The New Eng l a nd Jour na l of Me dic i ne

Review Article

Drug Therapy
A L A S T A I R J . J . W O O D , M. D. , Editor

G ROWTH H ORMONE T HERAPY

IN A DULTS AND C HILDREN
MARY LEE VANCE, M.D.,

AND

NELLY MAURAS, M.D.

ROWTH hormone is produced by the somatotroph cells of the anterior pituitary. Its
secretion is stimulated by growth hormone
releasing hormone and inhibited by somatostatin,
which are both produced by the hypothalamus.
Growth hormone secretion is pulsatile, and the amplitude of the pulses is greatest at night. Twentyfour-hour growth hormone secretion is maximal during puberty and declines gradually thereafter in both
women and men. Growth hormone acts by binding
to receptors on liver cells and other cells. One growth
hormone molecule binds to two receptor molecules
on the target cell, initiating a cascade of events that results in the secretion of insulin-like growth factor I,
which mediates many of the biologic actions of growth
hormone. Some of the extracellular domain of the receptor is released into the serum, and approximately
50 percent of growth hormone in serum is bound
to this part of the receptor. Despite its name, growth
hormone has other actions in addition to promoting
growth in children.
The goals of growth hormone therapy differ somewhat in adults and children. In adults the goals are
to restore normal body composition, improve muscle and cardiac function, normalize serum lipid concentrations, and improve the quality of life. In children
the goals are to promote linear growth, restore body
composition, and improve the quality of life.
GROWTH HORMONEREPLACEMENT
THERAPY IN ADULTS

Growth hormone has been administered not only

to adults of all ages with growth hormone deficiency,

From the Department of Internal Medicine, University of Virginia Medical

Center, Charlottesville (M.L.V.), and the Nemours Childrens Clinic, Jacksonville, Fla. (N.M.). Address reprint requests to Dr. Vance at Box 601, University of Virginia Medical Center, Charlottesville, VA 22908, or to Dr. Mauras at the Nemours Childrens Clinic, 807 Nira St., Jacksonville, FL 32207.
1999, Massachusetts Medical Society.

1206

but also to adults with catabolic illnesses, such as burn

injuries, and to older adults with decreased growth
hormone secretion. However, studies in adults without growth hormone deficiency are limited.
Causes of Growth Hormone Deficiency in Adults

Over 90 percent of adults with growth hormone

deficiency have overt pituitary disease, which is usually caused by a pituitary adenoma or by surgery or
radiation therapy for a pituitary adenoma.1 Among
patients with pituitary adenomas, those with a deficiency of one or more other pituitary hormones are
also likely to have growth hormone deficiency.
Diagnosis of Growth Hormone Deficiency

Growth hormone deficiency has been diagnosed

primarily on the basis of subnormal growth hormone
secretion in response to stimuli. In the United States
the Food and Drug Administration (FDA) has approved growth hormone therapy for adults only if
there is evidence of hypothalamic or pituitary disease
and a subnormal serum growth hormone response
to one stimulation test. The FDA has stipulated that
the peak serum growth hormone concentration in
response to hypoglycemia or another stimulus should
be less than 5 mg per liter, if measured by radioimmunoassay, or less than 2.5 mg per liter, if measured by
immunoradiometric assay. The Growth Hormone Research Society has recommended that the diagnosis be
based on a stimulated serum growth hormone value
of less than 3 mg per liter during hypoglycemia, and
this value is widely accepted as diagnostic in Europe.2
Measurements of serum insulin-like growth factor I
or insulin-like growth factorbinding protein 3, both
of which are growth hormonedependent, are not
reliable indicators of growth hormone deficiency in
adults.3 Insulin-induced hypoglycemia is the preferred provocative stimulus, because in patients with
pituitary disease the response to this stimulus is more
likely to be abnormal than are the responses to levodopa, arginine, growth hormonereleasing hormone,
glucagon, and clonidine. However, the insulin test is
contraindicated in patients with coronary artery disease, generalized debility, or seizure disorders.
Clinical Manifestations

There is evidence that growth hormone deficiency

in adults is deleterious, increasing the risk of death
from cardiovascular disease. In three retrospective
studies of 849 patients with varying degrees of hypopituitarism and presumed growth hormone deficiency, the rate of mortality from cardiovascular disease was 1.9, 1.35, and 1.4 times as high as that of

