Advertisement

Reviews in Endocrine and Metabolic Disorders

, Volume 19, Issue 4, pp 325–333 | Cite as

Thyroid disorders induced by checkpoint inhibitors

  • Silvia Martina Ferrari
  • Poupak Fallahi
  • Fabio Galetta
  • Emanuele Citi
  • Salvatore Benvenga
  • Alessandro AntonelliEmail author
Article

Abstract

Immune checkpoint inhibitors are drugs that inhibit the “checkpoint molecules”. Different types of cancer immune checkpoint inhibitors have been approved recently: CTLA-4 monoclonal antibodies (as ipilimumab); anti-PD-1 monoclonal antibodies (as pembrolizumab and nivolumab); and anti-PD-L1 monoclonal antibodies (as atezolizumab, avelumab, and durmalumab). The increased immune response induced by these agents leads to immune-related adverse events (irAEs), that can vary from mild to fatal, according to the organ system and severity. Immune-related endocrine toxicities are thyroid dysfunctions, hypophysitis, adrenal insufficiency, and type 1 diabetes mellitus, and are usually irreversible in 50%. In particular, hypophysitis is the most frequent anti-CTLA-4-antibodies-related irAE, while thyroid abnormalities (as hypothyroidism, thyrotoxicosis, painless thyroiditis, or even “thyroid storm”) are more frequently associated with anti-PD-1-antibodies. The combination of anti-CTLA-4-antibodies, with anti-PD-1-antibodies, is associated with about 30% of irAEs. Clinical signs and symptoms vary according to the influenced target organ. Endocrinopathies can often be managed by the treating oncologist. However in more severe cases (i.e. in the presence of insulin-dependent diabetes, adrenal insufficiency, or disorders of gonadal hormones, or severe hyperthyroidism, or hypothyroidism, or long-lasting management of hypophysitis) an endocrinological evaluation, and a prompt therapy, are needed.

