Anders Lindberg

Observed and Predicted Growth Responses in Prepubertal Children with Growth Disorders: Guidance of Growth Hormone Treatment by Empirical Variables

CONTEXT Information about the expected growth response of children to GH therapy is currently inadequate. OBJECTIVES The aim of the study was to compare observed and expected growth in response to GH in prepubertal children and to propose how these parameters can be used to optimize GH therapy. Indices considered were observed growth, observed growth relative to reference data [height sd score (Ht SDS), change in (Delta) Ht SDS, height velocity (HV)], and observed growth relative to growth predicted from prediction models [Studentized residual (SR)]. Design/Setting/Patients/Intervention: Growth data from KIGS-Pfizer International Growth Database-on prepubertal children aged 1-13 yr with severe GH deficiency (GHD; maxGH <5 microg/liter; n = 2129), with less-severe GHD (maxGH of 5-10 microg/liter; n = 3075), and with Turner syndrome (n = 2350), and short children born small for gestational age (n = 993) were analyzed before and during 2 yr of GH treatment. MAIN OUTCOME MEASURE For each patient group, growth responses during the first 2 yr of GH treatment were established. The relationships of HV and DeltaHt SDS with SR were determined. RESULTS Reference data were generated for assessing adequate individual responses. Responses to GH in terms of HV and DeltaHt SDS were greatest in children with severe GHD. HV and DeltaHt SDS were highly correlated with SR during only the first year of GH treatment (R approximately 0.7; P < 0.001). CONCLUSIONS Decisions on GH therapy regimens should be made using both traditional (HV or DeltaHt SDS) and prediction model-derived (SR) indices of growth response.

Age at Growth Hormone Therapy Start and First-Year Responsiveness to Growth Hormone Are Major Determinants of Height Outcome in Idiopathic Short Stature

Aim: To develop methods to identify factors associated with a favorable outcome in GH-treated children with idiopathic short stature (ISS). Methods: From 4,685 children listed as having ISS within KIGS (Pfizer International Growth Database), we studied (a) the prediction model group (n = 657) to develop the first-year prediction model, and (b) the near adult height group (NAH; n = 256) which received GH for >4 years to develop descriptive models for adult height and overall height gain. Results: NAH group at GH start: age was 10.0 years, height –2.5 SD score (SDS), weight –2.3 SDS, height minus mid-parental height (MPH) –1.5 SDS; GH dose 0.19 mg/kg/week. Height gain was 1.1 SDS at a median age of 17.2 years. Growth response correlated positively with GH dose and weight at the start of GH treatment, and negatively with age and height SDS minus MPH SDS. The model explains 39% (error SD 1.2 cm) of the variability. Adult height correlated (R2 = 0.64) positively with height at GH start, MPH and the first-year responsiveness to GH, and negatively with age. Conclusions: Prepubertal children with ISS who show an appropriate first-year response to GH are likely to benefit from long-term treatment, even on low GH dosages.

Factors Determining Pubertal Growth and Final Height in Growth Hormone Treatment of Idiopathic Growth Hormone Deficiency

