1. No category

Growth Hormone: Health Considerations Beyond Height Gain
Judith Ross, Paul Czernichow, Beverly M. K. Biller, Annamaria Colao, Ed Reiter,
Wieland Kiess and on behalf of the participants in the advisory panel meeting on the
effects of growth hormone
Pediatrics 2010;125;e906; originally published online March 22, 2010;
DOI: 10.1542/peds.2009-1783
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/125/4/e906.full.html
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2010 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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Growth Hormone: Health Considerations Beyond
Height Gain
abstract
The therapeutic benefit of growth hormone (GH) therapy in improving
height in short children is widely recognized; however, GH therapy is
associated with other metabolic actions that may be of benefit in these
children. Beneficial effects of GH on body composition have been documented in several different patient populations as well as improvements in lipid profile. Marked augmentation of bone mineral density
also seems evident in many pediatric populations. Some of these benefits may require continued therapy past the acquisition of adult
height. With long-term therapy of any kind, the adverse consequences
of treatment should also be considered. Fortunately, long-term GH
treatment seems to be safe and well-tolerated. This review describes
the long-term metabolic effects of GH treatment in the pediatric population and considers how these may benefit children who are treated
with GH. Pediatrics 2010;125:e906–e918
AUTHORS: Judith Ross, MD,a Paul Czernichow, MD,b
Beverly M. K. Biller, MD,c Annamaria Colao, MD, PhD,d
Ed Reiter, MD,e and Wieland Kiess, MD,f on behalf of the
participants in the advisory panel meeting on the effects
of growth hormone
aDepartment of Pediatrics, Thomas Jefferson University,
Philadelphia, Pennsylvania; bDepartment of Pediatric
Endocrinology and Diabetes, Necker-Enfants Malades Hôpital,
Paris, France; cDepartment of Medicine, Massachusetts General
Hospital, Boston, Massachusetts; dDepartment of Molecular and
Clinical Endocrinology and Oncology, Federico II University of
Naples, Naples, Italy; eDepartment of Pediatrics, Baystate
Children’s Hospital, Springfield, Massachusetts; and
fDepartment of Women and Child Health, Hospital for Children
and Adolescents, University of Leipzig, Leipzig, Germany
KEY WORDS
growth hormone, body composition, metabolism, safety
ABBREVIATIONS
GH— growth hormone
GHD— growth hormone deficiency
LBM—lean body mass
FM—fat mass
QoL— quality of life
BMD— bone mineral density
SDS—SD score
LDL-C—low-density lipoprotein cholesterol
HDL-C— high-density lipoprotein cholesterol
CVD— cardiovascular disease
IGF-I—insulin-like growth factor I
BMC— bone mineral content
LV—left ventricular
SGA—small for gestational age
TS—Turner syndrome
PWS—Prader-Willi syndrome
ISS—idiopathic short stature
IGFBP-3—insulin-like growth factor binding protein 3
CI— confidence interval
www.pediatrics.org/cgi/doi/10.1542/peds.2009-1783
doi:10.1542/peds.2009-1783
Accepted for publication Nov 16, 2009
Address correspondence to Judith Ross, MD, Department of
Pediatrics, Thomas Jefferson University, 1025 Walnut St, Suite
726, Philadelphia, PA 19107. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2010 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: All authors are members of the Global
Norditropin Advisory Panel. Dr Reiter is a consultant for Novo
Nordisk, Altus, and Indevus; Dr Kiess is a member of the
advisory board and received grant support from Novo Nordisk,
Pfizer, Serono, and Ipsen; Dr Colao has no financial
relationships relevant to this article to disclose; Dr Biller has
received research grants from Eli Lilly, Novo Nordisk, Pfizer and
consultant/advisory honoraria from Novo Nordisk, Pfizer, and
(Continued on last page)
e906
ROSS et al
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In children with growth hormone (GH)
deficiency (GHD), the primary role of
GH treatment is to increase linear
growth.1 Nevertheless, GH is known to
have a large number of metabolic effects, involving glucose and lipid homeostasis, as well as beneficial effects
on lean body mass (LBM) and fat mass
(FM). Studies in adults have highlighted the role of GH in the regulation
of protein, carbohydrate, and lipid
metabolism; in adults, lack of GH is associated with abnormal body composition, increased cardiovascular morbidity, a poorer quality of life (QoL),
and decreased bone mineral density
(BMD).2,3 Evidence from studies of adults
supports beneficial metabolic effects associated with GH replacement.4,5
Recently, attention has focused on the
metabolic consequences of discontinuing GH treatment in adolescents at
the cessation of linear growth. In patients who received GH during childhood, discontinuation of treatment has
been associated with abnormal body
composition (mostly increased FM),6
whereas accumulated data to date
suggest that the continuation of GH
may help in achieving normal adult
body composition.2,7–9 Although the
long-term benefits of continuation of
GH remain to be firmly established, the
aim of this review was to evaluate the
metabolic consequences of GH treatment in children and adolescents and
the potential beneficial effects of the
treatment in this population.
