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Clinical Studies |
Department of Pediatrics, Baylor College of Medicine (P.D.K.L., S.K.D., D.R.P.), Houston, Texas 77030; Department of Research and Scientific Affairs, Diagnostic Systems Laboratories, Inc. (P.D.K.L.), Webster, Texas 77598; and Institute of Endocrinology, Metabolism and Reproduction, (V.M., O.V., J.G.-A.), Quito, Ecuador
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The short term kinetic responses of serum IGFs and IGFBPs to GH have not been fully investigated. Such data may give clues to the in vivo physiological relationships of these proteins and guide the clinical and research use of IGF and IGFBP assays, particularly in relation to GH therapy. Therefore, we have conducted studies of short term IGF and IGFBP responses to single doses of GH in GH-deficient subjects at the initiation of and during GH replacement therapy.
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Materials and Methods |
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A total of 23 subjects with untreated GH deficiency (GHD) and 2 subjects with untreated GH receptor deficiency (GHRD) were recruited from the patient population at the Institute of Endocrinology, Metabolism, and Reproduction (Quito, Ecuador); all studies were performed in the clinical research unit at Institute of Endocrinology, Metabolism, and Reproduction. Signed, informed consent was obtained from each subject and/or their guardian before beginning the study. During each study period, subjects were examined, heights were measured using a fixed and calibrated stadiometer, and weights were determined using a calibrated scale. Subjects were studied as a group; all samples and data for each study period were obtained within a 2-week interval.
The 5 women and 18 men with GHD had the following baseline characteristics (mean \ SD): chronological age of 15.0 \ 5.9 yr (range, 7.6–30.8), body mass index (BMI) of 19.3 \ 2.4 kg/m2 (range, 15.4–24.0), and height SD score (z-score, normalized for age and sex) of -4.4 \ 2.2 SD (range, -10.1 to -1.5). Height velocities were less than 3% for age and sex. GH deficiency was defined by standard clinical criteria and GH stimulation testing (GH peak, <5 ng/dL in response to at least two separate tests). Subjects with thyroid or cortisol deficiencies were receiving stable replacement therapy.
At baseline, subjects were admitted to the in-patient study center, and an iv catheter was placed for blood sampling. After an overnight fast, a sc dose of recombinant human GH (rhGH; Kabi-Pharmacia, Stockholm, Sweden; 2.85 IU/m2) was administered, and blood was sampled 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 20, and 24 h after injection. Subjects were permitted a normal oral diet (three major meals and one or two snacks), with monitoring of meal times and intake. No iv calories were administered during the study period.
Subjects were then treated with daily rhGH (2.85 IU/m2, sc)
each morning (
0.7 IU/kg·wk). After an overnight fast, a single
venous blood sample was obtained immediately pretreatment at 3 months
(n = 22). The timed sampling protocol was repeated at 6 months
(n = 21). Blood samples were collected in glass tubes and allowed
to clot, and the serum was aliquoted, frozen, and shipped on dry ice to
the laboratory (S.K.D.) for assay. Serum aliquots were stored at -70 C
and were allowed a maximum of two freeze-thaw cycles before assay. To
minimize the effects of interassay variability, all samples for each
analyte at each interval were measured in a single assay.
To determine whether the GH injections might have a nonspecific effect on the measured parameters, limited timed sampling studies (0, 6, 12, 18, and 24 h post-rhGH treatment) were performed in two patients with GHRD (both female, aged 0.1 and 2.4 yr) (13, 14). These subjects were studied once and were not continued on rhGH treatment.
Assays
Serum levels of GH, IGF-I, free IGF-I, IGF-II, IGFBP-1, IGFBP-2,
IGFBP-3, and IGFBP-6 were determined using commercial assay kits
(Diagnostic Systems Laboratories, Webster, TX). For the IGF-I and
IGF-II assays, samples were prepared using the acid-ethanol extraction
methods included in the respective kits. These extraction methods have
been validated against acid-column chromatography (15, 16). Free IGF-I
(fIGF-I) was determined using a direct method in which unaltered serum
samples (0.2 mL) are added to tubes coated with anti-IGF-I capture
antibody (17, 18, 19). The relevant performance characteristics of each
assay are described in Table 1
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Descriptive data are presented as the mean and SEM unless otherwise specified. Regression analyses and paired and unpaired t tests were performed using StatMost 2.5 for Windows (DataMost Corp., Salt Lake City, UT). Statistical significance is defined as P < 0.05. Immunoassay data were analyzed using a four-parameter logistic curve fit (for competitive RIAs) or a log-linear curve fit (for two-site immunoradiometric assays). Height z-scores were calculated using North American height standards (20).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows age, height, height z-score, and BMI
for the 23 GHD and 2 GHRD subjects at baseline. Heights after 6 months
of treatment are also listed for the GHD subjects who continued on rhGH
treatment. All subjects were clinically well nourished, as indicated by
the normal BMI calculations. Given the relatively short duration of the
study, linear growth was not considered to be a primary measure.
