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From the Clinical Research Centers |
Division of Endocrinology and Metabolism, Department of Medicine (I.M.C., M.L.H., E.H.S., S.S.P., M.O.T.), and Division of Biostatistics and Epidemiology, Department of Health Evaluation Sciences (K.S.P.), University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; and the Department of Pediatrics, Stanford University Medical Center (R.L.H.), Stanford, California 94305
Address all correspondence and requests for reprints to: Dr. Michael O. Thorner, Department of Medicine, Box 466, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mechanisms responsible for IGF-I suppression of GH secretion have not been clearly established. IGF-I receptors are present in both the pituitary and hypothalamus, and the suppressive effects of IGF-I are exerted at the pituitary (12, 13) and possibly also the hypothalamus, where IGF-I has been variously reported to increase hypothalamic production and secretion of somatostatin, to decrease hypothalamic production and secretion of GHRH, or both (4, 12, 14, 15, 16). In particular, it has not been established whether the GH-suppressive effects of IGF-I are exerted via its protein-bound and/or unbound components. Depending on the circumstances, association of IGF-I with its binding proteins is capable of either enhancing or inhibiting its metabolic effect (1). The time course of recovery of GH release from suppression by IGF-I is also unknown. IGF-I bound to IGFBPs in the circulation, particularly the approximately 80% bound to IGFBP-3 (1), has a much longer half-life than unbound (free) IGF-I (17). Therefore, the relative contribution of bound and unbound IGF-I to its various metabolic actions can be studied by examining the time course of these effects in relation to changes in circulating total and free IGF-I concentrations (18).
We have previously demonstrated that euglycemic iv infusions of recombinant human IGF-I (rhIGF-I) at 10 µg/kg·h suppress fasting-enhanced GH secretion in healthy young adults within 60 min (3). In both young and older adults, the minimum effective dose of iv infused rhIGF-I to suppress fasting-enhanced GH release is 3 µg/kg·h (19). In the present study, a similar protocol was used to determine the time course of recovery of GH release from suppression by exogenous rhIGF-I in relation to changes in plasma total and free IGF-I concentrations.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The study was approved by the Human Investigation and General Clinical Research Center Advisory Committees of the University of Virginia. All subjects gave written informed consent.
Eleven young adults (six men and five women, aged 18–29 yr) were studied. Their body mass indices ranged from 21–27 kg/m2 (mean ± SD, 23.2 ± 1.5). All subjects were nonsmokers, were taking no medications, had not undertaken transmeridian travel within 6 weeks, and had unremarkable clinical histories and normal physical examinations. All had normal biochemical indices of renal, hepatic, and hematological function and normal levels of glycated hemoglobin, T4, TSH, PRL, LH, FSH, testosterone (men), and estradiol (women).
Experimental protocol
Each subject was studied on two occasions, separated by at least 4 weeks, and took ferrous sulfate between study days. The young women were studied between days 1–6 of their menstrual cycle (20) and had a negative hCGß pregnancy test immediately before each admission. For each study the subjects consumed a standard breakfast (900 Cal for men and 700 Cal for women; made up of 15% protein, 30% fat, and 55% carbohydrate) between 0700–0730 h on study day 1 and then fasted for 47.5 h, during which time they ingested only water, potassium chloride (20 mEq/day), and multivitamins (one tablet per day). Compliance with the fast was monitored by daily measurement of weight and urinary ketone levels. On each morning of the fast and at the end of the study, blood was obtained for determinations of serum chemistries and hepatic enzymes to monitor for adverse effects of the fast and rhIGF-I infusion.
The studies were performed on days 2 and 3 (23.5–47.5 h of fasting). Subjects remained in bed from 0700 h on study day 2 to the end of the study, except for walks to the bathroom, which were permitted after 1630 h on study day 2. Subjects remained awake until at least 2200 h on study day 2, after which lights were turned out. In a single blind manner, the subjects were given, in randomized order, infusions of rhIGF-I on one admission and normal saline on the other. Dextrose was infused as necessary during both admissions to prevent hypoglycemia.
rhIGF-I admission. By 0600 h on study day 2, a cannula was placed in an antecubital vein for continuous infusion of test substances, and another was placed in a vein of the other arm for blood sampling. From 0700 h on study day 2 to 0700 h on study day 3, venous blood samples (1 mL) were obtained at 10-min intervals for measurement of GH. Serum glucose concentrations (0.5-mL blood samples) were measured at 0700, 0800, 0840, and 0850 h; every 10 min from 0900–1600 h; every 30 min from 1600–1800 h; then every hour until 0700 h on study day 3. Blood samples for measurements of insulin, free IGF-I, and total IGF-I were collected at 0700, 0900, and 1100 h; hourly from 1300–2100 h; at 2300 h on study day 2; and at 0700 h on study day 3. Serum IGFBP-1 and IGFBP-3 were measured at 0700, 1300, and 1900 h on study day 2 and at 0100 and 0700 h on study day 3.
