S y m p o s i u m on G r o w t h and Its Disorders

Growth Hormone Therapy

Anurag Bajpai 1 and P.S.N. M e n o n

1Division of Pediatric Endocrinology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi,
India and Department of Pediatrics, Armed Forces Hospital, Kuwait.

Abstract. Growth hormone (GH) therapy has revolutionized treatment of children with growth hormone deficiency (GHD).
Improved height outcome with final height in the target height range has been achieved in these children. Identification of
Creutzfeldt-Jakob disease, a deadly prion mediated disorder, in recipients of pituitary GH accelerated the transition from pituitary
derived GH to recombinant GH. Once daily subcutaneous administration of the freeze-dried preparation at evening is the
recommended mode of GH therapy. Studies have led to use of higher dose of GH for improving height outcome (0.33 mg/kg/
week or 0.14 IU/kg/day) albeit at a significantly high cost. Growth velocity increases from 3-4 cm/year before therapy to 10-
12 cm/year during the first two years of therapy and is maintained at 7-8 cm/year after a period of two years. Close follow-up
with regular clinical and laboratory monitoring is essential for achieving a desirable height outcome. A theoretical unlimited
supply has led to wide spread use of GH in a variety of disorders other than GHD. Initially started in children with Turner
syndrome, GH has now been used in chronic renal failure, idiopathic short stature and intrauterine growth restriction besides
a wide array of newly emerging indications. [Indian J Pedlatr 2005; 72 (2) : 139-144] Emaih psnmenon@hotmail.com

Key words : Growth hormone; Growth hormone deficiency; Idiopathic short stature; Tumer syndrome

Growth hormone (GH) therapy forms the cornerstone of
management of children with growth hormone deficiency
(GHD). Pituitary derived GH was used for over 25 years
with r e m a r k a b l e success. Limited s u p p l y h o w e v e r
r e s t r i c t e d its w i d e s p r e a d use. I d e n t i f i c a t i o n of
Creutzfeldt-Jakob disease, a d e a d l y p r i o n - m e d i a t e d
disorder, in recipients of pituitary GH accelerated the
transition from pituitary derived GH to recombinant GH.
A theoretical unlimited supply has led to widespread use
of GH in a variety of disorders other than GHD.
Route of Administration
Intramuscular route was initially recommended for GH
due to the possible immunogenic effect of subcutaneous
injection. Efficacy, p h a r m a c o k i n e t i c effects and
immunogenic potential of subcutaneous injection of GH
are similar to i n t r a m u s c u l a r a d m i n i s t r a t i o n . 1.2
Subcutaneous injection is currently the route of choice for
GH administration. Trials on intranasal administration of
GH are under way.
Time of Administration
Pituitary derived GH was administered two to three times
in a week. Studies have shown that daily GH is superior
to intermittent administration with regard to growth, IGF
response and serum GH levels.3 Twice daily GH has not
b e e n s h o w n to be s u p e r i o r to once daily. 4 E v e n i n g
administration of GH leads to higher GH levels, greater
IGF response and better metabolic profile compared to
m o r n i n g or a f t e r n o o n a d m i n i s t r a t i o n . -~Once d a i l y
administration at evening is the recommended mode of
GH therapy.
Preparations and Mode of Administration
Freeze-dried preparations are the commonest forms of
G H available. Liquid p r e p a r a t i o n s of G H h a v e the
advantage of ease of administration. A long acting analog
of GH has shown promising results in initial studies. 6 GH
has traditionally been injected with a syringe. Automated
pen devices have the advantage of ease of administration,
accuracy of dose and less inconvenience to the patient.
Dose Expression
The dose of GH has traditionally been expressed as unit/
kg/day. Recently there is a trend of using m g / k g / d a y or
m g / m 2 / w e e k for calculation of dose of GH. As per WHO
standards 1 mg of recombinant G H has a bioactivity
e q u i v a l e n t to 3 IU. Expressing dose by surface area
compared to b o d y weight has the advantage of lower
v a r i a t i o n f r o m infancy to a d o l e s c e n c e and is m o r e
representative of body requirement. 7 Estimation of GH
dose a c c o r d i n g to b o d y w e i g h t is in p a r t i c u l a r
nonphysiological in obese children as GH levels correlate
negatively with body fat content. Despite these limitations
GH dose is expressed according to body weight in most
countries.

