Mikkel Andreassen

IGF1 as predictor of all cause mortality and cardiovascular disease in an elderly population.

BACKGROUND IGF1 is believed to influence ageing and development of cardiovascular disease (CVD) through complex mechanisms. Reduced IGF1 levels might be causally associated with conditions accompanying ageing including development of CVD. However, in animal models reduced GH-IGF1 signalling increases lifespan. Reduced IGF1 activity might also be associated with longevity in humans. OBJECTIVE The objective was to investigate if plasma IGF1 levels were associated with all cause mortality, and the development of chronic heart failure (CHF) and a major CV event. PATIENTS AND DESIGN A population based study of 642 individuals, aged 50-89 years. Development of CHF was evaluated in 576 individuals with normal systolic function assessed by echocardiography and without the history of CHF or myocardial infarction. Development of the first major CV event was evaluated in 504 individuals with normal systolic function and without prevalent CVD. Outcomes were ascertained after 5 years using hospital discharge diagnoses. RESULTS Adjustment for risk factors IGF1 values in the fourth quartile versus values below the fourth quartile was associated with increased mortality (n=103), hazard ratio (HR) 1.52 (95% confidence interval (CI) 1.01-2.28; P=0.044). IGF1 in the fourth quartile was also independently associated with risk of development of CHF (n=19), HR 5.02 (95% CI 2.00-12.64; P=0.001) but showed no association with the overall incidence of major CV events (n=58), HR 1.05 (95% CI 0.59-1.90; P=0.861). CONCLUSIONS High IGF1 levels were independently associated with increased all cause mortality and risk of development of CHF, whereas no relation with the overall incidence of CVD was observed.

Plasma insulin-like growth factor I as predictor of progression and all cause mortality in chronic heart failure.

OBJECTIVES Insulin-like growth factor I (IGF-I) is an anabolic growth factor that seems to increase cardiac contractility. Reduced levels of IGF-I may be implicated in progression of CHF. The objective was to compare plasma IGF-I in CHF patients with healthy controls, and to examine the associations between baseline IGF-I levels, cardiac contractility and the prognosis as judged by all cause mortality and progression of CHF requiring admission to hospital. METHODS A prospective study comprising 194 CHF outpatients, and 169 matched controls. All patients and controls underwent echocardiographic examination at baseline. Patients were followed for a median of 30 months. RESULTS There was no difference in IGF-I levels between patients and controls (median and interquartile range), 78 (58-91) vs. 77 (57-94)ng/mL (P=0.92). Age-adjusted IGF-I levels were not related to left ventricular ejection fraction (LVEF) (P=0.58) or levels of N-terminal B-Type natriuretic peptide (NT-proBNP) (P=0.42). During follow-up 44 patients died and 94 were admitted to hospital due to worsening of CHF. Adjusted for cardiovascular risk factors (age, gender, NT-proBNP, lipids, diabetes mellitus, blood pressure, renal function and LVEF) IGF-I levels did not influence the overall mortality risk or the admission rate to hospital, hazard ratio (HR) (95% confidence intervals) 1.05 (0.75-1.47) (P=0.77) and 1.00 (0.80-1.26) (P=0.96), respectively per each SD increase in log IGF-I levels. CONCLUSIONS IGF-I levels were not reduced in patients with CHF and did not influence cardiac status at baseline or the prognosis.

GH activity and markers of inflammation: a crossover study in healthy volunteers treated with GH and a GH receptor antagonist.

INTRODUCTION The GH/IGF1 axis may modulate inflammatory processes. However, the relationship seems complicated as both pro- and anti-inflammatory effects have been demonstrated. METHODS/DESIGN Twelve healthy volunteers (mean age 36, range 27-49 years) were treated in random order with increasing doses of GH for 3 weeks (first week 0.01  mg/kg per day, second week 0.02  mg/kg per day, and third week 0.03  mg/kg per day) or a GH receptor antagonist (pegvisomant; first week 10  mg/day and last two weeks 15  mg/day), separated by 8 weeks of washout. Circulating levels of the pro-inflammatory cytokines tumor necrosis factor α (TNFα (TNFA)), interleukin 6 (IL6), and IL1β (IL1B) and the acute phase proteins (APPs) C-reactive protein (CRP), haptoglobin, orosomucoid, YKL40 (CHI3L1), and fibrinogen were measured. RESULTS During GH treatment, IGF1 (median 131 (Inter-quartile range (IQR) 112-166) vs 390 (322-524) μg/l, P=0.002) increased together with TNFα (0.87 (0.74-1.48) vs 1.27 (0.80-1.69) ng/l, P=0.003), IL6 (1.00 (0.83-1.55) vs 1.35 (0.80-4.28) ng/l, P=0.045), and fibrinogen (9.2 (8.8-9.6) vs 11.1 (9.4-12.4) μM, P=0.002). By contrast, orosomucoid decreased (18.0 (15.5-24.3) vs 15.0 (15.0-17.0) μM, P=0.018). CRP, YKL40, and haptoglobin were unchanged. During pegvisomant treatment, IGF1 decreased (139 (117-171) vs 91 (78-114) ng/ml, P=0.005). Orosomucoid (21.0 (16.3-23.8) vs 22.0 (17.0-29.3) μM, P=0.036) and CRP (1.00 (0.62-1.77) vs 1.43 (0.71-3.29) mg/l, P=0.074) increased without an increase in pro-inflammatory cytokines. CONCLUSIONS GH/IGF1 action appears to modulate the initial stage of the inflammatory response as well as downstream processes elucidated by levels of APPs. The data suggest a complicated relationship not allowing any simple conclusions as to whether GH/IGF1 actions have mainly pro- or anti-inflammatory effects in vivo.

