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Department of Family and Preventive Medicine, University of California-San Diego School of Medicine, La Jolla, California 92093-0607
Address all correspondence to: Elizabeth Barrett-Connor, M.D., Department of Family and Preventive Medicine, School of Medicine, Mail Code 0607, University of California-San Diego, 9500 Gilman Drive, La Jolla, California 92093-0607. E-mail: ebarrettconnor{at}ucsd.edu.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In cross-sectional studies, lower IGFBP-1 levels have been associated with less favorable levels of CVD risk factors, such as lipoproteins and blood pressure (5, 6, 7) and the presence of hypertension, macrovascular disease, and carotid atherosclerosis among diabetics (8, 9). IGF-I levels are lower in individuals with atherosclerotic plaque (7, 10, 11), in men and women who developed ischemic heart disease (IHD) during a 15-yr follow-up (12), and in survivors of myocardial infarction (13, 14, 15). In the only published study of components of the IGF system and CVD mortality, older Finnish men with high serum IGFBP-1 levels had increased total, CVD, and IHD mortality; IGF-I and IGFBP-3 levels were not related to mortality, and women were not studied (16).
We report here the prospective association of serum IGF-I and IGFBP-1 with all cause, non-IHD CVD, and IHD mortality among community-dwelling older men and nonestrogen-using postmenopausal women from the Rancho Bernardo Study cohort. To our knowledge this is the first prospective mortality study of the IGF system to include both men and women.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Between 1988 and 1992, 80% (n = 1727) of surviving men and women from the Rancho Bernardo Study, an on-going community-based study of healthy aging among middle and upper-middle class Caucasian adults, participated in a follow-up clinic visit. The study protocol was approved by the institutional review board of University of California-San Diego; all participants gave written informed consent. During this visit, information regarding medication use, exercise three or more times per week (yes/no), current smoking (yes/no), and alcohol consumption (number of drinks per day during the last 30 d) was obtained using standard questionnaires. Women were asked the date of their last menses and type of menopause (natural or surgical). Current medication use was validated by examination of pills and prescriptions brought to the clinic for that purpose. Height, weight, and waist and hip girths were measured in the clinic with participants wearing light clothing and no shoes. Body mass index (BMI; kilograms per square meter) and waist circumference were used as estimates of overall and central adiposity, respectively. Systolic and diastolic blood pressures were measured twice in seated resting subjects using the Hypertension Detection and Follow-Up Program protocol (17).
Eligibility criteria for this study included 1) evaluation at the 1988–1992 clinic visit, 2) age 50 yr and older, 3) availability of stored serum, 4) postmenopausal status for women, and 5) no estrogen or insulin use at the time of the baseline visit. Of the 1727 men and women who attended the 1988–1992 clinic visit, 1538 (638 men and 900 women) had sufficient stored serum for measurement of IGF-I and IGFBP-1. Of these, 9 were excluded for age less than 50 yr, 1 for premenopausal status, 9 because of insulin use, and 337 for estrogen use. The remaining 633 men and 552 postmenopausal, nonestrogen-using women are the subject of this report. The 189 men and women without sera did not differ (P > 0.10) from those studied in terms of risk factors such as age, BMI, and blood pressure (data not shown).
Blood measures
Blood samples were obtained by venipuncture between 0800–1300 h; serum was separated and frozen at -70 C. Subjects were not required to be fasting when blood was collected, but the exact time of blood sampling and the time of last consumption of any food or drink were recorded. IGF-I and IGFBP-1 levels were measured on twice-thawed samples 8–11 yr later (between 2000 and 2001) in the Maine Center for Osteoporosis Research and Education Laboratory under the direction of Dr. Clifford J. Rosen. Serum IGF-I was determined by RIA using a commercial kit (Nichols Institute Diagnostics, San Clemente, CA) modified to optimize sensitivity and specificity; samples were diluted 1:105 (instead of 1:225) and were pretreated by acid-ethanol cryoprecipitation to remove IGFBPs. The assay sensitivity was 6.3 ng/ml; intra- and interassay coefficients of variation were 3.3% and 11.4%, respectively. IGFBP-1 levels were measured by an immunoradiometric assay kit (Diagnostics Systems Laboratories, Inc., Webster, TX) with a sensitivity of 0.33 ng/ml and intra- and interassay coefficients of variation of 3.9% and 13.5%, respectively.
