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Objective: IGFs and their binding proteins (IGFBPs) are produced both systemically and locally by cells of the cardiovascular system. As growth promoters, they may play a role in atherosclerosis., Design: Case-control, cross-sectional., Patients: A total of 95 nondiabetic male patients with coronary heart disease (CHD) and 92 probands from the Prospective Cardiovascular Munster (PROCAM) who were below the age of 60 years and matched by age, body mass index (BMI) and smoking habits., Measurements: We analysed the strength and independence of associations of angiographically assessed presence of CHD with BMI, systolic and diastolic blood pressure, total, high-density lipoprotein (HDL) and LDL cholesterol, triglycerides, lipoprotein(a), apolipoproteins A-I and B, total and free IGF-I, IGF-II, IGFBP-1, IGFBP-3, IGFBP-5, acid-labile subunit (ALS), insulin, C-peptide, testosterone, DHEAS and sex hormone binding globulin., Results: Using multivariate statistical analysis, the presence of CHD had significant positive associations with total IGF-I, IGFBP-5, ALS and IGFBP-3. These associations were independent of each other as well as of traditional risk factors, insulin and sex hormones., Conclusion: These observations may indicate a pathogenetic role of the GH/IGF axis in coronary atherosclerosis.

Objective While low high-density lipoprotein cholesterol ( HDL- C) is associated with increased risk of cardiovascular ( CV) events, there are limited data evaluating the association of longitudinal change in HDL- C with CV event risk in older populations. The aim of this study was to examine the association between within-subject changes in HDL- C levels and CV events in an older population. Design Observational cohort study. Patients 1293 men and 1422 women age ≥50 years, with ≥2 consecutive HDL measurements, and no prior CVD as part of Framingham Offspring Study. Measurements A clinical CV event was defined as the first occurrence of any of the following: coronary heart disease (coronary death, myocardial infarction, coronary insufficiency and angina), cerebrovascular event, peripheral artery disease or heart failure. Results Median total follow-up time across subjects was 9·6 years. Change in HDL- C was evaluated as between-exam (approximately 3·5 years) percentage change in HDL- C, categorized as ≥10% decrease, <10% change (stable) and ≥10% increase. Crude and adjusted sex-specific Cox hazards regression models with change in HDL- C as a time-dependent covariate quantified the association with CV events. Mean baseline age of the analysis sample was 53 years. There were 233 and 111 CV events among men and women, respectively. Change in HDL- C was not significantly associated with CVD incidence in men or women, without or with adjustment for confounders including baseline HDL- C or use of relevant medications. Conclusion In conclusion, relatively short-term (3·5 years) changes in HDL- C levels do not affect CV events in men and women. [ABSTRACT FROM AUTHOR]

Summary Objective There is growing evidence for an increased cardiovascular (CV) risk in untreated growth hormone deficiency of adults (GHD). We aimed at estimating CV risk with established algorithms before and during GH replacement in GHD and in healthy controls and at identifying predictors of risk reduction. Design A prospective, nested case-control study. Patients We included 344 patients (44·7 ± 14·9 years) from the German Pfizer (formerly Kabi) International Metabolic Database (KIMS) cohort and included a healthy sex- and age-matched control group from a primary care cohort. Measurements We calculated Framingham, Prospective Cardiovascular Münster Heart Study (PROCAM) and European Society of Cardiology (ESC) Score algorithms at all time points. In multivariate analyses, we analysed potential predictors of 2-year reduction in CV risk, defined as a higher than median reduction in risk. Results In KIMS, the estimated 10-year risks of CV events or CV mortality calculated with Framingham, PROCAM and ESC Score algorithms at baseline were 4·6%, 6·0% and 2·3%, respectively. These dropped to 2·4%, 4·8% and 0·8%, respectively, after 2 years of GH replacement (all P < 0·001 vs baseline) and returned to baseline levels after four years of GH replacement. In controls, the Framingham risk estimates were lower than in KIMS at baseline. All risk estimates increased during follow-up and were significantly higher than in KIMS after four years (all P < 0·01). In backward-selection models, high total cholesterol, low high-density lipoprotein (HDL) cholesterol and male sex were significant predictors of response in most scores. Conclusion Two years of GH replacement decreased CV risk estimates approximately by half. Male sex, high total and low HDL cholesterol levels are potential predictors of good response. [ABSTRACT FROM AUTHOR]