However, all 21 GH-deficient subjects who were studied at both baseline
and 6 months had increases in height.
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for the GHD subjects, baseline (fasting)
levels of serum GH, IGF-I, fIGF-I, IGF-II, IGFBP-3, and insulin
significantly increased with 3 months of GH treatment, whereas IGFBP-1
and IGFBP-2 did not change. There were no significant differences
between the 3 and 6 month measurements for any of these analytes. Mean
IGFBP-6 levels increased only after 6 months of rhGH treatment.
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As shown in Table 3 and Fig. 2, serum GH levels were low at time zero, peaked 3 h post-rhGH
treatment, and gradually returned to the baseline by 24 h. Initial
increases in serum IGF-I and fIGF-I were concurrent with peak GH
levels. Serum IGF-I levels increase progressively throughout the 24-h
period (Fig. 2), reaching 77.6 \ 17.2 ng/mL, nearly 5-fold higher
than baseline and approximately 75% of the fasting levels observed at
3 and 6 months. Serum fIGF-I levels paralleled IGF-I to 14 h,
after which they showed a downward trend.
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) were significantly higher than
baseline only 20 h post-rhGH treatment. IGFBP-2 concentrations
increased at 2 h posttreatment and decreased to baseline by
20 h, whereas IGFBP-6 levels showed no consistent significant
changes in response to rhGH.
Serum IGFBP-1 levels declined precipitously after the first morning
meal (Fig. 2, bottom), remained relatively suppressed during
the day, and returned to baseline levels between 14–24 h. An inverse
trend in serum insulin concentrations was observed. Multiple regression
analysis with insulin and GH as independent variables revealed
P < 10-6 and 0.72, respectively, with a
regression equation of IGFBP-1 = -0.58[insulin] 37.3.
Month 6 kinetics
As shown in Table 3 and Fig. 1, fasting measurements of all
analytes except IGFBP-1 and IGFBP-2 were significantly higher at 6
months than at month 0. During the 6-month timed sampling study, serum
GH levels peaked 2 h posttreatment (Table 3 and Fig. 3); peak levels were approximately 2-fold higher than
those at month 0. Despite this higher peak, beginning at 6 h
posttreatment, GH levels were comparable to or lower than those at
similar points in the 0 month study.
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and Fig. 3) at the early time points
(i.e. 0–12 h post-GH treatment) were generally similar to
those observed in the 0 month study. However, at 6 months, absolute
levels of IGF-I and fIGF-I were more than 7-fold and more than 10-fold
higher, respectively, and the posttreatment increase reached
statistical significance only after 6 h. In addition, IGF-I levels
plateaued during the later time points, and fIGF-I levels decreased
after 14 h.
IGFBP-3 and IGF-II levels again showed a late rise, occurring 20 h
posttreatment. IGFBP-2 showed small and transient fluctuations at 2 and
8–14 h post-rhGH treatment, whereas no consistent changes occurred in
IGFBP-6. As shown in Fig. 3, changes in IGFBP-1 and insulin over the
24-h sampling period were nearly identical to the patterns seen in the
0 month timed sampling study, although insulin levels were
significantly higher at 6 months. Multiple regression analysis with
IGFBP-1 as dependent and insulin and GH as independent variables
revealed P values of 10-7 and 0.002,
respectively, and the following regression equation: IGFBP-1 =
-0.44[insulin] -0.69[GH] 48.0.
