The role of recombinant insulin-like growth factor I in the
treatment of the short child
Arlan L. Rosenbloom
Purpose of review
Commercial preparations of recombinant human insulin-like
growth factor I became available in 2005. Off-label use has
been promoted because of the paucity of patients having
approved indications; I review the background and rationale
for such use.
Attempts to identify growth hormone unresponsiveness in
children with idiopathic short stature have been
unequivocal growth hormone insensitivity improves but
does not correct growth failure, in contrast to the typical
experience with growth hormone replacement of growth
hormone deficiency. This emphasizes the importance of
direct effects of growth hormone at the growth plate, which
cannot be duplicated by administration of recombinant
insulin-like growth factor I. Adverse effects testify to the
more than adequate delivery of administered recombinant
human insulin-like growth factor I to other tissues, including
lymphoid hyperplasia, coarsening of the facies, and
increased body fat.
In view of the risk profile, the limited ability of endocrine
insulin-like growth factor I to restore normal growth,
and the suppression of endogenous growth hormone
(and therefore local effects on growth) that occurs with
insulin-like growth factor I administration, the use of
recombinant insulin-like growth factor I should be
limited to those with well-documented growth hormone
unresponsiveness and severe short stature.
growth hormone, idiopathic short stature, insulin-like
growth factor I, insulin-like growth factor I-binding protein-
3, mecasermin, mecasermin rinfabate
Curr Opin Pediatr 19:458–464. ? 2007 Lippincott Williams & Wilkins.
Division of Endocrinology, Department of Pediatrics, University of Florida College
of Medicine, Gainesville, Florida, USA
Correspondence to Arlan L. Rosenbloom, MD, Children’s Medical Services Center,
1701 Southwest 16th Avenue, Gainesville, FL 32608-1153, USA
Tel: +1 352 334 1393; fax: +1 352 334 1476; e-mail: firstname.lastname@example.org
Current Opinion in Pediatrics 2007, 19:458–464
growth hormone deficiency
growth hormone receptor
growth hormone receptor deficiency
insulin-like growth factor I-binding protein 3
insulin-like growth factor I deficiency
insulin-like growth factor I
idiopathic short stature
recombinant human growth hormone
recombinant human insulin-like growth factor-binding protein 3
recombinant human insulin-like growth factor I
standard deviation score
? 2007 Lippincott Williams & Wilkins
approved recombinant human insulin-like growth factor
I (rhIGF-I; mecasermin, Increlex; Tercica, Brisbane,
California, USA) and an equimolar complex of rhIGF-I
and rhIGF-binding protein 3 (rhIGF-I/rhIGFBP3; meca-
sermin rinfabate, Iplex; Insmed, Glen Allen, Virginia,
USA) as orphan drugs. Approved indications are ‘severe
growth hormone receptor (GHR) or post-GHR signaling
pathway, or insulin-like growth factor I (IGF-I) gene
defects, and thedevelopment
antibodies in children with GH gene deletion. Because
these conditions are rare, comprising at most several
hundred children worldwide, there has been a concerted
off-label promotion [1??,2??]. This article will briefly
outline growth physiology in relation to the GH–IGF-I
axis, discuss diagnostic terminology, review thesafetyand
efficacy experience with rhIGF-I treatment of growth
disorders, and consider the evidence for broadening the
The GH–insulin-like growth factor I axis and
GH release from the anterior pituitary is controlled by
the balance between stimulatory GH-releasing hormone
and inhibitory somatostatin from the hypothalamus.
This balance is under feedback control by IGF-I of
somatostatin and GH-releasing hormone release, and
regulated by neurologic, metabolic, and other hormonal
influences, including numerous neurotransmitters and
neuropeptides which respond to various circumstances
that affect GH secretion, such as sleep, nutritional state,
stress, and exercise.
