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*Hormone Replacement Therapy
The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 4 1801-1807
Copyright © 2004 by The Endocrine Society

Effects of Growth Hormone (GH) Replacement Therapy on Low-Density Lipoprotein Apolipoprotein B100 Kinetics in Adult Patients with GH Deficiency: A Stable Isotope Study

E. R. Christ, M. H. Cummings, N. Jackson, M. Stolinski, P. J. Lumb, A. S. Wierzbicki, P. H. Sönksen, D. L. Russell-Jones and A. M. Umpleby

Department of Endocrinology and Diabetology (E.R.C.), University Hospital of Bern, Bern CH-3100, Switzerland; and Diabetes and Endocrinology (M.H.C., N.J., M.S., P.H.S. D.L.R.-J., A.M.U.) and Chemical Pathology (P.J.L., A.S.W.), Guy’s, King’s, and St. Thomas’ School of Medicine, St. Thomas’ Hospital, London SE1 7EH, United Kingdom

Address all correspondence and requests for reprints to: E. Christ, M.D., Ph.D., Department of Endocrinology and Diabetology, University Hospital of Bern, Inselspital, CH-3010 Bern, Switzerland. E-mail: emanuel.christ{at}insel.ch.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
GH replacement therapy has been shown to improve the dyslipidemic condition in a substantial proportion of patients with adult GH deficiency. The mechanisms are not yet fully elucidated. Low-density lipoprotein (LDL) apolipoprotein B100 (apoB) formation and catabolism are important determinants of plasma cholesterol concentrations. This study examined the effect of GH replacement therapy on LDL apoB metabolism using a stable isotope turnover technique. LDL apoB kinetics was determined in 13 adult patients with GH deficiency before and after 3 months GH/placebo treatment in a randomized, double-blind, placebo-controlled study. LDL apoB 13C-leucine enrichment was determined by isotope-ratio mass spectrometry. Plasma volume was assessed by standardized radionuclide dilution technique.

GH replacement therapy significantly decreased LDL cholesterol, LDL apoB concentrations, and LDL apoB pool size compared with placebo. Compared with baseline, GH replacement therapy resulted in a significant increase in plasma volume and fractional catabolic rate, whereas LDL formation rate remained unchanged. LDL lipid content did not significantly change after GH and placebo.

This study suggests that short-term GH replacement therapy decreases the LDL apoB pool by increasing removal of LDL particles without changing LDL composition or LDL apoB production rate. In addition, it is possible that the beneficial effects of GH on the cardiovascular system contribute to these findings.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
EPIDEMIOLOGICAL STUDIES SUGGEST that patients with hypopituitarism are at increased risk of cardiovascular mortality (1, 2). A substantial number of these patients present with elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) concentrations (3, 4, 5, 6), decreased high-density lipoprotein cholesterol (HDL-C) (6, 7), or elevated triglyceride (TG) concentrations (6, 7). It is tempting to speculate that the dyslipidemic condition of these patients contributes to the observed epidemiological findings.

The atherogenic potential of LDL particles does not only depend on the quantity (i.e. concentrations) but also on their quality (i.e. composition and size of LDL particles). For instance, TG enrichment of LDL results in small, dense LDL, which are known to be particularly atherogenic (8). Data on lipoprotein composition in patients with hypopituitarism are scarce. TG enrichment of LDL particles have been reported in childhood onset with pituitary insufficiency and GH deficiency (9) in keeping with a reduction in LDL size in hypopituitary adult patients (10).

GH deficiency may be critical in the dyslipidemic condition of patients with hypopituitarism because GH replacement therapy has been shown to reduce TC and LDL-C in a substantial number of reports (11, 12, 13, 14). Data on the effect of GH replacement therapy on LDL composition are scarce and controversial (15, 16, 17).

Although measurement of plasma lipid concentrations and composition provides useful information for clinical management of dyslipidemia, it cannot identify any mechanisms for abnormalities of these concentrations. Metabolite enrichment with stable isotopes is an established method (18) to investigate kinetic behavior (i.e. production or catabolic rate) of lipoproteins. GH therapy is known to up-regulate hepatic LDL-receptor in normal (19) and hepG2 cells (20), in rats (21) and humans (22), suggesting that an increase in LDL catabolism may explain the lipid-lowering effect of GH.