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D RUG TH ER A PY

TABLE 1. PHYSICAL

STUDY

NO. OF
PATIENTS

AND

BIOCHEMICAL ALTERATIONS

BODY
COMPOSITION

NA

NA

NA

NA

NA

Cuneo et al.8

24

Cuneo et al.9

24

Lehmann et al.10

10

NA

Bing-You et al.11

14

NA

Markussis et al.12

34

NA

12% increase in thickness of

carotid intima and media

Cuneo et al.13

24

NA

NA

Merola et al.14

11

NA

Holmes et al.15

26

Nass et al.16

20

20

GROWTH HORMONE DEFICIENCY.*

NA

1822% increase
in fat mass 1 yr
after discontinuation of GH
therapy
16% decrease in
quadriceps area
NA

Longobardi et al.17

WITH

BONE MINERAL DENSITY

11

106

ADULTS

CARDIOVASCULAR SYSTEM

Rutherford et al.7

Attanasio et al.1

IN

23% decrease in aortic distensibility

NA

NA
Total body, 8% decrease;
femoral neck, 14% decrease; Wards triangle,
18% decrease; trochanter, 10% decrease
NA

NA

EXERCISE AND
STRENGTH

SERUM LIPIDS

58% decrease in
NA
strength 1 yr after discontinuation of GH
therapy
26% decrease in
NA
quadriceps force
2028% decrease
NA
in maximal oxygen uptake
NA
18% increase in serum
cholesterol
NA
NA

NA

NA

Serum cholesterol, 19% increase; LDL cholesterol,

23% increase; HDL
cholesterol, no change
Percentage of patients
with abnormal values:
serum cholesterol, 39;
LDL cholesterol, 39;
HDL cholesterol, 75;
TG, 26
NA

Interventricular septal thickNA

NA
ness, 22% decrease; posterior ventricular-wall thickness, 33% decrease; LV
mass index, 36% decrease;
ejection fraction, 14%
decrease
NA
NA
Changes in z score: verteNA
NA
bral column, 1.07;
lumbar spine, 0.76;
femoral neck, 0.38;
forearm, 0.86
NA
No change in LV mass or
NA
18% decrease in
NA
chamber size
maximal oxygen
uptake
2.4-kg increase in
NA
NA
NA
Percentage of patients
fat mass in men,
with low serum HDL
3.3-kg increase
cholesterol: AO, 72;
in fat mass in
CO, 54
women
NA
Ejection fraction at rest,
NA
NA
NA
17% decrease; ejection
fraction during exercise,
29% decrease

*GH denotes growth hormone, NA not assessed, LDL low-density lipoprotein, HDL high-density lipoprotein, TG triglycerides, LV left ventricular, AO
adult-onset growth hormone deficiency, and CO childhood-onset growth hormone deficiency.

age- and sex-matched normal subjects.4-6 The rate of

mortality from cancer was either half the rate for normal subjects or similar to it.5,6
As compared with age- and sex-matched normal
subjects, adults with growth hormone deficiency have
increased fat mass, reduced muscle mass and strength,
smaller hearts and lower cardiac output, lower bone

density, and higher serum lipid concentrations (Table 1).1,18,19 They also have decreased vitality, energy,
and physical mobility; emotional lability; feelings of
social isolation; and disturbances in sexual function,
despite adequate correction of hormonal deficiencies
other than growth hormone deficiency.20-22 These
symptoms occur both in patients with childhoodVol ume 341

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The Ne w Eng l a nd Jour na l of Me dic i ne

