Recombinant growth hormone (GH) was first made available in 1985 and was initially used exclusively to treat children with
short stature caused by growth hormone deficiency. In the ensuing years, however, the use of GH as a pharmacologic agent to
improve linear growth in short children without GH deficiency has been explored, leading to approval by the Food and Drug
Administration of a number of indications for GH use in non-GH-deficient children. Children with chronic renal insufficiency,
Turner syndrome, or Prader-Willi syndrome, children who are born small for gestational age, and children with idiopathic short
stature (Table 1) are all now eligible for recombinant GH therapy.
An overview of GH therapy
Table 1
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General pediatricians are often the first physicians to detect abnormalities in growth and development in children. It is
therefore essential that pediatricians understand pertinent issues related to GH treatment for each of the approved non-GH-deficient
conditions because timely and appropriate referral to the pediatric endocrinologist is important for achieving optimal outcomes
with GH therapy. We will first review practical aspects of GH therapy, then discuss each of the FDA-approved GH indications.
Given that this article focuses on non-GH-deficient conditions, we will not discuss GH use for GH deficiency.
An overview of GH therapy
Table 2
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Six brands of recombinant GH are available in the United States for use in children, each with its own FDA-approved indications
and indication-specific dosing (Table 2). No generic forms of GH are available at this time.
Route of administration. GH is given daily by subcutaneous injection, and parents are trained by health-care providers to administer injections.1 Previously, GH was given three times a week, but it is now recommended that it be given six or seven times a week because
studies have shown that outcomes are improved with more frequent dosing.2
Duration of treatment. On average, the mean age of initiation of GH treatment is around 10 years,3 and because GH is usually given until children reach final adult height, treatment can last five years or longer.4,5
Contraindications. GH is contraindicated for children who have active malignancies or closed epiphyses.
Table 3
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Safety. Since 1985, post-marketing surveillance studies have monitored more than 200,000 patients on GH therapy for adverse events;
overall, GH is regarded as a safe medication.6,7 Table 3 lists known side effects for all of the indications. More common side effects include edema and reactions at the
site of injection. Scoliosis, hypothyroidism, and otitis media are also risks.
Other serious adverse events, including slipped capital femoral epiphysis (SCFE) and benign intracranial hypertension (IH),
have been reported but are rare. Any child receiving GH who complains of knee or hip pain or a limp should be evaluated for
SCFE. Any child on GH who complains of visual changes, headache, nausea, or vomiting should be assessed for papilledema and
IH, especially within the first few months after initiating treatment.4,5 Fortunately, IH is reversible, and GH can usually be restarted at lower doses.7
Although GH causes a transient decrease in insulin sensitivity, discontinuing treatment reverses the effect.6 However, children who are born small for gestational age are thought to be at greater risk of having insulin resistance and
developing type 2 diabetes.8 Therefore, it is recommended that fasting insulin and glucose be monitored yearly during GH treatment for this group of children.8
There is also a theoretical concern about increased risk of malignancy because GH treatment leads to production of insulin-like
growth factor-1 (IGF-1), which promotes cell proliferation and growth.9 To date there is no evidence of an increased risk of new tumors or tumor recurrence in GH-treated children. However, longer-term
follow-up studies are needed to address this concern.4
Quality of life. The treatment of non-GH-deficient short stature implies that psychosocial or quality-of-life improvements occur as a result
of height gain from GH therapy. However, studies have failed to demonstrate improvements in the quality of life of non-GH-deficient
short children treated with GH.10,11 Therefore, GH outcomes in this article refer solely to improvements in final adult height.
Chronic renal insufficiency
Children with chronic renal insufficiency are at significant risk of short stature because of a multitude of factors, including
inadequate caloric intake, degree of renal insufficiency, metabolic acidosis, sodium wasting, renal osteodystrophy, and glucocorticoid
use.12,13 In 1993, growth failure associated with renal disease became the first FDA-approved indication for the use of GH in non-GH-deficient
children.
Studies have shown that children with chronic renal insufficiency or renal failure on dialysis who are treated with GH have
improvements in growth velocity and sustained catch-up growth compared with untreated controls.14 Greater height gains have been shown to be associated with younger age at the time of diagnosis, longer duration of GH therapy,
and lower percentage of time spent on dialysis.14,15 Therefore, it is recommended that early GH therapy (before dialysis or renal transplantation) be given to children in order
to prevent irrecoverable height loss. Although pediatric endocrinologists are the primary prescribers for most GH indications,
pediatric nephrologists often initiate therapy and administer GH to their renal patients, so it is important for pediatricians
to determine whether an endocrinology referral is needed.
