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Effect of Growth Hormone Treatment on Adult Height of Children with Idiopathic Short Stature
Abstract
Short-term administration of growth hormone to children with idiopathic short stature results in increases in growth rate and standard-deviation scores for height. However, the effect of long-term growth hormone therapy on adult height in these children is unknown.
We studied 121 children with idiopathic short stature, all of whom had an initial height below the third percentile, low growth rates, and maximal stimulated serum concentrations of growth hormone of at least 10 microg per liter. The children were treated with growth hormone (0.3 mg per kilogram of body weight per week) for 2 to 10 years. Eighty of these children have reached adult height, with a bone age of at least 16 years in the boys and at least 14 years in the girls, and pubertal stage 4 or 5. The difference between the predicted adult height before treatment and achieved adult height was compared with the corresponding difference in three untreated normal or short-statured control groups.
In the 80 children who have reached adult height, growth hormone treatment increased the mean standard-deviation score for height (number of standard deviations from the mean height for chronologic age) from -2.7 to -1.4. The mean (+/-SD) difference between predicted adult height before treatment and achieved adult height was +5.0+/-5.1 cm for boys and +5.9+/-5.2 cm for girls. The difference between predicted and achieved adult height among treated boys was 9.2 cm greater than the corresponding difference among untreated boys with initial standard-deviation scores of less than -2, and the difference among treated girls was 5.7 cm greater than the difference among untreated girls.
Long-term administration of growth hormone to children with idiopathic short stature can increase adult height to a level above the predicted adult height and above the adult height of untreated historical control children.
... Short stature is not a disease, so objective studies of the effectiveness of treatment with growth hormone in youths with sufficient growth hormone are only partially useful in establishing utility. 7,20 The psychosocial morbidity associated with being short is assumed to be more substantial than the data summarized here would seem to indicate. The preference or value that the patient (and often the parents) ascribes to being taller is what becomes important. ...
... Gathering such de-tailed information is important because patients who are not deficient in growth hormone but are treated with it will reach adults heights that are still below average and in many cases are not significantly different from the predicted adult height. 7,16,20 In the pediatric endocrine clinic at our hospital, all families bringing their child for an evaluation of short stature receive a brochure on the medical and psychosocial aspects of short stature as part of the routine psychosocial assessment. The guide includes information on practical strategies for coping with being short and for achieving independence both inside and outside the home. ...
... Isto então se refletiria na criança. Esta pesquisa também está de acordo com Harter (1985), segundo o qual a baixa estatura não se refletia na auto-avaliação física das crianças como um todo, mas apenas quando eram questionadas especificamente sobre a altura, o que indica apenas uma tentativa de conformidade com a norma. ...
... Segundo Calman (1984), quanto menor o intervalo entre a expectativa e o que foi alcançado, melhor será a qualidade de vida relacionada à saúde. As crianças que esperam atingir benefícios psicossociais do crescimento podem ficar frustradas mesmo porque o efeito do GH é de um aumento na estatura que varia de 3 a 9 cm apenas, e sua eficácia no caso de baixa estatura por insuficiência de GH é incerta (Hintz et al., 1999). Esse aumento pode ser muito maior do que o genótipo do paciente permitiria potencialmente, mas, neste caso, seriam necessárias doses muito altas de GH, colocando a saúde da criança em risco. ...
The Turner's syndrome is characterized by an anomaly on the sexual chromosome, which occurs on female's phenotypes usually with 45,X cariotype. This anomaly is responsible by the high taxes of fetal mortality, and spontaneous aborts. Among the characteristics of Turner's women, the most important are: low height and sterility. To reduce the low stature is common the treatment with hormones, such as oxalondrone, growth hormone, and estrogen, that can increase their stature around 5-10 cm. Analyzing the psychological aspects of this syndrome, it is not observed any personality changes. In this way, psychosocial identification is not modified. Initially, the Turner's syndrome porters were observed to present a type of mental retarded, what is not real. It was verified that syndromics present a spatial perception and motor-visual deficit, having general difficulties on non-verbal tasks. On the other hand, they present a non-verbal IQ normal or under the rate, compensated by a verbal IQ normal or higher.
... In case of GH deficiency, average increase in final height attributable to GH therapy is about 30 cm compared with predicted adult height [9,10]. In the case of ISS, the US FDA approved GH therapy in ISS children shorter than´2.25 SDS in 2003 based on the evidence derived from two clinical studies [11,12], nevertheless, the average increase in final height attributable to GH therapy in children with ISS is just 3.5-7.5 cm (4-7 years) [11,[13][14][15][16]. In this case of ISS, the effect remains controversial because the estimated cost of GH therapy for adult height gain is about 10,000-20,000 dollars/cm [1,15]. ...
... In case of GH deficiency, average increase in final height attributable to GH therapy is about 30 cm compared with predicted adult height [9,10]. In the case of ISS, the US FDA approved GH therapy in ISS children shorter than´2.25 SDS in 2003 based on the evidence derived from two clinical studies [11,12], nevertheless, the average increase in final height attributable to GH therapy in children with ISS is just 3.5-7.5 cm (4-7 years) [11,[13][14][15][16]. In this case of ISS, the effect remains controversial because the estimated cost of GH therapy for adult height gain is about 10,000-20,000 dollars/cm [1,15]. ...
This study aimed to investigate the effects of Phlomis umbrosa root on bone growth and growth mediators in rats. Female adolescent rats were administered P. umbrosa extract, recombinant human growth hormone or vehicle for 10 days. Tetracycline was injected intraperitoneally to produce a glowing fluorescence band on the newly formed bone on day 8, and 5-bromo-2′-deoxyuridine was injected to label proliferating chondrocytes on days 8–10. To assess possible endocrine or autocrine/paracrine mechanisms, we evaluated insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3) or bone morphogenetic protein-2 (BMP-2) in response to P. umbrosa administration in either growth plate or serum. Oral administration of P. umbrosa significantly increased longitudinal bone growth rate, height of hypertrophic zone and chondrocyte proliferation of the proximal tibial growth plate. P. umbrosa also increased serum IGFBP-3 levels and upregulated the expressions of IGF-1 and BMP-2 in growth plate. In conclusion, P. umbrosa increases longitudinal bone growth rate by stimulating proliferation and hypertrophy of chondrocyte with the increment of circulating IGFBP-3. Regarding the immunohistochemical study, the effect of P. umbrosa may also be attributable to upregulation of local IGF-1 and BMP-2 expressions in the growth plate, which can be considered as a GH dependent autocrine/paracrine pathway.
... 1,8,9) GH treatment improves linear growth and can restore body composition, promote linear growth by increasing growth velocity, and improve quality of life. [10][11][12] Idiopathic scoliosis is one of the major concerns in GH treatment as the two might be associated. Several studies have demonstrated the impact of GH treatment on the progression of scoliosis. ...
Purpose:
Idiopathic scoliosis is the most common form of scoliosis, and the risk of both its onset and progression has been found to correlate with growth spurts. Therefore, recombinant human growth hormone (GH) treatment used in short children may affect both the initiation and aggravation of scoliosis. The aim of this study was to investigate the relationship between idiopathic scoliosis and GH treatment in short children.
Methods:
The medical records of 113 subjects who were diagnosed with growth hormone deficiency, small for gestational age, and idiopathic short stature between January 2010 and December 2020 were reviewed. Scoliosis was defined as a Cobb angle of over 10° assessed using a spine X-ray. Clinical data and laboratory findings were compared between before and 12 months after GH treatment.
Results:
There was a significant increase in height, height-standard deviation scores, insulin-like growth factor 1, and insulin-like growth factor binding protein 3 (P < 0.001) with GH treatment. However, there were no significant differences in the average Cobb angle (6.2±3.3° vs. 6.1±3.5°, P = 0.842) and the prevalence of scoliosis (9.7% vs. 13.3%, P = 0.481) between before and after one year of GH treatment. A comparative analysis of both the initial Cobb angle and the change in Cobb angle during GH treatment showed no relationship with other factors.
Conclusion:
Although GH treatment in short children increases height and growth velocity, it is not associated with developing or aggravating idiopathic scoliosis.
... Importantly, patients with "normal variant short stature" specifically those with familial short stature and constitutional growth delay were not excluded from the "ISS" designation. Randomized clinical trials with rhGH were led by the Pharma Industry and produced positive growth-promoting results (37,38) and ISS was soon referred to as 'a condition termed idiopathic short stature' or a 'diagnostic category' (39). Positive data confirmed the effects of rhGH therapy, notably compared with placebo-treated controls (38). ...
Idiopathic short stature (ISS) is a term used to describe a selection of short children for whom no precise aetiology has been identified. Molecular investigations have made notable discoveries in children with ISS, thus removing them from this category. However, many, if not the majority of children referred with short stature, are designated ISS. Our interest in defects of GH action, i.e. GH resistance, has led to a study of children with mild GH resistance, who we believe can be mis-categorised as ISS leading to potential inappropriate management. Approval of ISS by the FDA for hGH therapy has resulted in many short children receiving this treatment. The results are extremely variable. It is therefore important to correctly assess and investigate all ISS subjects in order to identify those with mild but unequivocal GH resistance, as in cases of PAPP-A2 deficiency. The correct identification of GH resistance defects will direct therapy towards rhIGF-I rather than rhGH. This example illustrates the importance of recognition of GH resistance among the very large number patients referred with short stature who are labelled as ‘ISS’.
... cm in girls although only a few achieved their mid-parental target height. (10) In clinical practice the predictor of GH therapy in individual children is to monitor height velocity and adjust the dose of GH accordingly. Many studies have demonstrated the predictors for final height outcome such as age at diagnosis and treatment, mid-parental height, GH doses, sex, and presence of abnormal MRI, but no prediction models are accepted in routine practice. ...
The diagnosis of growth hormone deficiency (GHD) needs consideration of both clinical and biological aspects such as auxological data, GH provocative tests, and active metabolites of GH including IGF-I and IGFBP-3. In children with GHD, recombinant human GH (rhGH) replacement therapy has been used worldwide with minimal serious side effects. This study aimed to report the results of an investigation for GHD, to describe the growth responses to rhGH in deficient children compared to those without GH deficiency, to evaluate the relationship between clinical and biochemical responses, and to describe the experience of diagnosis and treatment with rhGH at Hamad General Hospital, the main hospital in Qatar where most short children are referred for further investigation. The clinical records of 116 short children were reviewed retrospectively. Forty-six failed the clonidine test and 42 of these also failed the glucagon test and were confirmed with GHD. These and 16 children without GDH were treated with rhGH (25 mcg/kg/ day) and were evaluated in terms of growth response, HtSDS, changes of IGF-I concentration, and the relationship between these parameters. Treatment with GH of short children with GHD does produce a satisfactory growth response but the HtSDS gain was significantly higher in those with GHD compared to children without GHD. Measurement of IGF-I was found not to be a useful diagnostic test in GHD.
