Idiopathic Isolated Growth Hormone Deficiency Research Articles

6877 Withdrawing Growth Hormone Treatment at Mid-Puberty in Idiopathic Isolated Growth Hormone Deficiency: Baseline Characteristics in Patient-Preference Design Study

Abstract Disclosure: J. Vliegenthart: None. J. Wit: None. B. Bakker: None. A. Boot: None. C. de Bruin: None. M. Finken: None. J.V. Heyden: None. M. Houdijk: None. H. van der Kamp: None. E. Van Mil: None. A. Reedijk: None. T. Sas: None. D.A. Schott: None. P. van Setten: None. S. Straetemans: None. V. van Tellingen: None. B. Touwslager: None. A.V. Trotsenburg: None. P. voorhoeve: None. A.C. Hokken-Koelega: None. D.C. van der Kaay: None. Background: The majority of children diagnosed with idiopathic isolated growth hormone deficiency (IIGHD) show a normal growth hormone (GH) secretion (assessed by GH stimulation tests) when retested at near adult height (NAH). It appears plausible that, if normal stimulated GH secretion is observed in mid-puberty, continuing recombinant human GH (rhGH) treatment may only have a minor effect on NAH. The effect on NAH has never been investigated in a prospective study. Aim: To evaluate patient preference in the choice to (dis-)continue GH treatment from mid-puberty, and to study whether patients who discontinued treatment differed in baseline characteristics from those who continued treatment. Methods: The study population consisted of adolescents who were diagnosed in childhood with IIGHD (GH peak at diagnosis between 1.7 ug/L and 10 ug/L) and who had started rhGH therapy between 2005-2018. According to the national treatment protocol, GH secretion was retested in mid-puberty (males: Tanner stage G3/4, testicular volume >12 ml and bone age (BA) 13-16 years; females: Tanner stage B3/4 and BA 11-14 years). In this multicentre prospective patient-preference design study, adolescents who tested GH sufficient at mid-puberty (GH peak >6.7 ug/L) had the choice to discontinue or continue rhGH treatment until NAH (height velocity <2cm/year). Results: In total 127 patients (95 male, 75%) participated in this study. Forty-four patients (35%) chose to continue GH treatment until NAH (group 1), and 83 patients (65%) chose to discontinue GH treatment (group 2). Mean height at inclusion (group 1: -0.76±0.69 SDS vs group 2: -0.47±0.85 SDS; P=0.055), target height SDS (group 1: -0.73±0.54 SDS and -0.58±0.53 SDS, P=0.15) and age at inclusion (group 1: 14.0±1.1y and 13.9±1.1y, P=0.69) did not significantly differ between groups. Males and females did not differ in these characteristics. Currently, 109 patients (86%) have reached NAH. Conclusions: The majority of patients (65%) preferred to discontinue rhGH treatment after sufficient GH retesting in mid-puberty. An anticipated difference in baseline data between the groups (adolescents who choose to discontinue treatment may be taller and older) could not be confirmed. Data are being collected until all patients reach near adult height. Presentation: 6/3/2024

9262 Withdrawing Growth Hormone Treatment at Mid-Puberty in Idiopathic Isolated Growth Hormone Deficiency: Baseline Characteristics in Patient-Preference Design Study

