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Effect of Growth Hormone Therapy on Height in Children With Idiopathic Short Stature
A Meta-analysis
Beth S. Finkelstein, PhD;
Thomas F. Imperiale, MD;
Theodore Speroff, PhD;
Ursula Marrero, MSSA;
Deborah J. Radcliffe, PhD;
Leona Cuttler, MD
Arch Pediatr Adolesc Med. 2002;156:230-240.
ABSTRACT
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Context Use of growth hormone (GH) therapy to promote growth in children with
idiopathic short stature is controversial. A fundamental issue underlying
the controversy is uncertainty about the magnitude of effectiveness of GH
for this condition.
Objective To determine the effect of GH on short- and long-term growth in idiopathic
short stature.
Study Design Systematic review of controlled and uncontrolled studies.
Data Sources MEDLINE (1985-2000), key journals, cross-referencing of bibliographies,
abstract booklets, and experts.
Study Selection and Data Extraction We performed a meta-analysis of all studies satisfying the inclusion
criteria for idiopathic short stature: initial height below the 10th percentile,
normal stimulated GH levels (>10 µg/L), absence of comorbid conditions,
no previous GH therapy, treatment with biosynthetic GH, and inclusion of major
outcome measures.
Primary Outcome Measures Growth velocity and height SD score (number of SDs from mean height
for age and sex) at baseline and after 1 year to evaluate the short-term effect
of GH. Adult height was analyzed to evaluate the long-term effect of GH.
Data Synthesis Ten controlled trials (434 patients) and 28 uncontrolled trials (655
patients) met the inclusion criteria. While baseline growth velocities were
equivalent at baseline, 1-year growth velocity of the GH-treated group significantly
exceeded that of controls by 2.86 cm/y. Similarly, in uncontrolled trials,
growth velocity increased after 1 year, and height SD score increased from -2.72
at baseline to -2.19. In controlled studies, the adult height of the
GH-treated group significantly exceeded controls by 0.84 SD, and in uncontrolled
trials the adult height attained after GH treatment (-1.62 SDs) exceeded
that predicted at baseline (-2.18 SDs). These results suggest an average
gain in adult height of approximately 4 to 6 cm (range, 2.3-8.7 cm) with GH
therapy. Given current treatment costs, this corresponds to more than $35 000
per inch (2.54 cm) gained in adult height in idiopathic short stature.
Conclusions Treatment with GH results in short-term increases in growth for children
with idiopathic short stature, and long-term GH can increase adult height.
These results are fundamental to decisions about GH use and raise questions
about the goals of treatment. Use of GH for idiopathic short stature in clinical
practice will depend on its efficacy in promoting growth and the value of
this effect to families, physicians, and third-party payers.
INTRODUCTION
THE USE of biosynthetic growth hormone (GH) to treat children with idiopathic,
familial, or constitutional short stature (hereafter referred to as idiopathic short stature) is controversial. There is ongoing
debate among the medical community, third-party payers, and families of affected
children about the appropriateness and effectiveness of treatment.1-17
More than 1 million children in the United States are potential candidates
for GH treatment2, 18 and are thus
affected by decisions about GH use. Corresponding annual expenditures for
GH potentially range from $196 million to $18 billion, depending on the criteria
for treatment.2 Although historically reserved
and approved by the Food and Drug Administration for treatment of short stature
in children with classic GH deficiency, Turner syndrome, renal failure, or
Prader-Willi syndrome, GH therapy has been suggested for many other conditions
(including idiopathic short stature),7, 10-11,19-23
and the literature13, 24 suggests
that its use in such children is expanding.
Children with idiopathic short stature constitute the largest population
of potential pediatric candidates for GH. For this reason, together with controversy
about the distinction between disorder and the bounds of natural variation,
idiopathic short stature represents a major threshold in the expansion of
nontraditional use of GH. Despite several studies, the effectiveness of GH
in increasing growth for children with idiopathic short stature is not clear.
Interpretation of the literature has been hampered by studies involving small
numbers of participants, variation in outcome measures (eg, short term vs
long term and height vs growth velocity), differing treatment effects reported,
and absence of structured synthesis of data.13, 16, 24-30
In addition, ethical and practical issues, such as long-term daily injections
of placebo to children, have made randomized controlled trials of GH challenging.31-32
The lack of clear data on effectiveness of GH therapy in idiopathic
short stature is particularly important. Differing perceptions of GH effectiveness
result in marked variation among physicians about recommending GH therapy,
and there are striking inconsistencies among third-party payer policies for
coverage of GH.2, 14, 23
This variation, together with the controversies surrounding GH use, the vast
number of children affected by decisions about GH, and the high cost of treatment,
underscores the importance of quantifying the short- and long-term effects
of biosynthetic GH therapy on growth in idiopathic short stature.10, 13, 16-17,24-25,33
Previous reviews11, 13, 20
have primarily been narrative, without structured synthesis and quantitative
combination of results. Recent articles call for such outcome data, including
structured synthesis of the existing literature, to provide clearer guidance
on GH use and to form the foundation for dialogue among physicians, families,
and policy makers.10, 17, 34-35
The goal of this study, therefore, was to perform a systematic review of the
contemporary literature on GH treatment of idiopathic short stature in children
to quantify the effects of GH on short- and long-term growth.
MATERIALS AND METHODS
A computerized literature search using MEDLINE was conducted to identify
all published articles from 1985 to 2000 on treatment of children with biosynthetic
GH. (Biosynthetic GH became widely available and supplanted pituitary GH for
patients in 1985, the first year in which it was approved by the Food and
Drug Administration for children lacking adequate endogenous GH.) The search
terms used were (growth hormone or somatotropin or somatropin or somatrem)
+ (therapy or treatment) + (growth or height) + (child or adolescent), limited
to the English language. In addition, manual searches of 4 journals (JAMA: the Journal of the American Medical Association, The Journal of Pediatrics, Pediatrics, and Acta Paediatrica) from 1996 to 2000
were conducted, and meeting abstract books in these journals were reviewed
as well as those of the Lawson Wilkins Pediatric Endocrine Society and the
Endocrine Society. Bibliographic references from all retrieved articles also
were reviewed. Pharmaceutical companies were contacted. To ensure complete
collection of data and to avoid inadvertent exclusion of negative results,
external experts reviewed the list of eligible studies.
STUDY SELECTION
Two reviewers (B.S.F. and U.M.) screened all citation abstracts obtained
from the literature and manual searches (n = 1823) to determine whether each
study met basic criteria for further in-depth review (ie, primary studies
of GH use in children). For all abstracts meeting these basic criteria (n
= 761), the published article was retrieved for further review.
Three reviewers then conducted detailed assessments of each article
to identify all those appropriate for inclusion in the systematic review.
