• Association between hepatic steatosis and serum IGF1 and IGFBP-3 levels in a population-based sample.

      Völzke, Henry; Nauck, Matthias; Rettig, Rainer; Dörr, Marcus; Higham, Claire E; Brabant, Georg E; Wallaschofski, Henri; Institute of Community Medicine Institute of Clinical Chemistry and Laboratory Medicine Institute of Physiology Department of Internal Medicine B, University of Greifswald, Greifswald D-17487, Germany. voelzke@uni-greifswald.de (2009-11)
      CONTEXT: It is assumed that hepatic steatosis plays a role in the development and progression of the metabolic syndrome and its cardiovascular sequelae. Low serum IGF1 levels might mediate these associations. OBJECTIVES: The aims of this study were i) to investigate the associations of hepatic steatosis with serum IGF1 and IGF binding protein-3 (IGFBP-3) levels using ultrasound and serum alanine aminotransaminase (ALT) data to define hepatic steatosis, and ii) to analyze the specific role of alcohol consumption in this context. DESIGN: We analyzed data from the population-based Study of Health in Pomerania. METHODS: We used data from 3863 subjects (1971 women) aged 20-79 years who had no history of viral hepatitis, liver cirrhosis, or malignant diseases. Liver hyperechogenicity was diagnosed using ultrasound. Serum IGF1 and IGFBP-3 levels were determined by automated two-site chemiluminescence immunoassays. RESULTS: Hyperechogenic liver pattern was associated with low serum IGF1 levels and low serum IGF1/IGFBP-3 ratios. The lowest serum IGF1 and IGF1/IGFBP-3 values and highest IGFBP-3 levels were present in subjects who had a hyperechogenic liver pattern and increased serum ALT levels. All of these associations were independent of alcohol consumption. CONCLUSIONS: Our data show that hepatic steatosis is associated with low serum IGF1 levels. This association is independent of alcohol consumption.
    • Growth hormone excess and the development of growth hormone receptor antagonists.

      Higham, Claire E; Trainer, Peter J; Department of Endocrinology, Christie Hospital, Manchester M20 4BX, UK. (2008-11)
      In 1990, a single amino acid substitution in the growth hormone (GH) gene at position 119 was found to transform the consequent protein from an agonist to an antagonist at the growth hormone receptor (GHR). Further amino acid substitutions plus prolongation of the half-life of the protein by pegylation resulted in the first clinically effective GHR antagonist, pegvisomant. Following extensive clinical trials, this medication has emerged as the most efficacious therapy for treatment-resistant acromegaly. Subsequent advances in our understanding of GH-GHR interactions and downstream GH signalling pathways suggest that pegvisomant binds to preformed GHR dimers and prevents rotational changes within the receptor-GH complex necessary for intracellular signalling to occur. This article reviews the discovery of pegvisomant, from initial experimental data to successful licensing of the drug for treatment-resistant acromegaly, and discusses its other potential therapeutic uses in diseases with abnormalities in the GH-IGF-I axis.
    • Long-term experience of pegvisomant therapy as a treatment for acromegaly.

      Higham, Claire E; Chung, T T; Lawrance, Jeremy A L; Drake, William M; Trainer, Peter J; Department of Endocrinology, Christie Hospital, Manchester, UK. (2009-07)
      AIMS: To evaluate the long-term efficacy and safety of pegvisomant as a treatment for acromegaly. DESIGN: Retrospective analysis of clinical and trial data from all patients treated with pegvisomant since 1997 at two centres with common protocols. RESULTS: Fifty-seven patients (age range 27-78 years) have been treated with pegvisomant since 1997 for up to 91 months (median 18 months). Before commencing pegvisomant, patients had an IGF-I above the upper limit of normal (ULN) of the age-related reference range (median 1.8 x ULN, range 1.2-4.1). Ninety-five per cent normalized IGF-I using a median dose of 15 mg daily (range 10 mg alternate day to 60 mg daily) with no influence of gender on dose requirement. Five patients had combination therapy with either somatostatin analogues (SSA) or cabergoline. Two patients initially controlled on 10 mg and 20 mg required dose increases (to 20 mg + 40 mg) over 24 months to reduce IGF-I. Twenty-seven patients stopped pegvisomant. Reasons included side-effects [abnormal liver function tests (LFTs)] and patient choice. Two patients developed elevated liver transaminases, which normalized on stopping pegvisomant. Patients had 6-12-monthly pituitary magnetic resonance imaging (MRI) scans. One patient had significant tumour size increase. CONCLUSION: This long-term experience in 57 patients indicates pegvisomant to be effective, safe and well-tolerated. Raised transaminases occurred within the first month of therapy in two patients, and tumour growth was seen in one patient (tumour was growing prior to pegvisomant). In two patients increasing doses of pegvisomant were required to keep IGF-I within the target range.
    • Pegvisomant improves insulin sensitivity and reduces overnight free fatty acid concentrations in patients with acromegaly.