Determinants of fIGF-I
Multiple regression analysis was performed to determine whether
IGFBP-1, IGFBP-2, and/or IGFBP-3 might be related to fIGF-I
concentrations. Analyses were performed both with and without IGF-I
included. Table 4 shows the analysis with all data
points included; results were essentially unchanged when analyzed
according to baseline or 6-month study period. With IGF-I included,
fIGF-I has a positive relationship with IGF-I and a negative
correlation with IGFBP-1 and IGFBP-3. With IGF-I excluded, IGFBP-6 also
correlates with fIGF-I, and the overall estimate is degraded. IGFBP-2
levels were not related to fIGF-I in either analysis.
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Results for the two GHRD subjects are shown in Table 5. As expected, serum GH levels were high throughout the
sampling periods. Unfortunately, the limited sample sizes prevented
reassay at higher dilutions. IGF-I, fIGF-I, IGF-II, and IGFBP-3 were
all far below the normative ranges for these assays (DSL; data not
shown) and showed no response to exogenous rhGH. IGFBP-6 levels were
comparable to those in the GH-deficient subjects and showed no response
to rhGH. Insulin levels were considerably lower than those in the
GH-deficient group, although both groups of subjects were fed similar
meals.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Serum levels of GH in response to a parenteral dose are similar to those reported by other investigators, with peak levels observed approximately 2–4 h posttreatment (21, 22, 23, 24, 25, 26, 27), although some studies have shown a later peak (4–6 h) after a sc GH dose in older, non-GHD adults (28) and GHD children (29). During the 6-month timed sampling study, the 24 h GH levels were considerably lower than those at time zero, probably reflecting interindividual variability in the timing and clearance of the preceding GH dose. However, this variability is unlikely to account for the higher peak levels coupled with a relatively rapid rate of disappearance during the 6-month study. These latter results could be due to GH-induced changes in GH-binding protein concentrations and/or GH clearance mechanisms; additional studies will be needed for clarification.
IGF-I, IGF-II, and IGFBP-3 are known to be stimulated by GH in GH-deficient subjects. However, the sequence of these changes has been only partially defined. Laursen et al. (30) reported no changes in IGF-I or IGFBP-3 concentrations measured over a 24-h period in 13 treated GHD adult patients (mean age, 25.4 yr; range, 15–57 yr) who were given an average rhGH dose of 1.7 IU/m2·day by either sc injection or continuous infusion. Similar absent or blunted responses were observed in other studies of GH-treated GHD subjects (31, 32) and women undergoing fertility therapy (33). However, progressive increases in serum IGF-I have been reported in treated patients given a sc or im dose of GH after a 1-day wash-out (29). Furthermore, rhGH infusion (25 ng/kg·min) in a similar group of subjects, studied at the initiation of treatment and after both 3 days and 3 weeks of daily GH replacement therapy, exhibited progressively increasing IGF-I levels over a 24-h period (34).
In a study of elderly women (mean age, 71.9 yr) given rhGH 0.025 mg/kg, sc, serum IGF-I concentrations showed a small, but significant, increase within 1–3 h posttreatment; however, levels did not progressively increase over the 12-h period (35). Moreover, IGF-II and IGFBP-3 levels did not change over this short term study, although over a treatment period of several days, IGF-II decreased and IGFBP-3 increased. Other studies have shown that serum IGF-I increases within 8 h of GH treatment, whereas IGF-II shows a delayed rise at 24–72 h (23, 36, 37).
Our data demonstrate that in a population of young, untreated, GHD subjects, a single sc dose of rhGH leads to a progressive increase in serum IGF-I concentrations beginning 3 h posttreatment, coincident with peak GH concentrations. These results are similar to an early study of hypophysectomized rats given ovine GH, in which extractable tissue IGF-I concentrations increased as early as 2 h posttreatment, and serum IGF-I levels increased approximately 4 h posttreatment (38). The duration of this progressive increase after the initial dose of rhGH cannot be determined from our study. Other studies have found a plateau in IGF-I concentrations within approximately 24 h post-GH treatment (29) and 1–2 weeks during daily GH administration (39, 40), although progressive increases after 2 weeks have also been reported (36). Although fasting levels appear to reach a stable level by 3 months, IGF-I levels continue to respond acutely to rhGH at 6 months; this increase is relatively blunted and unsustained compared to that in the 0 month study.