TABLE 2. EFFECTS

OF

NO. OF
PATIENTS

STUDY

GROWTH HORMONEREPLACEMENT THERAPY ON BODY COMPOSITION

IN ADULTS WITH GROWTH HORMONE DEFICIENCY.*

DURATION
OF THERAPY

Salomon et al.23

11

6 mo

Jorgensen et al.24

22

4 mo

Whitehead et al.25

14

6 mo

Bengtsson et al.26

6.5 mo

Cuneo et al.13
OHalloran et al.27

24
12

6 mo
1 yr

Mardh et al.28

115

6 mo

Rosen et al.19

25

1 yr

Hansen et al.29

13

1 yr

Beshyah et al.30
Baum et al.31

25
16

1 yr
1.5 yr

10
Al-Shoumer et al.32
Attanasio et al.1 AO, 52;
CO,
32

Cuneo et al.33

70

4 yr
6 mo

6 mo

LEAN BODY
FAT-FREE
MASS

OR

ADIPOSE
MASS

BONE
MINERAL
DENSITY

5.5-kg in- 5.7-kg decrease

NA
crease
5% increase 7% decrease in
NA
in thigh
thigh adipose
muscle
volume
volume
7% increase 10% decrease
No change in
spine
3.9-kg in- 6-kg decrease
NA
crease
NA
NA
NA
6% increase 11% decrease
Spine, 6% increase;
forearm, 4% increase
2.6-kg in- 3.2-kg decrease
NA
crease
4% increase 8% decrease
Total body, 1% decrease; femoral
neck, 5% increase; trochanter, 5% increase
3.3-kg in- 4.9-kg decrease
NA
crease
NA
NA
NA
4% increase 11% decrease
Lumbar spine, 5%
increase; femoral neck, 2.4%
increase; no
change in proximal radius
9% increase 14% decrease
NA
AO, 3.5-kg AO, 4.9% deNA
increase;
crease; CO,
CO,
5.5% decrease
3.7-kg
increase
6% increase 14% decrease in
NA
skin-fold
thickness

SERUM
TOTAL
CHOLESTEROL

12% decrease
NA

No change
No change
12% decrease
NA

NA
No change

NA
26% decrease
NA

AND

SERUM LIPID CONCENTRATIONS

SERUM HDL
CHOLESTEROL

SERUM LDL
CHOLESTEROL

NA

NA

NA

NA

No change
NA
No change
NA

No change
NA

No change

No change

NA

No change

24% decrease 24% decrease

NA
NA

NA

NA

NA

12% increase

NA

No change

NA

NA

NA

5% increase
NA

26% decrease 8% increase

NA
NA

NA
NA
NA
AO, 8% decrease; AO, 23% in- AO, 11% deCO, 5% decrease;
crease; CO,
crease
CO, 12%
5% decrease
increase
3% decrease

TRIGLYCERIDES

NA
NA

8% increase 13% decrease No change

*HDL denotes high-density lipoprotein, LDL low-density lipoprotein, NA not assessed, AO adult-onset growth hormone deficiency, and CO childhoodonset growth hormone deficiency.
Results are for 12 to 18 months of treatment.
Results are for 51 patients after one year of treatment.

onset deficiency and in those with adult-onset deficiency, but they are more severe in the latter group.1
However, not all adults with growth hormone deficiency have these symptoms.
Response to Growth Hormone

Although the administration of growth hormone

to adults with growth hormone deficiency reverses
many of the changes listed in Table 1, the ultimate
clinical efficacy of growth hormone treatment is not
known. In the various treatment studies, the daily dose
of growth hormone ranged from 6 to 26 mg per kilogram of body weight. The doses were intended to
1208

raise the serum concentrations of insulin-like growth

factor I to well within the normal range. However,
it is not possible to reproduce the normal daily pulsatile pattern of growth hormone secretion with a
single daily injection. It will probably require more
than 20 years of growth hormone replacement to
know whether the rates of cardiovascular disease, bone
fracture, and mortality, as well as the quality of life,
are affected substantially.
The salient changes in body composition and serum lipid concentrations that occur in growth hormonedeficient adults treated with growth hormone
are summarized in Table 2. There are regional effects

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D R UG TH ER A PY

TABLE 3. ADVERSE EFFECTS

STUDY

Mardh et al.28
Attanasio et al.1

Cuneo et al.33

NO.

OF

OF

PATIENTS

Growth hormone, 115;

placebo, 118
Growth hormone, 52
with AO, 46 with
CO; placebo, 32 with
AO, 35 with CO
Growth hormone, 83;
placebo, 80

GROWTH HORMONEREPLACEMENT THERAPY

DURATION
THERAPY

ADULTS.*

ARTHRALGIA
MYALGIA

EDEMA

OF

IN

OR

DISCONTINUED
THERAPY

mo

percent of patients

Growth hormone, 37; Growth hormone, 19; Both groups, 7

placebo, 3
placebo, 2
Growth hormone: AO, Growth hormone: AO, Both groups: AO,
29; CO, 6; placebo:
23; CO, 6; placebo:
4; CO, 5
AO, 4; CO, 6
AO, 7; CO, 0

