without rhGH treatment. After more than 20 yr, leukemia, a major safety issue initially believed associated with GH, has not been confirmed, but other signals, including risk of second malignancies in patients previously treated with irradiation, have been detected or confirmed through the NCGS. These data further clarify the events associated with rhGH and, although confirming a favorable overall safety profile, they also highlight specific populations at potential risk.

Stimulant Medication Use and Response to Growth Hormone Therapy: An NCGS Database Analysis

Background/Aims: Determine (1) frequency of attention-deficit hyperactivity disorder (ADHD) treatment and (2) growth responses in growth hormone (GH)-treated children who are receiving ADHD medication versus GH alone. Methods: Prepubertal children with idiopathic short stature (ISS) or GH deficiency (IGHD) enrolled in Genentech’s National Cooperative Growth Study. ADHD treatment was determined by documentation of psycho-stimulant medication use at enrollment. Results: ADHD medication use increased from 0.8% (7/850) in 1985 to 5.8% (752/12,113) in 2005. First-year GH treatment response for ADHD + IGHD versus IGHD: 8.5 ± 2.0 vs. 9.4 ± 2.6 cm/year, but when adjusted for age, sex, and enrollment body mass index, the difference is clinically insignificant (–0.4 cm/year). First-year growth was similar in all ISS: 8.1 ± 1.9 versus 8.6 ± 2.1 cm/year (ADHD + ISS vs. ISS, an adjusted –0.2-cm/year difference). Conclusion: Increasing numbers of GH-treated children are taking ADHD medications and their growth responses during the first year of GH therapy are similar to those not taking ADHD medications.

Growth Response, Near-Adult Height, and Patterns of Growth and Puberty in Patients with Noonan Syndrome Treated with Growth Hormone

Noonan syndrome (NS) is a heterogeneous genetic disorder characterized by short stature. The National Cooperative Growth Study (NCGS), a postmarketing observational study of recombinant human GH (rhGH)-treated children, includes a large cohort of children with NS. We studied NCGS-enrolled prepubertal and pubertal children with NS. Baseline characteristics and growth responses in NS patients with reported near-adult height (NAH) (n = 65) were compared to patients with idiopathic GH deficiency (n = 3007) and Turner syndrome (TS; n = 1378) with reported NAH to identify factors contributing to NAH optimization in NS. NS patients (mean enrollment age, 11.6 yr) received rhGH (mean, 0.33 mg/kg . wk) for a mean of 5.6 yr. No significant difference was observed in Delta height sd score (SDS) between NS (+1.4 +/- 0.7) and TS (+1.2 +/- 0.9). However, Delta height SDS for NS and TS differed significantly from idiopathic GH deficiency (+1.7 +/- 1.0) (P < 0.0001). Mean gain in NAH above projected was 10.9 +/- 4.9 cm (males) and 9.2 +/- 4.0 cm (females). Duration of prepubertal rhGH was an important contributor to prepubertal change in height SDS (r(2) = 0.97). Height SDS at pubertal onset highly correlated with NAH SDS (rho = 0.783; P < 0.0001). Duration of puberty highly correlated with pubertal height gain in centimeters for males (rho = 0.941) and females (rho = 0.882) (P < 0.01). No new adverse events were observed. rhGH significantly improved height SDS for children with NS at NAH. Duration of prepubertal rhGH and height SDS at puberty were important contributors to NAH. Because starting age of the patients in this report was 11.6 yr, these data suggest that greater growth optimization is possible with earlier initiation of therapy.

A Stepwise Increase in Recombinant Human Growth Hormone Dosing During Puberty Achieves Improved Pubertal Growth: A National Cooperative Growth Study Report

The magnitude of the pubertal growth spurt contributes to adult height. Children treated with increased doses of recombinant human growth hormone (rhGH) during puberty have shown improved near adult height (NAH) outcomes that varied by treatment duration. Males, in a single clinic, treated with a prepubertal dose of rhGH (0.3 mg/kg/wk) received 0.1 mg/kg/wk dose increases with successive Tanner stages up to 0.6 mg/kg/wk. Changes in height and height SDS from pubertal onset to NAH were assessed in patients attaining NAH after > or =3 years (n = 23) and > or =4 years (n = 16). Using ANCOVA, outcomes were compared to closely matched patients (n = 758) from the National Cooperative Growth Study treated with a fixed dose (0.3 mg/kg/wk) throughout puberty. Compared to matched patients, a 3.6 cm greater increase in mean height gain and a 0.49 greater increase in mean height SDS (p <0.0001) during puberty was observed in patients attaining NAH after > or =3 years. Corresponding values were 3.9 cm and 0.54 (p <0.0001) in patients attaining NAH after > or =4 years. Stepwise increases in rhGH improved pubertal height gain when compared to a fixed dose and may represent an alternate approach to managing the patient during puberty.