Interestingly, although IGFBP-3 is the major serum carrier protein for the IGFs, IGF-I levels increase before any significant change in IGFBP-3 concentrations. During the 0 month study, the mean increase in IGF-I concentrations over the first 14 h was approximately 50 ng/mL or about 6.5 nmol/L. If all of the "new" IGF-I was associated with IGFBP-3, e.g. in the ternary complex, the expected increase in IGFBP-3 levels at 12 h would be more than 185 ng/mL, which was not observed. This early IGF-I rise could not be accounted for by changes in unbound IGF-I, as fIGF-I levels were only a fraction of the total IGF-I levels throughout the sampling period. The possibility that IGF-I may be displacing IGF-II for binding to IGFBP-3 seems unlikely because IGF-II levels do not decrease. Instead, IGF-II levels appear to increase in parallel with IGFBP-3. Moreover, changes in IGFBP-1, IGFBP-2, and IGFBP-6 concentrations did not quantitatively parallel changes in IGF-I. Even at 24 h posttreatment, the total increase in IGF-I and IGF-II (23 nmol/L) is greater than that in IGFBP-3 (13 nmol/L).
These results suggest that the new IGF-I pool may be initially associated in a binary complex with one of the unmeasured IGFBPs or a portion of the measured IGFBPs that is unsaturated. This hypothesis agrees with previously published information regarding the mol wt distribution of IGF-I after GH administration (23, 37, 41); however, the identity of the IGFBP(s) responsible for this phenomenon remains uncertain. If this hypothesis is valid, the blunted acute response of IGF-I during daily GH treatment, e.g. during our 6-month timed sampling studies and in the studies cited above (30, 31, 32), may be due to a reduction in the pool of unsaturated serum IGFBP. Early studies of IGFBP demonstrating increased amounts of unsaturated IGF-binding activity in serum from untreated hypopituitary subjects compared to normal and GH-treated hypopituitary subjects (42, 43) are relevant to this model.
Serum IGFBP-2 may be suppressed by GH and insulin under certain conditions, although the published data are not always in agreement (9, 10, 44). In the current study, fasting IGFBP-2 levels did not change after 3 and 6 months of rhGH treatment despite significant changes in GH and insulin concentrations. During the 0 month timed sampling protocol, mean IGFBP-2 concentrations increased significantly 2 h post-GH treatment (1 h after the initial postprandial increase in insulin concentrations), subsequently declining to baseline by 20 h. Similar changes were not observed during the 6-month study. IGFBP-6 concentrations also showed no significant trends during the timed sampling protocols, and fasting IGFBP-6 levels were significantly higher after 6 months, but not 3 months, of GH treatment. Overall, our data tend to argue against a major physiological role for GH and insulin in regulating serum IGFBP-2 or IGFBP-6 levels in well nourished, GHD individuals. However, given the complex concurrent changes in several factors that may influence IGFBP-2 and IGFBP-6 serum concentrations in this study (e.g. GH, insulin, IGF-I, and IGF-II), additional studies will be needed to clarify this issue.
A placebo-controlled trial was not feasible for the GHD group. However, our studies in two GHRD subjects indicate that nonspecific reactions to rhGH do not account for the findings in the GHD group. The GHRD subjects are physiologically unable to respond to exogenous GH due to a lack of normal GH receptors. The extremely low serum concentrations of IGF-I, fIGF-I, IGF-II, and IGFBP-3 and the lack of response to GH in these subjects are consistent with the supposition that GH-related changes in these analytes in the GHD group are mediated by the GH receptor.
It has been estimated that more than 95% of the total serum IGF-I circulates in association with IGFBPs (1, 2, 3, 41) and that most of this amount is accounted for by the ternary complex (IGF, IGFBP-3, and acid-labile subunit). Although IGF-enhancing effects of IGFBPs have been reported in in vitro studies, the bulk of both in vitro and in vivo data to date indicates that the IGFBPs inhibit the biological actions of IGF-I (2, 3, 8). Therefore, the concept and possible measurement of a free or easily dissociated bioactive fraction of serum IGF-I are of special interest. The direct fIGF-I assay used in the current study has been previously suggested to measure both a true free fraction and a portion of IGF-I that can be easily dissociated from low mol wt IGF/IGFBP binary complexes (17, 45).
Using this assay, we have found that both acute and chronic GH treatments of GHD lead to dramatic increases in serum fIGF-I. Although the pool of fIGF-I is clearly dependent on the available pool of total IGF-I, acute changes in fIGF-I are inversely related to acute changes in serum IGFBP-1 and, to a lesser degree, IGFBP-3. A similar inverse relationship between IGFBP-1 and fIGF-I was reported by Frystyk et al. (46) using a sensitive IGF-I assay preceded by a validated centrifugal ultrafiltration sample preparation step to separate free and bound forms of IGF-I and by Bereket et al. (18, 45) using the direct assay reported here. These data suggest that IGFBP-1 may play a key role in acute regulation of serum IGF-I bioavailability.