Growth hormone, 48;

placebo, 30

Growth hormone, 30; Growth hormone,

placebo 13
23; placebo, 14

*The side effects occurred with growth hormone doses higher than those currently recommended. AO denotes adultonset growth hormone deficiency, and CO childhood-onset growth hormone deficiency.

on body composition. For example, in one study of

adipose mass, treatment for 26 weeks resulted in a 13
percent decrease in subcutaneous fat mass and a 30
percent decrease in intraabdominal fat mass.26 These
changes persisted during one year of treatment, with
a 22 percent reduction in overall adipose mass and
a 61 percent reduction in trunk fat; conversely, lean
body mass increased by 3 to 11 percent.29,34 In several studies, exercise capacity increased by 11 to 19
percent, and muscle strength increased by 7 to 19 percent, reaching values similar to those in normal subjects.9,18-22,24-26,29,34-36 These increases occurred within
four months after the initiation of treatment and persisted during treatment periods of up to three years.36
Cardiac function did not change after six months of
treatment in one study.16 In another study, however,
there was a 26 percent increase in the left ventricular
mass index and a 12 percent increase in systolic function, with a return to pretreatment values six months
after the discontinuation of growth hormone treatment.37 There are no data on the effect of treatment
on cardiovascular-related morbidity or mortality.
In several studies, growth hormone therapy resulted in small increases in fasting serum glucose and insulin concentrations and in glycosylated hemoglobin
values, but all these values remained within the normal range.23,25,26,28,30,33 Treatment for five years did not
alter oral glucose tolerance or overall insulin sensitivity, but hepatic insulin sensitivity was less than that
of normal subjects.38 After six months of treatment,
the basal metabolic rate increased by 6 percent in
one study23 and by 11 percent in another.39 Other reported metabolic changes have been small increases
in serum triiodothyronine concentrations and transient decreases in serum thyroxine concentrations.26
Growth hormone therapy may increase cortisol degradation, and patients receiving glucocorticoid-replacement therapy may therefore need higher doses.
In some studies, quality-of-life measures, including
energy level, mood, sensitivity to pain, emotional la-

bility, and physical mobility, as measured by standardized psychological tests, improved with growth
hormone therapy.1,21,33 The effects of growth hormone on these measures appear to differ between
adults with adult-onset growth hormone deficiency
and those with childhood-onset deficiency. The former had significant improvements in scores for social isolation and physical mobility, whereas the latter had no changes in these scores.1 Among 125
adults treated with placebo or growth hormone for
12 months, the growth hormonetreated patients
had significant improvements in scores on standard
psychological tests of energy, emotional reactions to
stress, and social isolation, so that their scores were
similar to those of normal subjects.28 A possible explanation for the improvement in energy is that the
changes in the metabolic rate and in muscle and fat
mass allowed the patients to become more physically
active, but a direct effect of growth hormone on the
brain cannot be ruled out.
Side Effects

The most common side effects of growth hormone treatment in adults are edema and arthralgia
or myalgia (Table 3). These effects are dose-dependent. The daily dose of growth hormone used in these
trials ranged from 6 to 26 mg per kilogram, with
dose reductions of 25 to 50 percent if side effects
developed or if the serum concentration of insulinlike growth factor I increased above normal. In most
patients these effects resolved with a reduction in
the dose.
Any patient with a pituitary tumor or craniopharyngioma is at risk for a recurrence of the tumor, but
there is no evidence that growth hormonereplacement therapy increases this risk. Another concern is
the risk of cancer and cardiovascular disease. This concern arises because of the increased prevalence of
these diseases in patients with acromegaly, who have
high serum growth hormone concentrations for many
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The New Eng l a nd Jour na l of Me dic i ne

years. However, there is at present no evidence that

growth hormonereplacement therapy affects the
risk of cancer or cardiovascular disease.
Dose of Growth Hormone