Safety of Growth Hormone for Children with Turner Syndrome

Endocrinology| June 01 2008 Safety of Growth Hormone for Children with Turner Syndrome AAP Grand Rounds (2008) 19 (6): 69–70. https://doi.org/10.1542/gr.19-6-69 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Safety of Growth Hormone for Children with Turner Syndrome. AAP Grand Rounds June 2008; 19 (6): 69–70. https://doi.org/10.1542/gr.19-6-69 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search nav search search input Search input auto suggest search filter All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: somatotropin, somatropin, turner's syndrome Source: Bolar K, Hoffman AR, Maneatis T, et al. Long-term safety of recombinant human growth hormone in Turner syndrome. J Clin Endocrinol Metab. 2008;93(2):344–351; doi:10.1210/ jc.2007-1723. To assess the safety of treating children with Turner Syndrome (TS) with recombinant human growth hormone (rhGH), researchers from the University of Texas-Galveston, Stanford, and Genentech, Inc. reviewed data collected as part of the National Cooperative Growth Study (NCGS). The NCGS is an ongoing project of Genentech. Investigators beginning patients on a Genentech rhGH product are required to provide reports of serious adverse events (AEs) and targeted AEs, irrespective of relationship to rhGH, including malignancy, diabetes mellitus, intracranial hypertension (IH), scoliosis, slipped femoral epiphysis (SCFE), and pancreatitis. For the current study, safety data for 5,220 children with TS and almost 50,000 non-TS patients treated with rhGH from 1985 until 2006 were compared. Age at enrollment was 0.1–21.2 years for TS patients with a mean age of 9.8 years. Safety data were presented in four categories: overall safety including deaths; targeted events associated with rhGH; events associated with TS; and other serious AEs. The incidence of reported serious AEs among patients with TS was 2.2% compared to 2.9% for the non-TS population. The incidence of targeted AEs among the 5,220 TS patients was 8.5% (442) compared with 7.3% in the non-TS population. Seven TS patients died, five from aortic dissection or rupture, a known complication of TS.1,–3 The incidence of events known to be associated with rhGH including IH, SCFE, scoliosis, diabetes, and pancreatitis were all higher in TS patients than in those without TS. The incidence of new-onset malignancies in patients without other risk factors was 0.11% for TS patients compared with 0.06% for non-TS patients. The authors conclude that patients with TS who were treated with rhGH had an increased risk for selected AEs. However, the rate of death from aortic dissection/rupture in TS patients in this study is similar to that found in previous studies of TS patients not receiving growth hormone;1,–3 thus, it is unlikely that rhGH contributed to these patients’ deaths. It is uncertain whether the reported malignancies represent an inherited increased risk in TS patients. The NCGS and similar registries, although focused in the years during rhGH treatment, may provide valuable information regarding the natural history of TS in childhood. Dr. Varma has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. This study, which was organized and supported by Genentech, drew on the largest database of TS individuals in the US. TS is a common chromosomal anomaly which is seen in about 1:2,500 live female births.4 At any given time in the US there are about 50,000 girls and women who are affected by this disorder. Patients with TS are at increased risk for a variety of problems including coarctation of aorta, bicuspid aortic valve, aortic dilation, dissection, and rupture.... You do not currently have access to this content.

Long-Term Safety of Recombinant Human Growth Hormone in Turner Syndrome

Turner syndrome (TS) affects more than 50,000 girls and women in the United States. The National Cooperative Growth Study (NCGS) has collected efficacy and safety data for 5220 TS children treated with recombinant human GH (rhGH) during the last 20 yr. Our objective was to determine frequencies of specific targeted adverse events (AEs) and additional AEs of interest in TS patients. Corresponding safety data in non-TS patients or normal populations were compared for selected AEs. Patients may be enrolled at rhGH initiation and followed until discontinuation. Investigators submit AE reports describing any event that is potentially rhGH related or is a targeted event. The Genentech Drug Safety department received 442 AE reports for TS NCGS patients as of June 30, 2006, including 117 serious AEs. Seven deaths occurred; five resulted from aortic dissections/ruptures. The incidence of certain events known to be associated with rhGH (targeted events), including intracranial hypertension, slipped capital femoral epiphysis, scoliosis, and pancreatitis, was increased compared with other non-TS patients in NCGS. There were 10 new-onset malignancies that occurred, including six in patients without known risk factors. Type 1 diabetes also appeared to be increased compared with other NCGS groups. Children with TS who were treated with rhGH exhibit an increased underlying risk for selected AEs associated with rhGH and for type 1 diabetes, which is likely unrelated to rhGH. The aortic dissection/rupture incidence reflects the higher baseline risk for these events in TS, was consistent with current epidemiological data in smaller TS populations, and is likely unrelated to rhGH. It is not known whether the reported malignancies represent an inherently increased risk in TS patients. Twenty years of experience in 5220 patients indicates no new rhGH-related safety signals in the TS population. The NCGS and similar registries, although focused on the years during rhGH treatment, may also be a window into the natural history of TS in childhood.