A subset of 1092 participants had attended a previous follow-up clinic visit in 1984–1987 at which fasting blood samples were collected and a 75-g oral glucose tolerance test was performed. Fasting plasma cholesterol, triglyceride, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol levels were measured in a Center for Disease Control-Certified Lipid Research Clinic laboratory. Total cholesterol and triglyceride levels were measured by enzymatic techniques using an ABA-200 biochromatic analyzer (Abbott Laboratories, Irving, TX). HDL was measured after precipitation of the other lipoproteins with heparin and manganese chloride. LDL was estimated using the Friedewald formula (18). Fasting and postchallenge plasma glucose levels were measured by the glucose oxidase method; fasting and postchallenge plasma insulin levels were determined by double-antibody RIA (19). Standardized insulin assays became available in November 1984; thus, insulin levels were obtained for the last 795 adults examined.
Prevalent diseases
Prevalent CVD disease information was obtained from standard interview questionnaires administered at clinic visits in 1988–1992 and 1992–1996 and from self-administered follow-up questionnaires mailed in 1988–1989 and 1990–1991. Prevalent IHD was defined as a history of coronary artery bypass surgery, angioplasty, or myocardial infarction. Prevalent non-IHD CVD was defined as a history of angina, congestive heart failure, stroke or transient ischemic attack, carotid surgery, peripheral arterial surgery, or physician-diagnosed intermittent claudication. Individuals who responded affirmatively for a particular condition or procedure and gave a date of onset before the date of assessment of IGF-I and IGFBP-1 were considered to be prevalent for that disease.
Insulin resistance, diabetes, and impaired glucose tolerance diagnoses were based on measurements from the 1984–1987 clinic visit and, in the case of diabetes, on physician diagnosis. Insulin resistance was defined as the highest quintile of fasting insulin (equivalent to 
17 mU/liter for this cohort). Fasting insulin was highly correlated (r = 0.98; P < 0.0001) with the homeostasis model assessment for insulin resistance in this cohort (20) and is an accepted surrogate for insulin resistance (21). Definitions of type 2 diabetes and impaired glucose tolerance were based on WHO criteria (22).
Vital status
Vital status was determined annually by mailed questionnaires through July 2001, a 13-yr follow-up. Vital status was known for 96% of participants. Death certificates, obtained for 88% of decedents, were coded for the underlying cause of death by a certified nosologist using the ninth revision of the International Classification of Disease. CVD mortality included deaths assigned codes 401–414, 426–438, and 440–448. IHD deaths were those assigned codes between 410–414. Information on date of death for decedents for whom death certificates were not available (included in all cause mortality analyses only) was obtained from a family member or published obituary.
Statistical analyses
Data were analyzed using SAS (version 8.2, SAS Institute, Inc., Cary, NC) and SPSS (version 10.1, SPSS, Inc., Chicago, IL). Values for IGF-I, IGFBP-1, triglycerides, HDL cholesterol, and fasting insulin were log-transformed to decrease skewness; results are reported for geometric means. Descriptive statistics were obtained using analyses of covariance for continuous variables and 
2 tests for categorical variables. The association of IGF-I and IGFBP-1 levels with CVD risk factors was examined using Pearson correlations adjusted for sex, age, and BMI. IGF-I and IGFBP-1 levels were compared for those with and without diabetes and prevalent non-IHD CVD and IHD at baseline and by vital status at follow-up using analysis of covariance, adjusted for age, sex, and BMI. Cox proportional hazards models were used to assess the independent and combined contributions of IGF-I and IGFBP-1 levels to the risk of all cause, non-IHD CVD, and IHD mortality. Preliminary analyses established optimal functional forms for exposure variables. Accordingly, IGF-I was modeled as a continuous variable, and IGFBP-1 was dichotomized to values above and below the lowest sex-specific quintile (8 ng/ml for men, 11 ng/ml for women). Models were first adjusted for sex, age, BMI, and prevalent non-IHD CVD or IHD; subsequent models were adjusted for additional CVD risk factors, including systolic and diastolic blood pressures, waist circumference and waist to hip ratio, smoking, physical activity, and alcohol consumption. Only those variables that were independently and significantly related to mortality risk or that changed the risk estimate for either IGF-I or IGFBP-1 by at least 20% were retained in the final model. Secondary analyses using the final model separately tested whether 1) lipids, 2) insulin and glucose levels, 3) glucose tolerance status, and 4) insulin resistance altered the associations of IGF-I and IGFBP-1 with mortality. Changes in risk estimates greater than 20% were considered significant. Interactions of sex with IGF-I and IGFBP-1 levels, with prevalent disease, and with CVD risk factors were tested; none was significant. Analyses were not adjusted for multiple comparisons; 95% confidence intervals (CIs) are shown instead. All P values were based on two-tailed tests of significance, defined as P < 0.05.
