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Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:2142-2150

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:2142-2150.)
© 1995 American Heart Association, Inc.

Articles

Effects of 1 Year of Growth Hormone Therapy on Serum Lipoprotein Levels in Growth Hormone–Deficient Adults

Influence of Gender and Apo(a) and ApoE Phenotypes

Presented in part at the First International Meeting of the Growth Hormone Research Society, Aarhus, Denmark, June 1-4, 1994.

Gudmundur Johannsson; Jan Oscarsson; Thord Rosén; Olov Wiklund; Gun Olsson; Lars Wilhelmsen; Bengt-Åke Bengtsson

From the Research Centre for Endocrinology and Metabolism (G.J., J.O., T.R., B.-Å.B.) and the Wallenberg Laboratory (O.W., G.O.), Sahlgrenska University Hospital, and the Department of Medicine (L.W.), Östra University Hospital, Göteborg, Sweden.

Correspondence to Gudmundur Johannsson, MD, Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail gudmundur.johannsson@ ss.gu.se.


*    Abstract
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Abstract We investigated the influence of gender and apoE and apo(a) phenotypes as well as the effect of the metabolic effects of growth hormone (GH) on the effect of GH therapy on serum lipoprotein concentrations in GH-deficient (GHD) adults. Forty-four consecutive patients, 30 men and 14 women aged 46.5 (range, 19 to 76) years with GHD due mainly to pituitary tumors, were treated with recombinant human GH for 12 months. Serum concentrations of lipoproteins, insulin, thyroxine, and insulin-like growth factor–I were determined, body composition was assessed by bioelectrical impedance, and apo(a) and apoE phenotypes were analyzed. Lipoprotein(a) [Lp(a)] concentrations in the GHD subjects were compared with a gender- and apo(a) phenotype–matched control group. After 12 months of GH treatment, the total cholesterol, LDL cholesterol, and apoB concentrations decreased, the HDL cholesterol and apoE concentrations increased, and the apoA-I and triglyceride concentrations were unchanged. Before treatment, the Lp(a) concentration was similar to that in the control group. However, after 12 months of treatment, the Lp(a) concentration had increased by 44% and 101% above baseline and the control group, respectively. Men and women responded differently to GH, with a more marked increase in Lp(a) concentration and fat-free mass and a more pronounced decrease in body-fat mass in men. Apo(a) phenotypes had no major influence on the effect of GH therapy. The only significant difference between apoE phenotypes was a higher baseline Lp(a) concentration among apoE4 heterozygotes. Changes in body composition, insulin, insulin-like growth factor–I, and thyroxine concentrations explained at most 27% of the changes that occurred in serum lipoprotein levels during GH treatment. The effects of GH therapy on serum lipoprotein levels and body composition in GHD adults were dependent in part on gender or current sex hormone therapy. However, no major influence by apo(a) or apoE phenotype or changes in metabolic variables were detected on the effects of GH therapy on serum lipoprotein levels.


Key Words: growth hormone • lipoproteins • apo(a) phenotype • apoE phenotype • gender


*    Introduction
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Dyslipoproteinemia1 2 3 4 5 6 and increased amounts of body fat with an abdominal preponderance7 may help to explain the premature atherosclerosis6 and the almost doubled cardiovascular mortality8 observed in adults with hypopituitarism receiving routine replacement therapy but not GH therapy.

The importance of GH as a regulating factor for serum lipoprotein levels was suggested decades ago,9 10 but early treatment trials with GH11 12 and the more recent ones3 13 14 15 16 using recombinant human GH in GHD adults have produced conflicting results in terms of the effects on serum TC, LDL-C, HDL-C, and apoB concentrations. Serum TG and apoA-I concentrations have not been significantly affected in most studies.3 14 15 17 Populations heterogeneous with respect to age, gender, and the genetic factors that control lipoprotein metabolism might explain these discrepant results.