To prevent dehydration, 0.9% saline was infused iv at 50 mL/h from 0700–1600 h on study day 2, and subjects were required to drink a minimum of 250 mL water every 3 h between 0700–2200 h study day 2. rhIGF-I (3 µg/kg·h) was administered iv from 0900–1300 h on study day 2. The rhIGF-I (Genentech, South San Francisco, CA) was prepared in normal saline from a stock 5 mg/mL solution and was infused iv at 60 µL/kg/h. The infusions were delivered by microprocessor pumps (model 22, Harvard Apparatus, South Natick, MA).
Between 0900–1600 h on study day 2, an infusion of 20% dextrose was
started if plasma glucose fell more than 15% below the baseline
values, defined as the mean of the plasma glucose concentrations at
0840 and 0850 h. The rate of the dextrose infusion was adjusted
every 10 min to keep the plasma glucose level within 10% of this value
(15% below baseline concentrations) on the basis of the plasma glucose
measurements and a negative feedback algorithm (21). The actual glucose
concentration of the 20% dextrose solution was measured for each
experiment. A glucose analyzer (Beckman Analytical System Group,
Columbia, MD) was used to measure plasma glucose concentrations during
the study, and dextrose infusions were delivered by a Harvard
microprocessor pump controlled by a computer program (running on an
IBM-compatible computer) written and supplied by Dr. David Krusch
(University of Rochester, Rochester, NY). From 1600 h on study day
2 to 0700 h on study day 3, 5% dextrose was infused iv according
to a sliding scale, at rates between 30–120 mL/h, if the blood glucose
concentration was less than or equal to 2.8 mmol/L (or 
3.3 mmol/L
with symptoms of hypoglycemia). Blood sampling was finished, and the
subjects were fed at 0700 h on study day 3.
Control admission (saline infusion). The protocol was the same as that on the rhIGF-I admission, except that saline was infused instead of rhIGF-I. Dextrose (20%) was administered, as described for the rhIGF-I admission, as needed to prevent plasma glucose from decreasing by more than 15% from baseline values.
Assays
GH. Serum GH concentrations were measured in duplicate by a commercially available chemiluminescence assay (Nichols Institute, San Juan Capistrano, CA); the protocol was modified as previously described (22). The sensitivity of the assay is 0.002 µg/L. The interassay coefficients of variation (CVs) were 7.2% at 1.7 µg/L and 7.2% at 4.2 µg/L. The intraassay CVs were 4.9% at 0.2 µg/L, 6.7% at 2 µg/L, and 6.4% at 4.9 µg/L.
IGF-I. Total plasma IGF-I was measured by RIA after acid-ethanol extraction, using a commercially available kit (Nichols Institute). Interassay CVs were 5.2% at 122 µg/L and 8.4% at 185 µg/L. Intraassay CVs were 2.4% at 119 µg/L and 3% at 207 µg/L. The sensitivity of this assay is 32 µg/L. Free IGF-I was measured by immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX). This is a noncompetitive, two-site immunoradiometric assay that uses an 125I-labeled free IGF-I antibody in liquid phase and tubes coated with a second free IGF-I antibody. The free IGF-I standards are calibrated to the WHO International Reference Reagent for IGF-I (code 87/518). Interassay CVs were 8.4% at 0.26 µg/L, 3.6% at 5.52 µg/L, and 10.8% at 13.87 µg/L. Intraassay CVs were 10.4% at 0.29 µg/L, 5.2% at 6.26 µg/L, and 3.3% at 14.2 µg/L. The sensitivity is 0.03 µg/L.
IGFBP-1 and -3. Serum IGFBP-1 was measured by immunochemiluminometric assay at Endocrine Sciences (Calabasas Hills, CA). The sensitivity of the assay was 0.1 µg/L. Serum IGFBP-3 was measured by RIA at Endocrine Sciences, and the sensitivity was 0.03 mg/L.