According to FDA recommendations, the starting

dose of growth hormone in adults is 3 to 4 mg per
kilogram given once daily by subcutaneous injection, with a maximal daily dose of 25 mg per kilogram for patients up to 35 years of age and 12.5 mg
per kilogram for older patients. These recommendations are based on clinical trials in which growth
hormone was administered according to body weight.
However, the Growth Hormone Research Society
consensus conference has recommended a starting
dose of 150 to 300 mg per day, regardless of body
weight.2 The goal of therapy is to restore the serum
concentration of insulin-like growth factor I to the
middle of the normal range for persons of the same
sex and similar age. Initially, patients should be evaluated at one-to-two-month intervals by means of
clinical observation and measurement of serum insulin-like growth factor I, and the dose of growth hormone should be adjusted as needed to maintain the
target value for serum insulin-like growth factor I.
OTHER USES OF GROWTH HORMONE
IN ADULTS

In 1996, growth hormone was approved by the

FDA for treatment of wasting or cachexia in patients
with the acquired immunodeficiency syndrome
(AIDS). This approval was based on evidence that
growth hormone increased lean body mass and decreased fat mass in patients with AIDS, although no
survival benefit was observed. The use of growth
hormone has also been studied in small numbers of
adults with other catabolic illnesses, including those
associated with respiratory failure, burn injuries, recovery from surgery, congestive cardiomyopathy, liver transplantation, and renal failure. No consistent
benefit has yet been demonstrated. In a doubleblind, placebo-controlled study involving patients in
intensive care units with severe systemic illnesses, the
administration of high doses of growth hormone
was associated with increased mortality.40
Growth hormone has been given to patients with
obesity, osteoporosis, muscular dystrophy, and infertility, but with no consistent benefit. The administration of growth hormone to elderly ambulatory
patients resulted in changes in body composition similar to those that occur in adults with growth hormone deficiency. However, no statistically significant
improvement in muscle strength or exercise tolerance
occurred. Short-term administration of growth hormone to increase strength and endurance in athletes
is no more effective than training alone. Growth hormone should therefore not be administered to older
adults or to athletes.
1210

GROWTH HORMONE THERAPY

IN CHILDREN
Definition of Growth Hormone Deficiency in Children

The spectrum of growth hormone deficiency in

children ranges from the complete absence of growth
hormone, resulting in severe growth retardation, to
a partial deficiency, resulting in slightly short stature.
Complete absence of growth hormone also results in
a pudgy appearance and delayed skeletal maturation,
but the body proportions are normal.
The standard method of assessing growth hormone secretion in children is to measure the serum
growth hormone response to insulin and other stimuli. Another method is to make frequent measurements of serum growth hormone during the day
and night, but this is no more effective than the
standard method for detecting growth hormone deficiency.41 Formerly, the diagnosis of growth hormone deficiency in children was based on a peak serum growth hormone concentration of 5 mg per liter
or less in response to a provocative test, but a peak
serum growth hormone concentration of less than
10 mg per liter is now considered abnormal by many
clinicians.42 However, because the available growth
hormone assays have not been standardized, the cutoff value of less than 10 mg per liter is of limited usefulness, especially in borderline cases.43 Instead, the
diagnosis should be based on very short height, as
defined by the standard-deviation score (more than
2.5 SD below the mean height for normal children
of the same age), delayed bone age, poor growth velocity (less than the 25th percentile), and a predicted
adult height substantially below the mean parental
height. When used in conjunction with these measures, however, a peak serum growth hormone value
of less than 10 mg per liter in response to stimulation
is a reasonable definition of growth hormone deficiency, with values of less than 5 mg per liter reflecting the most severe deficiency. The problem facing the
clinician is to decide which of the children who have
some, but not all, of the abnormalities of growth and
the other abnormalities associated with growth hormone deficiency are likely to grow taller with growth
hormone therapy.
Other markers of growth hormone secretion, such
as concentrations of serum insulin-like growth factor I
and insulin-like growth factorbinding protein 3, are
not consistently abnormal in children with growth
hormone deficiency.44 In short children, findings of
normal or high serum concentrations of growth hormone and low serum concentrations of insulin-like
growth factor I suggest the diagnosis of growth hormone insensitivity (Larons syndrome), which can be
confirmed by measurement of serum growth hormonebinding protein and studies of the growth hormonereceptor gene.45 Some children with short stature have a partial insensitivity to growth hormone46

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D RUG TH ER A PY

that is associated with heterozygosity for mutations

of the growth hormonereceptor gene.47
Causes of Growth Hormone Deficiency and Its Variants
in Children
Congenital Growth Hormone Deficiency