Abstract Disclosure: J. Vliegenthart: None. J. Wit: None. B. Bakker: None. A. Boot: None. C. de Bruin: None. M. Finken: None. J.V. Heyden: None. M. Houdijk: None. H. van der Kamp: None. E. Van Mil: None. A. Reedijk: None. T. Sas: None. D.A. Schott: None. P. van Setten: None. S. Straetemans: None. V. van Tellingen: None. B. Touwslager: None. A.V. Trotsenburg: None. P. voorhoeve: None. A.C. Hokken-Koelega: None. D.C. van der Kaay: None. Background: The majority of children diagnosed with idiopathic isolated growth hormone deficiency (IIGHD) show a normal growth hormone (GH) secretion (assessed by GH stimulation tests) when retested at near adult height (NAH). It appears plausible that, if normal stimulated GH secretion is observed in mid-puberty, continuing recombinant human GH (rhGH) treatment may only have a minor effect on NAH. The effect on NAH has never been investigated in a prospective study. Aim: To evaluate patient preference in the choice to (dis-)continue GH treatment from mid-puberty, and to study whether patients who discontinued treatment differed in baseline characteristics from those who continued treatment. Methods: The study population consisted of adolescents who were diagnosed in childhood with IIGHD (GH peak at diagnosis between 1.7 ug/L and 10 ug/L) and who had started rhGH therapy between 2005-2018. According to the national treatment protocol, GH secretion was retested in mid-puberty (males: Tanner stage G3/4, testicular volume >12 ml and bone age (BA) 13-16 years; females: Tanner stage B3/4 and BA 11-14 years). In this multicentre prospective patient-preference design study, adolescents who tested GH sufficient at mid-puberty (GH peak >6.7 ug/L) had the choice to discontinue or continue rhGH treatment until NAH (height velocity <2cm/year). Results: In total 127 patients (95 male, 75%) participated in this study. Forty-four patients (35%) chose to continue GH treatment until NAH (group 1), and 83 patients (65%) chose to discontinue GH treatment (group 2). Mean height at inclusion (group 1: -0.76±0.69 SDS vs group 2: -0.47±0.85 SDS; P=0.055), target height SDS (group 1: -0.73±0.54 SDS and -0.58±0.53 SDS, P=0.15) and age at inclusion (group 1: 14.0±1.1y and 13.9±1.1y, P=0.69) did not significantly differ between groups. Males and females did not differ in these characteristics. Currently, 109 patients (86%) have reached NAH. Conclusions: The majority of patients (65%) preferred to discontinue rhGH treatment after sufficient GH retesting in mid-puberty. An anticipated difference in baseline data between the groups (adolescents who choose to discontinue treatment may be taller and older) could not be confirmed. Data are being collected until all patients reach near adult height. Presentation: 6/3/2024

6860 Cognitive Capacity in Children with Growth Hormone Deficiency

Abstract Disclosure: V. leal: None. V. Alvarez: None. S.S. Awadalla: None. Growth hormone (GH) is necessary for longitudinal growth and also has multiple other functions including neurologic development. Cognitive function in children with idiopathic isolated growth hormone deficiency (IGHD) has been poorly studied. This study aims to prospectively investigate cognitive capacity in children with IGHD.Cognitive function of 10 children with IGHD (peak GH <10 μg/L) was studied using Wechsler Intelligence Scales for Children IV: Intelligence Quotient, Verbal Comprehension Index, Perceptual Reasoning Index, and Working Memory and Processing Speed Indices.6 females and 4 males were included , Age was 10.04 ±2.01 years (M± DS) , height SDS was -1.86 ±0.19 . The IQ was 100.6 ±8.5, Verbal Comprehension was 99.3 ±8.5, Perceptual Reasoning was 102.5 ±9.1, Working Memory was 99.9 ±9.8, and Processing Speed was 98.9 ±13.1. Using Spearman correlation test ; a moderate positive correlation was observed between the GH peak and the intellectual coefficient IQ and peak GH: r=0.45, p=0.18, Perceptual reasoning and GH: r=0.43, p=0.2 without a statistical significance probably because of the sample size. In conclusion; The overall IQ score fell within the normal range, with lower scores in processing speed and working memory. These findings underscore the importance of considering not only the impact on linear growth but also on cognitive development when addressing growth hormone deficiency in the pediatric population Presentation: 6/3/2024

Growth Hormone Dosing Estimations Based on Body Weight Versus Body Surface Area

Both body weight (BW)- and body surface area (BSA)-based dosing regimens have been recommended for growth hormone (rhGH) replacement. The aim was to compare the two regimens to determine if either resulted in inadequate treatment depending on anthropometric factors. The retrospective study included children diagnosed with idiopathic isolated growth hormone deficiency. BW-based dosing in mcg/kg/day was converted to BSA in mg/m2/day to determine the equivalent amounts of the given rhGH. Those with a BW-to-BSA ratio of more than 1 were allocated to the “relatively over-dosed group”, while the remaining patients with a ratio of less than 1 were assigned to the “relatively under-dosed” group. Patients with a height gain greater than 0.5 standard deviation score (SDS) at the end of one year were classified as the height gain at goal (HAG), whereas those with a height gain of less than 0.5 SDS were assigned as the height gain not at goal (NHAG). The study included 60 patients (18 girls, 30%). Thirty-six (60%) patients were classified as HAG. The ratio of dosing based on BW-to-BSA was positively correlated both with the ages and body mass index (BMI) levels of the patients, leveling off at the age of 11 at a BMI of 18 kg/m2. The relative dose estimations (over- and under-dosed groups) differed significantly between the patients classified as HAG or NHAG. Fifty-six percent of NHAG compared to 44% of HAG patients received relatively higher doses, while 79% of HAG compared to 21% of NHAG received relatively lower doses (p=0.006). When the patients were subdivided according to their pubertal status, higher doses were administrated mostly to the pubertal patients in both the NHAG and HAG groups. In the pre-pubertal age group, 73% of NHAG compared to 27% of HAG received relatively higher doses, while 25% of NHAG compared to 75% of HAG received relatively lower doses (p=0.01). Dosing based on BW may be preferable in both prepubertal and pubertal children who do not show adequate growth responses. In prepubertal children, relatively lower doses calculated based on BW rather than BSA provide similar efficacy at lower costs.