Other assays. Plasma insulin was measured at Endocrine Sciences by RIA. The sensitivity of the insulin assay was 7.2 pmol/L. Previously described methods were used to measure serum PRL, LH, and FSH (3). Samples with undetectable amounts of the above hormones were assigned the value of the sensitivity of the assay for statistical analysis. Other studies were performed in the Clinical Laboratories of the University of Virginia Health Sciences Center using standard methods.
Statistical analysis
Results are expressed as the mean ± SE unless
otherwise stated. For analytes measured at intervals of 1 h or
less frequently (total and free IGF-I, insulin, IGFBP-1, and IGFBP-3),
comparisons between the results from rhIGF-I and control treatments
were made with paired t tests, with each subject serving as
his/her own control. All hypothesis testing was two-tailed. Statistical
significance was assumed when P 0.05. When multiple
comparisons were made over time, P 0.05 was accepted
if a clear trend toward increasing statistical significance over time
was evident (23).
As GH and glucose were measured at 10-min intervals for extended
periods of time, paired comparisons at each time point were not
appropriate. To objectively assess the suppression and recovery of
serum GH concentrations by rhIGF-I over time against a background of
spontaneous GH secretion that includes both basal and varying amplitude
bursts of secretion, we used random coefficient models (24). To do
this, we first fitted the GH concentrations over time for each
condition (rhIGF-I day and saline day) using a flexible modeling method
called restricted cubic spline transformations. Then three models were
compared: one with the time effect only, one with time and treatment
main effects only, and one with time, treatment, and the interaction
between the two. From these three models, we derived tests of the
overall treatment effect and of the equivalence of the change in
concentration over time for subjects on the control day vs.
the rhIGF-I day. These tests determine the statistical significance of
overall differences between the two treatment conditions, but do not
determine at which time points the differences exist. For this
analysis, we sought to normalize each subject’s GH concentration-time
trend during the rhIGF-I infusion for the subject’s GH
concentration-time trend during the control (saline) infusion. Both
absolute change and percent change have been used to analyze such data
(19, 25). We had previously determined that for pulsatile GH data,
differences were more independent of control conditions than ratios;
therefore, we chose differences as the method to analyze rhIGF-I
effects over time (19). We subtracted each subject’s serum GH
concentration at each time point during the control day from his/her GH
concentration at the same time point during the rhIGF-I day (rhIGF-I
day - control day). We then derived a regression curve for the
change in serum GH concentrations (
serum GH, rhIGF-I day -
control day) over time with simultaneous (taking into account multiple
time points) 95% confidence bands, as previously described (19).
Significant suppression of serum GH was defined as occurring when the
upper 95% confidence limit for the regression curve was less than
zero. Significant rebound GH release was defined as occurring when the
lower 95% confidence limit for the regression curve was more than
zero. For periods of significant suppression and rebound, the median,
25th percentile, and 75th percentile serum GH concentrations were
calculated from the cubic spline transformations of the GH
concentration-time series for each condition. This same method was used
to compare the glucose concentrations during the rhIGF-I and control
(saline) infusions.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Mean plasma glucose concentrations decreased 12% during the control study and 14% during the rhIGF-I study in these fasting subjects. Dextrose infusions were required for 2 of 11 subjects during their control admissions and for 3 (different) subjects during their rhIGF-I admissions to prevent plasma glucose concentrations from falling more than 15% below baseline values. All plasma glucose concentrations were between 2.8–6 mmol/L. The total amount of glucose infused per subject was not significantly different between the control and rhIGF-I days, either for the entire study (control day vs. rhIGF-I day, 19.8 ± 16 vs. 9.4 ± 6 mg/kg) or during the 7-h (0900–1600 h) 20% dextrose clamp (control day vs. rhIGF-I day, 3.4 ± 3 vs. 9.4 ± 6 mg/kg). Mean plasma glucose concentrations were similar, but slightly (<10%) higher, on the rhIGF-I day than on the control day at most time points. The difference between plasma glucose concentrations on the 2 days (rhIGF-I - control) was statistically significant only between 0920–1340 and 1440–1900 h (P < 0.05). However, the magnitude of these differences was small. During these time periods, the median differences ranged from 0.11–0.39 mmol/L (2–7 mg/dL), the 25th percentile of these differences ranged from -0.11 to 0.17 mmol/L (-2 to 3 mg/dL), and the 75th percentile of these differences ranged from 0.39–0.66 mmol/L (7–12 mg/dL).
