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Pediatric Endocrinology |
Instituto Endocrinologia, Metabolismo y Reproduccion (J.G.A., O.V., V.M.) Quito, Ecuador; University of Florida College of Medicine (A.L.R., L.A.), Gainesville, Florida 32610; and Oregon Health Sciences University (S.E.G., R.G.R.), Portland, Oregon 97201
Address all correspondence and requests for reprints to: Dr. Jaime Guevara, Iemir, Casilla 6337-CCI, Quito, Ecuador.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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There were no baseline differences between the low and high dose groups for growth velocity (GV), bone age (BA), SD score for height, or percent mean body weight for height (MBWH). Over 2 yr of rhIGF-I treatment, there were no differences in GV or in changes in height SD score, height age (HA), or BA between the two groups; a subgroup of six subjects at the higher dose followed for a third year continued at the second year GV. The higher dose resulted in a greater change in percent MBWH.
GV in yr 1 and 2 for the entire group and in yr 3 for a subgroup were
greater for GH-treated GHD (n = 11). The GHD group showed a
greater change in SD score for height and HA, but did not
differ from the rhIGF-I-treated GHRD group in the change in BA (
BA)
or HA/BA over 2 yr. There was a greater change in percent MBWH in
GHRD.
There were no differences between dosage groups for serum IGF-I levels at baseline or the near-normal trough levels 12 h after rhIGF-I injection; these individual levels correlated with HA gain in yr 1 and 2. IGFBP-3 levels were markedly low, with no changes of significance with treatment.
Comparable growth responses to the two dosage levels and the
biochemical changes indicate a plateau effect at or below 80 µg/kg BW
twice daily. The growth response and favorable trough levels of IGF-I
despite the overall lack of increase in circulating IGFBP-3 levels
suggest an alternative mechanism for sustaining IGF-I levels and
avoiding rapid clearance of rhIGF-I. The greater increase in MBWH with
treatment of GHRD than with treatment of GHD may reflect comparable
effects on lean body mass without the lipolytic effects of GH in the
GHRD subjects. The difference in growth response between
rhIGF-I-treated GHRD and rhGH-treated GHD groups is consistent with the
hypothesis that 20% or more of GH-influenced growth is due to the
direct effects of GH on bone. Nonetheless, the comparable HA/BA
suggests similar long term effects of replacement therapy in the two
conditions.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The placebo-controlled trial also demonstrated that the persistent low levels of IGFBP-3 did not result in increased risk for hypoglycemia from the expected surge in free IGF-I after injection. The growth responses we reported, as well as those from other reports, in the absence of an increase in IGFBP-3 levels, suggested an alternative mechanism for sustaining therapeutic levels of IGF-I in the circulation or at the tissue level. The growth response to rhIGF-I injection was also thought to argue against the importance of the direct effects of GH on prechondrocyte maturation and local (autocrine/paracrine) IGF-I elaboration, a mechanism postulated to account for 20% of GH-influenced growth (4).
Initial enthusiasm for the response to rhIGF-I in GHRD was tempered by a comparison of first year growth velocities (GV) to those of children with isolated GH deficiency (GHD) treated with rhGH (5). This report extends our observations of growth response to rhIGF-I in the Ecuadorian population with GHRD to 2 yr for 22 patients at 2 dosage levels and to 3 yr for 6 of them receiving the higher dose. Their growth responses are also compared to those of 11 patients with isolated GHD in the same setting who were being treated with rhGH.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects with GHRD were aged 3.1–17.1 yr, with height SD scores of -5.8 to -11.5. Fifteen of the 22 subjects were female, consistent with the disparate sex ratio in 1 of the 2 provinces that are the origin of the Ecuadorian population (1). All had typical phenotypic features of GHRD, very low or unmeasurable levels of GH-binding protein in the circulation, random GH levels above 10 µg/L, and homozygosity for the alternative splice mutation site of codon 180 in exon 6 of the GH receptor gene (6). All were prepubertal, and bone age estimations were 1.5–9.3 yr (7).
GH-deficient patients without organic etiology were from the same Andean population. All had serum GH responses to 2 or more stimuli of less than 4.5 µg/L by RIA using a polyclonal antibody. They were treated with 3–7 injections per week of rhGH in doses of 0.16–0.30 mg/kg BW·wk. Five had associated TSH deficiency that was treated with T4 replacement, and 1 also had ACTH deficiency treated with cortisol replacement. These 11 subjects were predominantly male (n = 8), which corresponds precisely to the sex distribution for idiopathic GHD in the large U.S. postmarketing survey (8). Ages were 3–15.2 yr, and bone ages ranged from 4 months to 8.8 yr.