Secreted GH binds to its specific cell-surface dimeric
receptor (GHR); the complex thus formed links to and
activates the kinase enzyme Janus kinase 2 (JAK2),
resulting in a cascade of phosphorylation of cellular
proteins. The most critical of these proteins is the signal
transducer and activator of transcription 5b (STAT5b),
which couples GH binding to the activation of gene
expression that leads to the intracellular effects of GH,
including synthesis of IGF-I, IGF-binding protein 3
(IGFBP3), and acid-labile subunit (ALS).
The growth effect of GH has at least three components,
their relative contributions being a subject of continuing
IGF-I, IGFBP3, and ALS, because they are synthesized
by the liver and secreted into the circulation, allowing
measurement as circulating concentrations. The other
GHeffectsarenotdirectly measurable butinferredfrom
much animal and some human data; they are epiphyseal
prechondrocyte differentiation and enhancement of
local (autocrine/paracrine) production of IGF-I, thereby
stimulating clonal expansion of the differentiating
chondrocytes [3??,4]. Hepatic IGF-I circulates almost
entirely (>99%) bound to IGFBPs, principally IGFBP3,
as part of a large (150–200kDa) ternary complex
consisting of IGFBP3, ALS, and the IGF molecule.
The ALS stabilizes the IGF–IGFBP3 complex and
extends its half-life .
Children with genetically determined severe GH
deficiency (GHD) or GHR deficiency (GHRD; Laron
terine growth. In these conditions, however, standard
deviation score (SDS) for length declines rapidly after
birth, demonstrating the immediate need for GH for
postnatal growth. Growth velocity in the absence of
GHistypicallyhalfnormal (?3cm/year afterinfancy).
Diagnosis and classification of disorders of
insulin-like growth factor I production and
A pragmatic classification comprising a listing of specific
their accepted designations, which is already the practice
for defects in pituitary differentiation factors, has been
proposed to replace obfuscatory terminology [7??]. The
need for this revision has been disputed on the basis of
rapidly evolving knowledge [8?], but such a classification
permits ready insertion of new discoveries (Table 1).
The approval of mecasermin and mecasermin rinfabate
adopted the designation ‘severe primary IGFD’, a novel
label that surfaced simultaneously with the availability of
these products; a search for the term primary IGFD yields
only four hits, three from a single group [9,10,11??] and a
fourth from a manufacturer’s scientific director . The
terms primary and secondary are ambiguous, nonspecific,
and manipulable for marketing purposes; indeed, pro-
motional and packaging materials have dropped the word
severe. This ambiguity is reflected in the dual use of the
term primary in a recent etiologic classification where the
term is used to define genetic defects (as opposed to sec-
ondary or acquired dysfunction), but within this category
definitions is consistent with severe primary IGFD, which
its users apply to all abnormalities resulting in IGF-I
deficiency that do not precede the GHR .
The definition adopted by the US Food and Drug
Administration for severe primary IGFD was height
SDS less than or equal to ?3, basal IGF-I SDS less than
or equal to ?3, and normal or elevated GH concentration.
There is no mention of growth velocity, osseous
maturation, or projected height relative to mean parental
stature, factors that are traditionally considered in evalu-
ation of short children. Younger children may have quite
at any age a single measurement may vary considerably
from a subsequent determination . There is also
inconsistency between laboratories, and normal ranges
vary widely. In a recent analysis, three of four laboratories
failed to identify 15–20% of Ecuadorian patients with
molecularly proven GHRD using the FDA criterion for
IGF-I concentration less than ?3 SD . Values may be
spuriously low as a result of high susceptibility of IGF-I to
post-sampling proteolysis . Boys
growth and maturation and lacking biochemical markers
erroneous diagnosis [18?].