Plasma IGF-I concentrations (Figs. 1
and 2)
Total and free IGF-I concentrations decreased during the 24 h
of the control admission, as the fast continued [total IGF-I, 267
± 26 to 202 ± 23 µg/L (P = 0.001; Fig. 1); free IGF-I, 1.2 ± 0.4 to
0.71 ± 0.2 µg/L (P = 0.01; Fig. 2)]. Total IGF-I concentrations
increased during infusion of rhIGF-I and were significantly greater
than control day values within 2 h of the start of the rhIGF-I
infusion (P = 0.002; Fig. 1). They peaked at the end of
the infusion, approximately 65% above the baseline (432 ± 43
vs. 263 ± 44 µg/L; P < 0.001), but
were still within the age-adjusted assay normal range (182–780 µg/L
for ages 18–24 yr and 114–492 µg/L for ages 25–39 yr). Total IGF-I
concentrations then decreased until 1900 and 2000 h, at which
times the difference between control and rhIGF-I infusion day values
was no longer statistically significant (Fig. 1). After this time (7 h
post-rhIGF-I infusion), total IGF-I concentrations increased again and
were significantly greater than control day values for the remainder of
the study (Fig. 1). At the end of the study, at 0700 h on study
day 3, mean total IGF-I concentrations were approximately 75% higher
than control day values (360 ± 36 vs. 202 ± 23
µg/L; P = 0.001).
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). Free IGF-I values then declined
rapidly, and by 2 h after the end of the rhIGF-I infusion were no
longer statistically different from control day values. For the
remainder of the rhIGF-I admission, free IGF-I levels were not
different from control values, except for a transient rise at 1900
h (Fig. 2).
Serum GH concentrations (Figs. 3 and 4)
Figure 3 depicts the mean
(±SE) serum GH concentrations throughout the entire 24-h
study periods during the rhIGF-I and control admissions. Serum GH
concentrations were significantly decreased by infusion of rhIGF-I
compared to those after the saline infusion
(
25 = 130; P < 0.001). This
effect was strongly reflected in the differential effect of treatment
over time (24 = 122; P <
0.001). This indicates that the treatment effect was not constant, but
varied according to the time of day, as expected because the rhIGF-I
infusion was only 4 h in duration. A regression curve of the
difference in serum GH concentrations over time (rhIGF-I day -
control day) with simultaneous 95% confidence bands was calculated and
is shown in Fig. 4. Serum GH was
maximally suppressed by rhIGF-I within 2 h and remained suppressed
for 2 h after cessation of the rhIGF-I infusion; during this 4-h
period (1100–1500 h), serum GH concentrations were approximately 25%
of control day levels [median (interquartile range), 1.2 (0.4–4.0)
vs. 4.8 (2.8–7.9) µg/L; P < 0.05].
After cessation of rhIGF-I infusion, serum GH concentrations began to
recover during the third hour, and a rebound increase occurred 5–7 h
later (1800–2000 h), such that GH levels were nearly 2-fold higher
than at this time on the control day [median (interquartile range),
7.6 (4.6–11.7) vs. 4.3 (2.5–6.0) µg/L; P
< 0.05]. Thereafter, serum GH concentrations were similar on both
study days, indicating that the effects of the rhIGF-I infusion on GH
secretion had completely dissipated.
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). As shown in Fig. 4, the difference in serum GH concentrations
(rhIGF-I - control) rapidly increased after 1500 h. In
contrast, total IGF-I concentrations remained elevated well after the
resolution of GH suppression (Fig. 1). Throughout the last 10 h of
the study, when the control and rhIGF-I day GH concentrations were
virtually superimposable (Fig. 3), mean total IGF-I concentrations were
significantly higher after rhIGF-I infusion than after the control
infusion (Fig. 1). During these 10 h, total IGF-I concentrations
were also higher than after 2 h of rhIGF-I infusion (1100 h), a
time point at which GH concentrations were significantly suppressed to
half the control day values.