Most participants were not fasting at the time blood samples were collected for IGF-I and IGFBP-1 measurements. The median interval between last dietary intake and time of venipuncture was 3 h; 78% of subjects reported eating 1–4 h before blood sampling. IGF-I levels were not related to postprandial sampling interval. Age- and BMI-adjusted IGFBP-1 levels differed significantly (P < 0.001) by the number of hours since last dietary intake in a pattern consistent with the time course of the postprandial inhibitory effect of insulin (23). Statistical analyses were conducted with and without a factor for hours since last intake; results were indistinguishable for most analyses. The strength of IGFBP-1 associations for proportional hazards regressions were marginally (<10%) stronger when adjusted for postprandial sampling interval. Adjusted results are presented.
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Results |
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Baseline characteristics of the study population are summarized in Table 1
. The 1185 men and women ranged in age from 51–98 yr, with a mean BMI of 25.3 kg/m2. IGF-I levels were similar among men and women, ranging from 4–295 ng/ml (median, 94). Levels of IGFBP-1 ranged from 1–158 ng/ml (median, 24) and were lower overall (P = 0.003) among men than women. A total of 328 individuals (28% of the population) had preexisting CVD; of these, 54% (n = 177) had IHD. Age- and sex-adjusted baseline concentrations of IGF-I did not differ for individuals with prevalent IHD (84.5 ± 2.9 ng/ml) or prevalent non-IHD CVD (89.3 ± 3.8 ng/ml) compared with those without preexisting CVD (87.9 ± 1.5 ng/ml). Adjusted IGFBP-1 levels were also similar for those with prevalent IHD (20.4 ± 1.5 ng/ml) or prevalent non-IHD CVD (21.2 ± 1.5 ng/ml) compared with those without (20.7 ± 0.6 ng/ml). Among the subset of participants for whom glucose tolerance status was available (n = 1092), a total of 156 (14.3%) had diabetes, and 222 (20.3%) had impaired glucose tolerance. Levels of IGF-I did not differ by glucose tolerance status or for those with insulin resistance (data not shown). In contrast, sex- and age-adjusted IGFBP-1 levels were lower (P < 0.005) among those with diabetes (18.7 ± 1.3 ng/ml) or IGT (18.3 ± 1.1 ng/ml) compared with those with normal glucose tolerance (22.2 ± 0.8 ng/ml; P < 0.001 for both) and were nearly 50% lower among those with insulin resistance (11.5 ± 0.8 ng/ml) compared with those without (22.3 ± 0.9 ng/ml; P < 0.001).
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IGF-I and IGFBP-1 concentrations were inversely correlated with each other (r = -0.33; P < 0.001). As shown in Table 2, IGF-I levels were lower, and IGFBP-1 levels were higher at older ages. Serum IGF-I levels were positively related to BMI, waist to hip ratio, and waist girth, whereas IGFBP-1 concentrations were inversely related to adiposity measures. IGF-I had a weak, positive association with total and LDL cholesterol. Lower IGFBP-1 levels were associated with lower concentrations of HDL cholesterol, higher triglycerides, and higher concentrations of insulin and glucose, independent of age, sex, and BMI. Age-, sex-, and BMI-adjusted IGF-I and IGFBP-1 levels did not differ by physical activity, alcohol consumption, or current cigarette smoking (data not shown).
