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A Dose-Response Study of Growth Hormone (GH) Replacement on Whole Body Protein and Lipid Kinetics in GH-Deficient Adults

Department of Internal Medicine, Endocrine and Metabolic Sciences, University of Perugia, Perugia; and the National Research Council, Institute for Agroforestry (M.L.), Porano, Italy

Address all correspondence and requests for reprints to: Dr. Pierpaolo De Feo, DIMISEM, Via E. Dal Pozzo, 06126 Perugia, Italy. E-mail: defeo{at}dimisem.med.unipg.it

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study was designed to establish the lower dose of effective GH replacement therapy in severe GH-deficient (GHD) adults. Whole body protein and lipid kinetics were determined in six GHD men in the basal state (B) and after 1 week of treatment with placebo (PL) or 3.3 (GH3.3) or 2 (GH2) µg/kg·day recombinant human GH (rhGH). The rates of whole body proteolysis, oxidation, and synthesis were estimated by infusing [1-¹³C]leucine (prime, 1 mg/kg; infusion rate, 1 mg/kg·h); those of lipolysis (measured in four of the six patients) were estimated by infusing [1,1,2,3,3-D₅]glycerol (prime, 1.8 µmol/kg; infusion rate, 0.06 µmol/kg·min). Serum insulin-like growth factor I (IGF-I) concentrations (picograms per mL; mean ± SE) similarly increased from the basal level (39 ± 7) after 3.3 (108 ± 18) or 2 (109 ± 24) µg/kg·day rhGH (P < 0.001 vs. basal), whereas they did not change with placebo (41 ± 8). Leucine Ra was unaffected by the treatments. GH3.3 reduced by 30% the rate of leucine oxidation (P = 0.0069 vs. basal) and increased by 11% nonoxidative leucine disposal (P = 0.0095 vs. basal) and by 21% glycerol Ra (0.0035 vs. basal); GH2 and placebo had no significant effect. In conclusion, 1) at least 3.3 µg/kg·day rhGH are required to increase whole body protein synthesis and lipolysis in male GHD adults; 2) 2 µg/kg·day rhGH normalize serum IGF-I concentrations, but do not modify protein and lipid metabolism; and 3) a normal serum IGF-I concentration does not guarantee that rhGH treatment is also effective on intermediate metabolism.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE MOST important signs of adult GH deficiency (GHD) syndrome, such as reduced lean body mass, reduced muscle strength, and increased fat mass, are ameliorated or normalized by the administration of recombinant human GH (rhGH) (1). However, despite almost a decade of experience, the more appropriate dose regimen for GHD adults is still uncertain (1). Due to the absence of specific dose-response studies evaluating the effects of treatment on protein and/or lipid metabolism, rhGH dosage has been chosen on an empirical basis. Specifically, in the initial clinical trials the patients have been treated with supraphysiological amounts of rhGH that resulted in significant dose-related side-effects (1). More recently, the prevailing trend has been to start the treatment with lower rhGH doses (generally ranging between 2.5–10 µg/kg·day) and then adjust the dose so as to normalize serum insulin-like growth factor I (IGF-I) concentrations (1, 2). Certainly, this approach offers practical advantages, but is questionable because there is indirect evidence that the increase in serum IGF-I is not positively associated with the expected modifications of protein and lipid metabolism. It has been reported that serum IGF-I concentrations can be in the normal range in some adults with evident GHD syndrome (3), and that in GHD adults the increase in lean body mass induced by rhGH treatment does not correlate with serum IGF-I concentrations (4, 5).

This study was designed to establish the minimal dose of rhGH required by adults with severe GHD syndrome to reverse the signs of GH deficiency. Our aim was to identify the lowest effective treatment able to increase the rates of whole body protein synthesis and lipolysis. In fact, these metabolic changes are responsible for the improvements in body composition of GHD patients receiving long term therapy. The rates of protein and lipid metabolism were estimated by infusing stable isotopes of leucine and glycerol in GHD adult males before and after treatment with placebo or two very low doses of rhGH [3.3 (GH3.3) or 2 (GH2) µg/kg·day].