Objective Endogenous hyperthyroidism is associated with altered coagulation. The aim of the present study is to investigate the effect of levothyroxine (LT4) suppression treatment for benign thyroid nodules on coagulation system. Design Prospective case-control study. Patients Thirty consecutive euthyroid pre-menopausal women with nodular goitre disease and 28 healthy controls were included in the study. Measurements Plasma fibrinogen, d-dimer, von Willebrand factor (vWF), tissue factor (TF), tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1) and tissue factor pathway inhibitor (TFPI) levels were measured at baseline and after LT4 suppression therapy. Results Plasma levels of fibrinogen, d-dimer, vWF, TF and PAI-1 increased significantly after treatment with LT4 for 1 year. Serum FT4 was a significant predictor of increased fibrinogen, vWF and PAI-1 levels, when the data was controlled for age and BMI. Conclusions Our results suggest that LT4 suppression therapy for benign thyroid nodules is associated with enhanced coagulation. [ABSTRACT FROM AUTHOR]

Introduction The postprandial lipid metabolism in metabolic syndrome patients is disturbed and may add to the increased cardiovascular risk in these patients. It is not known whether postprandial high density lipoprotein-cholesterol (HDL-c) metabolism is also affected and whether this can be influenced by statin and/or ezetimibe treatment. Methods Prospective, randomized, double blind, crossover trial comparing simvastatin 80 mg with simvastatin/ezetimibe 10 mg/10 mg treatment for 6 weeks on postprandial HDL-c metabolism in 15, nonsmoking, male, obese metabolic syndrome patients (Adult Treatment Panel III, ATPIII). Only study medication was allowed. HDL-c concentrations, cholesteryl ester transfer (CET), CET protein (CETP) mass and adiponectin were measured before and after oral fat loading. ClinicalTrials.gov NCT00189085. Results Plasma HDL-c levels remained stable during continuous fasting following an overnight fast. Pre-fat load HDL-c concentrations without treatment, after simvastatin and simvastatin/ezetimibe treatment were 1·15 ± 0·04, 1·16 ± 0·05 and 1·11 ± 0·04 mmol/l. Fat load induced a 11% drop in HDL-c plasma levels; 1·02 ± 0·05 mmol/l ( P < 0·001) which was not affected by either therapy. Triglyceride levels during fat load were similar after both treatments. Total CET increased from 9·73 ± 0·70 to 12·20 ± 0·67 nmol/ml/h ( P = 0·004). Four hours after fat loading CETP mass was increased while adiponectin levels were decreased, irrespective of treatment. Discussion HDL-c levels decrease as CET increases after fat loading in obese metabolic syndrome patients. This is not influenced by either simvastatin or simvastatin/ezetimibe treatment. After fat loading, CETP mass and CET increased, and adiponectin decreased pointing towards a potential role for intra-abdominal fat. Decreased postprandial HDL-c levels may contribute to the increased cardiovascular risk in metabolic syndrome patients on top of already low HDL-c levels. [ABSTRACT FROM AUTHOR]

