Adult-Onset Growth Hormone Deficiency: Relation of Postprandial Dyslipidemia to Premature Atherosclerosis

A complex relationship exists between disease of the cardiovascular system and a spectrum of neural and humoral factors. Recently, the modulating role of hormones, such as thyroid hormone (1–4), in the atherosclerotic process has been emphasized. However, several other hormones in addition to thyroid hormone may contribute to atherogenesis, thereby constituting a key element in the concept of cardiovascular endocrinology (5). Recently, evidence has been provided to suggest that disturbances of the pituitary GH axis and its mitogenic partners, including IGF-I and IGF-binding proteins (IGFBP), are critical actors in the initiation of the atherosclerotic process (6–8). Indeed, disturbances in the GH axis/IGF system appear to be intimately related to the perturbed postprandial lipoprotein metabolism that is typical of subjects presenting premature atherosclerosis (9, 10). Furthermore, a high baseline plasma GH concentration is associated with increased cardiovascular mortality (11, 12). These observations suggest a U-shaped relationship between disturbances in the GH axis/IGF system and increased cardiovascular morbidity and mortality. In the present review we explore the key pathways of lipid metabolism in adult-onset GH deficiency (AGHD) that may be involved in the initiation of atherosclerosis and that result in elevated cardiovascular risk. In the last 15 yr, GH deficiency in adulthood has been focused on (pan-) hypopituitarism (depletion of (all) hormones that originate in the pituitary as a consequence of pituitary damage) or on transition from childhood-onset GH deficiency. In such cases of GH deficiency, one deals with an absolute deficiency state. Currently, a new group of patients with disturbances in the GH/IGF system have been defined who are characterized by a relative deficiency in optimal GH secretion; this group includes subjects displaying obesity and noninsulin-dependent diabetes mellitus (13). Moreover, aging is associated with a reduction in plasma GH and IGF-I levels; indeed, subjects with low serum IGF-I levels display an increased risk of ischemic heart disease (14). In addition, patients with heart failure in a catabolic condition, with progression of cancer, or with end-stage renal failure (15, 16) were characterized with GH resistance. With the growing clinical importance of GH deficiency, knowledge of the physiological function of the GH/IGF system has progressed. The GH axis originates in the cerebrum, with the hypothalamus and the pituitary as regulation centers (Fig. 1). GH, whose release is induced by GH-releasing hormones from the hypothalamus, is secreted by the pituitary in a diurnal pattern, with the highest serum GH levels occurring early during the night. After secretion into the circulation, GH is primarily bound to GH-binding protein. The circulating bound fraction of GH is thought to be biologically inactive, and GH must be present in an unbound configuration for the expression of biological activity. GH stimulates a spectrum of metabolic processes and is a major factor in the generation of IGF-I and its binding proteins. The liver secretes IGF-I into the circulation; by contrast, GH stimulates IGF-I gene expression in a wide range of tissues, leading to local autocrine and paracrine actions of biological active IGF-I in tissues such as the endothelium, and is active in cellular processes such as cell proliferation and protection from apoptosis. Recent data from hepato-specific IGF-I knockout mice indicate that circulating IGF-I should be considered more as a marker of GH action in the liver. A, The GH axis IGF system in normal conditions (A) and in GH deficiency (B). GH directly stimulates the generation of IGF-I and its binding proteins in the liver. GH has an indirect effect via IGF-I on local NO-dependent endothelial function. B, The GH axis in AGHD is disrupted, and the inducible effect on IGF-I secretion is defective, with consequences for the proportion of exchangeable IGF-I that acts as a local paracrine/autocrine growth factor. The IGF system consists of two major growth factors, IGF-I and IGF-II, and six IGFBP1–6. IGF-I (17) and IGF-II are primarily synthesized in the liver. IGF-I and IGF-II are biological active in the unbound form. When IGF-I or IGF-II are bound to IGFBPs, then loss of biological activity occurs. Independent effects of the IGFBPs themselves have been reported. Plasma levels of IGFBPs have recently emerged as IGF-independent regulators of cell growth and are consequently associated with an increased development of malignancies (18, 19). For instance, IGFBP-3 in vitro