Advertisement

Endocrine

, Volume 51, Issue 2, pp 298–307 | Cite as

Preoperative octreotide therapy and surgery in acromegaly: associations between glucose homeostasis and treatment response

  • R. Helseth
  • S. M. Carlsen
  • J. Bollerslev
  • J. Svartberg
  • M. Øksnes
  • S. Skeie
  • S. L. Fougner
Original Article

Abstract

In acromegaly, high GH/IGF-1 levels associate with abnormal glucose metabolism. Somatostatin analogs (SSAs) reduce GH and IGF-1 but inhibit insulin secretion. We studied glucose homeostasis in de novo patients with acromegaly and changes in glucose metabolism after treatment with SSA and surgery. In this post hoc analysis from a randomized controlled trial, 55 de novo patients with acromegaly, not using antidiabetic medication, were included. Before surgery, 26 patients received SSAs for 6 months. HbA1c, fasting glucose, and oral glucose tolerance test were performed at baseline, after SSA pretreatment and at 3 months postoperative. Area under curve of glucose (AUC-G) was calculated. Glucose homeostasis was compared to baseline levels of GH and IGF-1, change after SSA pretreatment, and remission both after SSA pretreatment and 3 months postoperative. In de novo patients, IGF-1/GH levels did not associate with baseline glucose parameters. After SSA pretreatment, changes in GH/IGF-1 correlated positively to change in HbA1c levels (both p < 0.03). HbA1c, fasting glucose, and AUC-G increased significantly during SSA pretreatment in patients not achieving hormonal control (all p < 0.05) but did not change significantly in patients with normalized hormone levels. At 3 months postoperative, HbA1c, fasting glucose, and AUC-G were significantly reduced in both cured and not cured patients (all p < 0.05). To conclude, in de novo patients with acromegaly, disease activity did not correlate with glucose homeostasis. Surgical treatment of acromegaly improved glucose metabolism in both cured and not cured patients, while SSA pretreatment led to deterioration in glucose homeostasis in patients not achieving biochemical control.

Keywords

Somatostatin analogues Acromegaly Glucose homeostasis Medical treatment of acromegaly Pituitary surgery 

Notes

Acknowledgments

The study was performed by the POTA study group which is a subgroup of the “Norwegian Neuroendocrine Interest group” (NNI). The annual meetings of NNI are supported by Novartis Norway. The study was also directly supported by Novartis Norway who paid the salary for a part-time study nurse (20 % position), supported the drug used (Sandostatin® and Sandostatin LAR®) free of charge, and carried the expenses when the study nurse checked the raw data at each study site.

Compliance with Ethical Standards

Conflict of interest

SLF has received speaker honorariums from Ipsen and Novartis. The other authors have nothing to declare.

Supplementary material

12020_2015_679_MOESM1_ESM.pptx (935 kb)
Supplementary material 1 (PPTX 934 kb)