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During the 13-yr follow-up, 44% (n = 522) of the cohort died (Table 3). Forty-nine percent (n = 224) of classifiable deaths were attributable to cardiovascular causes, and 47% of these (n = 105) were due to IHD. Age-, sex-, and BMI-adjusted baseline IGF-I levels were lower among individuals with IHD mortality at follow-up (P < 0.01; Table 3). Adjusted baseline IGFBP-1 levels were also lower among IHD decedents; however, differences were not statistically significant. Baseline IGF-I and IGFBP-1 did not differ by all cause or non-IHD CVD mortality. Sixty-five percent of individuals with prevalent CVD died during follow-up compared with 36% of those without known CVD (P < 0.001). The mean (SD) time between blood sampling and death due to any cause was 8.8 (3.8) yr and ranged from 0.1–13.1 yr. The mean times to non-IHD CVD death and IHD death were similar [5.6 (2.9) and 5.5 (3.1) yr, respectively].
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Because of the potential complexity of the biological interaction between IGF-I and IGFBP-1, we were interested in knowing whether each predicted mortality independently and whether the associations were altered when the two were considered together. As shown in Table 4, IGF-I and IGFBP-1 levels were not related to all cause and non-IHD CVD mortality, either separately or jointly, in proportional hazards models adjusted for age and other potential confounders. In contrast, low IGF-I and low IGFBP-1 individually increased the risk of fatal IHD independent of age, sex, BMI, and prevalent disease, although the IGF-I association failed to reach significance (P = 0.087). When the two were considered together, the risk estimates increased in magnitude, and the IGF-I association became statistically significant (P = 0.031). No interaction between IGF-I and IGFBP-1 was found in this (P = 0.59) or subsequent models.
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. To facilitate comparison of the magnitude of risk associated with each factor, relative risks (RRs) for continuous variables are presented for 1-SD intervals. In this multiply-adjusted model, the RR of fatal IHD was 38% higher for a 40 ng/ml decrease in IGF-I and 3-fold higher for those with IGFBP-1 levels in the lowest quintile vs. those with higher levels. Older age, prevalent IHD, male gender, and higher systolic blood pressure significantly increased the risk of IHD mortality, whereas higher BMI, higher diastolic blood pressure, and physical activity three or more times per week were protective. The effects of IGF-I and IGFBP-1 were similar in magnitude, respectively, to those of systolic blood pressure and male gender. Current cigarette smoking, alcohol consumption, and waist to hip ratio were not significantly related to IHD mortality in this multivariate analysis and were not included in the final model. Using waist circumference instead of BMI in the final model did not alter IGF-I and IGFBP-1 associations.
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Sex-specific analyses yielded similar risk estimates for men (IGF-I: RR = 1.49; IGFBP-1: RR = 2.89) and women (IGF-I: RR = 1.23; IGFBP-1: RR = 3.08). IGF-I and IGFBP-1 remained significantly related to IHD mortality when individuals with prevalent IHD were excluded (IGF-I: RR = 1.37; 95% CI, 1.03–1.82; IGFBP-1: RR = 2.30; 95% CI, 1.19–4.47). Likewise, findings remained essentially the same after excluding the 16 subjects who died within 2 yr of the blood sample collection. The associations of IGF-I and IGFBP-1 with IHD mortality were not materially changed when total cholesterol, HDL cholesterol, LDL cholesterol, or triglyceride levels were added to the model (data not shown).
In separate analyses excluding individuals with diabetes and/or impaired glucose tolerance or those with insulin resistance, IGF-I associations were essentially unchanged. The strength of the association of IGFBP-1 with IHD mortality was increased in each case, however, by less than 20% (data not shown). Likewise, adding glucose and/or insulin measures to the final model had little effect on IGF-I associations and increased the magnitude of IGFBP-1 associations, but by less than 20% (data not shown).