Insulin-like growth factor I treatment of GH
Treatment of the short child Rosenbloom459
Table 1 Classification of disorders affecting insulin-like growth
factor-I synthesis and action
Mutations resulting in IGHD or MPHD [HESX1, LHX3, LHX4, SOX3,
GLI2, PITX2, PROP1, PIT1 (POU1F1), GHRH receptor, GH1]
Other causes of IGHD, MPHD, congenital and acquired
Acquired GH-inhibiting antibodies
GH–GH-receptor signal transduction factor mutation (STAT5b)
IGF-I gene mutation
IGF-I binding protein 3/acid-labile subunit mutations
Catabolic states, chronic illness (may have effects on GH secretion,
GH-receptor sensitivity, IGF-I synthesis, or IGF-binding protein
3, and may or may not be responsive to recombinant human GH)
GH, growth hormone; GHRH, growth hormone releasing hormone; IGF-
I, insulin-like growth factor-I; IGHD, isolated growth hormone deficiency;
MPHD, multiple pituitary hormone deficiencies; STAT5b, signal transdu-
cer and activator of transcription 5b.
approximately 150 individuals, mostly with GHRD, and
[13??,19–21,22??,23??]. The growth-velocity increment in
the first year was 4.3cm in the European and mecasermin
study populations, and 5.6cm in the Ecuadorian popu-
lation, all groups receiving comparable doses of rhIGF-I
administered twice daily [19,20,22??]. In the Israeli popu-
lation given a single injection of a comparable total daily
dose, the increment was only 3.6cm . For the group
200mg/kg per day, comparable to the European,
Ecuadorian, and mecasermin populations, the increment
was only 3cm, whereas in the higher dose providing
400mg/kg per day the increment was 6.3cm. Height
SDS improvement in the first year of treatment paralleled
these increments at 0.7, 0.8, and 0.6 for the twice-daily
rhIGF-I in the European, Ecuadorian, and International
mecasermin groups, respectively, 0.2 for the Israeli popu-
lation, 0.4 for the lower-dose and 0.7 for the higher-dose
mecasermin rinfabate groups. These data suggest that
administered in combination with IGFBP3 to obtain
growth responses comparable to those with lower doses
of rhIGF-I alone. The stimulatory effect on growth wanes
rapidly after the first year, with only modest continued
improvement. Among 76 patients treated for a mean
4.4years, overall height SDS improvement was 1.4 [22??].
In a comparison of growth response of 22 rhIGF-I-treated
GHRD patients with 11 recombinant human GH
(rhGH)-treated GHD patients in the same setting and
with comparable growth impairment, the increase in
growth velocity in those with GHRD over the first year
of treatment with rhIGF-I was 63% of that for patients
receiving rhGH treatment for GHD; in the second year
the increment was less than 50% of that for patients with
rhGH-treated GHD .
Limitations of endocrine insulin-like growth
factor I replacement
The incomplete correction of growth failure with endo-
crine IGF-I replacement is not explained by concomitant
IGFBP3 deficiency. Profound effects on adipose tissue,
facies, and lymphoid tissue in treated patients (see
below) attest to substantial tissue delivery. Also, com-
parative growth data between rhIGF-I and rhIGF-I/
rhIGFBP3 demonstrate a need for larger amounts of
IGF-I in the combination for comparable growth effects.
Pharmacokinetic studies in patients with GHRD demon-
strated comparable maximum concentrations (Cmax) for
circulating IGF-I with twice-daily rhIGF-I injections of
80mg/kg and daily rhIGF-I/rhIGFBP3 in a dose of either
0.5 or 1.0mg/kg [24??,25]. The time of maximal concen-
tration (Tmax; mean?SD) for the rhIGF-I treatment was
8?5.8h and for the combination treatment was
19?8.3h at the low dose and 15?6.2h at the higher
dose. The 24-h area under the curve was comparable for
rhIGF-I and the higher dose of the combination, while
that for the lower dose was ?20% less. These results
indicate that the single daily injection of rhIGF-I/
rhIGFBP3 is effective in sustaining physiologic concen-
trations of IGF-I, despite ALS deficiency, and that the
despite both IGFBP3 and ALS deficiency, which are
not corrected by rhIGF-I treatment. The maintenance
of circulating levels of IGF-I despite severe IGFBP3 and
ALS deficiency may be the result of binding to other
IGFBPs; IGFBP-2 is elevated in GHRD and increases
further with rhIGF-I therapy .