Several studies have established a strong relation between Lp(a) and coronary heart disease.18 19 Lp(a) is similar to LDL in terms of its lipid and apoB content, but it also contains apo(a), a glycosylated protein that is covalently linked to apoB. The plasma level of Lp(a) is mainly genetically determined and is related to the size polymorphism of apo(a), which is inversely related to the plasma concentration of Lp(a).20 Moreover, subjects with HMW and LMW isoforms of apo(a) respond differently to disease and therapy. Thus, in patients with end-stage renal disease, only those with HMW apo(a) isoforms have elevated Lp(a) concentrations,21 which decline after renal transplantation.22 GH may play a role in the regulation of Lp(a), producing increased Lp(a) concentrations during GH administration in GHD adults14 and decreased concentrations in patients with acromegaly who are successfully treated.23 However, it is not known whether the Lp(a) concentration in GHD adults differs from that in healthy control subjects or whether the apo(a) isoforms influence the response to GH therapy.

ApoE is a ligand for the apoE and LDL receptors. The three major isoforms of apoE that appear in the population, E2, E3, and E4, determine six different apoE phenotypes with varying affinity for the LDL receptor and contribute considerably to the normal variance in serum lipoprotein levels within populations.24 The E3 isoform is the most common; the E2 and E4 isoforms have both been associated with dyslipoproteinemia when interacting with other genetic or environmental factors.24 Whether the apoE phenotypes influence the effects of GHD or the response to GH administration in terms of serum lipoprotein levels is unknown.

In this trial, the effects of a 12-month treatment with GH on lipoprotein levels in GHD adults were analyzed, and the effects of gender and apo(a) and apoE phenotypes were studied. We also explored the possibility that changes in serum concentrations of insulin, T4, IGF-I, and body composition might influence the effects of GH on serum lipoprotein levels.


*    Methods
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Subjects
Forty-four consecutive patients, 30 men and 14 women (mean age, 46.5 years; range, 19 to 76 years) with known pituitary disease and verified GHD were included in the study. The pituitary deficiency was most frequently caused by pituitary tumors. Most of the patients had multiple hormonal deficiencies, and 4 had isolated GHD (Table 1Down). The diagnosis of GHD was based on a maximum peak GH response of <5 mIU/L during an insulin tolerance test (blood glucose <2.2 mmol/L).25 All the patients were receiving stable replacement therapy with glucocorticoids (cortisone acetate 10 to 37.3 mg/d), thyroid hormones (l-T4 0.05 to 0.2 mg/d), sex steroids, and desmopressin when needed. This replacement therapy was unchanged during the 12 months of GH treatment, except in 1 man for whom the l-T4 dose was increased from 0.05 to 0.15 mg/d due to low free T4 concentrations after 6 months of treatment. Four women (61.5±4.9 years) with gonadotropin deficiency were not receiving gonadal steroid replacement therapy because of previously experienced side effects. Two women (56.5±1.5 years) were receiving only estrogen therapy, while 7 (44.6±1.9 years) were on cyclic estrogen/progestin treatment (4 women, medroxyprogesterone 5 mg/d; 3 women, levonorgestrel 250 µg/d). Four patients had received GH treatment in childhood, and 8 had received GH treatment in a previous trial.26 These patients had been without GH for 13±4 (range, 3 to 28) months before the present study.


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  		Table 1. Characteristics of the Cohort of 44 GHD Patients Treated With GH for 12 Months

Lp(a) concentration and apo(a) phenotype were determined in 100 men and 96 women (53.6±0.5 years) who had been selected at random from the 39- to 69-year-old age group from the World Health Organization MONICA (MONItoring trends and determinants in CArdiovascular disease) project in Göteborg.27 Patients and control subjects were matched for gender and apo(a) phenotype (HMW or LMW). The control group for Lp(a) consisted of 118 subjects, 72 men and 46 women, aged 53.8±0.6 years.