We, therefore, aimed to test the hypothesis that the lipid-lowering effect of GH is due to an increase in LDL catabolism. Using a stable isotope technique, LDL kinetics was investigated in adult patients with GH deficiency before and after 3 months of GH replacement therapy in a randomized double-blind, placebo-controlled study. In addition, fasting lipid profile and LDL composition were assessed, and plasma volume was measured using a standardized radionuclide dilution technique.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Thirteen patients with adult GH deficiency (seven women and six men) volunteered for the study. All patients had multiple pituitary deficiencies, had suffered from GH deficiency for at least 1 yr, and were receiving stable conventional replacement therapy. GH deficiency was defined as a peak GH of less than 3 mU/liter during an insulin provocation test with nadir plasma glucose less than 2.2 mmol/liter. None of the patients and control subjects had diabetes mellitus, abnormal liver function, or were taking drugs known to affect lipid metabolism. All patients provided informed written consent and the study was approved by St. Thomas’ Hospital Ethics Committee. Data on very LDL (VLDL) apolipoprotein B100 (apoB) metabolism of 12 of the 13 patients has previously been published (14).

Study protocol

The study was randomized, double-blind, and placebo-controlled. Patients were instructed in self-administration of GH using a pen device (Genotropin-pen, Pharmacia-Upjohn, Milton-Keynes, UK) and injected GH (Genotropin, Pharmacia Upjohn; 0.018 IU/kg·d for the first week, followed by 0.036 IU/kg·d for the remainder of the study) or placebo sc at bedtime.

The study protocol has been described elsewhere (14). Briefly, all subjects were admitted to the metabolic ward at 0830 h after a 12-h overnight fast. They were studied in a semirecumbent position and allowed to drink water. At the beginning of the study, blood was taken for baseline biochemical parameters. 1-13C-Leucine (15 mg/ml, 13C enrichment 99%, Tracer Technologies, Sommerville, MA) was administered as a primed (1 mg/kg) constant infusion (1 mg/kg·h) for 9 h. Regular blood samples were taken throughout the study to determine LDL apoB enrichment and 13C enrichment of {alpha}-ketoisocaproate ({alpha}-KIC), the deaminated product of leucine that provides a measure of intracellular leucine enrichment (23). Plasma volume was measured by a standardized radionuclide dilution technique (24).

Isolation and measurement of isotopic enrichment of LDL apoB

The detailed protocol is outlined elsewhere (14). Briefly, after removal of VLDL and intermediate density lipoprotein (IDL), LDL was isolated after ultracentrifugation. ApoB was precipitated by the tetramethylurea method (25). The precipitate was delipidated using ether-ethanol solution and the delipidated apoB precipitate was hydrolyzed in 6 M hydrochloric acid (14). Samples were derivatized to their N-acetyl, n-propyl-ester derivatives (26) and analyzed on a Sira Series 2, Isotope Ratio Mass Spectrometer (VG Instruments, Hellingly, UK) coupled to an Orchid Gas Chromatograph Interface Module (Europa Scientific, Crewe, UK). The GC was equipped with an AT-1 capillary column (60 m, 0.25 mm internal diameter, 1.0-µm film thickness, Alltech, UK). The carrier gas was helium and the column head pressure set to 22 {psi}. The injector temperature was set to 250 C. For sample analysis, the column was held isothermal at 70 C for 1 min, then programmed to increase at 20 C min–1 up to 200 C, 3 C min–1 from 200–250 C, 30 C/min from 250–300 C, and was held at 300 C for 5 min. Isotope abundance was expressed relative to pulse peaks of reference CO2 gas. Data were analyzed using the manufacturers’ software (Orchid Post Processor, Version 2.3c; Europa Scientific).

Quantification of LDL apoB and other analytes

LDL apoB concentration was determined by a modified Lowry-method [interassay coefficient of variation (CV) of 4%; (27)]. Plasma TC and TG concentrations were measured by an enzymatic method (Boehringer Mannheim, Mannheim, Germany) using a Cobas Fara II analyzer (Roche, Welwyn Garden City, UK). HDL-C was separated by precipitation of apoB-containing lipoproteins with dextran sulfate/magnesium chloride and measured enzymatically. LDL-C was measured enzymatically (Boehringer Mannheim) after ultracentrifugation and lipoprotein(a), [Lp(a)] by an immunological turbidometric assay (interassay CV, 7.2%). HbA1c was measured by anion exchange liquid chromatography (interassay CV, 8%). Plasma immunoreactive insulin concentration was determined by double-antibody RIA [(28); interassay CV, 6%]. Serum IGF-I concentrations were measured by a double antibody RIA after an ethanol/hydrochloric acid extraction (29). The interassay CVs were 10, 9, and 8% at 13, 35, and 173 nmol/liter, respectively.