In analyses stratified by time to death, the associations of low IGF-I and low IGFBP-1 with increased risk of IHD mortality were stronger for deaths occurring within 5 yr (n = 50) and were absent for deaths occurring more than 5 yr (n = 55) after baseline (data not shown). Lower IGFBP-1 (but not IGF-I) was also associated with increased risk of all cause (RR = 1.64; 95% CI, 1.07–2.53) and CVD (RR = 2.31; 95% CI, 1.30–4.11) mortality in analyses restricted to the first 5 yr of mortality; however, removal of deaths due to IHD from each category eliminated these associations.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This study adds to a growing body of evidence linking the IGF system to cardiovascular risk. Patients with hypopituitarism have premature atherosclerosis (24), high cardiovascular morbidity (25), and premature cardiovascular death (26); this is hypothesized to be due to GH/IGF-I deficiency (27). Low IGF-I levels have also been observed in adults with manifest IHD. IGF-I levels were low in relatively young (age, 35–65 yr) men with angiographically documented IHD (28) and in both younger (14) and older (13, 14) survivors of myocardial infarction. Among 218 apparently healthy, 50- to 80-yr-old men and women from the Rotterdam study (7), low serum free IGF-I, but not total IGF-I, was associated with an increased presence of atherosclerotic plaques and other signs and symptoms of coronary artery disease. Free IGF-I levels were not measured in the Rancho Bernardo cohort, and total IGF-I levels did not differentiate individuals with and without a history of IHD in the present study. Other investigators (5, 29, 30) have also failed to identify low IGF-I levels in IHD patients. These discrepancies may be due to the cross-sectional nature of these analyses or to differences in the timing and severity of disease.
Only one prospective study has examined the role of the IGF system in the development of IHD. In a population-based, nested, case-control study, Juul and colleagues (12) found that individuals without IHD, but with low serum IGF-I, had twice the risk of developing IHD during a 15-yr follow-up. Those with both low IGF-I and high IGFBP-3 (which would further decrease the bioavailability of IGF-I) were at an even greater risk of IHD. A recent genetic study has identified a polymorphism in the promoter region of the IGF-I gene associated with low circulating IGF-I levels and increased risk of myocardial infarction in noncarriers, particularly among those with type 2 diabetes (31). Thus, low circulating IGF-I seems to play a role in atherosclerotic processes leading to IHD.
In the present study low IGFBP-1 independently increased the risk of IHD mortality. The RR was 2.7 times greater among those with IGFBP-1 levels in the lowest 20% (<8 ng/ml for men, <11 ng/ml for women) after adjusting for CVD risk factors, and increased to 3.1 when adjusted for IGF-I. Low IGFBP-1 levels have been consistently associated with an adverse cardiovascular risk profile, including higher BMI, greater central adiposity, lower HDL cholesterol levels, and higher triglycerides, in this and other populations (5, 6, 7, 8, 32). In addition, IGFBP-1 is inversely related to fasting and postchallenge insulin and glucose levels and insulin resistance in this study and in both diabetic (32, 33) and nondiabetic populations (5, 34), consistent with the suppressive effect of insulin on hepatic IGFBP-1 production (3). The present study shows that low IGFBP-1 is an independent risk factor for IHD mortality in a predominantly nondiabetic population (only 14% of participants were diabetic at baseline), both before and after adjustment for lipids and insulin and glucose measures and after excluding those with insulin resistance, diabetes, or impaired glucose tolerance.
Our results are in contrast with those of the only other study to examine the relation of components of the IGF system and mortality in an older population. In a Finnish population of 622 men, aged 65–84 yr, high serum IGFBP-1 levels were independently related to increased 5- and 10-yr IHD mortality and predicted 5-yr all cause and CVD mortality (16). The researchers stated that no associations were seen for IGF-I or IGFBP-3 with any category of mortality, although data were not presented. In the present study IGFBP-1 was associated with 5-yr all cause, CVD, and IHD mortality with RRs similar in magnitude to those reported by the Finnish study. In the Rancho Bernardo Study, however, low, not high, IGFBP-1 predicted mortality, and removal of IHD deaths eliminated the associations with 5-yr all cause and CVD mortality.
