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Original Studies |
Division of Endocrinology, Nemours Children’s Clinic and Research Programs (N.M., S.W., A.R.), and Baptist Medical Center Physical Therapy Department (K.H.), Jacksonville, Florida 32207; The Johns Hopkins School of Public Health and Hygiene (K.O.O.), Baltimore, Maryland 21205-2179; and National Institutes of Health (N.E.V., A.L.Y.), Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Nelly Mauras, M.D., Nemours Children’s Clinic, 807 Nira Street, Jacksonville, Florida 32207. E-mail: nmauras{at}nemours.org
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Abstract |
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In the doses administered, rhIGF-I and rhGH both increased fat-free mass and decreased the percent fat mass, with a more robust decrease in the percent fat mass after rhGH; both were associated with an increase in whole body protein synthesis rates and a decrease in protein oxidation. Neither hormone affected isokinetic or isometric measures of skeletal muscle strength. However, rhGH was more potent than rhIGF-I at increasing lipid oxidation rates and improving plasma lipid profiles. Both hormones increased hepatic glucose output, but rhGH treatment was also associated with decreased carbohydrate oxidation and increased glucose and insulin concentrations, indicating subtle insulin resistance. Neither hormone significantly affected bone calcium fluxes, supporting the concept that these hormones, by themselves, are not pivotal in bone calcium metabolism. In conclusion, rhIGF-I and rhGH share common effects on protein, muscle, and calcium metabolism, yet have divergent effects on lipid and carbohydrate metabolism in the GH-deficient state. These differences may allow for better selection of treatment modalities depending on the choice of desired effects in hypopituitarism.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Most studies directly comparing the metabolic effects of these hormones have been short term (7–10 days) in both normal volunteers and GH-deficient patients (5, 12, 13). The effects of IGF-I on bone, however, are less well studied in humans, even though animal data and short term human studies suggest a positive bone anabolic effect as well (14, 15, 16). The specific mechanisms involved in the effects of these two hormones on bone calcium metabolism are not well characterized.
Available techniques using stable isotope infusions of different natural compounds now allow us to further characterize the specific changes in the intermediate metabolism of protein, glucose, and calcium in a noninvasive, well tolerated way. Indirect calorimetry and body composition assessment also add substantial information regarding the effects of hormones and nutrients at the whole body level. We set up the present studies to further characterize the in vivo effects of GH vs. IGF-I after more prolonged administration (8 weeks for each study arm) in the GH-deprived state. To accomplish this we recruited eight subjects with profound GH deficiency and treated them with rhIGF-I and rhGH for 8 weeks, each with a 4-week washout period in between. Marked differences in the metabolic effects of these peptides were observed.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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These studies were approved by the Nemours Children’s Clinic
Clinical Research review committee and the Baptist Medical Center
Institutional Review Board. Eight patients with clinical and
biochemical evidence of GH deficiency were recruited for these studies
after informed written consent was obtained. Their clinical
characteristics are summarized in Table 1
. Those with other pituitary hormone
deficiencies were receiving replacement treatment during these studies.
All but two subjects (no. 2 and 6) had childhood-onset GH deficiency.
Those patients previously treated with GH had been off GH for at least
1.5 yr before these studies.
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For 3 days before admission, subjects were encouraged to consume a weight maintenance diet consisting of approximately 30 Cal/kg and 1 g/kg protein·day; they were admitted to the Wolfson Children’s Hospital Clinical Research Center the afternoon before the first study. Assessment of body composition was obtained using skin fold calipers, bioelectrical impedance analysis, as well as dual emission x-ray absorptiometry (DEXA), using a tissue bar (Hologic, Inc., Waltham, MA). Isokinetic and isometric dynamometry of the anterior quadriceps was performed in our physical therapy department using a Biodex dynamometer (Biodex Corp., Shirley, NY). After a 10-min training session and 30 min of rest, maximum work and torque measures for isometric and isokinetic tests were performed. Isometric tests were performed with 5 contractions of 5 s each, with the knee placed at 45° of flexion, and 10 s of rest between contractions. Isokinetic tests were performed for knee extension and flexion at 60°/s for 5 repetitions and at 180°/s for 21 repetitions as described previously (17).