A total of 195 children (117 males and 78 females) with idiopathic growth hormone deficiency (IGHD) treated with growth hormone (GH) for at least 1 year before puberty onset and who had completed treatment to adult height, were selected from the KIGS database for study of growth during puberty. Spontaneous and induced puberty started at 13.8 and 14.9 years in boys and at 12.9 and 13.7 years in girls, respectively. Duration of GH treatment and height gained prepubertally were greater when puberty was induced; prepubertal catch up growth (expressed as a percentage of the difference between target height and height at start of GH) was greater when puberty was induced in boys (59% induced vs. 45% spontaneous, p < 0.001), and in girls (72% induced vs. 53.9% spontaneous, p < 0.01). Final height was attained at 17.8 and 19.2 years in boys and at 16.0 and 17.0 years in girls following spontaneous and induced puberty, respectively. Final heights were greater after induced puberty compared with spontaneous puberty in boys (171.3 vs. 166.0 cm, p < 0.001) and in girls (157.0 vs. 155.0 cm, n.s.). Target height was also significantly greater in boys with spontaneous puberty (172.2 cm vs. induced = 174.2 cm) as compared to girls (spontaneous = 158 cm vs. induced = 160 cm). Duration of pubertal growth was longer in boys compared to girls (3.6 vs. 3.0 years, p < 0.001) and was negatively correlated with age, height, and distance from target height at onset of puberty, but was not correlated with the dose of GH. Catch-up growth during puberty (expressed as a percentage of the difference between target height and height at puberty onset) after induced and spontaneous puberty was 87.9% and 80.5% (not significant) in boys and 66.4% and 75.5% (not significant in girls. Total pubertal growth (TPG) (cm) was inversely correlated with prepubertal growth by simple linear regression. Multiple linear regression analysis indicated 5 independent predictors of TPG accounting for 78% of the variability, namely sex (boys grew more), distance of target height from height at onset of puberty (+), dose of GH at onset of puberty (+), age at onset of puberty (-), and age at end of growth (+).

Factors predicting the near-final height in growth hormone-treated children and adolescents with chronic kidney disease.

CONTEXT GH therapy is an accepted measure to increase adult height in young prepubertal patients suffering from growth failure related to chronic kidney disease (CKD). The impact of GH therapy on final height (FH) in CKD patients of pubertal age is unclear. OBJECTIVE This study set out to analyze near-FH in a cohort of GH-treated CKD patients. DESIGN, SETTINGS, AND PATIENTS Of 240 evaluable patients in the Pfizer International Growth Database (KIGS) with CKD, 39% were prepubertal and 61% were pubertal at baseline; 45% were on conservative treatment for CKD, 28% were on dialysis, and 27% were in the period after renal transplantation. MAIN OUTCOME MEASURES Near-FH, relation to pubertal stage, and factors predictive of growth response were the main outcome measures. RESULTS Mean height sd scores increased continuously during GH treatment until near-FH by 1.2 and 1.6 in boys and girls, respectively. Mean near-FH differed significantly from prepubertal patients showing severely delayed puberty (-3.6), late pubertal patients (-2.9), early pubertal patients (-2.2), and prepubertal patients with normal onset of puberty (-2.0). The initial degree of stunting, degree of bone age retardation, duration of GH therapy, time spent on conservative treatment/dialysis, pubertal delay (>2 sd), gender, and age at start of GH treatment were significant predictors of growth response to GH therapy, explaining between 33 and 61% of the overall variability. CONCLUSIONS Long-term GH therapy of CKD patients in prepubertal and pubertal age results in an increased adult height, but response is diminished in patients on dialysis and/or with severely delayed puberty.

Predicting growth in response to growth hormone treatment

The use of growth hormone (GH) to treat children who have disturbances of growth is complicated by variability both within and across diagnostic groups, and at the start of and throughout treatment. Growth prediction models are important tools in the effort to account for these sources of variability and tailor GH treatment to each patients needs. This review considers the methodological approach taken to the development of models from data in large databases such as the Pfizer International Growth Database (KIGS); it also assesses the limitations of these models and their data sources, and the potential for improvements. While all aspects of model development bear continued scrutiny and improvement, the incorporation of more predictors is key if treatment outcomes are to be optimized in terms of efficacy, safety and cost.

Growth hormone treatment completely normalizes adult height and improves body composition in Prader-Willi syndrome: experience from KIGS (Pfizer International Growth Database).