The reviewers independently assessed descriptive information about each study
using a standardized abstraction form, then met to review each study's appropriateness
for inclusion. Before discussion, there was 92% agreement regarding study
inclusion and exclusion, and after discussion, there was 100% agreement. Articles
were included if (1) the topic was short stature (height below the 10th percentile
for age); (2) the children presented as GH-naive patients (ie, no previous
GH treatment) and had an absence of classic GH deficiency (peak GH levels 10
µg/L on 1 standard stimulation tests)1, 10, 24, 36-37;
(3) there was an absence of comorbid conditions that impair growth (such as
Turner syndrome, renal failure, intrauterine growth retardation, and GH insensitivity)
or, as in 2 studies,38-39 if raw
data were available to enable reanalyses without such patients; (4) the treatment
was biosynthetic (not pituitary-derived) GH in the range of 0.14 to 0.40 mg/kg
per week1, 10-11,40-44
for a minimum of 6 months (studies using pituitary-derived GH may not be directly
applicable to current treatment regimens because biosynthetic GH has been
available only since 1985, and questions about equivalence in potency and
dosing would limit interpretation of results); (5) the study contained at
least 5 patients; (6) patients did not have previous treatment with sex steroids
or anabolic agents potentially affecting growth; (7) the last outcome data
for analysis were obtained on a minimum of 50% of the original subjects; and
(8) the study presented primary data and included appropriate height outcome
measures (growth velocity [in centimeters or inches per unit time] or height
[SD score; height Z score]). Of the 761 studies reviewed, 53 qualified for
inclusion. More than 90% of excluded studies either included comorbid conditions
or lacked primary data.
DATA ABSTRACTION
Abstraction of primary data was performed independently by 3 reviewers
using a standardized form. Data abstracted were sample size, mean age, sex
distribution, study design (controlled or uncontrolled trial), baseline pubertal
status, growth variables (ie, height, growth velocity, and predicted adult
height), and growth outcome measures (height, growth velocity, and adult height
[defined in the articles as advanced bone age (>16 years in boys and >14 years
in girls) and/or slowing of growth rate (0.5-2.0 cm/y)]). Height was expressed
as the mean height SD score (ie, number of SDs from the mean height for age
and sex). The Tanner-Whitehouse or the Bayley-Pinneau method was used to predict
adult height in all articles reporting this growth variable.45-46
For 5 studies in which data were stratified by covariates that were not of
primary importance to the analysis (eg, age or sex), we combined strata weighted
by sample size. Authors were contacted to clarify questions about published
and unpublished data. The 3 reviewers discussed each article to reach consensus
on abstracted data. If a series of related articles was published from a single
trial or study group (as occurred in 6 trials), each article was reviewed,
although only one data abstraction form was used to avoid overrepresenting
a single study population.
STATISTICAL ANALYSIS
We analyzed controlled trials and uncontrolled trials separately.47-49 Statistical testing
for homogeneity was performed for each planned meta-analysis.50
Based on the results of this testing and clinical variation realized during
data abstraction, a random-effects model was used to combine data for all
outcomes.50 In combining data across studies,
we weighted studies by the reciprocal of their SE and expressed results as
pooled estimates with 95% confidence intervals (CIs).47-48
For controlled trials, weighted mean pooled
differences between treated and control groups were calculated for each growth
variable (eg, growth velocity and height SD score) at baseline and at time
points representing short (1-year) and long-term (adult height) outcomes.
For uncontrolled trials, weighted mean pooled estimates
for each growth variable before and after treatment were calculated. Growth
data for controlled trials were therefore reported primarily as differences
between treatment and control groups, whereas data for uncontrolled studies
are reported primarily as the mean for the single group under study.
Because all studies did not report all outcome measures, we performed
2 main types of analyses for each growth variable. First, we calculated a
pooled estimate across all studies reporting each growth variable (eg, in
assessing baseline growth velocity in controlled studies, we pooled the differences
in growth velocities between treatment and control groups across all 8 studies
reporting this measure), subsequently referred to as an "aggregate analysis."
Second, we limited pooling of the baseline growth variable to the subgroup
of studies that also reported the variable as an outcome (eg, for growth velocity
in controlled trials, we pooled only the 6 studies reporting this measure
at baseline and after 1 year); this second method yields a more direct comparison
between baseline and the major postintervention periods and is subsequently
referred to as a "paired analysis."
To assess the robustness of the results, several additional analyses
were conducted, including analyses of the subgroup of controlled studies that
were randomized; paired analyses in which only studies reporting baseline
and outcome measures for each growth variable were included; and analyses
of within-group (ie, treatment or control) changes in growth variables from
baseline to follow-up, using the SDs for the pretreatment and posttreatment
phases and their correlations, which were estimated from available data. For
calculation of the latter correlations, we used the following formula:
 ,
where Var(x - y)
is the variance for the change between the pretreatment and posttreatment
periods, Var(x) is the variance for the baseline
period and SD(x) is the SD, Var(y) is the variance for the posttreatment period and SD(y) is the SD, and r is the correlation between
the pretreatment and posttreatment values. For controlled and uncontrolled
trials, we also determined that the aggregate (or pooled) results were robust
by omitting the study with the largest sample size (and, separately, the study
with the most extreme results) and then recalculating the effect size.
RESULTS
Ten controlled trials (reported in 19 separate articles) and 28 uncontrolled
trials (reported in 34 separate articles) met the inclusion criteria for meta-analysis
of GH treatment of idiopathic short stature.
CONTROLLED TRIALS
The 10 controlled trials involved a total of 434 children; 6 were randomized
controlled trials39, 51-56
(239 children) and 4 were nonrandomized57-68
(195 children) (Table 1). There
was little or no information about the method of randomization or masking.
Baseline data for demographic variables were similar for the treatment and
control groups. The weighted pooled estimate for age at baseline was 10.1
± 0.6 years in the treatment group and 9.8 ± 0.7 years in the
control group. Growth variables reported in each of the studies are given
in Table 1.
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Table 1. Controlled Trials of GH Therapy in Idiopathic Short Stature:
Study Characteristics*
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Table 2 gives the results
of the meta-analysis for controlled studies of idiopathic short stature. The
short-term (1-year) effects of GH treatment on growth velocity and height
SD score were assessed, as were the long-term effects of GH on adult height;
these are the primary outcome measures. Results for each growth variable are
expressed as the pooled estimate of the difference between the treatment and
control groups.
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Table 2. Results of Meta-analysis for Controlled Trials of GH Therapy in Idiopathic Short Stature*
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Effect of Short-term (1-Year) GH Therapy on Growth Velocity
Baseline pretreatment growth velocities of treatment and vcontrol groups
were equivalent (pooled difference between treatment and control groups: -0.05
± 0.15 cm/y; Table 2),
with respective mean baseline growth rates of 4.22 ± 0.21 and 4.30
± 0.25 cm/y. Similarly, for the 6 studies reporting baseline and 1-year
growth velocity, growth velocity at baseline was equal in treatment and control
groups (pooled difference of 0.08 ± 0.14 cm/y; Table 2).
After 1 year, however, growth velocity was significantly greater in
the GH-treated group than in controls; the pooled estimate for the difference
in growth velocity between the 2 groups was 2.86 ± 0.37 cm/y (Table 2). As shown in Figure 1, there was consistency among individual studies. In the
2 studies reporting data after 2 years of GH use, growth velocity in the treatment
group remained greater than in controls (pooled difference between treatment
and control groups, 2.36 ± 0.36 cm/y).
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Figure 1. Results of individual controlled
trials of growth hormone therapy for idiopathic short stature included in
the meta-analysis. A, Mean ± SE difference in growth velocity between
treatment and control groups at baseline and after 1 year. B, Mean difference
in height SD scores between treatment and control groups for predicted adult
height (at baseline) and achieved adult height. Asterisk indicates that no
measure of variation was provided for predicted adult height in this study;
therefore, it was not included in the analysis of differences between treatment
and control groups.
