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sleep stage 3-4 EEG sleep.
77,78
Therefore, single random
samples of GH are often quite low and not helpful. In
many cases, pharmacologic provocative stimuli are nec-
essary in order to determine whether a patient has GH
deficiency,
79
and although testing with two concomitant
stimuli is the standard at this point in time in pediatric
endocrinology and is considered the best measure, this
testing is neither totally sensitive nor specific.80,81
80,81
The
stimuli typically used include a combination of two
of the following: arginine, insulin, clonidine, L-dopa
and glucagon.
82
Two stimuli are used because 20% of
GH-replete children can fail any given provocative
test.
83
Growth hormone releasing hormone (GHRH also
known as GRF, growth hormone releasing factor) is no
longer available, but this was another agent used in the
past in provocative testing. Normal serum levels of GH
are lab dependent, and in most labs, a normal peak from
sequential blood draws is >7-10 ng/ml.
84-86
stimulation testing), GH deficiency was not found in OI
in the overall population. Another study by some of the
same investigators of 22 subjects with mild to moderate
OI revealed again that the standard stimulation testing
criteria for GH deficiency was not fulfilled.87
87
Thirteen
of the 22 subjects in this second study had a less than
two-fold stimulation with exogenous GH in terms of
their IGF-1 response, but there was no overlap in this
group with the decreased GHRH response. Both of
these studies suggested GH resistance with blunting of
the somatomedin generation tests and GHRH responses
but overall an appropriate response of GH to pharma-
cologic criteria consistent with GH sufficiency.
Even though GH deficiency does not appear to be the
mechanism underlying growth retardation in OI, a num-
ber of studies have investigated the possibility that GH
treatment may nevertheless still be beneficial in improv-
ing growth in these patients (discussed later). In fact,
there are several conditions marked by severe short stat-
ure in which growth hormone treatment has been suc-
cessful and FDA approved. It is thought that many of the
children treated for “idiopathic short stature” are indeed
GH resistant, as may be the case in OI. Therefore, there
are precedents for the use of GH to increase growth even
in clinical settings of GH sufficiency.
The rationale for the potential role of GH treatment
in OI is based on the osteoblast-stimulating actions of
the hormone, and its potential to increase collagen
synthesis. GH stimulates the expression of IGF-I and
IGF binding protein-3 in cultured osteoblasts, indi-
rectly increasing synthesis of type I collagen.
89
On the
other hand, the genetic defect remains, and this effect
is potentially ineffective to improve bone biomechan-
ics in cases where abnormal collagen is produced. As
the understanding of OI and related syndromes pro-
gresses
13
it appears clear that different mutations affect
collagen in different ways. The autosomal dominant
forms of OI are caused by primary defects in type I col-
lagen, whereas autosomal recessive syndromes resem-
bling OI are caused by deficiency of proteins which
interact with type I procollagen for post-translational
modification and/or folding. In the latter, the bone
defect is caused by deficiency of any of the three com-
ponents of the collagen prolyl 3-hydroxylation complex.
Absence of 3-hydroxylation is associated with increased
modification of the collagen helix (consistent with
delayed collagen folding). Other causes of syndromes
resembling OI include deficiency of the collagen chap-
erones FKBP10 or Serpin H1.
11
Furthermore, during the
first 6 months of GH therapy in GH deficiency (GHD)
patients, bone resorption is usually greater than bone
formation, as reflected in a higher increase in resorption
markers,
90
and the effects on bone biomechanics may
not be beneficial.91
91
GROWTH HORMONE AND IGF-1
TE
STING IN PATIENTS WITH
OI
Due to the growth impairment in OI, investiga-
tors have evaluated the GH-IGF-1 axis in this patient
population. Both IGF-1 and IGFBP-3 levels have been
measured and found to be in the low normal range
for age,
1,2,87,88
although the relationship in the various
analyses performed do not detail the nutritional status,
pubertal status or bone age, all of which can affect the
accuracy in the interpretation of IGF-1 levels. In isolated
studies, bone age measurements have been found to be
similar to chronologic age in children with OI
3,88
which
would tend to go against growth hormone deficiency,
a clinical scenario usually accompanied by a delay
in bone age. Twenty-eight children with OI (13 with
type III, 12 with type IV, 3 with type I) were evaluated
with provocative growth hormone stimulation testing
including combined pharmacologic stimuli, the current
standard for the diagnosis of GH deficiency.18
18
Utilizing
the arginine/insulin tolerance test as well as L-dopa, all
but one of the patients had a normal response. Growth
hormone releasing hormone [GHRH or GRF(factor)]
stimulation tests, 24-hour GH samplings and IGF-1
generation tests were also performed, with the results
demonstrating some patients to have blunted responses
but without correlation with growth, OI type or the
results of other testing performed.
18
Eighteen out of
these 28 children examined had less than a two-fold
stimulation with the IGF-1 generation test, but this
finding was non-specific, and the values did not reveal
a correlation with baseline IGF-1 levels or the other
testing performed. Therefore, by standard criteria for
the diagnosis of GH deficiency (i.e., AITT and L-dopa
