• 5 years later - overview of the data collected in ACROSTUDY - different treatment regimens, database structure, basic strategies and safety.

      Trainer, Peter J; P Trainer, Department of Endocrinology, Christie Hospital, Manchester, United Kingdom. (2009-08-14)
      ACROSTUDY is an observational registry intended to collect safety and efficacy data on pegvisomant therapy. 792 patients have been enrolled, of whom 83% had commenced pegvisomant prior to recruitment. The mean follow-up is 1.66 years with the mean duration of pegvisomant therapy 3.31 years representing 2625 patient years of treatment. 90% of patients were on once daily pegvisomant, and 67% were on monotherapy. Disappointingly IGF-I was normalised in less than 70% of patients, furthermore in 80% of patients with an elevated IGF-I the daily dose of pegvisomant was 20 mg or less. 56 Serious Adverse Events (SAEs) were reported, 13 of which were related to pegvisomant. 276 Adverse Events (AEs) were reported, of which 56 were considered related to pegvisomant. The AEs most frequently attributed to pegvisomant were disturbed liver function tests and injection site reactions. MRI imaging was available in 684 patients. 411 patients had at least one MRI on pegvisomant compared to a baseline. In 31 patients a decrease in tumour size has been reported, of whom 20 had previously received radiotherapy. An increase in tumour size has been reported and confirmed in 22 patients. In 11 patients there was contradictory data on tumour size, while in 6 patients central review of the films failed to confirm increase in tumour size. In conclusion the safety data are generally reassuring while the IGF-I normalisation rate is disappointing which probably reflects a failure of dose titration. Further effort is needed to understand the reasons for the failure of dose titration.
    • ACTROSTUDY: the first 5 years

      Trainer, Peter J; Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, UK (2009)
    • Changes in arterial stiffness but not carotid intimal thickness in acromegaly.

      Paisley, Angela N; Banerjee, M; Rezai, M; Schofield, R E; Balakrishnannair, S; Herbert, A; Lawrance, Jeremy A L; Trainer, Peter J; Cruickshank, J K; Department of Endocrinology, The Christie National Health Service Foundation Trust, Manchester M20 4BX, United Kingdom. anpaisley@doctors.org.uk (2011-05)
      Acromegaly increases cardiovascular morbidity. We tested the hypothesis that increased arterial stiffness together with left ventricular hypertrophy may be a contributory factor.
    • Clinical features of GH deficiency and effects of 3 years of GH replacement in adults with controlled Cushing's disease.

      Höybye, Charlotte; Ragnarsson, Oskar; Jönsson, Peter J; Koltowska-Häggström, Maria; Trainer, Peter J; Feldt-Rasmussen, Ulla; Biller, Beverly M K; Department of Endocrinology, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. charlotte.hoybye@karolinska.se (2010-04)
      OBJECTIVE: Patients in remission from Cushing's disease (CD) have many clinical features that are difficult to distinguish from those of concomitant GH deficiency (GHD). In this study, we evaluated the features of GHD in a large cohort of controlled CD patients, and assessed the effect of GH treatment. DESIGN AND METHODS: Data were obtained from KIMS, the Pfizer International Metabolic Database. A retrospective cross-sectional comparison of background characteristics in unmatched cohorts of patients with CD (n=684, 74% women) and nonfunctioning pituitary adenoma (NFPA; n=2990, 39% women) was conducted. In addition, a longitudinal evaluation of 3 years of GH replacement in a subset of patients with controlled CD (n=322) and NFPA (n=748) matched for age and gender was performed. RESULTS: The cross-sectional study showed a significant delay in GHD diagnosis in the CD group, who had a higher prevalence of hypertension, fractures, and diabetes mellitus. In the longitudinal, matched study, the CD group had a better metabolic profile but a poorer quality of life (QoL) at baseline, which was assessed with the disease-specific questionnaire QoL-assessment of GHD in adults. After 3 years of GH treatment (mean dose at 3 years 0.39 mg/day in CD and 0.37 mg/day in NFPA), total and low-density lipoprotein cholesterol decreased, while glucose and HbAlc increased. Improvement in QoL was observed, which was greater in the CD group (-6 CD group versus -5 NFPA group, P<0.01). CONCLUSION: In untreated GHD, co-morbidities, including impairment of QoL, were more prevalent in controlled CD. Overall, both the groups responded similarly to GH replacement, suggesting that patients with GHD due to CD benefit from GH to the same extent as those with GHD due to NFPA.
    • Comparison of serum cortisol measurement by immunoassay and liquid chromatography-tandem mass spectrometry in patients receiving the 11β-hydroxylase inhibitor metyrapone.