References

  1. 1.
    N. Moller, J.O. Jorgensen, Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr. Rev. 30(2), 152–177 (2009). doi: 10.1210/er.2008-0027 CrossRefPubMedGoogle Scholar
  2. 2.
    E. Resmini, F. Minuto, A. Colao, D. Ferone, Secondary diabetes associated with principal endocrinopathies: the impact of new treatment modalities. Acta Diabetol. 46(2), 85–95 (2009). doi: 10.1007/s00592-009-0112-9 CrossRefPubMedGoogle Scholar
  3. 3.
    G. Bardini, C.M. Rotella, S. Giannini, Dyslipidemia and diabetes: reciprocal impact of impaired lipid metabolism and Beta-cell dysfunction on micro- and macrovascular complications. Rev. Diabet. Stud. 9(2–3), 82–93 (2012). doi: 10.1900/rds.2012.9.82 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    M.R. Soeters, P.B. Soeters, M.G. Schooneman, S.M. Houten, J.A. Romijn, Adaptive reciprocity of lipid and glucose metabolism in human short-term starvation. Am. J. Physiol. Endocrinol. Metab. 303(12), E1397–E1407 (2012). doi: 10.1152/ajpendo.00397.2012 CrossRefPubMedGoogle Scholar
  5. 5.
    J.O. Jorgensen, M. Krag, N. Jessen, H. Norrelund, E.T. Vestergaard, N. Moller, J.S. Christiansen, Growth hormone and glucose homeostasis. Horm. Res. 62(Suppl 3), 51–55 (2004). doi: 10.1159/000080499 PubMedGoogle Scholar
  6. 6.
    N. Moller, P.C. Butler, M.A. Antsiferov, K.G. Alberti, Effects of growth hormone on insulin sensitivity and forearm metabolism in normal man. Diabetologia 32(2), 105–110 (1989)CrossRefPubMedGoogle Scholar
  7. 7.
    N. Moller, J.O. Jorgensen, N. Abildgard, L. Orskov, O. Schmitz, J.S. Christiansen, Effects of growth hormone on glucose metabolism. Horm. Res. 36(Suppl 1), 32–35 (1991)PubMedGoogle Scholar
  8. 8.
    N. Moller, O. Schmitz, J.O. Joorgensen, J. Astrup, J.F. Bak, S.E. Christensen, K.G. Alberti, J. Weeke, Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy. J. Clin. Endocrinol. Metab. 74(5), 1012–1019 (1992). doi: 10.1210/jcem.74.5.1569148 PubMedGoogle Scholar
  9. 9.
    O. Alexopoulou, M. Bex, P. Kamenicky, A.B. Mvoula, P. Chanson, D. Maiter, Prevalence and risk factors of impaired glucose tolerance and diabetes mellitus at diagnosis of acromegaly: a study in 148 patients. Pituitary 17(1), 81–89 (2014). doi: 10.1007/s11102-013-0471-7 CrossRefPubMedGoogle Scholar
  10. 10.
    A. Colao, R. Baldelli, P. Marzullo, E. Ferretti, D. Ferone, P. Gargiulo, M. Petretta, G. Tamburrano, G. Lombardi, A. Liuzzi, Systemic hypertension and impaired glucose tolerance are independently correlated to the severity of the acromegalic cardiomyopathy. J. Clin. Endocrinol. Metab. 85(1), 193–199 (2000). doi: 10.1210/jcem.85.1.6318 PubMedGoogle Scholar
  11. 11.
    M. Stelmachowska-Banas, P. Zdunowski, W. Zgliczynski, Abnormalities in glucose homeostasis in acromegaly. Does the prevalence of glucose intolerance depend on the level of activity of the disease and the duration of the symptoms? Endokrynol. Pol. 60(1), 20–24 (2009)PubMedGoogle Scholar
  12. 12.
    T. O’Connell, D.R. Clemmons, IGF-I/IGF-binding protein-3 combination improves insulin resistance by GH-dependent and independent mechanisms. J. Clin. Endocrinol. Metab. 87(9), 4356–4360 (2002). doi: 10.1210/jc.2002-020343 CrossRefPubMedGoogle Scholar
  13. 13.
    H. Fukuoka, Y. Takahashi, K. Iida, T. Kudo, H. Nishizawa, M. Imanaka, R. Takeno, G. Iguchi, K. Takahashi, Y. Okimura, H. Kaji, K. Chihara, Low serum IGF-I/GH ratio is associated with abnormal glucose tolerance in acromegaly. Horm. Res. 69(3), 165–171 (2008). doi: 10.1159/000112590 CrossRefPubMedGoogle Scholar