The landscape of retesting in childhood-onset idiopathic growth hormone deficiency and its reversibility: a systematic review and meta-analysis.

Children diagnosed with idiopathic isolated growth hormone deficiency (IGHD) are frequently observed to no longer be GH-deficient at a later stage of growth as a result of 'GHD reversal'. Reevaluation of GH status by stimulation test is currently incorporated into management guidelines at attainment of final height (FH). Over the past three decades, numerous studies have evaluated reversal rates using different methodologies including crucial parameters like GHD aetiology, GH cut-off and retesting time point, with heterogeneous results. We aimed to systematically analyse the reversibility of childhood-onset IGHD dependent on retesting GH cut-offs and retesting time points. PubMed, Cochrane Library, TRIP database and NHS Evidence were searched for publications investigating the reversibility of IGHD from database initiation to 30 June 2020 following PRISMA recommendations. Study cohorts were pooled according to retesting GH cut-off and time point. Reversal rates were calculated using random-effects models. Of the 29 studies initially identified, 25 provided sufficient detail for IGHD analysis, resulting in 2030 IGHD patient data. Reversal rates decreased significantly as the retesting GH cut-off increased (P = 0.0013). Pooled (95% CI) reversal rates were 80% (59-92%, n = 227), 73% (62-81%, n = 516) and 55% (41-68%, n = 1287) for cohorts using retesting GH cut-offs of 3-4 ng/mL, 5-6 ng/mL and 7.7-10 ng/mL, respectively. Individuals retested at FH (n = 674) showed a pooled reversal rate of 74% (64-82%) compared to 48% (25-71%) when retested before FH (n = 653). Provided evidence supports reevaluation of current IGHD management guidelines. The high reversal rates should instigate consideration of early retesting.

Common Polymorphisms of Growth Hormone: Growth Hormone Receptor Axis in Turkish Children with Short Stature.

Objective: A single-nucleotide polymorphism of the growth hormone 1 gene, GH1IVS4+90A>T (rs2665802), associated with short stature and a polymorphism of the growth hormone receptor gene, exon 3 deleted variant, associated with increased responsiveness to growth hormone have been reported previously. We aimed to investigate the frequency of both polymorphisms and their correlation to height in Turkish short children. Also, we aimed to evaluate the effect of exon 3 deleted variant on response to 1-year growth hormone therapy.Materials and Methods: Children with idiopathic isolated growth hormone deficiency (n = 39) and with idiopathic short stature (n = 10) and 50 control subjects were evaluated for anthropometric parameters, annual growth velocity, and annual height gain. Growth hormone receptor gene polymorphisms were analyzed via multiplex polymerase chain reaction; growth hormone 1 gene polymorphism was analyzed via polymerase chain reaction and single-strand conformation polymorphism techniques.Results: The frequency of genotypes carrying the “A” allele was not significantly higher in the idiopathic isolated growth hormone deficiency group than in the idiopathic short stature and control groups (P = .03 for each). The exon 3 deleted variant genotype was significantly lower in the idiopathic short stature group compared to the control group (P = .01). There was no effect of exon 3 deleted variant, on response to the first-year growth hormone therapy.Conclusion: In Turkish population, no correlation was found between the “A” allele of GH1IVS4+90A>T polymorphism and idiopathic isolated growth hormone deficiency and short stature, and a significant negative correlation was found between exon 3 deleted variant and idiopathic short stature and short stature. Exon 3 deleted variant has no effect on response to growth hormone treatment.