● intervention was biosynthetic hu-
man GH (somatropin);
● participants were children who
were receiving GH;
● outcomes were changes in meta-
bolic parameters in response to GH
treatment, including body composition, lipids, and bone density and
content; QoL and psychosocial measures were reported when available; and
● we included all studies regardless
of design that included primary
data about key metabolic end points
as well as systematic reviews of
randomized clinical trials that assessed the effects of GH (compared
with placebo or no intervention) on
the basis of any of the mentioned
patient-relevant outcomes.
GH Deficiency
Body Composition
In untreated children with GHD, there
is increased FM, predominantly distributed centrally, and decreased LBM
(mostly muscle mass).10,11 Treatment
with GH normalizes percentage FM
within 6 months.10 This reduction in total percentage of body fat and regional
reductions in percentage of fat of the
arms, legs, and trunk is attributable to
nonsignificant reductions in FM and
significant increases in LBM.12 Classically, there is a reduction of central fat
in children who have GHD and are
treated with GH.12 Height, LBM, and
bone mass also increase with GH therapy but remain lower than normal,
even after 6 years of treatment.13 In a
2-year follow-up of 55 prepubertal children who had GHD and were treated
with recombinant human GH (30 ␮g/kg
per day), muscle mass increased from
⫺2.4 to ⫺1.0 SD score (SDS).11
Most2,3,6–8 but not all9 studies indicated
that continuation of GH after adult
height can help normalize body composition by continuing to increase the
proportion of LBM to FM. In 2 studies,
seamless continuation of GH treatment after adult height was achieved
demonstrated modest changes in body
composition (4%– 6% increase in LBM;
6%– 8% decrease in FM) that were consistent with the body composition
changes expected in a normal, healthy
population of similar age (Fig 1).2,8 On
restarting GH, an increase in LBM of
13% to 14% was observed,2,6,14 which
equates to 65% to 85% of the deficit in
LBM reported in young adults with
childhood-onset GHD compared with
age-matched patients with adult-onset
GHD.15 This divergence of gain in LBM
with continuous GH treatment, versus
with an interval of discontinuation
of GH, is of importance because increases in muscle mass occur as a feature of healthy late-adolescent devel-
METHODS
A systematic review of the literature
was undertaken. We searched Medline
(1950 through July 2009) for Englishlanguage articles. Bibliographies of related articles were assessed for relevant studies to identify additional
published references. Studies were included when they fulfilled the following
criteria:
PEDIATRICS Volume 125, Number 4, April 2010
FIGURE 1
A and B, Total body fat (A) and LBM (B) as assessed from dual-energy radiograph absorptiometry scan
at baseline, and after 12 months of placebo followed by 12 months of GH treatment in young adults
with GHD. P values versus baseline. Data from ref 2.
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e907
opment.8 A divergent pattern in the
body composition response to GH therapy by gender was reported by Attanasio et al,6 who showed that the reduction in FM in young female adults was
less than that in similar-aged male patients. It is suggested that the pattern
of response to GH replacement reflected developmental gender dimorphism. In normal development, young
male adults lose up to 8% FM, whereas
female adults gain up to 6% FM.16
GH is also recognized to have anabolic
effects on whole-body protein turnover
and cell growth. In children with GHD,
GH therapy results in marked nitrogen
retention, accelerated linear growth,
and weight gain.17
Cardiovascular Effects
Discontinuation of GH replacement in
adolescents with severe GHD is associated with an increase of several markers of cardiovascular risk as well as an
increase in total body and abdominal
fat and total and low-density lipoprotein cholesterol (LDL-C) concentrations7,18,19 (Fig 2); however, no apparent
change in morphologic parameters
measured at the common carotid arteries is evident on stopping GH.18,20
The abnormalities in lipid profile are of
particular clinical relevance because
they are associated with increased
risk for coronary events in the adult
population with GHD.21 In addition to
the noted increase in total and LDL-C
levels, the total and high-density lipoprotein cholesterol (HDL-C) ratio in
adult patients was increased after
stopping GH treatment.
