• Differential effects of GH replacement on the components of the leptin system in GH-deficient individuals.

      Randeva, Harpal S; Murray, Robert D; Lewandowski, Krzysztof C; O'Callaghan, Chris J; Horn, Rüdiger; O'Hare, Paul; Brabant, Georg E; Hillhouse, Edward W; Shalet, Stephen M; Sir Quinton Hazel Molecular Medicine Research Center, Biological Sciences, University of Warwick, Coventry, United Kingdom CV4 7AL. (2002-02)
      GH therapy is associated with a reduction in fat mass and an increase in lean mass in subjects with GH deficiency (GHD). Leptin, like GH, plays an important role in the regulation of body composition. GH treatment has been shown to reduce serum leptin; however, the physiological interactions between the leptin system (free leptin, bound leptin, and soluble leptin receptor) and the GH/IGF-I system largely remain unknown. Twenty-five patients with childhood (n = 10) and adult-onset (n = 15) GHD were studied. GH status had previously been determined using an insulin tolerance test and/or an arginine stimulation test. The following parameters were recorded at baseline (V1) and then after 3 months (V2) and 6 months (V3) on GH treatment: fat mass, body mass index (BMI), and waist/hip ratio (WHR); blood samples were taken after an overnight fast for free leptin, bound leptin, soluble leptin receptor, insulin, and IGF-I. At V2 and V3, respectively, a fall in free leptin (P < 0.001 for each), and at V3 a fall in in percent fat mass (P < 0.001) were observed. There were no significant changes in BMI or WHR. Simultaneously, there was a rise in insulin (P = 0.068 and P < 0.001), IGF-I (P < 0.001 and P < 0.001), bound leptin (P = 0.005 and P < 0.001), and soluble leptin receptor (P = 0.61 and P < 0.001). A positive relationship was noted between free leptin and BMI (P < 0.001) and between free leptin and fat mass (P < 0.001), and a negative relationship was found between free leptin and IGF-I (P < 0.001) and, within patient, between free leptin and insulin (P < 0.001). There was no significant correlation between free leptin and WHR. Bound leptin had a positive association with IGF-I (P < 0.001) and insulin (P = 0.002) and a negative relationship with percent fat mass (P = 0.023). Soluble leptin receptor was also positively related to IGF-I (P < 0.001). In conclusion, our data suggest that the reduction in serum leptin with GH treatment, as noted by others, is mediated through a fall in free leptin. The fall in free leptin and in part the rise in bound leptin are most likely through a reduction in percent fat mass. However, the observed changes in free leptin and bound leptin and, more importantly, the rise in soluble leptin receptor, are not explained entirely by modifications in body composition and may be a direct result of GH/IGF-I.
    • Growth hormone replacement decreases plasma levels of matrix metalloproteinases (2 and 9) and vascular endothelial growth factor in growth hormone-deficient individuals.

      Randeva, Harpal S; Lewandowski, Krzysztof C; Komorowski, Jan; Murray, Robert D; O'Callaghan, Chris J; Hillhouse, Edward W; Stepien, Henryk; Shalet, Stephen M; Molecular Medicine Research Group, Department of Biological Sciences, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. hrandeva@bio.warwick.ac.uk (2004-05-25)
      BACKGROUND: Matrix metalloproteinases (MMP) are implicated in cardiovascular disease. Growth hormone (GH) deficiency is associated with increased cardiovascular mortality. We assessed whether GH replacement, in GH-deficient adults, has any effect on plasma levels of MMP-2 and MMP-9 and on vascular endothelial growth factor (VEGF), known to activate MMPs. METHODS AND RESULTS: The study comprised 66 GH-deficient adults, 37.8+/-14.7 years of age (37 female). Plasma MMP-2 and MMP-9, VEGF, and insulin-like growth factor-1 (IGF-1) were measured at baseline (V1), at 12 months (V2), and at 24 months of GH treatment (V3). IGF-1 levels rose under GH replacement (mean+/-SD): V1, 151.6+/-91.9 microg/mL; V2, 270.2+/-114.8 microg/mL; and V3, 266.2+/-109.8 (V1 versus V2; P<0.001: V2 versus V3; P=0.76). MMP-9 exhibited the most pronounced and sustained decline from 1248.0+/-651.1 ng/mL at V1, 949.2+/-457.7 ng/mL at V2, and 760.8+/-386.1 ng/mL at V3 (P<0.001 at all time points). A similar pattern was detected for VEGF levels: 358.5+/-209.0 pg/mL at V1, 310.6+/-225.7 pg/mL at V2 (P<0.001), and 283.7+/-202.7 pg/mL at V3 (V2 versus V3; P=0.005). MMP-2 demonstrated a significant decline initially from V1 to V2 (1134.4+/-217.8 ng/mL versus 1074.5+/-203.0 ng/mL, respectively; P=0.031), reaching a plateau at V3 (1072.3+/-220.2 ng/mL) (V2 versus V3; P=0.93). A negative relation existed between MMP-9 versus IGF-1 and MMP-2 versus IGF-1 (P<0.001 and P=0.007, respectively) as well as between VEGF and IGF-1 (P<0.001). CONCLUSIONS: These changes in MMPs and VEGF may contribute to the anticipated reduction in vascular mortality in hypopituitary adults receiving GH replacement.
    • Plasma total homocysteine concentrations in adults with growth hormone (GH) deficiency: effects of GH replacement.