Congenital growth hormone deficiency can occur

as a result of anatomical malformations of the brain
or genetic defects (Table 4).48-58 The latter include
not only mutations of the growth hormone gene
but also inactivating mutations of the gene for Pit-1,
a pituitary transcription factor involved in transactivation of the growth hormone and prolactin genes and
in the differentiation of anterior pituitary cells,51-55
and inactivating mutations of the PROP-1 gene,
which encodes for an embryonic pituitary protein
necessary for expression of the Pit-1 gene.56 A kindred in Pakistan with clinical and biochemical features
of growth hormone deficiency has been identified
with an inactivating autosomal recessive mutation of
the gene for the growth hormonereleasing hormone
receptor.57 The clinical manifestations of these inherited forms of growth hormone deficiency may be indistinguishable from one another. As more children
are studied, many of those previously considered to
have idiopathic growth hormone deficiency may be
found to have mutations in these or related genes.
Acquired Growth Hormone Deficiency

Tumors of the hypothalamic, pituitary, and pineal

region and optic gliomas can cause growth hormone
deficiency (Table 4). Among them, craniopharyngiomas are the most common; pituitary tumors are less
common in children than in adults.59 Central nervous system irradiation may impair pituitary function;
younger children given high doses of radiation for
the treatment of brain tumors are at highest risk.60
Chronic Renal Insufficiency

Chronic renal insufficiency is another condition

associated with marked growth retardation. It is not
completely reversed by renal transplantation, but it
improves with growth hormone therapy. Children
with chronic renal insufficiency often have heights
more than 2 SD below the mean for their age.
Turners Syndrome

Turners syndrome in girls is associated with short

stature (mean final height, 143 cm), ovarian failure,
and a variety of dysmorphic features, resulting from
deletions or mutations in one of the X chromosomes.61,62 The growth of these girls may also improve with growth hormone therapy.
Treatment Indications and Response to Growth Hormone
Classic Growth Hormone Deficiency

The administration of growth hormone to children

with growth hormone deficiency results in marked

TABLE 4. CAUSES OF CHILDHOOD-ONSET GROWTH

HORMONE DEFICIENCY.*
Congenital conditions
Anatomical anomalies
Pituitary aplasia
Hypoplasia
Stalk dysgenesis, with or without ectopic posterior
pituitary
Septo-optic dysplasia
Holoprosencephaly
Midline defects (cleft lip or palate)
Encephalocele, empty sella, solitary central incisor
Genetic factors
Idiopathic GH deficiency
Type IA autosomal recessive, GC mutation in
intron 4 of GH-1 gene, frameshift reading of mature
GH protein; high GH antibody titer; some patients
have a flat nasal bridge and a large head48,49
Type IB autosomal recessive, no GH-1 mutation;
may be associated with GHRH deficiency50
Type II autosomal dominant, TC mutation in
intron 3 of GH-1 gene50
Type III X-linked recessive, no GH-1 mutation; associated with agammaglobulinemia50
Mutations in the Pit-1 gene typical GHD phenotype;
abnormality in GH transcription factor51-55; other
anterior pituitary hormones may be present
Mutations in the PROP-1 gene combined anterior
pituitary hormone deficiency56
Mutations in the GHRH-receptor gene autosomal
recessive, nonsense mutation in exon 3 of the
GHRH-receptor gene; typical GHD phenotype;
no GH response to exogenous GHRH
Fanconis syndrome autosomal recessive; associated
with idiopathic GHD
Panhypopituitarism
Type I autosomal recessive
Type II X-linked recessive
Idiopathic
Acquired
Central nervous system tumors hypothalamic, pineal, and
pituitary tumors; craniopharyngiomas
Cranial irradiation administered for tumors or infiltrative
diseases
Infiltrative diseases histiocytosis X, sarcoidosis, tuberculosis, lymphocytic hypophysitis, hemochromatosis
Trauma
Hypoxic insult
Idiopathic causes
*GH denotes growth hormone, GHRH growth hormonereleasing hormone, and GHD growth hormone deficiency.
The specific gene mutations have not been characterized.