Study Design
The study is an ongoing open-label treatment trial of the long-term administration of recombinant human GH. This study has analyzed the effects of 12 months of GH treatment. During the first 4 weeks of treatment, the GH dose was 4.8 µg·kg-1·d-1 (0.125 IU·kg-1·wk-1), and the target dose thereafter was 11.9 µg·kg-1·d-1 (0.25 IU·kg-1·wk-1) for the rest of the treatment period. The daily dose was given subcutaneously at bedtime. The dose was reduced in the event of side effects.

The patients were studied as outpatients. At the beginning of the study and every subsequent 6 months, a physical and laboratory examination, including an estimation of body composition, was performed. In addition, every 3 months the patients were seen for a physical examination and safety laboratory investigation. Body weight was measured to the nearest 0.1 kg by using a Stathmos balance in the morning with the patients in the fasting state and wearing indoor clothes after having urinated. Body height was measured barefoot and to the nearest 0.01 m. Body mass index was calculated as body weight in kilograms divided by height in meters squared.

Informed consent was obtained from all patients. The study was approved by the Ethics Committee at the University of Göteborg and by the Swedish Medical Products Agency.

Biochemical Assays
Blood samples were drawn in the morning after an overnight fast. Serum samples for lipoprotein determinations were stored at -20°C to -30°C until assay. Serum TC and TG concentrations were determined by using fully enzymatic methods (Boehringer). The within-assay coefficients of variation for TC and TG determinations were 0.9% and 1.1%, respectively. ApoA-I and apoB concentrations were determined by using an immunoturbidometric assay (UniKit Roche, Hoffmann–La Roche), and the apoE concentration was determined by using an electroimmunoassay. The within-assay coefficients of variation for the apoA-I, apoB, and apoE assays were 2.3%, 1.9%, and 4.8%, respectively. HDL-C levels were determined after the precipitation of apoB-containing lipoproteins with MgCl2 and heparin.28 The LDL-C concentration was calculated according to Friedewald's formula adjusted to SI units.29 The Lp(a) concentration was determined with a radioimmunoassay (Pharmacia). This Lp(a) assay was standardized against an electroimmunoassay.28 The within-assay coefficient of variation for the Lp(a) assay was 4.4%.

Apo(a) isoforms were determined by using electrophoresis followed by Western blot analysis.30 We divided apo(a) phenotypes into two isoform subgroups, LMW and HMW.19 The LMW group included all subjects with at least one of the isoforms F, B, S1, or S2, and the HMW group comprised all subjects with S3, S4, S5, 0, or S3/S4.

The phenotyping of apoE was performed by using isoelectric focusing.31 The method was modified to permit the analysis of whole serum instead of isolated lipoproteins. Briefly, 100 µL serum was diluted with 400 µL HEPES 20 (5 mmol/L HEPES, 20 mmol/L NaCl, 2 mmol/L MgCl2, and 0.1% sodium azide). The samples were mixed with 100 µL heparin–Sepharose CL-6B gel (Pharmacia Fine Chemicals) and incubated for 30 minutes. After sedimentation the buffer was aspirated, and the gel was washed. The proteins were eluted from the gel with 150 µL of 0.5 mol/L NaCl. An aliquot of the eluate (75 µL) was then delipidated with ethanol/acetone (1:1, vol/vol) at -20°C overnight. The precipitated proteins were dried under nitrogen and dissolved in 50 µL of 2% dithioerythritol (Sigma Chemical Co) in 8 mol/L urea and heated to 65°C for 10 minutes. Isoelectric focusing was performed32 with modification for use in a vertical slab gel isoelectric focusing system (Mini Protean II electrophoresis system, Bio-Rad). Isoelectric focusing was run overnight at 150 V. Immunoblotting of the gels was then performed,33 and the membranes were stained with a rabbit anti-human apoE antiserum (dilution, 1:100) as the first antibody and a peroxidase-conjugated swine anti-rabbit IgG (Dakopats) as the secondary antibody. A horseradish-peroxidase conjugate substrate kit (Bio-Rad) was used to detect the apoE bands. Control subjects' samples with known isoforms were analyzed in parallel.