Subjects were fed dinner at 1800 h and were given 0.3 mg/kg of a stable isotope of calcium (44Ca) orally mixed with milk or juice prepared at least 12 h before equilibration. A urine collection was begun after the oral Ca tracer and continued for the next 28 h. The patients were subsequently fasted except for water ad libitum until the completion of the studies at 1300 h the next day. The following morning (baseline study), at 0600 h, two iv needles were placed in each antecubital vein. One was kept heated for arterialized blood sampling (18). At 0800 h (time zero), three stable isotope tracers were given. One, a primed, dose constant infusion of L-[1-13C]leucine (4.5 µmol/kg; 0.07 µmol/kg·min) was begun and continued uninterrupted for the next 240 min. Concomitantly, a primed infusion of [6,6, 2H2]glucose (33 µmol/kg; 0.33 µmol/kg·min) was begun and continued also for 240 min. At time zero, 0.15 mg/kg 42Ca was also given as a slow iv push over 5 min. Frequent blood samples were collected for determination of isotopic enrichment of the different tracers in plasma as well as the concentrations of hormones, substrates, and growth factors, as detailed below. Frequent breath samples were also obtained for determination of 13CO2 enrichment in expired breath. Indirect calorimetry was performed three times during the 4 h of isotope infusion using a mouthpiece and a CPX max indirect calorimeter (Medical Graphics, St. Paul, MN). After the isotope infusions were completed, the patients were fed lunch, and one iv line was discontinued. Subjects were subsequently free to move around, and at 1600 h another blood sample was obtained for determination of Ca enrichment. Subjects were then sent home to complete the urine collection. For the next 5 days, twice daily urine samples were obtained for determination of the Ca isotopic enrichments.
After the baseline study and all urine collections were completed, patients were started on rhIGF-I at 60 µg/kg, sc, twice daily. Subjects were instructed to monitor their blood glucose concentrations using home glucose-monitoring equipment for the first week after initiation of rhIGF-I therapy and any other time there were any symptoms of hypoglycemia. They were also instructed to take the rhIGF-I injection with their meals to avoid hypoglycemia. Blood was withdrawn 4 weeks after the initiation of treatment for determination of hormone concentrations and safety laboratories. Eight weeks from the baseline study an identical study was performed. The night before the second study, starting at 2000 h, the second dose of rhIGF-I was substituted for a continuous sc infusion of the peptide at 10 µg/kg·h, which was continued uninterrupted for the next 17 h until completion of the studies the following morning. This was done to prevent hypoglycemia during the administration of rhIGF-I while the patients were fasting, while maintaining plasma IGF-I concentrations constant. We have successfully used this strategy in similar experiments (4, 5, 19). Afterward, rhIGF-I treatment was discontinued, and a washout period of 4 weeks was observed without any treatment. Blood samples were again withdrawn at the end of the washout period. rhGH was started as a single sc injection of 12.5 µg/kg at bedtime and was continued for another 8 weeks when the studies were repeated a third time. The treatment order was randomized: D1, baseline study; D2, rhIGF-I for 8 weeks; followed by 4-week washout; and then rhGH was administered for 8 weeks, followed by D3.
Blood and breath samples
The isotopic enrichments of 
-ketoisocaproic acid
(13C labeled), and
2H2-glucose were measured
at -20, 160, 180, 200, 220, and 240 min. The Ca isotopic enrichments
were measured at 0, 5, 10, 15, 20, 30, 40, 60, 120, 180, 240, and 480
min. Plasma IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-2, IGFBP-3,
insulin, and glucose concentrations were measured three times during
the 240 min of tracer infusions. Serum GH concentrations were measured
at 10-min intervals for the 4 h of the studies. Serum lipids were
also measured while fasting on each study day. Breath samples were
obtained for the measurement of expired labeled
CO2 at -20, -10, -5, 160, 180, 200, and 220
min. A small aliquot of the urine collected during the 4 h of the
morning study was used for determination of urea nitrogen
concentration.