Keywords

Immune checkpoint inhibitors CTLA-4 PD-1 PD-L1 Thyroid disorders Hypophysitis 

Notes

Compliance with ethical standards

Research involving human participants

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Emens LA, Ascierto PA, Darcy PK, Demaria S, Eggermont AMM, Redmond WL, et al. Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer. 2017;81:116–29.CrossRefGoogle Scholar
  2. 2.
    Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109–17.CrossRefGoogle Scholar
  3. 3.
    Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32:1020–30.CrossRefGoogle Scholar
  4. 4.
    Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33:2780–8.CrossRefGoogle Scholar
  5. 5.
    Antonelli A, Ferrari SM, Fallahi P, Frascerra S, Piaggi S, Gelmini S, et al. Dysregulation of secretion of CXC alpha-chemokine CXCL10 in papillary thyroid cancer: modulation by peroxisome proliferator-activated receptor-gamma agonists. Endocr Relat Cancer. 2009;16:1299–311.CrossRefGoogle Scholar
  6. 6.
    Antonelli A, Ferrari SM, Fallahi P, Piaggi S, Di Domenicantonio A, Galleri D, et al. Variable modulation by cytokines and thiazolidinediones of the prototype Th1 chemokine CXCL10 in anaplastic thyroid cancer. Cytokine. 2012;59:218–22.CrossRefGoogle Scholar
  7. 7.
    Antonelli A, Ferrari SM, Frascerra S, Galetta F, Franzoni F, Corrado A, et al. Circulating chemokine (CXC motif) ligand (CXCL)9 is increased in aggressive chronic autoimmune thyroiditis, in association with CXCL10. Cytokine. 2011;55:288–93.CrossRefGoogle Scholar
  8. 8.
    Antonelli A, Ferrari SM, Fallahi P. Current and future immunotherapies for thyroid cancer. Expert Rev Anticancer Ther. 2018;18:149–59.CrossRefGoogle Scholar
  9. 9.
  10. 10.
  11. 11.
    Hansen ED, Wang X, Case AA, Puzanov I, Smith T. Immune checkpoint inhibitor toxicity review for the palliative care clinician. J Pain Symptom Manage. 2018 May 21.  https://doi.org/10.1016/j.jpainsymman.2018.05.015. [Epub ahead of print], Immune Checkpoint Inhibitor Toxicity Review for the Palliative Care Clinician.
  12. 12.
    Ascierto PA, Marincola FM. What have we learned from cancer immunotherapy in the last 3 years? J Transl Med. 2014;12:141.CrossRefGoogle Scholar
  13. 13.
    Maio M, Danielli R, Chiarion-Sileni V, Pigozzo J, Parmiani G, Ridolfi R, et al. Efficacy and safety of ipilimumab in patients with pre-treated, uveal melanoma. Ann Oncol. 2013;24:2911–5.CrossRefGoogle Scholar
  14. 14.
    Luke JJ, Callahan MK, Postow MA, Romano E, Ramaiya N, Bluth M, et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer. 2013;119:3687–95.CrossRefGoogle Scholar
  15. 15.
    Kelderman S, van der Kooij MK, van den Eertwegh AJ, Soetekouw PM, Jansen RL, van den Brom RR, et al. Ipilimumab in pretreated metastatic uveal melanoma patients. Results of the Dutch working group on immunotherapy of oncology (WIN-O). Acta Oncol. 2013;52:1786–8.CrossRefGoogle Scholar
  16. 16.
    Zimmer L, Vaubel J, Mohr P, Hauschild A, Utikal J, Simon J, et al. Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic uveal melanoma. PLoS One. 2015;10:e0118564.CrossRefGoogle Scholar
  17. 17.
    Del Vecchio M, Di Guardo L, Ascierto PA, Grimaldi AM, Sileni VC, Pigozzo J, et al. Efficacy and safety of ipilimumab 3mg/kg in patients with pretreated, metastatic, mucosal melanoma. Eur J Cancer. 2014;50:121–7.CrossRefGoogle Scholar
  18. 18.
    Postow MA, Luke JJ, Bluth MJ, Ramaiya N, Panageas KS, Lawrence DP, et al. Ipilimumab for patients with advanced mucosal melanoma. Oncologist. 2013;18:726–32.CrossRefGoogle Scholar
  19. 19.
    Ascierto PA, Simeone E, Sileni VC, Pigozzo J, Maio M, Altomonte M, et al. Clinical experience with ipilimumab 3 mg/kg: real-work efficacy and safety data from an expanded access programme cohort. J Transl Med. 2014;12:116.CrossRefGoogle Scholar
  20. 20.
    Lebbé C, McDermott DF, Robert C, Lorigan P, Ottensmeier CH, Wolchok J, et al. Ipilimumab improves survival in previously treated, advanced melanoma patients with poor prognostic factors: subgroup analysis from a phase III trial [abstract]. Ann Oncol. 2010;21(suppl 8):13240.Google Scholar
  21. 21.
    Chandra S, Madden KM, Kannan R, Pavlick AC. Evaluating the safety of anti-CTLA-4 therapy in elderly patients with unresectable melanoma [abstract]. J Clin Oncol. 2013;31(suppl):9063.Google Scholar
  22. 22.
    Queirolo P, Spagnolo F, Ascierto PA, Simeone E, Marchetti P, Scoppola A, et al. Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J Neuro-Oncol. 2014;118:109–16.Google Scholar
  23. 23.
    Emens LA. Breast Cancer immunotherapy: facts and hopes. Clin Cancer Res. 2018;24:511–20.CrossRefGoogle Scholar
  24. 24.
    Hodi FS, Topalian SL, Brahmer JR, McDermott DF, Smith DC, Gettinger S, et al. Survival and long-term safety in patients (pts) with advanced solid tumors receiving nivolumab (anti-PD-1; BMS-936558; ONO-4538) [abstract]. Eur J Cancer. 2013;49(suppl 2):880.Google Scholar