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Meta-analysis of the randomized controlled trials was consistent with
that for all controlled trials. For the subset of 5 randomized studies reporting
baseline and 1-year outcome data, the difference in growth velocity between
treatment and control groups was not significant at baseline (-0.08
cm/y [95% CI, -0.44 to 0.28]); however, after 1 year, the growth velocity
of the GH-treated group exceeded that of controls by 2.53 cm/y (95% CI, 1.72-3.35).
In addition to the primary analyses comparing differences between treatment
and control groups, we also assessed the change in growth velocity from baseline
to 1 year. For the GH-treated group, the pooled change in growth velocity
from baseline to 1 year was 3.63 ± 0.32 cm/y (95% CI, 3.00-4.25 cm/y),
whereas for the control group, the change in growth velocity was only 0.93
± 0.35 cm/y (95% CI, 0.25-1.62 cm/y). These results indicate that the
GH-treated group experienced a significantly greater increment in growth velocity,
and they are consistent with the analyses of the aggregate data, paired data,
and randomized trials.
Effect of Short-term (1-Year) GH Therapy on Height SD Score
At baseline, the mean SD scores for height in the treatment and control
groups were equivalent (difference between treatment and control groups =
0.02 SD; 9 studies [One article that otherwise met entry criteria was not
included in this analysis because of a significant difference between baseline
height SD scores in the treatment and control groups.]) (Table 2), and were similar for the 2 paired randomized controlled
studies with 1-year data. However, after 1 year, the height of the GH-treated
group exceeded that of the control group by 0.60 SD (Table 2).
Effect of GH Therapy on Adult Height
Four controlled trials reported data on adult height. The mean duration
of treatment was 5.3 years. At baseline, the mean height SD scores for GH-treated
and control groups were equivalent. However, the adult height achieved by
the GH-treated group significantly exceeded that of controls, with a weighted
aggregate difference in height between treatment and control groups of 0.84
SD (Table 2). In the GH-treated
group, the pooled estimate for adult height was -1.51 SDs (95% CI, -1.70
to -1.32 SDs), whereas in the control group, adult height was significantly
shorter at -2.29 SDs (95% CI, -2.63 to -1.96 SDs). (Some
articles assess the effect of GH by comparing height SD score at baseline
with that in adulthood. We did not use this approach because the current data
and previous work24, 63, 69
indicate that the adult height SD score often exceeds that in childhood, even
for children with idiopathic short stature who do not receive GH.) Similarly,
for the group of studies with paired data, adult height in the treated group
exceeded that in controls by 0.78 SD (Table
2). Based on the US population,18
these data indicate an average difference in adult height between treatment
and control groups of 5 to 6 cm (range, 2.3-8.7 cm).
In addition to comparing adult height of GH-treated and control groups,
we also compared adult height achieved with that predicted at baseline. Data
for individual studies are shown in Figure
1B, and results of the meta-analyses are given in Table 2. For the aggregate analysis, pooled predicted adult height
was similar but not identical in treatment and control groups (-1.76
± 0.08 and -2.01 ± 0.14 SDs, respectively), so that the
GH-treated group was predicted to be approximately 0.3 SDs taller than the
control group as adults (Table 2).
However, for the 3 paired studies reporting predicted and achieved adult heights,
the baseline predictions for treatment and control groups were similar (-1.73
± 0.10 and -1.85 ± 0.13 SDs, respectively), and the pooled
difference in predicted adult height SD score was 0.13 (Table 2). Yet, the GH-treated group reached adult heights that were
0.78 SD greater than controls, as described in the previous paragraph. These
data suggest that the adult height achieved by the GH-treated group exceeds
that predicted at baseline by 0.54 SD (aggregate data) to 0.65 SD (paired
data), or 3.6 to 4.6 cm.
UNCONTROLLED TRIALS
Twenty-eight uncontrolled trials of GH therapy for idiopathic short
stature (reported in 34 published articles and involving 655 children)26, 29, 38, 70-100
met the entry criteria (Table 3). The pooled mean age of the patients was 10.8 ± 0.4 years. The proportion
of males ranged from 0% to 100%, with a mean of 71%. Figure 2 shows the results of individual trials included in the
meta-analysis. Table 4 gives the
results of the meta-analysis.
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Table 3. Uncontrolled Trials of GH Therapy
in Idiopathic Short Stature: Study Characteristics*
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Figure 2. Results of individual uncontrolled
trials of growth hormone therapy for idiopathic short stature included in
the meta-analysis. For a complete listing of author names, reference citation,
and study year, see Table 3. A,
Mean ± SE growth velocity at baseline and after 1 year. Asterisk indicates
that this study addressed the effect of growth hormone treatment in older
children during the decelerating phase of the pubertal growth spurt. B, Mean
adult height SD scores predicted at baseline and achieved.
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Table 4. Results of Meta-analysis for Uncontrolled Trials of GH Therapy in Idiopathic Short Stature*
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Effect of Short-Term (1-Year) GH Therapy on Growth Velocity
The pooled estimate of baseline growth velocity was 4.29 ± 0.15
cm/y for the 21 studies reporting this measure (Table 4). In the paired analysis of 14 studies reporting baseline
and 1-year data, growth velocity was the same at baseline and rose significantly
to 7.57 ± 0.30 cm/y after 1 year of GH treatment; the increase in growth
velocity after 1 year of GH use in uncontrolled trials is similar to the difference
in growth rates between treated and untreated groups in controlled studies.
Results were similar for the 5 studies in which all patients were prepubertal
at baseline and at 1-year follow-up. With continued GH treatment, growth velocity
was 7.54 ± 0.17 and 5.81 ± 1.42 cm/y during the second and third
years of treatment, respectively (2 studies for each year).
Effect of Short-term GH Therapy on Height SD Score
At baseline, the height SD score for 25 studies was -2.72. In
the 10 studies reporting baseline and 1-year data, the height SD score at
baseline was similar (-2.62), and it increased significantly to -2.19
after 1 year of GH (Table 4).
After 2 and 3 years of treatment, the mean SD scores for height were -1.99
(4 studies) and -1.77 (6 studies), respectively (Figure 3).
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Figure 3. Mean height SD scores (and 95%
confidence intervals) at baseline and after 1 to 3 years of growth hormone
treatment. These meta-analyses data are pooled from all qualifying uncontrolled
trials of growth hormone therapy in idiopathic short stature.
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Effect of Long-term GH Therapy on Adult Height
In uncontrolled trials, the assessment of effect of GH on adult height
was based on comparison of adult height achieved with that predicted at baseline
(individual trial data are shown in Figure
2; the meta-analysis data are given in Table 4). The mean duration of treatment was 4.7 years. At baseline,
the mean predicted adult height was -2.18 SDs; in the aggregate analysis,
after GH treatment, the adult height attained was significantly greater at -1.62
SDs (Table 4). Results for the
paired analyses (n = 6) were similar, with predicted adult height at baseline
of -2.25 SDs, whereas the height actually achieved after GH therapy
was greater at -1.62 SDs (Table 4). The data suggest a difference of 0.56 to 0.63 SD, or 3.8 to 4.5
cm, between predicted height before GH therapy and attained height after GH
therapy. These results are similar to those for the controlled trials. We
reanalyzed the data with omission of the trials with largest sample size or
largest effect size, and the results were unchanged.
