Kardiovaskuläres Risiko unter Androgendeprivationstherapie zur Behandlung des hormonabhängigen Prostatakarzinoms

Unterschiede zwischen GnRH-Antagonisten gegenüber GnRH-Agonisten

Cardiovascular risk of androgen deprivation therapy for treatment of hormone-dependent prostate cancer

Differences between GnRH antagonists and GnRH agonists

Zusammenfassung

Aus mehreren Studien geht hervor, dass das Absenken der Testosteronspiegel bei Patienten mit Prostatakarzinom im Rahmen einer Androgendeprivationstherapie (ADT) mit einem erhöhten Risiko für das Auftreten kardiovaskulärer Ereignisse einhergehen kann, was besonders beim Einsatz von GnRH („gonadotropin-releasing hormone“)-Agonisten aufgefallen ist. Eine ADT mit GnRH-Antagonisten muss jedoch in diesem Zusammenhang aufgrund ihres anderen Wirkmechanismus separat betrachtet werden. In dieser Übersichtsarbeit werden Ursachen für das Auftreten kardiovaskulärer Ereignisse unter ADT diskutiert, die Unterschiede zwischen GnRH-Agonisten und GnRH-Antagonisten im Hinblick auf ihren Wirkmechanismus erläutert, relevante Studien präsentiert und praktische Empfehlungen für den Arzt abgeleitet. Dazu wurde eine Literaturrecherche zu Veröffentlichungen im Zeitraum von 2005 bis September 2015 durchgeführt. Diese ergab, dass Patienten mit Prostatakarzinom unter GnRH-Antagonisten ein geringeres kardiovaskuläres Risiko aufwiesen als Patienten, die mit GnRH-Agonisten behandelt wurden. Dies galt insbesondere für Patienten, die kardiovaskulär erkrankt waren. Die unterschiedlichen Wirkmechanismen beider Substanzklassen liefern erste Erklärungen für das geringere kardiovaskuläre Risiko unter GnRH-Antagonisten. Patienten mit kardiovaskulärer Vorerkrankung oder dem Risiko für ein kardiovaskuläres Ereignis sollten vorzugsweise mit einem GnRH-Antagonisten behandelt werden.

Abstract

Background

Several studies have indicated that reduction of testosterone levels in patients with prostate cancer undergoing androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists can be associated with an increased risk of cardiovascular events. The GnRH antagonists have a different mode of action compared with GnRH agonists and may be preferred in ADT for patients with cardiovascular disease.

Objective

This review article discusses potential mechanisms underlying the development of cardiovascular events associated with ADT when using GnRH agonists and explains the differences in mode of action between GnRH agonists and GnRH antagonists. Additionally, relevant studies are presented and practical recommendations for the clinical practice are provided.

Material and methods

A literature search was performed. Full publications and abstracts published in the last 10 years up to September 2015 were considered to be eligible.

Results

The GnRH antagonists were associated with a decreased risk of cardiovascular events compared with GnRH agonists in prostate cancer patients undergoing ADT and particularly in patients with cardiovascular risk factors or a history of cardiovascular disease. This decrease may be due to the different mode of action of GnRH antagonists compared with GnRH agonists.

Conclusion

Prostate cancer patients with either cardiovascular disease or an increased risk of experiencing a cardiovascular event undergoing ADT should be preferentially treated with GnRH antagonists.

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Literatur

  1. 1.

    Conteduca V et al (2013) The cardiovascular risk of gonadotropin releasing hormone agonists in men with prostate cancer: an unresolved controversy. Crit Rev Oncol Hematol 86(1):42–51

    Article  PubMed  Google Scholar 

  2. 2.

    Shahani S, Braga-Basaria M, Basaria S (2008) Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. J Clin Endocrinol Metab 93(6):2042–2049

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Otten JD et al (2008) Impressive time-related influence of the Dutch screening programme on breast cancer incidence and mortality, 1975–2006. Int J Cancer 123(8):1929–1934

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Smith MR et al (2002) Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 87(2):599–603

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Collins L et al (2012) Androgen deprivation therapy for prostate cancer: implications for cardiometabolic clinical care. J Endocrinol Invest 35(3):332–339

    CAS  PubMed  Google Scholar 

  6. 6.

    Edelman S et al (2014) The Effects of Androgen Deprivation Therapy on Cardiac Function and Heart Failure: Implications for Management of Prostate Cancer. Clin Genitourin Cancer 12(6):399–407

    Article  PubMed  Google Scholar 

  7. 7.