      Monaghan, Phillip J; Owen, L J; Trainer, Peter J; Brabant, Georg E; Keevil, B G; Darby, Denise; Biochemistry Department, The Christie NHS Foundation Trust, Withington, Manchester M20 4BX, UK. phillip.monaghan@nhs.net (2011-09)
      The accurate measurement of cortisol by immunoassay is compromised by the potential for cross-reactivity of reagent antibodies with structurally related steroids present in serum. This susceptibility is potentiated when normal steroid metabolism is altered pharmaceutically by antisteroidogenic drugs utilized in the management of Cushing's syndrome to moderate cortisol production. The clinical implications of falsely elevated cortisol results include over-treatment and unrecognized hypoadrenalism. To investigate the effect of the 11β-hydroxylase inhibitor metyrapone on serum cortisol assay, a comparison of measurement by immunoassay versus liquid chromatography-tandem mass spectrometry (LC-MS/MS) was conducted.
    • A consensus on criteria for cure of acromegaly.

      Giustina, A; Chanson, P; Bronstein, M D; Klibanski, A; Lamberts, S; Casanueva, F F; Trainer, Peter J; Ghigo, E; Ho, K; Melmed, S; et al. (2010-07)
      OBJECTIVE: The Acromegaly Consensus Group met in April 2009 to revisit the guidelines on criteria for cure as defined in 2000. PARTICIPANTS: Participants included 74 neurosurgeons and endocrinologists with extensive experience of treating acromegaly. EVIDENCE/CONSENSUS PROCESS: Relevant assays, biochemical measures, clinical outcomes, and definition of disease control were discussed, based on the available published evidence, and the strength of consensus statements was rated. CONCLUSIONS: Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines. Appropriate methods of measuring and achieving disease control were summarized.
    • Corticosteroid-binding globulin regulates cortisol pharmacokinetics.

      Perogamvros, Ilias; Aarons, Leon; Miller, A G; Trainer, Peter J; Ray, David W; Department of Endocrinology, Christie Hospital and Endocrine Sciences Research Group, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK . School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK . Department of Biochemistry, University Hospital of South Manchester, Wythenshawe, UK. (2010-11-05)
      Objective:  Corticosteroid-binding globulin (CBG) is the principal carrier for cortisol in the circulation. Variations in CBG binding capacity are predicted to alter total serum cortisol disposition, but free serum cortisol is believed to be unaffected. Unbound cortisol pharmacokinetics (PK) have not been studied in the context of CBG changes. We aimed to assess the regulation of cortisol PK by CBG. Design and subjects:  Women on oestrogens (OCP), patients homozygous for a non-functioning CBG variant (CBG null) and healthy controls (HV) were studied before and after IV and oral administration of hydrocortisone 20mg. Measurements:  PK parameters were studied for total serum cortisol (SerF), free serum cortisol (FreeF) and cortisone (FreeE), and salivary cortisol (SalF) and cortisone (SalE): area under the curve (AUC), clearance (CL), half-life, and volume of distribution (Vd). Results:  Following IV hydrocortisone, AUC and half-life of SerF were significantly higher in the OCP group and lower in the CBG null. SerF CL and Vd were significantly lower in the OCP group and increased in the CBG null, compared to HV. PK parameters for FreeF and the salivary biomarkers were not different between the CBG null and HV, although OCP patients still had higher AUC compared to HV and prolonged half-life. These findings were confirmed following oral hydrocortisone, but concentration-time profiles were highly heterogeneous and SalF interpretation was problematic due to oral contamination. Conclusions:  We have demonstrated that CBG has a distinct effect on cortisol PK. When CBG binding is disrupted, FreeF retains normal PK characteristics, although CBG null patients lack a CBG-bound pool of readily releasable cortisol. Women on oestrogens may have altered free serum cortisol kinetics and thus may be potentially overexposed to glucocorticoids.
    • Current management practices for acromegaly: an international survey.