Correspondence and Reprint requests : Dr. P.S.N. Menon, Dosage

Consultant & Chairman, Department of Pediatrics, Armed Forces The endogenous production rate of GH is variable and
Hospital, PO Box 5819,Salmiya 22069,Kuwait. Fax : (965)4760324

Indian Journal of Pediatrics, Volume 72--February, 2005 139

 Anurag Bajpai and P.S.N. Menon
ranges from 20 ~tg/kg/day during pre-pubertal period to
35 ~tg/kg/day during puberty? Dose of 0.16 m g / k g /
week (0.07 I U / k g / d a y , 22 ~ t g / k g / d a y ) therefore
represents physiological replacement dose for GH. Initial
dose recommendations for patients with GHD have been
based on these estimates. Studies on GH therapy in GHD
have shown that this dose is unlikely to produce
sustained catch-up growth and have led to use of higher
dose for improving height outcome (0.33 mg/kg/week,
0.14 IU/kg/day, 45 Ilg/kg/day). In conditions other than
GHD higher doses of GH are required to achieve
pharmacological effects.
GH THERAPY IN DIFFERENT DISORDERS
The scope of GH therapy has been expanded dramatically
in the last two decades with use in a variety of genetic
syndromes, skeletal dysplasias and chronic diseases.
GHD however remains the most important indication of
GH therapy.
Growth Hormone Deficiency
GH therapy has been shown to significantly improve
height outcome in GHD. Close follow-up with regular
clinical and laboratory monitoring.is essential for
achieving desirable height outcome.
Diagnosis
The diagnosis of GHD should be based on a combination
of auxological and laboratory parameters. Compromised
height (standard deviation score, SDS < -2) with low
growth velocity (SDS < -1) in the presence of
inappropriate response to two stimulation tests is
required for establishing the diagnosis of GHD. 9 Recent
recommendations suggest that peak GH levels below 10
ng/ml are diagnostic of GHD compared to previously
used levels of 5-7 ng/ml.
Initiating Therapy
GH therapy should be initiated only after other anterior
pituitary hormone deficiencies have been excluded or
treated. Parents should be explained about the cost of
therapy and the need of long-term follow-up. Giving GH
for less than two years is futile and should be strongly
discouraged. Initial GH dose is determined according to
age, skeletal maturation and pubertal status of the patient.
Thus while lower dose may be acceptable in a four-year-
old child, higher doses are definitely indicated in a nine-
year-old girl approaching puberty. Prediction models, a
recent advance in the management of children with GHD,
may be used for determining appropriate GH dose for the
patient. ~~ Initial dose of 0.17-0.33 m g / k g / w e e k (0.07-
0.14 IU/kg/day, or 4.6-9.2 mg/m2/week) has been used
for treatment of GHD. Studies have however shown that
higher doses of GH may be helpful in improving height
outcome albeit at a significantly higher cost. ~2,13
140
Treatment of Concomitant Anterior Pituitary
Deficiencies
Cortisol should be the first hormone to be replaced in a
child with multiple pituitary hormone deficiency.
Replacement doses of glucocorticoids in these patients (8-
12 mg/m2/day) are low compared to those with primary
adrenal insufficiency (12-15 mg/m2/day).
Mineralocorticoid replacement is not required. Free
thyroxine (FF4) levels should be maintained in the normal
range. It is important to emphasize that overtly aggressive
thyroid replacement may lead to inappropriate skeletal
maturation and compromised height. Replacement of sex
hormones should be delayed (12 years in girls and 14
years in boys) to provide adequate time for GH therapy.
Follow-up
Children on GH therapy should be followed-up every
three months. Evaluation at each visit should include
measurements of height, weight, height SDS, growth
velocity SDS and assessment for complications of therapy.
Bone age is of limited utility in follow-up of children on
GH therapy except for the patient nearing completion of
statural growth. IGF-1 and IGFBP-3 levels should be
measured annually and maintained at high normal range
for the age and gender of the child. ~4GH therapy may
unmask hypothyroidism in children with borderline
thyroid status. Diabetogenic effect of GH may induce
insulin resistance and result in impaired glucose tolerance
or overt type 2 diabetes mellitus. Blood sugar and FT4
levels should be estimated after an interval of three, six
and twelve months of initiation of GH therapy. Thereafter
annual estimation of blood sugar and FT4 levels should
be performed. It is important to emphasize that intra-
cranial tumors may be missed on initial CNS imaging
leading to a misdiagnosis of idiopathic GHD. These
children should be closely monitored for development of
features indicating CNS involvement.
Response to Therapy
GH therapy is associated with significant improvement in
growth velocity, which increases from 3-4 cm/year before
therapy to 10-12 cm/year during the first two years of
treatment. ~s This catch-up response, however is not
maintained and growth velocity declines to 7-8 cm/year
after a period of two years. This apparent loss of effect of
GH does not represent failure of therapy but
demonstrates growth at a normal rate following
correction of GH deficient state. ~6Inappropriate response
to GH therapy should prompt evaluation of compliance,
injection technique, hypothyroidism or reconsideration of
the diagnosis of GHD (Table 2). Decline in growth
velocity following an initial increase suggest the
possibility of unmasking of hypothyroidism while no
response should prompt reconsideration of the diagnosis
of GHD (Fig 1). Doses of GH should be adjusted
according to growth velocity, pubertal status and IGF-1
Indian Journal of Pediatrics, Volume 72--February, 2005
 Growth Hormone Therapy