Objectives IGF-1 and its binding proteins are involved in the pathogenesis of atherosclerosis. We designed this study to unravel the relationship of the IGF system with peripheral arterial disease (PAD). Design Case-control, cross-sectional study. Measurements Serum levels of IGF-1, IGFBP-3 and acid labile subunit (ALS) were measured in 96 PAD patients and 89 controls. In 28 patients who underwent peripheral angiography, C-reactive protein (CRP), IGF-1, IGFBP-3 and ALS were measured in blood from femoral vein of the affected limb and aorta. Results Compared to controls, PAD patients showed lower levels of IGFBP-3 (3569 ± 115 vs. 3106 ± 107 µg/l, P < 0·01), and ALS (12·2 ± 0·5 vs. 8·3 ± 0·5 mg/l, P < 0·01). In PAD, concentrations of IGFBP-3 and ALS were significantly lower in patients with ankle/brachial index less than median than in those with a less severe PAD. In the affected limb, CRP venous-arterial difference correlated negatively with that of IGF-1 (ρ = −0·57, P < 0·01), and positively with that of IGFBP-3 (ρ = 0·63, P < 0·01). At multivariate analysis, a high transfemoral gradient of CRP was independently associated with a low transfemoral gradient of IGF-1 (β coefficient = −0·48, P < 0·01), and a high transfemoral gradient of IGFBP-3 (β coefficient = 0·22, P < 0·05). Conclusions This study is the first to demonstrate that the systemic levels of IGF axis components are associated with the presence and severity of PAD, and that the inflammatory status of the ischaemic limb affects the transfemoral concentrations of IGF-1 and IGFBP-3. Due to the importance of IGF axis in modulating atherosclerotic plaque progression, our data may contribute to a better understanding of PAD pathophysiology. [ABSTRACT FROM AUTHOR]

Objective To determine the potential role of glycohaemoglobin as a possible determinant of increased fibrinogen concentrations and low-grade inflammation in a group of apparently healthy, nondiabetic individuals not expressing clinically overt atherothrombosis. Design and Main Outcome Measures We performed a cross-sectional analysis of the concentrations of glycohaemoglobin alongside the concentrations of quantitative fibrinogen and high-sensitivity C-reactive protein (hs-CRP). In all, 1511 males and 757 apparently healthy females, without diabetes mellitus or clinically evident atherothrombotic disease, were enrolled in the study during their routine annual health check-up. Results Glycohaemoglobin entered the linear regression models as a significant determinant of quantitative fibrinogen in both genders and of hs-CRP in men. We found this to be true even following the inclusion of multiple variables known to influence the intensity of low-grade inflammation, such as age, gender, waist circumference, body mass index, blood pressure, medications, hormone therapy, glucose levels (normal or impaired fasting glucose), smoking habits, family history of coronary artery disease, lipid profile as well as alcohol consumption and sports intensity. We found glycohaemoglobin to be a significant determinant of fibrinogen concentrations in apparently healthy nondiabetic individuals not yet presenting with evident atherothrombosis. Conclusions This observation supports the idea that glycohaemoglobin might have an effect on fibrinogen concentrations in both genders and on hs-CRP in men. Moreover, our results suggest that glycohaemoglobin should be perceived as a continuous variable without a ‘normal’ cut-off point, as it may exhibit a detrimental role even when present in relatively low levels. [ABSTRACT FROM AUTHOR]

Objectives IGF-I, IGFBP-1 and IGFBP-3 are putative mediators in cardiovascular disease. The present study examined (i) the correlations of circulating IGF-I, IGFBP-1 and IGFBP-3 to established cardiovascular risk factors and signs of early atherosclerosis as reflected by ultrasound measurement of common carotid intima–media thickness (IMT), and (ii) whether serum concentrations of these analytes are modulated during alimentary lipaemia. Design Cross-sectional clinical study. Patients A biobank and clinical database based on 96 healthy Caucasian men, aged 50 years, with an apolipoprotein (apo) E3/E3 genotype, who had originally undergone investigations of postprandial lipoprotein metabolism was used for the study. Measurements Total IGF-I, IGFBP-1 and IGFBP-3 were determined in serum by radioimmunoassay (RIA). Free IGF-I was measured by a commercial two-site immunoradiometric assay (IRMA). Results In multivariate analyses, fasting serum free IGF-I correlated inversely with IMT and accounted for 5% of the variation in multiple R2. When fasting serum IGFBP-1 was entered in the models instead of IGF-I, IGFBP-1 correlated positively with IMT and accounted for 6% of the variation in IMT. IGFBP-3 and total IGF-I were unrelated to IMT. There were no associations between free IGF-I and cardiovascular risk factors, whereas IGFBP-1 behaved like a component of the insulin resistance syndrome. Serum free IGF-I increased and IGFBP-1 decreased postprandially. Conclusion The data indicate that serum free IGF-I and IGFBP-1 are implicated in early atherosclerosis. [ABSTRACT FROM AUTHOR]