    Bai CX et al (2005) Nontranscriptional regulation of cardiac repolarization currents by testosterone. Circulation 112(12):1701–1710

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Brouillette J et al (2005) Sex and strain differences in adult mouse cardiac repolarization: importance of androgens. Cardiovasc Res 65(1):148–157

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Pham TV et al (2002) Testosterone diminishes the proarrhythmic effects of dofetilide in normal female rabbits. Circulation 106(16):2132–2136

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Tsang S et al (2008) Testosterone protects rat hearts against ischaemic insults by enhancing the effects of alpha(1)-adrenoceptor stimulation. Br J Pharmacol 153(4):693–709

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Herring MJ et al (2013) Testosterone and the cardiovascular system: a comprehensive review of the basic science literature. J Am Heart Assoc 2(4):e000271

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Er F et al (2004) Testosterone induces cytoprotection by activating ATP-sensitive K+ channels in the cardiac mitochondrial inner membrane. Circulation 110(19):3100–3107

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Bourghardt J et al (2010) Androgen receptor-dependent and independent atheroprotection by testosterone in male mice. Endocrinology 151(11):5428–5437

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Kelly DM, Jones TH (2013) Testosterone: a vascular hormone in health and disease. J Endocrinol 217(3):R47–71

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Langer C et al (2002) Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages. Biochem Biophys Res Commun 296(5):1051–1057

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Tivesten A et al (2015) Cardiovascular risk with androgen deprivation therapy for prostate cancer: Potential mechanisms. Urol Oncol 33(11):464

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Rettew JA, Huet-Hudson YM, Marriott I (2008) Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity. Biol Reprod 78(3):432–437

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Ammar EM, Said SA, Hassan MS (2004) Enhanced vasoconstriction and reduced vasorelaxation induced by testosterone and nandrolone in hypercholesterolemic rabbits. Pharmacol Res 50(3):253–259

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Cavasin MA et al (2006) Testosterone enhances early cardiac remodeling after myocardial infarction, causing rupture and degrading cardiac function. Am J Physiol Heart Circ Physiol 290(5):H2043–50

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Keating NL, O’Malley AJ, Smith MR (2006) Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 24(27):4448–4456

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Albertsen PC et al (2014) Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol 65(3):565–573

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Taylor LG, Canfield SE, Du XL (2009) Review of major adverse effects of androgen-deprivation therapy in men with prostate cancer. Cancer 115(11):2388–2399

    Article  PubMed  Google Scholar 

  23. 23.

    Bhasin S et al (2003) The mechanisms of androgen effects on body composition: mesenchymal pluripotent cell as the target of androgen action. J Gerontol A Biol Sci Med Sci 58(12):M1103–10

    Article  PubMed  Google Scholar 

  24. 24.

    Traish AM, Saad F, Guay A (2009) The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J Androl 30(1):23–32

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Smith MR et al (2008) Adipocytokines, obesity, and insulin resistance during combined androgen blockade for prostate cancer. Urology 71(2):318–322

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Smith MR, Lee H, Nathan DM (2006) Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab 91(4):1305–1308

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Harle LK et al (2006) Endocrine complications of androgen-deprivation therapy in men with prostate cancer. Clin Adv Hematol Oncol 4(9):687–696

    PubMed  Google Scholar 

  28. 28.

    Dockery F et al (2003) Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinaemia. Clin Sci (Lond) 104(2):195–201

    CAS  Article  Google Scholar 

  29. 29.

    Eri LM, Urdal P, Bechensteen AG (1995) Effects of the luteinizing hormone-releasing hormone agonist leuprolide on lipoproteins, fibrinogen and plasminogen activator inhibitor in patients with benign prostatic hyperplasia. J Urol 154(1):100–104

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Smith MR et al (2008) Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer: differences from the classic metabolic syndrome. Cancer 112(10):2188–2194

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Skinner DC et al (2009) Effects of gonadotrophin-releasing hormone outside the hypothalamic-pituitary-reproductive axis. J Neuroendocrinol 21(4):282–292

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Dong F et al (2011) The heart: a novel gonadotrophin-releasing hormone target. J Neuroendocrinol 23(5):456–463

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Chen HF et al (1999) Human peripheral blood mononuclear cells express gonadotropin-releasing hormone (GnRH), GnRH receptor, and interleukin-2 receptor gamma-chain messenger ribonucleic acids that are regulated by GnRH in vitro. J Clin Endocrinol Metab 84(2):743–750

    CAS  PubMed  Google Scholar 

  34. 34.

    Knutsson A et al (2015) Treatment with an LRHR agonist, but not the LHRH antagonist degarelix, induces atherosclerotic plaque instability in ApoE-/- mice in EAU 2015, Poster 5592015: Madrid

    Google Scholar 

  35. 35.