TASTE1. Follow-up of Patients on GH Therapy height SDS -1.3) c o m p a r e d to GH alone (height SDS -
Parameter Frequency 2.7). ~ GnRH analog therapy should be used for a period
of at least two years as treatment for shorter duration may
Clinical lead to initial acceleration of puberty due to the agonist
Height SDS 3 months activity of the hormone.
Growth velocity SDS 3 months
Complications of therapy 3 months D i s c o n t i n u a t i o n of Therapy
Injection technique, compliance 3 months
GH therapy should be continued till final height has been
Laboratory achieved. Growth velocity below 2 cm in the preceding
Free thyroxine (FT4) At 3, 6 and 12 mo of therapy, year with bone age of 14 years in girls and 16 years in
Annually thereafter boys is considered as indicator of final height. The issue of
Blood sugar Annually
IGF-1, IGFBP-3 Annually continuation of GH therapy during adulthood should be
discussed with the family.
TAerE2. Reasons for Poor Response to GH Therapy Effect o n Final H e i g h t
Drug related Lower dose Studies involving a large number of patients with GHD
Poor compliance have s h o w n significant i m p r o v e m e n t in final height
Improper technique following GH therapy. 2~26Most of these studies however
Disease related Wrong diagnosis
GHD type IA with anti GH antibodies have used historical controls for comparison. Untreated
Patient related severe G H D is associated with final height SDS in the
Poor nutrition range of--4 to -6 while long term GH therapy is associated
Malabsorption with final height SDS in the range of -1 to -2. This could
Complication related Hypothyroidism translate in a height gain of 20-30 cm. The efficacy of GH
in children with severe G H D remains unequivocal; its
12 impact on milder forms of disease may not be as dramatic.
Factors I n f l u e n c i n g O u t c o m e
GHD
An understanding of factors influencing height outcome
thyrodism is helpful in appropriate management of these children.
~" 4 Studies have shown that early diagnosis, higher dose,
J ~ Non-GHD higher target height SDS, greater height SDS at the time of
~2
onset of p u b e r t y and longer d u r a t i o n of t h e r a p y are
0 associated with better height outcome. 2~29Height gain
0 1 yr 2 yr 3 yr 4 yr 61ff during first year of therapy is an important predictor of
Treatment Duration (Years) overall response. This emphasizes the need of appropriate
Fig 1. Response following GH therapy management and close monitoring during initial part of
GH therapy. Table 3 s u m m a r i z e s factors influencing
and IGFBP-3 levels. Prediction models have been used for height outcome in GHD and interventions directed at
optimizing GH dose. 1~ improving outcome. Children with combined pituitary
Optimization of Therapy During Puberty deficiency have better height outcome compared to those
with isolated GHD. ~ This may be due to delay in puberty
Pubertal g r o w t h in children with G H D is similar to due to concomitant gonadotropin deficiency.
normal individuals27,~8 Compromised height at puberty is
therefore invariably associated with compromised final TABrE3. Factors Influencing Height Outcome in GHD and
height. Two different approaches have been tried for Possible Intervention for Improving Outcome
maximizing benefits of GH therapy in individuals who
are short at the onset of puberty. In the first approach Factor influencing outcome Impact Intervention
higher doses of GH (up to 0.15-0.2 I U / k g / d a y ) have been Age at initiation Negative Early diagnosis
used during puberty. 19In a randomized controlled trial Initial height SDS Positive Early diagnosis
high dose GH during puberty (0.7 m g / k g / w e e k , 0.3 IU/ Height SDS at puberty Positive
kg/day) was associated with significantly higher growth Pubertal height gain Positive GnRH analog,
velocity compared to lower dose (0.3 m g / k g / w e e k , 0.13 higher dose
Duration of therapy Positive Increaseduration
I U / k g / d a y ) ? ~ Prolongation of puberty with the use of Dose Variable Higher dose
gonadotropin releasing hormone analogs forms the basis Target height Positive -
of the other approach. 21 In a randomized controlled trial Height gain during first year Positive High initial dose,
combination of GnRH analog with GH for a period of close monitoring
three years was associated with better outcome (final Multiple pituitary defects Positive

