• 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)
    • Altered phenotype of NK cells from obses rats can be normalized by transfer into lean animals.

      Lautenbach, Anne; Wrann, Christiane D; Jacob, Roland; Muller, Guenter; Brabant, Georg E; Nave, Heike; Institute for Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany. (2009)
    • Assessment of quality of life in adult patients with GH deficiency: KIMS contribution to clinical practice and pharmacoeconomic evaluations.

      Koltowska-Häggström, Maria; Mattsson, Anders F; Shalet, Stephen M; KIMS Medical Outcomes, Pfizer Health AB, Endocrine Care, Sollentuna, Sweden. maria.koltowska-haggstrom@pfizer.com (2009-11)
      Quality of life (QoL) has emerged as an important construct that has found numerous applications across healthcare-related fields, ranging from research and clinical evaluation of treatment effects to pharmacoeconomic evaluations and global healthcare policy. Impairment of QoL is one of the key clinical characteristics in adult GHD and has been extensively studied in the Pfizer International Metabolic Database (KIMS). We provide summarized evidence on GH treatment effects for both clinical and health economic applications based on the KIMS data. The primary focus is on those aspects of QoL research that cannot be investigated in the traditional clinical trial setting, such as specific patient subgroups, cross-country comparisons and long-term follow-up. First, the impact of age, gender, disease onset, primary aetiology, extent of hypopituitarism, previous radiotherapy and obesity on QoL before and during long-term GH replacement is discussed. Secondly, the studies on QoL in relation to country-specific normative values are reviewed. Finally, health economic data derived from KIMS including both burden of disease and utility assessment are evaluated. We conclude that the wide spectrum of analyses performed on the KIMS data allows for practical application of the results not only to research and clinical practice but also to health policy and global medical decision making.
    • 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.
    • Central insulin action regulates peripheral glucose and fat metabolism in mice.

      Koch, Linda; Wunderlich, F Thomas; Seibler, Jost; Könner, A Christine; Hampel, Brigitte; Irlenbusch, Sigrid; Brabant, Georg E; Kahn, C Ronald; Schwenk, Frieder; Brüning, Jens C; et al. (2008-06)
      Insulin resistance is a hallmark of type 2 diabetes, and many insights into the functions of insulin have been gained through the study of mice lacking the IR. To gain a better understanding of the role of insulin action in the brain versus peripheral tissues, we created 2 mouse models with inducible IR inactivation, 1 in all tissues including brain (IRDeltawb), and 1 restricted to peripheral tissues (IRDeltaper). While downregulation of IR expression resulted in severe hyperinsulinemia in both models, hyperglycemia was more pronounced in IRDeltawb mice. Both strains displayed a dramatic upregulation of hepatic leptin receptor expression, while only IRDeltaper mice displayed increased hepatic Stat3 phosphorylation and Il6 expression. Despite a similar reduction in IR expression in white adipose tissue (WAT) mass in both models, IRDeltawb mice had a more pronounced reduction in WAT mass and severe hypoleptinemia. Leptin replacement restored hepatic Stat3 phosphorylation and normalized glucose metabolism in these mice, indicating that alterations in glucose metabolism occur largely as a consequence of lipoathrophy upon body-wide IR deletion. Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation.
    • 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.
    • Cranially irradiated adult cancer survivors may have normal spontaneous GH secretion in the presence of discordant peak GH responses to stimulation tests (compensated GH deficiency).

      Darzy, Ken H; Thorner, Michael O; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Manchester, UK. (2009-02)
      CONTEXT: We have previously demonstrated that spontaneous (physiological) GH secretion was entirely normal in cranially irradiated patients who had normal individual peak GH responses to the insulin tolerance test (ITT) but reduced maximal somatotroph reserve as indicated by substantially reduced group GH responses to the GHRH + arginine stimulation test (AST). The normality of spontaneous GH secretion was attributed to a compensatory increase in hypothalamic stimulatory input within a partially damaged hypothalamic-pituitary (h-p) axis. It is unknown, however, if such compensatory stimulation can also maintain normality of GH secretion in those who fail the ITT but pass the GHRH + AST. STUDY SUBJECTS AND DESIGN: We studied 24-h spontaneous GH secretion by 20-min sampling both in the fed state (n = 11) and in the last 24 h of a 33-h fast (n = 9) in adult cancer survivors with subnormal peak GH responses to the ITT but either normal or relatively less attenuated peak GH responses to the GHRH + AST. The study was conducted 8.3 +/- 1.8 (range 2-23) years after cranial irradiation for nonpituitary brain tumours (n = 9) or leukaemia/lymphoma (n = 2) in comparison with 30 normal controls (fasting, 14). RESULTS: Previously published diagnostic thresholds for the ITT, GHRH + AST and spontaneous GH secretion were used to characterize GH secretion. Four of the 11 patients with impaired stimulated responses to both tests showed only minor discordancies between stimulated and spontaneous GH secretion. Two of the remaining seven patients had subnormal spontaneous GH secretion. However, spontaneous GH secretion, both individually and as a group, was entirely normal in the remaining five patients who had impaired GH responses to the ITT but normal individual responses to the GHRH + AST; in these five patients, IGF-I standard deviation scores (SDS; -2.7 to -0.8) were significantly reduced to a moderate degree compared with normals. CONCLUSIONS: In cranially irradiated adult cancer survivors, it cannot be assumed that failure to pass the ITT in isolation reflects severe GH deficiency (GHD). It appears that in some patients near-maximal compensatory overdrive of the partially damaged somatotroph axis may result in near-normal quantitative restoration of spontaneous GH secretion, thus limiting further stimulation with the ITT to the extent that impaired GH responses can be seen even before spontaneous GH secretion starts to decline in adults. However, IGF-I status continues to provide useful information about the adequacy of the compensatory process and therefore the degree of normality of GH secretion.
    • 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.
    • Diet-induced obesity alters behavior as well as serum levels of corticosterone in F344 rats.