... Predicting adult height is important to monitoring childhood growth and development, particularly for children in some jurisdictions who may be considered for growth hormone therapy for "idiopathic short stature" [1][2][3] . Various approaches have been developed and clinically adopted for adult height prediction, based on current height measures and bone age as measured by hand and wrist X-ray, such as the Bayley-Pinneau method 4 , the Tanner-Whitehouse methods 5,6 , and the Roche-Wainer-Thissen method 7 . ...
Context
Adult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared to mid-parental height.
Objective
To develop a polygenic risk score for adult height and evaluate its clinical utility.
Design
A polygenic risk score was constructed based on meta-analysis of genome-wide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.
Subjects
Participants included 442,599 genotyped White British individuals in the UK Biobank, and 941 genotyped child-parent trios of European ancestry in the ALSPAC cohort.
Interventions
None.
Main Outcome Measures
Standing height was measured using stadiometer; Standing height two standard deviations below the sex-specific population average was considered as short stature.
Results
Combined with sex, a polygenic risk score captured 71.1% of the total variance in adult height in the UK Biobank. In the ALSPAC cohort, the polygenic risk score was able to identify children who developed adulthood short stature with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of mid-parental height. Combining this polygenic risk score with mid-parental height, or only one of the child’s parent’s height, could improve the AUROC to at most 0.90. The polygenic risk score could also substitute mid-parental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood.
Conclusions
A polygenic risk score could be considered as an alternative or adjunct to mid-parental height to improve screening for children at risk of developing short stature in adulthood in European ancestry populations.
... In 2003, rhGH was approved in the USA for the treatment of children with ISS, whose height was below -2.25 SD the mean for age and gender, who had undergone detailed diagnostic evaluation that excluded other causes of short stature, and who grew at a growth velocity unlikely to allow them to attain an AH within the normal range [11][12][13][14][15][16]. Since then, rhGH has been extensively used in the treatment of children with ISS [17]. ...
Objectives
Idiopathic short stature (ISS) is a recognized, albeit a controversial indication for treatment with recombinant human growth hormone (rhGH).
The objective of the present study was to conduct a systematic review of the literature and meta-analyses of selected studies about the use of rhGH in children with ISS on linear growth and adult height (AH).
Methods
A systematic literature search was conducted to identify relevant studies published till February 28, 2017 in the following databases: Medline (PubMed), Scopus and Cochrane Central Registry of Controlled Trials. After exclusion of duplicate studies, 3,609 studies were initially identified. Of those, 3,497 studies were excluded during the process of assessing the title and/or the abstract. The remaining 112 studies were evaluated further by assessing the full text; 21 of them fulfilled all the criteria in order to be included in the current meta-analysis.
Results
Children who received rhGH had significantly higher height increment at the end of the first year, an effect that persisted in the second year of treatment and achieved significantly higher AH than the control group. The difference between the two groups was equal to 5.3 cm (95% CI: 3.4–7 cm) for male and 4.7 cm (95% CI: 3.1–6.3 cm) for female patients.
Conclusion
In children with ISS, treatment with rhGH improves short-term linear growth and increases AH compared with control subjects. However, the final decision should be made on an individual basis, following detailed diagnostic evaluation and careful consideration of both risks and benefits of rhGH administration.
... However, the use of this medication in ISS might result in a rapid increase in bone age and early closure of the epiphyseal plate, which could eventually affect these patients' ability to attain expected adult height [9][10][11][12][13]. In contrast, many published research papers documented the efficacy of using rhGH in increasing the expected final adult height and growth velocity in patients with ISS [14][15][16][17][18][19][20][21][22][23][24]. In our study, we aimed mainly to compare the effect on height in patients with GHD and ISS after one year of treatment with rhGH. ...
Objective
The use of recombinant human growth hormone (rhGH) in patients with idiopathic short stature (ISS) has been an area of concern since some studies reported less desired effects of the drug in this group of patients as compared to patients with growth hormone deficiency (GHD). In addition, there were no studies addressing the effects of rhGH in Saudi children. Therefore, we conducted a retrospective study to observe the effects one year of treatment with rhGH on the mean height gain in patients with ISS and GHD.
Methods
This retrospective study took place at King Abdulaziz Medical City in Jeddah. The study subjects included two groups of patients (GHD vs ISS). Patients' files were reviewed from January 2000 to January 2018 using the following parameters: chronological age, bone age, height, weight, body mass index (BMI), insulin-like growth factor (IGF-1), growth hormone stimulation test, and growth velocity (GV). After one year of treatment, the height, weight, and BMI of the study subjects were monitored and assessed.
Results
The total number of patients was 55, 36 of which were diagnosed with GHD while 19 were diagnosed with ISS. The mean age of patients with GHD and ISS were 10.7±2.38 and 10.91±2.74 years, respectively. Both groups showed a significant increase in height. The initial height for patients with GHD was 125.26±12.27 cm, and they achieved a mean height of 134.231±12.88 cm after one year of treatment. For the other group, the initial height for ISS patients was 125.51±10.94 cm, and they achieved a mean height of 134.04±10.90 cm after one-year therapy. However, after the treatment, there was no significant difference in the height gain between GHD and ISS patients (134.231±12.88, 134.04±10.90, respectively, P=0.437).
Conclusion
The short-term use of rhGH has a potent and similar effect on increasing the height of both patients diagnosed with ISS as well as GHD.
... Short children due to specific conditions like growth hormone deficiency (GHD) occupy 20% of short stature but the other 80% is undetermined, which is called idiopathic short stature (Cohen et al., 2008). In case of GHD, mean final height gain due to GH treatment is approximately 30 cm in comparison with expected final height ( Hindmarsh and Dattani, 2006;Wit et al., 1996), but in case of idiopathic short stature, mean final height gain due to GH treatment is only about 1 cm when treated for a year (August et al., 1998;Bajpai and Menon, 2005;Bryant et al., 2007;Finkelstein et al., 2002;Hintz et al., https://doi.org/10.1016/j.jep.2019.01.048 Received 5 August 2018; Received in revised form 15 January 2019; Accepted 21 January 2019). ...
... There is still room for controversy over whether growth hormone should be actively administered to children with short stature, but many studies have reported positive effects of growth hormone [1]. Particularly in Korea, interest in short stature is increasing with socially increasing interest in appearance [2]. ...
... In 2003, the FDA approved the use of growth hormone (GH) for children with idiopathic short stature (ISS). This was based on several studies documenting an increase in adult height relative to an untreated control group (1,2) or predicted height at the start of treatment (3,4). To meet this criterion, height needed to be below the 1.2%ile (<-2.25 SD) without any evidence for underlying growth-limiting disease or GH deficiency, and the children should have "a growth rate that is unlikely to attain an adult height within the normal range". ...
Background:
Despite FDA approval of growth hormone(GH) for idiopathic short stature(ISS), many providers face challenges obtaining insurance coverage. We reviewed the insurance coverage experience for ISS at our hospital to identify factors predictive of approval or denial.
Methods:
We reviewed charts of patients who underwent GH stimulation testing from 07/01/09 to 04/30/17 to identify ISS patients (height <-2.25SD, subnormal predicted adult height(PAH) and peak GH >10ng/ml) Results: 87 patients met ISS criteria, of whom 47(29M/18F) had GH request submitted to insurance. Mean age, height and growth velocity were 8.6±2.7years, -2.83±0.4SD and 4.4±1.7cm/yr respectively. Mean PAH based on bone age was -2.50±0.9SD, equaling 62″for males and 58″ for females. Most had private managed care insurance (74%). 17/47(36%) received treatment approval, 7 immediately and 10 more on appeal. There were no differences in age, height SD, growth rate, insurance type or PAH between the 17 who were approved and the 30 denied. For 21 patients who were treated, a mean increase in 0.6 SD in height was seen after one year.
Conclusion:
At our institution, GH coverage requests for ISS included very short children mostly ages 6-11, with heights well below -2.25 SD and poor PAH. Only 36% were approved even after appeal. This highlights the challenge in our area to secure GH treatment for a FDA approved indication. Collaboration between pediatric endocrinologists and insurers focusing on height SD and PAH, may improve cost-effective coverage to deserving short children who meet FDA guidelines for ISS treatment.
Abbreviations:
ISS = idiopathic short stature; GH = growth hormone; PAH = predicted adult height; FDA = Food and Drug Administration ; IGF-1 = insulin-like growth factor 1.
... From these results, the difference of Δheight SDS for bone age between HT042 and placebo groups increased more than twice that of the Δheight SDS (0.10 vs. 0.04 score). Accordingly, 0.3-cm-difference seems to be attenuated and the actual effect on final height would be greater considering the fact that bone age is less advanced in the HT042 group (Kawai et al., 1997;Hintz et al., 1999). In the HT042 group whose starting height was below the 10th percentile, height SDS for bone age was significantly increased by 0.20 compared with the placebo group. ...
HT042 is a standardized functional food ingredient approved by Korean Food and Drug Administration with a claim ‘HT042 can help height growth of children’. We aimed to evaluate the safety and efficacy of HT042 on height growth in children with mild short stature. A multicenter, randomized, double-blind, placebo-controlled parallel study was performed on children aged 6–8 years with height ranked below the 25th percentile. In 129 children, height gain was significantly higher in HT042 group than placebo group after 24 weeks (mean difference, 0.29 cm; 95% CI, 0.01 to 0.57 cm; p = 0.027). The difference was elevated when the efficacy analysis was restricted to children below the 10th percentile (mean difference, 0.45 cm; 95% CI, 0.04 to 0.87 cm; p = 0.031). Because bone age advancement was lower in HT042 group, height standard deviation score gain for bone age was higher in HT042 group and the difference was significant in children below the 10th percentile (mean difference, 0.20 score; 95% CI, 0.00 to 0.39 points; p = 0.045). Serum IGF-1 and IGFBP-3 levels were significantly increased compared with baseline within HT042 group, but group difference was not significant. HT042 supplementation helped to increase height growth in children without skeletal maturation and was more effective in much shorter children. The effects might be mediated by increases in serum IGF-1 and IGFBP-3 levels. Copyright
... Compared to the cited study, we enrolled approximately twice as many subjects, and analyzed the efficacy and safety of GH therapy over a longer treatment period. Several studies suggested that long-term GH treatment increases adult height [1,3,13]. It has already been reported that GH therapy using rhGH, such as Humatrope ® (Eli Lilly) [14] or Genotropin ® (Pfizer) [15], increases final height in children with ISS. ...
Purpose:
Several studies have evaluated the effects of growth hormone (GH) on auxological and biochemical parameters in children with non-GH-deficient, idiopathic short stature (ISS). This study evaluated the efficacy and safety of Growtropin(®)-II (recombinant human GH) in Korean patients with ISS.
Methods:
This was a 1-year, open-label, multicenter, phase III randomized trial of Growtropin(®)-II in Korean patients with ISS. In total, 70 prepubertal subjects (39 males, 31 females) between 4 and 12 years of age were included in the study. All patients were naive to GH treatment.
Results:
Annual height velocity was significantly higher in the treatment group (10.68 ± 1.95 cm/year) than the control group (5.72 ± 1.72, p < 0.001). Increases in height and weight standard deviation scores (SDSs) at 26 weeks were 0.63 ± 0.16 and 0.64 ± 0.46, respectively, for the treatment group, and 0.06 ± 0.15 and 0.06 ± 0.28, respectively, for the control group (p < 0.001). Serum insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) increased significantly in the treatment group at week 26 compared to baseline. However, the SDS for body mass index (BMI) at 26 weeks did not change significantly in either group. Growtropin(®)-II was well tolerated and safe over 1 year of treatment.