  14. 14.
    D. Niculescu, M. Purice, M. Coculescu, Insulin-like growth factor-I correlates more closely than growth hormone with insulin resistance and glucose intolerance in patients with acromegaly. Pituitary 16(2), 168–174 (2013). doi: 10.1007/s11102-012-0396-6 CrossRefPubMedGoogle Scholar
  15. 15.
    J.J. Puder, S. Nilavar, K.D. Post, P.U. Freda, Relationship between disease-related morbidity and biochemical markers of activity in patients with acromegaly. J. Clin. Endocrinol. Metab. 90(4), 1972–1978 (2005). doi: 10.1210/jc.2004-2009 CrossRefPubMedGoogle Scholar
  16. 16.
    T. Ueland, S.L. Fougner, K. Godang, T. Lekva, L.J. Schurgers, H. Scholz, B. Halvorsen, T. Schreiner, P. Aukrust, J. Bollerslev, Associations between body composition, circulating interleukin-1 receptor antagonist, osteocalcin, and insulin metabolism in active acromegaly. J. Clin. Endocrinol. Metab. 95(1), 361–368 (2010). doi: 10.1210/jc.2009-0422 CrossRefPubMedGoogle Scholar
  17. 17.
    J. Ayuk, M.C. Sheppard, Does acromegaly enhance mortality? Rev. Endocr. Metab. Disord. 9(1), 33–39 (2008). doi: 10.1007/s11154-007-9067-8 CrossRefPubMedGoogle Scholar
  18. 18.
    O.M. Dekkers, N.R. Biermasz, A.M. Pereira, J.A. Romijn, J.P. Vandenbroucke, Mortality in acromegaly: a metaanalysis. J. Clin. Endocrinol. Metab. 93(1), 61–67 (2008). doi: 10.1210/jc.2007-1191 CrossRefPubMedGoogle Scholar
  19. 19.
    I.M. Holdaway, M.J. Bolland, G.D. Gamble, A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur. J. Endocrinol. 159(2), 89–95 (2008). doi: 10.1530/eje-08-0267 CrossRefPubMedGoogle Scholar
  20. 20.
    R.N. Clayton, Cardiovascular function in acromegaly. Endocr. Rev. 24(3), 272–277 (2003). doi: 10.1210/er.2003-0009 CrossRefPubMedGoogle Scholar
  21. 21.
    A.N. Paisley, M. Banerjee, M. Rezai, R.E. Schofield, S. Balakrishnannair, A. Herbert, J.A. Lawrance, P.J. Trainer, J.K. Cruickshank, Changes in arterial stiffness but not carotid intimal thickness in acromegaly. J. Clin. Endocrinol. Metab. 96(5), 1486–1492 (2011). doi: 10.1210/jc.2010-2225 CrossRefPubMedGoogle Scholar
  22. 22.
    G. Brevetti, P. Marzullo, A. Silvestro, R. Pivonello, G. Oliva, C. di Somma, G. Lombardi, A. Colao, Early vascular alterations in acromegaly. J. Clin. Endocrinol. Metab. 87(7), 3174–3179 (2002). doi: 10.1210/jcem.87.7.8643 CrossRefPubMedGoogle Scholar
  23. 23.
    A.N. Paisley, A.S. Izzard, I. Gemmell, K. Cruickshank, P.J. Trainer, A.M. Heagerty, Small vessel remodeling and impaired endothelial-dependent dilatation in subcutaneous resistance arteries from patients with acromegaly. J. Clin. Endocrinol. Metab. 94(4), 1111–1117 (2009). doi: 10.1210/jc.2008-0948 CrossRefPubMedGoogle Scholar
  24. 24.
    M. Otsuki, S. Kasayama, H. Yamamoto, H. Saito, S. Sumitani, H. Kouhara, Y. Saitoh, T. Ohnishi, N. Arita, Characterization of premature atherosclerosis of carotid arteries in acromegalic patients. Clin. Endocrinol. (Oxf.) 54(6), 791–796 (2001)CrossRefGoogle Scholar
  25. 25.
    H. Akutsu, J. Kreutzer, G. Wasmeier, D. Ropers, C. Rost, M. Mohlig, H. Wallaschofski, M. Buchfelder, C. Schofl, Acromegaly per se does not increase the risk for coronary artery disease. Eur. J. Endocrinol. 162(5), 879–886 (2010). doi: 10.1530/eje-09-0945 CrossRefPubMedGoogle Scholar
  26. 26.