COMMENT
A fundamental issue in the debate about GH treatment for idiopathic
short stature is uncertainty about its degree of effectiveness in promoting
growth.3, 10, 13-16,25, 37, 40
This meta-analysis shows that 1 year of GH therapy causes a clear increase
in growth velocity and suggests that long-term GH therapy increases adult
height in children with idiopathic short stature. The adult height achieved
by GH-treated individuals exceeded that of untreated controls by 0.78 to 0.84
SD. Similarly, comparisons of predicted and achieved adult height in controlled
and uncontrolled trials show a gain of 0.54 to 0.65 SD. The weight of the
evidence, therefore, indicates that GH treatment increases short-term growth
velocity and can increase adult height in idiopathic short stature.
Limitations of this analysis deserve comment. One potential limitation
of any meta-analysis is pooling studies with heterogeneous populations. However,
the rigorous entry criteria and review procedures for the current analyses
were instituted to exclude studies in which patients had known causes of short
stature. A second potential limitation involves the effect of study dropouts
on the validity of study findings. To minimize this effect, we excluded any
study with a dropout rate of 50% or greater; 27 of 38 qualifying studies for
idiopathic short stature had no dropouts and, of the remainder, the mean dropout
rate was 20%. Nevertheless, there remains the possibility that, particularly
for uncontrolled studies, effects may differ in children lost to follow-up.
A third potential limitation is the use of uncontrolled studies, since unrecognized
variables may affect results. However, in situations in which randomized controlled
studies are limited and the field requires evidence-based analyses, a rigorous
approach including observational studies is indicated.49, 101
We followed guidelines for such meta-analyses, analyzed controlled and uncontrolled
trials separately, and, whenever possible, triangulated conclusions using
both analyses. A fourth potential limitation of any meta-analysis is the "file
drawer" effect, in which studies with negative results might remain unpublished,
tending to bias the published literature toward positive findings. We attempted
to minimize this bias by examining sources of unpublished studies and by having
independent GH experts review the list of studies to ensure that all trials
meeting entry criteriapublished or unpublishedwere included.
The results of these analyses have implications for clinical practice
and health policy. Much of the debate about GH use for children with idiopathic
short stature has centered on whether treatment actually increases adult height.
The current findings indicate that long-term GH treatment can increase adult
height. These results, therefore, suggest that the emphasis and debate shift
to whether the gain in adult height is of sufficient clinical importance and
value to warrant more widespread treatment of short children. In controlled
trials, the average adult height SD score achieved after GH therapy was -1.51
(ie, 166.3 cm for US males and 153.5 cm for US females), whereas that for
untreated controls was -2.29 (ie, 160.7 cm in males and 148.3 cm in
females).18 Similarly, the difference between
adult height of GH-treated and control groups was 0.78 to 0.84 SD, or 5 to
6 cm (range, 2.3-8.7 cm). The difference between predicted and attained height
in controlled and uncontrolled trials of GH (0.54-0.65 SD) similarly suggests
a gain of 4 to 5 cm in adult height from GH therapy.
Practitioners and policy makers now need to address the clinical importance
and value of the height gained in relation to the goals of treatment. Consideration
of additional factors will be important for deciding whether GH should be
used for idiopathic short stature in practice, including the impact of the
height gained on physical and psychosocial well-being, adverse effects, cost
of therapy, patients' expectations and values, and ethical considerations.*
To date, adverse effects of GH (including fluid retention, benign intracranial
hypertension, insulin resistance, and growth of nevi10, 108-109)
have been reported in a few patients, and long-term surveillance is ongoing.
In the trials included in the current analyses, mild increases in serum insulin
levels and/or the presence of GH antibodies were occasionally reported.56, 60, 63, 96 Although
a full economic analysis is beyond the scope of this article, cost and resource
allocation have been core concerns for GH treatment; a gain of 4 to 6 cm in
adult height, together with an average of 5 years of GH therapy beginning
at age 10 years, and prices of $11 000 to $18 000/y as the child
grows,2, 25, 110 corresponds
to more than $35 000 per 2.54 cm gained. The ethical issues are also
significant.6, 10, 13
Short stature may be seen as disabling, and taller stature may be associated
with improved quality of life102-107;
in this sense, treatment of idiopathic short stature may be considered appropriate,
particularly with difficulty reaching consensus on clinical and/or biochemical
criteria for GH use. Alternatively, GH treatment may be considered inappropriate
for short, otherwise healthy children.
The data on short-term effects of GH in idiopathic short stature also
are relevant for practice. The increase in growth velocity observed during
the first year of GH treatment raises questions about the practical application
of 6- to 12-month therapeutic trials of GH in individual patients as a method
to determine their need for long-term GH therapy1, 8-9,25, 110
because even the lower end of the observed range for growth velocity exceeds
many recommended thresholds for considering such trials successful.
In a separate meta-analysis, we found in children with classic GH deficiency
that growth velocity increased from 3.61 ± 0.12 cm/y at baseline to
9.77 ± 0.18 cm/y after 1 year of GH treatment and that height increased
from -3.47 ± 0.31 SDs to -2.51 ± 0.11 SDs during
that time, confirming earlier results in this population.111-112
Although it may be tempting to consider growth velocity after 1 year of treatment
in GH deficiency as exceeding that for idiopathic short stature (and therefore
capable of differentiating the 2 conditions), this is not warranted because
the data are based on separate studies rather than on direct comparisons of
GH effectiveness for the conditions.
This analysis has also illuminated gaps in the literature that can affect
interpretation of data on the effectiveness of GH therapy and suggests areas
for future research. First, standardization of reporting requirements for
clinical studies of GH treatment (eg, inclusion of predicted and midparental
heights, baseline and outcome growth velocity, and height SDs) would enhance
the clarity of results for clinicians and researchers. Second, although we
used standard definitions of classic GH deficiency and idiopathic short stature,1, 10, 16, 24, 36-37,113
few studies meeting the entry criteria also reported supplemental or alternative
methods for assessing GH reserve (eg, insulin-like growth factor I, insulin-like
growth factor binding protein 3, and spontaneous GH secretion)5, 10, 37;
however, such analyses would be useful. Third, although idiopathic short stature
currently describes a group of children with short stature not attributable
to a known disease, future advances may distinguish subgroups with distinct
genetic disturbances or subtle forms of GH deficiency who may respond differentially
to treatment. Fourth, randomized controlled trials of the effect of GH therapy
on adult height would be useful. Although such studies have potential ethical
problems (eg, placebo injections to controls31-32)
and practical hurdles (eg, patient retention), one is under way. Finally,
further research is needed to identify factors that predict long-term responsiveness
to GH therapy in individual patients.
In summary, this analysis addresses the fundamental issue of the effectiveness
of GH for promoting growth in children with idiopathic short stature. The
results indicate that GH therapy augments short- and long-term growth. These
data are necessary to inform clinical decision making and policy. However,
alone they are not sufficient to define the clinical value of treatment. We
believe that the focus of assessment should increasingly shift from efficacy
in promoting growth to effectiveness in promoting health and well-being as
a function of increased growth. Use of GH will ultimately depend on its efficacy
in increasing height, along with the morbidity of the treated and untreated
states, and on the value of the height gain to families, physicians, third-party
payers, and society.
| What This Study Adds
Growth hormone (GH) has been suggested as a potential treatment for
children with idiopathic short stature, a condition affecting many US children.