Conclusions:
One-year GH treatment for prepubertal children with ISS demonstrated increased annualized velocity, height and weight SDSs, and IGF-1 and IGFBP-3 levels, with a favorable safety profile. Further evaluations are needed to determine the optimal dose, final adult height, and long-term effects of ISS treatment.
... 8,13 Children with short stature without GH deficiency have also been treated with biosynthetic GH. However, there has been much controversy regarding the effects of systemic GH administration in patients with familial short stature who are not deficient in GH. 14,15 Because of the competitive nature of Korean society, GH therapy is frequently recommended by many growth clinics, even to adolescents who are not particularly small or not deficient in GH. There have been attempts to treat malocclusion patients orthodontically while they were simultaneously receiving GH therapy. ...
The purpose of this study was to illustrate the effects of growth hormone (GH) therapy and fixed functional appliance treatment in a 13-year-old Class II malocclusion patient without GH deficiency. GH has been shown to effectively increase endochondral growth and induce a more prognathic skeletal pattern. Although a major concern in Class II retrognathic patients is chin deficiency, long-term studies have shown that the mandibular growth enhancement effects of functional appliances are clinically insignificant. This case report demonstrates that the mandible grew significantly during fixed functional appliance treatment combined with GH therapy, with stable results during 2 years 11 months of retention. More studies are needed to evaluate GH therapy as a supplement in Class II treatment.
... The current study was a systematic review conducted from 1995 to March 2016. Twenty studies related to the effect of treatment with growth hormone on the adult height of children with ISS with a total sample size of 1,517 were included in the meta-analysis ( Fig. 1 and Table 1 [10,11,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]). ...
Idiopathic short stature (ISS) is a kind of low height among children in which children's height is more than 2 standard deviation (SD) scores below the mean score of the height of other children with the same age and gender. It is one of the disorders that physicians use growth hormone for its treatment. Therefore, the purpose of the current study was to investigate the effect of growth hormone treatment on the adulthood height of children with ISS through me-ta-analysis method. In total 20 studies with a sample size of 1,517 were included in the meta-analysis through searching in external databases, including Web of science, Pubmed, Cochran, Medline, Embase, Springer, Scopus, and Science Direct using mesh keywords as growth hormone, final height, adult height, and idiopathic short stature. Mean score and SD were utilized for measuring any increase in height growth and random effect model was used for combining studies. Further, I 2 index was used for determining the heterogene-ity of studies. Results indicated that before treatment, according to standard mean difference percentile of children's height was-1.64 (95% confidence interval (CI):-2.01 to-1.28) which is equal to 5%. After treatment, according to standard mean difference percentile of children's height came out to be 0.11 (95% CI: 0.07-0.14) which is equal to 54.38%. This indicates that percentile of children's height has increased as a result of treatment with growth hormone. Through combining the results of all studies, the mean score for participants' height before treatment was 5% and after treatment it reached 54%. Therefore, obtained mean difference for adult height after treatment with growth hormone was reported to be more than 1.4 SD score (about 7.6 cm). Growth hormone can be influential in increasing the adult height of children with ISS.
... In case of GH deficiency, mean increase in final height due to GH therapy is about 30 cm compared to predicted adult height 9,10) . In case of ISS, mean increase in final height attributable to GH therapy is just 3.5-7.5 ㎝ (4-7 years) 11,[13][14][15][16] . High cost of treatment, estimated 10,000-20,000 dollars/㎝ 1,15) , injection pain, and limitations of use that it can only be used for short stature patients are also considered controversial 17,18) . ...
Objectives : This study aimed to investigate the effects of Angelicae sinensis Radix on longitudinal bone growth rate in rats. We have screened traditional medicinal herbs to develop the longitudinal bone growth stimulator by well-established rat model. A. sinensis was identified as one of the effective herbs in the screening process. Methods : Adolescent female rats were administered A. sinensis at doses of 30 mg/kg and 300 mg/kg for 10 consecutive days. To observe the rate of longitudinal bone growth, tetracycline was injected intraperitoneally on day 8 to stain a fluorescent band on the anew formed bone. To elucidate the mode of action, we observed insulin-like growth factor-1 (IGF-1) and bone morphogenetic protein-2 (BMP-2) expression after A. sinensis administration in growth plate. Results : In the 300 mg/kg A. sinensis group, the length between the proximal endpoint of the tetracycline label and the division line between growth plate and bone was significantly increased compared with vehicle-treated control group. Height of the proximal tibial growth plate was higher in the A. sinensis group compared with control group. A. sinensis also upregulated the expressions of IGF-1 and BMP-2 in the proliferative zone and hypertrophic zone of the proximal tibial growth plate. Conclusions : A. sinensis increases longitudinal bone growth rate in rats. According to immunohistochemistry, A. sinensis increases local IGF-1 and BMP-2 expressions in the growth plate which can be considered as direct stimulation of GH on the local growth plate.
... The growth response to GH is unpredictable in ISS (93), and the outcome of treatment is generally not dramatic (94). In fact, clinicians do not routinely predict an adult height that surpasses midparental height, which is often shorter than average. ...
... A number of meta-analyses have reviewed the efficacy of rhGH treatment in children with ISS, such studies suggest average height gains between 3 and 7 cm [91,92]. As with all rhGH treatment indications, responses vary among patients (table 7) [92][93][94][95][96][97]. In GH trials with children with ISS reported to date, small sample sizes remain a major problem, as well as the relatively high percentage of dropouts of non-responders in studies with longer duration of treatment. ...
... In another small study, GH therapy effectively increased height SDS in short normal girls who were started on treatment in early to mid childhood, without any effect on pubertal progression [4]. Other studies show higher mean adult heights in treated participants who generally reach their target height and predicted height [15][16][17][18][19][20][21][22][23]. These authors conclude that therapy appears to be safe, notwithstanding that the more efficacious doses of GH are higher than those used in GHD children [24]. ...
Background:
In recent years, several studies have been published showing different responses to growth hormone (GH) treatment in idiopathic short stature children. The aim of the present study was to investigate whether non-growth-hormone-deficient (non-GHD) short children could benefit from long-term GH treatment as GHD patients.
Methods:
We enrolled 22 prepubertal children and 22 age- and sex-matched GHD patients, with comparable height, body mass index (BMI), bone age, and insulin-like growth factor 1 (IGF-I) circulating levels. The patients were treated with recombinant human GH (rhGH) and followed until they reach adult height.
Results:
During GH treatment, the two groups grew in parallel, reaching the same final height-standard deviation score (SDS) and the same height gain. On the contrary, we found significantly lower IGF-I serum concentrations in non-GHD patients than in GHD ones, at the end of therapy (p=0.0055).
Conclusions:
In our study, the response to GH treatment in short non-GHD patients proved to be similar to that in GHD ones. However, a careful selection of short non-GHD children to be treated with GH would better justify the cost of long-term GH therapy.
... The mean first-year height velocities for rhIGF-Itreated subjects in this study were similar to those reported for rhIGF-I-treated subjects with severe primary IGF-I deficiency (8.0 cm/yr at doses of 40 -120 g/kg twice-daily) (14), and rhGH-treated prepubertal children with idiopathic short stature (7.3-8.6 cm/yr at rhGH doses equivalent to 33-53 g/kg/d) (25)(26)(27)(28). However, the mean firstyear height velocities for both rhIGF-I-treated short children with low IGF-I and rhGH-treated children with idiopathic short stature were lower than the mean height velocities of Ն10 cm/yr reported for rhGH-treated children with GH deficiency (29,30). ...
Introduction This review aims to systematically determine the effect of growth hormone (GH) therapy on adult height of children and adolescents with idiopathic short stature (ISS).
Methods A systematic review was conducted to assess the effectiveness of GH therapy in children with ISS. Databases like ProQuest Central, journal @ Ovoid, EBSCOhost Medline Complete, Oxford University Press Journals, KB + JISC Collections Elsevier Science Direct Freedo, and BMJ, and cross-referencing of bibliographies were searched electronically. The randomized trials from 1989 to January 2023 were retrieved. Randomized trials with final adult height measurements and fit the inclusion criteria (height >2 standard deviation [SD] score below the mean with no comorbid conditions that would impair growth, peak growth hormone responses >10 μg/L, no previous history of GH therapy) were included in this review. The exclusion criteria are nonrandomized trials; trials include causes of short stature other than ISS, and studies include interventions other than GH and gonadotropin-releasing hormone analog (GnRH-a). A structured approach to the critical appraisal program by Oxford was used to analyze and extract the data.
Results The study reviewed 14 eligible randomized trials, which recruited 2,206 assessable children for analysis. Seven trials compared different GH doses, four trials compared GH therapy with controls, and three trials compared a combination of GH and GnRH therapy with GH alone. Apart from one study, the overall dropout rate was not high. The high percentage of boys was a potential source of heterogeneity between trials. The change in height (HT)-SD score was 1.06 ± 0.30 and 0.18 ± 0.27 with treatment and control children, respectively, and the difference is statistically significant (p < 0.001). The overall mean height gain was 5 cm (0.84 SD score) more in treated children. The height velocity was found to be decreased significantly (p < 0.001) in the second and third years of treatment in the GH + GnRH-a treated group from 7 cm/year during the first year of treatment to 5.4 cm during the second year and 4.9 cm/year during the third year. They also found that using a higher dose of GH at 9 mg/m²/week leads to approximately 7 cm mean final height gain; however, lower dose regimens are less effective.
Conclusion Although the magnitude of the effectiveness of GH therapy is, on average, less than that achieved in other conditions for which GH is licensed, GH therapy seems to be effective in children with idiopathic short stature, and it reduces the deficit in height as adults. Moreover, the effect seems to be dose-dependent, with better results at high GH doses, and the response variability is seen in different individuals. The use of combined GH with GnRH therapy needs to be balanced with their side effects.
Human growth hormone (hGH) is a protein hormone essential for normal growth and development in humans. In this chapter, the hGH structure, its mechanism of action, delivery routes, pharmacokinetics, and clinical use are discussed. Table 20.1 lists marketed products, including hGH analogs with prolonged action.
The terms idiopathic short stature (ISS) and small for gestational age (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecular era, ISS is still used as a diagnostic label today. The term SGA was adopted by paediatric endocrinologists to describe children born with low birth weight and/or length, some of whom may experience lack of catch-up growth and present with short stature. GH treatment was approved by the FDA for short children born SGA in 2001, and by the EMA in 2003, and for the treatment of ISS in the US, but not Europe, in 2003. These approvals strengthened the terms SGA and ISS as clinical entities. While clinical and hormonal diagnostic techniques remain important, it is the emergence of genetic investigations that have led to numerous molecular discoveries in both ISS and SGA subjects. The primary message of this article is that the labels ISS and SGA are not definitive diagnoses. We propose that the three disciplines of clinical evaluation, hormonal investigation and genetic sequencing should have equal status in the hierarchy of short stature assessments and should complement each other to identify the true pathogenesis in poorly growing patients.