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

After receiving local ethical committee approval, informed written consent was obtained from six male GHD adults (Table 1). GHD was defined biochemically as a serum GH response of less than 6 ng/mL to an arginine plus GHRH test (6). A single patient affected with isolated GHD was receiving no medications at the time of the study, whereas the other five patients were receiving stable (no change in the last 6 months) replacement treatment for secondary gonadal, thyroid, and adrenal insufficiency (Table 1). The patients treated with long acting testosterone were switched (at least 6 weeks before the study) to oral daily formulations until study completion.

All subjects were studied on four different occasions, 3 days after consuming a weight maintenance diet of 35–38 Cal/kg·day containing 55%, 30%, and 15% carbohydrate, fat, and protein, respectively. After the first study, which was performed to measure whole body protein (n = 6) and lipid (n = 4) kinetics in the basal state, the patients were given (in a randomized, double blind study) daily bedtime injections of a placebo or GH3.3 (donated by Pharmacia & Upjohn, Metabolic Diseases, Milan, Italy) for 7 consecutive days. On the morning of the 8th day of each treatment, whole body protein (n = 6) and lipid (n = 4) kinetics were again estimated. Starting on the evening of the 8th day, the subjects received for 7 consecutive days daily bedtime injections of a placebo or GH3.3. On the morning of the 15th day, whole body protein (n = 6) and lipid (n = 4) kinetics were again estimated. Two to 3 weeks after completing this third study, the patients were treated for another week, in a single (patient) blind manner, with daily bedtime injections of GH2, and on the morning of the 8th day, protein kinetics were measured (n = 6).

Assessment of protein and lipid kinetics

The patients were admitted to the Clinical Research Center of the Dipartimento di Medicina Interna Scienze Endocrine e Metaboliche of the University of Perugia (I) at about 0730 h after the overnight fast. At about 0800 h, an 18-gauge plastic catheter needle was placed in an antecubital vein for the infusion of [1-¹³C]leucine and [1,1,2,3,3-D₅]glycerol (purchased from Mass Trace, Woburn, MA) by a Harvard syringe pump (Harvard Apparatus, Ealing, South Natick, MA) and saline (0.5 mL/min; Vial Médical pump, Grenoble, France). A contralateral hand vein was cannulated in a retrograde fashion with a 19-gauge butterfly needle, and the hand was maintained at 65 C in a thermo-regulated Plexiglas box for intermittent sampling of arterialized venous blood (7). At about 0900 h (0 min), primed constant iv infusions of L-[1-¹³C]leucine (prime, 1 mg/kg; infusion rate, 1 mg/kg·h) and [1,1,2,3,3-D₅]glycerol (prime, 1.8 µmol/kg; infusion rate, 0.06 µmol/kg·min) were started and continued for 3 h. Four milliliters of blood and breath samples were collected at -15, 0, 150, 165, and 180 min to measure the plasma concentration and enrichment of leucine, -ketoisocaproic acid (KIC), and glycerol and the enrichment of expired ¹³CO₂. Over the last hour of the study (120–180 min), the rate of CO₂ production was determined by indirect calorimetry (Deltatrac, Datex Instrument Co., Helsinki, Finland). Ten milliliters of blood were collected at 0 and 180 min to measure the plasma concentrations of glucose, nonesterified fatty acids (NEFA), insulin, C peptide, GH, IGF-I, cortisol, free T₃ (FT₃), T₄ (FT₄), PRL, and testosterone.

Analytical methods

The plasma concentrations of glucose were determined using a Beckman glucose analyzer (Beckman Instruments, Palo Alto, CA); those of NEFA were determined using an enzymatic colorimetric method (NEFA C test kit, Wako Chemicals, Neuss, Germany). The serum concentrations of insulin (Biosource Europe, Fleurus, Belgium) and GH (Biodata, Ares Serono, Norwell, MA) were measured using commercial immunoradiometric assays. Those of serum IGF-I (acid alcohol extraction), C peptide, and testosterone were determined using RIAs (Diagnostic Systems Laboratories, Webster, TX). The serum concentrations of FT₃, FT₄, PRL, and cortisol were determined by enhanced chemiluminescence using kits from Ortho-Clinical Diagnostics (Johnson & Johnson, New Brunswick, NJ).