Assays
Plasma enrichments of
[13C]-ketoisocaproic acid and
2H2-glucose were determined
at the Nemours metabolic core laboratory by mass chromatography mass
spectrometry as previously described (20, 21).
13CO2 was measured by
isotope ratio mass spectrometer as described previously (22). Urinary
Ca was determined by flame atomic absorption spectrophotometry at the
laboratory of Dr. O’Brien. A dual filament thermal ionization
quadrapole mass spectrometer (Model THQ, Finnigan MAT, Bremen,
Germany) was used to measure the Ca isotopic enrichments as
previously described (23). All insulin and lipid concentrations were
determined at the immunochemical core laboratory at the Mayo Clinic
General Clinical Research Center (Rochester, MN) using commercial kits.
IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3 concentrations were measured by
radioimmunometric assays at Endocrine Sciences, Inc.
(Calabassas Hills, CA), and insulin concentrations were determined by
chemiluminescence assay. Serum GH concentrations were measured by a
highly sensitive chemiluminescence assay at the University of Virginia
Clinical Research Center core laboratory (Charlottesville, VA). Plasma
glucose concentrations were measured with a glucose oxidase method
using a glucose analyzer (Beckman Coulter, Inc., Palo
Alto, CA) at the bedside. Serum lipids [cholesterol, triglycerides,
and high and low density (LDL) lipoproteins] concentrations were
measured using high performance liquid chromatography methods. Urea
nitrogen was measured using a Kodak Ektakem urease method
(Eastman Kodak Co., Rochester, NY).
Calculations
The reciprocal pool model was used to estimate rates of whole body protein turnover at steady state as previously described (24). The rate of appearance (Ra) of glucose, a measure of hepatic glucose output, was calculated as: Ra = [(Ei/Ep) - 1]F, where Ei is the isotopic enrichment of the infusate, Ep is the enrichment of glucose in plasma, and F is the infusion rate.
For the Ca kinetic analysis, the fractional Ca absorption () was
calculated from the ratio of the cumulative excretion of the oral
tracer (44Ca) in urine divided by the cumulative
excretion of the iv tracer (42Ca) as previously
described (25, 26).
True Ca absorption was calculated as Va = Vi x , where Vi
is the dietary Ca intake. Ca kinetic analysis was performed by
measuring the isotopic enrichments of the Ca tracers in blood and urine
over time using the three-pool multicompartmental model and the
simulation analysis and modeling program, SAAM, as previously described
(27, 28). Other absorption and kinetic terms used are: Vu, urinary Ca
excretion; Vf, endogenous fecal Ca excretion (estimated as 1.5
mg/kg·day) (29); Vo+, the rate of bone Ca
deposition; and Vo-, rate of bone Ca resorption.
Substrate oxidation rates for protein, glucose, lipid, and resting
energy expenditure were calculated using the rate of gas exchange
(VO2 and VCO2) from the
indirect calorimetry as previously described (30).
Fat free mass (FFM) and percent fat mass (FM) were measured using DEXA and the tissue bar as well as by the sum of skin folds as described previously (31).
Isotopes and drugs
L-[1-13C]Leucine (99% enriched; Cambridge Isotopes, Andover, MA), [6,6-2H2]glucose (99.7% enriched, MSD Isotopes, St. Louis, MO), and 42Ca/44Ca (93.5% and 96% enriched, respectively; Trace Sciences International, Richmond Hill, Canada) were determined to be sterile and pyrogen free and were mixed with 0.9% nonbacteriostatic saline. rhIGF-I (10 mg/mL) and rhGH (Nutropin; 10 mg/mL) were provided by Genentech, Inc. (South San Francisco, CA).