Decreased Thyroxine Levels during rhGH Therapy in Children with Growth Hormone Deficiency.

Background: Hypothyroidism in children leads to growth retardation. However, there is some evidence that recombinant human growth hormone (rhGH) therapy could suppress thyroid function. The most common observation in rhGH-treated patients is a decrease in thyroxine levels, which is reported as transient, but the studies in the field are inconsistent. We aimed to evaluate thyroid function in initially euthyroid children with idiopathic isolated GH deficiency during long-term rhGH therapy and to determine who is at a higher risk of thyroid function alterations during the therapy. Methods: The study group consisted of 101 children treated with rhGH for at least three years. Serum TSH and fT4 levels were determined at baseline, after the first six months and after each full year of therapy. The associations between changes in thyroid hormone levels during rhGH therapy and GH deficit, insulin-like growth factor-1 levels and growth response were investigated. Results: A significant decrease in fT4 levels (p = 0.01) was found as early as after the first six months of rhGH therapy. This effect persisted in the subsequent years of treatment without any significant changes in TSH values and tended to be rhGH dose related. Children with a greater fT4 decrease after the initiation of rhGH therapy were older, had higher bone age and responded to that therapy worse than children with lower fT4 changes. Conclusions: Our study revealed a long-term decrease in fT4 levels during rhGH therapy in initially euthyroid GHD children. The decrease in fT4 levels was associated with a lower growth response to rhGH therapy.

Contribution of functionally assessed GHRHR mutations to idiopathic isolated growth hormone deficiency in patients without GH1 mutations.

Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in an unusually large group of patients. All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with nonsyndromic IGHD. Functional consequences of all newly identified missense variants were assessed in vitro (i.e., study of the expression of recombinant GHRHRs and their ability to activate the cyclic adenosine monophosphate (cAMP) signaling pathway). Genotype-phenotype correlation analyses were performed according to the nature of the identified mutation. We identified 20 different disease-causing GHRHR mutations (truncating and missense loss-of-function mutations), among which 15 are novel, in 24 unrelated patients. Of note, about half (13/24) of those patients represent sporadic cases. The clinical phenotype of patients with at least one missense GHRHR mutation was found to be indistinguishable from that of patients with bi-allelic truncating mutations. This study, which unveils disease-causing GHRHR mutations in 8% (24/312) of IGHD cases, identifies GHRHR as the second IGHD gene most frequently involved after GH1. The finding that 8% of IGHD cases without GH1 mutations are explained by GHRHR molecular defects (including missense mutations), together with the high proportion of sporadic cases among those patients, has important implications for genetic counseling.

SUN-258 Prediction of Height Two Years after Start Treatment in Children with Growth Hormone Deficiency

Background: Various prediction models for the growth response to recombinant human growth hormone (rhGH) have been published, but none of these have been able to incorporate data on adherence to rhGH treatment. Previous studies have shown that suboptimal adherence negatively affects the growth response in the first two years of rhGH treatment. The availability of the easypod electronic drug-delivery device which continuously assesses adherence, enables to develop a prediction model taking adherence into account. Aim: To develop a model for prediction of height standard deviation score (HSDS) two years after start treatment, using information available at the start of GH treatment and adherence in the first two years. Patients and Methods: We included prepubertal children with idiopathic isolated growth hormone deficiency (GHD) participating in the easypod connect observational study (ECOS), a 5-year, Phase IV open-label study to continuously assess real-world adherence via the easypod device. Inclusion criteria were GHD, naïve to rhGH treatment, age <10y in girls and <12y in boys, height and adherence available in the first and second year, target height, birth weight, gestational age, and information on GH dose. Linear regression analyses were performed to construct a prediction model for HSDS 2y after start treatment, with age at start, HSDS at start, target height (TH) SDS, birth weight SDS, GH dose, gestational age (<37 weeks vs ≥37 weeks), sex, and adherence in the first and second year as potential predictors. Stepwise backward regression analyses were performed to simplify the model without a statistically significant loss of fit with a model fit criterion of p<0.1 for each predictor. Results: In total, 132 patients complied with the inclusion criteria. Mean (SD) HSDS was -2.4 (0.9) and age at start 6.5 (2.0) yrs. The prediction model was: HSDS at 2y after start treatment = 0.4699 - 0.0627 x Age at start + 0.7904 x HSDS at start + 0.1216 x TH SDS + 0.0418 x birth weight SDS + 0.1659 x sex (male) + 0.0050 x adherence in the second year. P-values were <.001 for HSDS at start and adherence in the second year, .002 for Age at start, and .07 for TH SDS, birth weight SDS and sex. This model explained 76% of the total variance. For example, if a girl starts with GH treatment at 6.5y with a HSDS of -2.4, TH SDS of 0, birth weight SDS of 0 and 100% adherence in the second year, her predicted HSDS 2y after start treatment is -1.3 SD. If she misses 2 injections/week in the second year, the predicted HSDS 2y after start treatment is -1.5 SD. Conclusion: We have developed a prediction model for height two years after start treatment for children with GHD. This model can be used to study the impact of information available at the start of GH treatment and adherence in the second year. More research is needed to explore the effect of individual patterns of adherence on growth in real word settings.