In this chapter, we want to give an overview on what we have learned from more than 30 years ago on the use of recombinant human growth hormone (rhGH) and later recombinant human IGF-1 which was introduced for the treatment of short children and what are the safety issues concerned with this treatment. However, rhGH is used not solely in conditions where short stature is the consequence of GH deficiency but also in various disorders without a proven GH deficiency. In clinical studies, growth responses to various forms of rhGH therapy were analyzed, adding to our concept about the physiology of growth. Most patients under rhGH treatment show a considerable short-term effect; however, the long-term gain of height in a child obtained by a year-long treatment until final height remains controversial in some of the growth disorders that have been treated with rhGH or IGF-1. Today the first studies on the long-term safety of rhGH treatment have been published and raising some questions whether this treatment is similarly safe for all the patient groups treated with rhGH. Although there is a long-standing safety record for these hormone replacement therapies, in the face of the considerable costs involved, the discussion about the risk to benefit ratio is continuing. Newer developments of rhGH treatment include long-term preparations, which have only to be injected once a week. Although some of these drugs already have proven their non-inferiority to conventional rhGH treatment, we have to await further results to see whether they show improvements in treatment adherence of the patients and prove their long-term safety.
Idiopathic short stature (ISS) comprises a wide range of conditions associated with short stature that elude the conventional diagnostic work-up and are often caused by still largely unknown genetic variants. In the last decade, the improvement of diagnostic techniques has led to the discovery of causal mutations in genes involved in the function of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis as well as in growth plate physiology. However, many cases of ISS remain idiopathic. In the future, the more frequent identification of the underlying causes will allow a better stratification of subjects and offer a tailored management. GH therapy has been proposed and approved in some countries for the treatment of children with ISS. To improve the efficacy of GH therapy, trials with GH combined with GnRH agonists, aromatase inhibitors, and even IGF-I have been conducted. This review aims to revise the current definition of ISS and discuss the management of children with ISS on the basis of the most recent evidence.
Background:
Variability still exist about the growth response to growth hormone (GH) therapy in children with idiopathic short stature (ISS). We describe the growth response to rhGH therapy for >2 years in 20 prepubertal children with idiopathic short stature (ISS) and 18 children with GH deficiency (GHD) and compared them with 15 children with ISS who did not receive rhGH therapy.
Patients and methods:
Our study included 35 prepubertal and peripubertal (Tanner 1 and 2) children with short stature (Ht-SDS <-2) and/or Ht-SDS >1SD below their mid parental height SD (MP-Ht-SDS) with slow growth velocity (<-1 SD), with normal peak GH response to provocation tests (15.5±6.5 ng/dl), normal IGF-I SDS (-0.9±0.6), and no bone age delay (± 1 year from chronological age) (ISS). 20 children were treated for 2.5±1.5 years with rhGH 0.05 mg/kg/day and 15 children were not treated with rhGH. 18 children with diagnosis of GHD, diagnosed in the same period, receiving rhGH therapy served as controls. We assessed the linear growth and IGF-I levels of all children for an average of 2 years.
Results:
Children with ISS on rhGH therapy had a height gain of 0.77 SD in 2 years versus 1.05 SD in GHD children, with significant increase in IGF-I and normal progression of bone age and puberty. Children with ISS who did not receive rhGH had no gain in the changes of Ht-SDS inspite of normal progression of bone age and puberty. The difference between children Ht-SDS and mid-parental height SDS (MP-Ht-SDS) changed significantly from -1.1±3 to -0.3±0.5 in the ISS group and from -1.35±0.5 to -0.3±0.25 in the GHD group, after an average of 2 years of treatment. In the treated ISS group, the Ht-SDS gain was correlated positively with the duration of rhGH therapy (r = 0.82, p<0.0001), negatively with the age at the start of treatment (r = -0.544, p = 0.01), and positively with the bone age (r =-0.44, p = 0.04).
Discussion:
The Ht-SDS of children with ISS on rhGH treatment closely approached their MP-Ht-SDS after 2 years of rhGH therapy while those who did not receive rhGH kept the same distance from their MP-Ht-SDS after 2 years. Analysis of possible factors affecting linear growth in children with ISS on rhGH therapy showed that children below 9 years with Ht-SDS <-2.5 SD and those with Ht-SDS >1SD below MP-Ht-SDS grew better on rhGH therapy compared to older children and those with Ht-SDS >-2.5 and were less than 1SD from their MP-HT-SD. Higher doses of rhGH (to keep IGF-I in high normal levels) and longer duration of therapy improved the Ht-SDS gain of these children.
Conclusion:
We report significant gain in Ht-SDS in prepubertal children with ISS on rhGH therapy and better response in younger children and in those with Ht-SDS > 1 SD below their MP-Ht-SDS.
Background/objectives:
Growth hormone (GH) treatment of idiopathic short stature (ISS) received US Food and Drug Administration approval in 2003. We assessed height gain and safety in 2,450 children with ISS treated with GH in US clinical practice.
Methods:
Short-term height gain, near-adult height (NAH), and safety outcomes were investigated using Genetics and Neuroendocrinology of Short Stature International Study data.
Results:
Compared to children with isolated idiopathic GH deficiency (IGHD), those with ISS were shorter at baseline but had similar age and GH dose. Mean ± SD height SD score (SDS) increase was similar for ISS and IGHD, with 0.6 ± 0.3 (first), 0.4 ± 0.3 (second), 0.3 ± 0.3 (third), and 0.1 ± 0.3 (fourth year) for ISS. Girls with ISS (27% of subjects) were younger and shorter than boys but had similar height gain over time. At NAH in the ISS group (n = 467), mean ± SD age, GH duration, and height SDS were 17.3 ± 2.3 years, 4.6 ± 2.7 years, and -1.2 ± 0.9, respectively. Height gain from baseline was 1.1 ± 1.0 SDS and was greater for boys than girls (1.2 ± 1.0 vs. 0.9 ± 0.9), but boys were treated longer (5.1 ± 2.8 vs. 3.6 ± 2.5 years). Adverse events were reported for 24% with ISS versus 20% with IGHD - most were common childhood conditions or previously reported in GH-treated patients.
Conclusions:
GH-treated children with ISS achieved substantial height gain, similar to patients with IGHD. Fewer GH-treated girls were enrolled than boys, but with similar height SDS gain over time. No ISS-specific safety issues were identified. Thus, GH treatment of ISS appears to have a safety/effectiveness profile similar to that of IGHD.
Human growth hormone (hGH) is a protein hormone essential for normal growth and development in humans. hGH affects many aspects of human metabolism, including lipolysis, the stimulation of protein synthesis, and the inhibition of glucose metabolism. Human growth hormone was first isolated and identified in the late 1950s from extracts of pituitary glands obtained from cadavers and from patients undergoing hypophysectomy. The first clinical use of these pituitary-extracted hGHs for stimulation of growth in hypopituitary children occurred in 1957 and 1958 (Raben, J Clin Endocrinol Metab 18:901–903, 1958). From 1958 to 1985 the primary material used for clinical studies was pituitary-derived growth hormone (pit-hGH). Human growth hormone was first cloned in 1979 (Goeddel et al., Nature 281:544–548, 1979; Martial et al., Science 205:602–607, 1979). The first use in humans of recombinant human growth hormone (rhGH) was reported in the literature in 1982 (Hintz et al., Lancet 1:1276–1279, 1982). The introduction of rhGH coincided with reports of a number of cases of Creutzfeldt-Jakob disease, a fatal degenerative neurological disorder, in patients receiving pituitary-derived hGH. Concern over possible contamination of the pituitary-derived hGH preparations by the prion responsible for Creutzfeldt-Jakob disease led to the removal of pit-hGH products from the market in the US in 1985 followed by the FDA approval of rhGH later in the year. The initial rhGH preparations were produced in bacteria (E. coli) but, unlike endogenous hGH, contained an N-terminal methionine group (met-rhGH). Natural sequence recombinant hGH products have subsequently been produced in bacteria, yeast, and mammalian cells.
GH insensitivity (GHI) presents in childhood with growth failure and in its severe form is associated with extreme short stature, dysmorphic and metabolic abnormalities. In recent years, the clinical, biochemical and genetic characteristics of GHI and other overlapping short stature syndromes have rapidly expanded. This can be attributed to advancing genetic techniques and a greater awareness of this group of disorders. We review this important spectrum of defects, which present with phenotypes at the milder end of the GHI continuum. We discuss their clinical, biochemical and genetic characteristics. The objective of this review is to clarify the definition, identification and investigation of this clinically relevant group of growth defects. We also review the therapeutic challenges of mild GHI.
Background
Short stature in children represents a heterogeneous group with different etiologies. Primary Insulin like growth factor 1 (IGF - 1) deficiency in short stature can present with normal or elevated growth hormone (GH) production. Currently there is no model that can reliably predict response to recombinant (r)GH therapy and/or rIGF - 1 therapy in children with non - GH deficient short stature.
Hypothesis
Baseline Insulin like growth factor binding protein 3 (IGFBP - 3) along with ∆ IGF - 1 in the first 3 months of GH therapy level can be a marker of growth response to the rGH and/or rIGF - 1 therapy in children with non - growth hormone deficiency short stature.
Objectives
To study the relationship between baseline IGFBP - 3 and IGF - 1 levels and the response to rGH and rIGF - 1 therapy in children with short stature, normal GH secretion and low IGF - 1 SDS.
Methods
43 children, age 9.07 ± 2.75 years with height -2.72 ± 0.7 SD and baseline IGF - 1 of -2.76 ± 0.58 SD, who passed the growth hormone releasing hormone (GHRH) stimulation test were included in a retrospective chart review. They were treated with rGH therapy with a mean dose of 0.46 ± 0.1 mg/kg/week. Growth velocity (GV), IGF - 1 and IGFBP - 3 levels were done at 3 and 6 months of therapy. Subjects with poor response to rGH after 6 months of therapy were switched to rIGF - 1 therapy at 0.24 mg/kg/day for the next 6 months. Subjects were divided according to their growth rate into responders to rGH (N = 23); non - responders to rGH, responders to rIGF - 1 (N = 14) and non - responders to rGH and rIGF-1 (N = 6).
Results
There was no correlation between GV and peak GH level at GHRH test. Growth velocity positively correlated with ΔIGF - 1 SD among subjects treated with rGH therapy. Height SD positively correlated with IGFBP - 3 SD. Baseline IGFBP - 3 also inversely correlated with GH peak during GHRH test.
Conclusions
In subjects with short stature and low IGF - 1 level, baseline IGFBP - 3 levels can predict the growth response to rGH and/or rIGF - 1 therapy.
