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Department of Molecular & Clinical Endocrinology and Oncology, Section of Endocrinology, "Federico II" University of Naples (A.C., C.D.S., F.R., R.P., M.C.S., G.L.), Naples, Italy; and Emergency Unit, "S. Maria degli Incurabili" Hospital of Naples (S.S.), Naples, Italy
Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, via S. Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it.
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Abstract |
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After the first 6 months, we observed a significant increase in IGF-I levels and of high-density lipoprotein (HDL)-cholesterol together with a significant decrease in diastolic blood pressure, the total/HDL-cholesterol ratio, and C-reactive protein in the patients in group A, whereas vascular parameters did not significantly change. In the patients in group B, none of the parameters studied significantly changed. After 6 months of GH withdrawal in the patients in group A, a significant decrease in IGF-I levels, a significant increase in the total/HDL-cholesterol ratio and C-reactive protein, and a trend toward an impairment of carotid IMT and peak velocities were observed. In the patients in group B, the addition of GH to the standard replacement induced a significant increase in IGF-I levels together with a decrease in systolic and diastolic blood pressure, total cholesterol and total/HDL-cholesterol ratio, and C-reactive protein, and an increase in HDL-cholesterol levels with a trend toward an improvement of vascular parameters. At the end of the study, mean IMT was significantly lower than at baseline both in group A (from 0.88 ± 0.28 to 0.85 ± 0.27 mm, P = 0.0003) and in group B (from 0.83 ± 0.21 to 0.80 ± 0.20 mm, P = 0.003).
In conclusion, 6 months of GH replacement has beneficial effects whereas 6 months of GH deprivation has detrimental effects on cardiovascular risk factors and atherosclerosis. These findings support the indication for GH replacement in severe GH deficiency adult patients.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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To further explore the short-term effects of GH treatment and deprivation on common cardiovascular risk factors and carotid IMT as a marker of cerebrovascular disease, we designed this randomized, cross-over, controlled study in a large series of patients with severe GHD.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Among eighty-four adult patients diagnosed with severe GHD in our Department from January 1997 to December 2000, 34 patients (19 women, 15 men; 25–50 yr) with partial or complete hypopituitarism were enrolled in this study. Exclusion criteria were: 1) age greater than 50 yr (n = 8); 2) body mass index (BMI) greater than or equal to 30 (n = 9); 3) familial or personal history of cardiovascular diseases (n = 8); 4) previous treatments with drugs known to interfere with glucose or lipid metabolism or to influence blood pressure (n = 12); 5) GHD with childhood onset (n = 8); and 6) GHD in patients previously affected with Cushing’s disease (n = 5). All of the patients had been previously operated on via transsphenoidal and/or transcranic route for prolactinomas, nonfunctioning pituitary adenoma, or craniopharyngioma and none of them had been irradiated. At study entry, GHD was diagnosed by a GH peak less than 9 µg/liter after arginine plus GHRH testing in all patients (19, 20). In detail, GHD was associated with panhypopituitarism in 20 patients, FSH/LH and TSH deficiency in four, FSH/LH and ACTH deficiency in four, and FSH/LH deficiency in six; nine of the 20 patients with hypopituitarism also had diabetes insipidus. Hormone replacement therapy with L-T4 (50–100 µg per os daily), cortisone acetate (25–37.5 mg/d), and DDAVP (5–20 µg/d) was given when appropriate. Hypogonadism was treated in men with testosterone enanthate (250 mg im monthly) and in women with standard oral estrogen/progestinic association. Adequacy of hormone replacement therapy was periodically assessed by serum-free thyroid hormones, testosterone, serum Na+ and K+ measurements, and blood pressure. At study entry, these hormonal parameters were in the normal range for age in all patients. None of the patients had ever received GH treatment. According to a previous study (21), the duration of GHD was calculated from the time of diagnosis of the pituitary tumor and was 7.9 ± 2.6 yr (mean ± SD).