Risk of Diabetes Treated in Early Adulthood After Growth Hormone Treatment of Short Stature in Childhood.

Growth hormone (GH) is known to be diabetogenic, but the risk of diabetes in individuals treated with GH in childhood has been little evaluated, and conflicting results have been obtained. To investigate the prevalence of diabetes and gestational diabetes in a population-based cohort of patients treated with GH for short stature in childhood in France. Participants were a population-based cohort of 5100 children with idiopathic isolated GH deficiency, idiopathic short stature, or short stature in children born short for gestational age who started GH treatment between 1985 and 1996. Data on the delivery of diabetes drugs in 2009 and 2010 were obtained from the French national health insurance database. Cases in patients and controls were identified from diabetes drugs deliveries. The prevalence of diabetes was calculated and compared with that in the general population, determined on the basis of data from the same source, with the same definition. At a mean age of 30 years, no difference in the prevalence of treated diabetes (oral drugs or insulin) was found between subjects treated with GH and the general population in France, regardless of sex. Similarly, the risk of insulin-treated gestational diabetes was similar in patients and in the reference population. No difference in the risk of diabetes was found between GH-treated patients and the reference population. These results are reassuring, but further studies with a longer follow-up are required to evaluate the risk of diabetes with age in these patients.

Mortality Is Not Increased in Recombinant Human Growth Hormone-treated Patients When Adjusting for Birth Characteristics.

This study aimed to investigate whether reported high mortality in childhood recombinant human GH (rhGH)-treated patients was related to birth-characteristics and/or rhGH treatment. We sought to develop a mortality model of the Swedish general population born between 1973 and 2010, using continuous-hazard functions adjusting for birth characteristics, sex, age intervals, and calendar year to estimate standardized mortality ratio (SMR) and to apply this model to assess expected deaths in Swedish rhGH-treated patients with idiopathic isolated GH deficiency (IGHD), idiopathic short stature (ISS) or born small for gestational age (SGA). The general population: Swedish Medical Birth Register (1973-2010: 1 880 668 males; 1 781 131 females) and Cause of Death Register (1985-2010). Intervention Population: Three thousand eight hundred forty-seven patients starting rhGH treatment between 1985 and 2010 and followed in the National GH Register and/or in rhGH trials diagnosed with IGHD (n = 1890), ISS (n = 975), or SGA (n=982). Death. Using conventional models adjusting for age, sex, and calendar-year, the SMR was 1.43 (95% confidence interval, 0.89-2.19), P = .14, observed/expected deaths 21/14.68. The rhGH population differed (P < .001) from the general population regarding birth weight, birth length, and congenital malformations. Application of an Advanced Model: When applying the developed mortality model of the general population, the ratio of observed/expected deaths in rhGH-treated patients was 21/21.99; SMR = 0.955 (0.591-1.456)P = .95. Model Comparison: Expected number of deaths were 14.68 (14.35-14.96) using the conventional model, and 21.99 (21.24-22.81) using the advanced model, P < .001, which had at all ages a higher gradient of risk per SD of the model, 24% (range, 18-42%; P < .001). Compared with the general Swedish population, the ratio of observed/expected deaths (21/21.99) was not increased in childhood rhGH-treated IGHD, ISS, and SGA patients when applying an advanced sex-specific mortality model adjusting for birth characteristics.