Statistical analysis
Results are expressed as the mean ± SE. Paired Student’s t test was used to estimate differences between baseline studies and rhIGF-I and rhGH treatments for all parameters tested. Wilcoxon signed ranks test was used for those parameters with results not normally distributed. Significance was established at P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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shows the plasma IGF-I
concentrations at baseline, after 8 weeks of rhIGF-I, after 4 weeks of
washout, and after 8 weeks of rhGH. Plasma IGF-I concentrations
returned to baseline levels in the study subjects after 4 weeks of
discontinuation of hormone treatment.
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There was a modest increase in weight after rhIGF-I treatment, but
not after rhGH. There were comparable trends in body composition using
either DEXA or sum of skin folds; hence, data are shown for DEXA only.
Body composition, however, changed comparably after either hormone,
with a 3.1-kg (6%) increase in FFM after rhIGF-I and a 3.6-kg (6.8%)
increase after rhGH (P 
0.01 for both) and decreases
in %FM of 1.2% and 3% after rhIGF-I and rhGH, respectively. The
decrease in %FM was greater after rhGH than after rhIGF-I
(P = 0.02 between the two hormone treatments). There
were no detectable changes in isometric or isokinetic measures of
muscle strength of the leg extensors or leg flexors (data for the
latter not shown).
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)There were no changes in the Ra of leucine, a measure of whole body proteolysis, after rhIGF-I, yet there was a clear trend toward higher protein turnover after rhGH administration (P = 0.06). Protein oxidative rates decreased comparably with both hormones (approximately -27–29%) with increases in nonoxidative leucine disposal, a measure of whole body protein synthesis, after the administration of both hormones; this was more pronounced after rhGH.
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Clear differences in the metabolic effects of these hormones on
intermediate metabolism in the GHD state were observed. Carbohydrate
oxidation rates were unaltered after rhIGF-I treatment, whereas they
decreased after rhGH [baseline, 18.2 ± 3.7 Cal/FFM·day;
rhIGF-I, 15.3 ± 4.1 (P = NS); rhGH, 13.5 ±
3.8 (P < 0.05 vs. baseline)]. Protein
oxidation decreased comparably after both treatments [baseline,
3.8 ± 0.4 Cal/kg FFM·day; rhIGF-I, 2.7 ± 0.3
(P = 0.0002); rhGH, 2.5 ± 0.2 (P
= 0.001 vs. baseline)]. Lipid oxidation rates increased
only after rhGH, not rhIGF-I, treatment [14.6 ± 1.6 Cal/kg
FFM·day at baseline; 15.6 ± 1.7 after rhIGF-I
(P = NS); 20.1 ± 2.1 after rhGH
(P = 0.04 vs. baseline)]. There were no
detectable changes in resting energy expenditure (baseline, 33.4
± 2.0 Cal/kg FFM·day; rhIGF-I, 30.3 ± 2.0; rhGH, 32.8 ±
3.0), as shown in Fig. 2.
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)Using glucose tracer data, measures of hepatic glucose output increased comparably and significantly after the administration of both rhIGF-I and rhGH. However, circulating fasting glucose concentrations only increased after rhGH therapy, whereas insulin concentrations decreased after rhIGF-I and increased after rhGH.
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Complete datasets for all 3 study days were available for only
five patients due to missed urine collections. Measures of fractional
and total calcium absorption ( and Va, respectively) as well as
kinetic measures of bone calcium deposition
(Vo+), bone calcium resorption
(Vo-), and total calcium turnover rates remained
invariant during both rhIGF-I and rhGH therapy. However, measures of
urinary calcium excretion were greatly increased after rhIGF-I, but not
rhGH, therapy.