Calculation of LDL apoB secretion and clearance rate

LDL apoB fractional secretion rate was calculated using a simple linear regression model as previously described (30) using LDL enrichment between 4 and 9 h when the enrichment curves were linear. The precursor compartment for the incorporation of 13C-leucine into the LDL particles was the steady-state tracer/tracee of {alpha}-KIC. A total of 11 time points over the 9-h tracer infusion were included in the linear regression model.

Throughout the study the patients were in steady state supported by constant LDL apoB concentrations (data not shown). In this case, FSR equals fractional catabolic rate (FCR).

The absolute LDL apoB secretion rate was calculated as the product of FCR and the LDL apoB pool size divided by body weight. Pool size was determined as the product of plasma volume and LDL apoB concentration taken as the mean of six samples taken during the study. Residence time (i.e. the time a LDL particle spends within the circulation) was calculated as 1/FCR.

Data presentation and statistics

Normally distributed data [age, body mass index (BMI)] were described using the mean and the SEM. Insulin, IGF-I, TG, LDL-TG, and Lp(a) concentrations and all kinetic data were nonparametric in distribution and were described using the median and interquartile range (IQR). Insulin, IGF-I, TG, LDL-TG, and Lp(a) concentrations were analyzed after log transformation. Parametric data were analyzed using the paired Student’s t test. Nonparametric testing was performed to analyze kinetic data (Wilcoxon Rank test). In addition, the effect of GH was compared with the effects of placebo using unpaired Student’s t test for parametric data and nonparametric testing (Mann-Whitney U test) for the kinetic data. Statistical significance was assumed at a 5% level.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patients

The patients in the GH-treated and the placebo group were well matched in terms of age, sex, and duration of hypopituitarism and BMI. Eleven patients were overweight (BMI, >25 kg/m2) (five in the placebo group and six in the GH-treated group). During the study period, GH was well tolerated, and there was no need for dose reduction in the GH-treated group.

Body composition

Total body weight and BMI did not significantly change in either group. All seven patients with GH treatment exhibited an increase in lean body mass (GH group: lean body mass 48.5 ± 3.9 vs. 51.5 ± 4.4 kg, mean ± SEM; placebo group: 56.3 ± 6.6 vs. 54.1 ± 6.6 kg; P < 0.01 for comparison between GH-treated and placebo group). Fat mass decreased in all GH-treated patients (GH group: fat mass, 26.3 ± 2.7 vs. 22.8 ± 2.5 kg; placebo group: 28.5 ± 4.5 vs. 30.4 ± 4.5 kg; P < 0.03 for comparison between GH-treated and placebo group).

Insulin, IGF-I, and HbA1c (Table 1Go)

Before treatment, values of these variables were not statistically different in the GH-treated group compared with the placebo group. Mean IGF-I concentrations were at the lower end of the normal range in both groups and significantly increased compared with baseline after GH replacement therapy in parallel with fasting insulin concentrations and HbA1c, whereas no significant changes were observed in the placebo group (IGF-I, P < 0.001; insulin, P < 0.02; HbA1c, P < 0.002). Compared with placebo, GH replacement therapy resulted in a significant increase in IGF-I, insulin concentrations, and HbA1c (IGF-I, P < 0.002; insulin, P < 0.01; HbA1c, P < 0.02).


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  		TABLE 1. The effect of GH/placebo on IGF-I, insulin concentrations, and HbA1c

 
Lipid profile (Table 2Go)

There were no significant differences in the fasting plasma lipid profile between the two groups before treatment. Compared with baseline, GH replacement therapy significantly decreased TC concentrations (P < 0.02) and LDL-C concentrations (P < 0.02) whereas TG, HDL-C, and Lp(a) concentrations did not significantly change. Compared with placebo, GH replacement therapy resulted in a significant decrease in LDL-C concentrations (P < 0.04).


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  		TABLE 2. The effect of GH/placebo on fasting plasma lipid concentrations and LDL composition

 
LDL composition (Table 2Go)

Compared with baseline, GH replacement therapy resulted in a decrease in LDL apoB concentrations (P < 0.02). In addition, there was a tendency for a reduction in LDL-TG (P = 0.06). LDL-C/LDL apoB and LDL-TG/LDL apoB ratios did not significantly change after GH replacement therapy. No significant changes were observed in the placebo group. Compared with placebo, GH replacement therapy significantly decreased LDL apoB concentrations (P < 0.01).