Cortisol responses to the insulin tolerance test and glucagon stimulation tests in children with idiopathic short stature and idiopathic isolated growth hormone deficiency

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Early retesting by GHRH+arginine test shows normal GH response in most children with idiopathic GH deficiency.

Most children with idiopathic isolated GH deficiency (IGHD) normalize GH response to stimulation tests when retested at the completion of growth. The objective of this study was to test the effectiveness of early retesting in challenging the diagnosis of idiopathic IGHD and critically review the diagnostic workup leading to this diagnosis in children with short stature. We cross-sectionally retested 38 children with idiopathic IGHD and still on GH treatment. The initial diagnosis of idiopathic IGHD was based on subnormal GH responses to two stimulation tests and normal brain imaging or minor/nonspecific findings at magnetic resonance. The GH response normalization at retesting was considered as the main outcome measure. Clinical features of children who were falsely classified as idiopathic IGHD based on first GH testing were retrospectively analyzed. GH secretion was normal in 36/38 children (95%). Two children showed slightly reduced peak GH responses and normal IGF-I levels. Fourteen children underwent GH retesting before puberty, 24 children during puberty. The diagnostic process should be improved to minimize the rate of false positive at GH testing and, in case of unsatisfactory response to GH treatment, the diagnosis of isolated idiopathic GHD should be challenged with early retesting.

Growth Hormone Dose-Dependent Pubertal Growth: A Randomized Trial in Short Children with Low Growth Hormone Secretion

Background/Aims: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i.e. idiopathic isolated GH deficiency. Methods: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH 33 µg/kg/day for ≥1 year. They were randomized to receive 67 µg/kg/day (GH⁶⁷) given as one (GH^67×1; n = 35) or two daily injections (GH^33×2; n = 36), or to remain on a single 33 µg/kg/day dose (GH^33×1; n = 40). Growth was assessed as height_SDSgain for prepubertal, pubertal and total periods, as well as AH_SDS versus the population and the midparental height. Results: Pubertal height_SDSgain was greater for patients receiving a high dose (GH⁶⁷, 0.73) than a low dose (GH^33×1, 0.41, p < 0.05). AH_SDS was greater on GH⁶⁷ (GH^67×1, -0.84; GH^33×2, -0.83) than GH³³ (-1.25, p < 0.05), and height_SDSgain was greater on GH⁶⁷ than GH³³ (2.04 and 1.56, respectively; p < 0.01). All groups reached their target height_SDS. Conclusion: Pubertal height_SDSgain and AH_SDS were dose dependent, with greater growth being observed for the GH⁶⁷ than the GH³³ randomization group; however, there were no differences between the once- and twice-daily GH⁶⁷ regimens.

Growth hormone treatment for childhood short stature and risk of stroke in early adulthood.

We investigated the incidence of stroke and stroke subtypes in a population-based cohort of patients in France treated with growth hormone (GH) for short stature in childhood. Adult morbidity data were obtained in 2008-2010 for 6,874 children with idiopathic isolated GH deficiency or short stature who started GH treatment between 1985 and 1996. Cerebrovascular events were validated using medical reports and imaging data and classified according to standard definitions of subarachnoid hemorrhage, intracerebral hemorrhage, and ischemic stroke. Case ascertainment completeness was estimated with capture-recapture methods. The incidence of stroke and of stroke subtypes was calculated and compared with population values extracted from registries in Dijon and Oxford, between 2000 and 2012. Using both Dijon and Oxford population-based registries as references, there was a significantly higher risk of stroke among patients treated with GH in childhood. The excess risk of stroke was mainly attributable to a very substantially and significantly higher risk of hemorrhagic stroke (standardized incidence ratio from 3.5 to 7.0 according to the registry rates considered, and accounting or not accounting for missed cases), and particularly subarachnoid hemorrhage (standardized incidence ratio from 5.7 to 9.3). We report a strong relationship between hemorrhagic stroke and GH treatment in childhood for isolated growth hormone deficiency or childhood short stature. Patients treated with GH worldwide should be advised about this association and further studies should evaluate the potentially causal role of GH treatment in these findings.