Data suggest a strong link between serum cholesterol levels measured in
early adult life and risk for cardiovascular disease (CVD) in middle to late
adult life,22 reinforcing the need to reduce cholesterol levels in young patients with GHD. Increased levels of
fasting and postprandial triglyceriderich lipoproteins have also been ree908
ROSS et al
FIGURE 2
Lipid levels in 10 adolescent patients with GHD at study entry, 6 months after withdrawal of GH, and 6
months after GH replacement was restarted. A, total cholesterol. B, LDL-C. C, HDL-C. D, Triglycerides.
Data from ref 19.
ported in untreated adolescents with
GHD and may be related to increased
levels of proinflammatory and fibrinolytic markers such as C-reactive protein, interleukin-6, and tumor necrosis
factor ␣.18,23–25
Although GH treatment improves lipid
profiles in the majority of studies
in adults with GHD, results from studies in adolescents are not conclusive.2,6,8,14,19,26 In 1 study, restarting GH
treatment (at a mean dose of 0.01
mg/kg per day), after discontinuation
of therapy at completion of linear
growth, was associated with an improvement in lipid and cardiac parameters in young adults with severe GHD19
(Fig 2); however, insulin-like growth
factor I (IGF-I) levels were still not completely normalized, remaining lower
than in those in healthy control subjects, and the total cholesterol/HDL-C
ratio, as a relevant predictive parameter for the cardiovascular risk, was
still higher than that in control sub-
jects. No modification of hemodynamic
parameters was observed after restarting GH treatment, although, similar to adult GHD patients, heart rate,
systolic blood pressure, and diastolic
filling tended to increase.19 In another
study,25 improved endothelial function
and reduced arterial stiffness occurred after GH replacement. In that
study, hyperemia-induced blood flow
increase was greater (P ⬍ .001) in the
GH-treated than in age-matched untreated control subjects with GHD or in
healthy control subjects.
Together, these findings support the
idea that GH discontinuation in adolescents with GHD may be problematic because of the potential for adverse
changes in the lipid profile, in cardiac
morphology, and in performance. Conflicting results are available from studies in children with GHD with respect to
plasma lipoprotein levels. In the majority of studies, no abnormalities in the
lipid profile were evident at base-
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REVIEW ARTICLES
line10,13,23,27; however, Ciresi et al28 observed significantly increased total
cholesterol and LDL-C levels in untreated children with GHD relative to
healthy control subjects, although levels were still within the normal range.
A beneficial effect of GH treatment on
the atherogenic index has been reported in several studies that evaluated the efficacy of short-term and
long-term GH treatment on the lipid
profile in children with GHD.10,29,30 After
6 years of GH treatment, Van der Sluis
et al13 documented a beneficial effect
on the atherogenic index as well as on
HDL-C in children with GHD.