Controls
Thirty-four healthy subjects, among the medical and paramedical personnel of the Department of Molecular and Clinical Endocrinology and Oncology of the University "Federico II" of Naples, matched for sex, age (±1 yr), and BMI (±1) with the patients agreed to participate in this study and were used as controls. As for the patients, familial or personal history of cardiovascular diseases and previous treatments with drugs known to interfere with glucose or lipid metabolism or to influence blood pressure were exclusion criteria for controls. The characteristics of patients and controls at study entry are shown in Table 1
. All patients and controls gave their informed consent to participate in this study, which was designed in accordance with the Helsinki II Declaration on human experimentation. Twenty-seven patients (79.4%) and 26 controls (76.5%) were nonsmokers, three and four were ex-smokers, four and four were mild smokers (<15 cigarettes/d), and all had a sedentary lifestyle.
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At study entry, all 68 subjects underwent serum assay of IGF-I; systolic and diastolic blood pressure (SBP, DBP) and heart rate measurement; total- and high-density lipoprotein (HDL)-cholesterol, triglycerides, and C-reactive protein levels after an overnight fast; and common carotid arteries ultrasonography. We also calculated the total/HDL-cholesterol ratio, as an index of cardiovascular risk (22). Blood pressure was measured at the right arm, with the subjects in a relaxed sitting position. The average of six measurements (three taken by each of two examiners) with a mercury sphygmomanometer was used for analysis. The fourth Korotkoff phase was considered as diastolic blood pressure. Hypertension was diagnosed in the presence of diastolic blood pressure above 90 mm Hg (23). None of the subjects had hypertension. The oral glucose tolerance test (oGTT) was performed by measuring blood glucose every 30 min for 2 h after the oral administration of 75 g of glucose diluted in 250 ml of water solution. Diabetes mellitus was diagnosed when fasting glucose was above 126 mg/dl (7 mmol/liter) at two consecutive measurements or when 2 h after the oGTT glucose was greater than or equal to 200 mg/dl (11.1 mmol/liter). Impaired glucose tolerance was diagnosed when fasting glucose was less than 126 and greater than or equal to 140 (7.8 mmol/liter) and less than 200 mg/dl 2 h after the oGTT (24). Hypertriglyceridemia was diagnosed when triglycerides levels were more than 150 mg/dl (1.7 mmol/liter) (25), whereas hypercholesterolemia was diagnosed when total cholesterol levels were more than 200 mg/dl (5.2 mmol/liter) (26). The conversion factors (milligrams per deciliter to millimoles per liter) for lipids and glucose were as follows: cholesterol, 0.02586; triglycerides, 0.01129; and glucose, 0.05551. Biochemical markers and carotid ultrasonography were re-evaluated after 6 and 12 months in only the patients.
Study design
This is a 12-month randomized, cross-over, interventional study designed to explore the efficacy of GH replacement at standard doses on cardiovascular risk factors and carotid IMT. Randomization was carried out by one investigator (A.C.) not directly involved in patient treatment and follow-up. At study entry after the diagnosis of GHD, the patients were randomized into two groups (A and B), with 17 patients in each group; group A received appropriate replacement therapy including GH at standard doses for 6 months and then were withdrawn from GH for the subsequent 6 months; group B received appropriate replacement therapy excluding GH for 6 months with the addition of GH in the subsequent 6 months. The characteristics of groups A and B after randomization are shown in Table 1
. Recombinant GH was given at the starting dose of 3–4 µg/kg·d as suggested for the young-adult population. After 3 months, the dose was adjusted aiming at reaching the 50-degree percentile of normal serum IGF-I concentrations for sex and age, as previously reported (27). At the end of the 6 months of the study period, the median GH dose was 8 µg/kg·d in males and 10 µg/kg·d in females; the maximal dose was 8 µg/kg·d in males and 11 µg/kg·d in females.