acceleration in linear growth, which is most pronounced during the first two years of treatment. According to data from more than 12,000 children in
the United States, collected by Genentech as part of
the National Cooperative Growth Study, the average
(SD) age at which growth hormone therapy was begun was 9.24.1 years. Growth velocity increased
from 4.42.8 cm per year to 10.03.1 cm per year
after one year of treatment, and the standard-deviation
score for height changed from 2.61.1 to 0.5
1.1 after seven years (Fig. 1). Similar results were reported by the Kabi International Growth Study.63 In
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Chronic Renal Insufficiency

Treatment with growth hormone increases linear

growth in prepubertal children70-72 and infants72 with
chronic renal insufficiency or kidney transplants,73-75
and is not associated with a decline in kidney function.
The effects of growth hormone therapy on the final
height of these children remain to be established.
The recommended dose of growth hormone for children with chronic renal insufficiency is higher (0.35
mg per kilogram per week) than that for children
with classic growth hormone deficiency. Chronic renal
insufficiency is an approved indication for growth
hormone therapy in the United States and many other
countries.
Turners Syndrome

In a study of girls with Turners syndrome, growth

hormone therapy resulted in a final height of 150.4
5.5 cm, which was 8.44.5 cm more than the predicted height in the absence of therapy. In 43 girls
treated with growth hormone and oxandrolone, an
anabolic steroid, the increase was greater (10.34.7
cm).76 Early initiation of treatment may result in
heights that exceed those predicted. The recommended dose is 0.375 mg per kilogram per week, given
in daily divided doses. Turners syndrome is an approved indication for growth hormone therapy in the
United States and other countries.
Idiopathic Short Stature

A heterogeneous group of otherwise apparently

normal children who are at or below the 5th percentile for height and have normal serum growth hormone responses to stimuli are classified as having genetic short stature (an inappropriate term, because
some forms of growth hormone deficiency and skeletal dysplasias are genetic), normal-variant familial
short stature if their parents are also short, constitutional delay of growth if there is a delay in skeletal
1212

Growth Velocity6
(cm/yr)

16
12
8
4
0
Before6 1
treatment

557

270

111

548

253

111

Year
No. of patients

5345 5187 3253 1961 1098

Standard-Deviation6
Score for Height

another U.S. study, involving 121 children (72 boys

and 49 girls) treated for an average of eight years, the
boys final height was 171.68.2 cm (standard-deviation score, 0.71.2), and the girls final height was
158.57.1 cm (standard-deviation score, 0.71.1).64
The average dose of growth hormone in the U.S.
studies was 0.3 mg per kilogram per week, given in
divided daily doses, but a lower dose may be effective in children with severe growth hormone deficiency.65 The younger the patient and the more severe the growth hormone deficiency, the better the
anticipated response to treatment.
Growth hormone production doubles during puberty,66-68 and consideration has been given to increasing the dose of growth hormone during this
period. However, doubling the dose during puberty
does not appreciably increase growth rates in children previously treated for leukemia.69

0
1
2
3
4
Before6 1
treatment

Year
No. of patients

8439 5221 3429 2048 1104

Figure 1. Mean (+SD) Growth Velocity and Standard-Deviation

Score for Height in Children with Growth Hormone Deficiency
Who Were Treated with Recombinant Human Growth Hormone
Daily for up to Seven Years.
Data are from the National Cooperative Growth Study (Genentech, South San Francisco, Calif.).

maturation, or idiopathic short stature if no other

cause is evident. Treatment of these children with
growth hormone is controversial with regard to both
efficacy and ethics.42
Studies have demonstrated an acceleration of linear growth during the first two to three years of
growth hormone treatment in short children.77-80
However, among 15 short children treated with
growth hormone for 4 to 10 years, the standarddeviation score for final height did not differ significantly from the predicted score in the absence of
therapy.79 Others have reported similar results.80,81 A
different result was reported in a recent multicenter
trial of growth hormone therapy (0.3 mg per kilogram per week) in 101 short children without growth
hormone deficiency who were treated for up to nine
years. In this study, the final height exceeded the predicted height in the 80 patients who reached their final height, by an average of 5.0 cm in boys and 5.9 cm
in girls.82 However, there was no prospective way to