The 622 men in the Finnish study (16) were of similar age and body size as the 633 men in the present report. The number of deaths overall during the 10-yr follow-up were similar in the 2 cohorts, as was the proportion due to CVD. More CVD deaths were due to IHD in the Finnish study than the Rancho Bernardo Study (71% vs. 51%), possibly because twice as many men were current smokers and twice as many had diabetes. The reason for the discrepant results in the 2 studies is not evident. Interestingly, high IGFBP-1 was associated with protective differences in a number of cardiovascular disease risk factors in the Finnish men, including reduced levels of adiposity, LDL cholesterol, and triglycerides, in agreement with our results and compatible with our finding that low IGFBP-1 increases IHD risk.
IGF-I has endocrine, paracrine, and autocrine actions. Measurement of the circulating fraction yields information about the endocrine activity of IGF-I, but may not reflect paracrine and autocrine activities that might be important in the pathogenesis of atherosclerosis. Nonetheless, this and several other studies cited above have found significant associations of serum IGF-I levels with IHD risk, IHD morbidity, and, now, IHD mortality. Although the majority of early animal and cell culture studies suggested that IGF-I promotes atherosclerotic processes (see review in Ref. 35), cardioprotective effects have now been identified. IGF-I stimulates nitric oxide production from both the endothelium and VSMC, and increases forearm blood flow (see review in Ref. 1). Low tissue IGF-I levels and reduced IGF-I receptor expression have been identified in early and advanced atherosclerotic lesions and have been speculated to contribute to processes leading to plaque weakening, plaque rupture, and acute coronary events (36). The beneficial effects of IGF-I on cardiomyocyte function and survival (reviewed in Ref. 37) may also contribute to an increased risk of fatal ischemic events among those with lower IGF-I levels.
The molecular basis for a cardioprotective effect of IGFBP-1 is unclear. In vitro, IGFBP-1 has both inhibitory and stimulatory effects on the metabolic and mitogenic activities of IGF-I. Because of its small size, IGFBP-1 is not restricted to the circulation and can function as a transport protein that shuttles IGF-I from the intravascular space through the endothelial walls of the capillaries. As proposed by Jannsen and Lamberts (2), IGFBP-1 in the circulation may inhibit IGF-I-mediated remodeling of the vasculature, whereas in other tissues IGFBP-1 may facilitate IGF-I delivery to cell surface receptors. Adding to the complexity is the ability of IGFBP-1 to associate with specific cell surface integrins and increase cellular migration independent of IGF-I (38). Low IGFBP-1 may act via any or all of these mechanisms, or as proposed by Jannsen and colleagues (2), it may simply be an independent marker of metabolic disturbances related to increased IHD risk.
The prospective design, relatively large sample size, and inclusion of both sexes are major strengths of this study. The fact that associations are based on only one measurement of IGF-I and IGFBP-1 and that most subjects were not fasting at the time of the sample collection may have introduced misclassification bias. However, a single nonfasting IGF-I and IGFBP-1 measurement has been shown to effectively characterize individual levels over at least 1 yr (39). In addition, expected associations of IGFBP-1 with CVD risk factors were observed in this study. Finally, misclassification bias would be more likely to diminish than to cause associations, as demonstrated by the slight increase in the strength of risk estimates for IGFBP-1 when analyses were adjusted for nonfasting status. Thus, misclassification of the exposure is unlikely to account for these results.
In conclusion, this prospective study of older, community-dwelling men and postmenopausal women is the first to show that low circulating IGF-I and IGFBP-1 levels are associated with increased risk of IHD mortality during the following 9–13 yr. These findings suggest that the IGF-I/IGFBP-1 system is involved in the development and progression of fatal coronary atherosclerotic disease in elderly men and women. Measurement of circulating IGF-I and IGFBP-1 levels may prove to be a useful marker to identify adults who are at increased risk of fatal IHD and who might benefit from risk-reducing interventions.
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Acknowledgments |
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Footnotes |
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Abbreviations: BMI, Body mass index; CI, confidence interval; CVD, cardiovascular disease; HDL, high-density lipoprotein; IGFBP, IGF-binding protein; IHD, ischemic heart disease; LDL, low-density lipoprotein; RR, relative risk; VSMC, vascular smooth muscle cell.
Received June 4, 2003.
Accepted September 15, 2003.
