Advertisement

Hormones

, Volume 16, Issue 2, pp 115–123 | Cite as

Adverse effects of androgen deprivation therapy in patients with prostate cancer: focus on metabolic complications

  • Vasileios Tzortzis
  • Michael Samarinas
  • Ioannis Zachos
  • Athanasios Oeconomou
  • Louis L. Pisters
  • Alexandra Bargiota
Review

Abstract

Prostate cancer is the most common cancer among men and androgen deprivation therapy (ADT) is the most effective treatment for this disease. The cornerstone of the treatment of prostate cancer is inhibition of testosterone production which interrupts testosterone-induced growth of the prostate tumor. The dramatic decrease in testosterone levels, however, has several undesirable effects on the metabolic profile and bone metabolism and can also lead to fatigue, loss of libido, gynecomastia, and anemia, provoke vasomotor flushing, and generally affect the quality of life. Due to the long-term survival rates of patients with prostate cancer, treatment-related adverse effects are highly relevant and thus, in each clinical setting, the benefits of ADT must be weighed against treatment-related adverse effects. The current review focuses on the more recently described metabolic complications of androgen deprivation therapy, including obesity, diabetes, lipid alterations, metabolic syndrome, and cardiovascular disease. In addition, it provides practical management recommendations drawn from the available guidelines issued by the American Diabetes Association and American Heart Association.