      Lewandowski, Krzysztof C; Murray, Robert D; Drzewoski, J; O'Callaghan, Chris J; Czupryniak, L; Hillhouse, Edward W; Shalet, Stephen M; Randeva, Harpal S; Molecular Medicine Research Group, Biomedical Research Institute, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. (2003-11)
      Growth hormone (GH) deficiency is associated with increased cardiovascular morbidity and mortality. GH treatment improves the profile of many cardiovascular risk markers in individuals with GH deficiency (GHD). The aim of the present was to assess whether GH replacement may decrease plasma total homocysteine, an independent cardiovascular risk factor, thus potentially contributing to benefits of GH replacement in adult subjects with GHD. Twenty-five patients (17 female, 8 male), mean age 39-years, with GHD were studied. GH status had been determined by an insulin tolerance test and/or arginine stimulation test. After an overnight fast, plasma insulin, IGF-1, total homocysteine (Hcy), free thyroxine (FT4), creatinine, vitamin B12, and folate were measured at baseline (V1), 3 months (V2) and then at 6 months (V3) on GH treatment. The data were analysed by hierarchical statistical models, univariate and multivariate correlation. GH treatment resulted in an increase in IGF-1 (p<0.001, p<0.001), and insulin (p=0.068, p<0.001), at each visit, respectively. Hcy levels increased from V1 to V2 (7.7+/-0.53 to 9.15+/-0.45 micromol/L; p=0.051), but this was followed by a decline at V3 (to 8.8+/-0.59), so that the overall change of Hcy levels from V1 to V3, once individuals had achieved 'adequate' GH replacement, was no longer significantly different (p=0.090). When separated by gender, at 6 months (V3) there was a small, but significant increase in Hcy in men (p=0.028), but not in women (p=0.58). There was no significant change in B12, folate, free T4 or creatinine levels. Univariate analysis revealed that only B12 and folate showed significant negative relationships with Hcy (B12: parameter= -0.013, p<0.001; folate: parameter=-1.31, p<0.001), but not between Hcy and IGF-1 (p=0.18). In a multiple variable model, both B12 and folate remained significantly negatively associated with plasma total homocysteine (p=0.018; p<0.001, respectively). In this observational study normalisation of IGF-1 levels in adult subjects with growth hormone deficiency was not associated with a fall in total homocysteine. Before firm conclusions can be drawn about the contribution of changes in plasma homocysteine concentrations to cardiovascular prognosis in adult GHD patients receiving GH replacement, further controlled studies are required.
    • Reductions of circulating matrix metalloproteinase 2 and vascular endothelial growth factor levels after treatment with pegvisomant in subjects with acromegaly.

      Paisley, Angela N; O'Callaghan, Chris J; Lewandowski, Krzysztof C; Parkinson, Craig; Roberts, Margaret E; Drake, William M; Monson, John; Trainer, Peter J; Randeva, Harpal S; Department of Endocriniology, Christie Hospital, Manchester, United Kingdom. (2006-11)
      BACKGROUND: Vascular endothelial growth factor (VEGF) is involved in activation of the matrix metalloproteinase (MMP) system; the latter is implicated in atherosclerosis and cardiovascular disease. Patients with acromegaly have reduced life expectancy primarily due to cardiac disease. AIM: This study assessed plasma MMPs and VEGF levels in patients with active acromegaly (IGF-I > 130% upper limit of normal), and on treatment with pegvisomant. SUBJECTS AND METHODS: Twenty patients [nine female, mean age 56.1 +/- 13.8 yr (mean +/- sd)] were studied at baseline and on pegvisomant therapy and compared with data from 25 healthy volunteers (12 female; 56.6 +/- 14.2 yr). Plasma MMP-2, MMP-9, and VEGF levels were measured. RESULTS: Serum IGF-I fell from a baseline (mean +/- sd) level of 620.1 +/- 209.3 ng/ml to 237.5 +/- 118.5 ng/ml on pegvisomant (doses 10-60 mg; P < 0.001). MMP-2 levels at baseline were significantly higher in patients compared with healthy controls (380.7 +/- 204.8 vs. 207.4 +/- 62.6 ng/ml; P < 0.001), but with treatment a significant reduction in MMP-2 [380.7 +/- 204.8 vs. 203.0 +/- 77.4 ng/ml; P < 0.001] and VEGF (283.4 +/- 233.6 vs. 229.1 +/- 157.4 pg/ml; P = 0.008) was noted. There was no significant difference in MMP-9 levels between patients and controls at baseline (797.5 +/- 142.1 vs. 788.3 +/- 218.0 ng/ml; P = 0.87) or between baseline and posttreatment levels (797.5 +/- 142.1 vs. 780.0 +/- 214 ng/ml; P = 0.76). CONCLUSIONS: Our novel data demonstrate that treatment of acromegaly with pegvisomant leads to reductions in MMP-2 and VEGF concentrations. Further studies are required to determine the significance of these findings with relation to cardiac disease.