      Giustina, A; Bronstein, M D; Casanueva, F F; Chanson, P; Ghigo, E; Ho, K K Y; Klibanski, A; Lamberts, S; Trainer, Peter J; Melmed, S; et al. (2011-06)
      To determine whether peer-reviewed consensus statements have changed clinical practice, we surveyed acromegaly care in specialist centers across the globe, and determined the degree of adherence to published consensus guidelines on acromegaly management. Sixty-five acromegaly experts who participated in the 7th Acromegaly Consensus Workshop in March 2009 responded. Results indicated that the most common referring sources for acromegaly patients were other endocrinologists (in 26% of centers), neurosurgeons (25%) and primary care physicians (21%). In sixty-nine percent of patients, biochemical diagnoses were made by evaluating results of a combination of growth hormone (GH) nadir/basal GH and elevated insulin like growth factor-I (IGF-I) levels. In both Europe and the USA, neurosurgery was the treatment of choice for GH-secreting microadenomas and for macroadenomas with compromised visual function. The most widely used criteria for neurosurgical outcome assessment were combined measurements of IGF-I and GH levels after oral glucose tolerance test (OGTT) 3 months after surgery. Ninety-eight percent of respondents stated that primary treatment with somatostatin receptor ligands (SRLs) was indicated at least sometime during the management of acromegaly patients. In nearly all centers (96%), the use of pegvisomant monotherapy was restricted to patients who had failed to achieve biochemical control with SRL therapy. The observation that most centers followed consensus statement recommendations encourages the future utility of these workshops aimed to create uniform management standards for acromegaly.
    • Early diagnosis of acromegaly: computers vs clinicians.

      Miller, Ralph; Learned-Miller, Erik G; Trainer, Peter J; Paisley, Angela N; Blanz, Volker; Division of Endocrinology, Department of Medicine, University of Kentucky, Lexington, KY (2011-08)
      Background  Early diagnosis of a number of endocrine diseases is theoretically possible by the examination of facial photographs. One of these is acromegaly. If acromegaly were found, early in the course of the disease, morbidity would be lessened and cures more likely. Objectives, design, patients, measurements  Our objective was to develop a computer program which would separate 24 facial photographs, of patients with acromegaly, from those of 25 normal subjects. The key to doing this was to use a previously developed database that consisted of three-dimensional representations of 200 normal person's heads (SIGGRAPH '99 Conference Proceedings, 1999). We transformed our 49, two-dimensional photos into three-dimensional constructs and then, using the computer program, attempted to separate them into those with and without the features of acromegaly. We compared the accuracy of the computer to that of 10 generalist physicians. A second objective was to examine, by a subjective analysis, the features of acromegaly in the normal subjects of our photographic database. Results  The accuracy of the computer model was 86%; the average of the 10 physicians was 26%. The worst individual physician, 16%, the best, 90%. The faces of 200 normal subjects, the original faces in the database, could be divided into four groups, averaged by computer, from those with fewer to those with more features of acromegaly. Conclusions  The present computer model can sort photographs of patients with acromegaly from photographs of normal subjects and is much more accurate than the sorting by practicing generalists. Even normal subjects have some of the features of acromegaly. Screening with this approach can be improved with automation of the procedure, software development and the identification of target populations in which the prevalence of acromegaly may be increased over that in the general population.
    • Endoscopic transsphenoidal pituitary surgery: evidence of an operative learning curve.