The inferior correction of growth failure in GH insensi-
tivity with IGF-Ireplacementtherapy,inmarkedcontrast
to full restoration of normal growth with GH replacement
in GHD, testifies to the importance of GH effects beyond
hepatic IGF-I, IGFBP3, and ALS synthesis. The direct
Endocrinology and metabolism
Table 2 Treatment with recombinant human insulin-like growth factor I for 1–2years of children with GH insensitivity
80 or 120mg bid
International (mecasermin rinfabate) [23??]
Height velocity (cm/year)
Height SDS (SD)
recombinant human insulin-like growth factor I; Rx, treatment.
aIncludes two patients with GH-neutralizing antibodies.
bIncludes eight patients with GH-neutralizing antibodies.
cIncludes three patients with GH-neutralizing antibodies.
d1mg of rhIGF-I/rhIGFBP3 contains 200 mg of IGF-I.
stimulationby GH of mitosis in cartilage precursor cellsof
local production of IGF-I, led to the hypothesis that
autocrine/paracrine IGF-I was the main determinant of
GH-dependent postnatal body growth, and that hepatic
or endocrine IGF-I served predominantly as a negative-
feedback regulator of GH secretion . Later studies of
mice with selective deletion of the hepatic IGF-I gene
described unaffected growth [28,29]. Deletion of the ALS
circulating IGF-I and IGFBP3 concentrations, but only
15% reduction in postnatal growth in the mice . It is
uncertain whether there was any growth effect in the two
patients with ALS mutations, one of whom reached
a stature of ?0.9 SDS and the other a height that was
0.4 SDS greater than the mean parental height [11??,30].
of hypoglycemia which may be severe, similar to what is
seen with severe GHD. Whereas rhGH-replacement
therapy corrects the hypoglycemia of GHD, rhIGF-I
injection enhances the risk. GH increases hepatic
glucose output and decreases muscle glucose uptake,
while IGF-I has the opposite effects. Hypoglycemia
seizures [22??]. A somewhat lower frequency of 31% was
reported with rhIGF-I/rhIGFBP3, although in a smaller,
slightly older population observed over a shorter period
of time [23??]. In a 6-month placebo-controlled study
hypoglycemia was reported in 67% of those receiving
placebo and 86% of those treated with rhIGF-I, an
insignificant difference . More recently, monitoring
of fingerstick blood-glucose concentrations in 23 sub-
jects residing in a research unit documented frequent
hypoglycemia before breakfast and lunch preceding
initiation of rhIGF-I treatment. There was no increase
in the frequency of blood glucose measurements below
50mg/dl in these patients with rhIGF-I administration.
Five of the subjects participated in a crossover placebo-
controlled study for 6months with a 3-month washout
period with fasting glucose determinations done thrice
daily by caregivers for the entire 15-month study. The
on placebo and 5.5% on rhIGF-I, not a significant differ-
ence; values over 140mg/dl were 1.4% for placebo and
3.9% with IGF-I, also not significant [22??]. In practice
hypoglycemia appears reasonably controllable with
adequate food intake. In a study of 18 adolescents
selected for low IGF-I and IGFBP3 levels who were
monitored for 24h at the end of 2weeks of rhIGF-I
60mg/dl were detected, and there were no symptoms
of hypoglycemia throughout the study [32?].