Turner syndrome
Short stature is a hallmark of Turner syndrome, which is characterized by the absence of all or part of a normal second sex
chromosome in females.16 Although GH therapy was approved for girls with Turner syndrome in 1996, the results of the first randomized, controlled
trial of GH treatment for Turner syndrome were released only this year.17
The study definitively showed that GH treatment resulted in an adult height 7.2 cm beyond that of the untreated control group.17 Age at initiation was the most important variable associated with adult height, with a benefit of 1.5 cm for each year of
earlier GH initiation.17 Given that as many as 22% of girls with Turner syndrome are diagnosed only after 12 years of age, it is recommended that
physicians perform a karyotype analysis for any girl with unexplained short stature and a height more than 2 standard deviations
(SD) below the mean adjusted for age and sex.18 Early diagnosis and referral will likely lead to improved final height outcomes.
Because girls with Turner syndrome also usually have gonadal failure, they require estrogen replacement therapy as well as
GH therapy.16 Because estrogen leads to closure of the growth plates, previous GH protocols delayed the onset of estrogen replacement to
improve final height outcomes.19 However, one recent study demonstrated that age-appropriate estrogen replacement does not appear to change the magnitude
of height gain, and, therefore, age-appropriate pubertal induction is likely indicated.17
One particular side effect to watch for during GH treatment of girls with Turner syndrome is otitis media because two separate
studies demonstrated a doubling in the risk of otitis media with GH treatment.17,20 Given that otologic conditions were found to be one of the strongest predictors of health-related quality of life in young
adults with Turner syndrome,21 meticulous otologic follow-up is recommended.
Prader-Willi syndrome
Prader-Willi syndrome (PWS) is caused by loss of an imprinted gene or genes on the long arm of chromosome 15.22 In infancy, affected children exhibit poor feeding, developmental delay, and muscle hypotonia. By 2 or 3 years of age, hyperphagia
develops, resulting in morbid obesity if dietary intake is not strictly controlled.22 Children with PWS also have abnormal body composition, characterized by decreased fat-free mass and increased fat mass, short
stature, and hypogonadism.23 The major clinical manifestations of PWS are thought to result from hypothalamic dysfunction and possible GH deficiency,
although GH stimulation tests in children with PWS confirm deficiency only in a subset of patients.22
GH therapy for PWS was approved in 2000. In addition to improving linear growth, GH appears to have other important metabolic
effects in children with PWS, including increasing lean body mass, decreasing body fat, and improving bone mineral density.
The most striking results occur in the first 12 months of therapy.24,25 The metabolic effects of GH have led some physicians to initiate GH treatment in infants and toddlers with PWS in the hope
of improving body composition and motor development in these children.24 However, there is controversy about the safety of GH therapy in all children with PWS, regardless of age.
When parents ask about GH for a child in the normal height range
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A number of sudden deaths have been reported among children with PWS within three to seven months of initiation of GH therapy.26-28 It is unclear whether the deaths resulted from underestimated spontaneous mortality caused by PWS or the effects of GH therapy.
The cause of death in most cases is presumed to be of respiratory origin, resulting from possible hypoventilation, aspiration,
or infection. At baseline, children with PWS suffer from pharyngeal narrowness, insufficiency of the respiratory muscles,
and hypoventilation.29 In addition, many children have morbid obesity, which can lead to significant obstructive sleep apnea. GH therapy may exacerbate
these risks because it causes lymphoid tissue growth, which may worsen airway obstruction.29Before initiating GH therapy, therefore, a sleep study and referral to an otolaryngologist for consideration of possible tonsillectomy
are recommended. Once a child with PWS has been started on GH therapy, parents should look for new onset or worsening of snoring
by the child and report this to the physician. If the child develops respiratory infections during the course of therapy,
aggressive treatment with antibiotics and hospitalization for respiratory monitoring are also recommended.29
Small-for-gestational-age infants
Small for gestational age (SGA) is defined as birth weight or birth length at least 2 SD below the mean for the infant's gestational
age, or approximately below the third percentile. The Usher and McLean charts are the most widely used instruments in the
US for classifying infants as SGA.27
One commonly held misperception is that SGA is synonymous with intrauterine growth retardation (IUGR). An infant with a history
of IUGR, defined as diminished fetal growth velocity documented by at least two intrauterine growth assessments, will not
be designated as SGA if the birth weight or length is greater than minus 2 SD. On the other hand, a child who is born SGA
may not have a history of IUGR.8
Most children who are born SGA experience postnatal catch-up growth, defined as reaching a height above the third percentile,