Leucine and KIC were extracted from plasma samples as previously described (8) after the addition of 50 µL/mL plasma norleucine (160 µmol/mL) and 20 µL/mL -ketocaproate (20 µmol/mL) as internal standards. Glycerol was extracted from plasma as previously described (9) after the addition of [2-¹³C₁]glycerol (0.1 µmol/mL solution) as internal standard (10 µL/1 mL plasma).

Leucine enrichment and concentration were determined on its propyl ester/heptafluorobutyryl derivative (10) using gas chromatography-mass spectrometry (GCMS) in positive chemical ionization (GC HP 5890 II, MS HP 5972A, Hewlett Packard, Palo Alto, CA) and monitoring ions 370 and 371. The enrichment and concentration of KIC were determined on its silylquinoxalinol derivative (11) using GCMS in electron impact ionization mode monitoring ions 232 and 233. Glycerol enrichment and concentration were measured on its Tris-trimethylsilyl derivative (12) using GCMS in electron impact ionization mode monitoring ions 205, 206, and 208.

Breath ¹³CO₂ enrichment was measured on a SIRA series II isotope ratio mass spectrometer (VG Isothech, Cheshire, UK).

Calculations

The enrichments of leucine, KIC, and glycerol were expressed as the tracer to tracee ratio (TTR), accounting for isotopomer skewed distribution and spectra overlapping when appropriate (13).

The rates of appearance (Ra; micromoles per kg/min) of leucine and glycerol were calculated as follows: Ra = I/E_P, where I is the isotope infusion rate of leucine or glycerol, and E_P is the plasma enrichment (TTR) of KIC or glycerol, respectively.

The leucine oxidation rate (micromoles per kg/min) was calculated as follows: oxidation = [(E_CO2 x VCO₂)/(E_P x c) x (1/BW)], where E_CO2 is the expired CO₂ enrichment, VCO₂ is the CO₂ production rate, E_P is the enrichment of the precursor (KIC TTR), c is the CO₂ fractional recovery factor, and BW is the body weight. As the CO₂ fractional recovery factor, we used a value of 0.8 (14).

Nonoxidative leucine disposal (NOLD; micromoles per kg/min), an index of protein synthesis, was estimated as follows: NOLD = leucine Ra - leucine oxidation.

Statistical analysis

Statistical analysis was carried out with JMP software (version 3.2, SAS Institute, Cary, NC).

The effects of treatments on response variables were evaluated using ANOVA with repeated measures. Contrasts were used to evaluate the differences between the treatments and the control study. Differences were considered significant at P < 0.05. All data are expressed as the mean ± SE; hormone and substrate data are presented as the average of 0 and 180 min samples.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Plasma concentrations of glucose, insulin, and C peptide

Compared to the basal study, placebo and GH2 did not affect plasma glucose (basal, 4.1 ± 0.1; placebo, 4.2 ± 0.1; GH2, 4.2 ± 0.1 mmol/L), serum insulin (basal, 35 ± 6; placebo, 36 ± 7; GH2, 38 ± 5 pmol/L), or C peptide (basal, 0.39 ± 0.08; placebo, 0.42 ± 0.09; GH2, 0.48 ± 0.09 nmol/L) concentrations. In contrast, treatment with GH3.3 increased serum insulin (49 ± 8 pmol/L; P = 0.0036) and C peptide (0.54 ± 0.08 nmol/L; P = 0.0034) concentrations without changes in the plasma glucose concentration (4.3 ± 0.1 mmol/L).

