Letters to the Editor 593 hypermetabolic tissues. We adopted this screening methodology and further reinforced it using two independent experienced physicians who verified that all PET/CT results did not include cancerous tumours. Finally, the Discussion section of our original paper provides extensive information on the potential physiological differences between patients with cancer and healthy subjects with respect to the study findings. All the above demonstrate a well-designed and thorough process as well as that the reader of our original paper6 is able to recognize the potential limits of performing our study in a group of individuals undergoing 18F-FDG PET/CT scanning, the majority of which pertained to cancer detection. In this light, it becomes clear that the concerns of Ruiz et al.7 have been already addressed in our original paper.6 We view differences in opinion as a reason for discussion, not a reason for rejection. In this light, the letter of Ruiz et al.7 is most welcome and exemplifies the need for further research, reflection and debate required to elucidate the physiological and molecular pathways related to the function of BAT. Having written that, however, we are compelled to note that – as shown in the previous paragraphs – three of the four issues raised by Ruiz et al.7 have been effectively addressed in our original paper.6
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Andreas D. Flouris* and Petros C. Dinas*,† *Department of Exercise Science, FAME Laboratory, University of Thessaly, Trikala, Greece †Institute of Sport, Faculty of Education, Health, and Wellbeing, University of Wolverhampton, Walsall, UK E-mail: [email protected] doi: 10.1111/cen.12716
References 1 Carrillo, A.E. & Flouris, A.D. (2011) Caloric restriction and longevity: effects of reduced body temperature. Ageing Research Reviews, 10, 153–162. 2 van Marken Lichtenbelt, W.D. & Schrauwen, P. (2011) Implications of nonshivering thermogenesis for energy balance regulation in humans. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 301, R285–R296. 3 Baar, K., Wende, A.R., Jones, T.E. et al. (2002) Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB Journal, 16, 1879–1886. 4 Seale, P., Bjork, B., Yang, W. et al. (2008) PRDM16 controls a brown fat/skeletal muscle switch. Nature, 454, 961–967. 5 Xu, X., Ying, Z., Cai, M. et al. (2011) Exercise ameliorates highfat diet-induced metabolic and vascular dysfunction, and increases adipocyte progenitor cell population in brown adipose tissue. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 300, R1115–R1125. 6 Dinas, P.C., Nikaki, A., Jamurtas, A.Z. et al. (2015) Association between habitual physical activity and brown adipose tissue activity in individuals undergoing PET-CT scan. Clinical Endocrinology, 82, 147–154. 7 Ruiz, J.R., Sanchez-Delgado, G., Martınez-Tellez, B. et al. (2015) RE: Association between habitual physical activity and brown © 2015 John Wiley & Sons Ltd Clinical Endocrinology (2015), 83, 590–595
adipose tissue activity in individuals undergoing PET-CT scan. Clinical Endocrinology (Oxford), 83, 590–591. Papathanasiou, G., Georgoudis, G., Papandreou, M. et al. (2009) Reliability measures of the short International Physical Activity Questionnaire (IPAQ) in Greek young adults. Hellenic Journal of Cardiology, 50, 283–294. Metsios, G.S., Stavropoulos-Kalinoglou, A., Douglas, K.M. et al. (2007) Blockade of tumour necrosis factor-alpha in rheumatoid arthritis: effects on components of rheumatoid cachexia. Rheumatology (Oxford), 46, 1824–1827. Gianinis, H.H., Antunes, B.O., Passarelli, R.C. et al. (2013) Effects of dorsal and lateral decubitus on peak expiratory flow in healthy subjects. Brazilian Journal of Physical Therapy, 17, 435–441. Valente, A., Jamurtas, A.Z., Koutedakis, Y. et al. (2015) Molecular pathways linking non-shivering thermogenesis and obesity: focusing on brown adipose tissue development. Biological Reviews of the Cambridge Philosophical Society, 90, 77–88. Persichetti, A., Sciuto, R., Rea, S. et al. (2013) Prevalence, mass, and glucose-uptake activity of 18F-FDG-detected brown adipose tissue in humans living in a temperate zone of Italy. PLoS One, 8, e63391. Baba, S., Jacene, H.A., Engles, J.M. et al. (2010) CT Hounsfield units of brown adipose tissue increase with activation: preclinical and clinical studies. Journal of Nuclear Medicine, 51, 246–250. Cypess, A.M., Lehman, S., Williams, G. et al. (2009) Identification and importance of brown adipose tissue in adult humans. New England Journal of Medicine, 360, 1509–1517.