Pain at the injection site is common. Injection-site lipo-
hypertrophy is frequent, affecting at least one-third of
subjects; this is related to failure to rotate injections and
injection into the lumps can attenuate growth response
[22??]. Hair growth at the injection site has only been
IGF-I results in asymptomatic tachycardia in all treated
patients, which clears after several months of continued
Intracranial hypertension or papilledema occurs in ?5%
of IGF-treated subjects. While headache is frequent,
the placebo-controlled study found
between those receiving placebo injections and those
receiving rhIGF-I . Parotid swelling and facial nerve
palsy have been described. Lymphoid tissue hypertro-
phy occurs in upwards of one-quarter of patients, with
hypoacusis, snoring, and tonsillar/adenoidal hypertro-
phy that required surgical intervention in over 10% of
patients. Thirty-five percent of subjects having regular
chest radiographs showed thymic hypertrophy [22??].
Some of these side effects may be more frequent
than reported because they take time to develop; for
example, snoring incidence in the first year for the
25 longest-treated subjects in the mecasermin study
was only 4%, but increased to 65% for the entire period
Anti-IGF-I antibodies have developed in approximately
half of the rhIGF-I-treated patients during the first year,
but these have had no effect on response [22??,31].
Transient elevation of liver enzymes has also been noted
Coarsening of facial features reminiscent of acromegaly
has been noted in many patients, particularly those of
pubertal age. In contrast to the increase in lean body mass
and decreasing percentage of body fat that occur with
rhGH treatment of GHD, both lean and fat mass increase
with rhIGF-I therapy . Mean body mass index
increased from þ0.6 SDS to þ1.8 SDS during 4–7years
of treatment with rhIGF-I in the European multicenter
trial, and severe obesity has occurred occasionally .
Measurement of body mass index may not accurately
reflect the degree of obesity, which can be a doubling or
tripling of body fat as demonstrated by dual-energy X-ray
Nothing is known about the long-term mitogenic effects
of extended therapy with rhIGF-I in growing children.
The role of IGF-I in carcinogenesis, the increased cancer
risk in hypersomatotropic states, and the evidence for
aberrant tissue effects in rhIGF-I-treated patients dictate
caution and a need for long-term follow-up of rhIGF-I-
treated patients [35??,36?,37].
Treatment of the short child Rosenbloom 461
The absolute indications for rhIGF-I therapy are those
conditions resulting in unresponsiveness to endogenous
or administered GH as the result of GHR mutation,
mutation, or GH-inactivating antibodies. Increasing but
still small numbers of more rare post-receptor defects are
being identified among those abnormally short individ-
uals with previously unexplained growth failure who fail
to respond to GH administration [9,10]. Another likely
indication for IGF-I treatment is Noonan syndrome
with gain-of-function mutations of the PTPN11 gene
[which encodes the protein tyrosine phosphatase SHP-
2 (Src-homology 2 domain-containing protein tyrosine
phosphatase), a widely expressed protein with a negative
effect on intracellular signaling downstream from several
growth factors, cytokines, and hormone receptors],
resulting in interruption of intracellular signaling; these
individuals, comprising approximately half of patients
with Noonan syndrome, have a response to rhGH that
is substantially less than in those with Noonan syndrome
who do not carry one of these mutations, with a bio-
chemical profile suggesting a post-receptor defect [38??].
It has also been suggested that children with short
stature due to renal failure, who are GH-sufficient with
some evidence of GHR signaling capacity, might be
logical treatment candidates for rhIGF-I ora combination
of rhIGF-I with rhGH .
Off-label promotion of rhIGF-I is based on two consider-
ations that lack convincing evidence: that a substantial
proportion of children with idiopathic short stature (ISS)
therapy for these individuals. These assumptions have
been repeatedly stated by both manufacturers [1??].