Its use for idiopathic short stature is highly controversial, in large part
because its efficacy in promoting growth in this condition is not known.
We performed a systematic, meta-analytical review of all controlled
and uncontrolled studies in the literature meeting strict entry criteria to
define the short- and long-term effects of GH in children with idiopathic
short stature. The results indicate that GH has a strong short-term growth-promoting
effect and can increase adult height for this condition. These data provide
evidence of GH efficacy and indicate that GH therapy, on average, increases
adult height by 4 to 6 cm for children with idiopathic short stature. The
results raise fundamental questions about the use of therapeutic trials of
GH and the impact of height gained on well-being.
|
|
AUTHOR INFORMATION
Accepted for publication November 9, 2001.
This work was supported by a grant from the National Institutes of Health,
Bethesda, Md.
This study was presented in part at the annual meeting of the Endocrine
Society, San Diego, Calif, June 1999.
We thank the external expert reviewers, Melvin M. Grumbach, MD, John
Chipman, MD, and John S. Parks, MD, PhD, for reviewing the list of articles
ascertained for analysis and providing helpful suggestions; the authors of
the studies included in this analysis for providing information on request;
and Duncan Neuhauser, PhD, for reviewing the manuscript.
Corresponding author and reprints: Leona Cuttler, MD, Department
of Pediatrics, Rainbow Babies and Children's Hospital, Room 737, Case Western
Reserve University, 11100 Euclid Ave, Cleveland, OH 44106.
From the Departments of Pediatrics (Drs Finkelstein, Radcliffe, and
Cuttler and Ms Marrero) and Pharmacology (Dr Cuttler), Rainbow Babies and
Children's Hospital, Case Western Reserve University, Cleveland, Ohio; the
Divisions of Gastroenterology and General Internal Medicine, Indiana University
Medical Center and Roudebush Veterans Medical Center, Indianapolis (Dr Imperiale);
and the Division of Health Services Research, the Departments of Medicine
and Preventive Medicine, Center for Clinical Improvement, Vanderbilt University
Medical Center, Nashville, Tenn (Dr Speroff). Dr Cuttler has been an invited
symposium speaker, participated in multisite clinical studies, consulted,
or participated in basic science research grants for AstraZeneca Pharmaceuticals,
London, England; Eli Lilly & Co, Indianapolis, Ind; Merck and Co, Rahway,
NJ; Novo Nordisk, Bagsværd, Denmark; Genentech, Inc, South San Francisco,
Calif; Pharmacia & Upjohn, Kalamazoo, Mich; Athersys, Cleveland, Ohio;
and Serono, Norwell, Mass
REFERENCES
 |  |
1. Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrinology
Society. Guidelines for the use of growth hormone in children with short stature. J Pediatr. 1995;127:857-867.
FULL TEXT
|
ISI
| PUBMED
2. Finkelstein BS, Silvers JB, Marrero U, Neuhauser D, Cuttler L. Insurance coverage, physician recommendations, and access to emerging
treatments: growth hormone therapy for childhood short stature. JAMA. 1998;279:663-668.
FREE FULL TEXT
3. van Rikjom J, Leufkens H, Crommelin D, Rutten R, Brockmans A. Assessment of biotechnology drugs: what are the issues? Health Policy. 1999;47:255-274.
FULL TEXT
|
ISI
| PUBMED
4. Silink M. Alternative methods of diagnosis of growth hormone deficiency. J Pediatr Endocrinol. 1992;5:43-52.
5. Rosenfeld RG, Albertsson Wikland K, Cassorla F, et al. Diagnostic controversy: the diagnosis of childhood growth hormone deficiency
revisited. J Clin Endocrinol Metab. 1995;80:1532-1540.
FREE FULL TEXT
6. Lantos J, Siegler M, Cuttler L. Ethical issues in growth hormone therapy. JAMA. 1989;261:1020-1024.
FREE FULL TEXT
7. Bierich JR. Therapy with growth hormoneold and new indications. Horm Res. 1989;32:153-165.
ISI
| PUBMED
8. Frasier SD, Lippe BM. Clinical review 11: the rational use of growth hormone during childhood. J Clin Endocrinol Metab. 1990;71:269-273.
FREE FULL TEXT
9. Underwood LE. Growth hormone therapy for short stature: yes or no? Hosp Pract (Off Ed). 1992;27:192-198.
10. American Academy of Pediatrics. Considerations related to the use of recombinant human growth hormone
in children. Pediatrics. 1997;99:122-129.
FREE FULL TEXT
11. Vance ML, Mauras N. Growth hormone therapy in adults and children. N Engl J Med. 1999;341:1206-1216.
FREE FULL TEXT
12. Weiss R. Are short kids "sick"? Washington Post. 1994;March 15:Z10.
13. Guyda HJ. Use of growth hormone in children with short stature and normal growth
hormone secretion: a growing problem. Trends Endocrinol Metab. 1994;5:334-340.
FULL TEXT
|
ISI
| PUBMED
14. Cuttler L, Silvers JB, Singh J, et al. Short stature and growth hormone therapy: a national survey of physician
recommendation patterns. JAMA. 1996;276:531-537.
FREE FULL TEXT
15. Oberfield SE. Growth hormone use in normal, short childrena plea for reason. N Engl J Med. 1999;340:557-559.
FREE FULL TEXT
16. Hailey JA, Bath LE, Kelnar CJH. Idiopathic short stature: diagnostic and therapeutic dilemmas. Growth Horm Growth Factors. 1999;14:61-65.
17. Brook CG, Kelnar CJH, Betts PR. Which children should receive growth hormone treatment? Arch Dis Child. 2000;83:176-178.
FREE FULL TEXT
18. Najjar MF, Rowland M. Anthropometric Reference Data and Prevalence of Overweight,
United States, 1976-1980. Washington, DC: National Center for Health Statistics; 1987:11.
19. Kamel A, Norgren S, Elimam A, Danielsson P, Marcus C. Effects of growth hormone treatment in obese prepubertal boys. J Clin Endocrinol Metab. 2000;85:1412-1419.
FREE FULL TEXT
20. Tritos NA, Mantzoros CS. Recombinant human growth hormone: old and novel uses. Am J Med. 1998;105:44-57.
FULL TEXT
|
ISI
| PUBMED
21. Lippe BM, Nakamoto JM. Conventional and nonconventional uses of growth hormone. Recent Prog Horm Res. 1993;48:179-223.
22. Neely EK, Rosenfeld RG. Use and abuse of human growth hormone. Annu Rev Med. 1994;45:407-420.
FULL TEXT
|
ISI
| PUBMED
23. Wyatt DT, Mark D, Slyper A. Survey of growth hormone treatment practices by 251 pediatric endocrinologists. J Clin Endocrinol Metab. 1995;80:3292-3297.
ABSTRACT
24. Guyda HJ. Four decades of growth hormone therapy for short children: what have
we achieved? J Clin Endocrinol Metab. 1999;84:4307-4316.
