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Journal of Endocrinology & Metabolism

Review

Volume 7, Number 2, April 2017, pages 45-54

The Effect of Growth Hormone Treatment on Adult Height of Children With Idiopathic Short Stature: A Systematic Review and Meta-Analyses

Growth hormone which is secreted from hypophysis due to proteins metabolism would increase their biosynthesis in cells which, in turn, increases the number and the dimensions of cells. Furthermore, growth hormone would stimulate growth plate of long bones before maturity. After maturation, these growth plates will become bony, thus the linear growth of bones stops and their diagonal growth will continue. Any kind of disorder in growth hormone secretion would decrease the growth rate and cause growth disorder in children. As a result, height of these children would be lower than the average height of other children of the same age and gender [1-3]. According to the reports of UNISEF regarding nourishment in 2013, approximately one child of every four children less than 5 years of age suffer from short stature in the world, 3.4% of which are living in Africa and South Asia. Further, in this report, Iran was among no data countries [4]. Short stature is classified into three main groups: initial growth disorder (regarding growth plate), secondary growth disorder (changes in the growth plate physiology), and the third group for which there is no specified reason, i.e. idiopathic short stature (ISS) [5]. ISS is predicated upon the assumption that the child’s height is more than two standard deviation (SD) scores below the average height of children of the same age and gender on the condition that he/she has no systematic, trophic, or chromosomal disorder [6, 7]. It is estimated that approximately 80% of children were diagnosed with ISS [8]. Although growth hormone treatment increases the height growth rate, there is disagreement over its use for the treatment of ISS and how much it can increase the height [9-12]. In this regard, many studies have been conducted throughout the world; accordingly, the purpose of this study was to conduct a meta-analysis in order to bring all documents together and arrive at a more accurate conclusion as to the effectiveness of growth hormone treatment among children with ISS.

The present study was a systematic review and meta-analysis and has been conducted based on PRISMA guideline that reviewed articles and theses investigating the effect of growth hormone treatment on children diagnosed with ISS from 1995 to March 2016 [13]. Articles were collected through using mesh keywords from external databases including Web of science, Pubmed, Cochran, Medline, Embase, Springer, Scopus, and Science Direct. Also, Google scholars search engine was utilized. Moreover, searching was carried out using keywords such as “growth hormone”, “final height”, “adult height”, and “idiopathic short stature” and their Persian equivalents using “and” and “or” conjunctions. In addition, a list of related articles was also utilized for finding articles.

In the current study, main inclusion criteria for the studies were initial short stature, defined as height more than 2 SD scores below the mean; peak growth hormone responses greater than 10 μg/L; prepubertal stage; no previous growth hormone therapy; and no comorbid conditions that would impair growth, such as chromosomal abnormalities, bone diseases, chronic diseases interfering with growth, treatment with steroids or sex steroids, and dysmorphic syndromes. Adult height was considered achieved when growth rate was < 1.5 cm/year or bone age was 15 years in females and 16 years in males [14].

Exclusion criteria included: 1) exclusion of studies not involving children with ISS; 2) non-random sample size; 3) unrelated topics; 4) insufficient data; 5) lack of required information and unavailability of the full text of the studies; and 6) studies with low quality. In order to reduce tropism, searching and data extraction were carried out by two researchers independently.

Study selection was carried out by two reviewers independently. At first, duplicate studies were removed and studies’ abstracts were investigated; then, if related, they were included. Finally, the full texts of the remained articles were read and if unrelated they were excluded. Following that, randomized controlled trials and cohort studies in which SD and 95% CI were reported were included in the meta-analysis.

In order for decreasing bias and error in data gathering, data extraction was done by two researchers independently using data extraction form (author name, publication year, country, continent, number of participants, average treatment start age, SD of treatment start age, mean score of treatment start height, SD of treatment start height, amount of consumed dose, mean score of treatment duration, SD of treatment duration, estimation of final adult height, SD of final adult height and P-value). If articles were available, special questions or ambiguities about the data were asked from the author through email. Each of researchers compared the extracted data and any conflict as to the data was discussed in the presence of a third party as a consultant in order to come to an agreement.

Mean, SD and z-score of height before and after treatment were defined as effects size. Z-score was computed using normal distribution. Standard mean difference (SMD) for each study was computed. To pool effects size (ES) or SMD among studies, random effects models were used. Heterogeneity of studies was checked using Q and I² statistics and meta-regression. We considered a mean difference in adult height of more than 0.9 SD scores (about 6 cm) as a satisfactory response to growth hormone therapy [13]. Subgroup analysis was done according to the dose of growth hormone and duration of treatment. Publication bias was checked with funnel plot and Egger test. A P-value < 0.05 was considered as significance level. Data were analyzed using STATA software, Ver. 11.

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, 15-32]).

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Figure 1. The flowchart stages of entering the articles into meta-analysis.

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Table 1. Characteristics of Studies Qualified for Meta-Analysis Review

Generally, there were 20 related studies including four studies of cohort type with an SMD of 11.34 (95% CI: 10.48 - 12.20) for treatment start age, six clinical trial studies without a control group with an SMD of 9.73 (95% CI: 8.84 - 10.63) for treatment start age, seven non-random clinical trial studies with a control group and an SMD of 10.63 (95% CI: 9.83 - 11.48) for treatment start age, and three random clinical trial studies with a group and an SMD of 10.07 (95% CI: 5.90 - 14.25). After combining studies using random effects model, SMD at treatment start age was 10.42 years (95% CI: 9.90 - 11.24) (Fig. 2).

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Figure 2. Mean score of participants’ treatment start age.