Hormone concentrations

Compared to the basal value (39 ± 7 pg/mL), serum IGF-I similarly increased after GH2 (109 ± 24 pg/mL) or GH3.3 (108 ± 18 pg/mL; P < 0.001) and were unchanged by placebo (41 ± 8 pg/mL). There was no effect of treatments on serum concentrations of GH, cortisol, FT₃, FT₄, testosterone, or PRL. The serum concentrations of cortisol, FT₃, FT₄, testosterone, and PRL were in the normal range.

Protein metabolism

The plasma concentrations of leucine and KIC were unaffected by the treatments. In the four studies, enrichments of plasma leucine, KIC, and CO₂ were at steady state over the last 30 min (used to estimate leucine kinetics) of each study.

Leucine Ra was unchanged by either treatment (Table 2). Compared to the basal value, the rate of leucine oxidation decreased by 30% (P = 0.0069) with GH3.3, whereas it remained unaffected by GH2 or placebo (Table 2). Conversely, the rate of NOLD increased by 11% (P = 0.0095) over the basal value after GH3.3 and remained unchanged after GH2 or placebo (Table 2).

The plasma concentrations of NEFA (millimoles per L) did not change significantly with any treatment (basal, 534 ± 45; placebo, 442 ± 45; GH3.3, 623 ± 45; GH2, 477 ± 43). The plasma concentration of glycerol (micromoles per L) increased over the basal value (62 ± 5) with GH 3.3 (83 ± 5; P = 0.007), whereas it remained unaffected by GH2 (64 ± 3) or placebo (64 ± 3).

The enrichment and the concentration of plasma glycerol were at steady state over the last 30 min of the three studies in the four patients in whom glycerol Ra was measured. Glycerol Ra increased over the basal value by 21% (P = 0.0035) after GH3.3 and remained unaffected by placebo (Table 2).

The increase in the serum IGF-I concentration induced by GH3.3 or GH2 was not correlated with the changes in leucine oxidation, NOLD, glycerol concentration, and Ra.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The results of this study demonstrate that the lowest effective dose of rhGH required to increase protein anabolism and lipolysis in GHD is about GH3.3. The dose of GH2 increased only serum IGF-I, not leucine, estimates of protein synthesis, plasma glycerol, and NEFA concentrations. This indicates that compared to protein and lipid metabolism, IGF-I is more sensitive to rhGH replacement therapy. Consequently, an increase in its serum concentration should not be used to monitor the metabolic effects of treatment.

In the basal study, leucine estimates of whole body proteolysis of GHD patients were approximately 20% lower than those in normal age-matched controls previously measured in our laboratory. According to Hoffman et al., who designed a study to compare leucine kinetics between untreated GHD and normal subjects, this difference can be partially explained by the reduced lean body mass of GHD patients (15). In our study the treatment period was too short (1 week) to induce any substantial modification in body composition and the dose of GH3.3 did not change leucine estimates of whole body proteolysis. Protein anabolism improved as a result of an effect on the rates of leucine disposal; the rate of leucine oxidation decreased and, conversely, that of leucine incorporation into protein increased. In normal humans, GH has a similar mechanism of action; it increases protein synthesis by reducing amino acid catabolism without changing whole body proteolysis (16). The fact that rhGH administration stimulates IGF-I production raises the question of whether the anabolic effects on protein metabolism are directly or indirectly (IGF-I) induced by GH. Leucine kinetics of our treated GHD adults suggest a direct effect of GH on protein metabolism, because despite the fact that serum IGF-I concentrations were similarly normalized by the two dose regimens, protein synthesis increased only after GH3.3 not after GH2.