Insulin, IGFBP-1, and IGFBP-3 (Fig. 5)
Plasma insulin concentrations were low at the beginning of both
rhIGF-I and saline infusions as the subjects were fasting. However,
insulin levels were further decreased during the infusion of rhIGF-I,
and by the end of this infusion were significantly lower than those on
the control day (12.9 ± 2.2 vs. 21.5 ± 3.6
pmol/L; P = 0.02). After cessation of rhIGF-I infusion,
the suppression of insulin levels rapidly resolved (Fig. 5). Serum IGFBP-1 and -3 concentrations
were not significantly changed by the 4-h rhIGF-I infusion compared to
levels on the control day (Fig. 5).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We used the lowest dose of iv rhIGF-I (3 µg/kg·h) that has been shown to suppress fasting-enhanced GH release; this dose has less of a hypoglycemic effect than higher doses of rhIGF-I (19). To avoid a greater than 15% decrease in plasma glucose concentrations during rhIGF-I infusion, 3 of 11 subjects required dextrose infusion. However, it is unclear whether this decrease in plasma glucose levels was an effect of rhIGF-I, because 2 different subjects among the 11 also required dextrose infusion during the saline infusion. Thus, the decrease in glucose levels may have been primarily an effect of fasting. Mean plasma glucose concentrations were slightly, but significantly, higher for several hours on the rhIGF-I study day than those on the control day, probably as a result of the dextrose infusions. However, the median difference in plasma glucose between the 2 study days during these periods was very small (0.11–0.39 mmol/L or 2–7 mg/dL) and was unlikely to have had any physiological significance. Previous reports have suggested that much larger increments in plasma glucose are necessary to suppress serum GH concentrations (26, 27).
More than 97% of circulating IGF-I is carried bound to IGFBPs (1). This binding serves to slow the clearance of IGF-I from the circulation. Approximately 70–80% of circulating IGF-I is carried in a 150-kDa ternary complex made up of IGF-I, IGFBP-3, and an 85-kDa acid-labile subunit (1, 28). This complex has a circulating half-life of 12–15 h, compared to 10–15 min for unbound or free IGF-I (17, 29). These differences were reflected in the postinfusion plasma concentrations of total and free IGF-I in the present study. Total IGF-I concentrations were significantly greater than control day values at all but two postinfusion time points and were still nearly 2-fold higher than control day values 18 h after the end of the rhIGF-I infusion. In contrast, free IGF-I concentrations, which were comparable to those measured by other methods in other studies (3, 30), decreased to control day levels within 2 h of cessation of the rhIGF-I infusion.
In the case of many hormones that circulate bound to carrier proteins, such as the thyroid hormones, testosterone, estradiol, and cortisol, only the unbound (free) component is considered biologically active in most tissues (31). The situation with IGF-I is less clear. Some IGF-I actions appear to be mediated by free IGF-I and others by bound IGF-I. Binding of IGF-I to the IGFBPs, even the same IGFBP under different circumstances, can produce either enhancement or inhibition of its metabolic effects. Binding of IGF-I to IGFBPs 1–5 and possibly IGFBP-6 in biological fluids has been shown to reduce the binding of IGF-I to cell surface IGF-I receptors (1). In addition, binding of IGF-I to IGFBP-3 in the 150-kDa complex serves to trap IGF-I in the circulation and inhibits the effects of IGF-I exerted outside the vascular space. There is evidence suggesting that free IGF-I is a more important mediator than bound IGF-I of some actions of IGF-I. For example, the hypoglycemic actions of IGF-I are related to circulating levels of free IGF-I and are reduced by binding to IGFBPs (18, 29, 30). Obese children are, on the average, taller than their lean counterparts despite having lower GH concentrations and total IGF-I levels that are probably not significantly different. The increased linear growth in these children may be mediated by free IGF-I, serum concentrations of which are increased in obesity due to an insulin-mediated reduction in IGFBP-1 concentrations (32). In contrast, the growth-promoting effects of exogenous rhIGF-I are enhanced by coadministration of rhIGFBP-3 to hypophysectomized rats, suggesting that prolonging the plasma half-life of IGF-I is important for this effect (33). Although circulating concentrations of free IGF-I are closely related to those of total IGF-I, there are situations, including pregnancy (34), early infancy (35), and obesity (32), where the ratio of free to total IGF-I is increased. We, therefore, speculate that under some circumstances it may be more appropriate to monitor the functional status of the GH-IGF-I axis or the effects of GH and IGF-I treatment by measuring free rather than total IGF-I. This remains to be established. The measurement of free IGF-I is reported to be no better than that of total IGF-I in diagnosing GH deficiency (36). In addition, the short half-life of free IGF-I and its inverse relation to circulating IGFBP-1 levels make its circulating concentrations very dependent on nutritional state, probably limiting the diagnostic and therapeutic usefulness of a single measurement of free IGF-I.