Effect of Growth hormone replacement therapy on soluble Klotho in patients with Growth hormone deficiency Dear Editors, Klotho, a lifespan-influencing protein, exists in a membranebound (mKlotho) and in a soluble (sKlotho) form. mKlotho serves as a coreceptor for fibroblast growth factor 23 (FGF23, a bone-derived, phosphaturic hormone) and is mainly expressed in the kidneys.1 Enzymes can split the extracellular part of mKlotho, thereby forming sKlotho.1 sKlotho is released into the circulation and can be measured by ELISA. Both growth hormone (GH) and sKlotho play important roles in renal function and phosphate handling. In patients with acromegaly, serum FGF23 and phosphate are increased despite increased glomerular filtration rate (GFR).2 sKlotho levels (markedly increased at baseline) decline after successful removal of the GH-secreting adenoma,3 suggesting a causal relationship between GH excess, phosphate and sKlotho. Monitoring growth hormone replacement therapy (GHRT) by the sole measurement of insulin-like growth factor-1 (IGF-1) is established, but mainly reflects hepatic GH actions. A liver-independent marker would be desirable, for monitoring not only GH excess control but also GHRT. A recent cross-sectional study found significantly lower sKlotho in children with severe organic growth hormone deficiency (GHD) compared to GHsufficient children.4 It remains unknown whether adult patients with GHD have decreased sKlotho levels and whether GHRT
594 Letters to the Editor guidelines in order to obtain IGF-1 concentrations in the upper half of the age-adjusted normal reference range. Results concerning the effect of GHRT on different fat compartments have been previously published.5 Blood samples were drawn after overnight fasting. Serum IGF1 was measured by an immunoradiometric assay (Nichols Institute, San Juan Capistrano, CA, USA),5 and sKlotho by an enzyme-linked immunosorbent assay (ELISA, IBL, Japan) according to the manufacturer’s protocol.3 Inorganic phosphate (formation of phosphomolybdenum blue, end-point test procedure) and creatinine concentrations (isotope dilution mass
results in an increase in sKlotho. We, therefore, aimed at investigating the effect of GHRT on sKlotho in GHD adult patients in a well-controlled prospective single-centre open case–control pilot study (ClinicalTrials.gov Identifier: NCT00491582) performed at the University Hospital of Bern, Switzerland. Four women and six men (age, 426 125 years; BMI, 266 38 kg/m2) with severe GHD and ten sedentary control subjects (CS) matched for age, gender, BMI and waist were recruited. Patients with GHD (GH treatment na€ıve at baseline) were treated with GH (Genotropinâ, Pfizer, Switzerland) for 6 months; the dose was gradually increased according to the current
(a)
(b)
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Fig. 1 (a) IGF-1 concentrations in GHD patients before (pre-) and after (post-)GHRT compared to the matched CS. IGF-1 concentrations were decreased in GHD patients compared with CS (Mann–Whitney U-test, P = 00005). IGF-1 concentrations increased after GHRT in patients (Wilcoxon signed rank test, P = 0002). (b) sKlotho in GHD patients pre- and post-GHRT compared to the matched CS. sKIotho concentrations in GHD patients did not significantly differ from CS. GHRT resulted in an increase in sKIotho (Wilcoxon signed rank test, P = 0002). (c) Phosphate concentrations in GHD patients before (pre-) and after (post-)GHRT compared to the CS. Phosphate concentrations in GHD patients were not significantly different from CS. GHRT resulted in an increase in serum phosphate (Wilcoxon signed rank test, P = 003). (d) Creatinine concentrations in GHD patients before (pre-) and after (post-)GHRT compared to the matched CS. Creatinine concentrations in GHD patients were not different from CS. GHRT resulted in a decrease in creatinine concentrations (Wilcoxon signed rank test, P = 002). © 2015 John Wiley & Sons Ltd Clinical Endocrinology (2015), 83, 590–595