Serum-free T4 was determined by using a luminometric labeled antibody immunoassay (MAB Free T4, Kodak Clinical Diagnostics Ltd). The serum concentration of IGF-I was determined by using a hydrochloric acid–ethanol extraction radioimmunoassay with authentic IGF-I for labeling (Nichols Institute Diagnostics).34 Serum insulin was determined by using a radioimmunoassay (Phadebas, Pharmacia), and blood glucose was measured by using the glucose-6-phosphate dehydrogenase method (Kebo Labs).

Determination of Body Composition
Body composition was determined by assessing bioelectrical impedance with BIA-101 equipment (RJL Systems, Inc) according to the manufacturer's instructions with the patient in the supine position. The total body water (data not shown), fat-free mass, and body fat were calculated by using equations supplied by the manufacturer. The day-to-day coefficient of variation for bioelectrical impedance was 1.7%.35

Statistical Methods
Statistical results are presented as mean±SEM. Because the distribution of Lp(a) is highly skewed, results for Lp(a) are expressed as median and 25th and 75th percentiles. Comparisons between baseline and 6 and 12 months of GH treatment were made by using an ANOVA for repeated measurements followed by the Student-Neuman-Keuls multiple-range test. The Mann-Whitney U test was used to compare baseline values and the percentage changes between baseline and 12 months in men and women and in patients with HMW and LMW apo(a) phenotypes. This test was also used to discriminate for differences in Lp(a) levels between GHD patients and control subjects. The Kruskal-Wallis test was used to compare baseline values and the percentage changes in lipoprotein levels in patients with different apoE phenotypes. Correlations were sought by calculating the Pearson linear correlation coefficient. To study the effect of changes in other metabolic variables and body composition on the changes occurring in serum lipoprotein concentrations, we conducted a standard linear multiple regression analysis. The input variables were the percentage changes between baseline and 12 months in serum insulin, IGF-I, free T4, body fat, and fat-free mass. These variables were then correlated to the percentage change in each lipoprotein fraction. Because of the highly skewed distribution of Lp(a) serum concentrations, a logarithmic transformation of Lp(a) concentration was used in all statistical analyses, assuming a normal distribution. Pearson's {chi}2 test was used to test the independence of apo(a) phenotype frequency between patients with E4-containing apoE alleles and those not having E4. A probability value of less than .05 was considered significant.


*    Results
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The daily dose of GH was reduced during the treatment period due to side effects, most of which occurred in the initial phase of treatment. The concentrations of serum IGF-I, blood glucose, and serum insulin increased, while the free T4 concentration decreased after both 6 and 12 months of treatment (Table 2Down). The reduction in the GH dose between baseline and 12 months (men, 21±6%, and women, 4±11%) and the increases in IGF-I (men, 445±82%, and women, 469±85%) and serum insulin (men, 51±13%, and women, 68±22%) concentrations did not significantly differ between men and women.


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  		Table 2. Effects of 6 and 12 Months of GH Treatment in 30 Men and 14 Women With GHD

The mean body height and fat-free mass increased, body mass index and body-fat mass decreased, and body weight remained stable after 6 and 12 months of treatment (Table 2Up). There was, however, a gender difference with respect to the effect on body composition. Both sexes showed a reduction in body fat, but the percentage decrease was more pronounced in men than women (-18.1±3.0% versus -8.6±2.4%; P<=.01). Only the men demonstrated a significant increase in the fat-free mass, and the percentage increase in fat-free mass was therefore more marked in men (7.4±1.3% versus 1.9±1.5%; P<=.01) (Table 2Up).

Serum Lipoprotein Levels
After both 6 and 12 months of treatment, the serum TC and LDL-C concentration decreased, HDL-C concentration increased, and mean serum TG concentration remained unchanged (Table 3Down). The LDL-C concentration was decreased after 12 months in both men and women. In women, TC and HDL-C concentrations remained unchanged, while the TG concentration increased slightly after 12 but not 6 months. Moreover, the number of women with serum TG levels >2.0 mmol/L increased from 3 to 6 and 7 (n=14) after 6 and 12 months of GH treatment, respectively. In men, TC decreased after 6 but not after 12 months, HDL-C concentration increased after 6 and 12 months, and TG concentrations did not change (Table 3Down and Fig 1ADown).