counteracted the angioproliferative effect of vascular endothelial growth factor (20), supporting the independent role of IGFBP-3 in the strictly controlled balance of vascular growth factors (21). Recently, it has been shown in a twin study that serum levels of IGFBPs are primarily genetically determined (22), but fine-tuning control of the GH axis is needed to respond to local tissue requirements of IGF-I and IGF-II (23, 24). The majority of circulating IGF-I in healthy subjects is bound to IGFBP-3 together with the acid-labile subunit in a 140-kDa complex with a relatively long residence time (Fig. 1A). In GH deficiency, IGF-I shifts toward a IGFBP-IGF complex with a molecular weight of 40 kDa, which does not contain the acid-labile subunit, and which is capable of crossing the capillary endothelium (25) (Fig. 1B). In addition to elevated circulating levels of IGFBP-3-bound IGF-I, local tissue levels of biologically active IGF-I are increased by proteolysis of the IGF/IGFBP-3 complex; this process is mediated by proteases on the apical side of the capillary endothelium and in plasma (Fig. 1, A and B). Plasma levels of biologically active IGF-I are inversely related to age. In AGHD, this relationship is not present. Despite the fact that total IGF-I levels are lower in AGHD than in healthy subjects, the IGF-I/intact IGFBP-3 ratio is similar (26). In several retrospective studies, cardiovascular mortality in AGHD is increased compared with that in a matched healthy population. The first report by Rosèn and Bengston (27) revealed increased cardiovascular mortality in subjects with panhypopituitarism substituted with adrenal, gonadal, and thyroid hormones compared with an age- and gender-matched control population (standard mortality rate, 1.8). Subsequent reports have confirmed this observation (28–30). In another Scandinavian population displaying panhypopituitarism supplemented with adrenal, gonadal, and thyroid hormones, the standard mortality rate was increased (2.2), but female GH-deficient subjects displayed a higher mortality rate than male subjects, whereas atherosclerosis-related events originated more in cerebrovascular than in coronary arteries (31). These results were confirmed in a Swedish population with pituitary adenoma in which the increased cardiovascular mortality was higher among women than men, and in which atherosclerosis was preferentially located in the cerebrovascular than in the coronary vascular region (28). On the other hand, no increase in cardiovascular mortality was observed in an AGHD population in the United Kingdom (32). In conclusion, most retrospective observational reports noted an increased cardiovascular mortality in subjects with panhypopituitarism substituted with adrenal, gonadal, and thyroid hormones, but with GH deficiency. One prospective observational study found a limited effect of GH on the increased mortality in hypopituitarism. However, no extended data on GH status were presented (33). These limitations may have underestimated the effect of GH. Long-term randomized follow-up GH intervention trials will definitively answer the question of whether GH treatment will result in reduced cardiovascular mortality in AGHD. Atherosclerotic disease is a complex disorder involving several coexisting features, such as dyslipidemia, inflammation, and a prothrombotic state (34). Disturbances in the GH/IGF system may be directly related to the progressive development of atherosclerosis. In GH deficiency, increased intima media thickness in both femoral and carotid arteries is found (34), and endothelial function is impaired (35, 36). Endothelial dysfunction is considered an early feature of atherogenesis (37–39) and involves reduced availability of endothelial NO, a vasodilatory compound (40, 41). It has been shown that IGF-I has a direct nitric oxide (NO)-releasing effect on NO in cultured human endothelial cells (42), and that low basal IGF-I levels in serum are associated with low basal urinary nitrate and cAMP excretion (17). Decreased biological activity of NO in the endothelium may account for the increased occurrence of hypertension in AGHD, another risk factor for the development of premature atherosclerotic disease (43) (Fig. 1). The composition of the extracellular matrix is relevant to the development of atherosclerosis (44, 45). Proteoglycans, key components of the extracellular matrix, accumulate in the intimal layer of the artery. Based on earlier studies, it has been proposed that the small IGF-I/IGFBP-3 complex in GH deficiency is capable of crossing the capillary endothelium, leading to enhanced concentrations of IGF-I in the subendothelial space (26). However, in vitro studies with