Kinetic characteristics of LDL apoB metabolism (Table 3Go);T3,AQ:V

ApoB kinetics was in a steady state supported by the fact that LDL apoB concentrations did not show a significant change at the selected time points throughout the study (data not shown). Precursor pool enrichment as measured by 13C-{alpha}-KIC occurred rapidly and remained constant throughout the study periods as shown previously (14). LDL enrichment curve was linear between 4 and 9 h of tracer infusion (data not shown).


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  		TABLE 3. The effect of GH and placebo on LDL apoB kinetics

 
The calculated values of all the kinetic measurements were not statistically different between the groups before treatment. Compared with baseline, a significant increase in plasma volume (P < 0.04) and FCR (P < 0.02) and a significant decrease in LDL apoB pool size (P < 0.03) and LDL residence time (LDL-RT) was observed with GH treatment, whereas no change was seen in the placebo group [LDL-RT: GH-treated group, 2.9 (2.6–7.2) vs. 2.6 (2.4–3.9) d, median and IQR, P < 0.02; LDL-RT: placebo group, 5.6 (2.9–8.5) vs. 5.3 (3.6–7.2) d, median and IQR, P = not significant]. Absolute LDL apoB formation rate remained unchanged after GH replacement and placebo therapy. Compared with placebo, LDL apoB pool size was significantly reduced after GH replacement therapy (P < 0.02), and there was a tendency for an increase in LDL apoB FCR (P = 0.08).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The main findings of the present study are a decrease in LDL apoB pool size after GH replacement therapy, most likely due to an increase in LDL apoB catabolism, whereas LDL formation rate (mainly resulting from the degradation of VLDL and IDL) did not significantly change. LDL-C concentrations were significantly reduced in parallel with a reduction in LDL-apoB concentrations without impacting on LDL composition.

The significant decrease in TC and LDL-C with GH replacement therapy with no significant changes in TG and HDL-C concentrations is consistent with some (12, 14, 31) but not all (32, 33, 34) reports. The duration of GH replacement therapy appears to be critical for changes in fasting lipid profile. Short-term therapy (i.e. 2–3 months) usually induces a moderate decrease in TC and LDL-C (35) whereas an increase in HDL-C concentrations has been reported after long-term (i.e. >6 months) GH replacement therapy (17). The mechanisms for this observation are ill defined. It is possible that the GH-induced short-term increase in insulin resistance, as evidenced in the current study by an increase in fasting insulin concentrations and HbA1c, may counterbalance a possible direct effect of GH on reverse cholesterol transport as suggested by a recently published report (36). Long-term GH replacement therapy may reduce insulin resistance to baseline values (37), which may lead to a more prominent effect of GH on reverse cholesterol transport.

Lp(a) concentrations have been demonstrated to be an independent, mainly genetically determined cardiovascular risk factor (38). GH replacement therapy has been shown to increase Lp(a) concentrations in a substantial number of patients with GH deficiency (39). The importance of this observation is currently not clear. Lp(a) concentrations in the present study did not significantly change in keeping with some (12), but not all, previous reports (40, 41).

LDL-C concentrations significantly decreased in parallel with a decrease in LDL-apoB concentrations resulting in unchanged LDL-C/apoB ratio. TG enrichment within the LDL particles is known to be associated with small, dense LDL (8). There was a tendency for a reduction in LDL-TG after GH replacement therapy suggesting a decrease in small, dense LDL. However, the ratio of LDL-TG to apoB did not significantly change. These findings suggest that GH replacement therapy does not significantly impact LDL composition, in keeping with earlier reports (16, 17).

LDL apoB pool size decreased after GH replacement therapy. In parallel, FCR increased whereas LDL production rate remained unchanged, suggesting that GH may impact LDL catabolism. Based on LDL turnover studies using radioactive tracers, different mathematical approaches have shown that only approximately two thirds of the LDL pool is degraded by a saturable, receptor-dependent pathway; the remainder is cleared by a receptor-independent pathway in humans (42). Furthermore, LDL catabolism is a function of LDL concentrations and, due to saturable LDL-receptors, the receptor-independent pathway becomes the dominant feature with increasing LDL-C concentrations (42). The present LDL-C concentrations are within the range (i.e. 100–200 mg/dl) in which the receptor-mediated pathway is not saturated and, therefore, changes in number of LDL receptors may be able to affect LDL catabolism (42). Although GH has been shown to up-regulate hepatic LDL-receptor in humans (22)—consistent with an increase in LDL catabolism—the observed increase in LDL catabolism cannot imply that the underlying mechanism is only related to an increase in number of LDL receptors.