Background: Abnormal body composition, with low muscle mass and increased fat mass, as well as short adult stature are common features in Prader-Willi syndrome (PWS), as in growth hormone (GH) deficiency. Methods: We followed a cohort of 22 genetically verified patients with PWS from the start of GH (Genotropin®) treatment at the median age of 6.9 years (4.9–11.3) to near-adult height at 18.1 years (16.4–21.2). The patients were treated with a median GH dose of 0.03 mg/kg/day (0.02–0.03) for a median duration of 10.2 years (6.9–11.5). Results: All patients reached near-adult height within midparental height median –0.5 SDS (–1.4 to 0.7) and 0.9 SDS (0.1–1.9) for girls and boys, respectively. The body composition improved but did not normalize. Only 7 of the 22 patients were reported to be in puberty. None of the patients were reported to be on sex hormone substitution which might contribute to not reaching a normal body composition. No serious side effects were reported when the caloric intake was controlled to maintain an appropriate body weight. Conclusion: GH treatment in children with Prader-Wili syndrome normalizes adult height and improves body composition.

Major determinants of height development in Turner syndrome (TS) patients treated with GH: Analysis of 987 patients from KIGS.

Little is known about factors determining height outcome during GH treatment in Turner syndrome (TS). We investigated 987 TS children within the Kabi International Growth Study (KIGS) who had reached near adult height (NAH) after >4 y GH treatment (including >1 y before puberty). Through multiple regression analysis we developed a model for NAH and total gain. Our results were as follows (median): 1) At start, age 9.7 yrs, height (HT) 118.0 cm (0.0 TS SDS), projected adult height 146.1 cm, GH dose 0.27 mg/kg wk; 2) NAH HT 151.0 cm (1.5 TS SDS); 3) Prepubertal gain 21.2 cm (1.6 TS SDS); 4) Pubertal gain 9.4 cm (0.0 TS SDS). NAH correlated (r2 = 0.67) with (ranked) HT at GH start (+), 1st year responsiveness to GH (+), MPH (+), age at puberty onset (+), age at GH start (−), and dose (+). The same factors explained (R2 = 0.90) the total HT gain. However, HT at GH start correlated negatively. Karyotype had no influence on outcome. Evidently, height at GH start (the taller, the better), age at GH start (the younger, the better), the responsiveness to GH (the higher, the better) and age at puberty (the later, the better) determine NAH.

Safety of Growth Hormone Treatment in Children Born Small for Gestational Age: The US Trial and KIGS Analysis

Background: Recently, growth hormone (GH) therapy for children with short stature born small for gestational age (SGA) has been approved in the USA and Europe. There have been few reports examining adverse events during GH treatment of these children. Aims: (i) To examine glucose tolerance and insulin sensitivity during GH treatment of children born SGA in a US trial. (ii) To determine and compare adverse events reported in children born SGA with those reported in children with idiopathic short stature (ISS) enrolled in KIGS – Pfizer International Growth Database. Methods: In the US SGA trial, an oral glucose tolerance test was performed and fasting plasma glucose, insulin and glycosylated haemoglobin (HbA1C) concentrations were measured at baseline and after 12 months of GH therapy. Insulin sensitivity was calculated using the homeostasis model assessment (HOMA) and the quantitative insulin sensitivity check index (QUICKI). In the KIGS analysis, a retrospective audit of spontaneously logged cumulative adverse events in children born SGA and those with ISS was undertaken. Adverse events are reported per 1,000 patients. Values are expressed as mean with 10th–90th percentiles. Results: In the US trial, 84 patients had complete data sets for analysis. Median birth weight was 1.78 kg (SDS, –2.5) and birth length 43 cm (SDS, –2.2) at a median gestational age of 36.5 weeks; 79% were Caucasian. At entry, median age of the patients analysed was 6.6 years, and 65% were male. Median height was 104.3 cm (SDS, –2.97), median weight 15.95 kg (SDS, –2.21) and body mass index 14.66 kg/m2 (SDS, –0.67). No patients developed impaired glucose tolerance or overt diabetes mellitus. The 0-min glucose concentration was 81 mg/dl at baseline and 86 mg/dl at 1 year, while the 120-min glucose concentration was 90 mg/dl at baseline and 96 mg/dl at 1 year. The 0-min insulin concentrations were 2.9 mU/l at baseline and 5.3 mU/l at 1 year, while the 120-min insulin levels were 7.7 mU/l at baseline and 11 mU/l at 1 year. The proportions of HbA1C were 5.2 and 5.4% at baseline and 1 year, respectively. HOMA and QUICKI values were 0.59 and 0.42, respectively, at baseline, and 1.13 and 0.38 at 1 year. In KIGS, there were 1909 children born SGA aged 9.1 (3.9–13.3) years with a birth weight SDS of –2.6 (–4.0 to –1.5), birth length SDS of –2.7 (–4.3 to –1.3) and height SDS of –2.71 (–3.9 to –1.8) prior to treatment. GH doses ranged from 0.032 to 0.037 in the USA and from 0.022 to 0.023 mg/kg/day in the remaining countries in KIGS. Neither total (187 vs. 183) nor serious (14 vs. 10) adverse events occurred more commonly in the SGA group than in the ISS group. Although respiratory adverse events occurred more commonly in children born SGA (34.3 vs. 16.8; p < 0.05), endocrine (12.0 vs. 2.7; p < 0.05) and hepatobiliary (6.2 vs. 1.1; p < 0.05) adverse events occurred more commonly in children with ISS. Conclusions: As expected, a reduction in insulin sensitivity occurred during GH treatment of children born SGA; however, glucose tolerance remained normal. No adverse events were reported more commonly in children born SGA than in those with ISS. Minor differences in adverse events reporting within organ systems between children born SGA and those with ISS are probably due to variable under-reporting of adverse events. GH appears to be a safe drug to use at current doses as a growth-promoting agent in short children born SGA.