      Higham, Claire E; Rowles, Susannah V; Russell-Jones, D; Umpleby, A M; Trainer, Peter J; Department of Endocrinology, Christie Hospital, Manchester M20 4BX, United Kingdom. (2009-07)
      INTRODUCTION: Acromegaly is complicated by an increased incidence of diabetes mellitus caused by impaired insulin sensitivity and reduced beta-cell function. Pegvisomant blocks activity at GH receptors, normalizing IGF-I in over 90% of patients and improving insulin sensitivity. The mechanisms for this increase in insulin sensitivity are not fully determined. We used stable isotope techniques to investigate the effects of pegvisomant on glucose and lipid metabolism in acromegaly. METHODS: Five patients (age, 43 yr +/- sd) with active acromegaly were studied on two occasions: before pegvisomant and after 4 wk of pegvisomant (20 mg daily sc). (2)H(5)-glycerol was infused overnight to measure overnight and early morning (basal) glycerol production rate (Ra). The next morning (2)H(2)-glucose was infused for 2 h before and throughout a hyperinsulinemic euglycemic (1.5 mU/kg x min insulin) clamp to measure basal glucose Ra and insulin-stimulated peripheral glucose disposal (Rd). RESULTS: Mean IGF-I was significantly reduced after pegvisomant treatment (mean, 539 +/- 176 vs. 198 +/- 168 microg/ml; P = 0.001). The insulin sensitivity of endogenous glucose production was significantly increased after pegvisomant [mean glucose Ra *insulin, 118.5 +/- 28 vs. 69.2 +/- 22 micromol/kg x min *(mU/liter); P = 0.04]. No differences in glucose Rd were seen after pegvisomant. All patients showed a reduction in glycerol Ra adjusted for insulin [mean, 18.12 +/- 1.75 vs. 14.4 +/- 4.75 micromol/kg x min *(mU/liter); P = 0.08] and overnight FFA concentrations (mean area under the curve, 278 +/- 84 vs. 203 +/- 71; P < 0.05) after pegvisomant. CONCLUSION: Short-term administration of pegvisomant leads to a reduction in overnight endogenous glucose production, and this may be related to reduced levels of FFA.
    • Successful use of weekly pegvisomant administration in patients with acromegaly.

      Higham, Claire E; Thomas, J; Bidlingmaier, M; Drake, William M; Trainer, Peter J; C Higham, Endocrinology, Christie Hospital, Manchester, M20 4BX, United Kingdom. (2009-05-01)
      Context Clinical trials using 80 mg once-weekly pegvisomant in active acromegaly led to a 30% fall in serum IGF-I. Subsequent studies demonstrated that daily administration of up to 40 mg/day achieved an IGF-I within reference range in 97% of patients. Pegvisomant has a half-life of >70hrs suggesting weekly dosing may be possible but using higher doses than in the initial trials. Objective To determine the efficacy of weekly dosing of pegvisomant. Design A two-center, open-label prospective study in patients with acromegaly converted from a stable daily dose of pegvisomant (median dose 15 mg daily [range 10-20 mg od], IGF-I normal for 3 months prior to inclusion) to twice-weekly (week 0-16) followed by once-weekly (week 16-32) administration. Results Seven patients (4M, age 57+/-7 yrs, 6/7 prior trans-sphenoidal surgery, 7/7 prior radiotherapy) were recruited. Six patients completed the twice-weekly and five patients both the twice-weekly and once-weekly administration. Headaches led to 2 patient withdrawals at 0 + 24 weeks. Mean pre-dose serum IGF-I levels remained stable with the different administration regimens (IGF-I baseline 145+/-39 ng/ml, twice-weekly 124+/-39 ng/ml and once-weekly 127+/-22 ng/ml) and all values were within age adjusted IGF-I reference range. Pegvisomant dose was reduced in 2 patients and 5 opted to continue weekly administration at trial termination. Safety and QOL parameters remained stable. Conclusions Twice and once-weekly administration of pegvisomant is effective in controlling serum IGF-I levels in acromegaly and although not formally assessed, continuation of weekly dosing in 5 patients at study conclusion suggests patient preference for this regimen.