      Leach, P; Abou-Zeid, A H; Kearney, T; Davis, J R E; Trainer, Peter J; Gnanalingham, K K; Department of Neurosurgery, Greater Manchester Neurosciences Centre, Salford Royal Foundation Trust, Salford, UK. (2010-11)
      BACKGROUND: The use of the fiberoptic endoscope is a recent innovation in pituitary surgery. OBJECTIVE: To investigate the evidence of an operative learning curve after the introduction of endoscopic transsphenoidal surgery in our unit. METHODS: The first 125 patients who underwent endoscopic transnasal transsphenoidal surgery for pituitary fossa lesions between 2005 and 2007 performed by 1 surgeon were studied. Changes in a number of parameters were assessed between 2 equal 15-month time periods: period 1 (53 patients) and period 2 (72 patients). RESULTS: There were 67 patients (54%) with nonfunctioning adenomas, 22 (18%) with acromegaly, and 10 (8%) with Cushing's disease. Between study periods 1 and 2, there was a decrease in the mean duration of surgery for nonfunctioning adenomas (from 120 minutes to 91 minutes; P < .01). This learning effect was not apparent for functioning adenomas, the surgery for which also took longer to perform. The proportion of patients with an improvement in their preoperative visual field deficits increased over the study period (from 80% to 93%; P < .05). There were nonsignificant trends toward improved endocrine remission rates for patients with Cushing's disease (from 50% to 83%), but operative complications, notably the rates of hypopituitarism, did not change. Overall length of hospital stay decreased between time periods 1 and 2 (from 7 to 4 days median; P < .01). CONCLUSION: The improvements in the duration of surgery and visual outcome noted after about 50 endoscopic procedures would favor the existence of an operative learning curve for these parameters. This further highlights the benefits of subspecialization in pituitary surgery.
    • Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency.

      Alatzoglou, Kyriaki S; Turton, James P; Kelberman, Daniel; Clayton, Peter E; Mehta, Ameeta; Buchanan, Charles; Aylwin, Simon; Crowne, Elizabeth C; Christesen, Henrik T; Hertel, Niels T; et al. (2009-09)
      CONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.
    • Giant leaps forward.

      Trainer, Peter J; Christie Hospital, Manchester. peter.trainer@manchester.ac.uk (2009-08)
    • 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.
    • Measurement of salivary cortisol with liquid chromatography-tandem mass spectrometry in patients undergoing dynamic endocrine testing.

      Perogamvros, Ilias; Owen, Laura J; Keevil, Brian G; Brabant, Georg E; Trainer, Peter J; Department of Endocrinology, Christie Hospital, Manchester, UK. (2009-03-19)
      Objective: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) eliminates cross-reactivity, which is a major limitation of immunoassays used for the measurement of salivary cortisol (SalC). We aimed to evaluate the potential of SalC measured by LC-MS/MS in patients undergoing assessment of the HPA axis. Design and patients: Cross-sectional study of 78 patients admitted for routine testing in a specialized endocrine unit. Measurements: Matched serum and saliva samples were collected from 68 patients who had a Short Synacthen Test (SST, 250 mcg IM) and 10 patients who had an Insulin Tolerance Test (ITT, insulin 0.15 U/kg IV). Serum cortisol (SerC) was measured with an automated immunoassay and SalC with LC-MS/MS. Adequate SerC responses were >500 nmol/l. Results: In all patients with adequate responses the relative increase in SalC was significantly higher than in SerC [6.4(0.3-26.1) vs 1.0(0.3-4.9), P<0.0001)]. The SerC-SalC relationship was better explained by an exponential rather than a linear model (R(2)=0.83 vs R(2)=0.65, both P<0.0001). Based on 59 patients with adequate SerC responses to an SST, an adequate SalC response was defined as 8.3 nmol/l. 7 patients following an SST and 3 patients following an ITT showed inadequate responses in both SerC and SalC, but two patients with CBG deficiency showed a low SerC with normal SalC. Conclusions: We have shown an excellent diagnostic sensitivity and specificity of LC-MS/MS SalC in the assessment of the HPA axis and superiority over SerC when CBG levels are altered. The exponential relationship between SerC and SalC supports the concept of CBG binding capacity saturation.
    • Novel corticosteroid-binding globulin variant that lacks steroid binding activity.