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)Both rhIGF-I and rhGH markedly increased plasma IGF-I concentrations, but the increase was substantially greater after rhIGF-I treatment. Fasting concentrations of IGFBP-1 did not change after either hormone, whereas IGFBP-2 increased only during rhIGF-I therapy, and IGFBP-3 increased only after rhGH. IGF-II concentrations plummeted after rhIGF-I and remained invariant after rhGH therapy. Total cholesterol and high density lipoprotein cholesterol concentrations were not changed during either treatment; however, a substantial decrease in LDL cholesterol was observed after 8 weeks of rhGH treatment. Circulating triglyceride concentrations were only affected by rhGH treatment with a 44% increase. A trend toward suppressed GH pulsatility was observed after rhIGF-I treatment, but it did not reach statistical significance.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Body composition and protein metabolism
Body composition, as measured by DEXA, was comparably affected after rhIGF-I and rhGH treatment, with measurable increases in FFM and decreased %FM even after 8 weeks of continuous therapy. This strongly suggests that long term rhIGF-I treatment may have beneficial effects comparable to those of rhGH on body composition in GH-deficient subjects, particularly as it pertains to FFM accumulation. There appears to be a more robust decline in %FM after rhGH than after rhIGF-I. Even though DEXA cannot compartmentalize if these changes were due solely to changes in lean soft tissue vs. water, the changes in FFM were accompanied by a 20% increase in the total rate of whole body protein synthesis, as measured by the leucine tracer studies, indicating that both hormones affect large body protein pools. These results are similar to those observed by us and others in both healthy volunteers and volunteers made catabolic with either glucocorticosteroid treatment or during caloric deprivation treated with rhGH, rhIGF-I, or both (4, 5, 12, 32). However, contrary to the results found in the normal subjects, where administration of both of these hormones was associated with a selective increase in whole body protein synthesis with no effects on proteolysis, in the GH-deficient state studied here, rates of proteolysis were also markedly increased after rhGH, but not rhIGF-I, treatment, indicating a differential effect of GH in GH-depleted states. The latter may be secondary to the relative insulin resistance typically observed after GH therapy, particularly in GH-deficient states (7) as insulin inhibits proteolysis (33); hence, in insulin resistance states increased proteolytic rates would be expected (34). Previous reports in GH-deficient subjects studied with comparable isotope tracer methods showed diminished rates of whole body leucine turnover compared to those in healthy controls (35). Other reports, also in GH-deficient patients in whom leucine turnover was measured before and after GH therapy, showed a selective increase in protein synthesis after GH treatment (36) similar to that observed in healthy controls treated with GH (32). This difference is probably related to dose, as in the study of GH-deficient subjects (36) the highest dose of GH administered was 3.3 µg/kg·day, almost a fourth of the dose used in the present studies performed in younger patients; again, the higher dose was associated with greater insulin resistance.
Muscle strength
Skeletal muscle has few GH receptors, yet type I IGF-I receptors are rather ubiquitous in skeletal tissue, suggesting that IGF-I is the main mediator of the actions of GH in myocytes (37). In the present studies we raised plasma IGF-I concentrations to levels observed in the midst of puberty, particularly after rhIGF-I, yet there were no detectable changes in skeletal muscle strength in these individuals, as neither isokinetic nor isometric measures of strength were altered by rhGH or rhIGF-I treatment. These results parallel those observed in elderly subjects treated with rhGH (38) and in GH-deficient subjects treated with rhGH for up to 6 months where similar measures of muscle strength were used (39, 40). Even though the length of treatment (8 weeks each) might arguably not be enough to detect an effect on muscle strength, in similar experiments conducted by us in healthy subjects rendered intentionally hypogonadal pharmacologically, we detected significant decreases in muscle strength after only 10 weeks of sustained hypogonadism (17). The latter suggests that sex steroids may play a more pivotal role than the GH/IGF-I axis in enhancing skeletal muscle strength in humans. There are, to our knowledge, no published results to date on similar trials using rhIGF-I examining muscle strength; however, the present results suggest that neither rhIGF-I nor rhGH per se affects muscle strength in the absence of significant exercise training. The use of these agents as ergogenic agents thus appears unsubstantiated by the available data.