Carotid ultrasonography
Common carotid arteries ultrasound imaging was carried out with a Vingmed Sound CMF 725 equipment (Horten, Norway) by means of a 7.5-MHz annular phased array transducer. Details on the technique were reported elsewhere (28, 29). Right and left carotid arteries were scanned longitudinally, 2.5 cm proximal and 1 cm distal to the bifurcation. When satisfactory B-mode imaging of common carotid artery wall was achieved, M-mode images were taken for several cardiac cycles to obtain the best quality measurements of IMT. Quantitative and semiquantitative indices were evaluated by echo-Doppler ultrasonography placing the sample volume (set at 75% of lumen caliber) in the middle of the vessel lumen. The variability in the IMT measurement for our instrument was 0.03 mm. Our intraobserver variability for repeated measurements of carotid artery diameter is 0.01 ± 0.02 mm. The average value of IMT between right and left common carotid arteries was calculated and reported as mean IMT. Flow indices of both carotids were investigated by measuring blood systolic and diastolic peak velocities. The epidemiological data currently available indicate that a value of IMT at or above 1 mm at any age is associated with a significantly increased risk of myocardial infarction and/or cerebrovascular disease (30). Presence, location, and size of plaques were also evaluated at the level of common carotid arteries. A type IV plaque featured by thickening of vascular wall and increased density of all ultrasound-detectable layers without any hemodynamic alteration was defined as a well-defined plaque (31). All measurements were made by one investigator (S.S.) who was blind in respect to the results of patients randomization and treatment.
Assays
Serum GH levels were measured by immunoradiometric assay (IRMA) using commercially available kits (HGH-CTK-IRMA; Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 µg/liter. The intra- and interassay coefficients of variation (CVs) were 4.5 and 7.9%, respectively. Plasma IGF-I was measured by IRMA after ethanol extraction using Diagnostic System Laboratories Inc. (Webster, TX). In our laboratory the normal IGF-I range was 110–500 µg/liter in 18- to 30-yr-old patients, 100–450 µg/liter in 31- to 40-yr-old patients, and 100–300 µg/liter in 41- to 50-yr-old subjects. The sensitivity of the assay was 0.8 µg/liter. The intraassay CVs were 3.4, 3.0, and 1.5% for the low, medium, and high points of the standard curve, respectively. The interassay CVs were 8.2, 1.5, and 3.7% for the low, medium, and high points of the standard curve. Fasting total-, LDL-, and HDL-cholesterol, and triglycerides levels were measured by standard procedures. C-reactive protein was measured by a sensitive ELISA (DSL-10-42100 Active ELISA kit; Diagnostics Systems Laboratories, Inc.).
Statistical analysis
Results were expressed as mean ± SD unless otherwise specified. The statistical analysis was performed by SPSS Inc. (Cary, NC) package using nonparametric tests. The comparison between controls and patients and between the groups A and B of the GHD patients at baseline, 6 months, and 12 months was performed by the Wilcoxon matched paired test. Comparison among time 0, 6, and 12 months in the GHD patients was analyzed using the Kruskal-Wallis test followed by the Dunn’s test for paired data. The significance was set at 5%.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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. As expected, severe GHD patients had a profound impairment of lipid profile associated with a significant increase in C-reactive protein and of IMT at both common carotid arteries compared with controls. Individual mean values of IMT in controls and in GHD patients (at baseline after randomization) are shown in Fig. 1. In this series, seven GHD patients (20.6%) and none of the controls (P = 0.017) had, in one or both common carotid arteries, a value of IMT greater than or equal to 1 mm (Fig. 1), also showing well-defined plaques. Nineteen patients (55.9%) and two controls (5.9%, P < 0.0001) had increased blood cholesterol levels, and 12 patients (35.3%) and none of the controls (P < 0.0001) had increased triglycerides levels. None of the patients and controls had hypertension and diabetes, and nine patients (26.5%) and none of the controls (P = 0.004) had impaired glucose tolerance. At study entry, female patients had lower IGF-I levels (77.1 ± 45.2 vs. 156.4 ± 118.5 µg/liter, P = 0.011) and BMI (23.0 ± 2.1 vs. 24.8 ± 1.3 kg/m2, P = 0.006) than males, without any difference in the other parameters.
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). Only IMT at the right common carotid artery was higher in the patients in group A than in those in group B (Table 1). Presumed duration of GHD was similar in the two groups (8.2 ± 3.3 vs. 7.6 ± 1.9 yr, P = 0.63).