There were four cohort studies with an SMD of -1.24 (95% CI: -1.69 to -0.79) for treatment start height, six clinical trial studies without a control group with an SMD of -1.83 (95% CI: -2.70 to -0.97), seven non-random clinical trial studies with a control group and an SMD of -1.70 (95% CI: -2.01 to -1.40) for treatment start height, and three random clinical trial studies without a control group with an SMD of -1.62 (95% CI: -1.82 to -1.41) for treatment start height. When results of studies were combined using random effects model, SMD for treatment start height was -1.64 (95% CI: -2.01 to -1.28) which is equal to 5% (their height was higher than 5% of participants) (Fig. 3).

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Figure 3. Mean score of height before treatment start.

It has been indicated that the standardized mean score of height in the three cohort studies was 0.11 (95% CI: 0.08 - 0.14), the standardized mean score of height in the six clinical trial studies without control group was 0.06 (95% CI: 0.05 - 0.07), standardized mean score of height in the seven non-random clinical trial studies with a control group was 0.19 (95% CI: 0.07 - 0.32), and the standardized mean score of height in the three random clinical trial studies with a control group was 0.17 (95% CI: 0.01 - 0.33). Generally, after combining studies through random effects model, the standardized mean score of height after treatment was estimated to be 0.11 (95% CI: 0.07 - 0.14) which is equivalent to 54.38% (mean score of their height came out to be than 54% of participants) (Fig. 4).

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Figure 4. Mean score of height after treatment.

Before treatment, percentile of children’s height according to mean of SD (MSD) was obtained to be -1.64 (95% CI: -2.01 to -1.28) that was equal to 5%. In the same way, after treatment according to MSD, percentile of children’s height came out to be 0.11 (95% CI: 0.07 - 0.14) that was equal to 54.38%. This shows that increase in the percentile of children’s height is due to treatment with growth hormone.

Therefore, through combining the results of all studies, the mean score of participants’ height before treatment was higher than 5% of participants; however, after treatment, 54% of participants grew taller, so in the absence of treatment, it is expected to remain at the same 5%.

Differences in the mean score of adult height after treatment with growth hormone was reported to be more than 1.4 SD score (about 7.6 cm).

In addition, heterogeneity of studies was, totally, 60.2% which is considered as moderate heterogeneity which is significant with a P-value of 0.000.

Treatment duration has been classified into three groups. SMD among persons whose treatment duration was 4 years or less was reported to be 0.12 (95% CI: 0.10 - 0.14), it was 0.06 (95% CI: 0.05 - 0.07) in persons whose treatment duration was 4 - 6 years, and finally among those with a treatment duration of 6 years or more was 0.08 (95% CI: 0.00 - 0.15). Generally, according to the combination of studies through random effect model, SMD for height was calculated to be 0.11 (95% CI: 0.07 - 0.15) which is equivalent to 54.38% (Fig. 5).

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Figure 5. The effect of treatment duration on the final height.

Received doses are divided into two classes. SMD in persons receiving doses less than 0.04 mg/kg/day was 0.12 (95% CI: 0.10 - 0.14) and among person receiving doses more than 0.04 mg/kg/day was 0.06 (95% CI: 0.05 - 0.07) (Fig. 6).

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Figure 6. The effect of received dose on the final height increase.

The longer the treatment duration, the more the mean score of height, but this increase is not statistically significant (P > 0.05) (Fig. 7).

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Figure 7. Relationship between treatment duration and final height increase.

Treatment with growth hormone has had an incremental effect on the final height; however, the relationship between height increase and increasing the consumed dose was statistically insignificant (P > 0.05) (Fig. 8).

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Figure 8. Relationship between the consumed dose and increase in final height.

This plot was used to check publication bias and showed that the effect of publication bias was not significant with a P-value more than 0.05 (Fig. 9).

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Figure 9. Begg’s funnel plot.

In this meta-analysis study, there were 20 clinical trial studies investigating the effect of growth hormone on the adult height of children with ISS. It was attempted to select only studies with high quality. Results of the current study indicated that before treatment, SMD for height was -1.64 (95% CI: -2.01 to -1.28) which was equal to 5% and after treatment SMD for height increased to 0.11 (95% CI: 0.07 - 0.14) which is equal to 54.38%. The obtained mean difference for adult height after treatment with growth hormone was estimated to be approximately equal to SD score (about 6.7 cm) while according to a meta-analysis conducted by Deodati et al [14], mean difference for adult height after treatment with growth hormone was equal to SD score (0.57 - 0.70 (3.4 - 4.2 cm)); therefore, the differences between the results of the current study and Deodati’s study indicate that SMD for adult height has increased due to growth hormone as compared to before treatment.

Most of studies were clinical trial studies and results of these studies are more reliable. In the current study, analysis was carried out according to cohort and clinical trial classification of studies and SMD for height has been calculated for each group. Then, random effect model was utilized to combine the studies and overall results were also estimated. Just studies of high quality and weight were included in the meta-analysis. Throughout all process of meta-analysis heterogeneity was estimated.

The most important limitation of this study was the heterogeneity of the population understudy. Some studies were excluded because the reason of low height was not specified. Further, there were some studies that had a small sample size; in such studies, the existence of bias is more probable. It was impossible to accomplish searching process through combined use of keywords in external and internal data bases. Many studies were excluded due to insufficient epidemiologic information.

The present meta-analysis contained cohort, randomized controlled trials and non-randomized controlled trials studies of growth hormone therapy. Growth hormone can be influential in increasing the adult height of children with ISS up to the achievement of adult height in children with ISS.

Acknowledgments

The authors gratefully acknowledge the Research Council of Ilam University of Medical Sciences for the financial support.

Conflicts of Interest

There are no conflicts of interest.

Funding Source

Vice-chancellor of Ilam University of Medical Sciences supports the funding of this work.

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