  25. 25.
    Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51–60.CrossRefGoogle Scholar
  26. 26.
    Postow MA. Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol Educ Book. 2015;35:76–83.CrossRefGoogle Scholar
  27. 27.
    Prete A, Salvatori R. Hypophysitis. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, et al. editors. Source Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–2018 Aug 15.
  28. 28.
    Sarne D. Effects of the Environment, Chemicals and Drugs on Thyroid Function. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–2016 Sep 27.
  29. 29.
    Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med. 2015;13:211.CrossRefGoogle Scholar
  30. 30.
    Weber JS, Postow M, Lao CD, Schadendorf D. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist. 2016;21:1230–40.CrossRefGoogle Scholar
  31. 31.
    Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab. 2013;98:1361–75.CrossRefGoogle Scholar
  32. 32.
    Joshi MN, Whitelaw BC, Palomar MT, Wu Y, Carroll PV. Immune checkpoint inhibitor related hypophysitis and endocrine dysfunction: clinical review. Clin Endocrinol. 2016;85:331–9.CrossRefGoogle Scholar
  33. 33.
    Byun DJ, Wolchok JD, Rosenberg LM, Girotra M. Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol. 2017;13:195–207.CrossRefGoogle Scholar
  34. 34.
    Sznol M, Postow MA, Davies MJ, Pavlick AC, Plimack ER, Shaheen M, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. 2017;58:70–6.CrossRefGoogle Scholar
  35. 35.
    Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–7.CrossRefGoogle Scholar
  36. 36.
    González-Rodríguez E, Rodríguez-Abreu D. Spanish Group for Cancer Immuno-Biotherapy (GETICA). Immune checkpoint inhibitors: review and management of endocrine adverse events. Oncologist. 2016;21:804–16.CrossRefGoogle Scholar
  37. 37.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34.CrossRefGoogle Scholar
  38. 38.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372:2521–32.CrossRefGoogle Scholar
  39. 39.
    Min L, Vaidya A, Becker C. Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur J Endocrinol. 2011;164:303–7.CrossRefGoogle Scholar
  40. 40.
    Borodic G, Hinkle DM, Cia Y. Drug-induced graves disease from CTLA-4 receptor suppression. Ophthal Plast Reconstr Surg. 2011;27:e87–8.CrossRefGoogle Scholar
  41. 41.
    Faje AT, Sullivan R, Lawrence D, Tritos NA, Fadden R, Klibanski A, et al. Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab. 2014;99:4078–85.CrossRefGoogle Scholar
  42. 42.
    Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer. 2014;21:371–81.CrossRefGoogle Scholar
  43. 43.
    Mellati M, Eaton KD, Brooks-Worrell BM, Hagopian WA, Martins R, Palmer JP, et al. Anti-PD-1 and Anti-PDL-1 Monoclonal Antibodies Causing Type 1 Diabetes. Diabetes Care. 2015;38:e137–8.CrossRefGoogle Scholar
  44. 44.
    Hughes J, Vudattu N, Sznol M, Gettinger S, Kluger H, Lupsa B, et al. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care. 2015;38:e55–7.CrossRefGoogle Scholar
  45. 45.
    Martin-Liberal J, Furness AJ, Joshi K, Peggs KS, Quezada SA, Larkin J. Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunol Immunother. 2015;64:765–7.CrossRefGoogle Scholar
  46. 46.
    Gaudy C, Clévy C, Monestier S, Dubois N, Préau Y, Mallet S, et al. Anti-PD1 Pembrolizumab can induce exceptional fulminant type 1 diabetes. Diabetes Care. 2015;38:e182–3.CrossRefGoogle Scholar
  47. 47.
    Min L, Ibrahim N. Ipilimumab-induced autoimmune adrenalitis. Lancet Diabetes Endocrinol. 2013;1:e15.CrossRefGoogle Scholar
  48. 48.
    Bacanovic S, Burger IA, Stolzmann P, Hafner J, Huellner MW. Ipilimumab-induced Adrenalitis: a possible pitfall in 18F-FDG-PET/CT. Clin Nucl Med. 2015;40:e518–9.CrossRefGoogle Scholar
  49. 49.
    Hamnvik OP, Larsen PR, Marqusee E. Thyroid dysfunction from antineoplastic agents. J Natl Cancer Inst. 2011;103:1572–87.CrossRefGoogle Scholar
  50. 50.
    Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.CrossRefGoogle Scholar
  51. 51.
    Maker AV, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother. 2006;29:455–63.CrossRefGoogle Scholar
  52. 52.
    Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM, Royal RE, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 2007;13:6681–8.CrossRefGoogle Scholar
  53. 53.
    Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer. 2010;116:1767–75.CrossRefGoogle Scholar
  54. 54.
    Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:522–30.CrossRefGoogle Scholar
  55. 55.
    Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res. 2007;13:1810–5.CrossRefGoogle Scholar
  56. 56.
    Weber JS, O'Day S, Urba W, Powderly J, Nichol G, Yellin M, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008;26:5950–6.CrossRefGoogle Scholar