Bone Metabolism and BMD
It is well-established that GH promotes
longitudinal bone growth. In addition,
a universal finding in children with
GHD is the increase in levels of bone
metabolism parameters, reflecting increased bone turnover after the start
of GH therapy.31,32 Markers of bone metabolism, including serum alkaline
phosphatase, procollagen 1 carboxylterminal propeptide, and deoxypyridinoline, were found to increase significantly during the first 3 months of
GH treatment in 45 prepubertal children with GHD.32 This increase in bone
modeling and remodeling, together
with the catch-up growth, results in an
increase in total bone area and lowering of bone mineral content (BMC) during the first 12 months, followed by an
increase in BMC and cortical thickness
thereafter.10,11,32–35 The changes in
bone geometry are associated with
improvements in muscle mass,11
changes that are complementary to
the GH-induced increase in height. Radial and lumbar spine BMD in children
who had GHD and had received GH
treatment for 4 to 7 years was within
0.5 SD of that of age-matched healthy
peers34; however, in suboptimally
treated patients with GHD, lumbar BMD
at adult height was reduced.36,37 Continuation of GH in patients with GHD afPEDIATRICS Volume 125, Number 4, April 2010
ter reaching adult height was reported
to be associated with a 6% greater increase in BMC and a 5% greater increase in lumbar spine BMD compared
with patients who discontinued GH.38
To put this in perspective, an increase
in BMC of 6% could be expected in
healthy adolescents during a similar
time frame.39 Recommencement of GH
treatment resulted in an improvement
in total body and lumbar spine BMD in
adolescents with GHD in 3 additional
studies.14,40,41 Conversely, in a 2-year
study, Mauras et al9 found no effect of
GH treatment on total or lumbar spine
BMD. These discrepant results may be
attributable to differences in GH treatment regimens or treatment durations
or to differences in the populations being studied. Because the magnitude of
the increase in BMD after 2 years of GH
treatment was similar to the increase
observed with 1 year of continuous GH
treatment, discontinuation of GH in
adolescents with sustained GHD may
limit progression toward peak bone
mass accrual. These results suggest a
key role for GH in the acquisition of
bone mass during childhood and adolescence and suggest that GH should
be administered in adequate doses
and for an adequate length of time to
help achieve a BMD within the normal
range.42
Carbohydrate Metabolism
GH is regarded as an insulin antagonist with respect to carbohydrate metabolism. It has a physiologic role in
the maintenance of normoglycemia,
especially during fasting, via stimulation of hepatic gluconeogenesis and
suppression of insulin-stimulated glucose uptake in peripheral tissues. Supraphysiologic GH concentrations may
increase glucose production by stimulating insulin secretion and, thus, may
potentially induce insulin resistance
or diabetes; however, no impairment
of glucose tolerance has been observed during GH treatment of chil-
dren who have short stature with and
without GHD or in several studies of
adults with GHD, although some results vary.43–50 Some studies have suggested a decreased ␤-cell capacity in
untreated children with GHD, with a
beneficial effect of GH treatment.51 Nevertheless, positive changes in body
composition may counter negative effects on insulin sensitivity.43 In agreement with this, GH treatment of obese
adults improves insulin sensitivity,52
and Leunissen et al53 showed that
higher body FM at age 21 years was
associated with reduced insulin sensitivity irrespective of birth size.
Cardiac Effects
Evidence accumulated to date suggests that long-term administration of
GH does not seem to have adverse
cardiac effects in children. In 42 GHtreated children with GHD (mean GH
duration: 35 months), there was no significant difference in systolic function
and left ventricular (LV) volume and
mass, compared with age-, gender-,
and body size–matched normal patients.54 Likewise, no alterations in cardiac mass or function were reported in
GH-treated adolescents with GHD
(mean age: 14.2 years) compared with
untreated adolescents with GHD.18 Furthermore, treatment with GH (30 IU/m2
per week [0.05 mg/kg per day]) for up
to 4 years was not associated with adverse effects on LV wall thickness or
mass in short normal children.55
Small for Gestational Age
Body Composition
Untreated short children who were
born small for gestational age (SGA)
are lean (BMI SDS: ⫺1.3) and tend to
have a low to normal FM with low fatfree mass.56–60 Treatment with GH
leads to gains in height and weight,
with the latter composed predominantly of increased fat-free mass.58,61
In a randomized, double-blind, dose-
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e909
response trial of 79 short children who
were SGA, GH treatment (0.033 or 0.067
mg/kg per day) for up to 6 years normalized BMI without overall changes in
subcutaneous fat, compared with ageand gender-matched references.61 The
increase in LBM is likely attributable to
a significant increase in muscle tissue,
because body composition remained
within the normal range.62 This seems
to be sustained even after discontinuation of GH.63 Two years of GH treatment (55 ␮g/kg per day) in 35 prepubertal short children who were born
SGA was associated with an increase in
muscle mass from ⫺3.0 to ⫺1.5 SDS.11
higher risk for CVDs in later life in children who were born SGA, additional research into adulthood remains warranted in this population.
Turner Syndrome
Body Composition
BMD is moderately reduced in untreated
short children who were born SGA.67 GH
treatment, however, was associated
with a significant increase in lumbar
spine BMD after 3 years that was
strongly correlated with the increase in
height SDS.60,67 Hence, children with the
best growth response also had the
greatest increase in BMD.