In our study, leucine estimates of whole body protein synthesis remained unchanged after GH2 and increased by 11% after GH3.3. In a previous study, Russell-Jones et al. showed an increase in leucine estimates of whole body protein synthesis of 20–25% after treatment of GHD adults with 12 µg/kg·day rhGH (17). Our data combined with those of Russell-Jones indicate that the dose-response curve of protein synthesis has a sigmoidal shape, with the threshold located between GH2 and GH3.3. The 12 µg/kg·day dose normalizes the body composition of GHD subjects after a few months (1), but also induces a number of side-effects that suggest supraphysiological replacement (1). However, a physiological dose of rhGH is expected to restore the metabolic effects of the hormone without inducing side-effects. Considering that many GHD patients might be rhGH replaced for as long as 30–40 yr, a prudent treatment should use the lowest effective dose of rhGH able to induce the desired metabolic effects of the hormone, i.e. the dose that will be unlikely to cause side-effects. In this regard, the dose of GH3.3 appears to be very promising. The present study has proven its short term efficacy demonstrating significant and concomitant increases in the rates of protein synthesis and lipolysis. It is possible to extrapolate from leucine kinetics that such a dose will increase body protein by approximately 60 g every month of therapy. This means that lean body mass of GHD patients is expected to be normalized within 1–2 yr of treatment. As far as fat mass is concerned, this study is the first to measure the effects of rhGH administration on the rate of lipolysis in GHD patients. The 21% increase in glycerol kinetics after GH3.3 suggests that long term treatment with this dose should normalize fat mass more rapidly than lean body mass. Compared to integrated GH production in normal adult males, estimated to be approximately 1 µg/kg·day (18), the dose of GH3.3 still appears to be a supraphysiological replacement. However, it must be considered that the bioavailability of sc injected rhGH is about 60% (20), and daily bedtime injections cannot reproduce the normal pulses of GH secretion. This might explain the lack of efficacy of GH2. It must be stressed that in our study we studied only males, and integrated GH production of normal adult females is about 3-fold greater than that of males (18). Thus, it is likely that, analogous to what was observed for the IGF-I response (19), rhGH requirements of GHD females are higher than those of males. On the other hand, adults with partial GHD might require replacement doses lower than 3 µg/kg·day rhGH. Thus, studies establishing the lowest doses that are effective on protein and lipid metabolism in GHD females and in partial GHD adults are warranted to identify a correct starting dose.

Side-effects after long term treatment with GH3.3 are unlikely to occur, considering that studies employing 3 times higher doses (20) did not report fluid retention or other GH-related side-effects. One potential risk of treatment that requires alertness is GH-induced insulin resistance. It has been reported by Beshyah et al. (21) that the area under the curve of plasma glucose and insulin during an oral glucose tolerance test is significantly higher after 6, 12, and 18 months of rhGH therapy (mean daily dose, 13 µg/kg·day). Our dose of GH3.3 increased by about 35% serum insulin and C-peptide without changes in plasma glucose, which indicates a reduction in insulin sensitivity compared to that during the pretreatment period. However, compared to those in normal subjects the basal serum concentrations of C peptide and insulin in GHD patients were about 30% lower. Thus, we believe that replacement therapy normalized the serum concentrations of insulin more than inducing a pathological insulin resistance state. In any case, during long term treatment, it would be better to also follow potential changes in insulin sensitivity in GHD adults treated with low replacement doses.

In conclusion, this study demonstrates that GH3.3 (10 mU/kg·day) is the lowest dose of rhGH able to induce substantial increments in whole body protein synthesis and lipolysis in male GHD adults. Therefore, we suggest this as the starting dose in adult males with complete GHD. As no data are available on the effects of this dose on body composition, clinical trials are required to validate its long term efficacy. Recently, using a slightly higher dose (4 µg/kg·day) of rhGH, Biller et al. reported significant decreases in body fat and increases in lean body mass and bone density of the lumbar spine and femoral neck in GHD men after 18 months of treatment (22). We would not recommend starting treatment with doses lower than 3 µg/kg·day rhGH because they will only normalize serum IGF-I (20), not protein and lipid kinetics. For this reason we suggest assessing the metabolic efficacy of the treatment by yearly measurements of body composition rather than of serum IGF-I concentrations.

	Acknowledgments

 
The authors are indebted to Vania Cesarini for skillful technical assistance.

Received August 26, 1997.

Revised October 3, 1997.

Accepted October 20, 1997.

	References

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