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References |
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5ß1 integrin by means of its Arg-Gly-Asp sequence. Proc Natl Acad Sci USA 90:10553–10557This article has been cited by other articles:
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J. L. M. Oliveira, M. H. Aguiar-Oliveira, A. D'Oliveira Jr, R. M. C. Pereira, C. R. P. Oliveira, C. T. Farias, J. A. Barreto-Filho, F. D. Anjos-Andrade, C. Marques-Santos, A. C. Nascimento-Junior, et al. Congenital Growth Hormone (GH) Deficiency and Atherosclerosis: Effects of GH Replacement in GH-Naive Adults J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4664 - 4670. [Abstract] [Full Text] [PDF]
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 M. Maggio, F. Lauretani, G. P. Ceda, S. Bandinelli, S. M. Ling, E. J. Metter, A. Artoni, L. Carassale, A. Cazzato, G. Ceresini, et al. Relationship Between Low Levels of Anabolic Hormones and 6-Year Mortality in Older Men: The Aging in the Chianti Area (InCHIANTI) Study Arch Intern Med, November 12, 2007; 167(20): 2249 - 2254. [Abstract] [Full Text] [PDF]
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 M. A. Marini, E. Succurro, S. Frontoni, M. L. Hribal, F. Andreozzi, R. Lauro, F. Perticone, and G. Sesti Metabolically Healthy but Obese Women Have an Intermediate Cardiovascular Risk Profile Between Healthy Nonobese Women and Obese Insulin-Resistant Women Diabetes Care, August 1, 2007; 30(8): 2145 - 2147. [Full Text] [PDF]
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R. C. Kaplan, A. P. McGinn, M. N. Pollak, L. H. Kuller, H. D. Strickler, T. E. Rohan, A. R. Cappola, X. Xue, and B. M. Psaty Association of Total Insulin-Like Growth Factor-I, Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1), and IGFBP-3 Levels with Incident Coronary Events and Ischemic Stroke J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1319 - 1325. [Abstract] [Full Text] [PDF]
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 T. Thum, S. Hoeber, S. Froese, I. Klink, D. O. Stichtenoth, P. Galuppo, M. Jakob, D. Tsikas, S. D. Anker, P. A. Poole-Wilson, et al. Age-Dependent Impairment of Endothelial Progenitor Cells Is Corrected by Growth Hormone Mediated Increase of Insulin-Like Growth Factor-1 Circ. Res., February 16, 2007; 100(3): 434 - 443. [Abstract] [Full Text] [PDF]
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 C. D. Tran, C. Diorio, S. Berube, M. Pollak, and J. Brisson Relation of insulin-like growth factor (IGF) I and IGF-binding protein 3 concentrations with intakes of fruit, vegetables, and antioxidants Am. J. Clinical Nutrition, December 1, 2006; 84(6): 1518 - 1526. [Abstract] [Full Text] [PDF]
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M. Yazdanpanah, F. A Sayed-Tabatabaei, J. A M J L Janssen, I. Rietveld, A. Hofman, T. Stijnen, H. A P Pols, S. W J Lamberts, J. C M Witteman, and C. M van Duijn IGF-I gene promoter polymorphism is a predictor of survival after myocardial infarction in patients with type 2 diabetes. Eur. J. Endocrinol., November 1, 2006; 155(5): 751 - 756. [Abstract] [Full Text] [PDF]
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 E. A. Jankowska, B. Biel, J. Majda, A. Szklarska, M. Lopuszanska, M. Medras, S. D. Anker, W. Banasiak, P. A. Poole-Wilson, and P. Ponikowski Anabolic Deficiency in Men With Chronic Heart Failure: Prevalence and Detrimental Impact on Survival Circulation, October 24, 2006; 114(17): 1829 - 1837. [Abstract] [Full Text] [PDF]
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M. Bondanelli, M. R. Ambrosio, A. Onofri, A. Bergonzoni, S. Lavezzi, M. C. Zatelli, D. Valle, N. Basaglia, and E. C. degli Uberti Predictive Value of Circulating Insulin-Like Growth Factor I Levels in Ischemic Stroke Outcome J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3928 - 3934. [Abstract] [Full Text] [PDF]