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  		Table 3. Effects of 6 and 12 Months of GH Treatment on Serum Lipid Concentrations in 30 Men and 14 Women With GHD



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  		Figure 1. Bar graphs showing mean percentage changes between baseline and 12 months in concentrations of (A) LDL-C, HDL-C, and TG; (B) apoB, apoA-I, and apoE; and (C) Lp(a) during administration of GH in 30 GHD men and 14 GHD women. Horizontal bars indicate SEM. *P<.05 and {dagger}P<.01 vs percentage change in men and women and §P<.05 vs percentage change in men.

The Lp(a) concentration increased and the serum concentration of apoB decreased after 6 and 12 months of treatment (Table 4Down). The apoB concentration decreased significantly in men but not women. The apoE concentration increased after 12 months of treatment in both genders, while the apoA-I concentration was unchanged (Fig 1BUp). The percentage increase in Lp(a) was more pronounced in men than women (59.0±8.0% versus 27.4±9.4%; P<.05) (Fig 1CUp).


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  		Table 4. Effects of 6 and 12 Months of GH Treatment on Serum Apolipoprotein and Lp(a) Concentrations in 30 Men and 14 Women With GHD

The baseline concentration of serum TGs showed an inverse correlation with the percentage change in the TG concentration between baseline and 12 months (r=-.42, P<=.01) (Fig 2ADown). Furthermore, the baseline concentration of LDL-C demonstrated an inverse relation with the changes in LDL-C (r=-.37, P<=.05) (Fig 2BDown) and Lp(a) (r=-.33, P<=.05) (Fig 2CDown) during treatment. The baseline level of Lp(a), however, was not correlated with the change in Lp(a) (r=-.07).



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  		Figure 2. Scatterplots showing correlations between concentrations of baseline (A) TG and percentage change in serum TGs (r=-.42, P<=.01), (B) LDL-C and percentage change in serum LDL-C (r=-.37, P<=.05), and (C) LDL-C and percentage change in serum Lp(a) (r=-.33, P<=.05) in 44 GHD adults during 12 months of GH treatment.

Influence of Apo(a) and ApoE Phenotypes
Sixteen men and 7 women had LMW apo(a) phenotypes, and 14 men and 7 women had HMW isoforms (Table 5Down). At baseline subjects with LMW apo(a) phenotypes tended to have higher Lp(a) concentrations than did subjects with HMW phenotypes (P=.06), but the response to treatment was similar. Subjects with LMW phenotypes had higher TG concentrations at baseline than those with HMW apo(a) phenotypes, and the increase in TG concentration in response to treatment tended to be more marked in HMW subjects (P=.07). Thus, after 12 months, serum TG concentrations in both phenotypes were similar (1.97±0.16 versus 1.67±0.17 mmol/L; NS). The apo(a) phenotype did not, however, affect the baseline TC concentration or its response to GH treatment.


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  		Table 5. Influence of Apo(a) Phenotype on Baseline Levels of Lp(a), TC, and TGs and Effects of 12 Months of GH Treatment in 44 GHD Adults

Four different apoE phenotypes were found. The phenotype 4/3 was found in 20.4% of the subjects, 4/2 in 11.4%, 3/3 in 45.5%, and 3/2 in 22.7% (Table 6Down). No significant differences in baseline values or changes in serum lipoprotein concentrations between the different apoE phenotypes were observed. However, by comparing pooled data from phenotypes 4/3 and 4/2 with pooled data from phenotypes 3/3 and 3/2, we found that the baseline Lp(a) concentration was higher in the group containing E4 than in the group not containing E4 (431±102 versus 173±27 mg/L, respectively; P<=.05). This could not be explained by a different LMW/HMW apo(a) phenotype distribution between the groups, which was 16/14 in the group with E4 and 7/7 in the group not having E4 ({chi}2=0.04, P=.84).