FREE FULL TEXT
25. Bercu BB. The growing conundrum: growth hormone treatment of the non-growth hormone
deficient child. JAMA. 1996;276:567-568.
FREE FULL TEXT
26. Zadik Z, Chalew S, Zung A, et al. Effect of long-term growth hormone therapy on bone age and pubertal
maturation in boys with and without classic growth hormone deficiency. J Pediatr. 1994;125:189-195.
ISI
| PUBMED
27. Kawai M, Momoi T, Yorifuji T, Yamanaka C, Sasaki H, Furusho K. Unfavorable effects of growth hormone therapy on the final height of
boys with short stature not caused by growth hormone deficiency. J Pediatr. 1997;130:205-209.
FULL TEXT
|
ISI
| PUBMED
28. Guyda HJ. Growth hormone therapy for non-growth hormone-deficient children with
short stature. Curr Opin Pediatr. 1998;10:416-421.
PUBMED
29. Loche S, Cambiaso P, Setzu S, et al. Final height after growth hormone therapy in non-growth-hormone-deficient
children with short stature. J Pediatr. 1994;125:196-200.
FULL TEXT
|
ISI
| PUBMED
30. Kaplowitz PB. Effect of growth hormone therapy on final versus predicted height in
short twelve- to sixteen-year-old boys without growth hormone deficiency. J Pediatr. 1995;126:478-480.
FULL TEXT
|
ISI
| PUBMED
31. Friedewald W, Kopelman L. Report of the National Institutes of Health, Human
Growth Hormone Protocol Review Committee. Bethesda, Md: National Institutes of Health; 1992:1-39.
32. Lehrman S. Challenge to growth hormone trial [letter]. Nature. 1993;364:179.
ISI
| PUBMED
33. Taback SP, Guyda HJ, Van-Vliet G. Pharmacological manipulation of height: qualitative review of study
populations and designs. Clin Invest Med. 1999;22:53-59.
ISI
| PUBMED
34. Hindmarsh P. Evidence-based medicine and "GH and growth factors." Growth Horm Growth Factors. 1999;14:31-35.
35. Pliskin JS. Towards better decision making in growth hormone therapy. Horm Res. 1999;51:30-35.
36. Cara JF, Johanson A. Growth hormone for short stature not due to classic growth hormone
deficiency. Pediatr Clin North Am. 1990;37:1229-1254.
ISI
37. Rosenfield RL, Cuttler L. Somatic growth and maturation. In: DeGroot L, Jameson L, eds. Endocrinology.
Philadelphia, Pa: WB Saunders; 2001:477-502.
38. Schwartz ID, Hu CS, Shulman DI, Root AW, Bercu BB. Linear growth response to exogenous growth hormone in children with
short stature. AJDC. 1990;144:1092-1097.
39. Wit JM, Fokker MH, de Muinck Keizer-Schrama SM, Oostdijk W, Gons MH (Dutch Growth Hormone Working Group). Effects of two years of methionyl growth hormone therapy in two dosage
regimens in prepubertal children with short stature, subnormal growth rate,
and normal growth hormone response to secretagogues. J Pediatr. 1989;115:720-725.
FULL TEXT
|
ISI
| PUBMED
40. Parks JS. Hypopituitarism. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson
Textbook of Pediatrics. Philadelphia, Pa: WB Saunders; 2000:1675-1680.
41. MacGillivray MH, Blethen SL, Buchlis JG, Clopper RR, Sandberg DE, Conboy TA. Current dosing of growth hormone in children with growth hormone deficiency:
how physiologic? Pediatrics. 1998;102:527-530.
FREE FULL TEXT
42. Yokoya S, Araki K, Igarashi Y, et al. High-dose growth hormone treatment in prepubertal GH-deficient children. Acta Paediatr Suppl. 1999;88:76-79.
43. Albertsson Wikland K, Alm F, Aronsson S, et al. Effect of growth hormone (GH) during puberty in GH-deficient children:
preliminary results from an ongoing randomized trial with different dose regimens. Acta Paediatr Suppl. 1999;88:80-84.
FULL TEXT
44. MacGillivray MH, Baptista J, Johanson A for the Genentech Study Group. Outcome of a four-year randomized study of daily versus three times
weekly somatropin treatment in prepubertal naive growth hormonedeficient
children. J Clin Endocrinol Metab. 1996;81:1806-1809.
ABSTRACT
45. Bayley N, Pinneau S. Tables for predicting adult height from skeletal age. J Pediatr. 1952;40:432-441.
46. Tanner JM, Whitehouse RH, Cameron N, Marshall WA, Healy MJR, Goldstein H. Assessment of Skeletal Maturity and Prediction of
Adult Height (TW2 Method). London, England: Academic Press; 1983.
47. Hedges LV. Meta-analysis. J Ed Stat. 1992;17:279-296.
48. Hedges LV, Olkin L. Statistical Methods in Meta-Analysis. San Diego, Calif: Academic Press; 1985.
49. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal
for reporting. JAMA. 2000;283:2008-2012.
FREE FULL TEXT
50. Der Sermonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-188.
FULL TEXT
|
ISI
| PUBMED
51. Soliman AT, abdul Khadir MM. Growth parameters and predictors of growth in short children with and
without growth hormone (GH) deficiency treated with human GH: a randomized
controlled study. J Trop Pediatr. 1996;42:281-286.
FREE FULL TEXT
52. Volta C, Bernasconi S, Tondi P, et al. Combined treatment with growth hormone and luteinizing hormone releasing
hormone-analogue (LHRHa) of pubertal children with familial short stature. J Endocrinol Invest. 1993;16:763-767.
ISI
| PUBMED
53. Volta C, Ghizzoni L, Muto G, Spaggiari R, Virdis R, Bernasconi S. Effectiveness of growth-promoting therapies: comparison among growth
hormone, clonidine, and levodopa. AJDC. 1991;145:168-171.
54. Genentech Collaborative Study Group. Idiopathic short stature: results of a one-year controlled study of
human growth hormone treatment. J Pediatr. 1989;115:713-719.
FULL TEXT
|
ISI
| PUBMED
55. Genentech Collaborative Study Group. Response to growth hormone in children with idiopathic short stature. Acta Paediatr Scand Suppl. 1990;366:24-26.
PUBMED
56. Wit JM, Rietveld DHF, Drop S, et al. A controlled trial of methionyl growth hormone therapy in prepubertal
children with short stature, subnormal growth rate and normal growth hormone
response to secretagogues. Acta Paediatr Scand. 1989;78:426-435.
ISI
| PUBMED
57. McCaughey ES, Mulligan J, Voss LD, Betts PR. Randomised trial of growth hormone in short normal girls. Lancet. 1998;351:940-944.
ISI
| PUBMED
58. Downie AB, Mulligan J, McCaughey ES, Stratford RJ, Betts PR, Voss LD. Psychological response to growth hormone treatment in short normal
children. Arch Dis Child. 1996;75:32-35.
FREE FULL TEXT
59. Daubeney PE, McCaughey ES, Chase C, et al. Cardiac effects of growth hormone in short normal children: results
after four years of treatment. Arch Dis Child. 1995;72:337-339.