Among 500 patients with ISS and normal GH stimulation
tests in the Genentech National Cooperative Growth
Study, 100 had low concentrations of GH-binding protein
and low concentrations of IGF-I. GH-binding protein is
the proteolytic cleavage product of the GHR, comprising
the extracellular domain, considered a proxy for GHR
function. However, there was no evidence of GH resist-
the GH-binding protein concentrations . In other
studies, the growth response to rhGH in both GHD and
ISS was inversely correlated with baseline IGF-I concen-
trations [37,40]. If GH resistance were contributing to a
substantial portion of ISS, the opposite correlation would
be seen, as those with the lowest IGF-I levels would be
expected to be the most GH-resistant, not the most
sensitive. Attempts to identify individuals within the
ISS group who might be GH-resistant or have molecular
defects in the GHR have been inconclusive atbest. IGF-I
generation tests may have poor reproducibility .
Molecular studies have suggested that, at most, 5% of
children with ISS have heterozygous mutations of the
GHR, but these are typically not associated with statural
effects in other family members with the mutation, have
not been associated with failure to respond to rhGH, and
have not been demonstrated by transfection studies to
impair GHR function [13??,42,43?]. In the largest study of
possible heterozygous effects of a mutation that results
in GHRD, there was a ?0.5 height SDS effect of
heterozygosity with near-complete overlap with homozy-
gous normalsofSDSrange,andnodifferences inIGF-Ior
IGFBP3 concentrations [44??].
Treatment of ISS with rhGH, approved since 2003,
remains controversial, related to lack of evidence of
psychological or physical morbidity or improved well
being with treatment, cost to the society, and possible
risks associated with the pharmacologic dosing [45?,46?].
There is no reason to expect better growth response with
rhIGF-I in these patients than with rhGH, based on the
absence of convincing evidence of GH resistance as a
cause of their short stature. There is, however, concern
that monotherapy with IGF-I in individuals who have
normal or even somewhat reduced GH production and
action will result in suppression of endogenous GH,
which occurs rapidly with rhIGF-I administration in both
normal and GHRD subjects . This will reduce
IGFBP3 and ALS production and, most importantly,
decrease the GH available to growing bone, with
reduction of chondrocyte proliferation and autocrine/
growth velocity. That the reduction in local effects of
GH cannot be compensated for by pharmacologic doses
of rhIGF-I is well demonstrated in the less-than-
adequate growth response of GH-resistant patients and
has also been demonstrated in hypophysectomized rats.
IGF-I alone is half as effective in restoring growth as GH
alone, while the effect of administering both is additive
. A further consideration in pondering the role of
IGF-I in ISS is the safety profile, which is far more
problematic for rhIGF-I than for other growth promotion
interventions, including rhGH, oxandrolone, and aroma-
The commercial availability of rhIGF-I and rhIGF-I/
rhIGFBP3 has led to consideration of their use in growth
promotion beyond those rare conditions for which they
were approved. In these conditions, height velocity is
improved, but growth is not normalized, in contrast to
the experience with rhGH-replacement therapy in
GHD, reflecting the limited effect of endocrine IGF-I
on growth. Patients with Noonan syndrome with
mutations of the PTPN11 gene [38??], those with renal
failure , and children with ISS who require growth
promotion and do not respond to rhGH may also be
candidates for rhIGF-I treatment. There is no evidence
for broader use of IGF-I for growth promotion, especially
Endocrinology and metabolism
considering the suppression of endogenous GH secretion
and its local effects, and safety concerns, and there are no
studies comparing treatment with rhIGF-I and rhGH in
ISS. For those children with ISS requiring treatment
and not adequatelyrespondingto rhGH,the combination
of rhGH and rhIGF-I or rhIGF-I/IGFBP3 might be
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 526–527).
of special interest
of outstanding interest
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information about mitogenic potential of elevated IGF-I levels to suggest caution
about enthusiastic therapeutic provision of IGF-I beyond absolute indications.
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Among 35 patients with Noonan syndrome, 20 had PTPN11 missense mutations
shorter stature, and decreased response to rhGH. IGF-I and ALS levels were low,
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mutation that causes GHRD/Laron syndrome in the Ecuadorian population.
Heterozygosity was associated with reduction in mean statural SDS, but this
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