Objective Sex steroids may contribute to the increased prevalence of heart disease (HD) in men compared to age-matched women. Androgens bind their cognate receptor, and androgen action is inversely proportional to the number of CAG repeats in exon 1 of the androgen receptor gene. Longer, less androgenic CAG repeats have been associated with higher high-density lipoprotein (HDL) levels, which might protect against HD. Therefore, we hypothesized that CAG repeat length contributes to HD risk in men. Design Longitudinal, population-based cohort study. Population One thousand thirty-four participants from the Massachusetts Male Ageing Study, a cohort of 1709 men from the Boston area, aged 40-70, observed at three time points over 15 years. Methods Poisson regression. Measurements Heart disease was determined by self-report, medical records or from the National Death Index. Lipids and hormones were measured from blood samples drawn at each time point. CAG repeat length was assessed from DNA collected at the second time point. Results We found no increased risk of HD associated with CAG repeat length in our analyses. Moreover, CAG repeat length was not related to body mass index, HDL, low-density lipoprotein or waist to hip ratio in this cohort; nor did CAG repeat length predict changes in these variables over 15 years of follow-up. Conclusions In contrast to previous smaller, cross-sectional analyses, in this large cohort of community-dwelling men followed over 15 years, CAG repeat length was not related to the incidence or prevalence of HD or alterations in HDL. If androgens impact HD risk, this effect is unlikely to be mediated via CAG repeat length. [ABSTRACT FROM AUTHOR]

All endocrinologists would like to make glucocorticoid replacement therapy for their hypoadrenal patients as physiological as possible. Many would like the reassurance of a method of monitoring such treatment to confirm that they are achieving this aim. Advances in our knowledge of the normal physiology are relevant to our attempts to do this. The cortisol production rate in normal subjects is lower than was previously believed. The normal pattern of glucocorticoid secretion includes both a diurnal rhythm and a pulsatile ultradian rhythm. Glucocorticoid access to nuclear receptors is ‘gated’ by the 11-β-hydroxysteroid dehydrogenase enzymes, which interconvert active cortisol and inactive cortisone. Such complexities make the target of physiological glucocorticoid replacement therapy hard to achieve. The available evidence suggests that conventional treatment of hypoadrenal patients may result in adverse effects on some surrogate markers of disease risk, such as a lower bone mineral density than age-sex matched controls, and increases in postprandial glucose and insulin concentrations. Although the quality of life of hypoadrenal patients may be impaired, there is no evidence of an improvement on higher doses of steroids, although quality of life is better if the hydrocortisone dose is split up, with the highest dose taken in the morning. Thus the evidence suggests that most patients may safely be treated with a low dose of glucocorticoid (e.g. 15 mg hydrocortisone daily) in two or three divided doses, with education about the appropriate action to take in the event of intercurrent illnesses. [ABSTRACT FROM AUTHOR]

Although androgen replacement has been shown to have beneficial effects in hypogonadal men, there is concern that androgens may deleteriously affect cardiovascular risk in elderly men.Anastrozole is an oral aromatase inhibitor that normalizes serum testosterone levels and decreases oestradiol levels modestly in elderly men with mild hypogonadism. Thirty-seven elderly hypogonadal men were randomized to receive either anastrozole 1 mg daily (n = 12), anastrozole 1 mg twice weekly (n = 11), or daily placebo (n = 14) for 12 weeks in a double-blind fashion.Men aged 62–74 years with mild hypogonadism defined by testosterone levels less than 350 ng/dl.Serum levels of fasting lipids, C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and homeostatic model assessment (HOMA) scores were measured at 4-week intervals.Treatment with anastrozole did not significantly affect fasting lipids, inflammatory markers (IL-6, CRP), adhesion molecules (ICAM-1, VCAM-1) or insulin sensitivity (HOMA). There was, however, a positive correlation between changes in serum triglycerides and changes in serum oestradiol levels (P = 0·04).While short-term administration of anastrozole is an effective method of normalizing serum testosterone levels in elderly men with mild hypogonadism, it does not appear to adversely affect lipid profiles, inflammatory markers of cardiovascular risk or insulin resistance. [ABSTRACT FROM AUTHOR]