After the first 6 months, in the patients in group A, a significant increase in IGF-I levels and of HDL-cholesterol together with a significant decrease in diastolic blood pressure, the total/HDL-cholesterol ratio, and C-reactive protein levels (Table 2) was observed. Vascular parameters improved but did not reach statistical significance. In the patients in group B, none of the parameters studied significantly change (Table 2).
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) was observed. A trend toward an impairment of carotid IMT and peak velocities was also observed, but results did not differ from baseline (Table 2). In the patients in group B, the addition of GH to the standard replacement induced a significant increase in IGF-I levels together with a decrease in systolic and diastolic blood pressure, total cholesterol and total/HDL-cholesterol ratio, and C-reactive protein levels, and an increase in HDL-cholesterol levels (Table 2). As for group A, in the patients in group B, there was a trend toward an improvement of vascular parameters, but none of them reached the statistical significance. At the end of the study, however, mean IMT was significantly lower than at baseline both in group A (from 0.88 ± 0.28 to 0.85 ± 0.27 mm, P = 0.0003) and in group B (from 0.83 ± 0.21 to 0.80 ± 0.20 mm, P = 0.003). At the end of the study, there was no difference in IGF-I levels (184.9 ± 75.5 vs. 215.5 ± 81.8 µg/liter; P = 0.27) and BMI (23.3 ± 1.7 vs. 24.0 ± 21.1 kg/m2; P = 0.21) as well as in the other parameters, including mean IMT (0.83 ± 0.22 vs. 0.84 ± 0.26 mm; P = 0.96) between female and male patients.
Seven of the 34 patients, five in group A and two in group B, had well-defined atherosclerotic plaques. As shown in Fig. 2, GH replacement and/or deprivation induced changes in IMT and in peak velocities (data not shown), but the values of IMT remained above the threshold of 1 mm in all of the patients. Notably, all these patients had IGF-I levels below the lower limit of normal for age and gender (–2 SD).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients with GHD, either developed during childhood or adulthood, were shown to have unfavorable lipid profile, increased BMI and fat (7, 8, 32, 33), less distensibility of aorta (34), endothelial dysfunction (35, 36), and an increase in both common carotid arteries IMT in some (12, 13, 14, 15, 16, 17), but not all (37, 38), studies because an increase in IMT at common carotid arteries was found mainly in patients with GHD and low IGF-I levels (24). Additionally, abnormalities in markers of inflammation and endothelial cell activation (37, 38, 39, 40, 41) and increased storage of proatherogenic lipoproteins in macrophages, more easily converted to foam cells have been observed in GHD (42). Altogether, these findings substantiate the increased mortality for cardiovascular and cerebrovascular disease of hypopituitary patients (1, 2, 3, 4, 5, 6). The pathogenetic role of GHD in inducing abnormal vascular and endothelial function was supported by the beneficial effect of GH replacement in reversing such alterations. Previous studies have reported that GH replacement for 12–24 months decreases IMT (14, 15); normalizes levels of soluble P-selectin, E-selectin, intercellular adhesion molecule-1, matrix metalloproteinase-2, matrix metalloproteinase -9, and vascular endothelial growth factor as well as other inflammatory markers (38, 39, 40, 41, 43); increases skin microcirculation and vascular reactivity (44, 45); and improves endothelial dysfunction (46). However, the detrimental effect of GH withdrawal has never been documented. Moreover, the short-term effects of GH replacement on the atherosclerotic profile have been reported only by Pfeifer et al. (15) who found normalization of IMT already after 6 months of GH replacement in 11 men with GHD. In another study, Borson-Chazot et al. (14) reported a substantial reduction of IMT after 12 months in 22 patients, without any further IMT decrement after 24 months in a subset of them (11 patients). In the current study, which includes a larger cohort of severe GHD patients, we aimed at investigating the short-term effects of GH replacement and of GH deprivation on classical cardiovascular risk factors and on IMT and hemodynamics at common carotid arteries. To minimize the bias originated by the measurement of IMT and peak velocities, which are investigator dependent, we randomized the patients into two groups and analyzed the results in a cross-over study design.