Study design
Studies in the GHRD population were carried out under protocols approved by the ethics committee of the Institute of Endocrinology, Metabolism, and Reproduction (Quito, Ecuador) and the human subjects review boards of Stanford University (Stanford, CA) and the University of Florida (Gainesville, Florida) in compliance with the laws and regulations of the United States and Ecuador. All parents, and children over 7 yr of age, signed and received copies of informed consent forms written in Spanish.
Initiation of treatment was as previously described (3). The first 15 subjects received 120 µg/kg every 12 h throughout the study, and the next 7 patients received 80 µg/kg twice daily by sc injection.
Growth evaluation
Standing heights were determined as the means of three measurements made with a Harpenden stadiometer. The SD score for height was calculated using U.S. National Center for Health Statistics data (9). X-Ray films of the left hand and wrist were read for determination of bone age (BA) using the method of Greulich and Pyle (7). National Center for Health Statistics data for the U.S. population (9) was also used to estimate height age (HA) and percent mean body weight for height (% MBWH).
Measurements of IGF-I and IGFBP-3
Serum specimens were obtained before treatment and at regular
intervals during treatment 12 h after the evening rhIGF-I
injection; serum concentrations of IGF-I at these times are defined as
trough levels. IGF-I assays were performed by RIA after removal of
binding proteins by acid gel chromatography, as previously described
(3). IGFBP-3 concentrations were estimated by immunoradiometric assay
(Diagnostic Systems Laboratories, Webster, TX). This IGFBP-3
immunoradiometric assay has been validated in our laboratory and shown
to correlate with RIA results employing antibody 
-IGFBP-3-gl (10)
with r > 0.95 (data not shown).
Statistical analysis
Auxologic data are expressed as the mean ± SD, and means are compared using Student’s t test, with P < 0.05 considered significant. Biochemical data, age adjustment, and correlations were performed using the Statistical Analysis System (t test, general linear models).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Growth. As shown in Table 1
, there were no
significant differences in age, baseline GV, BA, SD score
for height, or % MBWH between the subjects receiving 120 µg/kg and
those receiving 80 µg/kg twice daily, although the latter were, on
the average, 2 yr younger. There were no significant differences in GV
in yr 1 or 2, or in changes of height SD score, HA, or BA
over these time periods when the 120 and 80 µg/kg groups were
compared. The higher dose, however, resulted in a greater change in %
MBWH (Table 2).
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IGF-I. Baseline IGF-I concentrations in serum ranged from less
than 2 to 26 µg/L, all well below -2 SD from normal
(Fig. 1). There were no significant differences in serum
IGF-I concentrations between the dosage groups (low dose, 4.4 ±
5.5 µg/L; high dose, 9.5 ± 8.5; P = 0.16). Mean
trough levels of IGF-I rose comparably after 12 months of rhIGF-I
treatment in both dosage groups (low dose, 68.8 ± 88.3 µg/L;
high dose, 102.2 ± 123.7; P = 0.52). All but one
of the high dose and one of the lower dose subjects showed a
substantial elevation of the IGF-I level. Three of the high dose and
two lower dose patients failed to show a persistent elevation of trough
levels of IGF-I at 24 months, but mean values were not significantly
changed (Fig. 1). There was a significant correlation between the
increases over baseline in serum IGF-I trough levels at 1 and 2 yr and
annual increments in HA for the entire group (Fig. 2).
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). Annual
growth responses for the entire group, measured as HA increase, did not
correlate significantly with the change in () IGFBP-3 levels at yr 1
(r = 0.18; P = 0.41) or yr 2 (r = 0.30;
P = 0.17).
