© 1995 American Heart Association, Inc.
Articles |
Hormonal Regulation of Serum Lipoprotein(a) Levels
Contrasting Effects of Growth Hormone and Insulin-Like Growth Factor–I
From the Metabolism Unit, Departments of Surgery (H.O.), Clinical Chemistry (L.B.), and Medicine (B.A.), and the Molecular Nutrition Unit, Center for Nutrition and Toxicology, Novum, Karolinska Institute at Huddinge University Hospital, Huddinge, and the Department of Internal Medicine (A.G.J., E.L., S.L.), Uppsala University Hospital, Uppsala, Sweden.
Correspondence to Bo Angelin, MD, Department of Medicine, Huddinge University Hospital, S-141 86 Huddinge, Sweden.
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Abstract |
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Abstract In response to treatment with growth hormone, serum levels of lipoprotein(a) increase, while those of LDL cholesterol decrease. To establish if increased levels of insulin-like growth factor–I may be of importance for these changes, we analyzed serum lipoprotein concentrations in 11 male patients with idiopathic osteoporosis who were treated with growth hormone (2 IU · m-2 · d-1) or insulin-like growth factor–I (80 µg · kg-1 · d-1) in a randomized, double-blind, crossover study. LDL cholesterol was reduced by 0.7 mmol/L (P<.01) during growth hormone treatment but was not affected when the same patients received insulin-like growth factor–I. In contrast, mean lipoprotein(a) levels increased from 519 to 571 mg/L (P<.03) in response to growth hormone but were reduced from 538 to 478 mg/L (P<.04) during treatment with insulin-like growth factor–I. These results indicate that growth hormone exerts its effects on lipoprotein metabolism independent of insulin-like growth factor–I. Furthermore, the results suggest that treatment with insulin-like growth factor–I may reduce lipoprotein(a) levels.
Key Words: growth hormone • insulin-like growth factor–I • lipoprotein
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Introduction |
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Lipoprotein(a) [Lp(a)], which is a complex between LDL and apo(a), is a strong independent risk factor for premature ischemic heart disease (for review, see References 1 through 31 2 3 ). While Lp(a) concentrations are relatively resistant to most forms of conventional lipid-lowering therapy, recent studies have indicated that hormonal treatments may clearly affect Lp(a) levels. Thus, serum Lp(a) is drastically reduced by estrogen4 5 6 and increased by growth hormone (GH).7 8 In contrast, both estrogen and GH induce hepatic LDL receptors and reduce serum LDL cholesterol (LDL-C).9 10 In view of the close structural relation between Lp(a) and LDL, this difference is not easily explained. However, estrogen reduces and GH increases the levels of insulin-like growth factor–I (IGF-I),11 and IGF-I may thus mediate the action of both hormones on Lp(a). It is well established that IGF-I mediates several of the cellular effects of GH, and it may therefore be hypothesized that it increases serum Lp(a) levels. To test this hypothesis directly, we determined the lipoprotein pattern and Lp(a) levels in otherwise healthy patients with idiopathic osteoporosis who were treated with low-dose GH or IGF-I in a double-blind, crossover study.
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Methods |
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Subjects and Experimental Procedure
Eleven men (age, 44±2 years; range, 32 through 57 years) with idiopathic osteoporosis were studied. This condition is characterized by decreased serum levels of IGF-I despite a normal GH secretion.12 The men were all nonobese and without clinical or laboratory evidence of diabetes or renal or hepatic disease. The study was approved by the ethics committee of Uppsala University Hospital. After informed consent was obtained from the patients, they were treated for 1 week with each drug. A randomized, double-blind, crossover design was used that had a 3-month washout period. Recombinant GH (Somatropin; Pharmacia) was given as 2 IU/m2 SC at 8 PM and IGF-I (Pharmacia) as 80 µg/kg SC at 8 AM; placebo was administered at the reciprocal time points.
Before and on the last day of treatment, fasting blood serum was obtained at 8 AM and analyzed for IGF-I, total cholesterol, HDL cholesterol (HDL-C), LDL-C, triglyceride, and Lp(a) concentrations.
Assays
Serum IGF-I was measured by using a radioimmunoassay after
acid-ethanol extraction and cryoprecipitation with des(1-3) IGF-I as
ligand.13 Total serum cholesterol and
triglycerides and blood glucose were determined by using
enzymatic techniques (Boehringer-Mannheim). HDL-C was
determined after the precipitation of apoB-containing lipoproteins with
phosphotungstic acid,14 and the concentration of LDL-C was
calculated according to the method of Friedewald et al.15
Duplicate determinations of serum Lp(a) concentration were performed in
all samples on one occasion by using a two-site immunoradiometric assay
(Pharmacia Diagnostics).4 The detection limit
of the assay is 12 mg/L. The intra-assay coefficients of variation were
3.4% and 2.5% at low (136 mg/L) and high (419 mg/L) standard
concentrations, respectively, and the interassay coefficient of
variation was 7.9% at the low and 6.5% at the high standard
concentration.
Statistics
Data are presented as mean±SEM or mean (range). The
significance of differences was assessed by Wilcoxon's test.
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Results |
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During GH therapy, the fasting serum levels of IGF-I increased 2.7-fold, from 162±60 to 439±102 µg/L (P<.005). The corresponding increase during IGF-I therapy was 2.2-fold, from 154±46 to 340±113 µg/L (P<.005). Fasting blood glucose averaged 4.0±0.4 and 4.3±0.6 mmol/L before and during GH therapy, and 3.9±0.4 and 3.8±0.4 mmol/L before and during IGF-I treatment, respectively; none of these differences were significant.