In girls with Turner Syndrome (TS), GH
treatment also increased lean mass
and decreased adiposity in 2 small
longitudinal studies.71–74 In a crosssectional study, GH-treated girls (N ⫽
76; age: 13.6 ⫾ 3.7 years) had ⬃50%
less total body and subcutaneous fat
compared with untreated girls (N ⫽
26; age: 13.8 ⫾ 3.5 years). Of note, the
GH-treated girls demonstrated lower
adiposity than the untreated girls
for up to 2 years after discontinuation
of GH.74
Body Proportions
Carbohydrate Metabolism
Body Proportions
Short children who were born SGA
have relatively large hands and feet
and relatively broad shoulders and
pelvis compared with their height but
a normal sitting height in proportion to
their height.61 The increase in height
during 6 years of GH treatment (0.033
or 0.067 mg/kg per day) was associated with a dose-independent improvement in body proportions. Head circumference, which is relatively large
in these children, especially those who
were born short and light, is also normalized during GH treatment.64
In short children who were born SGA,
conflicting results on the change in insulin sensitivity with GH treatment
have been reported.62,65,68–70 A reversible GH-associated decrease in insulin
sensitivity with GH treatment has been
reported in several larger studies after stopping treatment.62,65,68 In a longitudinal study,24 adolescents who were
born SGA were treated with GH to adult
height, then reevaluated 6 months after stopping GH.62 After cessation of
GH treatment, insulin sensitivity increased (P ⫽ .006), glucose effectiveness (P ⫽ .009) and ␤-cell function
(P ⫽ .024) increased, and insulin secretion decreased (Fig 3).62 Values after
stopping treatment were similar to
those in control subjects who were appropriate for gestational age. Van Dijk et
al65 investigated insulin sensitivity in previously GH-treated young adults who
were born SGA 6.5 years after discontinuation of GH and reported that their insulin sensitivity and ␤-cell function were
similar to untreated control subjects
who were born SGA. These data are reassuring because they suggest that longterm GH treatment does not increase the
risk for diabetes in this population, although additional long-term follow-up is
needed to confirm this finding.
In girls with TS, a moderate improvement of the disproportion between
height and sitting height was reported75 after 7 years of GH treatment. In 47
girls who had TS (median age at treatment start: 9.4 years) and were followed for 4 years on GH (median dose:
0.24 mg/kg per week), the effects on
height, arm span, sitting height, and
leg length were of similar magnitude.76
Over time, however, a higher gain in
sitting height than in leg length that
was most evident after puberty started
was observed, although body proportions did not change significantly relative to the normal population.
Cardiovascular Effects
GH therapy had a positive effect on the
lipid profile in short children were
born SGA.61 In 79 short children who
were born SGA, pretreatment values
for cholesterol, LDL-C, and HDL-C and
the atherogenic index were within the
normal range.61 During long-term continuous GH treatment, a significant reduction in the atherogenic index as
well as in the blood pressure SDS was
observed, indicating that GH has a positive effect on these parameters. Data
from reported studies suggested that
these effects seem to be maintained
even after stopping GH treatment, although longer term follow-up studies
are needed.65,66 In view of the reported
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ROSS et al
Bone Metabolism and Bone Density
Bone Density
Women with TS have cortical bone deficiency.77,78 Increased cortical bone
density was reported after 7 years of
GH treatment,43 especially in the higher
dose (0.09 mg/kg per day) group. In
contrast, in a comparison with 28 girls
who had TS and had never received GH
and 39 age-matched GH-treated TS
girls, no significant differences in BMD
were observed at the lumbar spine
(L1–L4) or one-third radius or cortical
bone thickness measured at the second metacarpal.73 These results suggest that GH treatment may not affect
cortical or trabecular BMD in TS.
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years) and were followed for ⬃5 years
after stopping GH treatment, there was
no evidence of myocardial hypertrophy, and biventricular function was
well-preserved.85 Compared with healthy
control subjects, patients showed
lower ventricular volume and increased heart rate. Because these latter observations are likely part of the
natural development of TS and unrelated to GH treatment, GH therapy does
not seem to have negative effects on
cardiac function in girls with TS.
Other Indications
Body Composition
Beneficial effects of GH on body composition have also been documented in
children with Prader-Willi syndrome
(PWS), for whom GH treatment was associated with an increase in lean mass
into the normal range and a relative
delay in FM accumulation.88,89 In glucocorticoid-treated patients who had
juvenile idiopathic arthritis and were
treated with GH (0.46 mg/kg per week)
for 3 years, lean mass increased by
33% from baseline values.90,91
FIGURE 3
Changes in frequently sampled intravenous glucose tolerance test parameters of adolescents who
were born SGA and treated with GH and then followed up 6 months after stoppage of treatment. P
values between GH treatment and after stoppage of treatment. Reprinted from ref 62, with permission. Copyright 2008, The Endocrine Society.