Concentrations of the acute phase reactants high‐sensitive C‐reactive protein and YKL‐40 and of interleukin‐6 before and after treatment in patients with acromegaly and growth hormone deficiency

Background  Acromegaly is accompanied by increased cardiovascular mortality and a cluster of proatherogenic risk factors. In the general population, ischaemic heart disease (IHD) is associated with elevated levels of inflammatory markers. The acute phase reactant (APR) C‐reactive protein (CRP) has been reported to be reduced in acromegaly and increase after treatment, suggesting that excess of GH/IGF‐I could have anti‐inflammatory effects. This is in accordance with results obtained in patients with growth hormone deficiency (GHD), where increased levels of CRP have been reported.

Characteristics and reference ranges of Insulin-Like Growth Factor-I measured with a commercially available immunoassay in 724 healthy adult Caucasians

Abstract Background and Objective: Measurements of Insulin-Like Growth Factor-I (IGF-I) play a pivotal role in the evaluation of the growth hormone-IGF-I axis. Due to assay variation IGF-I reference ranges are assay specific. We provide serum IGF-I reference ranges for adult men and women obtained by a commercially available assay. Method: IGF-I was measured by an enzyme-linked immunosorbent assay (R&D Systems). Assay precision was evaluated in low, medium and high IGF-I pools and in single samples from outpatients. The reference ranges were obtained in 724 healthy Caucasians, mean age 48 years (range 19–91). Results: IGF-I was measured higher in serum compared to plasma samples (p<0.001, R2=0.96). To convert EDTA plasma values to serum values a factor of 1.22 was calculated. The intraassay coefficients of variation (CV) for the low: 56.4±2.7ng/mL, medium: 179.7±5.9ng/mL and high pool: 445.61±3.2ng/mL (mean 1SD) were 5, 3 and 3%. Interassays CVs for the low, medium and high pool varied between 7–10, 5–7, and 6–9%. Reproducibility between 4 different lots showed a intraclass CV of 0.99 (95%CI 0.98–0.96). Logarithmically transformed IGF-I levels were linearly associated with age with a 13% reduction in IGF-I per decade in females and 11% in males. Conclusion: We have provided IGF-I reference ranges obtained by an assay that showed variations and reproducibility that was considered of sufficient high quality for clinical and scientific use.

Growth hormone (GH) activity is associated with increased serum oestradiol and reduced anti-Müllerian hormone in healthy male volunteers treated with GH and a GH antagonist.

Growth hormone (GH) and insulin‐like growth factor I (IGF‐I) receptors are present on pituitary gonadotrophs and on testicular Leydig and Sertoli cells. Thus, the GH/IGF‐I system may modulate the pituitary‐gonadal axis in males. This is a randomized cross‐over study. Eight healthy male volunteers (mean age 35, range 29–46 years) were treated with GH for 3 weeks (1st week 0.01, 2nd week 0.02, 3rd week 0.03 mg/day/kg) or a GH receptor antagonist (Pegvisomant) (1st week 10, last 2 weeks 15 mg/day), separated by 8 weeks of washout. Before and after the two treatment periods, concentrations of luteinizing hormone (LH), follicle‐stimulating hormone, testosterone, oestradiol, sex hormone–binding globulin, inhibin B and Anti‐Müllerian Hormone (AMH) were measured. During GH treatment, IGF‐I increased [(median (IQR)] 166 (162–235) vs. 702 (572–875) μg/L, p < 0.001) together with oestradiol [(mean ± SD) 78 ± 23 vs. 111 ± 30 pm, p = 0.019], and the oestradiol/testosterone ratio (p = 0.003). By contrast, AMH (42 ± 14 vs. 32 ± 7 pm, p = 0.018), Inhibin B (211 (146–226) vs. 176 (129–204) ng/L, p = 0.059) and LH (3.8 ± 1.5 vs. 3.2 ± 1.2 U/L, p = 0.096) decreased. During pegvisomant treatment IGF‐I (204 (160–290) vs. 106 (97–157) μg/L, p = 0.001) and oestradiol (86 ± 28 vs. 79 ± 25 pm, p = 0.060) decreased. No significant changes or trends in the other reproductive hormones occurred during the two treatment regimens. GH/IGF‐I activity was positively associated with serum oestradiol, suggesting that GH/IGF‐I stimulates aromatase activity in vivo. As a novel observation, we found that high GH activity was associated with reduced levels of the Sertoli cell marker AMH. Further studies are needed to evaluate possible effects of GH on Sertoli cell function and/or spermatogenesis.