    S. Melmed, A. Colao, A. Barkan, M. Molitch, A.B. Grossman, D. Kleinberg, D. Clemmons, P. Chanson, E. Laws, J. Schlechte, M.L. Vance, K. Ho, A. Giustina, Guidelines for acromegaly management: an update. J. Clin. Endocrinol. Metab. 94(5), 1509–1517 (2009). doi: 10.1210/jc.2008-2421 CrossRefPubMedGoogle Scholar
  27. 27.
    F. Pita-Gutierrez, S. Pertega-Diaz, S. Pita-Fernandez, L. Pena, G. Lugo, S. Sangiao-Alvarellos, F. Cordido, Place of preoperative treatment of acromegaly with somatostatin analog on surgical outcome: a systematic review and meta-analysis. PLoS ONE 8(4), e61523 (2013). doi: 10.1371/journal.pone.0061523 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    M.C. Sheppard, Primary medical therapy for acromegaly. Clin. Endocrinol. (Oxf.) 58(4), 387–399 (2003)CrossRefGoogle Scholar
  29. 29.
    S.M. Carlsen, M. Lund-Johansen, T. Schreiner, S. Aanderud, O. Johannesen, J. Svartberg, J.G. Cooper, J.K. Hald, S.L. Fougner, J. Bollerslev, Preoperative octreotide treatment in newly diagnosed acromegalic patients with macroadenomas increases cure short-term postoperative rates: a prospective, randomized trial. J. Clin. Endocrinol. Metab. 93(8), 2984–2990 (2008). doi: 10.1210/jc.2008-0315 CrossRefPubMedGoogle Scholar
  30. 30.
    Z.Q. Li, Z. Quan, H. Tian, M. Cheng, Preoperative lanreotide treatment improves outcome in patients with acromegaly resulting from invasive pituitary macroadenoma. J. Int. Med. Res. 40(2), 517–524 (2012)CrossRefPubMedGoogle Scholar
  31. 31.
    Z.G. Mao, Y.H. Zhu, H.L. Tang, D.Y. Wang, J. Zhou, D.S. He, H. Lan, B.N. Luo, H.J. Wang, Preoperative lanreotide treatment in acromegalic patients with macroadenomas increases short-term postoperative cure rates: a prospective, randomised trial. Eur. J. Endocrinol. 162(4), 661–666 (2010). doi: 10.1530/EJE-09-0908 CrossRefPubMedGoogle Scholar
  32. 32.
    M. Shen, X. Shou, Y. Wang, Z. Zhang, J. Wu, Y. Mao, S. Li, Y. Zhao, Effect of presurgical long-acting octreotide treatment in acromegaly patients with invasive pituitary macroadenomas: a prospective randomized study. Endocr. J. 57(12), 1035–1044 (2010). doi: 10.1507/endocrj.K10E-203 CrossRefPubMedGoogle Scholar
  33. 33.
    S.L. Fougner, J. Bollerslev, J. Svartberg, M. Oksnes, J. Cooper, S.M. Carlsen, Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial. Eur. J. Endocrinol. 171(2), 229–235 (2014). doi: 10.1530/eje-14-0249 CrossRefPubMedGoogle Scholar
  34. 34.
    S.M. Carlsen, J. Svartberg, T. Schreiner, S. Aanderud, A. Johannesen, S. Skeie, M. Lund-Johansen, S.L. Fougner, J. Bollerslev, Six-month preoperative octreotide treatment in unselected, de novo patients with acromegaly: effect on biochemistry, tumour volume, and postoperative cure. Clin. Endocrinol. 74(6), 736–743 (2011). doi: 10.1111/j.1365-2265.2011.03982.x CrossRefGoogle Scholar
  35. 35.
    B. Steffin, B. Gutt, M. Bidlingmaier, C. Dieterle, F. Oltmann, J. Schopohl, Effects of the long-acting somatostatin analogue Lanreotide Autogel on glucose tolerance and insulin resistance in acromegaly. Eur. J. Endocrinol. 155(1), 73–78 (2006). doi: 10.1530/eje.1.02185 CrossRefPubMedGoogle Scholar
  36. 36.
    M.Z. Strowski, R.M. Parmar, A.D. Blake, J.M. Schaeffer, Somatostatin inhibits insulin and glucagon secretion via two receptors subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice. Endocrinology 141(1), 111–117 (2000). doi: 10.1210/endo.141.1.7263 PubMedGoogle Scholar
  37. 37.
    M. Tzanela, D.A. Vassiliadi, N. Gavalas, A. Szabo, E. Margelou, A. Valatsou, C. Vassilopoulos, Glucose homeostasis in patients with acromegaly treated with surgery or somatostatin analogues. Clin. Endocrinol. (Oxf.) 75(1), 96–102 (2011). doi: 10.1111/j.1365-2265.2011.03996.x CrossRefGoogle Scholar