      Buchenauer, T; Behrendt, P; Bode, F J; Horn, R; Brabant, Georg E; Stephan, M; Nave, H; Institute for Functional and Applied Anatomy, Hannover Medical School, 30625 Hannover, Germany. (2009-12-07)
      Obesity is an increasing socio-economic health problem. Diet-induced obese (DIO) rodents are widely used as a model of obesity in humans. However, there is no comprehensive data about the behavioral phenotype of DIO rodents. Therefore, the aim of the present study was to determine whether a high-fat-diet changes behavioral patterns of DIO Fischer 344 (F344) rats in comparison with lean littermates. The behavioral tests (homecage, holeboard, social interaction, and hotplate) were performed in 28 normal-weight and 28 male DIO F344 rats (mean age: 16 weeks) and revealed a significantly higher level of anxiety- and aggression-related parameters in obese rats, whereas their pain threshold was significantly lower. Fitting to a different behavioral response, basal corticosterone levels (measured by RIA) of obese animals were significantly elevated (16.0ng/ml vs. 12.5ng/ml; p<0.01). We conclude that obese rats differ in various aspects from their lean littermates. The altered behavioral characteristics displayed by DIO F344 rats have to be considered in further experiments involving DIO rodents.
    • Diet-induced obesity, exogenous leptin-, and MADB106 tumor cell challenge affect tissue leukocyte distribution and serum levels of cytokines in F344 rats

      Behrendt, Patrick; Buchenauer, Tobias; Horn, Rüdiger; Brabant, Georg E; Jacobs, Roland; Bode, Felix; Stephan, Michael; Nave, Heike (2010)
    • Do doctors discuss fertility issues before they treat young patients with cancer?

      Anderson, R A; Weddell, A; Spoudeas, H A; Douglas, C; Shalet, Stephen M; Levitt, G; Wallace, W H B; Division of Developmental and Reproductive Science, University of Edinburgh, Edinburgh, UK. (2008-10)
      BACKGROUND: Many children treated for cancer are at risk of infertility, but for girls and prepubertal boys, all fertility preservation techniques remain experimental. We have assessed UK practice relating to information provision about the effects of cancer treatment on fertility and options for fertility preservation. METHODS: Paediatric oncologists prospectively completed a data form for each new patient registered over a 12 month period. RESULTS: Data were available on 1030 patients (68% of total registered). The effect of cancer treatment on fertility was discussed with 63% of patients. Of these, 61% were judged to be at high or medium risk of fertility problems. Discussions took place more commonly with boys than girls; the commonest reason for discussion not occurring was young age. The majority (83%) of post-pubertal boys assessed as high/medium risk of infertility were referred for semen cryopreservation. This rate fell to 39% of those in early puberty. Only 1% (n=4) of girls were referred to an assisted conception unit. CONCLUSIONS: These data indicate a high awareness of the potential adverse effects of therapy on fertility among UK paediatric oncologists. High referral rates for older boys indicate that current guidelines are followed, but there is a need for fertility preservation techniques for girls and younger boys.
    • Doxorubicin fails to eradicate cancer stem cells derived from anaplastic thyroid carcinoma cells: characterization of resistant cells.