This chapter reviews normal variant short stature, comprised of both familial short stature (FSS) and constitutional delay of growth and puberty (CDGP), as well as idiopathic short stature (ISS). FSS and CDGP are physiologic variants of short stature without an organic cause. Although ISS is not a “normal variant” of short stature, as with FSS and CDGP it does not have an underlying pathological etiology. A child with short stature requires a comprehensive history and physical examination and consideration for diagnostic studies prior to establishing these non-pathological causes of short stature. Once a diagnosis of either a normal variant short stature or ISS is established, then ongoing monitoring of auxologic parameters throughout childhood and adolescence is indicated. The Food and Drug Administration’s approval of growth hormone for ISS triggered considerable debate within the medical community in terms of costs, benefits, and the ethics of treating children with growth hormone for this form of non-pathological short stature. The treatment of normal variant short stature and ISS should be individualized for each child.
The aim of this review is explore the psychosocial aspects of height and the growth hormone (GH) replacement treatment in order to judge the extension of the validity of the latter. For that we juxtaposed the accessibility to this treatment and the necessity involved, and it was observed that this necessity is a direct consequence of an existing socially valued standard of height and of prejudice against height outside this standard, even when the person is healthy. People with heights below this standard search for this treatment for fear of suffering some kind of stigmatization, even when they have no hormone deficiency. Thus, more people are exposed to the expectations and frustrations involved in the treatment as it does not always have the expected results. © Ciências & Cognição 2004; Vol. 02: 50-60.
The aim of this paper is to present consensus guidelines for the diagnosis and treatment of children and adolescents with growth hormone deficiency, and to alert on several crucial points regarding the use of human biosynthetic growth hormone: a) the mechanism of action of natural human growth hormone; b) how to establish clinical suspicious of growth hormone deficiency; c) utility of different biochemical studies to confirm growth hormone deficiency; d) physical and chemical characteristics of the commercial kits of growth hormone; e) how to prepare and use the growth hormone kits to ensure their efficacy; f) general objectives of growth hormone treatment; g) formal indications for the use of human growth hormone; h) define dose, time and periodicity during treatment; i) efficacy parameters of growth hormone treatment; j) factors that modify the efficacy of growth hormone treatment; k) safety parameters during growth hormone treatment; l) when, how and in who stop the treatment with growth hormone.
Growth has been described as the work of childhood. Very few things are as important, or as good a barometer of a child’s health, as his or her growth. Under normal circumstances, growth proceeds in a predictable fashion from conception to adulthood. Abnormal growth can be a harbinger of a pathologic condition of any organ system, as well as a psychosocial problem.
Bei Entbindungen ohne prä- oder perinatale Risikofaktoren sind in der Regel für das Neugeborene keine Probleme zu erwarten. Trotzdem muss der verantwortliche Arzt einer geburtshilflichen Abteilung dafür Sorge tragen, dass bei jeder Geburt eine Person sofort erreichbar sein kann, die mit den Grundregeln der Reanimation von Neugeborenen vertraut ist. Ein neonatologisch versierter Pädiater sollte bei Risikoentbindungen zugegen sein. Notwendige Ausrüstungen (Reanimationsplatz mit Wärmestrahler, Absaugvorrichtung, Sauerstoff, Beatmungsbeutel, Laryngoskop, Tuben etc.) müssen vorhanden sein und ihre Funktion regelmäßig überprüft werden. Hochrisikoentbindungen sollten in einem Perinatalzentrum erfolgen.
Cody was always a short child with stature at the 5th percentile of a standard growth curve since he was a toddler. His weight was between the 10th and 25th percentiles. Developmental milestones and early learning achievement were normal. He played in a youth soccer league from 8 to 10 years of age, but he was not enthusiastic about group sports. In middle school, Cody excelled in the sciences and enjoyed tennis and swimming with his friends. In the 7th and 8th grades, his parents reported that Cody was teased frequently about his short stature. When the pediatrician asked Cody about the teasing, he was evasive.
Cody’s parents were concerned that experiencing adolescence as the shortest boy in the class would have a lasting negative effect on his self-esteem. His father, remembering his own painful childhood as a short boy who was bullied frequently by other children until late adolescence, read about growth hormone (GH) on the Internet and thought that it might help his son.
Cody’s father was 5 ft 5 inches, and his mother was 5 ft 2 inches. His father recalled initiating puberty later than his friends. The paternal grandparents were also short (5 ft 2 inches and 4 ft 8 inches). At the 14-year-old health-supervision visit, Cody’s height was now below the 5th percentile. Review of systems was negative, and he continued to do well in school. Genitalia showed 2.5 cm testes with minimal scrotal thinning, Tanner 2 pubic hair, and no enlargement of the phallus. The thyroid gland was not enlarged; blood pressure and neurological examinations were normal. A bone age was 12 years 6 months (chronological age: 14.0 years). The pediatrician ordered a complete blood count, erythrocyte sedimentation rate, chemistry panel, serum thyroxine, thyroid-stimulating hormone, insulin-like growth factor-1 (IGF-1), and IGF-binding protein-3 (IGFBP-3). All …
In the last two decades growth hormone (GH) therapy has expanded to include many children with non-GH deficient short stature such as idiopathic short stature (ISS), skeletal dysplasia, genetic syndromes and other chronic diseases associated with short stature. ISS now appears to be the most common indication for GH treatment. It is difficult to differentiate GHD from ISS with conventional GH testing alone. A number of abnormalities of the GH receptor have been identified in children with ISS. GH in a supraphysiological dosage generally increases height velocity in children with ISS and increases the adult height upto 7 cm. However, the height gain for an individual child cannot be predicted. Though GH is well tolerated without significant adverse effects, the risks of unwanted long-term sequelae of elevated serum GH and IGF-1 have not been evaluated. The psychosocial effects of short stature and the emotional benefits derived from GH therapy also need to be carefully evaluated. The results in skeletal dysplasia have been less rewarding. GH therapy does not benefit patients with achondroplasia much, but a subgroup of patients with hypochondroplasia may benefit significantly. Other uncommon forms of skeletal dysplasias have not benefited with GH treatment. The compromised final height, motor performance, muscle mass, the body composition and metabolic profile improve with GH therapy in Prader-Willi-Syndrome (PWS). However, these children need close monitoring for respiratory difficulties and apnea, disturbance of carbohydrate metabolism and scoliosis. In view of its safety, the use of GH is likely to be extended to many disorders where short stature may be an associated secondary problem. In future the use of growth hormone for disorders with non-GHD short stature is likely to increase further.
The purpose of this article is to review the characteristics of craniofacial morphology in children of short stature and the effects of human growth hormone (HGH) therapy on the craniofacial complex. Changes in body height, facial growth, and dental maturity of a 9-year-old girl who received HGH therapy during orthodontic treatment were observed. Orthodontists need to understand the skeletal characteristics of the craniofacial complex of short-stature patients before beginning orthodontic treatment and consider how the differences between chronologic and skeletal ages affect the timing and method of orthodontic treatment. If short-stature children are undergoing HGH therapy, its cranioskeletal effect should be considered; if possible, it is better to delay orthodontic treatment until HGH is finished. However, if orthodontic treatment is performed, the following should be considered: (1) HGH therapy affects the growth of the mandible more than the growth of the maxilla, (2) the amount and pattern of growth during HGH administration are unpredictable, and (3) HGH therapy rarely affects dental maturity.
While there has been a significant amount of work in the sociological literature looking at how short stature has become medicalized, virtually no research has been conducted as a comparison of the organizations that deal with issues of short stature. This dissertation examines how three such organizations mobilize around issues of stigma, normalcy, and difference. The data were collected through ethnographic fieldwork and 32 in-depth interviews with organization leaders and rank-and-file members of the following organizations: Little People of America (LPA), the MAGIC Foundation, and the National Organization of Short Statured Adults (NOSSA).
My dissertation addresses the following research questions: 1) How and why do parents and persons considered short (or different) mobilize? 2) How do these movements frame their stance toward short stature, and how does this framing reflect their ideas about difference, normalcy, and stigma? 3) How do these movements frame their stance toward technologies affecting short people? 4) What strategies and tactics do the organizations use in articulating and publicizing their stance on the Internet, in the mass media, and to the general public? 5) What causes some short statured organizations to succeed while others ultimately fail?
Utilizing previous research on social movements, I find that each organization has its own unique way of viewing short stature and subsequently how short stature should be dealt with, both within the organization and also within the general public; therefore, there is a chapter devoted to each organization. Using identity politics, assimilation, and normalization, respectively, each organization not only reacts to short stature differently, but also to the technologies that exist to mitigate the effects that short stature has, on both the individual and society-at-large. Drawing on previous work, we see how different types of social movement actors (e.g. parents, adult activists, etc.) mobilize around issues of difference, normalcy, and stigma, and whether a collective identity is created. Finally, through the dissolution of one of the three organizations during the course of this research, I directly compare the three organizations, pointing to characteristics that helped two succeed, while the other failed.
Human growth hormone (hGH) is a protein hormone essential for normal growth and development in humans. hGH affects many aspects of human metabolism, including lipolysis, the stimulation of protein synthesis, and the inhibition of glucose metabolism. Human growth hormone was first isolated and identified in the late 1950s from extracts of pituitary glands obtained from cadavers and from patients undergoing hypophysectomy. The first clinical use of these pituitary-extracted hGHs for stimulation of growth in hypopituitary children occurred in 1957 and 1958 (Raben 1958). From 1958 to 1985 the primary material used for clinical studies was pituitary-derived growth hormone (pit-hGH). Human growth hormone was first cloned in 1979 (Goeddel et al. 1979; Martial et al. 1979). The first use in humans of recombinant human growth hormone (rhGH) was reported in the literature in 1982 (Hintz et al. 1982). The introduction of rhGH coincided with reports of a number of cases of Creutzfeldt-Jakob disease, a fatal degenerative neurological disorder, in patients receiving pituitary-derived hGH. Concern over possible contamination of the pituitary-derived hGH preparations by the prion responsible for Creutzfeldt-Jakob disease led to the removal of pit-hGH products from the market in the US in 1985 followed by the FDA approval of rhGH later in the year. The initial rhGH preparations were produced in bacteria (E. coli) but, unlike endogenous hGH, contained an N-terminal methionine group (met-rhGH). Natural sequence recombinant hGH products have subsequently been produced in bacteria, yeast, and mammalian cells.
Das Wachstum stellt einen Schwerpunkt der alltäglichen pädiatrischen Praxis dar. Der häufigste Vorstellungsgrund in einer endokrinologischen Sprechstunde ist der Kleinwuchs. Etwa 75% dieser Patienten zeigen eine somatische Entwicklungsverzögerung, welche hauptsächlich konstitutionell (genetisch) bedingt ist. Diese Patientengruppe ist relativ leicht durch anamnestische, klinische und radiologische Kriterien von anderen schwierigeren endokrinologischen und nichtendokrinologischen Kleinwuchsformen zu differenzieren.
Girls with Turner syndrome were divided according to age (group A 6-12 years, and group B 12-19 years) and human growth hormone (GH) dose regimen (Al and Bl, three injections/week; A2 and B2, six injections/week). All groups responded to GH, 24 IU/m2/week, with an increase in height velocity, though in the older girls, the response was comparatively poor. Therefore, the dose regimens in groups B1 and B2 were increased to 36 IU/m2/week given as six injections in both groups. This change resulted in an increase in height velocity only in group B1. During the first 2 years only, the height velocity was greater in group A2 than group A1. The conclusion is that a regimen of six injections/week is more effective than one of three injections/week in terms of initial height gain and change in predicted adult height. In girls with Turner syndrome aged over 16 years, GH therapy has no significant effect.