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  		Table 6. Influence of ApoE Phenotype on Baseline Levels of Serum Lipoproteins and the Effect of 12 Months of GH Treatment in 44 GHD Adults

Lp(a) in GHD Patients Compared With Control Subjects
The control population was older than the GHD patients (54±1 versus 47±2 years; P<=.001), but there was no correlation between age and Lp(a) concentration either in control subjects (slope=.004, r=.06) or patients (slope=-.006, r=.07). Before treatment, serum Lp(a) concentrations in the GHD subjects and the control population were similar, but after 12 months of GH administration, the Lp(a) concentration had increased in the GHD subjects compared with control subjects (P<=.01) (Fig 3ADown). The control group included 59 subjects with LMW and 59 subjects with HMW apo(a) phenotypes. Before treatment, Lp(a) concentrations were similar in patients and corresponding control subjects with LMW and HMW isoforms. After a 12-month GH treatment period, patients with both LMW (P<=.05) and HMW (P<=.01) isoforms had increased Lp(a) concentrations compared with control subjects (Fig 3BDown).



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  		Figure 3. A, Bar graph shows median Lp(a) concentration and 25th and 75th percentiles for 118 control subjects matched for apo(a) phenotype and gender and 44 GHD adults before and after 12 months of GH treatment. B, Bar graph shows Lp(a) concentration in control subjects and GHD patients with LMW and HMW apo(a) phenotypes. Horizontal bars indicate SEM. *P<.05 and {dagger}P<=.01 vs control subjects.

Correlations Between Lipoprotein Levels, Age, T4, Insulin, IGF-I, and Body Composition
The baseline concentrations of TC and LDL-C showed a positive correlation with the age of the patients (r=.50, P<.001 and r=.46, P<.01, respectively). Lp(a) concentration at baseline correlated with the baseline concentration of IGF-I (r=.48, P<.001) but not with the baseline serum insulin concentration (r=-.02).

In the multiple regression analysis model used (Table 7Down), the changes between baseline and 12 months in apoA-I and TG concentrations correlated significantly with the metabolic variables included in the analysis. The changes in body composition, serum-free T4, serum IGF-I, and serum insulin explained 24% to 25% of the changes occurring in TC, LDL-C, and Lp(a) concentrations during the 12 months of GH treatment, but no significance was obtained in the analysis.


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  		Table 7. Multiple Regression Analysis of the Effects of Changes of Various Serum Concentrations and Body Composition on the Changes in Lipoproteins in 44 GHD Adults During 12 Months of GH Treatment


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The present study demonstrates that GH treatment has a significant and lasting effect on the lipoprotein pattern in GHD adults. The main findings are a reduction in LDL-C and apoB, an increase in serum apoE and HDL-C, and no change in TG concentrations. The Lp(a) concentrations of the GHD subjects before treatment were similar to those of healthy control subjects; after 12 months of GH administration, their Lp(a) concentrations had increased twofold compared with control subjects' levels. The increase in Lp(a) was not affected by the apo(a) phenotype but was dependent on gender. The observed changes in lipoprotein levels during GH treatment could only be explained to a minor extent by accompanying changes in body composition and serum concentrations of insulin, T4, and IGF-I.

Growth hormone is known to induce hepatic LDL receptors.36 37 The observed decreases in TC, LDL-C, and apoB concentrations in this study are therefore probably a result of increased LDL and apoB clearance. Serum concentrations of apoE increased, thereby indicating enhanced apoE production after GH administration. GH treatment increases hepatic apoE secretion in the VLDL fraction in the rat.38 Since apoE is also a ligand for the LDL receptor, enhanced VLDL apoE secretion would increase the clearance rate of VLDL remnants, which would in turn reduce the production rate of LDL and hence further reduce the LDL-C concentration. Interestingly, subjects with high LDL-C concentrations at baseline experienced a more pronounced decrease in LDL and a less marked increase in Lp(a) concentrations in response to GH. This finding could indicate a more marked induction of the LDL receptor during GH therapy in subjects with the lowest LDL receptor expression. The age-dependent increase in LDL-C occurring in the aging individual39 was also observed in this group of GHD adults, suggesting that the LDL increment with aging is not solely an effect of the decrease in GH secretion observed after the third decade of life,40 as has been suggested.41