FREE FULL TEXT
60. McCaughey ES, Mulligan J, Voss LD, Betts PR. Growth and metabolic consequences of growth hormone treatment in prepubertal
short normal children. Arch Dis Child. 1994;71:201-206.
FREE FULL TEXT
61. Walker JM, Bond SA, Voss LD, Betts PR, Wootton SA, Jackson AA. Treatment of short normal children with growth hormone: a cautionary
tale? Lancet. 1990;336:1331-1334.
FULL TEXT
|
ISI
| PUBMED
62. Buchlis JG, Irizarry L, Crotzer BC, Shine BJ, Allen L, MacGillivray MH. Comparison of final heights of growth hormonetreated vs untreated
children with idiopathic growth failure. J Clin Endocrinol Metab. 1998;83:1075-1079.
FREE FULL TEXT
63. Hindmarsh PC, Brook CG. Final height of short normal children treated with growth hormone. Lancet. 1996;348:13-16.
FULL TEXT
|
ISI
| PUBMED
64. Hindmarsh PC, Brook CGD. Effect of growth hormone on short normal children. Br Med J (Clin Res Ed). 1987;295:573-577.
65. Hindmarsh PC, Pringle PJ, Di Silvio L, Brook CG. Effects of 3 years of growth hormone therapy in short normal children. Acta Paediatr Scand Suppl. 1990;366:6-12.
PUBMED
66. Hindmarsh P, Brook CG. Final height is not improved in short normal children treated with
growth hormone. Paper presented at: The Endocrine Society Annual Meeting; June 1995;
Washington, DC. Abstract OR30-1.
67. Lanes R. Effects of two years of growth hormone treatment in short, slowly growing
nongrowth hormone deficient children. J Pediatr Endocrinol Metab. 1995;8:167-171.
ISI
| PUBMED
68. Zadik Z, Mira U, Landau H. Final height after growth hormone therapy in peripubertal boys with
a subnormal integrated concentration of growth hormone. Horm Res. 1992;37:150-155.
ISI
| PUBMED
69. Price DA. Spontaneous adult height in patients with idiopathic short stature. Horm Res. 1996;45:59-63.
70. Loche S, Pintor C, Cambiaso P, et al. The effect of short-term growth hormone or low-dose oxandrolone treatment
in boys with constitutional growth delay. J Endocrinol Invest. 1991;14:747-750.
ISI
| PUBMED
71. Pasquino AM, Pucarelli I, Roggini MSM. Adult height in short normal girls treated with gonadotropin-releasing
hormone analogs and growth hormone. J Clin Endocrinol Metab. 2000;85:619-622.
FREE FULL TEXT
72. Hershkovitz E, Belotserkovsky O, Limony Y, Leiberman E, Shany S, Phillip M. Increase of serum lipoprotein (a) levels during growth hormone therapy
in normal short children. Eur J Pediatr. 1998;157:4-7.
FULL TEXT
|
ISI
| PUBMED
73. Zadik Z, Zung A. Final height after growth hormone therapy in short children: correlation
with siblings' height. Horm Res. 1997;48:274-277.
ISI
| PUBMED
74. Hopwood NJ, Hintz RL, Gertner JM, et al. Growth response of children with nongrowth-hormone deficiency
and marked short stature during three years of growth hormone therapy. J Pediatr. 1993;123:215-222.
FULL TEXT
|
ISI
| PUBMED
75. Ito RK, Vig KW, Garn SM, et al. The influence of growth hormone (rhGH) therapy on tooth formation in
idiopathic short statured children. Am J Orthod Dentofacial Orthop. 1993;103:358-364.
ISI
| PUBMED
76. Hintz RL. Growth hormone treatment of idiopathic short stature. Horm Res. 1996;46:208-214.
ISI
| PUBMED
77. Hintz RL, Attie KM, Johanson A, Baptista J. Near final height in GH-treated short children without classical GH
deficiency [abstract]. Pediatr Res. 1995;37:91A.
78. Hintz RL, Attie KM, Johanson A, et al. Use of GH for promotion of growth in ISS children: final height results
of the US study [abstract]. 1997.
79. Hintz RL, Attie KM, Baptista J, et al for the Genentech Collaborative Group. Effect of growth hormone treatment on adult height of children with
idiopathic short stature. N Engl J Med. 1999;340:502-507.
FREE FULL TEXT
80. Bernasconi S, Street ME, Volta C, Mazzardo G and the Italian Multicentre Study Group. Final height in non-growth hormone deficient children treated with
growth hormone. Clin Endocrinol (Oxf). 1997;47:261-266.
FULL TEXT
| PUBMED
81. Schmitt K, Blumel P, Waldhor T, Lassi M, Tulzer G, Frisch H. Short- and long-term (final height) data in children with normal variant
short stature treated with growth hormone. Eur J Pediatr. 1997;156:680-683.
FULL TEXT
|
ISI
| PUBMED
82. Zadik Z, Segal N, Limony Y. Final height prediction models for pubertal boys. Acta Paediatr Suppl. 1996;417:53-56.
PUBMED
83. Lopez-Siguero JP, Martinez-Aedo MJ, Moreno-Molina JA. Final height after growth hormone therapy in children with idiopathic
short stature and a subnormal growth rate [abstract]. Acta Paediatr Suppl. 1996;417:121.
84. Spagnoli A, Branca F, Spadoni GL, et al. Urinary pyridinium collagen cross-links predict growth performance
in children with idiopathic short stature and with growth hormone (GH) deficiency
treated with GH: skeletal metabolism during GH treatment. J Clin Endocrinol Metab. 1996;81:3589-3593.
ABSTRACT
85. Chalew SA, Phillip M, Kowarski AA. Effect of six months of growth hormone therapy, followed by treatment
withdrawal in short children with normal quantitative indexes of growth hormone
secretion. J Pediatr. 1996;129:456-458.
FULL TEXT
|
ISI
| PUBMED
86. Low LC, Kwan E, Karlberg J. A partial transient effect of short-term growth hormone (GH) treatment
in short non-GH deficient prepubertal children. J Pediatr Endocrinol Metab. 1995;8:173-179.
ISI
| PUBMED
87. Spagnoli A, Spadoni GL, Boscherini B. Preliminary validation of a prediction model for the short term growth
response to growth hormone therapy in children with idiopathic short stature. Acta Paediatr Suppl. 1996;417:66-68.
PUBMED
88. Spagnoli A, Spadoni GL, Cianfarani S, Pasquino AM, Troiani S, Boscherini B. Prediction of the outcome of growth hormone therapy in children with
idiopathic short stature: a multivariate discriminant analysis. J Pediatr. 1995;126:905-909.
FULL TEXT
|
ISI
| PUBMED
89. Azzarito C, Boiardi L, Zini M, et al. Short and long-term effects of growth hormone treatment on lipid, lipoprotein,
and apolipoprotein levels in short normal children. Horm Metab Res. 1994;26:432-435.
ISI
| PUBMED
90. Job JC, Toublanc JE, Landier F. Growth of short normal children in puberty treated for 3 years with
growth hormone alone or in association with gonadotropin-releasing hormone
agonist. Horm Res. 1994;41:177-184.
ISI
| PUBMED
91. Zadik Z, Lieberman E, Altman Y, Chen M, Limoni Y, Landau H. Effect of timing of growth hormone administration on plasma growth-hormone-binding
activity, insulin-like growth factor-I and growth in children with a subnormal
spontaneous secretion of growth hormone. Horm Res. 1993;39:188-191.