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. Although the GHD subjects were
growing at a significantly slower pretreatment velocity, the GHRD
subjects had a significantly more deviant SD score for
height. The GVs in yr 1 and 2 for the entire group and in a third year
subgroup were significantly greater for the GHD patients treated with
rhGH than for the rhIGF-I-treated GHRD subjects (Table 4). The GHD subjects also had a greater height
SD score and HA over the 2 yr of treatment, although there
was no difference in BA or the ratio of HA to BA. The
% MBWH was significantly greater in the GHRD group (Table 4).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Improvement in mean height SD score over 2 yr was 1.2 in the European study (13), 1.3 for 5 patients with GHRD receiving 80–120 µg twice daily in the U.S. (14), and 1.4 for the 22 patients in this study. The European and Ecuadorian patients achieved two thirds of their improvement in the initial year; 1 yr data were not reported in the U.S. study. The Israeli study reported mean SD score improvement of only 0.4 at 1 yr, remaining at this level of improvement for the 6 completing 2 yr of treatment.
That the twice daily regimen is salutary is suggested by the trough levels of IGF-I noted 1 and 2 yr after the start of IGF-I therapy. These long term effects are consistent with our earlier findings of trough levels of IGF-I comparable to serum IGF-I concentrations in normal control subjects 12 h after injections of rhIGF-I (40 µg/kg twice daily) in six young adults with GHRD (15). The need for and efficacy of every 12 h administration is further supported by the response of six adults with GHD given sc injection of 40 µg/kg BW rhIGF-I. Serum IGF-I levels rose from markedly subnormal into the normal range over 1–3 h and were sustained for 10–16 h despite no increase in IGFBP-3 levels (16).
We have reported that adults with GHRD had significant correlation between both IGF-I and IGFBP-3 levels in serum and statural deviation (height SD score) and found comparable correlation for children between IGFBP-3 levels and SD score (1). Children in the European study of rhIGF-I treatment of GHRD had significant correlations between baseline SD score for height and SD score for serum IGF-I, IGF-II, and IGFBP-3 levels (17). In this study we demonstrated an important correlation between growth response to rhIGF-I injections in GHRD and trough levels of IGF-I 12 h after injection.
Maintenance of therapeutic levels of IGF-I in the absence of an increase in IGFBP-3 suggests an alternative mechanism for sustaining the circulating level of IGF-I and avoiding the clearance of free hormone too rapidly for therapeutic effect at the cellular level. A rise in the already elevated IGFBP-2 levels may be substituting for the absence of an IGFBP-3 response (15). The potential advantage of IGFBP-2 binding would be that this IGFBP diffuses more readily into the interstitial space than does IGFBP-3 and could improve the bioavailability of IGF-I (18).
Several studies have confirmed that rhIGF-I treatment of GHRD does not increase IGFBP-3 levels, in contrast to what occurs with rhGH treatment of GHD, indicating that the GH induction of IGFBP-3 is a direct effect (3, 13, 15). We also found that the acid-labile subunit of the IGFBP-3 is not increased by rhIGF-I therapy in these patients (data not shown). IGF-I administration also fails to raise serum IGFBP-3 levels in adults with GHD (16). The recent report of the first instance of GH insensitivity due to a defect in the IGF-I gene further confirms the direct role of GH in IGFBP-3 generation; despite absent IGF-I, the affected patient had normal levels of IGFBP-3 (19).
That IGF-I concentrations were not significantly different at the two dose levels suggests a plateau effect beyond 80 µg/kg twice daily, as does the similar clinical responses to the twice doses. The only noted difference in response to the dosages of IGF-I used was in MBWH, with the higher dose resulting in a greater weight for height increase. Similarly, the GHRD subjects as a group had a greater increase in MBWH than did the rhGH-treated GHD group. It would be expected that rhGH treatment in GHD would have a lipolytic effect that is absent in GHRD subjects treated with rhIGF-I, but that both forms of treatment would affect lean mass accretion comparably. Thus, total fat mass in GHRD would diminish relatively little, while lean mass increases, perhaps in a dose-dependent fashion, to explain these observations.
Daughaday and Rotwein (4) estimated that 20% of GH-influenced growth
is the result of direct effects of GH on bone. The difference between
average growth of GH-treated GHD patients and rhIGF-I-treated GHRD
patients is consistent with this estimate. It is not possible to
attribute this difference to direct GH effects on bone without the
ultimate experiment of treating naive GHD patients with IGF-I.
Comparable HA/ BA in the two groups over 2 yr of treatment
suggests that long term growth in rhIGF-I-treated GHRD may be
comparable to that in GH-treated GHD.
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Acknowledgments |
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Footnotes |
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Received June 28, 1996.
Revised October 3, 1996.
Accepted October 21, 1996.
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References |
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