      Perogamvros, Ilias; Underhill, C; Henley, D E; Hadfield, K D; Newman, W G; Ray, David W; Lightman, S L; Hammond, G L; Trainer, Peter J; Department of Endocrinology, Christie Hospital, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom. (2010-10)
      BACKGROUND: Corticosteroid-binding globulin (CBG) is the principal carrier for glucocorticoids in the circulation and a regulator of their bioavailability. Inherited CBG deficiencies are rarely reported, and only three causative mutations in four families have been described. PATIENTS, METHODS, AND RESULTS: In a 26-yr-old female with hypotension, fatigue, and undetectable total serum cortisol at presentation, we have identified a novel homozygous c.776g>t transversion in exon 3 of the CBG (SERPINA6) gene. This results in a p.Gly237Val substitution that is predicted to influence the positioning of two β-sheets that constitute part of the CBG steroid-binding site. Two siblings were also homozygous for the variant, whereas her mother and an unaffected sibling were heterozygous. No other symptomatic family members were identified apart from the proband. Individuals homozygous for the variant had serum CBG levels below the reference range when measured by RIA, but CBG was unmeasurable in cortisol-binding capacity assays. In the same individuals, we observed very low baseline and stimulated total serum cortisol levels but normal free serum and salivary cortisol and plasma ACTH. In a study of ultradian cortisol pulsatility, increased pulse frequency was only observed in the proband. CONCLUSION: We describe a novel CBG variant that lacks steroid binding activity. All mutant homozygotes have very low total serum cortisol, but normal free serum cortisol levels. The only biochemical feature to distinguish the symptomatic subject was increased cortisol pulsatility, and we suggest that this may influence glucocorticoid signaling and contribute to symptoms previously associated with CBG deficiency.
    • 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.
    • The pituitary gland and age-dependent regulation of body composition.

      Van Beek, André P; Wolffenbuttel, Bruce H R; Runge, Evelien; Trainer, Peter J; Jönsson, Peter J; Koltowska-Häggström, Maria; Department of Endocrinology, University Medical Center Groningen, University of Groningen, De Brug 4.069, AA 31, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. a.p.van.beek@int.umcg.nl (2010-08)
      CONTEXT: The prevalence of obesity is increased in hypopituitarism. In the general population, body mass index (BMI) and waist circumference increase with advancing age. It remains uncertain whether age-related changes in pituitary function contribute to the changes in body composition associated with advancing years. OBJECTIVE: Our objective was to study the relationship between pituitary function, body composition, and age in a large cohort of patients with hypopituitarism and a matched reference population. DESIGN, SETTING, AND PARTICIPANTS: A total of 3632 GH-deficient adults with hypopituitarism, adequately replaced with all pituitary hormones except for GH, from the prospective KIMS database (Pfizer International Metabolic Database) were included in present analysis. A random sample of the general population (3427 subjects) was used as reference. Patients and controls were grouped by gender in five age cohorts of 10 yr from 28 yr onward. MAIN OUTCOME MEASURES: Differences in BMI and waist circumference were evaluated. RESULTS: Patients had a significantly higher BMI and waist circumference than controls, with larger differences at younger age. With advancing age, an increase in BMI and waist circumference was seen in controls but was virtually absent in the patients with adult-onset GH deficiency and hypopituitarism. CONCLUSION: Patients with hypopituitarism have more excess body fat than age-matched controls, especially in the youngest age groups. The normal increase in fat mass with advancing age is not seen in adult-onset GH-deficient hypopituitarism, suggesting a potential role for the normal pituitary gland as an age-dependent regulator of body composition in adult life.
    • Pituitary-independent effect of octreotide on IGF-I generation.