Height at Start, First-Year Growth Response and Cause of Shortness at Birth Are Major Determinants of Adult Height Outcomes of Short Children Born Small for Gestational Age and Silver-Russell Syndrome Treated with Growth Hormone: Analysis of Data from KIGS

Background/Aims: There is limited information about adult height (AH) outcomes and the factors influencing outcomes of growth hormone (GH) therapy in short children born small for gestational age (SGA). Methods: AH (SDS) and Δheight (SDS) from GH start to AH were analyzed in 161 SGA children who had reached AH (55 with Silver-Russell syndrome, SRS). Results: SGA patients treated to AH were started on GH (median) 0.25 mg/kg/week at an age of 7.8 years with a height of –3.8 SDS. AH after 7.7 years was –2.2 SDS and –1.1 SDS below mid-parental height (MPH). AH (SDS) was explained by: height (SDS) at GH start (+), Δheight (SDS) 1st year on GH (+), years on GH (+), maternal height (SDS) (+), length (SDS) at birth (+), and the diagnosis of SRS (–) (explained variability 70%; error 0.6 SD). Gain in height (SDS) was explained by: Δheight (SDS) 1st year on GH (+), years on GH (+), height – MPH (SDS) at GH start (–) (explained variability 60%; error 0.7 SD). Conclusions: Algorithms for AH outcomes provides useful information about the potential of long-term growth on GH in short children born SGA.

Towards Optimal Treatment with Growth Hormone in Short Children and Adolescents: Evidence and Theses

Treatment with growth hormone (GH) has become standard practice for replacement in GH-deficient children or pharmacotherapy in a variety of disorders with short stature. However, even today, the reported adult heights achieved often remain below the normal range. In addition, the treatment is expensive and may be associated with long-term risks. Thus, a discussion of the factors relevant for achieving an optimal individual outcome in terms of growth, costs, and risks is required. In the present review, the heterogenous approaches of treatment with GH are discussed, considering the parameters available for an evaluation of the short- and long-term outcomes at different stages of treatment. This discourse introduces the potential of the newly emerging prediction algorithms in comparison to other more conventional approaches for the planning and evaluation of the response to GH. In rare disorders such as those with short stature, treatment decisions cannot easily be deduced from personal experience. An interactive approach utilizing the derived experience from large cohorts for the evaluation of the individual patient and the required decision-making may facilitate the use of GH. Such an approach should also lead to avoiding unnecessary long-term treatment in unresponsive individuals.