Growth, Maturation and Body Composition documents one of the most remarkable and significant studies in the field of human biology. The Fels Longitudinal Study is the longest, largest and most productive serial study of human growth, maturation and body composition. This book shows how data collected from more than 1000 participants during the past 60 years have been analysed to test a wide range of hypotheses, and describes how the findings have led to the development of improved research methods. Topics covered include the management and analysis of data, prenatal, familial and genetic studies, physical growth, development and maturation, bones and teeth, body composition, and risk factors for cardiovascular disease. With more than 1000 specialized publications of Fels data, the present book provides a unique overview of this fascinating research programme, which will be of interest to a wide range of researchers, including those in the fields of physical anthropology, nutrition science, pediatrics, gerontology, epidemiology, endocrinology, human genetics, as well as statistics.
A multicenter randomized trial of human growth hormone treatment was carried out in 121 children with short stature who did not meet the classic criteria for growth hormone deficiency. Patients treated for 1 year with recombinant somatropin, 0.1 mg/kg three times a week, had a significant increase in mean growth rate from 4.6 +/- 1.1 to 7.5 +/- 1.2 cm/yr, whereas untreated children's growth rate did not change significantly (4.2 +/- 1.3 vs 5.0 +/- 1.4 cm/yr). There was a 1-year advance in bone age for each group; thus there was a significant increase in the predicted height of the treated but not the control group. Among the treated children, the growth response did not differ among those classified on the basis of parental height and bone age as having familial short stature or constitutional delay of growth and development. Prestudy anthropomorphic features were not related to subsequent growth in either the treated or control groups. The baseline plasma insulin-like growth factor I concentration was inversely related to the growth response to growth hormone treatment (r = -0.50, p = 0.0003). By contrast, the serum growth hormone concentration measured in samples obtained at 20-minute intervals for 12 or 24 hours or after clonidine administration did not predict the future growth rate. There were no side effects of growth hormone treatment. The results suggest that children who have significant short stature and slow growth may benefit from a trial of growth hormone therapy.
The concept of donor-specific transfusion is not new; it has been used for the transplantation of organs, for plate-letpheresis, and for persons belonging to rare blood groups. The recent rapid growth of directed donation, however, has been generated not by medical necessity but by fear of traditional blood-transfusion therapy . The blood-banking community generally views directed-donation blood prod-ucts as no safer than those that are procured from regular donors. None-theless, in some locales -especially ones where HIV seroprevalence is high -there may be community pressure to provide a directed-donor program. It is emphasized that such a program should never replace an autologous blood-transfusion program. Rather, autologous transfusion should be the optimum practice, and only after it has been established should directed donation be considered. Screening and evaluation of di-rected donors must be done in the same manner as for regular blood donors. All three methods for evaluating the radiographs use such indicators as the ratios of various bones in the wrist and their overlapping, the onset of ossification, and the epiphyseal-diaphyseal fusion.
BACKGROUND AND OBJECTIVE Growth hormone treatment In children with Idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long-term effect of GH therapy in children with Idiopathic short stature.
DESIGN We have treated 27 prepubertal children with ISS with recombinant human GH (rhGH) in an initial dosage of 2 IU/m2 body surface/day subcutaneously, which was doubled either after the first year if the height velocity increment was less than 2 cm/year, or thereafter if height velocity fell below the P50 for bone age. Growth and bone maturation of the treatment group (ISS group, n= 21) were compared to those of an untreated control group with ISS (ISS controls, n= 27) and of a group of rhGH treated children with isolated GH deficiency (GHD group, n= 7).
RESULTS In 9 patients of the ISS group still on treatment, height standard deviation score (HSDS) for chronological age increased from −3.8±0.7 to −2.3±0.9 (mean±standard deviation) over 6 years, while in matched ISS controls HSDS for age did not change. HSDS for age in the GHD group increased from −3.9±0.6 to −1.8±0.7 after 4 years, significantly more than the ISS group. Bone maturation was accelerated In the ISS and GHD groups. HSDS for bone age and predicted adult height did not change in either group. Final height in 12 children of the ISS group was −2.6±1.0 SDS. In the untreated controls final height was similar. A low integrated GH concentration over 24 hours, a low GH peak to provocative stimuli, and minimal initial BA delay predicted a favourable outcome.
CONCLUSION rhGH treatment In this group of children with Idiopathic short stature did not increase average final height. Part of the heterogeneity of the response can be attributed to the variation in endogenous GH secretion and initial bone age delay.
Patients with Turner syndrome were treated with recombinant human growth hormone (GH) for 3 years. Sixty-eight patients received GH, 0.5 IU/kg/week, while 93 received GH, 1.0 IU/kg/week, by daily subcutaneous injection. Both treatment groups showed a statistically significant increase in growth during treatment. However, the higher dose increased height velocity to a significantly greater extent during the first and second year of treatment. The projected adult height was exceeded by 52 of 71 patients over the age of 14 years. Plasma insulin-like growth factor 1 levels were elevated and no remarkable advances in bone age were observed. There were no other significant changes in physical or laboratory parameters. No glucose intolerance was observed. These results indicate that GH treatment is useful for accelerating growth velocity in patients with Turner syndrome. However, further study will be required to find the most appropriate dose.
The FELS method of assessing the skeletal maturity of the hand-wrist differs from the Greulich-Pyle and Tanner-Whitehouse methods in the observations made, the provision of a range of shapes to which maturity indicator grades can be assigned and in the statistical methods used to construct the scale of skeletal maturity. The FELS method for the hand-wrist was developed using 13,823 serial radiographs of the left hand-wrist of boys and girls in the Fels Longitudinal Study. One hundred-thirty possible indicators were originally identified. Eighty-five graded and 13 metric indicators were selected on the basis of an indicator's ability to discriminate between children at the same chronological age, its universal appearance, reliability, validity, and completeness. The subset of FEELS maturity indicators assessed at a chronological age are analyzed with a microcomputer program that provides the skeletal age and the standard error of the estimate for that skeletal age. Comparison among hand-wrist skeletal age assessments for children in the Fels Longitudinal Study by the FELS, Greulich-Pyle, and Tanner-Whitehouse methods indicate that the FELS method is the more appropriate method for the present population of United States children.
The auxological characteristics and the response to growth hormone (GH) treatment of children with idiopathic short stature were studied, using the database of the Kabi Pharmacia International Growth Study. Pretreatment data from a total of 271 children were analysed. The children were selected for a birth weight above -2 SDS. The correlation coefficient of birth weight SDS and birth length SDS was 0.51, compared with 0.72 for the reference population. Median length at birth was -0.6 SDS, which fell to -2.5 SDS by 3 years of age. Thereafter, there was no further loss in height SDS. The response to GH treatment was studied in 222 of these prepubertal children who were given six or seven injectiodweek over a 3-year period. During this time, the median height SDS increased from -2.5 to -1.5, with those children receiving more than 0.65 IU/kg/week having a greater gain in height SDS than those on 0.5 IU/kg/week or less. The degree of bone age delay did not appear to influence the response to GH therapy.
Anthropometry is an effective and frequently performed child health and nutrition screening procedure. The value of physical growth data depends on their accuracy and reliability, how they are recorded and interpreted, and what follow-up efforts are made after identification of growth abnormality. The new National Center for Health Statistics percentiles can be used to improve identification of potential health and nutritional problems and to facilitate the epidemological comparison of one group of children with others.
During recent years numerous reports on the favourable results of short-term trials with GH in patients with constitutional delay of growth and adolescence (CDGA) have been published, but it has been unclear whether such treatment affects final height. In the present study, the results of long-term therapy with GH in replacement doses have been evaluated in 15 patients who were treated with GH for several years (three years on average). At the start of treatment, 10 of the children were prepubertal and 5 were in puberty. All patients were followed up until final height was reached. Mean final height of the 13 male patients was 170.0 +/- 4.4 cm, i.e. -1.58 SDS. In the two female patients, final height was 150.0 cm (-3.5 SDS) and 164.0 cm (-0.8 SDS), respectively. Adult height of the patients lagged behind target height by 5.4 +/- 3.2 cm (mean +/- SD). Measured adult height corresponded to adult height as predicted prior to treatment. In conclusion, GH treatment of patients with CDGA did not increase final height.
Seventy girls with Turner syndrome, verified by karyotype, were randomly assigned to observation or treatment with human growth hormone (hGH), oxandrolone, or a combination of hGH plus oxandrolone for a period of 12 to 24 months, to assess the effect of treatment on growth velocity and adult height. Subsequently, all subjects received either hGH alone or hGH plus oxandrolone. Data are presented for 62 subjects treated for a period of 3 to 6 years. When compared with the anticipated growth rate in untreated patients, the growth rate after treatment with hGH, both alone and in combination with oxandrolone, showed a sustained increase for at least 6 years. Treatment is continuing in over half of the subjects; at present, 14 (82%) of 17 girls receiving hGH alone and 41 (91%) of 45 girls receiving combination therapy exceeded their expected adult heights. Thirty girls have completed treatment; mean height for these 30 patients is 151.9 cm, compared with their mean original projected adult height of 143.8 cm. We conclude that therapy with hGH, alone and in combination with oxandrolone, can result in a sustained increase in growth rate and a significant increase in adult height for most prepubertal girls with Turner syndrome.
Both biochemical and auxological measurements can be used to assess growth. Quality control in routinely reported in laboratory studies, but the reproducibility of height measurements, and the height velocity data derived from them, is seldom considered. We have previously established our error and in this report we examine its implications for the screening of short children and subsequent monitoring of their growth. The 95% confidence interval for height for a 5 year old observed to be on the 3rd centile for height, spanned the 2nd-4th centile. However, the confidence interval for a 12 month height velocity appropriate to such a child spanned the 8th-52nd centiles, the lower limit pathological and the upper more than satisfactory. A single height velocity even over 12 months therefore lacks the precision to provide a reliable index of current growth in short children. Furthermore, serial height velocity calculations on a cohort of 78 short normal children showed no significant correlation from year to year, suggesting that velocity is also unable to predict future growth. Although the proportion of this cohort of short children lying beneath the 25th centile for velocity remained constant from year to year, the identity of the individuals comprising that proportion changed, a phenomenon which could be largely accounted for by the random error associated with height velocity. Our data suggest that, by the time a trend in abnormal velocity is reliably established, a deviation from the height centiles is clearly evident. Although velocity charts are attractive in concept, they seem to be no more discriminating than height charts in practice, and may be clinically deceptive unless interpreted with great care.