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency

We assessed the characteristics of children initially diagnosed with idiopathic isolated GH deficiency (IGHD) who later developed additional (multiple) pituitary hormone deficiencies (MPHD). Data were analyzed for 5805 pediatric patients with idiopathic IGHD, who were GH-naïve at baseline and GH-treated in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study. Development of MPHD was assessed from investigator diagnoses, adverse events, and concomitant medications. Analyses were performed for all patients and for those who developed MPHD within 4.5 years or had ≥3.5 years, follow-up and continued to have IGHD (4-year cohort). MPHD developed in 118/5805 (2.0%) children overall, and in 96/1757 (5.5%) in the 4-year cohort. Patients who developed MPHD had more profound GHD, with decreased height SDS, IGF1 SDS and peak stimulated GH, and greater height decrement vs target, compared with children who continued to have IGHD (P<0.001 for each variable). Delivery complications, congenital anomalies, and perinatal/neonatal adverse events occurred more frequently in patients who developed MPHD. The most frequent additional deficiency was TSH (82 patients overall); four patients developed two pituitary hormone deficiencies and one developed three deficiencies. Multivariable logistic regression indicated that years of follow-up (odds ratio 1.55), baseline age (1.17), baseline height SDS (0.69), and peak stimulated GH (0.64) were associated with the development of MPHD. MPHD is more likely to develop in patients with more severe idiopathic IGHD. Older baseline age, lower baseline height SDS, and longer follow-up duration are associated with increased risk of development of MPHD.

How safe is growth hormone therapy? SAGhE and beyond

Although short term health on growth hormone treatment has been extensively studied, little is known of the long-term health of subjects treated with growth hormone in childhood. Approximately 40 000 children are treated with growth hormone in the European Union and several hundred thousands in the world and it is essential to address this important question. SAGhE is an European consortium aimed at addressing this question as well as to gain further insight in the long term effect of growth hormone both in terms of height and of significance on quality of life. Eight countries participate in SAGhE: Belgium, France, Germany, Italy, Netherlands, Sweden, Switzerland, United Kingdom and have recruited approximately 25 000 patients who were treated for the most part in the late 80's and 90's and who are currently adults. The results of the SAGhE study as a whole are expected to be available to the investigators at the end of 2012 and will be disseminated in 2013. However, the study did not start synchronously in all countries and results from France and from 3 other countries have been made disseminated in late 2010 and published in early 2012. In the report from France, 6928 children with idiopathic isolated GH deficiency (n = 5162), neurosecretory dysfunction (n = 534) idiopathic short stature (n = 871) or born short for gestational age (n = 335) who started treatment between 1985 and 1996 were followed on vital status up to September 2009 for 94.7% of the patients. In this population of patients, all-cause mortality was increased with a standardized mortality ratio (SMR) of 1.33. 95% CI 1.08–1.64). In multivariate analysis adjusted for height, the use of GH doses >50 µg/kg/day was associated with mortality rates using external and internal references (SMR 2.94, 95%CI 1.22–7.07, HR 2.79, 95%CI 1.14–6.82). All type cancer-related mortality was not increased. Bone tumor-related mortality was increased (SMR 5.00, 95%CI 1.01–14.63). An increase in mortality due to diseases of the circulatory system (SMR 3.07, 95%CI 1.40–5.83), subarachnoid or intracerebral hemorrhage (SMR 6.66, 95%CI 1.79–17.05) was observed. Mortality rates were therefore increased in this population of adults treated as children with recombinant GH, particularly in those who had received the highest doses. In a parallel report, 3 additional countries (Belgium, Netherlands, Sweden) the cause of death from a cohort of 2543 patients could be identified and no cancer- or cardiovascular disease-related deaths were found. These results highlight the need for additional studies of long-term mortality and morbidity after GH treatment in childhood but do not change the risk benefit balance of growth hormone treatments, after careful evaluation by Medicine Agencies. Consolidated results of the SAGhE study are expected to be available at the end of 2012 and to be disseminated during 2013.