The effect of GH on lipoprotein levels (Table
) reflected
previous studies of short-term GH treatment.7 8 Thus, the
concentration of LDL-C fell (P<.01) in 9 of the 11
patients, whereas that of HDL-C remained stable. Serum
triglyceride levels increased in all subjects
(P<.005). After the treatment period with IGF-I, no
significant effects on LDL-C, HDL-C, or total triglycerides
were seen. In accordance with previous studies,7 8 GH
treatment increased serum Lp(a) levels in 9 of the 11 subjects
(P<.03). However, contrary to our hypothesis, treatment
with IGF-I reduced Lp(a) levels in 9 of the 11 subjects
(P<.04). Individual changes for all 11 subjects in Lp(a)
and LDL-C levels are shown in the Figure.
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Discussion |
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The main finding of this randomized, double-blind, crossover study was that GH and IGF-I have opposite effects on serum Lp(a) levels. These two hormones have a complex relationship. Several of the metabolic effects of GH are presumably mediated through IGF-I, but GH can also modulate the actions of IGF-I by influencing serum levels of insulin and IGF-binding proteins.11 In certain metabolic systems, eg, glucose and free-fatty-acid metabolism, the effects of GH and IGF-I are antagonistic.16 It is well known that GH stimulates lipolysis, resulting in an increased flow of free fatty acids to the liver. Serum levels of Lp(a) are under strong genetic regulation and are mainly influenced by the hepatic apo(a) production rate.17 18 It could therefore be hypothesized that an increased hepatic flux of fatty acids during GH administration, resulting in increased lipoprotein production,19 might be of importance for the stimulating effect of GH on Lp(a) levels. Of interest is that one of the few agents found to lower Lp(a) levels, nicotinic acid, is indeed a potent antilipolytic agent, decreasing the flux of fatty acids to the liver.20 21 Furthermore, it is notable that compatible with an increased VLDL production, serum triglyceride levels increased during GH administration although no significant correlation between the changes in triglyceride and Lp(a) levels was observed in the present study (data not shown). However, triglyceride metabolism is complex, and the exact mechanisms behind the effects of nicotinic acid and GH on Lp(a) remain to be established.
No significant changes in HDL-C, LDL-C, or
triglyceride levels were observed in the present study
during IGF-I administration. Furthermore, IGF-I treatment does not
influence the secretion of apoB or triglycerides in
cultured rat hepatocytes.22 It is therefore
more difficult to directly link the decrease in Lp(a) levels during
IGF-I administration (Table
), at least at the present doses, to an
effect on hepatic lipoprotein production. At any rate, our findings
underscore important differences between GH and IGF-I administration on
lipoprotein metabolism.
It must be emphasized that relatively low doses of IGF-I were used in this study on osteoporotic men, and IGF-I might have more drastic effects on lipoprotein levels at higher doses. This has been demonstrated by IGF-I treatment of subjects with type II diabetes, in which the administration of IGF-I interrupts the cycle of insulin resistance, hyperinsulinemia, and hyperglycemia, and results in improved lipid metabolism.23 Less is clear about the relationship between glucose homeostasis and Lp(a) in diabetic subjects,24 and it cannot be ruled out that the sensitivity in the response to IGF-I is different for Lp(a) and other lipoproteins. In rats, insulin secretion is reduced during IGF-I treatment25 ; clearly, the possible role of insulin as a regulator of Lp(a) levels needs to be further studied.
In the present experimental situation, in which relatively low doses of GH or IGF-I were administered, serum IGF-I levels were increased to approximately the same extent in both cases. Thus, as no significant changes in LDL-C levels were seen during IGF-I administration, this indirectly indicates that the previously demonstrated stimulatory effect of GH on hepatic LDL receptor expression10 may not be due to IGF-I. In contrast, during GH administration LDL-C decreased significantly, in agreement with an increased LDL receptor activity. These results disagree with previous studies that used cultured macrophages, in which the effect of IGF-I has been suggested as an explanation for the GH-induced stimulation of LDL receptor activity.26 In support of our present findings, however, we have found that IGF-I cannot substitute for GH to normalize the reduced hepatic LDL receptor activity resulting from hypophysectomy in the rat (M. Rudling, H. Olivecrona, G. Eggertsen, and B. Angelin, unpublished data, 1995). As LDL receptor activity appears to influence serum Lp(a) levels to only a minor extent, it is clear that the opposite effects of GH and IGF-I on this activity cannot explain the differing effects on Lp(a).
In conclusion, following low-dose treatment with IGF-I, serum Lp(a) levels were reduced, in contrast to the stimulatory effect observed in response to GH. The results do not support the contention that the effects of estrogen and GH on Lp(a) metabolism are mediated through IGF-I, but instead indicate that, analogously with their effects on glucose and free-fatty-acid homeostasis, IGF-I and GH have different effects on hepatic lipoprotein metabolism. Further studies on IGF-I at different dose levels are necessary to evaluate its potential therapeutic use in lipoprotein disorders. The present results, with a lowering of Lp(a), a lipoprotein that is implicated as a risk factor for cardiovascular disease, support the continued evaluation of IGF-I in the therapy of other metabolic disorders such as osteoporosis and diabetes.
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Acknowledgments |
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The study was supported by grants from the Swedish Medical Research Council (projects 03X-7137 and 03X-10349), the Nordic Insulin Fund, the Thuring Foundation, the Karolinska Institute, and Pharmacia. Dr Berglund is a Florence Irving associate professor of medicine and an established investigator of the American Heart Association, New York City Affiliate. The technical assistance of Lilian Larsson is gratefully acknowledged.
Received September 16, 1994; accepted April 11, 1995.
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