Previous studies have not determined whether the GH-suppressive effect of IGF-I is exerted by the protein-bound component or by unbound IGF-I. In the present study, the close temporal association between the resolution of GH suppression and the fall of free IGF-I concentrations, and the lack of any clear association with total IGF-I concentrations, suggests that unbound (free), not protein-bound, IGF-I is the major IGF-I component responsible for this suppression. The lack of GH suppression by protein-bound IGF-I may result from inhibition by IGFBPs of IGF-I binding to the pituitary and hypothalamic IGF receptors involved in mediating this suppression. In addition, IGF-I binding to IGFBP-3 as part of the 150-kDa complex may prevent IGF-I from reaching extravascular sites of action. This latter mechanism is unlikely to be the only explanation because a number of structures implicated in the mediation of this suppressive effect on GH secretion, including the pituitary and parts of the hypothalamus, lie outside the blood-brain barrier. Furthermore, approximately 20% of circulating IGF-I is bound to lower mol wt IGFBPs, including IGFBP-1, -2, and -4, all of which are capable of crossing endothelial barriers (1).
We found no evidence for a role of IGFBP-1 and -3 in mediating the IGF-I-induced suppression of GH release, as concentrations of neither were significantly affected by the rhIGF-I infusion. We believe it unlikely that changes in the concentrations of the other IGFBPs contributed in any way to the suppression of GH concentrations. The total rhIGF-I dose administered in this study (12 µg/kg) was almost certainly too low to affect any of these other proteins. At high doses (>500 µg/kg), rhIGF-I increases circulating levels of IGFBP-1 and -2 (28, 30, 37), but iv administration of 30 µg/kg, still more than twice the dose used in this study, has been reported to have no effect on IGFBP-2, -3, or -4 concentrations, with only a transient stimulatory effect on IGFBP-1 (29). Furthermore, the rapid time course of the onset and resolution of suppression of GH release by rhIGF-I is inconsistent with mediation by changes in levels of circulating binding proteins.
A statistically significant rebound increase in serum GH concentrations occurred 5–7 h after cessation of the rhIGF-I infusion. During this 2-h period, GH levels were nearly 2-fold higher on the rhIGF-I study day than at this time on the control day. This rebound increase in serum GH concentrations is consistent with cessation of an inhibitory effect of free IGF-I on GH release. In vitro, IGF-I decreases both GH secretion and messenger ribonucleic acid levels in cultured rat pituitary cells (13, 38), and when administered alone in low concentrations, it is more effective than IGF-II in suppressing GH secretion at the level of the somatotrope (38). Thus, the early phase of recovery from suppression by IGF-I may reflect a cessation of the inhibitory effects on GH release, and the later rebound increase may reflect synthesis of GH. Alternatively, the delayed rebound increase in serum GH concentrations may reflect the cessation of rhIGF-I effects on the hypothalamus. After the termination of a somatostatin infusion, there is a rebound increase in circulating GH concentrations in rats, dogs, and humans due to the release of accumulated pituitary GH stores (39, 40, 41). As IGF-I may stimulate somatostatin secretion by the hypothalamus (12, 14), it is possible that a similar period of somatostatin withdrawal occurs as free IGF-I levels fall after the termination of an rhIGF-I infusion. A role for somatostatin in the suppression of GH release by rhIGF-I has been suggested by the observations that rhIGF-I infusions in humans diminish the TSH response to an iv injection of TRH to a similar degree as somatostatin infusions (4, 42), whereas IGF-I does not inhibit the release of TSH from the pituitary in vitro (12).
The rhIGF-I infusion probably also affected endogenous IGF-I production. After termination of the rhIGF-I infusion, total IGF-I concentrations decreased steadily until 2000 h, at which point they were still higher than control day values, although not significantly so. Total IGF-I concentrations then increased during the next few hours until they were significantly higher than those on the control day and remained relatively unchanged for the last 10 h of the study. The rise in total IGF-I concentrations occurred about 6 h after the rise in serum GH concentrations began. Serum IGF-I concentrations have been reported to start to increase within 4–8 h after iv GH administration, but do not peak for 18–24 h (43, 44). These data are therefore consistent with a feedback effect of IGF-I on its own secretion that is mediated via its effects on GH secretion. Therefore, it is also possible that IGF-I may have a direct inhibitory effect on its own release.