Calcium flux
Calcium tracer studies have been extensively used in a variety of experimental situations in humans and offer the advantage of allowing the assessment of bone calcium fluxes in a noninvasive way (23, 24, 25, 26, 29, 41, 42). Using these tools, measures of calcium absorption (Va), bone calcium deposition (Vo+), and bone calcium resorption (Vo-) did not change after rhIGF-I or after rhGH therapy, suggesting that these peptides do not significantly affect bone calcium metabolism in the short term. Previous studies of the effects of GH on bone have yielded somewhat conflicting results, some showing no effect of GH on bone mass after 6 months of therapy, and others showing an actual decrease in bone mineral density after treatment (40). Histomorphometric analysis of transiliac bone biopsies in GH-deficient patients treated with rhGH for 1 yr showed that only cortical thickness, not trabecular bone, increases after GH therapy (43). It is now clear that GH increases bone formation in GH-deficient states only after prolonged treatment (>18 months) (9). IGF-I, on the other hand, has been shown to have potent bone anabolic actions in vitro and in vivo in the short term, stimulating collagen synthesis (15) as well as increasing the proliferation of osteoblast precursors (14, 15). In short term (6- to 7-day) experiments, the administration of rhIGF-I to normal women fasted for 10 days (16), to women with anorexia nervosa (44), or to healthy young adult volunteers (45) was associated with increased serum markers of bone formation. There is, however, a paucity of data on the effects of rhIGF-I on bone mineralization after long term exposure. The results presented here after 8 weeks of rhIGF-I or rhGH each contrast with the marked effects on calcium kinetics observed after 4 weeks of testosterone administration in boys (41) and 4 weeks of oral estrogen treatment in hypogonadal girls (42), where calcium absorption and bone calcium deposition were increased using identical calcium tracer tools. Selective suppression of gonadal steroids in normal young men was also associated with marked decreases in bone calcium fluxes (Vo+) and profound urinary calcium losses after even 4 weeks of sustained hypogonadism (46), indicating that the length of treatment in the present studies, i.e. 8 weeks of each hormone, might not be the main factor influencing the lack of effect, but, rather, it could be the fact that GH and IGF-I are not as potent as gonadal steroids in influencing calcium absorption and bone calcium deposition in the short term in the GH-deficient state. The observed increase in urinary calcium excretion with rhIGF-I is probably related to the increased renal filtration typically observed after rhIGF-I treatment (47). The physiological relevance of this observation would require further study, but chronic rhIGF-I treatment may need careful assessment of calcium balance.
Substrate oxidation rates and energy expenditure
rhIGF-I and rhGH had divergent effects on other pathways of intermediate metabolism, as measured by gas exchange and indirect calorimetry. Carbohydrate oxidation rates were decreased after rhGH, but not rhIGF-I, administration in these subjects. This is probably secondary to the relative insulin resistance caused by rhGH therapy, whereas the insulin-like effect of rhIGF-I compensated for the suppressed insulin production during rhIGF-I treatment. Hepatic glucose production (glucose Ra), on the other hand, was increased after both hormones, indicating that the hepatic sensitivity to insulin was diminished during both treatments, albeit possibly by different mechanisms: during rhGH by increased insulin resistance, and during rhIGF-I by diminished portal insulin secretion. This increase in hepatic glucose production after both rhGH and rhIGF-I is comparable to that observed after short term (7-day) rhIGF-I treatment in healthy volunteers reported by us previously (19). However, the present results contrast with those observed in GH-deficient subjects treated with both hormones reported previously (13), in whom there was no detectable effect of either hormone on carbohydrate oxidation when measured by the same tools, and hepatic glucose output was increased only after rhGH. The latter difference mostly likely relates to the length of treatment, as the present model of treatment for 8 weeks each was substantially longer than the 7 days previously reported, allowing the changes in insulin sensitivity to become apparent. rhIGF-I has been clearly shown to increase insulin sensitivity in healthy subjects (48). These results suggest that rhIGF-I may be advantageous over rhGH as a replacement therapy in GH-deficient subjects who also have carbohydrate intolerance. This observation would require further study.
Protein oxidation rates decreased comparably in both treatment arms, similar to the results observed in the leucine tracer studies. This suggests that both hormones affect protein metabolism comparably.