  57. 57.
    Ansell SM, Hurvitz SA, Koenig PA, LaPlant BR, Kabat BF, Fernando D, et al. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2009;15:6446–53.CrossRefGoogle Scholar
  58. 58.
    O’Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712–7.CrossRefGoogle Scholar
  59. 59.
    Hersh EM, O'Day SJ, Powderly J, Khan KD, Pavlick AC, Cranmer LD, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naive patients with advanced melanoma. Investig New Drugs. 2011;29:489–98.CrossRefGoogle Scholar
  60. 60.
    Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33:828–33.CrossRefGoogle Scholar
  61. 61.
    Ralph C, Elkord E, Burt DJ, O'Dwyer JF, Austin EB, Stern PL, et al. Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer Res. 2010;16:1662–72.CrossRefGoogle Scholar
  62. 62.
    Gan EH, Mitchell AL, Plummer R, Pearce S, Perros P. Tremelimumab-induced graves hyperthyroidism. Eur Thyroid J. 2017;6:167–70.CrossRefGoogle Scholar
  63. 63.
    Orlov S, Salari F, Kashat L, Walfish PG. Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies. J Clin Endocrinol Metab. 2015;100:1738–41.CrossRefGoogle Scholar
  64. 64.
    Narita T, Oiso N, Taketomo Y, Okahashi K, Yamauchi K, Sato M, et al. Serological aggravation of autoimmune thyroid disease in two cases receiving nivolumab. J Dermatol. 2016;43:210–4.CrossRefGoogle Scholar
  65. 65.
    Verma I, Modi A, Tripathi H, Agrawal A. Nivolumab causing painless thyroiditis in a patient with adenocarcinoma of the lung. BMJ Case Rep. 2016;2016.Google Scholar
  66. 66.
    Campredon P, Imbert P, Mouly C, Grunenwald S, Mazières J, Caron P. Severe inflammatory Ophthalmopathy in a Euthyroid patient during Nivolumab treatment. Eur Thyroid J. 2018;7:84–7.CrossRefGoogle Scholar
  67. 67.
    Badovinac S, Korsic M, Zarkovic K, Mursic D, Roglic M, Jakopovic M, et al. Nivolumab-induced synchronous occurrence of myositis and hypothyroidism in a patient with squamous cell lung cancer. Immunotherapy. 2018;10:427–31.CrossRefGoogle Scholar
  68. 68.
    Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17:1558–68.CrossRefGoogle Scholar
  69. 69.
    Osorio JC, Ni A, Chaft JE, Pollina R, Kasler MK, Stephens D, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol. 2017;28:583–9.Google Scholar
  70. 70.
    De Remigis A, de Gruijl TD, Uram JN, Tzou SC, Iwama S, Talor MV, et al. Development of thyroglobulin antibodies after GVAX immunotherapy is associated with prolonged survival. Int J Cancer. 2015;13:127–37.CrossRefGoogle Scholar
  71. 71.
    Scott ES, Long GV, Guminski A, Clifton-Bligh RJ, Menzies AM, Tsang VH. The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma. Eur J Endocrinol. 2018;178:175–82.CrossRefGoogle Scholar
  72. 72.
    Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) toxicity management working group. J Immunother Cancer 2017;5:95.Google Scholar
  73. 73.
    Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of Immune-Related Adverse Events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36:1714–68.CrossRefGoogle Scholar
  74. 74.
    National Comprehensive Cancer Network. Management of Immunotherapy-Related Toxicities. (Version 1.2018). https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. [Accessed 30 March 2018].
  75. 75.
    Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27:559–74.CrossRefGoogle Scholar
  76. 76.
    Merck. Pembrolizumab US full prescribing information. 2014. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. [Accessed April 2017].
  77. 77.
    Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26:2375–91.Google Scholar
  78. 78.
    Genentech. Atezolizumab US full prescribing information. 2016. http://www.gene.com/download/pdf/tecentriq_prescribing.pdf. [Accessed June 2018].
  79. 79.
    Alhusseini M, Samantray J. Hypothyroidism in Cancer patients on immune checkpoint inhibitors with anti-PD1 agents: insights on underlying mechanisms. Exp Clin Endocrinol Diabetes. 2017;125:267–9.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Silvia Martina Ferrari
    • 1
  • Poupak Fallahi
    • 2
  • Fabio Galetta
    • 1
  • Emanuele Citi
    • 1
  • Salvatore Benvenga
    • 3
    • 4
    • 5
  • Alessandro Antonelli
    • 1
    Email author
  1. 1.Department of Clinical and Experimental MedicineUniversity of Pisa, School of MedicinePisaItaly
  2. 2.Department of Translational Research and New Technologies in Medicine and SurgeryUniversity of PisaPisaItaly
  3. 3.Department of Clinical and Experimental MedicineUniversity of MessinaMessinaItaly
  4. 4.Master Program on Childhood, Adolescent and Women’s Endocrine HealthUniversity of MessinaMessinaItaly
  5. 5.Interdepartmental Program of Molecular and Clinical Endocrinology and Women’s Endocrine HealthAzienda Ospedaliera Universitaria Policlinico ‘G. Martino’MessinaItaly

Personalised recommendations