Constitutional delay of growth and puberty is believed to represent a variation of normal growth, and it is expected that children with this condition will grow for a longer duration than average and reach a height that is normal for their genetic potential. The records of children with constitutional delay of growth and puberty who were initially seen in the Pediatric Endocrine Clinic at the Oregon Health Sciences University between 1975 and 1983 were retrospectively reviewed. Criteria for study included a height more than 2 SD below the mean, a significantly delayed bone age, and a normal growth velocity on follow-up. Forty-two subjects were located and final adult height measurements were obtained. AT contact, the 29 male subjects (mean age = 23.9 years) were 169.5 +/- 4.5 cm tall (mean +/- SD), and the 13 female subjects (mean age = 20.5 years) were 156 +/- 3.8 cm tall. Adult height predictions during follow-up, using either the Bayley-Pinneau or Roche-Wainer-Thissen method, were close to final adult heights. The males were 1.2 SD and the females 1.3 SD below the 50th percentile as adults. This finding was not fully explained by genetic short stature; the males fell 5.1 cm and the females 5.3 cm below target heights based on midparental heights. It is concluded that this discrepancy is most likely explained by a selection bias of the shortest children referred to and observed in a subspecialty clinic, although a defect in human growth hormone secretion or function in children at the far end of the spectrum of constitutional delay of growth and puberty cannot be excluded.
Increased availability of growth hormone (GH) because of increased production using recombinant DNA technology has led to increased demand. Many children who do not have classic GH deficiency may respond to GH therapy. These observations require rethinking of the medical indications for GH therapy, and raise two central ethical questions: (1) Is it justified to discriminate on the basis of GH deficiency? (2) Whatever the indication for GH treatment, at what height should GH therapy be considered an entitlement? We argue, first, that GH responsiveness, not GH deficiency, should be the criterion for GH treatment, and that prior arguments emphasizing GH deficiency are based on vague or faulty notions of disease, handicap, or potential. Second, we argue that children who are handicapped (arbitrarily defined as including those whose height is below the 1st percentile) and GH responsive are entitled to treatment. Children above that height, whether GH deficient or not, may permissibly be treated, but there is no societal obligation to do so. Such an approach would reduce, though not eliminate, some of the more severe burdens of short stature without aggravating the pernicious effects of "heightism" in American society.
The effect of 3 years of growth hormone (GH) treatment on growth rate, predicted height, carbohydrate and metabolic status, and thyroid function was studied in 16 short prepubertal children growing with a normal pretreatment growth rate. The height velocity SDS increased from a pretreatment value of -0.44 +/- 0.33 (mean +/- SD) to a value of +2.20 +/- 1.03 during the first year of treatment. It was maintained at a value above zero over the subsequent 2 years. By the end of the third year of treatment, the predicted final height had increased by 6.8 cm in the boys and by 4.2 cm in the girls (p less than 0.001 and p less than 0.01, respectively). Increasing the dose of GH on a body surface area basis reduced the deceleration of growth observed during the second year of treatment, leading to an improvement in height prognosis over that year. Glucose homoeostasis was achieved initially at the expense of an elevation in fasting serum insulin concentration, but this had returned to pretreatment values by the end of the second year of therapy.
Evaluation of 24-hour endogenous growth hormone (GH) secretion was carried out in 62 children, aged 7-16 years, who did not have classic GH deficiency (GHD). The mean 24-hour GH concentration, determined at 20-minute intervals over 24 hours, was variable, ranging from 1.28 to 11.39 micrograms/l with a mean of 4.95 +/- 2.55 micrograms/l (+/- SD). There was a positive correlation between mean 24-hour GH concentration and plasma insulin-like growth factor I (IGF-I) values (r = 0.54; p less than 0.01). Recombinant human GH, 0.1 IU/kg/day was administered to 30 of the 62 children for 6 months followed by 6 months' observation without treatment. Thereafter, GH was administered at the same dose for a further 6 months to 16 children. The mean height velocities before, during, and after the first treatment period were 4.3 +/- 0.9, 7.3 +/- 1.9 and 4.9 +/- 2.0 cm/year (mean +/- SD), respectively. The height velocity during treatment was greater than pre- and post-treatment values (p less than 0.001). The height velocity increased again during the second treatment period to a mean of 8.5 +/- 2.0 cm/year (p less than 0.001). Nine other children were treated continuously in a similar manner for 1 year and their height velocity increased significantly from 4.1 +/- 1.4 to 6.0 +/- 1.9 cm/year (p less than 0.001). According to our criteria, 29 of the 39 children (74.4%) who were treated for 6-12 months showed a GH-dependent height increase during therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
The quantitation of human GH in a serum sample is not consistent among various commercially available immunoassays. We measured serum GH concentrations with four RIAs [Cambridge, Kallestad, National Hormone and Pituitary Program, and Radioassay Systems Laboratories (RSL)] and two immunoradiometric assays (IRMAs; Hybritech and Nichols). Serum GH concentrations measured by the RIAs were between 1.9 and 2.8 times higher than those determined by the Hybritech IRMA, whereas the concentrations measured by the Nichols IRMA were approximately 3.0 times higher than the Hybritech values. We evaluated the effects of differences in standards, assay diluents, and antibody specificity on GH measurement in the various assays. When GH standards from each of the assays were measured in the Hybritech IRMA, only the RSL standard was less immunoreactive than the other assay standards. Different assay diluents also resulted in varying GH values. In the RIAs, GH diluted in serum was more immunoreactive than GH diluted in phosphate-buffered saline-0.5% BSA. This enhanced immunoreactivity appeared to be due to a nonspecific effect generated by serum. The Nichols and Hybritech IRMAs provide standards diluted in horse serum. In the Nichols assay, GH diluted in human serum was more immunoreactive than GH diluted in horse serum, whereas the immunoreactivity of GH diluted in either serum was equal in the Hybritech IRMA. These IRMAs also differ in that the Nichols assay detected the 20K variant of GH, whereas the Hybritech assay did not. Considering these discrepancies, comparison of data obtained using different assays should be made carefully.
To clarify the relative usefulness of measuring stimulated as compared with spontaneous growth hormone levels in the diagnosis of growth hormone deficiency, we studied 54 short prepubertal children--23 with growth hormone deficiency identified by stimulation tests and 31 with idiopathic short stature who had normal responses to growth hormone stimulation. Growth hormone levels were measured in plasma samples obtained every 20 minutes for either 12 or 24 hours. The results were compared with those in 46 normal prepubertal children. Children with growth hormone deficiency had significantly lower mean 24-hour growth hormone levels (1.0 microgram per liter; range, 0.5 to 1.8) than normal children (2.8 micrograms per liter; range, 0.8 to 5.8; P less than 0.001). However, the diagnostic usefulness of the spontaneous growth hormone test was inferior to that of the stimulation tests, since it identified only 57 percent of the children with growth hormone deficiency identified by the stimulation tests. In the remaining children with growth hormone deficiency, spontaneous growth hormone levels were within the normal range. Children with idiopathic short stature had a normal mean 24-hour level of growth hormone (3.0 micrograms per liter; range, 1.1 to 6.7). No child in this group had low levels of spontaneous growth hormone secretion. We conclude that the measurement of the spontaneous secretion of growth hormone in prepubertal short children had lower sensitivity and offered no diagnostic advantage over stimulation tests. Our data do not support the routine measurement of spontaneous growth hormone secretion in the diagnosis of growth hormone deficiency.
Ten unselected, apparently healthy short children who were capable of normal growth hormone secretion were given human growth hormone (0.1 U/kg 1M thrice weekly) for 6 months to determine whether such treatment might lead to an increase in growth velocity. During treatment, all patients increased their growth rate (from 4.3 +/- 0.3 cm/yr to 7.4 +/- 0.5 cm/yr P less than 0.001). No adverse effects were detected. During the four-day IGF generation test, IGF I and IGF II levels rose significantly from 0.32 +/- 0.04 U/ml to 0.62 +/- 0.13 U/ml and from 279 +/- 36 ng/ml to 434 +/- 49 ng/ml, respectively. However, the growth response was not predicted by either the acute rise in IGF I or that in IGF II. Human growth hormone in standard doses may be capable of inducing accelerated growth in some short children without growth hormone deficiency. Measurements of IGF I and II cannot be used to predict which children will respond.
Children with growth failure, normal growth hormone responses to stimulation tests, and low somatomedin levels are being recognized with increasing frequency. Sixteen patients, aged 2 to 17 years, with these findings were studied. When treated with human growth hormone, the mean plasma somatomedin-C levels of these patients increased from 0.19 +/- 0.05 (SD) U/mL to 2.29 +/- 1.11 U/mL (P less than .001) and mean growth velocity increased from 3.6 +/- 1.6 (SD) cm/yr to 7.4 +/- 2.9 cm/yr at 8 months of treatment (P less than .001). The effect of human growth hormone therapy on the whole group was statistically significant, but the effect on individuals was highly variable. There was no correlation between magnitude of the increase in somatomedin-C and growth response (r = .26, NS). Thus, the long-term growth-promoting effect of human growth hormone therapy in this group of patients could not be predicted from the magnitude of the somatomedin-C responses.
Fifteen short but otherwise normal children, 4.3 to 15.5 years old, with heights greater than 3 S.D. below the mean value for age, growth rates less than or equal to 5.0 cm per year, and normal serum levels of immunoreactive growth hormone in response to provocative stimuli (peak greater than or equal to 10 ng per milliliter) were treated with intramuscular injections of pituitary growth hormone (0.1 U per kilogram) three times weekly for six months, as were 14 children with documented growth hormone deficiency. In all the latter children growth rate increased by more tan 2.0 cm per year during treatment. In 6 of the 14 short normal children who remained prepubertal, growth rate also increased, by 2.2 to 4.2 cm per year during treatment; four of these children had normal base-line serum somatomedin C concentrations. In both short normal children and children with growth hormone deficiency, the increment in serum somatomedin C concentrations after 4 or 10 daily injections of growth hormone correlated with bone age but not with later growth or growth hormone levels. Among the short normal children, those who responded to growth hormone were younger and had a greater delay in bone age and a slower pretreatment growth rate than the nonresponders. These observations suggest that a dose of growth hormone comparable to that used for the treatment of hypopituitarism increases growth rate in some short normal children.
Growth hormone treatment in children with idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long-term effect of GH therapy in children with idiopathic short stature.
We have treated 27 prepubertal children with ISS with recombinant human GH (rhGH) in an initial dosage of 2 IU/m2 body surface/day subcutaneously, which was doubled either after the first year if the height velocity increment was less than 2 cm/year, or thereafter if height velocity fell below the P50 for bone age. Growth and bone maturation of the treatment group (ISS group, n = 21) were compared to those of an untreated control group with ISS (ISS controls, n = 27) and of a group of rhGH treated children with isolated GH deficiency (GHD group, n = 7).
In 9 patients of the ISS group still on treatment, height standard deviation score (HSDS) for chronological age increased from -3.8 +/- 0.7 to -2.3 +/- 0.9 (mean +/- standard deviation) over 6 years, while in matched ISS controls HSDS for age did not change. HSDS for age in the GHD group increased from -3.9 +/- 0.6 to -1.8 +/- 0.7 after 4 years, significantly more than the ISS group. Bone maturation was accelerated in the ISS and GHD groups. HSDS for bone age and predicted adult height did not change in either group. Final height in 12 children of the ISS group was -2.6 +/- 1.0 SDS. In the untreated controls final height was similar. A low integrated GH concentration over 24 hours, a low GH peak to provocative stimuli, and minimal initial BA delay predicted a favourable outcome.
rhGH treatment in this group of children with idiopathic short stature did not increase average final height. Part of the heterogeneity of the response can be attributed to the variation in endogenous GH secretion and initial bone age delay.