  38. 38.
    G. Mazziotti, I. Floriani, S. Bonadonna, V. Torri, P. Chanson, A. Giustina, Effects of somatostatin analogs on glucose homeostasis: a metaanalysis of acromegaly studies. J. Clin. Endocrinol. Metab. 94(5), 1500–1508 (2009). doi: 10.1210/jc.2008-2332 CrossRefPubMedGoogle Scholar
  39. 39.
    R. Baldelli, C. Battista, F. Leonetti, M.R. Ghiggi, M.C. Ribaudo, A. Paoloni, E. D’Amico, E. Ferretti, R. Baratta, A. Liuzzi, V. Trischitta, G. Tamburrano, Glucose homeostasis in acromegaly: effects of long-acting somatostatin analogues treatment. Clin. Endocrinol. (Oxf.) 59(4), 492–499 (2003)CrossRefGoogle Scholar
  40. 40.
    N.C. Olarescu, T. Ueland, K. Godang, R. Lindberg-Larsen, J.O. Jorgensen, J. Bollerslev, Inflammatory adipokines contribute to insulin resistance in active acromegaly and respond differently to different treatment modalities. Eur. J. Endocrinol. 170(1), 39–48 (2014). doi: 10.1530/eje-13-0523 CrossRefPubMedGoogle Scholar
  41. 41.
    C.L. Ronchi, V. Varca, P. Beck-Peccoz, E. Orsi, F. Donadio, A. Baccarelli, C. Giavoli, E. Ferrante, A. Lania, A. Spada, M. Arosio, Comparison between six-year therapy with long-acting somatostatin analogs and successful surgery in acromegaly: effects on cardiovascular risk factors. J. Clin. Endocrinol. Metab. 91(1), 121–128 (2006). doi: 10.1210/jc.2005-1704 CrossRefPubMedGoogle Scholar
  42. 42.
    G. Tolis, N.G. Angelopoulos, E. Katounda, G. Rombopoulos, V. Kaltzidou, D. Kaltsas, A. Protonotariou, A. Lytras, Medical treatment of acromegaly: comorbidities and their reversibility by somatostatin analogs. Neuroendocrinology 83(3–4), 249–257 (2006). doi: 10.1159/000095535 CrossRefPubMedGoogle Scholar
  43. 43.
    C. Urbani, C. Sardella, A. Calevro, G. Rossi, I. Scattina, M. Lombardi, I. Lupi, L. Manetti, E. Martino, F. Bogazzi, Effects of medical therapies for acromegaly on glucose metabolism. Eur. J. Endocrinol. 169(1), 99–108 (2013). doi: 10.1530/eje-13-0032 CrossRefPubMedGoogle Scholar
  44. 44.
    P. Anagnostis, Z.A. Efstathiadou, S.A. Polyzos, F. Adamidou, A. Slavakis, M. Sapranidis, I.D. Litsas, S. Katergari, D. Selalmatzidou, M. Kita, Acromegaly: presentation, morbidity and treatment outcomes at a single centre. Int. J. Clin. Pract. 65(8), 896–902 (2011). doi: 10.1111/j.1742-1241.2011.02682.x CrossRefPubMedGoogle Scholar
  45. 45.
    V.M. Cambuli, M. Galdiero, M. Mastinu, F. Pigliaru, R.S. Auriemma, A. Ciresi, R. Pivonello, M. Amato, C. Giordano, S. Mariotti, A. Colao, M.G. Baroni, Glycometabolic control in acromegalic patients with diabetes: a study of the effects of different treatments for growth hormone excess and for hyperglycemia. J. Endocrinol. Invest. 35(2), 154–159 (2012). doi: 10.3275/7685 PubMedGoogle Scholar
  46. 46.
    M.M. Tai, A mathematical model for the determination of total area under glucose tolerance and other metabolic curves. Diabetes Care 17(2), 152–154 (1994)CrossRefPubMedGoogle Scholar
  47. 47.
    M. Stelmachowska-Banas, G. Zielinski, P. Zdunowski, J. Podgorski, W. Zgliczynski, The impact of transsphenoidal surgery on glucose homeostasis and insulin resistance in acromegaly. Neurol. Neurochir. Pol. 45(4), 328–334 (2011)PubMedGoogle Scholar
  48. 48.
    K.G. Alberti, N.J. Christensen, S.E. Christensen, A.P. Hansen, J. Iversen, K. Lundbaek, K. Seyer-Hansen, H. Orskov, Inhibition of insulin secretion by somatostatin. Lancet 2(7841), 1299–1301 (1973)CrossRefPubMedGoogle Scholar