Letters to the Editor 595 spectrometry traceable modified Jaffe method) were measured in serum using standard laboratory methods (Hitachi P-Modular system, Roche Diagnostics, Rotkreuz, Switzerland). IGF-1 concentrations were lower in GHD patients than in CS [GHD: 685 (403–876) ng/ml; median and interquartile range (IQR); CS: 1115 (938–1383) ng/ml; P < 0005]. GHRT increased IGF-1 concentrations [from 685 (403–876) to 1530 (112–1743) ng/ml; P < 0002] (Fig. 1a). sKlotho concentrations were not significantly different between GHD patients and CS at baseline [497 (419–658) and 558 (462–631) pg/ml, respectively]. GHRT increased sKlotho concentrations [from 497 (419–658) to 692 (590–1233) pg/ml; P = 0002] (Fig. 1b). Serum creatinine [74 (67–93) lmol/l and 70 (67–83) lmol/l, respectively] and serum phosphate [108 (098–119) mmol/l and 110 (095–128) mmol/l, respectively] were not different between GHD patients and CS. GHRT increased serum phosphate [108 (098–119) to 122 (104–135) mmol/l, P = 003] and decreased creatinine [74 (67–93) to 66 (64–87) lmol/l, P = 002] (Fig. 1c and d). To our knowledge, this is the first study which examined the effect of GHRT on sKlotho levels in adult GHD patients and compared them to matched healthy CS. The data show that: (1) sKlotho levels are not significantly lower in patients with GHD than in CS. sKlotho can therefore not be recommended as an additional marker for the diagnosis of GHD in adults; (2) GHRT increased sKlotho concentrations indicating a possible causal relationship between GH and sKlotho; (3) In keeping with previous data, GHRT resulted in an increase in phosphate levels in the presence of a decrease in creatinine concentrations, consistent with renal effects of GH on phosphate handling and GFR. Klotho (and phosphate) levels are higher in children than in adults and have recently been reported to be decreased in children (mean age, 9 years) with severe organic GHD.4 Our adult GHD patients did not have lower sKlotho, but lower IGF1 concentrations than CS (Fig. 1a and b), suggesting that at low ambient GH concentrations, such as in middle-aged GHD patients and CS, endogenous GH has no marked influence on circulating sKlotho. This is in contrast to GH excess where sKlotho appears to reflect GH action and disease control.3 GHRT significantly increased sKlotho and IGF-1 concentrations. The exact mechanism of action of GH on sKlotho remains to be elucidated. Phosphate and creatinine levels were not significantly different between GHD patients and CS, but phosphate increased and creatinine levels decreased in response to GHRT. The lack of baseline difference in creatinine and phosphate between GHD patients and CS, yet the response of the two parameters to GHRT is consistent with the pattern of sKlotho (Fig. 1b–d). The effect of GH administration on serum sKlotho is consistent with an important regulatory role of GH via the bone–FGF23–Klotho–kidney axis on phosphate homoeostasis.
© 2015 John Wiley & Sons Ltd Clinical Endocrinology (2015), 83, 590–595
This pilot study has its limitations. Calcitriol and FGF23 were not monitored, and only few patients were included. Nevertheless, GHRT resulted in a significant effect not only on creatinine and phosphate but also on sKlotho in this small group of individuals. Further studies with larger patient numbers are needed to confirm these findings.
Acknowledgements We thank all the enthusiastic patients and control subjects who agreed to participate in this study. The work was supported by grants from the Swiss National Foundation to Emanuel R. Christ (No. #32000B0-100146) and by the Independent Pfizer Research Grant (to E.C.). Pfizer AG Switzerland kindly provided GH.
Competing interests/financial disclosure The authors have no conflict of interest to disclose. Rebecca Locher*,†, Andrea Egger‡,§, Cornelia Zwimpfer*, Lisa Sze*,¶, Christoph Schmid* and Emanuel Christ‡ *Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland, †Division of Endocrinology and Diabetes, Cantonal Hospital of Graub€ unden, Chur, Switzerland, ‡Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Berne, Inselspital Berne, Berne, Switzerland, §Division of Internal Medicine, University Hospital of Basel, Basel, Switzerland, ¶Division of Endocrinology, Diabetes and Osteology, Cantonal Hospital of St. Gallen, St. Gallen, Switzerland E-mail: [email protected] doi: 10.1111/cen.12756
References 1 John, G.B., Cheng, C.Y. & Kuro-o, M. (2011) Role of Klotho in aging, phosphate metabolism, and CKD. American Journal of Kidney Diseases 58, 127–134. 2 Ito, N., Fukumoto, S., Taguchi, M. et al. (2007) Fibroblast growth factor (FGF)23 in patients with acromegaly. Endocrine Journal 54, 481–484. 3 Sze, L., Bernays, R.L., Zwimpfer, C. et al. (2012) Excessively high soluble Klotho in patients with acromegaly. Journal of Internal Medicine 272, 93–97. 4 Wolf, I., Shahmoon, S., Ben, A.M. et al. (2014) Association between decreased klotho blood levels and organic growth hormone deficiency in children with growth impairment. PLoS One 9, e107174. 5 Egger, A., Buehler, T., Boesch, C. et al. (2011) The effect of GH replacement therapy on different fat compartments: a wholebody magnetic resonance imaging study. European Journal of Endocrinology 164, 23–29.