In both the groups, the replacement with GH induced beneficial effects on lipid profile and decreased C-reactive protein levels, IMT, and systolic and diastolic peak velocities. In our series, however, IMT remained higher than controls, in contrast with the results reported by Pfeifer et al. (15). In our series, the baseline levels of IMT were higher than that found in the series of Pfeifer et al. (15) so that in our patients a longer period of GH replacement could potentially be required to normalize IMT. It should be also hypothesized, however, that in some cases, namely those with well-defined atherosclerotic plaques, GH replacement could be unable to normalize IMT and the atherosclerotic plaques could persist independently from replacement therapies. Interestingly, although the morphological characteristics of plaques at ultrasonography did not change, the mean values of IMT significantly decreased (by 3.6 ± 4.6%) even in these patients. This result indicates that with GH replacement the atherosclerotic plaques were likely to be stabilized. Long-term observation studies are required to address this issue.
There are no data on the detrimental effects of GH withdrawal in severe GHD patients on the atherosclerotic profile. Independent epidemiological studies (47, 48, 49) have recently reported the existence of a negative correlation between IGF-I levels and risk for ischemic heart disease. In our population of GHD patients, we found that low IGF-I levels after withdrawal from GH replacement were associated with an increase, even subtle, of IMT at common carotid arteries. This latter finding can be considered as a surrogate marker of coronary artery disease and can be taken as indirect confirmation of the requirement of normal IGF-I levels to limit vascular disease development or reduce vascular disease severity. To note, IMT after GH deprivation did not return to baseline levels. Six months after GH withdrawal, mean IMT increased by 3.3 ± 3.1%, ranging from 1–11.6%. The changes in IMT and hemodynamics at common carotid arteries were less evident in the patients undergoing GH deprivation during the first 6 months (group B). This likely depends on the evidence that IGF-I levels reduced less remarkably in the patients continuing the observation without starting GH replacement than in those experiencing GH withdrawal after a period of GH replacement. Similarly, in these patients, C-reactive protein levels remained stable. No similar data are available: the most important clinical implication of such a finding is that GH replacement is indicated in severe GHD adults, as further GH deprivation has detrimental effects on vascular properties and increases atherosclerosis. These data support previous findings from our group showing a significant impairment of left ventricular performance 12 months after GH deprivation in another cohort of patients (27). Our data are also supported by previous findings of Gibney et al. (51) who reported, in a study comparing two groups of severe GHD adults one receiving GH replacement for 10 yr and the other not receiving such a replacement, that IMT in the latter patients was significantly increased at the end of the study. Even considering that the study design by Gibney et al. (50) was not prospective, their results were in line with our findings, which have the limitation of a short follow-up.
In this current study, we did not find any significant difference between female and male patients except for lower IGF-I levels and BMI values in the former at baseline but not at the end of the study.
In conclusion, the results of this 6-month randomized, prospective, interventional study, which enrolled a large series of patients with severe GHD and aimed to compare them to a carefully matched healthy control series, show that GH replacement has beneficial effects on cardiovascular risk factors, inflammatory markers, and atherosclerosis, confirming previous results (14, 15, 43). Additionally, we demonstrated detrimental effects of GH deprivation on atherosclerosis, supporting the requirement of GH replacement in severe GHD adult patients. Because increased IMT in childhood is a negative prognostic factor for cardiovascular diseases in middle-age (51), patients with GHD in childhood and possibly in young adulthood should undergo careful screening of cardiovascular risk parameters and carotid ultrasonography to monitor the risk of cerebrovascular disease.
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Footnotes |
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First Published Online January 25, 2005
Abbreviations: BMI, Body mass index; CV, coefficient of variation; GHD, GH deficiency; HDL, high-density lipoprotein; IMT, intima-media thickness; IRMA, immunoradiometric assay; oGTT, oral glucose tolerance test.
Received November 16, 2004.
Accepted January 14, 2005.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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