  49. 49.
    S.L. Fougner, O. Casar-Borota, A. Heck, J.P. Berg, J. Bollerslev, Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clin. Endocrinol. (Oxf.) 76(1), 96–102 (2012). doi: 10.1111/j.1365-2265.2011.04163.x CrossRefGoogle Scholar
  50. 50.
    A. Heck, G. Ringstad, S.L. Fougner, O. Casar-Borota, T. Nome, J. Ramm-Pettersen, J. Bollerslev, Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly. Clin. Endocrinol. (Oxf.) 77(1), 72–78 (2012). doi: 10.1111/j.1365-2265.2011.04286.x CrossRefGoogle Scholar
  51. 51.
    A. Colao, R. Attanasio, R. Pivonello, P. Cappabianca, L.M. Cavallo, G. Lasio, A. Lodrini, G. Lombardi, R. Cozzi, Partial surgical removal of growth hormone-secreting pituitary tumors enhances the response to somatostatin analogs in acromegaly. J. Clin. Endocrinol. Metab. 91(1), 85–92 (2006). doi: 10.1210/jc.2005-1208 CrossRefPubMedGoogle Scholar
  52. 52.
    M.L. Jaffrain-Rea, G. Minniti, C. Moroni, V. Esposito, E. Ferretti, A. Santoro, T. Infusino, G. Tamburrano, G. Cantore, R. Cassone, Impact of successful transsphenoidal surgery on cardiovascular risk factors in acromegaly. Eur. J. Endocrinol. 148(2), 193–201 (2003)CrossRefPubMedGoogle Scholar
  53. 53.
    S. Kasayama, M. Otsuki, M. Takagi, H. Saito, S. Sumitani, H. Kouhara, M. Koga, Y. Saitoh, T. Ohnishi, N. Arita, Impaired beta-cell function in the presence of reduced insulin sensitivity determines glucose tolerance status in acromegalic patients. Clin. Endocrinol. (Oxf.) 52(5), 549–555 (2000)CrossRefGoogle Scholar
  54. 54.
    A. Saveanu, G. Gunz, H. Dufour, P. Caron, F. Fina, L. Ouafik, M.D. Culler, J.P. Moreau, A. Enjalbert, P. Jaquet, Bim-23244, a somatostatin receptor subtype 2- and 5-selective analog with enhanced efficacy in suppressing growth hormone (GH) from octreotide-resistant human GH-secreting adenomas. J. Clin. Endocrinol. Metab. 86(1), 140–145 (2001). doi: 10.1210/jcem.86.1.7099 PubMedGoogle Scholar
  55. 55.
    M. Andries, D. Glintborg, A. Kvistborg, C. Hagen, M. Andersen, A 12-month randomized crossover study on the effects of lanreotide Autogel and octreotide long-acting repeatable on GH and IGF-l in patients with acromegaly. Clin. Endocrinol. (Oxf.) 68(3), 473–480 (2008). doi: 10.1111/j.1365-2265.2007.03067.x CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • R. Helseth
    • 1
  • S. M. Carlsen
    • 2
    • 3
  • J. Bollerslev
    • 4
    • 5
  • J. Svartberg
    • 6
    • 7
  • M. Øksnes
    • 8
  • S. Skeie
    • 9
  • S. L. Fougner
    • 2
  1. 1.Department of Internal MedicineDrammen Hospital, Vestre VikenDrammenNorway
  2. 2.Department of Endocrinology, Medical ClinicSt. Olavs University HospitalTrondheimNorway
  3. 3.Unit for Applied Clinical ResearchNorwegian University of Science and Technology (NTNU)TrondheimNorway
  4. 4.Section of Specialized Endocrinology, Department of EndocrinologyOslo University Hospital, RikshospitaletOsloNorway
  5. 5.Faculty of MedicineUniversity of OsloOsloNorway
  6. 6.Division of Internal MedicineUniversity Hospital of North NorwayTromsøNorway
  7. 7.Tromsø Endocrine Research Group, Institute of Clinical MedicineUiT The Arctic University of NorwayTromsøNorway
  8. 8.Department of Medicine and Centre for Clinical ResearchHaukeland University HospitalBergenNorway
  9. 9.Division of MedicineStavanger University HospitalStavangerNorway

Personalised recommendations