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D RUG TH ER A PY

identify the short children who, when treated, had an

increase in height above that predicted. Some of the
children who had responses to growth hormone therapy may have had mild forms of insensitivity to
growth hormone, with or without mutations in the
growth hormonereceptor gene.46,47,58
Children with idiopathic short stature constitute
at least one third of all children receiving growth
hormone therapy in the United States,83 and many
children thought to have partial growth hormone
deficiency on the basis of stimulation testing may actually have idiopathic short stature. Parental pressure
to correct the perceived deficiency of short stature
has been responsible in part for the initiation of treatment in many of these children. However, growth
hormone administration may not increase the genetically determined final height of many children with
idiopathic short stature. Practitioners involved in the
care of short children should seek appropriate consultation and temper the expectations of the child and
the family with regard to the effectiveness of growth
hormone for the treatment of idiopathic short stature. Growth hormone should not be given routinely
but should be reserved for children who have severe
growth retardation (more than 2.5 SD below the
mean for age) and very slow growth velocity (less than
the 25th percentile), with no identifiable cause of
growth failure.
Other Conditions Impairing Growth

Growth hormone has been administered in an attempt to increase final height and overall quality of
life in children with other conditions resulting in
adult short stature. In one study, growth hormone
therapy increased linear growth in children with intrauterine growth retardation,84,85 although there was
no increase in final height.86 In another study, high
doses of growth hormone (0.7 mg per kilogram per
week) given for two years increased linear growth in
children with intrauterine growth retardation. However, the therapy also increased skeletal maturation,
so that the final height was no greater than the predicted height in the absence of therapy.87 In a group
of children with achondroplasia or hypochondroplasia, growth hormone therapy resulted in greater
growth than that predicted in the absence of therapy, but there was a worsening of body disproportion.88 Short-term acceleration of growth as a result
of growth hormone therapy has also been reported
in children with Downs syndrome, Noonans syndrome, the PraderWilli syndrome, spinal cord defects, hypophosphatemic rickets, and cystic fibrosis;
some of these children had impaired growth hormone
production.89-94 However, no studies have prospectively assessed linear growth until the achievement
of final height. Currently, growth hormone treatment cannot be recommended for children with these
conditions.

Transition from Adolescence to Adulthood

The use of growth hormone during the transition

from adolescence to adulthood is of interest because
this transition period involves the achievement not
only of adult height, but also of peak bone mass,
adult body composition, and reproductive maturity.
It is clear from studies of changes in body composition after the discontinuation of growth hormone
therapy that it should be continued in adolescents
with severe growth hormone deficiency who have
achieved their final height. However, in patients without pathologic disease, a stimulation test to confirm
growth hormone deficiency should be done at this
time, because growth hormone may no longer be
deficient. An unresolved issue is the appropriate dose
of growth hormone during this transition, since the
secretion of growth hormone during adolescence is
normally lower than during puberty but higher than
during adulthood.
Adverse Effects

The safety record of growth hormone treatment

is good, except for the development of Creutzfeldt
Jakob disease in children treated with pituitaryderived growth hormone.95-97 The disease has never
been reported in children treated with recombinant
growth hormone, the only form available since the
mid-1980s. Growth hormone may cause hyperinsulinemia, but there is no increase in the incidence of
diabetes mellitus. Children with other risk factors for
the development of insulin resistance, such as obesity or long-term glucocorticoid therapy, should have
periodic measurements of blood glucose during
growth hormone therapy. Growth hormone therapy
is not associated with an increase in the risk of leukemia or solid tumors or with an increase in the risk
of recurrence of any of these tumors.97-99 There is
general agreement, however, that children should
not be given growth hormone during the first year
after treatment for most tumors or leukemia and
during the first two years after treatment for medulloblastomas or ependymomas.97
Slipped capital femoral epiphyses have been associated with growth hormone deficiency and obesity.97 There is no evidence that this problem is caused
by growth hormone therapy, but children who have
hip pain or who begin to limp during therapy, particularly those with chronic renal insufficiency or
metabolic bone disease, should be evaluated appropriately. Other findings associated with growth hormone therapy that may or may not be effects of the
therapy include increased pigmentation and growth
of nevi, gynecomastia, pancreatitis, and benign intracranial hypertension. All these findings are rare.
CONCLUSIONS

Growth hormone therapy is beneficial in adults

and children primarily as replacement therapy. Other
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The New Eng l a nd Jour na l of Me dic i ne

uses of growth hormone are under investigation,

and the results of these studies will probably show additional benefits. Because growth hormonereplacement therapy has been administered for only 11 years
in adults, the long-term benefits and outcomes, including morbidity and mortality, are not yet known.
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