    Fachinformation, FIRMAGON 80 mg Pulver und Lösungsmittel zur Herstellung einer Injektionslösung. Ferring GmbH. 011697-7981 – Stand der Information: Oktober 2014

  36. 36.

    Keating NL et al (2012) Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 104(19):1518–1523

    Article  PubMed  Google Scholar 

  37. 37.

    Van Hemelrijck M et al (2010) Absolute and relative risk of cardiovascular disease in men with prostate cancer: results from the Population-Based PCBaSe Sweden. J Clin Oncol 28(21):3448–3456

    Article  PubMed  Google Scholar 

  38. 38.

    Jespersen CG, Norgaard M, Borre M (2014) Androgen-deprivation therapy in treatment of prostate cancer and risk of myocardial infarction and stroke: a nationwide Danish population-based cohort study. Eur Urol 65(4):704–709

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Tsai HK et al (2007) Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 99(20):1516–1524

    Article  PubMed  Google Scholar 

  40. 40.

    Saigal CS et al (2007) Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 110(7):1493–1500

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Hu JC et al (2012) Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism. Eur Urol 61(6):1119–1128

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Gandaglia G et al (2014) The impact of androgen-deprivation therapy (ADT) on the risk of cardiovascular (CV) events in patients with non-metastatic prostate cancer: a population-based study. BJU Int 114(6b):E82–9

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Alibhai SM et al (2009) Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol 27(21):3452–3458

    Article  PubMed  Google Scholar 

  44. 44.

    Schmid M et al (2015) Dose-dependent effect of androgen deprivation therapy for localized prostate cancer on adverse cardiac events. BJU Int : doi:10.1111/bju.13203

    Google Scholar 

  45. 45.

    Smith MR et al (2011) Association of baseline risk factors with cardiovascular (CV) events during long-term degarelix therapy in men with prostate cancer. J Clin Oncol 29(suppl 7):abstr 190

    Google Scholar 

  46. 46.

    Efstathiou JA et al (2009) Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31. J Clin Oncol 27(1):92–99

    Article  PubMed  Google Scholar 

  47. 47.

    Bolla M et al (2010) External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 11(11):1066–1073

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Wilcox C et al (2012) Androgen deprivation therapy for prostate cancer does not increase cardiovascular mortality in the long term. Oncology 82(1):56–58

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Nguyen PL et al (2011) Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 306(21):2359–2366

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Tombal B et al (2013) Degarelix versus luteinising hormone-releasing hormone (LHRH) agonists: Safety outcomes from six comparative randomised clinical trials. Eur J Cancer (suppl. 2):681

    Google Scholar 

  51. 51.

    Radu A et al (2010) Expression of follicle-stimulating hormone receptor in tumor blood vessels. N Engl J Med 363(17):1621–1630

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Hanke H et al (2001) Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation 103(10):1382–1385

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Ng MK et al (2003) Androgens up-regulate atherosclerosis-related genes in macrophages from males but not females: molecular insights into gender differences in atherosclerosis. J Am Coll Cardiol 42(7):1306–1313

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Klotz L et al (2014) Disease control outcomes from analysis of pooled individual patient data from five comparative randomised clinical trials of degarelix versus luteinising hormone-releasing hormone agonists. Eur Urol 66(6):1101–1108

    CAS  Article  PubMed  Google Scholar 

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Correspondence to Prof Dr. med C. Tschöpe.

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Interessenkonflikt

C. Tschöpe: „Steering-committee“- bzw. Vortragshonorare von Novartis, Berlin Chemie, Servier, BMS, Roche, Bayer Healthcare, Ferring, Impulse Dynamics. C. A. Schneider: Vortragshonorare von Ferring. B. Pieske: „Steering-committee“- bzw. Vortragshonorare von Bayer Healthcare, Servier, Stealth Peptides, Novartis, Medtronic.

B. Kherad, F. Spillmann und F. Krackhardt geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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Tschöpe, C., Kherad, B., Spillmann, F. et al. Kardiovaskuläres Risiko unter Androgendeprivationstherapie zur Behandlung des hormonabhängigen Prostatakarzinoms. Herz 41, 697–705 (2016). https://doi.org/10.1007/s00059-016-4422-8

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Schlüsselwörter

  • Prostatakarzinom
  • Androgendeprivationstherapie
  • Kardiovaskuläres Risiko
  • GnRH-Agonist
  • GnRH-Antagonist

Keywords

  • Prostatic neoplasms
  • Androgen deprivation therapy
  • Cardiovascular risk
  • GnRH agonist
  • GnRH antagonist