The observed increase in serum HDL-C concentrations in response to GH is in agreement14 16 with previous short-term placebo-controlled trials but in contrast13 15 with others. The mean serum TG concentration was unchanged, but a decrease was observed in subjects with a high baseline concentration, which is in accordance with data from our group.14

The finding of increased Lp(a) concentrations is in accordance with a study of GHD adults treated for 6 months14 but conflicts with a 1-month placebo-controlled trial.15 As LDL receptors possibly play a role in the clearance of Lp(a)42 and as GH administration induces LDL receptor activity,36 the finding of increased Lp(a) concentrations during GH treatment suggests an increase in hepatic Lp(a) secretion.20 The similar Lp(a) concentrations in the GHD subjects and matched control subjects before treatment could be due to low LDL receptor activity in the GHD state.37 However, as we observed, a presumed increase in LDL receptor activity after GH therapy could not counteract a possible effect by GH on hepatic Lp(a) secretion. The influence of the apo(a) phenotype was noted on the baseline Lp(a) concentration as in normal adults20 but not on the response to treatment. Positive correlations were noted between baseline levels and changes in IGF-I and Lp(a), which is in line with a previous observation in men with documented cardiovascular disease.43 These findings indicate a relation between the GH regulation of IGF-I and Lp(a) in humans.14 23 The doses of GH used in this trial resulted in abnormally high serum IGF-I concentrations.34 Since continuous infusion of GH results in higher IGF-I and Lp(a) levels than daily subcutaneous injections,44 the increased IGF-I and Lp(a) concentrations observed after 12 months of treatment compared with those in control subjects might be an effect of an abnormal serum pattern of GH during the subcutaneous administration of GH45 and/or an effect of overly high GH doses. Men increased their Lp(a) concentration more than women. Although both androgens and estrogens may decrease serum Lp(a) levels,46 it is conceivable that estrogens are more potent in lowering Lp(a) serum concentrations than androgens.46 As a result, the more marked increase in Lp(a) concentrations in men could also be explained by ongoing sex hormone treatment.

Lp(a) concentrations were significantly affected by apoE phenotype, which is in accordance with observations made in healthy adults.47 No significant differences in baseline TC, LDL-C, apoB, and apoE concentrations were noted between the apoE phenotypes, which is in contrast to observations in Northern Europeans.24 47 However, the reduction in TC, LDL-C, and apoB and the increase in apoE in response to GH tended to be more pronounced in apoE phenotype 3/2 than in 4/3, possibly reflecting a change toward normalization, as subjects with the E2 phenotype have lower TC and apoB concentrations and higher apoE concentrations compared with the E4 phenotype.24 This finding suggests that the presence of GH is necessary for the normal effects of different apoE phenotypes on serum lipoprotein levels. GHD subjects with HMW isoforms of apo(a) had lower TG concentrations at baseline, but after 12 months no difference remained in the TG concentration between HMW and LMW apo(a) phenotypes, possibly reflecting a normalization induced by GH treatment. This finding, together with findings by others,48 49 suggests an association between Lp(a) and TGs, but the mechanisms of this relation are unclear.

Accompanying changes in serum T4, insulin, and IGF-I concentrations and body composition could explain at most 27% of the changes in lipoprotein levels during GH treatment. This finding suggests that GH has direct effects on the regulation of lipoprotein levels in humans or that other GH-dependent factors not included in this study may mediate these effects.