Lipid oxidation rates were increased only after the administration of rhGH, not rhIGF-I. This contrasts with the report by Hussain et al. (19) in GH-deficient subjects treated with both hormones, in whom lipid oxidation rates increased significantly after both. Again, the significantly more prolonged treatment scheme in the present studies probably explains these differences, as there are no type I IGF-I receptors in adipocytes (8); hence, any short term increase in lipid oxidation observed after 7 days of treatment was attributed to the decrease in insulin production caused by rhIGF-I with the consequent increase in lipolysis and presumably lipid oxidation (19). In the present treatment paradigm, rhGH had a more pronounced effect than rhIGF-I on lipid oxidation and a modest, but significantly greater, decrease in %FM. The latter suggests that rhIGF-I may affect body composition differently than rhGH by promoting protein/muscle accretion and causing a nutrient shift, from adipose to lean body tissue, whereas GH acts in both adipocytes and whole body protein directly. Resting energy expenditure was unchanged after long term treatment with either hormone, underscoring the shift in nutrient utilization with preservation of total energy used.
The difference between the effects of rhIGF-I reported here and those observed in normal volunteers might also be due to the differences in the pharmacokinetics of IGF-I in the GH-deficient state. We recently reported our data from pharmacokinetic studies in GH-deficient patients treated with rhIGF-I, several of whom also participated in the present study, and showed that GH deficiency is associated with normal absorption and distribution of IGF-I, yet faster elimination kinetics than normal subjects (49). However, the higher IGF-I plasma concentrations after rhIGF-I observed here throughout the 8 weeks of the study make the consideration of these differences as being secondary to increased clearance of the peptide unlikely.
Hormones, growth factors, and plasma lipids
rhIGF-I and rhGH had divergent effects on the circulating concentrations of IGFBPs and GH, as previously observed (50); after rhIGF-I treatment, IGF-I concentrations were more increased than after rhGH as well as IGFBP-2 administration, whereas IGF-II concentrations were decreased only after rhIGF-I treatment, and IGFBP-3 levels were increased only after rhGH treatment. Interestingly, only prolonged rhGH, not rhIGF-I, had a significant lowering effect on the LDL concentration in these GH-deficient subjects.
We believe the washout period to be adequate to allow the effects of the two hormones to be detected. Even though the baseline study was not repeated before the initiation of the second hormone cycle, plasma IGF-I concentrations were measured and had clearly returned to baseline in the study subjects after 4 weeks of washout. Previously published studies assessing the effects of both of these hormones have used similar or shorter washout periods. Kupfer et al. (12), when studying healthy, GH-sufficient, calorically deprived volunteers, treated these subjects with either rhIGF-I alone or rhGH and rhIGF-I combined in random order with a 3-week washout in between and observed enhancement of the combination treatment on nitrogen balance studies. Moreover, Hussain et al. (13) evaluated intermediate metabolism in GH-deficient adults using a paradigm without any washouts, i.e. 7 days of observation, followed by 7 days of daily rhIGF-I, then 7 days of rhGH and 7 days of combined treatment. These investigators found divergent effects on lipid and glucose metabolism produced by the two treatment modalities. Also, Lucidi et al. (36), while investigating the relative dose response for rhGH in GH-deficient adults, used a paradigm of 1 week of treatment, 2–3 weeks of washout, and then another dose of rhGH. Differential effects of the two doses on protein metabolism were observed. In addition, Chapman et. al. (51) examined the temporal relation between discontinuation of rhIGF-I treatment and resumption of normal GH production in normal volunteers and found a rebound in GH production within 5–7 days after discontinuation. We have studied GH-deficient subjects, who show a marked decrease in the GH-dependent proteins, IGFBP-3 and acid-labile subunit during rhIGF-I administration and have shown normal absorption and distribution of IGF-I, yet faster elimination kinetics than normal subjects (49); hence, one would expect an even faster clearance of IGF-I in GH-deficient subjects after discontinuation of treatment.