Height Velocity Targets from the National Cooperative Growth Study for First-Year Growth Hormone Responses in Short Children

Although GH has been used to treat short stature in GH deficiency (GHD) and other conditions for more than 40 yr, criteria for satisfactorily defining targets for GH responsiveness have never been developed. The objective of this study was to present the first-year growth expressed as height velocity (HV) for prepubertal boys and girls with idiopathic GHD, organic GHD, idiopathic short stature, or Turner syndrome from Genentech's National Cooperative Growth Study to derive age-specific targets for GH responsiveness for each etiology and gender. Using data from the National Cooperative Growth Study, we constructed curves of response to GH during the first year of treatment with standard daily doses in naive-to-treatment prepubertal children with idiopathic GHD (2323 males, 842 females), organic GHD (582 males, 387 females), idiopathic short stature (1392 males, 465 females), or Turner syndrome (1367 females). For each category, mean pretreatment and mean +/-1 and +/-2 sd for the first-year HV on GH were assessed. Mean and mean +/- 1 sd for HV were plotted vs. age at baseline (initiation of GH treatment) and compared with mean pretreatment HV. HV plots for each category as a factor of age at baseline are presented. Mean - 2 sd HV plots approximated the pretreatment HV. Using baseline age- and gender-specific targets will assist clinicians in assessing a patient's first-year growth response. We propose that HV below the mean - 1 sd on these plots be considered a "poor" response. These curves may be used to identify patients who may benefit from GH dose adjustment, to assess compliance issues, or to challenge the original diagnosis.

Salutary Effects of Combining Early Very Low-Dose Systemic Estradiol with Growth Hormone Therapy in Girls with Turner Syndrome

Optimizing pubertal estrogen replacement in girls with Turner syndrome is important. The study objective was to test the hypotheses that physiological estradiol replacement administered early with GH will preserve height potential as much as if administered late and that it will bring about a greater height gain than standard oral estrogen therapy combined with GH. The study was randomized to early or late estrogen treatment; follow-up was at 3.5 yr or later. This was a multicenter outpatient study. Turner syndrome girls 12.0-12.9 yr (n = 7) or 14.0-14.9 yr (n = 7) of age who began GH before age 12.0 yr were the patients. The girls were matched to National Cooperative Growth Study registry patients who began GH and oral conjugated estrogen at similar ages and were similarly followed to adult or near-adult height. Depot estradiol, 0.2 mg/month i.m., was given initially and gradually increased; GH was 0.05 mg/kg daily. Adult or near-adult height was the main outcome variable. Depot estradiol treatment resulted in height significantly taller than predicted at 12 yr of age (P < 0.02). All height potential was gained in the first 2 yr of the study, during which the early group grew 3.5 cm more than the late group, which was receiving GH alone (P < 0.01). The early depot estradiol group also gained 5.9 cm more height after starting estrogen than did the early National Cooperative Growth Study group (P < 0.05). Although feminization proceeded slowly on the lowest dose of estradiol, it advanced normally thereafter. These results suggest that very low-dose parenteral estradiol permits relatively age-appropriate feminization without interfering with the effect of GH on the enhancement of height potential.

Efficacy and Safety Results of Long-Term Growth Hormone Treatment of Idiopathic Short Stature

Small clinical trials of GH treatment of idiopathic short stature (ISS) show variable efficacy. The study was an analysis of a large GH registry for efficacy and safety of GH treatment of ISS. There was also a comparison with a specific clinical trial. Up to 7 yr of GH treatment of ISS was evaluated for efficacy and safety in the National Cooperative Growth Study (NCGS). The NCGS study was conducted at Genentech, Inc. and included 47,226 patients. The ISS group included maximum stimulated GH 10 ng/ml or more and/or a report of ISS by investigator (n = 8018; all included for safety). Cohort 1 (n = 2520) was similar to the clinical trial, cohort 2 (n = 283) included subjects younger than 5 yr of age, and cohort 3 (n = 940) was pubertal at GH start. GH, approximately 0.30 mg/kg.wk, was given. These included growth velocities and height sd (HtSDS). Mean first-year growth velocities in cohorts 1, 2, and 3 increased 4.6, 3.9, and 4.4 cm/yr over pretreatment, respectively. Measures included: baseline mean HtSDS, -2.9, -3.2, and -2.8; mean HtSDS at 1 yr, -2.4, -2.3, and -2.3, respectively. Mean HtSDS after 7 yr in cohorts 1 (n = 303) and 2 (n = 85) and 5 yr in cohort 3 (n = 58) were: -1.2, -1.0, and -1.5, respectively. Cohort 3 shorter treatment time was due to advanced baseline age (mean 13.8 yr) and puberty. Mean HtSDS gain in cohort 1 was comparable with the clinical trial. No new safety signals specific to the NCGS ISS population were observed. ISS patients in the GH registry demonstrate a significant increase in HtSDS with the safety profile similar to GH-deficient patients. RESULTS were similar to the clinical trial.