The decrease in body fat and the increase in fat-free mass in response to GH treatment in GHD adults has been demonstrated in well-controlled trials.17 26 The present study, however, suggests for the first time a gender difference in terms of the effect of GH therapy on body composition, indicating that GHD men are more sensitive to GH in terms of its anabolic and lipolytic action. GH and testosterone might have a synergistic effect in promoting lipolysis in adipocytes,50 and estrogens antagonize several GH effects, such as the nitrogen-retaining effect.51 Patients' gonadal steroid substitution could thus explain this gender difference in response to GH administration on body composition.

The disturbed lipoprotein pattern found in untreated GHD adults consists of increased TC, LDL-C, apoB,1 3 4 5 6 and TG1 2 3 5 and decreased HDL-C2 3 and apoA-I4 5 concentrations. This serum lipoprotein pattern could be of importance in the increased cardiovascular mortality seen in these patients.8 The present study also found similar Lp(a) levels in GHD subjects and a control population. A reduction in TC and LDL-C reduces the incidence of cardiovascular disease in both men and women.52 The increase in HDL concentration in men in response to GH should be favorable when it comes to retarding the progress of atherosclerosis.53 54 In women, however, the absence of HDL increment and the increase in TG concentration could be unfavorable, as the association between TGs and cardiovascular risk appears to be stronger in women than in men.55 However, the higher HDL level in women throughout the study might reduce the importance of the TG increment.55 The increased cardiovascular risk associated with high Lp(a) levels is possibly dependent on the prevailing LDL-C concentration.56 A cross-sectional angiographic study of both men and women showed that Lp(a) did not predict the severity of coronary artery disease when other lipoprotein levels were adjusted for.49 Furthermore, Lp(a) was not as important a predictor of the progression of coronary artery disease as LDL-C and apoB in a prospective angiographic study of men with symptomatic coronary artery disease.57 This indicates that the increase in cardiovascular risk due to an increased level of Lp(a) is probably smaller than the decline in risk due to changes in LDL-C and apoB concentrations. Moreover, the observation that patients with high LDL-C concentrations showed a more marked decrease in LDL and a less pronounced increase in Lp(a) concentrations suggests a more favorable effect on the cardiovascular risk than can be predicted from the mean response to GH administration.

In conclusion, this study demonstrates that 12 months of GH treatment significantly affects the lipoprotein metabolism of GHD adults and that there is a gender difference with respect to GH effects on serum Lp(a) concentration and body composition. These results suggest that sex hormones modify the response to GH treatment. GH treatment appears to have favorable effects on a number of cardiovascular risk factors. However, Lp(a) concentrations increased after GH therapy to levels well above those of matched control subjects, which indicates that the dose or mode of administration of GH to GHD adults might not be adequate; further investigations are therefore called for. Moreover, long-term treatment trials are needed to clarify the effects that changes in lipoprotein levels in response to GH may have on the premature atherosclerosis and increased cardiovascular mortality observed in this group of patients.


*    Selected Abbreviations and Acronyms
 
GH = growth hormone
GHD = growth hormone–deficient
HDL-C = HDL cholesterol
HMW = high-molecular-weight
IGF-I = insulin-like growth factor–I
LDL-C = LDL cholesterol
LMW = low-molecular-weight
Lp(a) = lipoprotein(a)
T4 = thyroxine
TC = total cholesterol
TG = triglyceride


*    Acknowledgments
 
This work was supported by grants from the Medical Association of Göteborg, the Swedish Heart and Lung Foundation, and the Swedish Medical Research Council (project No. 4531 No. 11621). Dr Jan Oscarsson is the recipient of Swedish Medical Research Council grant 04P-11010. We are indebted to Dr Taddei-Peters at the Organon Teknika/Biotechnology Research Institute, Rockville, Md, for the determination of apo(a) isoforms and to Aira Lidell at the Wallenberg Laboratory and Lena Wirén, Anne Rosén, and Ingrid Hansson at the Research Centre for Endocrinology and Metabolism for their skillful technical support.

Received March 17, 1995; accepted September 19, 1995.


*    References
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