In an uncontrolled study, Kearney et al. (17) have recently reported an increase in LDL catabolism after long-term (40 wk) GH replacement therapy consistent with our findings. In addition, an increase in absolute LDL formation rate was observed that we cannot confirm. Whether this discrepancy is due to the difference in duration of GH replacement therapy remains to be established.

Investigations of dynamic metabolic processes do not only depend on cellular mechanisms (i.e. regulation of secretion and uptake through receptor-mediated pathways) but are also influenced by the performance of the cardiovascular system. This has been documented in the context of glucose metabolism and insulin during a hyperinsulinemic euglycemic clamp (43). GH replacement therapy has been shown to significantly influence cardiovascular performance, clinically reflected by an improvement in exercise capacity (44). GH impacts on cardiac preload by increasing total blood volume (45), decreasing afterload by improving endothelium function (46, 47) and possibly by a direct effect on the cardiac muscle (48). The present finding of an increase in plasma volume after GH replacement therapy suggests that the beneficial effect of GH on the cardiovascular performance may contribute to the reduction in LDL-C concentrations and LDL apoB pool size.

The observed decrease in LDL apoB residence time is related to the increase in LDL catabolism. Recently it has been shown that LDL apoB residence time, as assessed in vivo using a stable isotope technique, is closely and positively correlated to surrogate markers of LDL apoB oxidation (49) in healthy subjects and in patients with familiar defective apolipoprotein B100. Oxidized LDL, in turn, are known to be particularly atherogenic (50). The calculated residence times of the GH-deficient patients before GH replacement therapy were within the range of the mean residence time of the patients with familiar defective apoB (49), which was at least twice as high as in normal control subjects (49). The effect of GH replacement therapy on LDL oxidation was not assessed in the current study, and it remains to be determined whether a similar mechanism applies to hypopituitary patients with GH deficiency.

There are several complex models to fit apoB-containing lipoprotein turnover data obtained from stable isotope studies (51). These models try to estimate different metabolic pathways (i.e. direct uptake of VLDL, IDL vs. delipidation to form LDL) of apoB-containing lipoproteins (51). Because the present study focused only on the investigation of the most atherogenic apoB-containing lipoprotein, the LDL particle, a simple mathematical approach (linear regression) was used to calculate production and catabolic rate of LDL apoB (52). The accuracy of linear regression depends on the number of time points during the study (52). Because a total of 11 time points were obtained and the enrichment data resulted in a near linear curve in each patient, a linear regression model seems to be adequate to fit the present data. The fact that the absolute values of the kinetic parameters in the present study were similar to the kinetic parameters calculated by a multicompartmental model in patients with impaired LDL catabolism (49) further substantiates our approach.

Lipid metabolism depends on genetic and environmental factors and a collective of patients is, therefore, always heterogeneous with regard to lipid profile. The patients of the current study were more dyslipidemic than GH-deficient adults of previous kinetic studies (17), and it cannot be excluded that this may have influenced our findings. In addition, other concomitant pituitary hormone deficiencies, which cannot be replaced in a physiological manner, may significantly impact lipoprotein metabolism (53, 54, 55).

In summary, the present results suggest that short-term GH replacement therapy results in a decrease in LDL-C concentrations and LDL apoB pool size most likely due to an increase in LDL catabolism without changes in LDL composition. Controlled, long-term epidemiological studies are needed to determine whether GH replacement therapy can reduce the increased risk for cardiovascular mortality in hypopituitary patients.


   Acknowledgments
 
Pharmacia-Upjohn, United Kingdom, generously supplied us with GH.


   Footnotes
 
E.R.C. was supported by a grant from the Swiss National Foundation and the Walther and Margarethe Lichtenstein Foundation, Basel, Switzerland. M.H.C. was supported by a grant from the Special Trustees of St. Thomas’ Hospital.

Abbreviations: apoB, apolipoprotein B100; BMI, body mass index; CV, coefficient of variation; FCR, fractional catabolic rate; HDL-C, HDL cholesterol; IDL, intermediate density lipoprotein; IQR, interquartile range; {alpha}-KIC, {alpha}-ketoisocaproate; LDL, low-density lipoprotein; LDL-C, LDL cholesterol; LDL-RT, LDL residence time; Lp(a), lipoprotein(a); TC, total cholesterol; TG, triglyceride; VLDL, very LDL.

Received August 29, 2003.

Accepted December 17, 2003.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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