      Pokrajac, Ana; Frystyk, Jan; Flyvbjerg, Allan; Trainer, Peter J; Department of Endocrinology, Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom. (2009)
      Background: Somatostatin analogues (SSTAs) are frequently used for medical treatment of acromegaly. The rationale for their use is based on inhibition of pituitary GH secretion; however, there is in vitro evidence that octreotide also acts to inhibit hepatic IGF-I generation. Aim&Design: We studied the pituitary-independent effects of octreotide on IGF-I generation in 11 severely GH deficient humans (age 38, range 23-52; 7 male; BMI 24.7+/-3 kg/m2; peak stimulated GH <3mug/L; 3+/-1 pituitary hormone deficiencies) on a stable dose of GH replacement (0.4+/-0.1 mg) for at least 6 months. Patients were studied before and after 50 mug of subcutaneous octreotide three times a day for 7 days. Results: At study entry, all patients had total IGF-I within age- and gender-related reference range (SDS 0.4+/-1.0). Octreotide treatment resulted in a significant fall in total IGF-I (by 18%, 208+/-89 vs. 173+/-62 mug/L, P=0.04), free IGF-I (by 13%, 0.83+/-0.36 vs. 0.70+/-0.33 mug/L, P=0.01) and IGFBP-3 (6%, 4475+/-745 vs. 4209+/-912 mug/L, P=0.02). Octreotide suppressed fasting insulin from 8.1+/-3.4 to 6.3+/-4.1 mU/L (P=0.01) and was associated with a rise in fasting glucose from 5.2+/-0.9 to 5.8+/-0.9 mmol/L (P<0.01). IGFBP-1 increased by 84% from 42+/-26 to 95+/-52 mug/L (P=0.04). Conclusion: Our study demonstrates that octreotide induces a significant fall in IGF-I in severely GH deficient adults on fixed-dose of GH replacement. This is the evidence for a non-pituitary action of octreotide on the GH/IGF-I axis, most likely by antagonizing the action of GH on hepatic IGF-I generation and indirectly, by suppressing insulin secretion.
    • A randomized, controlled, multicentre trial comparing pegvisomant alone with combination therapy of pegvisomant and long-acting octreotide in patients with acromegaly.

      Trainer, Peter J; Ezzat, Shereen; D'Souza, Gwyn A; Layton, Gary; Strasburger, Christian J; Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester, UK. Peter.Trainer@manchester.ac.uk (2009-10)
      OBJECTIVE: For patients with acromegaly who are suboptimally controlled on long-acting octreotide (LAR), treatment options are to switch to pegvisomant monotherapy (PM) or add pegvisomant to LAR (P-LAR). Our objective was to evaluate if the safety and efficacy of these regimens differ. DESIGN: This was an open-label, multicentre, randomized, 40-week outpatient study. The control arm consisted of patients controlled on LAR (n = 28). PATIENTS: A total of 27 patients with suboptimally controlled acromegaly [as indicated by a serum IGF-I level > or = 1.3 x upper limit of normal (ULN) of the age-related reference range] were randomized to PM (10 mg once daily initially, then adjusted in 5-mg increments every 8 weeks based on IGF-I levels) and 29 to P-LAR (LAR dosing remained fixed). MEASUREMENTS: The primary end-point was adverse events (AEs). The secondary end-point was biochemical IGF-I-based efficacy. The RIA for IGF-I was discontinued by the manufacturer during the study and a chemiluminescent assay was subsequently used. Previously obtained IGF-I levels were re-analysed. RESULTS: PM and P-LAR were well tolerated and there were no differences in the number of AEs. Patients receiving P-LAR tended to be more likely to have clinically significant increases in hepatic transaminase levels, especially those receiving high-dose LAR. Normalization of IGF-I was similar with both regimens (56% and 62% of patients for PM and P-LAR respectively). The change in IGF-I assay resulted in lower rates of IGF-I normalization than expected. Reductions in fasting glucose levels were greater with PM than with P-LAR (-0.8 mmol/l; 95% confidence interval -1.16, -0.53 mmol/l). CONCLUSIONS: In patients suboptimally controlled on LAR, PM and P-LAR were equally well tolerated and effective in normalizing IGF-I, and overall clinical improvement was observed with both regimens. Thus, pegvisomant monotherapy and adjunctive therapy are equally viable options for the treatment of LAR-resistant acromegaly.