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Andreas D. Flouris* and Petros C. Dinas*,† *Department of Exercise Science, FAME Laboratory, University of Thessaly, Trikala, Greece †Institute of Sport, Faculty of Education, Health, and Wellbeing, University of Wolverhampton, Walsall, UK E-mail: [email protected] doi: 10.1111/cen.12716
References 1 Carrillo, A.E. & Flouris, A.D. (2011) Caloric restriction and longevity: effects of reduced body temperature. Ageing Research Reviews, 10, 153–162. 2 van Marken Lichtenbelt, W.D. & Schrauwen, P. (2011) Implications of nonshivering thermogenesis for energy balance regulation in humans. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 301, R285–R296. 3 Baar, K., Wende, A.R., Jones, T.E. et al. (2002) Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB Journal, 16, 1879–1886. 4 Seale, P., Bjork, B., Yang, W. et al. (2008) PRDM16 controls a brown fat/skeletal muscle switch. Nature, 454, 961–967. 5 Xu, X., Ying, Z., Cai, M. et al. (2011) Exercise ameliorates highfat diet-induced metabolic and vascular dysfunction, and increases adipocyte progenitor cell population in brown adipose tissue. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 300, R1115–R1125. 6 Dinas, P.C., Nikaki, A., Jamurtas, A.Z. et al. (2015) Association between habitual physical activity and brown adipose tissue activity in individuals undergoing PET-CT scan. Clinical Endocrinology, 82, 147–154. 7 Ruiz, J.R., Sanchez-Delgado, G., Martınez-Tellez, B. et al. (2015) RE: Association between habitual physical activity and brown © 2015 John Wiley & Sons Ltd Clinical Endocrinology (2015), 83, 590–595
adipose tissue activity in individuals undergoing PET-CT scan. Clinical Endocrinology (Oxford), 83, 590–591. Papathanasiou, G., Georgoudis, G., Papandreou, M. et al. (2009) Reliability measures of the short International Physical Activity Questionnaire (IPAQ) in Greek young adults. Hellenic Journal of Cardiology, 50, 283–294. Metsios, G.S., Stavropoulos-Kalinoglou, A., Douglas, K.M. et al. (2007) Blockade of tumour necrosis factor-alpha in rheumatoid arthritis: effects on components of rheumatoid cachexia. Rheumatology (Oxford), 46, 1824–1827. Gianinis, H.H., Antunes, B.O., Passarelli, R.C. et al. (2013) Effects of dorsal and lateral decubitus on peak expiratory flow in healthy subjects. Brazilian Journal of Physical Therapy, 17, 435–441. Valente, A., Jamurtas, A.Z., Koutedakis, Y. et al. (2015) Molecular pathways linking non-shivering thermogenesis and obesity: focusing on brown adipose tissue development. Biological Reviews of the Cambridge Philosophical Society, 90, 77–88. Persichetti, A., Sciuto, R., Rea, S. et al. (2013) Prevalence, mass, and glucose-uptake activity of 18F-FDG-detected brown adipose tissue in humans living in a temperate zone of Italy. PLoS One, 8, e63391. Baba, S., Jacene, H.A., Engles, J.M. et al. (2010) CT Hounsfield units of brown adipose tissue increase with activation: preclinical and clinical studies. Journal of Nuclear Medicine, 51, 246–250. Cypess, A.M., Lehman, S., Williams, G. et al. (2009) Identification and importance of brown adipose tissue in adult humans. New England Journal of Medicine, 360, 1509–1517.