Carbohydrate Metabolism
A lack of diabetogenic effect of GH therapy, consistent with observations in
children with GHD, has been reported
in girls with TS.45,61,66,79–82 In a crosssectional study of girls with TS, ⬃30%
of untreated girls with TS (n ⫽ 26)
demonstrated impaired glucose tolerance, whereas none of the GH-treated
(n ⫽ 76) girls with TS did (P ⫽ .001).74
Cardiac Effects
Patients with TS have a significant increase in congenital heart disease and
PEDIATRICS Volume 125, Number 4, April 2010
risk for aortic dilatation and dissection; it is reassuring, however, that GH
therapy does not seem to have any adverse effects on the heart in this population.83–85 No effect of GH treatment on
LV hypertrophy or hypertension has
been documented in girls with TS.86 A
retrospective, cross-sectional study
involving 53 GH-treated and 48 untreated girls with TS found no significant difference in ascending or descending aortic diameter associated
with GH treatment.87 Moreover, in 31
patients who had TS (mean age: 20
GH has been used to improve nutrition and protein catabolism in many
chronic illnesses, including patients
with burns, chronic renal failure, or
malnutrition after hemodialysis.92–94 In
children with cystic fibrosis, GH seems
to improve body weight and lean tissue
mass on the basis of reduced wholebody catabolism and increased efficiency of whole-body protein kinetics.95
Body Proportions
In children with severe growth retardation secondary to chronic renal failure,
GH therapy for 4 years did not negatively
influence body proportions96 and may
even improve body proportions.97
BMD and Metabolism
In children with PWS, whole-body BMD
is similar to that of age-matched control subjects until the teenage years,
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when evidence of osteopenia has been
reported.70 For young adults (mean
age: 24 years), Vestergaard et al98 reported low BMD as a result of high
bone turnover. Treatment with GH for
up to 4 years in 46 children with PWS
(mean age: 12 years) was associated
with significant improvements in BMD
(P ⬍ .01).99
Severe reduced BMC and osteoporosis
is common in glucocorticoid-treated
patients with juvenile idiopathic arthritis. Administration of GH to these patients is associated with an increase in
lumbar bone density, suggesting that
GH therapy may prevent additional
bone loss in this patient group.90,91 In
children with idiopathic short stature
(ISS), GH treatment increased vertebral BMD100 as well as phalangeal cortical thickness.101
Carbohydrate Metabolism
In children with ISS, no significant GH
effect on measures of carbohydrate metabolism have been reported.50,102,103 In 68 patients who had ISS
and were treated with GH (0.74 mg/kg
3 times weekly) until adult height was
achieved, levels of fasting insulin, fasting glucose, and hemoglobin did not
differ significantly between GH-treated
and placebo-treated groups.102
Psychological Development and
Intelligence
Short stature has been associated
with negative stereotypes and psychological disadvantages in some studies
but not in others.104 In a survey of 166
short children who were referred for
GH treatment, Stabler and colleagues76
reported an increased frequency of
underachievement, behavior problems, and reduced social competency
in short children, suggesting that
short stature itself may predispose
them to some of their difficulties.105
The published reports about perception by the child or the parents of psye912
ROSS et al
chosocial function may be related to
whether the short stature samples
were clinic-referred or derived from
the general population as well as
the age and gender of the population.
Comparisons between referred and
community-based short children revealed that just the referred group
experienced increased behavioral problems.106 Social competencies, behavioral
and emotional functioning, and QoL of
community-based children with short
stature generally falls within the normative range.107 Other clinic-based studies
failed to demonstrate that children with
short stature had a clinically meaningful
excess of problems compared with children in the general population.108
In GH-treated short children who were
born SGA, van Pareren et al109 reported
that GH treatment was associated with
significant improvements in [performance and total] IQ (P ⬍ .001) as well
as reduced externalizing behavior
(P ⬍ .01) and total problem scores (P ⬍
.05) and increased self-perception
scores (P ⬍ .001). Parents of prepubertal children who were born SGA
and treated with GH for 2 years (N ⫽
20) reported less teasing, compared
with the untreated group (10% [GHtreated] vs 45% [untreated]; P ⬍ .05).