cultured human smooth muscle cells have revealed that GH increased the accumulation of both hyaluronan and chondroitin sulfate proteoglycans (46), whereas administration of IGF-I in cell cultures in vitro was without effect (47). Thus, IGF-I does not affect the composition of the extracellular matrix. On the other hand, paracrine and autocrine IGF-I and insulin (48) play a role in smooth muscle cell hypertrophy and the local secretion of angiotensinogen. This observation is supported by studies in a diabetic rat model, with the restriction that only high systemic levels of IGF-I promote the growth of smooth muscle cells. In addition, no change in the elastin and collagen content of the thoracic aorta media layer was found (49). As stated above, plasma IGF levels in AGHD are decreased, but the biologically active, free IGF-I available in AGHD is not reduced, thereby suggesting that local IGF-I concentrations in tissues are distinct from plasma levels. The induction of smooth muscle cell growth may therefore account for the increased intima media thickness of the carotid artery in GH deficiency. The rapid regression of the thickened intima media layer measured with carotid intima media thickness at 3 and 6 months post-GH treatment is impressive (7, 50, 51). In comparison with previous results from dyslipidemic populations, such a reduction can only be obtained after extensive lipid lowering involving a decrease of 30–40% in low density lipoprotein (LDL) cholesterol (52–54). In general, the generation of a similar reduction in endothelial dysfunction by LDL cholesterol reduction requires 3–4 yr of therapy (52, 54). After 6–12 months of GH treatment in AGHD, brachial artery function (measured by flow-mediated dilation) is improved compared with pretreatment flow-mediated dilation values (55). In patients with long-term GH substitution, improvement in arterial performance is maintained (50). It is established that GH directly affects the expression of the hepatic LDL receptor and of key enzymes implicated in bile acid metabolism with effects on intracellular cholesterol homeostasis in the liver. This may be linked to the metabolism of triglyceride(TG)-rich particles [TRP; very low density lipoprotein (very low density lipoprotein) and remnant particles] (56). The indirect, metabolic effects of the GH-deficient state correspond more closely to factors that continuously interact with local arterial structures and may have proatherogenic effects, such as the induction of elevation in plasma VLDL and chylomicron remnant levels during the postprandial period. The dyslipidemia of adult-onset GH deficiency is characterized by lipid disturbances in LDL cholesterol and TRP as illustrated in Fig. 2 (57). The effect of GH therapy on lipid metabolism in AGHD before (A) and during GH therapy (B). In AGHD, VLDL secretion is enhanced, and LDL receptor activity is decreased, resulting in elevated levels of plasma TG, LDL cholesterol, RLP-C, and abnormal postprandial lipoprotein clearance despite normal lipoprotein lipase (LPL) activity. GH treatment resulted in an up-regulation of the LDL receptor, resulting in enhanced clearance of apo B-containing lipoprotein particles. However, VLDL synthesis remained elevated, so that plasma TG and RLP-C levels remained slightly elevated. LDLr, LDL receptor; LRP, LDL-receptor related protein; 7α-OH-ase, 7α-hydroxylase; IDL, intermediate density lipoprotein. In most published studies plasma levels of LDL cholesterol are only moderately increased (3.5–4.5 mmol/liter) in adult-onset GH deficiency compared with those in healthy age- and gender-matched control subjects (43, 58–62). In GH deficiency, hepatic LDL receptor activity is decreased, a process that can be reversed by GH substitution (Fig. 2, A and B). A small (10%), but significant, decrease in plasma LDL cholesterol levels occurs during GH therapy (63–67). Several studies detected no effect of short-term GH therapy on total and LDL cholesterol levels (67–71), whereas one report noted no difference in plasma lipid levels in AGHD even after 7 yr of GH therapy (72). The LDL cholesterol profile shifted from atherogenic dense particles toward larger, less dense particles after GH therapy (73). All of these beneficial changes contribute to attenuation of the atherogenic phenotype (74), which is characterized by elevated levels of LDL cholesterol, small dense LDL, and TG and decreased levels of HDL cholesterol. In AGHD, elevated levels of baseline plasma TG were found, which are considered to constitute an independent risk factor for cardiovascular disease (75). Elevated plasma levels of TG and TRP, consisting of VLDL containing apolipoprotein B100 (apo B100) of hepatic