Effect of Growth hormone replacement therapy on soluble Klotho in patients with Growth hormone deficiency Dear Editors, Klotho, a lifespan-influencing protein, exists in a membranebound (mKlotho) and in a soluble (sKlotho) form. mKlotho serves as a coreceptor for fibroblast growth factor 23 (FGF23, a bone-derived, phosphaturic hormone) and is mainly expressed in the kidneys.1 Enzymes can split the extracellular part of mKlotho, thereby forming sKlotho.1 sKlotho is released into the circulation and can be measured by ELISA. Both growth hormone (GH) and sKlotho play important roles in renal function and phosphate handling. In patients with acromegaly, serum FGF23 and phosphate are increased despite increased glomerular filtration rate (GFR).2 sKlotho levels (markedly increased at baseline) decline after successful removal of the GH-secreting adenoma,3 suggesting a causal relationship between GH excess, phosphate and sKlotho. Monitoring growth hormone replacement therapy (GHRT) by the sole measurement of insulin-like growth factor-1 (IGF-1) is established, but mainly reflects hepatic GH actions. A liver-independent marker would be desirable, for monitoring not only GH excess control but also GHRT. A recent cross-sectional study found significantly lower sKlotho in children with severe organic growth hormone deficiency (GHD) compared to GHsufficient children.4 It remains unknown whether adult patients with GHD have decreased sKlotho levels and whether GHRT
594 Letters to the Editor guidelines in order to obtain IGF-1 concentrations in the upper half of the age-adjusted normal reference range. Results concerning the effect of GHRT on different fat compartments have been previously published.5 Blood samples were drawn after overnight fasting. Serum IGF1 was measured by an immunoradiometric assay (Nichols Institute, San Juan Capistrano, CA, USA),5 and sKlotho by an enzyme-linked immunosorbent assay (ELISA, IBL, Japan) according to the manufacturer’s protocol.3 Inorganic phosphate (formation of phosphomolybdenum blue, end-point test procedure) and creatinine concentrations (isotope dilution mass
results in an increase in sKlotho. We, therefore, aimed at investigating the effect of GHRT on sKlotho in GHD adult patients in a well-controlled prospective single-centre open case–control pilot study (ClinicalTrials.gov Identifier: NCT00491582) performed at the University Hospital of Bern, Switzerland. Four women and six men (age, 426 125 years; BMI, 266 38 kg/m2) with severe GHD and ten sedentary control subjects (CS) matched for age, gender, BMI and waist were recruited. Patients with GHD (GH treatment na€ıve at baseline) were treated with GH (Genotropinâ, Pfizer, Switzerland) for 6 months; the dose was gradually increased according to the current
(a)
(b)
(c)
(d)
Fig. 1 (a) IGF-1 concentrations in GHD patients before (pre-) and after (post-)GHRT compared to the matched CS. IGF-1 concentrations were decreased in GHD patients compared with CS (Mann–Whitney U-test, P = 00005). IGF-1 concentrations increased after GHRT in patients (Wilcoxon signed rank test, P = 0002). (b) sKlotho in GHD patients pre- and post-GHRT compared to the matched CS. sKIotho concentrations in GHD patients did not significantly differ from CS. GHRT resulted in an increase in sKIotho (Wilcoxon signed rank test, P = 0002). (c) Phosphate concentrations in GHD patients before (pre-) and after (post-)GHRT compared to the CS. Phosphate concentrations in GHD patients were not significantly different from CS. GHRT resulted in an increase in serum phosphate (Wilcoxon signed rank test, P = 003). (d) Creatinine concentrations in GHD patients before (pre-) and after (post-)GHRT compared to the matched CS. Creatinine concentrations in GHD patients were not different from CS. GHRT resulted in a decrease in creatinine concentrations (Wilcoxon signed rank test, P = 002). © 2015 John Wiley & Sons Ltd Clinical Endocrinology (2015), 83, 590–595