In conclusion, serum GH concentrations recover rapidly from suppression by exogenous rhIGF-I (within 2–4 h) in fasted young adults, and this recovery parallels changes in free rather than total IGF-I concentrations. These data, albeit indirect, suggest that unbound (free), not protein-bound, IGF-I is the major IGF-I component responsible for the suppression of GH release. The rebound increase in GH concentrations that occurs several hours after terminating rhIGF-I infusion is consistent with cessation of an inhibitory effect of free IGF-I on GH release.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Medicine, Royal Adelaide Hospital,
North Terrace, Adelaide, South Australia 5000, Australia.
Received December 22, 1997.
Revised April 22, 1998.
Accepted May 11, 1998.
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J.-W. Chen, K. Hojlund, H. Beck-Nielsen, J. Sandahl Christiansen, H. Orskov, and J. Frystyk Free Rather than Total Circulating Insulin-Like Growth Factor-I Determines the Feedback on Growth Hormone Release in Normal Subjects J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 366 - 371. [Abstract] [Full Text] [PDF]
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 V. Cingel-Ristic, J. W. van Neck, J. Frystyk, S. L. S. Drop, and A. Flyvbjerg Administration of Human Insulin-Like Growth Factor-Binding Protein-1 Increases Circulating Levels of Growth Hormone in Mice Endocrinology, September 1, 2004; 145(9): 4401 - 4407. [Abstract] [Full Text] [PDF]
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K. Yuen, J. Frystyk, M. Umpleby, L. Fryklund, and D. Dunger Changes in Free Rather Than Total Insulin-Like Growth Factor-I Enhance Insulin Sensitivity and Suppress Endogenous Peak Growth Hormone (GH) Release following Short-Term Low-Dose GH Administration in Young Healthy Adults J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3956 - 3964. [Abstract] [Full Text] [PDF]
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S. Grinspoon, K. K. Miller, D. B. Herzog, K. A. Grieco, and A. Klibanski Effects of Estrogen and Recombinant Human Insulin-Like Growth Factor-I on Ghrelin Secretion in Severe Undernutrition J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3988 - 3993. [Abstract] [Full Text] [PDF]
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 H. M. Domene, S. V. Bengolea, A. S. Martinez, M. G. Ropelato, P. Pennisi, P. Scaglia, J. J. Heinrich, and H. G. Jasper Deficiency of the Circulating Insulin-like Growth Factor System Associated with Inactivation of the Acid-Labile Subunit Gene N. Engl. J. Med., February 5, 2004; 350(6): 570 - 577. [Full Text] [PDF]
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R. Nass, S. S. Pezzoli, I. M. Chapman, J. Patrie, R. L. Hintz, M. L. Hartman, and M. O. Thorner IGF-I does not affect the net increase in GH release in response to arginine Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E702 - E710. [Abstract] [Full Text] [PDF]
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 M. S. Sandhu, D. B. Dunger, and E. L. Giovannucci Insulin, Insulin-Like Growth Factor-I (IGF-I), IGF Binding Proteins, Their Biologic Interactions, and Colorectal Cancer J Natl Cancer Inst, July 3, 2002; 94(13): 972 - 980. [Abstract] [Full Text] [PDF]
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J. Frystyk, K. Hojlund, K. N. Rasmussen, S. P. Jorgensen, M. Wildner-Christensen, and H. Orskov Development and Clinical Evaluation of a Novel Immunoassay for the Binary Complex of IGF-I and IGF-Binding Protein-1 in Human Serum J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 260 - 266. [Abstract] [Full Text] [PDF]
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A. F. Muller, F. W. G. Leebeek, J. A. M. J. L. Janssen, S. W. J. Lamberts, L. Hofland, and A. J. van der Lely Acute Effect of Pegvisomant on Cardiovascular Risk Markers in Healthy Men: Implications for the Pathogenesis of Atherosclerosis in GH Deficiency J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5165 - 5171. [Abstract] [Full Text] [PDF]
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J. L. Clasey, A. Weltman, J. Patrie, J. Y. Weltman, S. Pezzoli, C. Bouchard, M. O. Thorner, and M. L. Hartman Abdominal Visceral Fat and Fasting Insulin Are Important Predictors of 24-Hour GH Release Independent of Age, Gender, and Other Physiological Factors J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3845 - 3852. [Abstract] [Full Text] [PDF]
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, Control day; 
, rhIGF-I day. *,
P < 0.05, rhIGF-I vs. control
day.