origin and chylomicrons containing apo B48 of intestinal origin, are associated with increased carotid intima media thickness and cardiovascular mortality (76–80). It has been shown in AGHD that VLDL apo B100 secretion is increased and that VLDL particles are enriched in TG (81) (Fig. 2A). Enrichment of VLDL with TG in AGHD gives rise to a dyslipidemic lipoprotein pattern including the presence of more small dense LDL (82). Zilversmit (83) postulated some decades ago that the increased susceptibility to premature atherosclerosis may be related to atherogenic factors occurring as a result of the continuous postprandial state that is a consequence of the consumption of a minimum of three meals a day in western societies (84). Indeed, elevated postprandial levels of TRP and especially of TRP remnants have been observed in subjects with cardiovascular disease, compared with age-, gender-, and BMI-matched control subjects (79, 85–88), and their postprandial lipemia is positively associated with atherosclerotic disease (89). The analyses of determinants of postprandial lipemia requires distinctive and laborious techniques, such as the determination of apoB48 or apoB100 in VLDL density fractions isolated by ultracentrifugation. The availability of an immunoaffinity separation method based on a Sepharose gel coated with apo AI and apoB100 monoclonal antibodies greatly improved the analysis of TRP remnants [remnant-like cholesterol In a population with coronary artery disease, plasma RLP-C levels the the occurrence of cardiovascular events more than LDL cholesterol. In an in vitro study induced a of in rat thoracic aorta may interact with the endothelial NO thereby for the observed endothelial dysfunction The postprandial rise in RLP-C levels in healthy subjects is associated with of endothelial function In patients with AGHD, postprandial levels of RLP-C are higher than in matched healthy control plasma RLP-C levels in GH deficiency from to baseline to after of an levels induced endothelial dysfunction in isolated rat and in healthy human subjects and are in with the observations of who noted an increase in postprandial plasma TG levels in AGHD after three meals during the A reduction in postprandial plasma RLP-C mmol/liter) was observed during GH substitution account for the postprandial increase in RLP-C levels in AGHD, several in postprandial TRP metabolism hepatic apoB100 secretion is increased in AGHD, no decrease in lipoprotein lipase activity in AGHD has been found (Fig. 2A). The accumulation of postprandial RLP-C in AGHD may be by a decrease in their from the via hepatic lipoprotein Indeed, the expression of several hepatic such as LDL and LDL-receptor related is lower in GH-deficient than in healthy subjects (Fig. The substitution of GH results in increased expression of these (Fig. For the GH-deficient LDL receptor knockout from GH substitution despite of the LDL Thus, treatment with GH resulted in increased expression of key enzymes involved in cholesterol synthesis A and bile acid metabolism resulting in an increased of intracellular cholesterol toward the bile acid with an in the with bile (Fig. The intracellular of cholesterol excretion is positively linked to the synthesis and secretion of VLDL in In a reduction of the intracellular hepatic cholesterol content may the secretion of the but not the Decreased levels of HDL cholesterol are associated with an increased risk of Plasma levels of HDL cholesterol in AGHD are decreased compared with those in healthy or It has been shown by that the HDL concentration is decreased in AGHD, whereas free cholesterol remained HDL a major role in the process of cholesterol thereby cholesterol from the tissues toward the liver for excretion into the and are key lipid proteins that play an role in HDL TG from lipoprotein particles to HDL in for from Plasma activity is lower in AGHD than in healthy subjects, whereas no difference was found for and This suggest that the decrease in activity resulted in impaired despite a higher concentration of lipoprotein resulting in impaired cholesterol from cells to the liver a decrease in activity on long-term GH It is that more studies have to be to the role of GH treatment in AGHD on improvement of the atherogenic lipoprotein profile with to HDL of postprandial atherogenic lipoprotein particles with the endothelium may an resulting in increased expression of and (Fig. Indeed, the addition of in the of to a decrease in the after of endothelial cells with with attenuation of NO-dependent endothelial dysfunction particles are to the endothelium with in the subendothelial or cellular matrix (Fig. elevated of in the space can no be resulting in enhanced of and