Circulating levels of pegvisomant and endogenous growth hormone during prolonged pegvisomant therapy in patients with acromegaly.

To investigate whether pegvisomant treatment in acromegaly induces gradual elevations in endogenous serum growth hormone (GH) levels and whether serum pegvisomant levels predict the therapeutic outcome.

Treatment of subclinical hyperthyroidism: effect on left ventricular mass and function of the heart using magnetic resonance imaging technique

Purpose The aim of this study was to investigate structure and function of the heart in subclinical hyperthyroidism (SH) before and after obtaining euthyroidism by radioactive iodine treatment, using high precision and observer-independent magnetic resonance imaging (MRI) technology. Methods Cardiac MRI was performed before and after euthyroidism was obtained by radioactive iodine treatment in 12 otherwise healthy patients (11 women and one man, mean age 59 years, range 44–71 years) with a nodular goiter and SH, and compared with eight healthy controls investigated at baseline. Cardiac data were expressed as an index, as per body surface area, except for heart rate (HR) and ejection fraction. Results Post-treatment cardiac MRI was performed in median 139 days after a normalized serum TSH value had been recorded. During treatment, serum TSH increased from (median (range)) 0.01 (0.01–0.09) to 0.88 (0.27–3.99) mU/l. Patients with untreated SH had increased resting HR (P<0.01) as well as cardiac index (cardiac output as per body surface area) (P<0.01) compared with controls. Obtaining euthyroidism resulted in a significant decrease in left ventricular mass index (LVMI) of 2.7 g/m2 (P=0.034), in HR of 8 bpm (P=0.001), and in cardiac index of 0.24 l/min per m2 (P=0.017). Conclusions Normalization of thyroid function by radioactive iodine treatment of SH resulted in significant reductions in clinically important heart parameters such as LVMI, HR, and cardiac index. SH should be regarded as a condition in which aggressive treatment should be considered to protect cardiac function.

Three Cases of ACTH-Producing Pheochromocytoma – Full Hormonal Workup in Patients With an Adrenal Mass May Be Crucial For Correct Management

ABSTRACT Objective: In rare cases, adrenal medullary tumors secrete adrenocorticotropic hormone (ACTH) in addition to catecholamines. Methods: We present 3 cases of ACTH-producing pheochromocytomas, highlighting the diagnostic challenges, clinical severity, and phenotypic diversity of this rare phenomenon. Results: Two of the patients (females aged 75 and 60 years) presented with typical Cushingoid phenotypes. Their biochemical profiles were consistent with ectopic ACTH-dependent Cushing syndrome with grossly elevated plasma ACTH and urinary free cortisol. One of the patients had vague symptoms of adrenergic hyperactivity and highly elevated levels of plasma metanephrines, whereas the other had no symptoms of pheochromocytoma. The third patient (male aged 64 years) presented with tachycardia, labile blood pressure, and sweating consistent with pheochromocytoma. He had no signs of Cushing syndrome. Plasma and urine samples showed highly elevated concentrations of catecholamines, ACTH, and cortisol. After a...

Association between GH receptor polymorphism (exon 3 deletion), serum IGF1, semen quality, and reproductive hormone levels in 838 healthy young men

INTRODUCTION GH activity may be involved in male reproductive function. A common genetic polymorphism in the gene encoding the GH receptor (GHR) results in deletion of the entire exon 3 sequence (GHRd3 isoform). The short GHRd3/d3 isoform seems more sensitive compared with full-length receptors (GHRfl/fl). AIM TO INVESTIGATE THE ASSOCIATIONS BETWEEN GH ACTIVITY, EVALUATED BY EXON 3 GHR POLYMORPHISM, AND SERUM IGF1 VS REPRODUCTIVE HORMONES, SEMEN QUALITY, AND PRE- AND POSTNATAL GROWTH IN HEALTHY YOUNG MALES (N=838, MEAN AGE: 19.4 years). RESULTS Compared with GHRfl/fl homozygous individuals (n=467) GHRd3/d3 homozygous individuals (n=69) tended to have larger semen volume (3.2 (2.4-4.3) vs 3.6 (2.6-4.7) ml, P=0.053) and higher serum inhibin-B levels (208 pg/ml (158-257) vs 227 pg/ml (185-264), P=0.050). Semen quality, levels of gonadotropins, testosterone, estradiol, sex hormone-binding globulin, and IGF1 were not associated with GHRd3 genotype. A twofold increase in serum IGF1 was associated with a 13% (4-23) increase in calculated free testosterone (P=0.004). By contrast IGF1 was inversely associated with serum inhibin-B (P=0.027), but showed no associations to semen quality. GHR genotype and serum IGF1 were not associated with size at birth or final height. CONCLUSIONS GHRd3 polymorphism seemed only to have a weak influence on male reproductive function of borderline significance. The sensitive GHRd3/d3 genotype may slightly increase testicular function, as evaluated by semen volume and levels of inhibin-B, but does not seem to influence Leydig cell steroidogenesis. GHR genotype did not influence pre- and postnatal growth.