Letters to the Editor 595 spectrometry traceable modified Jaffe method) were measured in serum using standard laboratory methods (Hitachi P-Modular system, Roche Diagnostics, Rotkreuz, Switzerland). IGF-1 concentrations were lower in GHD patients than in CS [GHD: 685 (403–876) ng/ml; median and interquartile range (IQR); CS: 1115 (938–1383) ng/ml; P < 0005]. GHRT increased IGF-1 concentrations [from 685 (403–876) to 1530 (112–1743) ng/ml; P < 0002] (Fig. 1a). sKlotho concentrations were not significantly different between GHD patients and CS at baseline [497 (419–658) and 558 (462–631) pg/ml, respectively]. GHRT increased sKlotho concentrations [from 497 (419–658) to 692 (590–1233) pg/ml; P = 0002] (Fig. 1b). Serum creatinine [74 (67–93) lmol/l and 70 (67–83) lmol/l, respectively] and serum phosphate [108 (098–119) mmol/l and 110 (095–128) mmol/l, respectively] were not different between GHD patients and CS. GHRT increased serum phosphate [108 (098–119) to 122 (104–135) mmol/l, P = 003] and decreased creatinine [74 (67–93) to 66 (64–87) lmol/l, P = 002] (Fig. 1c and d). To our knowledge, this is the first study which examined the effect of GHRT on sKlotho levels in adult GHD patients and compared them to matched healthy CS. The data show that: (1) sKlotho levels are not significantly lower in patients with GHD than in CS. sKlotho can therefore not be recommended as an additional marker for the diagnosis of GHD in adults; (2) GHRT increased sKlotho concentrations indicating a possible causal relationship between GH and sKlotho; (3) In keeping with previous data, GHRT resulted in an increase in phosphate levels in the presence of a decrease in creatinine concentrations, consistent with renal effects of GH on phosphate handling and GFR. Klotho (and phosphate) levels are higher in children than in adults and have recently been reported to be decreased in children (mean age, 9 years) with severe organic GHD.4 Our adult GHD patients did not have lower sKlotho, but lower IGF1 concentrations than CS (Fig. 1a and b), suggesting that at low ambient GH concentrations, such as in middle-aged GHD patients and CS, endogenous GH has no marked influence on circulating sKlotho. This is in contrast to GH excess where sKlotho appears to reflect GH action and disease control.3 GHRT significantly increased sKlotho and IGF-1 concentrations. The exact mechanism of action of GH on sKlotho remains to be elucidated. Phosphate and creatinine levels were not significantly different between GHD patients and CS, but phosphate increased and creatinine levels decreased in response to GHRT. The lack of baseline difference in creatinine and phosphate between GHD patients and CS, yet the response of the two parameters to GHRT is consistent with the pattern of sKlotho (Fig. 1b–d). The effect of GH administration on serum sKlotho is consistent with an important regulatory role of GH via the bone–FGF23–Klotho–kidney axis on phosphate homoeostasis.
© 2015 John Wiley & Sons Ltd Clinical Endocrinology (2015), 83, 590–595
This pilot study has its limitations. Calcitriol and FGF23 were not monitored, and only few patients were included. Nevertheless, GHRT resulted in a significant effect not only on creatinine and phosphate but also on sKlotho in this small group of individuals. Further studies with larger patient numbers are needed to confirm these findings.
Acknowledgements We thank all the enthusiastic patients and control subjects who agreed to participate in this study. The work was supported by grants from the Swiss National Foundation to Emanuel R. Christ (No. #32000B0-100146) and by the Independent Pfizer Research Grant (to E.C.). Pfizer AG Switzerland kindly provided GH.
Competing interests/financial disclosure The authors have no conflict of interest to disclose. Rebecca Locher*,†, Andrea Egger‡,§, Cornelia Zwimpfer*, Lisa Sze*,¶, Christoph Schmid* and Emanuel Christ‡ *Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Zurich, Zurich, Switzerland, †Division of Endocrinology and Diabetes, Cantonal Hospital of Graub€ unden, Chur, Switzerland, ‡Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Berne, Inselspital Berne, Berne, Switzerland, §Division of Internal Medicine, University Hospital of Basel, Basel, Switzerland, ¶Division of Endocrinology, Diabetes and Osteology, Cantonal Hospital of St. Gallen, St. Gallen, Switzerland E-mail: [email protected] doi: 10.1111/cen.12756
References 1 John, G.B., Cheng, C.Y. & Kuro-o, M. (2011) Role of Klotho in aging, phosphate metabolism, and CKD. American Journal of Kidney Diseases 58, 127–134. 2 Ito, N., Fukumoto, S., Taguchi, M. et al. (2007) Fibroblast growth factor (FGF)23 in patients with acromegaly. Endocrine Journal 54, 481–484. 3 Sze, L., Bernays, R.L., Zwimpfer, C. et al. (2012) Excessively high soluble Klotho in patients with acromegaly. Journal of Internal Medicine 272, 93–97. 4 Wolf, I., Shahmoon, S., Ben, A.M. et al. (2014) Association between decreased klotho blood levels and organic growth hormone deficiency in children with growth impairment. PLoS One 9, e107174. 5 Egger, A., Buehler, T., Boesch, C. et al. (2011) The effect of GH replacement therapy on different fat compartments: a wholebody magnetic resonance imaging study. European Journal of Endocrinology 164, 23–29.