within the first two years of life. Approximately 10% of children with SGA, however, do not achieve catch-up growth, maintaining
a height 2 SD below the mean throughout childhood and into adulthood.8 It has been recommended, therefore, that a short child with SGA who does not show catch-up growth by 2 to 3 years of age
be referred to a pediatric endocrinologist for evaluation for GH therapy.8
GH therapy for children born SGA was approved by the FDA in July 2001. Trials have demonstrated that treatment accelerates
growth velocity and results in catch-up growth to a height SD in the normal range (greater than the third percentile). Height
gain varies from 1 to 2 SD (about two to five inches).30,31 As with other conditions, starting treatment at an earlier age improves final height outcomes, so GH therapy is recommended
for children 4 years and older.8
Children who are SGA are thought to be at greater risk of metabolic syndrome and type 2 diabetes as adults, and studies have
shown that short SGA children have lower mean insulin sensitivity compared with age-matched, average-for-gestational-age controls.32 Because GH impairs insulin sensitivity, a recent consensus panel has recommended that insulin sensitivity be monitored by
obtaining fasting serum glucose and insulin levels before treatment with GH and on a yearly basis during therapy.8
Idiopathic short stature
In July 2003, the FDA approved GH for "the long-term treatment of idiopathic short stature (ISS)—also called non-growth hormone-deficient
short stature—defined as a height SD ≤ –2.25 that is associated with a growth rate unlikely to permit attainment of adult
height in the normal range, in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes
other causes associated with short stature that should be observed or treated by other means."33
The FDA based its approval, in part, on the results of a double-blind, placebo-controlled trial to final height performed
at the National Institutes of Health, which found that children with ISS who were treated with GH for an average of four years
gained approximately 3.7 cm (1.5 in) of final height compared with the placebo group.4 Moreover, a dose-response study found that higher GH doses lead to an improved adult height gain, or approximately 2.8 inches.5
Responsiveness to GH in ISS is variable, probably because of the heterogeneity of the conditions represented in ISS. For example,
half of the children in the NIH placebo trial had a significant response, but the remaining half did not grow beyond their
original projected height.4,34 Some physicians, therefore, suggest using a six-month to one-year trial of GH therapy to assess the growth response, with
discontinuation of therapy in children with a poor response.34
Two features set the approval of GH for ISS apart from previous non-GH-deficient indications:
- eligibility is not based on a specific diagnosis
- approval designates a specific height threshold (lower than –2.25 SD, or less than the 1.2 percentile).35
With regard to the lack of a specific diagnosis, some children with ISS may have previously unrecognized mechanisms to account
for their short stature—IGF-1 deficiency or GH resistance, for example.33 However, diagnoses such as familial short stature and constitutional delay could also fall under the ISS classification.36 Pediatric endocrinologists hold differing opinions as to whether children with these "normal variants" of short stature should
be treated with GH under the ISS indication.
The risks and benefits of daily GH injections in otherwise healthy children are unknown. Careful scientific studies have shown
that short children are not at greater risk of psychosocial adjustment disorders compared with peers of normal stature37 and, aside from a height gain of one or two inches, GH therapy has not been conclusively demonstrated to improve quality
of life.11 The long-term side effects of GH therapy remain to be determined,6 as do the negative consequences of long-term daily injections or unmet expectations of height gain.
Furthermore, the designated height threshold raises both economic and societal concerns. Children with ISS are the largest
cohort eligible for GH therapy to date—estimated at 400,000.38 At an annual cost of $30,000 for a 20-kg child, treatment of ISS will have a significant impact on health care spending.39 In addition, some have suggested that ISS is a "never-ending" disorder because it is based on a statistical definition of
short stature.34,38 For example, treatment of the bottom 1.2% of children will lead to improvements in their height; other children who were
marginally taller but did not previously qualify for treatment will then be in the bottom 1.2% and eligible for GH. Finally,
there are important ethical concerns about the "slippery slope" of prescribing GH for normal children who do not meet the
designated height threshold.38
Appropriate work-up, early referral
Any child with short stature requires an appropriate work-up to detect treatable causes or poor growth. Early referral to
a pediatric endocrinologist is important to identify possible GH deficiency and to facilitate timely consideration and initiation
of GH therapy for the non-GH-deficient indications discussed previously. The ISS indication is the most controversial non-GH-deficient
indication to date.
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