Indian Journal of Pediatrics, Volume 72--February, 2005 141

 Anurag Bajpai and P.S.N. Menon

Cost of T h e r a p y growth. Recent studies have shown that GHD in adults is

One of the major limitations of GH therapy is high cost. In
a study conducted in United States the cost of G H therapy
for a 20 kg child with G H D was estimated to be $15,000
per year. In India the approximate cost for a 20 kg child
would be Rs 200,000 per year. Cost considerations are the
major limiting factors of wide spread use of G H therapy
in resource-poor settings.
A d v e r s e Effects
Recombinant G H has been s h o w n to be safe during its
w i d e s p r e a d use (Table 4). The m o s t c o m m o n initial
adverse effects include headache and v o m i t i n g due to
pseudotumor cerebri and edema due to fluid and sodium
retention. 31 These effects improve over time without any
intervention. It is however important to emphasize that
headache in a child with a diagnosis of idiopathic G H D
m a y be a pointer of an intra-cranial t u m o r and should
p r o m p t a p p r o p r i a t e CNS i m a g i n g . Initial r e p o r t s
s u g g e s t e d an i n c r e a s e d risk of l e u k e m i a in subjects
receiving GH; subsequent studies have however failed to
substantiate these findings. 32-~The use of G H in children
with intra-cranial tumors is In particular a major cause of
concern due to the theoretical possibility of reappearance
of tumors. In a large study involving 1000 children with
intra-cranial malignancy G H therapy was not associated
with increased risk of t u m o r recurrence. ~ G H therapy
m a y u n m a s k h y p o t h y r o i d i s m and induction of insulin
resistance mandating the need of close follow-up for these
complications during therapy. 36 Slipped capital femoral
e p i p h y s e s and obstructive sleep a p n e a h a v e not b e e n
s h o w n to be higher in children receiving G H t h e r a p y
compared to children with G H D who are not on GH. 37~
Therapy F o l l o w i n g C o m p l e t i o n of Statural G r o w t h
Initially G H t h e r a p y w a s limited to p e r i o d s of active
associated with significant complications in the form of
risk of atherosclerosis, altered body composition and poor
quality of life. 39 These complications improve with G H ? ~
These observations have led to the recommendations of
G H t h e r a p y in adults with G H D . Retesting for G H D
should be performed after discontinuing the d r u g for a
period of 1 month. A significant number of children with
isolated idiopathic G H D (50-70%) w o u l d not be G H
deficient during re-testing. This m a y reflect inaccuracies
of initial G H test on one h a n d and transient nature of
G H D on the other. Patients with peak G H levels below 3
n g / m l (cutoff levels for adults) should be started on 0.5
m g / d a y of GH. These r e c o m m e n d a t i o n s h o w e v e r are
difficult to follow in resource-poor setting.
GH THERAPY IN NON-GHD SHORT STATURE
Turner S y n d r o m e
Turner syndrome was the first disorder besides G H D for
which G H therapy was a p p r o v e d . L o n g - t e r m studies
h a v e suggested significant i m p r o v e m e n t in final height
following G H ranging from 4-9 cm over predicted height
at initiation of therapy. 41-43The dose of G H in T u r n e r
s y n d r o m e is higher c o m p a r e d to G H D (0.35 m g / k g /
week or 0.15 I U / k g / d a y ) . Use of even higher dose (0.3
I U / k g / d a y ) has been s h o w n to produce height gain in
the range of 16 cm. 44 Early G H therapy is r e c o m m e n d e d
for maximizing benefits. G H therapy should be started in
girls with Turner syndrome when height falls below 5 th
centile for the normal growth curve. G H stimulation test
is not required. Oxandrolone (50 ~tg/kg/day) should be
added after the age of 8 years. Early initiation of G H along
with delayed induction of p u b e r t y (at least four years
a f t e r s t a r t i n g G H ) c o m b i n e d w i t h o x a n d r o l o n e is