      Zheng, Xuqin; Cui, Dai; Xu, Shuhang; Brabant, Georg E; Derwahl, Michael; Division of Endocrinology, Department of Medicine, St Hedwig Hospital and Humboldt University, D-10115 Berlin, Berlin, Germany. (2010-08)
      Current chemotherapy with doxorubicin fails to eradicate anaplastic thyroid cancer or even to stop tumor progress which may be due to the failure of these drugs to effectively target putative cancer stem cells. To test this hypothesis, anaplastic thyroid cell lines were characterized by FACS for their content of cancer stem cells, their in vitro sphere-forming capacity and their expression of multidrug resistance transporters of the ABC gene family which may confer drug resistance to the cells. Cells were treated with doxorubicin in short-term and long-term culture up to 6 months to establish a resistant cell line. The survival of cancer and cancer stem cells and the differential expression of transporters were analyzed. Anaplastic thyroid cancer cell lines that consisted of 0.4-0.8% side population cells, expressed ABCG2 and multi-drug-resistant 1 (MDR1) transporters. Treatment with doxorubicin gradually killed the non-side population of cancer cells derived from anaplastic thyroid carcinoma cells. This conferred a growth advantage to cancer stem cells which in turn overgrew the culture. Resistant cell line consisted of a 70% side population fraction enriched with Oct4-positive cancer stem cells. Inhibition of ABCG2 and/or MDR1 revealed that resistance of cancer stem cells to doxorubicin may be mainly due to the expression of these ABC transporters that were highly up-regulated in the resistant subline. The poor outcome of chemotherapy with doxorubicin in anaplastic thyroid carcinoma may be partly explained by up-regulation of ABCG2 and MDR1 transporters that confers resistance to cancer stem cells. Thus an effective treatment of anaplastic thyroid cancer has not only to destroy cancer cells that represent the bulk of tumor cell population but also cancer stem cells that may drive tumor progression.
    • 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.
    • Effect of aromatizable and unaromatizable androgen replacement in hypogonadal men on GH responsiveness.

      Gleeson, Helena K; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Wilmslow Road, Withington, Manchester, M20 4BX, UK. helena@kgleeson99.freeserve.co.uk (2009-01)
      OBJECTIVES: Although studies have clearly demonstrated that oestrogen replacement affects GH responsiveness by causing relative GH resistance, the effect of androgen replacement is unknown. Circumstantial evidence only suggests that androgen replacement may increase GH sensitivity and/or responsiveness. To examine the impact of androgens on GH responsiveness, hypogonadal men underwent the IGF-1 generation test in the unreplaced state, replaced with testosterone (T) and also replaced with dihydrotestosterone (DHT), its nonaromatizable metabolite. DESIGN AND PATIENTS: Twelve hypogonadal men with a normal GH axis were recruited. Each subject in random order had 4 weeks off T (NoRx), 4 weeks on T gel (TG) and 4 weeks on DHT gel (DHTG) applied daily, with 1 week washout between each preparation. An IGF-1 generation test using a subcutaneous injection of 7 mg of GH was performed at the end of each of these 4-week phases. MEASUREMENTS: Serum GHBP, total and free IGF-1, IGFBP-3 and acid-labile subunit (ALS) levels were measured at baseline and 24 h (peak) after GH administration. RESULTS: Despite a decrease in GHBP during the TG and DHTG phases, there were no observed differences in baseline, peak or increment (peak - baseline) total or free IGF-1 between the NoRx, TG or DHTG phases. CONCLUSIONS: There is no evidence of fluctuation in GH responsiveness in hypogonadal men, untreated or replaced with T or DHT alone. This implies that the increased level of oestradiol as a consequence of T replacement in hypogonadal men does not impact significantly on GH responsiveness, nor is there evidence of an androgen effect with elevated DHT levels as a consequence of either T or DHT replacement.
    • Effects of antiepileptic drug therapy on vitamin D status and biochemical markers of bone turnover in children with epilepsy.

      Nettekoven, Sina; Ströhle, Alexander; Trunz, Birgit; Wolters, Maike; Hoffmann, Susanne; Horn, R; Steinert, Martin; Brabant, Georg E; Lichtinghagen, Ralf; Welkoborsky, Hans-Jürgen; et al. (2008-12)
      Reports of decreased serum 25-hydroxyvitamin D (25-OHD) and altered bone metabolism associated with antiepileptic drug (AED) treatment are inconsistent and predominantly restricted to adults. In this cross-sectional observational study, the aim was to evaluate the influence of AED treatment on vitamin D status and markers of bone turnover in children with epilepsy. In 38 children taking AEDs and 44 healthy control subjects, blood samples were collected to determine the levels of serum 25-OHD, intact parathyroid hormone (iPTH), calcium (Ca), phosphate (P), bone alkaline phosphatase (BAP), osteocalcin (OC) and C terminal telopeptide of type I collagen (ICTP). More than 75% of the patients were vitamin D deficient (serum 25-OHD<20 ng/mL) and 21% of the patients had an insufficient vitamin D status (serum 25-OHD=20-30 ng/mL). In the patients, the serum levels of OC (p = 0.002) and BAP (p < 0.001) were significantly increased, but ICTP (p = 0.002) concentrations were significantly decreased compared with the control group. When patients where divided into two groups according to their medication (mono- or polytherapy), significantly lower 25-OHD (p = 0.038) and ICTP (p = 0.005) levels and elevated BAP (p = 0.023) concentrations were found in patients under polytherapy. An association between 25-OHD and the measured bone markers could not be determined. Our results indicate that the prevalence of vitamin D deficiency in epilepsy patients under AED treatment is high, especially under polytherapy, and alteration markers of bone formation and resorption suggests an accelerated skeletal turnover. The routine monitoring of serum 25-OHD and vitamin D supplementation on an individual basis should be considered.