induction of local vascular (Fig. Indeed, elevated concentrations of are as in the postprandial plasma and levels in GH deficiency are increased may to human LDL but of via a may The atherogenic of may the subendothelial space and cell After in the subendothelial the with cell that gives rise to and with local vascular directly with endothelial cell by induction of vascular increased expression of and increased protein. A tissue was considered an Recent has shown that especially in the elevated metabolic activity and may factors as and with Moreover, in of their and are the control of growth factors, such as IGF-I These cellular processes in may therefore be directly disturbances in the GH/IGF system with AGHD have increased of located in the increase in is associated with increased cardiovascular and increased susceptibility for insulin changes in local metabolism in tissue may be related to these clinical The via its action on and the action of GH 1, leading to increased activity in a GH deficiency state. the increased activity of in AGHD results in an accumulation of to increased of to which In the postprandial is an into from free and in addition to from of other biologically active factors, including and The postprandial balance of is by the system and of in AGHD patients have been but is the of and of in these and consequently the of in this GH-deficient to the effects of GH therapy on the during GH therapy Despite decrease in in AGHD as a result of GH the of GH substitution on is not and therapy with GH may therefore effects to that of in subjects have shown that increased of are associated with higher plasma and that plasma levels are higher in than in subjects secretion by is a function of and with optimal secretion limited to the of in AGHD patients are to those in baseline plasma levels in AGHD are lower than those in However, after GH baseline plasma levels similar levels in both AGHD and The induction of increased expression of effects of GH substitution on such as an increase in In addition, circulating GH levels may the metabolic activity of the may therefore an effect on atherosclerosis. is considered to be a of a and the increased postprandial release of these by the tissue in GH deficiency homeostasis via an increase in insulin a decrease in and an of into smooth muscle cells Moreover, secretion of remnant particles from tissue may contribute to the of of the beneficial effect of GH on the atherogenic lipoprotein phenotype may be to metabolic of Moreover, the in AGHD is in continuous with the metabolic profile that is in the postprandial period. may therefore be considered a to an atherogenic lipid phenotype in GH deficiency. Recently, of of the human GH axis/IGF system and its relationship to cardiovascular disease has progressed. In a retrospective for low total IGF-I levels in the population were shown to be associated with an increase in cardiovascular disease (14). In a was found between levels of free IGF-I and intima media thickness Indeed, it has been postulated in the free hormone that free IGF-I is a of the in biological activity of the axis prospective studies are to these with on the of free IGF-I and the IGFBPs in the development of atherosclerotic The synthesis of IGF-I and IGFBP-3 is by GH and status The gene for IGF-I is located on and the for IGFBPs are on 7 The proportion of in IGF-I concentration to effects is and for thereby a to in circulating plasma levels. of the GH system is status which is to increase susceptibility to the development of premature cardiovascular Based on this we that IGF-I and IGFBPs may be key intermediate factors in this atherogenic With to substitution of GH has to be plasma IGF-I and IGFBP-3 plasma concentrations are strictly in to and in to results obtained with IGF-I administration of the IGF-I/IGFBP-3 complex has to be in 2 diabetes rise to improvement in insulin However, no data are available on attenuation of cardiovascular risk. elevated expression of the local GH receptor in cardiovascular tissue can be induced by which may the processes involved in in patients with GH deficiency. In conclusion, observational studies in AGHD patients have revealed elevated of cardiovascular morbidity and mortality to atherosclerotic The atherogenic in GH deficiency are However, a dyslipidemic which is during the postprandial together with a of endothelial NO are considered key factors. The role of and growth factor disturbances in the development and of atherosclerotic disease is of a new and growing in that of cardiovascular This was supported by the a from the of and a from the is a of GH protein; IGF-binding protein; low density nitric lipoprotein very low density lipoprotein.