In previous studies in which GH, insulin, and glucose levels were separately controlled, we showed that insulin acutely suppresses serum IGFBP-1 concentrations and that GH does not have a significant acute independent action on IGFBP-1 in vivo (47). This is supported by the current study, in which IGFBP-1 varies inversely with insulin during each 24-h sampling period. Although the decline in IGFBP-1 levels also follows the posttreatment increase in GH levels during each timed sampling study, multiple regression analyses revealed a stronger inverse relationship of IGFBP-1 with insulin than with GH during both timed sampling studies despite the comparatively uncontrolled conditions compared to those of our previous investigations. This is consistent with the hypothesis that insulin is the primary regulator of IGFBP-1 production and serum levels in vivo (reviewed in 8 .
Longer term effects of insulin and GH on IGFBP-1 are less well characterized. We found that although insulin levels are higher during GH treatment, IGFBP-1 levels are not lower, suggesting a change in the sensitivity of IGFBP-1 production to insulin with prolonged GH replacement therapy. The increased insulin concentrations are consistent with previous reports that GH treatment decreases insulin sensitivity (48, 49, 50). However, the interrelationships of GH status and insulin sensitivity are likely to be complex. Untreated GH-deficient adults also have peripheral insulin resistance, perhaps related to increased abdominal fat (51). As IGFBP-1 is produced primarily by liver, our observations support previous data showing that GH treatment has specific effects on hepatic glucose metabolism and insulin sensitivity (48).
In the GHRD subjects, both IGFBP-1 and IGFBP-2 levels were elevated. This phenomenon has been observed in limited previous studies of individuals with GHRD; however, the levels in our study are substantially higher than those in previous reports (52, 53, 54). This difference could be due to the younger age of our subjects, differences in GHRD genotype, and/or the small numbers of subjects studied to date. The pathophysiology of the elevated IGFBP-1 and IGFBP-2 levels has not been defined, but may be related to the extremely low insulin concentrations. Interestingly, we found that the ability of insulin to acutely depress serum IGFBP-1 concentrations is apparently preserved in GHRD, which agrees with previous findings in three GHRD subjects (52, 54).
Finally, our results may be relevant to past and future studies of IGF generation tests, i.e. tests in which GH-related analytes are measured acutely, usually after a single GH dose. Such tests have been proposed as possibly predictive of the long term response to GH treatment (55); however, there are limited data regarding test performance and optimal timing intervals. Our data demonstrate that if IGF-I is used as the measured response parameter, a sampling interval of less than 24 h post-rhGH treatment in an untreated GHD patient may not provide an adequate indication of peak response. A longer sampling interval or measurements of incremental rates within the 24-h posttreatment period may be preferable. If IGFBP-3 or IGF-II is used as the response parameter, a sampling interval of less than 20 h may be deceptive in showing no apparent response.
In conclusion, we have presented studies characterizing the acute and chronic responses to exogenous GH of several elements of the IGF system in subjects with GHD. Our results show that serum IGF-I and fIGF-I clearly show the most dramatic acute responses to rhGH, whereas other measured analytes (i.e. IGF-II, IGFBP-3, IGFBP-2, and IGFBP-6) show delayed, small scale, or absent changes. Furthermore, our observations in both the GHD and GHRD subjects provide additional in vivo evidence for a primary role of insulin in the regulation of serum IGFBP-1. Acute changes in fIGF-I are inversely related to those in IGFBP-1, a physiological relationship consistent with a postulated role of IGFBP-1 in the regulation of metabolic substrate utilization. The changes in serum levels of IGFs and IGFBPs that we observed could reflect changes in tissue production, utilization, and/or metabolism. In addition, association of IGFs in binary or ternary complexes may affect rates of proteolysis and clearance. Therefore, additional studies will be needed to define the complex mechanisms underlying our observations.
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Acknowledgments |
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Footnotes |
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1 This work was supported by a grant from Diagnostic Systems
Laboratories (to J.G.A.). 
Received December 30, 1996.
Revised March 5, 1997.
Accepted March 20, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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