Presents the index for the December 2004 issue of the journal "Clinical Endocrinology."

Summary objective Androgens and other drugs that reduce plasma concentrations of high density lipoprotein (HDL) cholesterol are often considered to be pro-atherogenic. Tibolone lowers HDL-cholesterol by 20% but the clinical significance of this effect is unknown. methods In a randomized, double-blind study, 34 women received 2·5 mg tibolone daily and 34 women received placebo. Serum concentrations of lipids, lipoprotein subclasses and apolipoproteins, together with plasma activities of lipid transfer proteins and lipolytic enzymes and the capacity of plasma to induce cholesterol efflux from cultured cells, were measured. results Compared to placebo, tibolone reduced serum concentrations of HDL-cholesterol (-14%), HDL phosphatidylcholine (-14%), apolipoprotein (apo)A-I (-12%), HDL subclasses lipoprotein (Lp)A-I (-20%), HDL-apoE (-16%), preβ-LpA-I (-10%) and α-LpA-I (-12%) and increased hepatic lipase activity (+25%) and HDL sphingomyelin : phosphatidylcholine ratio (10·5%), but did not alter serum concentrations of HDL sphingomyelin, apoA-IV and LpA-I/A-II, lipoprotein lipase, the plasma activities of lecithin : cholesterol acyl transferase, cholesteryl ester transfer protein, phospholipid transfer protein or the plasma capacity to release cholesterol from cultured fibroblasts or Fu5AH hepatocytes. conclusions Tibolone lowers HDL-cholesterol in part by increasing hepatic lipase activity. Conservation of sphingomyelin and apoA-II in HDL, as well as cholesteryl ester transfer protein activity, preserves the capacity of plasma to release cholesterol, despite the lower concentrations of HDL-cholesterol. This may have important implications for the use of steroid effects on HDL concentrations as surrogates for atherosclerosis. [ABSTRACT FROM AUTHOR]

Summary objective Active acromegaly is associated with altered lipid metabolism. The purpose of this study was to investigate the effect of serum IGF-I normalization on serum lipoproteins and insulin, in patients with acromegaly receiving the GH receptor antagonist pegvisomant. patients Twenty patients (9 male, mean age 58·7 years, range 28–79) with active acromegaly (baseline serum IGF-I > 130% the age-related upper limit of normal) received pegvisomant and achieved a normal serum IGF-I [585·2 ± 54·3 (mean ± SEM) to 169·2 ± 13·9 ng/ml, P < 0·0001]. measurements Total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, triglyceride (TG), apolipoprotein B (apo B), apolipoprotein A1 (apo A1), lipoprotein a [Lp(a)] and insulin were measured in a single batch analysis on samples obtained at baseline and the first occasion of serum IGF-I normalization. Low-density lipoprotein (LDL) was calculated using the Friedewald formula. Paired analysis was performed using Student’s paired t -test and the Wilcoxon signed rank test. results Normalization of serum IGF-I resulted in an increase in TC (5·0 ± 0·3 to 5·7 ± 0·4 mmol/l, P = 0·0068), an increase in LDL (3·0 ± 0·25 to 3·7 ± 0·31 mmol/l, P = 0·0093) and an increase in apo B (110·6 ± 7·76 to 127·1 ± 8·86 mg/l, P = 0·0014). TC and LDL increased in all but four patients. Despite a significant fall in fasting insulin levels (9·9 to 8·3 mU/l, range 8·85–19·8 to 6·33–11·6, P < 0·001) and insulin resistance (2·7 to 1·9, range 1·2–10·4 to 1–6·2, P < 0·001), mean serum TG and HDL levels were unaffected by IGF-I normalization. The protein component of HDL, apo A1, increased (153 ± 4 to 166·4 ± 5·43 mg/l, P = 0·026) and Lp(a) declined (median 342... [ABSTRACT FROM AUTHOR]