We report the effect of growth hormone (GH) treatment for 4 to 10 years in 15 prepubertal non-GH-deficient short children (10 boys, 5 girls, aged 7.4 to 13.2 years). In 7 patients, GH was administered at a dosage of 0.5 U/kg per week (group 1: 4 boys, 3 girls) and in 8 patients (group 2: 6 boys, 2 girls) at a dosage of 1.0 U/kg per week. After the first year, mean linear growth velocity had significantly increased in both groups. The increase in growth velocity was sustained during the first 4 years and then declined to pretreatment values in the majority of subjects. Treatment with GH did not induce an earlier onset of puberty, but there was a tendency toward faster skeletal maturation. The mean final height standard deviation score (SDS) was similar in the two groups and was significantly higher than the height SDS for chronologic age before treatment, but it did not differ from mean pretreatment predicted adult height SDS nor from mean target height SDS in both groups. Final height was significantly correlated with target height in both groups. These preliminary observations indicate that GH treatment does not generally increase final height over target height in short non-GH-deficient children.
We evaluated the effect of growth hormone (GH) therapy on bone age, pubertal maturation and predicted adult height in two groups of boys treated for 4 years: 40 growth hormone-deficient boys who had growth hormone response to provocative stimulation < 10 micrograms/L (GHD group) and 43 boys whose stimulated growth hormone > or = 10 micrograms/L (group with neurosecretory dysfunction (NSD)). All patients had a subnormal integrated concentration of growth hormone < or = 3.2 micrograms/L, height < -2 SD, growth velocity < 4.5 cm/yr, and bone age < or = -2 SD for chronologic age. Patients were treated with recombinant growth hormone, 0.1 mg/kg per dose given three times a week. The pretreatment height SD of the GHD group (-3.6 +/- 1.0) was less than that of the NSD group (-2.7 +/- 0.7; p < 0.001). After 4 years of therapy, both groups had catch-up growth (GHD group to -2.0 +/- 1.3 height SD (n = 35), and NSD group to -1.4 +/- 0.7 height SD (n = 32)); the rate of height SD gain was better in patients with GHD (p < 0.01). The response to growth hormone was inversely related to pretreatment chronologic age (p < 0.001). The Tanner-Whitehouse II predicted adult height improved for both groups: +9.3 +/- 7.7 cm in the GHD group, giving an adult height SD of -0.9 +/- 1.0, and +5.4 +/- 5.5 cm in patients with NSD, for an adult height SD if -0.8 +/- 0.7. Testosterone levels became higher in the NSD group after 2 years and remained higher at year 4. We conclude that patients respond favorably to growth hormone therapy and in a manner similar to patients with GHD. Initiation of therapy at a younger age gives a greater improvement in gained height and predicted adult height.
To determine the effects of puberty and estrogen priming on the GH response to standardized treadmill exercise and arginine-insulin in normal boys and girls, we performed tests in 84 normal children (41 girls and 43 boys) representing all stages of puberty. A subset of the prepubertal children received the tests twice, with or without the administration of ethinyl estradiol (40 micrograms/m2 daily) for 2 days before the tests. The peak GH response to the three tests increased significantly with pubertal stage (r = 0.57; P < 0.0001), but did not differ between boys and girls at the same stage. With advancing puberty, the percentage of normal children who failed to attain a GH level greater than 7 micrograms/L during any of the three tests declined from 61% at pubertal stage 1 to 44% at stage 2, 11% at stage 3, and 0% at stages 4 and 5. Administration of estrogen to the prepubertal subjects raised the normal range for the peak GH response to the three tests from 1.9-20.3 to 7.2-40.5 micrograms/L. We conclude that both puberty and estrogen administration significantly increase the peak GH response to exercise, arginine, or insulin in normal subjects. Moreover, the conventional criterion that the peak GH response to three stimulation tests should exceed 7 micrograms/L was applicable in our study only to subjects who had attained pubertal stage 4 or 5 or who had received estrogen administration.
The auxological characteristics and the response to growth hormone (GH) treatment of children with idiopathic short stature were studied, using the database of the Kabi Pharmacia International Growth Study. Pretreatment data from a total of 271 children were analysed. The children were selected for a birth weight above -2 SDS. The correlation coefficient of birth weight SDS and birth length SDS was 0.51, compared with 0.72 for the reference population. Median length at birth was -0.6 SDS, which fell to -2.5 SDS by 3 years of age. Thereafter, there was no further loss in height SDS. The response to GH treatment was studied in 222 of these prepubertal children who were given six or seven injections/week over a 3-year period. During this time, the median height SDS increased from -2.5 to -1.5, with those children receiving more than 0.65 IU/kg/week having a greater gain in height SDS than those on 0.5 IU/kg/week or less. The degree of bone age delay did not appear to influence the response to GH therapy.
Short-term administration of human growth hormone to children with idiopathic short stature can improve mean growth rate and predicted adult height. It is yet unknown whether therapy would alter pubertal development or affect final height. Three-year treatment results in a group of children with idiopathic short stature are reported. For year 1 of the study, 121 prepubertal children were randomly selected to receive somatotropin, 0.3 mg/kg per week, administered subcutaneously three times weekly (n = 63), or to be nontreatment control subjects (n = 58). After 1 year, all subjects were again randomly selected to receive either three-times-weekly or daily dosing at the same total dose. For the 92 subjects who completed 36 months of treatment, mean growth rate increased from a mean of 4.6 cm/yr before treatment to a mean of 8.0 cm/yr in the first year of treatment. Daily dosing resulted in a significantly faster mean growth rate (9.0 cm/yr) than three-times-weekly dosing (7.8 cm/yr) (p = 0.0005). Mean growth rates were 7.6 and 7.2 cm/yr during years 2 and 3, respectively, and did not differ by dosing group. Mean standardized height for all subjects improved from -2.7 to -1.6 after 3 years. When the growth rate was standardized for bone age, however, subjects who remained prepubertal had a significantly greater gain in mean height SD score than subjects who became pubertal during that 3-year period (p < 0.02). Mean standardized Bayley-Pinneau predicted adult height SD score increased from -2.7 to -1.6 and was independent of the timing of pubertal onset, but for individuals this score was more variable. Year-1 growth response, expressed as growth rate or change in height SD score, was the best predictor of growth in subsequent years. Responses to therapy could not be reliably predicted from baseline anthropometric variables, plasma insulin-like growth factor I SD score, growth hormone levels. Final height assessment will be needed to determine the ultimate benefit of therapy.
Two hundred and thirty-six patients with idiopathic short stature (ISS) (184 m, 52 f) who presented at a mean age of 12.2 (range 2.8-17.5) years, a mean height of -2.16 standard deviation score (SDS), a mean target height (THT) of -0.27 SDS (m = f), were reinvestigated at a mean age of 20.5 (range 18-24) years. 182(142 m, 37 f) (67%) had reached normal adult height (AHT) while 54 (39 m, 15 f) (23%) had not. However, only 23 (17 m, 6 f) did not reach a height within their familial target. Patients were subdivided into 2 groups according to deviation from familial height target: 60(44 m, 16 f) were considered adequate for their families (group 1), while 176 (140 m, 39 f) were smaller (group 2). Children in group 1 were younger and bone age (BA) was less retarded. Patients in group 1 reached their THT, this was not the case in group 2. Young age, low THT and low predicted adult height (PAH) at presentation were the factors associated with poor stratural outcome, but AHT could not be predicted in individuals. In boys, PAH (Bayley-Pinneau) (0.0 SDS) exceeded AHT (-0.7 SDS), in girls, both were almost identical (-0.79, -0.77 SDS). Since most children with ISS reach an AHT within the normal range, attempts to improve AHT by means of growth-promoting therapies appear to be justified only in a minority of selected patients with ISS. Methods to improve the accuracy of individual height prognoses are needed.
Short-term studies have demonstrated acceleration of growth rate following administration of biosynthetic human growth hormone (r-hGH) to short normal children. We describe the effect of such treatment on final height.
This was an open study of consecutive referrals to a growth disorder clinic from which 16 short children (height standard deviation score [SDS] -2.17 [range -1.8 to -3.3]; height velocity SDS -0.44 [0.33]; peak serum GH response to stimulation 27.9 mU/L [9.2] were treated with r-hGH, and 7 short children who declined treatment (height SDS -2.34 [0.61]; height velocity SDS -0.36 [0.28]; peak serum GH response 28.2 mU/L [6.8]) acted as an observation group. Subcutaneous r-hGH dose ranged between 12.2 and 21.0 U/m2 per week (0.02-0.04 mg/kg per day) for the first 2 years of treatment and 20 U/m2 per week thereafter, 3 untreated children were lost to long-term follow-up.
r-hGH significantly increased the difference in final height compared with pretreatment predicted height (+0.42 SDS [0.79], p = 0.03) but this change was not significantly greater than that of the observation group (+0.16 SDS [0.20]). Treatment had no effect on the timing of puberty. Boys progressed slightly faster through puberty, associated with an acceleration in bone-age maturation. No untoward effects on glucose metabolism were observed. Long-term therapy did not alter body-fat distribution or blood pressure.
Long-term therapy in this group of children appears safe but the small increment in final height, approximately 2.8 cm in boys and 2.5 cm in girls, does not justify the widespread use of r-hGH for short normal children.
There are few data on the long-term outcome of growth-hormone treatment in short normal children. We assessed the impact of growth-hormone treatment on pubertal development and near-final height in girls.
In a randomised controlled trial, we studied ten girls, with a mean age of 8.07 years and height 2 SDs or more below the mean for their age, and eight short untreated controls matched for age, and 20 short untreated girls who did not give consent for randomisation. The girls received either 30 IU/m2 somatropin per week as daily subcutaneous injections or no treatment. We assessed pubertal staging and height gain every 6 months.
Eight treated girls completed a mean of 6.2 years' therapy. By a mean age of 16.4 years, their mean height SD score had changed significantly from -2.42 to -1.14 (p=0.008) and they were, on average, 7.5 cm taller than the girls in the control group (height SD scores did not change significantly from -2.55) and 6.0 cm taller than the non-consent group. The timing of each pubertal stage, and the age and amplitude of peak height velocity were similar for all groups.
Growth-hormone therapy effectively increased height SD score among short normal girls started on treatment in early to mid childhood, with no untoward effect on pubertal progression.
Growth hormone therapy for short stature: pan-acea or Pandora's box? For personal use only. No other uses without permission
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Allen DB, Fost NC. Growth hormone therapy for short stature: pan-acea or Pandora's box? J Pediatr 1990;117:16-21. The New England Journal of Medicine Downloaded from nejm.org at UNC CHARLOTTE on July 30, 2013. For personal use only. No other uses without permission. Copyright © 1999 Massachusetts Medical Society. All rights reserved.
Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards Physical growth: National Center for Health Statistics percentiles
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