The Effect of Recombinant Human Growth Hormone Therapy on Left-Ventricular Chamber Size and Function in Children With Growth Hormone Deficiency

This study was designed to assess the effect of recombinant human growth hormone (rhGH) therapy on left-ventricular (LV) chamber size and function in children with idiopathic isolated growth hormone deficiency (GHD) using conventional echocardiography and tissue Doppler imaging (TDI). Thirty patients (19 boys and 11 girls) with idiopathic isolated GHD were followed-up for 12 months. Mean age of patients was 11.0 ± 2.6 years (range 6.3-15.5). At baseline and at 3, 6, and 12 months of treatment, the structure of the left ventricle was assessed by conventional echocardiography and myocardial rates and time intervals by TDI. There was a significant increase in LV mass (LVM) compared with pretreatment values. Like LVM, relative wall thickness (RWT) was also increased significantly. The significant increase in LVM indexed to body surface area and RWT became apparent at month 3 of treatment with a significant increase in LVM indexed to height(2.7) at treatment month 6. Normalized LVM increased as early month 3 of treatment, and a steady increase was observed until month 12. However, no patient had LVM > +2 standard deviation scores at month 12 of treatment. No significant differences were observed in functional parameters of the left ventricle and the interventricular septum. The results of this study showed that rhGH therapy causes an increase in myocardial mass without changing the geometry or function of the myocardium. Therefore, the increase in myocardial mass appears to be concentric, thus causing remodeling instead of hypertrophy.

Height Gain at Adult-Height Age in 184 Short Patients Treated with Growth Hormone from Prepubertal Age to Near Adult-Height Age is Not Related to GH Secretory Status at GH Therapy Onset

Background: GH release after stimuli classifies short children as severe idiopathic isolated GH deficiency (IIGHD), mild IIGHD, dissociated GH release (DGHR) and normal GH release (NGHR) and anthropometric birth data as adequate for gestational age (AGA) or small for gestational age (SGA). GH release after stimuli classifies AGA patients as IIGHD or as idiopathic short stature (ISS). Aim: To compare height gain induced by GH therapy (31.8 ± 3.5 µg/kg/day, 7.7 ± 1.6 years) started at prepubertal age and stopped at near adult-height age. Methods: A retrospective longitudinal multicenter study including 184 short patients classified as severe IIGHD n = 25, mild IIGHD n = 75, DGHR n = 55 and NGHR n = 29; or as IIGHD n = 78, ISS n = 57 and SGA n = 49. Height gain was evaluated throughout GH therapy and at adult-height age. Results: Height-SDS gain at adult-height age was similar among severe IIGHD (1.8 ± 0.8 SDS), mild IIGHD (1.6 ± 0.6 SDS), DGHR (1.7 ± 0.7 SDS) and NGHR (1.6 ± 0.7 SDS), or among IIGHD (1.7 ± 0.7 SDS), ISS (1.7 ± 0.6 SDS) and SGA (1.6 ± 0.8 SD). Conclusion: GH-release stimuli are of little help for deciding on GH therapy in the clinical management of prepubertal children with IIGHD, ISS or SGA.

Long-Term Mortality after Recombinant Growth Hormone Treatment for Isolated Growth Hormone Deficiency or Childhood Short Stature: Preliminary Report of the French SAGhE Study

Little is known about the long-term health of subjects treated with GH in childhood, and Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) is a study addressing this question. The objective of the study was to evaluate the long-term mortality of patients treated with recombinant GH in childhood in France. This was a population-based cohort study. The setting of the study was a French population-based register. A total of 6928 children with idiopathic isolated GH deficiency (n = 5162), neurosecretory dysfunction (n = 534), idiopathic short stature (n = 871), or born short for gestational age (n = 335) who started treatment between 1985 and 1996 participated in the study. Follow-up data on vital status were available in September 2009 for 94.7% of the patients. All-cause and cause-specific mortality was measured in the study. All-cause mortality was increased in treated subjects [standardized mortality ratio (SMR) 1.33, 95% confidence interval (CI) 1.08-1.64]. In a multivariate analysis adjusted for height, the use of GH doses greater than 50 μg/kg · d was associated with mortality rates using external and internal references (SMR 2.94, 95% CI 1.22-7.07, hazard ratio 2.79, 95% CI 1.14-6.82). All type cancer-related mortality was not increased. Bone tumor-related mortality was increased (SMR 5.00, 95% CI 1.01-14.63). An increase in mortality due to diseases of the circulatory system (SMR 3.07, 95% CI 1.40-5.83) or subarachnoid or intracerebral hemorrhage (SMR 6.66, 95% CI 1.79-17.05) was observed. Mortality rates were increased in this population of adults treated as children with recombinant GH, particularly in those who had received the highest doses. Specific effects were detected in terms of death due to bone tumors or cerebral hemorrhage but not for all cancers. These results highlight the need for additional studies of long-term mortality and morbidity after GH treatment in childhood.