TaSLE4. Adverse Effects with GH Therapy

Adverse effect Incidence Suggested intervention

Psuedotumor cerebri* 0.16%/year Rule out CNS tumor
Glucose intolerance 1% Reversible
Slipped capital femoral epiphyses** 70-150/lO0000/year Orthopedic evaluation
Hypothyroidism Thyroxin replacement
Recurrence of tumor Unproven Delay treatment
Second malignancy Unproven
* Higher in Turner syndrome and chronic renal failure
**Higher in organic GHD

TABLE5. Benefits of GH Therapy for Established Indications

Disorder Indication Initial dose Benefit Evidence

GHD All subjects 0.07-0.1 IU/kg/d 15-20 cm Definite benefit
Turner Height < 5~'centile 0.14-0.2 IU/kg/d 6-8 cm Definite benefit
CRF All subjects 0.14-0.2 IU/kg/d 6-8 cm Unclear
ISS Height SDS < -3 0.14-0.2 IU/kg/d 4-6 crn Questionable
IUGR No catch up growth 0.10-0.2 IU/kg/d 8-10 cm Unclear
Prader Willi All subjects 0.14-0.2 IU/kg/d 15-20 cm Definite benefit
CRF - Chronic renal failure, ISS - Idiopathic short stature, IUGR - Intrauterine growth restriction

142 Indian Journal of Pediatrics, Volume 72--February, 2005

 Growth Hormone Therapy
a s s o c i a t e d w i t h best h e i g h t o u t c o m e in T u r n e r
syndrome. 45
Chronic Renal Failure (CRF)
Chronic renal failure is associated with significant growth
c o m p r o m i s e that persists despite renal r e p l a c e m e n t
therapy. High dose G H i m p r o v e s height o u t c o m e in
children with CRF. ~ In a randomized controlled study
involving 38 pre-pubertal children with CRF, treatment
with GH led to increase in height SDS by 1.4 compared to
decline in height SDS by 0.6 in the control group. 47 This
response however is not sustained over a long period of
time without kidney transplantation.
Idiopathic Short Stature (ISS)
Idiopathic short stature represents a mix of children with
mild defects of the GH and IGF axis and low genetic
potential. Marginal benefits have been reported with the
use of GH. A gain of 5-7 cm c o m p a r e d to historical
controls was observed in a study using high dose GH
(0.33 m g / k g / w e e k or 0.14 I U / k g / d a y ) . 4s In a meta-
analysis involving 1089 patients with idiopathic short
stature treated with GH height gain of 4-6 cm was noted. 49
The cost of therapy remains exorbitant at $13000 for every
cm of height gained. Trial of GH therapy in children with
idiopathic short stature should be continued for at least
six months. The d r u g m a y be discontinued in children
who do not show catch up growth. GnRH analog could be
combined with GH for maximizing height gain.
Intra-uterine Growth Restriction (IUGR)
IUGR comprises of a heterogeneous mix of individuals
with genetic, environmental and placental compromise.
Majority of these patients show catch up g r o w t h with
final height in the low normal range. H o w e v e r 15% of
these individuals have compromised height and are at
risk of s h o r t stature. In a r a n d o m i z e d c o n t r o l trial
i n v o l v i n g 54 c h i l d r e n w i t h IUGR, G H t h e r a p y w a s
a s s o c i a t e d w i t h i n c r e a s e in h e i g h t SDS by 2 SDS. 5~
Importantly, children receiving lower dose (0.1 I U / k g /
day) had similar height gain compared to those on higher
dose (0.2 I U / k g / d a y ) .
Prader-Willi S y n d r o m e
C h i l d r e n w i t h this s y n d r o m e h a v e s i g n i f i c a n t
complications like obesity, low muscle mass, hypotonia
and compromised height. GH therapy in a dose of 0.1 I U /
k g / d a y has been a s s o c i a t e d with i m p r o v e d h e i g h t
outcome, fat mass, b o d y composition and respiratory
functions. 5~
Other Disorders
The list of d i s o r d e r s for w h i c h GH has been used is
i n c r e a s i n g e v e r y day. F a v o r a b l e results h a v e b e e n
reported in dysmorphic syndromes like Seckel and Silver
Russel s y n d r o m e s a n d b o n e d i s o r d e r s like skeletal
dysplasia and h y p o p h o s p h a t e m i c rickets. Long-term
Indian Journal of Pediatrics, Volume 72--February, 2005
o u t c o m e h o w e v e r r e m a i n s u n c l e a r in m o s t of these
conditions. GH therapy has also been tried in catabolic
disorders like bums, HIV infection and anorexia nervosa.
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Indian Journal of Pediatrics, Volume 72--February, 2005