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R. M. Martin, J. M. P. Holly, G. Davey Smith, and D. Gunnell Associations of Adiposity from Childhood into Adulthood with Insulin Resistance and the Insulin-Like Growth Factor System: 65-Year Follow-Up of the Boyd Orr Cohort J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3287 - 3295. [Abstract] [Full Text] [PDF]
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J. L. Menezes Oliveira, C. Marques-Santos, J. A. Barreto-Filho, R. Ximenes Filho, A. V. de Oliveira Britto, A. H. Oliveira Souza, C. M. Prado, C. R. Pereira Oliveira, R. M. C. Pereira, T. de Almeida Ribeiro Vicente, et al. Lack of Evidence of Premature Atherosclerosis in Untreated Severe Isolated Growth Hormone (GH) Deficiency due to a GH-Releasing Hormone Receptor Mutation J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2093 - 2099. [Abstract] [Full Text] [PDF]
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H. J. Schneider, B. Saller, J. Klotsche, W. Marz, W. Erwa, H.-U. Wittchen, and G. K. Stalla Opposite associations of age-dependent insulin-like growth factor-I standard deviation scores with nutritional state in normal weight and obese subjects. Eur. J. Endocrinol., May 1, 2006; 154(5): 699 - 706. [Abstract] [Full Text] [PDF]
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 G. Efstratiadis, G. Tsiaousis, V. G. Athyros, D. Karagianni, A. Pavlitou-Tsiontsi, A. Giannakou-Darda, and C. Manes Total Serum Insulin-like Growth Factor-1 and C-Reactive Protein in Metabolic Syndrome With or Without Diabetes Angiology, May 1, 2006; 57(3): 303 - 311. [Abstract] [PDF]
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B. E. Engstrom, P. Burman, C. Holdstock, M. Ohrvall, M. Sundbom, and F A. Karlsson Effects of gastric bypass on the GH/IGF-I axis in severe obesity - and a comparison with GH deficiency Eur. J. Endocrinol., January 1, 2006; 154(1): 53 - 59. [Abstract] [Full Text] [PDF]
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 G. D. Batty, M. J. Shipley, C. Langenberg, M. G. Marmot, and G. Davey Smith Adult height in relation to mortality from 14 cancer sites in men in London (UK): evidence from the original Whitehall study Ann. Onc., January 1, 2006; 17(1): 157 - 166. [Abstract] [Full Text] [PDF]
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S. P. Johnsen, H. H. Hundborg, H. T. Sorensen, H. Orskov, A. Tjonneland, K. Overvad, and J. O. L. Jorgensen Insulin-Like Growth Factor (IGF) I, -II, and IGF Binding Protein-3 and Risk of Ischemic Stroke J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 5937 - 5941. [Abstract] [Full Text] [PDF]
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S. C Larsson, K. Wolk, K. Brismar, and A. Wolk Association of diet with serum insulin-like growth factor I in middle-aged and elderly men Am. J. Clinical Nutrition, May 1, 2005; 81(5): 1163 - 1167. [Abstract] [Full Text] [PDF]
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A. Colao, C. Di Somma, F. Rota, R. Pivonello, M. C. Savanelli, S. Spiezia, and G. Lombardi Short-Term Effects of Growth Hormone (GH) Treatment or Deprivation on Cardiovascular Risk Parameters and Intima-Media Thickness at Carotid Arteries in Patients with Severe GH Deficiency J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2056 - 2062. [Abstract] [Full Text] [PDF]
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T. Kalme, M. Seppala, Q. Qiao, R. Koistinen, A. Nissinen, M. Harrela, M. Loukovaara, P. Leinonen, and J. Tuomilehto Sex Hormone-Binding Globulin and Insulin-Like Growth Factor-Binding Protein-1 as Indicators of Metabolic Syndrome, Cardiovascular Risk, and Mortality in Elderly Men J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1550 - 1556. [Abstract] [Full Text] [PDF]
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E. Conti, C. Carrozza, E. Capoluongo, M. Volpe, F. Crea, C. Zuppi, and F. Andreotti Insulin-Like Growth Factor-1 as a Vascular Protective Factor Circulation, October 12, 2004; 110(15): 2260 - 2265. [Full Text] [PDF]
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