Reduced teasing was also reported in
104 GH-treated short children who
were born SGA after 2 years.110 Furthermore, adolescents who were born
SGA and treated with GH during childhood were reported to have a better
QoL in many aspects in addition to improved height compared with untreated adolescents who were born
SGA.111 A trend toward reduced externalizing problem behaviors, as assessed by the Child Behavior Checklist
(parent questionnaire), was also reported for 68 children with ISS (aged
9 –16 years) after GH therapy of up to
4 years.112 Furthermore, during 12
months of GH treatment, a significant
improvement in mental and motor de-
velopment was reported in 15 GHtreated infants and toddlers with PWS
compared with a non–GH-treated control group.89
In summary, short stature and chronic
illness can undermine a child’s selfimage. The results of these studies are
encouraging and suggest that the increased growth associated with GH
treatment may increase self-esteem
and acceptance by peers and warrant
additional collaborative investigations
into the potential psychological benefits of long-term GH treatment.
Safety
adverse effects related to carbohydrate metabolism and to cardiovascular changes were discussed already by
indication. In this section, other safety
issues related to GH administration
are addressed.
Other Adverse Effects
GH-associated adverse effects such as
edema and carpal tunnel syndrome
are attributed to fluid retention.113
Such effects are usually resolved
within the first few weeks of GH treatment or with dose reduction. Some adverse effects, including transient intracranial hypertension, gynecomastia,
and slipped capital femoral epiphysis,
are more likely in children than in
adult patients.114 Events such as intracranial hypertension seem to be more
common in children with diagnosed
endocrine disorders or those with
growth spurts but occur only in a small
number of patients, generally within
the first 2 months of treatment, and
seem to resolve after treatment stoppage or reduction of GH dose.115,116
Cancer Risk
During recent years, concerns have
been raised about a potential role for
GH, via its mediator IGF-I, in the development of cancer.117 These concerns
were based on the observations that
plasma IGF-I levels correlated with an
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increased risk for breast or prostate
cancer, and an increased risk for colon and rectum cancer has been reported in patients with acromegaly.118
There are conflicting data about
whether acromegaly, the most extreme state of substantial GH excess, is
associated with any increased risk for
cancer. A number of studies indicated
an increased risk for colon polyps;
whether this results in higher cancer
risk has been debated,119–123 and the incidence of other malignancies is not
clearly increased in patients with acromegaly. It is noteworthy, however, that
Friedrich et al124 reported inverse associations between IGF-I or insulin-like
growth factor binding protein 3
(IGFBP-3) levels and mortality from allcause, CVD, or cancer in men and between IGFBP-3 and all-cause mortality
in women, suggesting that additional
research is needed to establish a potential role for IGF-I in cancer risk.
Extensive studies of the outcome in
childhood cancer survivors who were
treated with GH and indeed of recent
outcome trials of children who were
treated with recombinant GH in modern dosage regimens has not revealed
an increased cancer risk.125 In a large
study by Swerdlow et al,126 which followed 180 children who had brain tumors and received GH and 434 children
who had brain tumors and received radiotherapy but not GH, there was a reduced relative risk for recurrence in
GH-treated versus untreated patients
(0.6 [95% confidence interval (CI): 0.4 –
0.9]) as well as a reduced risk for mortality (0.5 [95% CI: 0.3– 0.8]). Likewise,
Sklar et al127 observed a reduced risk
for disease recurrence, second malignant neoplasms, and death in 361 surviving patients who had cancer and
were treated with GH from among
13 359 cancer survivors. The relative
risk for disease recurrence was 0.83
(95% CI: 0.37–1.86; P ⫽ .65). A small
increase in the number of secondary
PEDIATRICS Volume 125, Number 4, April 2010
malignant neoplasms, however, was
observed in survivors of acute leukemia who were treated with GH compared with those who did not receive
GH (3 of 122 patients versus 2 of
45 000), although the overall small
number of events needs to be interpreted with caution. Current pediatric
data do not suggest an excess risk for
malignancy after GH treatment, especially when IGF-I levels are maintained
within the normal range.125
Taback et al128 analyzed the risk for
death between 1967 and 1992 in 1366
children who were treated with pituitary or biosynthetic GH. They found an
overall crude mortality rate of 2.7%. Although the most common cause of
mortality was tumor recurrence (11 of
37 deaths), a high proportion were
caused by endocrine complications, including adrenal crisis and hypoglycemia (9 of 37). Recommendations on the
basis of these findings are that aggressive management of these other endocrine conditions, especially among
very young children who are treated
with GH, is warranted.