ISI
| PUBMED
92. Zadik Z, Vaisman N, Lotan D, et al. Effect of growth hormone therapy on IGF-I, bone GLA-protein and bone
mineral content in short children with and without chronic renal failure. Horm Res. 1992;38:145-149.
ISI
| PUBMED
93. Bierich JR, Nolte K, Drews K, Brugmann G. Constitutional delay of growth and adolescence: results of short-term
and long-term treatment with GH. Acta Endocrinol (Copenh). 1992;127:392-396.
94. Low LC, Lau YL. Serum osteocalcin in normal and short Chinese children. J Paediatr Child Health. 1992;28:432-435.
ISI
| PUBMED
95. Colle M, Sagnard L, Ducret JP, Auzerie J. Growth response to growth-hormone administration during the decelerating
phase of the pubertal growth spurt in short normal children. Horm Res. 1990;34:204-208.
ISI
| PUBMED
96. Chanoine JP, Vanderschueren M, Maes M, Thiry G, Craen M, Van-Vliet G. Growth hormone (GH) treatment in short normal children: absence of
influence of time of injection and resistance to GH autofeedback. J Clin Endocrinol Metab. 1991;73:1269-1275.
FREE FULL TEXT
97. Hernandez M, Nieto JA, Sobradillo B, Pombo M, Ferrandez A, Rejas J. Multicenter clinical trial to evaluate the therapeutic use of recombinant
growth hormone from mammalian cells in the treatment of growth hormone neurosecretory
dysfunction. Horm Res. 1991;35:13-18.
98. Rochiccioli P, Dechaux E, Tauber MT, Pienkowski C, Tiberge M. Growth hormone treatment in patients with neurosecretory dysfunction. Horm Res. 1990;33(suppl 4):97-101.
99. Darendeliler F, Hindmarsh PC, Brook CG. Dose-response curves for treatment with biosynthetic human growth hormone. J Endocrinol. 1990;125:311-316.
FREE FULL TEXT
100. Lin TH, Kirdland RT, Sherman MD, Kirkland JL. Growth hormone testing in short children and their response to growth
hormone therapy. J Pediatr. 1989;115:57-63.
FULL TEXT
|
ISI
| PUBMED
101. Black N. What observational studies can offer decision makers. Horm Res. 1999;51:44-49.
102. Saenger P. Growth hormone therapy for the short normal child: who needs it and
who wants it? the case in support of GH therapy. J Pediatr. 2000;136:106-109.
FULL TEXT
|
ISI
| PUBMED
103. Zimet G, Owens R, Dahms WT, Cutler M, Litvene M, Cuttler L. The psychosocial outcome of children evaluated for short stature. Arch Pediatr Adolesc Med. 1997;151:1017-1023.
FREE FULL TEXT
104. Kranzler JH, Rosenbloom AL, Proctor B, Diamond FB, Watson M. Is short stature a handicap? a comparison of the psychosocial functioning
of referred and nonreferred children with normal short stature and children
with normal stature. J Pediatr. 2000;136:96-102.
FULL TEXT
|
ISI
| PUBMED
105. Voss LD. Growth hormone therapy for the short normal child: who needs it and
who wants it? the case against growth hormone therapy. J Pediatr. 2000;136:103-110.
FULL TEXT
|
ISI
| PUBMED
106. Dowdney L, Skuse D, Morris K, Pickles A. Short normal children and environmental disadvantage: a longitudinal
study of growth and cognitive development from 4 to 11 years. J Child Psychol Psychiatry. 1998;39:1017-1029.
FULL TEXT
|
ISI
| PUBMED
107. Rekers-Mombarg JM, Busschbach JJV, Massa GG, Dicke J, Wit JM. Quality of life of young adults with idiopathic short stature: effect
of growth hormone treatment. Acta Paediatr. 1998;87:865-870.
FULL TEXT
|
ISI
| PUBMED
108. Blethen SL, Allen DB, Graves D, August G, Moshang T, Rosenfeld R. Safety of recombinant deoxyribonucleic acidderived growth hormone:
the National Cooperative Growth Study experience. J Clin Endocrinol Metab. 1996;81:1704-1710.
ABSTRACT
109. Werber Leschek E, Troendle JF, Yanovski JA, et al. Effect of growth hormone treatment on testicular function, puberty,
and adrenarche in boys with nongrowth-hormonedeficient short
stature: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2001;138:406-410.
FULL TEXT
|
ISI
| PUBMED
110. Allen DB, Brook CG, Bridges NA, Hindmarsh PC, Guyda HJ, Frazier D. Therapeutic controversies: growth hormone (GH) treatment of non-GH
deficient subjects. J Clin Endocrinol Metab. 1994;79:1239-1248.
FULL TEXT
|
ISI
| PUBMED
111. Grumbach MM, Bin-Abbas BS, Kaplan SL. The growth hormone cascade: progress and long-term results of growth
hormone treatment in growth hormone deficiency. Horm Res. 1998;49 Suppl 2:41-57.
112. Blethen SL, Baptista J, Kuntze J, Foley T, Lafranchi S, Johanson A for the Genentech Growth Study Group. Adult height in growth hormone (GH)deficient children treated
with biosynthetic GH. J Clin Endocrinol Metab. 1997;82:418-420.
FREE FULL TEXT
113. Ranke MB. Towards a consensus on the definition of idiopathic short stature. Horm Res. 1996;45:64-66.
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Growth Hormone Effects on Adult Height in Idiopathic Short Stature
Varma
AAP Grand Rounds 2005;13:2-3.
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Parent Requests Growth Hormone for Child With Idiopathic Short Stature
Stein et al.
Pediatrics 2004;114:1478-1482.
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Height and Social Adjustment: Are Extremes a Cause for Concern and Action?
Sandberg et al.
Pediatrics 2004;114:744-750.
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Growth Hormone Use in Children with Idiopathic Short Stature
Weise and Nahata
The Annals of Pharmacotherapy 2004;38:1460-1468.
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Ethical Issues Raised by Expanded Access to Growth Hormone
Mears
AAP Grand Rounds 2004;12:14-15.
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Effect of Growth Hormone Treatment on Adult Height in Peripubertal Children with Idiopathic Short Stature: A Randomized, Double-Blind, Placebo-Controlled Trial
Leschek et al.
J. Clin. Endocrinol. Metab. 2004;89:3140-3148.
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Growth Hormone Treatment for Idiopathic Short Stature: Implications for Practice and Policy
Cuttler and Silvers
Arch Pediatr Adolesc Med 2004;158:108-110.
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Periplasmic expression of human growth hormone via plasmid vectors containing the {lambda}PL promoter: use of HPLC for product quantification
Soares et al.
Protein Eng Des Sel 2003;16:1131-1138.
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Treatment with a Luteinizing Hormone-Releasing Hormone Agonist in Adolescents with Short Stature
Yanovski et al.
NEJM 2003;348:908-917.
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Growth Hormone Therapy in Children With Idiopathic Short Stature
Bryant et al.
Arch Pediatr Adolesc Med 2002;156:946-947.
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Growth Hormone Augments Adult Height in Short Children
JWatch General 2002;2002:6-6.
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