If the metabolic effects observed after both hormones had been in parallel, then there could be legitimate concern about the adequacy of the washout period, but in the present work there were marked differences in specific metabolic paths after 8 weeks of each hormone, making the findings perhaps more compelling. There were clear differences in carbohydrate metabolism. There were no detectable effects on carbohydrate oxidation after rhIGF-I, yet a significant decrease after rhGH. Lipid oxidation did not change after rhIGF-I, yet it increased after rhGH. Insulin concentrations decreased after rhIGF-I, yet they increased after rhGH. IGFBP-2 increased only after rhIGF-I, not after rhGH. IGFBP-3 increased only after rhGH, not after rhIGF-I. LDL cholesterol decreased only after rhGH and not after rhIGF-I treatment. Taken in aggregate, the observed dichotomy of effects of both hormones is probably the result of the specific hormone treatment and not due to the carryover effect of the previous hormone administered.
Summary and conclusions
A direct comparison of the metabolic effects of IGF-I and GH in GH-deficient subjects shows that both hormones, in the doses administered, decrease the %FM and increase FFM; however, rhGH had a more potent effect in decreasing adiposity. Both are associated with an increase in whole body protein synthesis rates and a decrease in protein oxidation. Neither hormone affected isokinetic or isometric measures of skeletal muscle strength. However, rhGH was more potent than rhIGF-I at increasing lipid oxidation rates and improving plasma lipid profiles. Both hormones increased hepatic glucose output, but rhGH treatment was also associated with decreased carbohydrate oxidation and increased glucose and insulin concentrations, indicating subtle insulin resistance. Neither hormone significantly affected bone calcium fluxes, supporting the concept that these hormones by themselves are not pivotal in bone calcium metabolism. In conclusion, rhIGF-I and rhGH share common effects on protein, muscle, and calcium metabolism, yet have divergent effects on lipid and carbohydrate metabolism in the GH-deficient state. These differences may allow for better selection of treatment modalities depending on the choice of desired effects in hypopituitarism.
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Acknowledgments |
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Footnotes |
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Received August 19, 1999.
Revised November 2, 1999.
Accepted December 15, 1999.
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 K. de Picoli Souza, F. G. da Silva, and M. T. Nunes Effect of neonatal hyperthyroidism on GH gene expression reprogramming and physiological repercussions in rat adulthood. J. Endocrinol., August 1, 2006; 190(2): 407 - 414. [Abstract] [Full Text] [PDF]
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 P. G Voorhoeve, E. F C van Rossum, S. J te Velde, J. W Koper, H. C G Kemper, S. W J Lamberts, and H. A D.-v. de Waal Association between an IGF-I gene polymorphism and body fatness: differences between generations. Eur. J. Endocrinol., March 1, 2006; 154(3): 379 - 388. [Abstract] [Full Text] [PDF]
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J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers Endocrine Control of Body Composition in Infancy, Childhood, and Puberty Endocr. Rev., February 1, 2005; 26(1): 114 - 146. [Abstract] [Full Text] [PDF]
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 A. Battezzati, S. Benedini, A. Fattorini, M. Losa, P. Mortini, S. Bertoli, R. Lanzi, G. Testolin, G. Biolo, and L. Luzi Insulin action on protein metabolism in acromegalic patients Am J Physiol Endocrinol Metab, April 1, 2003; 284(4): E823 - E829. [Abstract] [Full Text] [PDF]
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J. J. Kopchick, C. Parkinson, E. C. Stevens, and P. J. Trainer Growth Hormone Receptor Antagonists: Discovery, Development, and Use in Patients with Acromegaly Endocr. Rev., October 1, 2002; 23(5): 623 - 646. [Abstract] [Full Text] [PDF]
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N. Mauras, V. Martinez, A. Rini, and J. Guevara-Aguirre Recombinant Human Insulin-Like Growth Factor I Has Significant Anabolic Effects in Adults with Growth Hormone Receptor Deficiency: Studies on Protein, Glucose, and Lipid Metabolism J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3036 - 3042. [Abstract] [Full Text]
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