CONCLUSIONS
In children, as in adults, GH has potent
metabolic effects. It usually improves
body composition in children and adolescents with GHD as well as without
GHD, with an increase in LBM. A less
consistent effect is observed for reduction in FM that may be attributed to
the effect of gender.2,6 GH treatment
also has beneficial effects on bone metabolism and BMD in children with GHD
and in other indications and hence
may be important in alleviating the
risk for osteoporosis and risk for fracture that are associated with some of
these conditions in adult life. A beneficial effect of GH treatment on plasma
lipoprotein profiles has been documented in children with GHD and in
short children who were born SGA. The
reduction in the atherogenic index
may lead to an overall reduction in
atherosclerotic risk, which may be of
relevance in view of the predisposition toward increased risk for coronary events in adults with GHD as
well as in untreated adults who were
born SGA.
It is widely known that GH treatment is
associated with reduced insulin sensitivity. Concerns have been raised regarding the long-term effects of GH
treatment on insulin-glucose homeostasis in some patient groups, especially in short children who were born
SGA, whose insulin sensitivity may already be reduced; however, data from
long-term studies suggested that
there is a lack of diabetogenic effect of
GH treatment in SGA and other pediatric patient populations and that accumulated data suggest that negative
changes in insulin sensitivity during
treatment are generally reversible on
discontinuing GH. Moreover, GH therapy does not seem to have adverse
cardiac effects in children. It should be
noted that the improvements in metabolic and cardiovascular measures
that are seen in pediatric studies have
not so far been followed up in these
subjects at older ages, and more research into the long-term consequences of these effects is warranted.
Adverse effects related to fluid retention are generally transient or may be
resolved with GH dose adjustment. No
evidence of an excess of de novo cancers and no increase in observed cancer risk have been shown. Careful
management of episodes of adrenal insufficiency or hypoglycemia is warranted. In summary, although the main
role of GH replacement therapy in a
pediatric population is generally considered to be an improvement of
height, it is evident that this linear
growth is accompanied by a number of
beneficial metabolic effects in these
patients.
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e913
ACKNOWLEDGMENTS
Novo Nordisk supported the advisory
panel meeting on the effects of
growth hormone, which was also at-
tended by Jens Sandahl Christiansen, Morey Haymond, Anita
Hokken-Koelega, Peter Lee, Keiichi
Ozono, and Akira Shimatsu. We thank
Dr Penny Butcher, (Watermeadow
Medical, Witney, United Kingdom) for
assistance in the preparation of this
manuscript.
ing transition of GH-deficient patients
from adolescence to adulthood: a phase III
multicenter, double-blind, randomized
two-year trial. J Clin Endocrinol Metab.
2005;90(7):3946 –3955
Boot AM, Engels MA, Boerma GJ, Krenning
EP, De Muinck Keizer-Schrama SM.
Changes in bone mineral density, body
composition, and lipid metabolism during
growth hormone (GH) treatment in children with GH deficiency. J Clin Endocrinol
Metab. 1997;82(8):2423–2428
Schweizer R, Martin DD, Haase M, et al.
Similar effects of long-term exogenous
growth hormone (GH) on bone and muscle
parameters: a pQCT study of GH-deficient
and small-for-gestational-age (SGA) children. Bone. 2007;41(5):875– 881
Roemmich JN, Huerta MG, Sundaresan SM,
Rogol AD. Alterations in body composition
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van der Sluis IM, Boot AM, Hop WC, De Rijke
YB, Krenning EP, de Muinck KeizerSchrama SM. Long-term effects of growth
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(Continued from first page)
Serono; Dr Czernichow is a consultant for Novo Nordisk, Pfizer, and Ipsen; Dr Ross is a consultant for Novo Nordisk and Eli Lilly and has received research grants
from Novo Nordisk, Eli Lilly, and Pfizer.
e918
ROSS et al
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Growth Hormone: Health Considerations Beyond Height Gain
Judith Ross, Paul Czernichow, Beverly M. K. Biller, Annamaria Colao, Ed Reiter,
Wieland Kiess and on behalf of the participants in the advisory panel meeting on the
effects of growth hormone
Pediatrics 2010;125;e906; originally published online March 22, 2010;
DOI: 10.1542/peds.2009-1783
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