BACKGROUND Hypopituitarism in adults is associated with increased vascular mortality, which has been attributed to GH deficiency. OBJECTIVE To compare the lipid profile and coronary risk predicted by the Framingham Heart Study equation in GH-deficient hypopituitary patients and healthy age and gender-matched controls. DESIGN A cross-sectional observational study. METHODS We studied 50 adult-onset growth hormone deficient hypopituitary patients (23F, 27M), on appropriate conventional hormone replacement and 45 controls (22F, 23M) matched for age, gender and smoking habit. The subjects (age range 30–75 years) were free from diabetes, hypertension, ischaemic heart disease (IHD) and peripheral vascular disease. All hypogonadal male patients were on testosterone replacement therapy. A similar proportion of female patients (8/23) and controls (7/22) were on HRT. Body mass index (BMI), waist–hip ratio (WHR) and blood pressure were recorded. After an overnight fast blood glucose, total-cholesterol, triglycerides, HDL-cholesterol, apolipoproteins A-I, B and Lp (a) were measured. Coronary risk was calculated for each individual from age, gender, systolic blood pressure, total and HDL cholesterol, smoking habit and presence of diabetes and left ventricular hypertrophy using the Framingham equation. RESULTS BMI and WHR were significantly increased in GHD hypopituitary adults of both sexes, but to a greater extent in females. Triglycerides were elevated in both sexes. Total and LDL-cholesterol were increased in both sexes (significantly only in males), and HDL cholesterol and apo A-I were lower (significantly only in females). The reduction in HDL cholesterol was correlated negatively with adiposity (BMI), particularly when centrally distributed (WHR) in patients and controls. LDL cholesterol did not correlate to adiposity but higher levels were present in GH-deficient subjects. The total to HDL cholesterol ratio was significantly increased in patients of both... [ABSTRACT FROM AUTHOR]

OBJECTIVE Long-term experience of growth hormone (GH) replacement therapy in a large population of hypopituitary adults with GH deficiency (GHD) is limited, and safety surveillance is clearly essential. KIMS, the Pharmacia & Upjohn International Metabolic Database, is a long-term, open, outcomes research programme of hypopituitary adult patients with GHD who are treated in a conventional clinical setting. PATIENTS The present analysis encompasses data from 1034 hypopituitary adult GHD patients treated with GH for a total of 818 patient years. RESULTS Prior to GH therapy, the KIMS patient population exhibited an increased prevalence of obesity, diabetes mellitus (in females) and hyperlipidaemia, compared with normal populations described in published studies. Quality of life, assessed using a disease-specific questionnaire (QoL-AGHDA), was also reduced in KIMS patients. The maintenance dose of GH was significantly higher in patients who were receiving GH prior to enrolment into KIMS (non-naive patients) compared with patients who commenced GH at the time of enrolment (naive patients). In addition, dose of GH correlated significantly with body weight in the former group of patients. Analysis of serum levels of IGF-I indicated that overtreatment with GH was markedly more common in non-naive than in naive patients. The frequency of adverse events in KIMS patients was no higher than that reported in patients receiving placebo in previous clinical trials. Recurrence of pituitary or CNS tumours was reported in six patients, a rate consistent with data from control series. Three deaths were reported, none of which was obviously associated with GH treatment. CONCLUSIONS Our data, drawn from a large population of hypopituitary adults treated with GH for a total of more than 800 patient years, confirm previous reports that untreated GHD in hypopituitary adults is associated with a number of important clinical problems. In addition, the results suggest that there has been a... [ABSTRACT FROM AUTHOR]