Key words

Androgen deprivation therapy Diabetes Metabolic complications Prostate cancer 

References

  1. 1.
    Ryan CJ, Small EJ, 2005 Early versus delayed androgen deprivation for prostate cancer: new fuel for an old debate. J Clin Oncol 23: 8225–8231.CrossRefGoogle Scholar
  2. 2.
    Shahinian VB, Kuo Yf, Freeman JL, Orihuela E, Goodwin JS, 2005 Increasing use of gonadotropin releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 103: 1615.CrossRefGoogle Scholar
  3. 3.
    Heidenreich A, Bastian PJ, Bellmunt J, et al, 2014 EAU guidelines on prostate cancer, part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol 65: 124–137.CrossRefGoogle Scholar
  4. 4.
    Bolla M, Collette L, Blank L, et al, 2002 Long term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet 360: 103–106.CrossRefGoogle Scholar
  5. 5.
    Messing EM, Manola J, Yao J, et al, 2006 Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 7: 472–479.CrossRefGoogle Scholar
  6. 6.
    Huggins C, Hodges CV, 1941 Studies on prostate cancer: II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg 43: 209–233.CrossRefGoogle Scholar
  7. 7.
    Heidenreich A, Bastian PJ, Bellmunt J, et al, 2014 EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 65: 467–479.CrossRefGoogle Scholar
  8. 8.
    Eisenberger MA, Blumenstein BA, Crawford ED, et al, 1998 Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 339: 1036–1042.CrossRefGoogle Scholar
  9. 9.
    Rosario DJ, Davey P, Green J, 2016 The role of gonadotrophin-releasing hormone antagonists in the treatment of patients with advanced hormone-dependent prostate cancer in the UK. World J Urol 34: 1601–1609.CrossRefGoogle Scholar
  10. 10.
    Albertsen P, 2009 Androgen deprivation in prostate cancer-step by step. N Engl J Med 360: 2572–2574.CrossRefGoogle Scholar
  11. 11.
    Sharifi N, Gulley J, Dahut W, 2005 Androgen deprivation therapy for prostate cancer. JAMA 294: 238–244.CrossRefGoogle Scholar
  12. 12.
    Finkelstein JS, Lee H, Burnett-Bowie SA, et al, 2013 Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 369: 1011–1022.CrossRefGoogle Scholar
  13. 13.
    Allan CA, McLachlan RI, 2010 Androgens and obesity. Curr Opin Endocrinol Diabetes Obes 17: 224–232.CrossRefGoogle Scholar
  14. 14.
    Brand JS, van der Tweel I, Grobbee DE, Emmelot-Vonk MH, van der Schouw YT, 2011 Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. Int J Epidemiol 40: 189–207.CrossRefGoogle Scholar
  15. 15.
    Smith MR, Lee H, Fallon M, Nathan DM, 2008 Adipocytokines, obesity and insulin resistance during combined androgen blockade for prostate cancer. Urology 71: 318–322.CrossRefGoogle Scholar
  16. 16.
    Smith MR, Finkelstein JS, McGovern FJ, et al, 2002 Change in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 87: 599–603.CrossRefGoogle Scholar
  17. 17.
    Stone P, Hardy J, Huddart R, et al, 2000 Fatigue in patients with prostate cancer receiving hormone therapy. Eur J Cancer 36: 1134–1141.CrossRefGoogle Scholar
  18. 18.
    Zamboni M, Mazzali G, Fantin F, Rossi A, Di Francesco V, 2000 Sarcopenic obesity: a new category of obesity in the elderly. Nutr Metab Cardiovasc Dis 18: 388–395.CrossRefGoogle Scholar
  19. 19.
    Simiao Tian and Yang Xu, 2016 Association of sarcopenic obesity with the risk of all-cause mortality: A meta-analysis of prospective cohort studies. Geriatr Gerontol Int 16: 155–166.CrossRefGoogle Scholar
  20. 20.
    Reis C, Liberman S, Pompeo AC, Srougi M, Halpern A, Filho WJ, 2009 Body composition alterations, energy expenditure and fat oxidation in elderly males suffering from prostate cancer, pre- and post-orchiectomy. Clinics (Sao Paulo) 64: 781–784.CrossRefGoogle Scholar
  21. 21.
    Chazenbalk G, Singh P, Irge D, Shah A, Abbott D, Dumesic D, 2013 Androgens inhibit adipogenesis during human adipose stem cell commitment to preadipocyte formation. Steroids 78: 920–926.CrossRefGoogle Scholar
  22. 22.
    Smith JC, Bennett S, Evans LM, et al, 2001 The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J Clin Endocrinol Metab 86: 4261–4267.CrossRefGoogle Scholar
  23. 23.
    Bourke L, Smith D, Steed L, et al, 2016 Exercise for men with prostate cancer: A systematic review and meta-analysis. Eur Urol 69: 693–703.CrossRefGoogle Scholar
  24. 24.
    Culos-Reed SN, Robinson JW, Lau H, 2010 Physical activity for men receiving androgen deprivation therapy for prostate cancer: benefits from a 16-week intervention. Support Care Cancer 18: 591–599.CrossRefGoogle Scholar
  25. 25.
    Wall BA, Galvão DA, Fatehee N, 2017 Exercise Improves VO2max and Body Composition in ADT-treated Prostate Cancer Patients. Med Sci Sports Exerc [Epub ahead of print].Google Scholar
  26. 26.
    Traish AM, Zitzmann M, 2015 The complex and multifactorial relationship between testosterone deficiency (TD), obesity and vascular disease. Rev Endocr Metab Disord 16: 249–268.CrossRefGoogle Scholar
  27. 27.
    Ullah MI, Washington T, Kazi M, Tamanna S, Koch CA, 2011 Testosterone deficiency as a risk factor for cardiovascular disease. Horm Metab Res 43: 153–164.CrossRefGoogle Scholar
  28. 28.
    Dockery F, Bulpitt CJ, Agarwal S, Donaldson M, Rajkumar C, 2003 Testosterone suppression in men with prostate cancer leads to an increase in arterial stiffness and hyperinsulinemia. Clin Sci (London) 104: 195–201.CrossRefGoogle Scholar
  29. 29.
    Keating NL, O Malley AJ, Smith MR, 2006 Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 24: 4448–4456.CrossRefGoogle Scholar
  30. 30.
    Hotamisligil GS, Spiegelman BM, 1994 Tumor necrosis factor α: a key component of the obesity-diabetes link. Diabetes 43: 1271–1278.CrossRefGoogle Scholar
  31. 31.
    Cutolo M, Sulli A, Capellino S, et al, 2004 Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus 13: 635–638.CrossRefGoogle Scholar
  32. 32.
    Smith RM, 2008 Androgen deprivation therapy and risk for diabetes and cardiovascular disease in prostate cancer survivors. Curr Urol Rep 9: 197–202.CrossRefGoogle Scholar
  33. 33.
    Alibhai SM, Duong-Hua M, Sutradhar R, et al, 2009 Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol 27: 3452–3458.CrossRefGoogle Scholar
  34. 34.
    Keating NL, O’Malley J, Stephen J, Smith MR, 2010 Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 102: 39–46.CrossRefGoogle Scholar
  35. 35.
    Tsai HT, Keating NL, Stephen K, et al, 2015 Risk of diabetes among patients receiving primary androgen deprivation therapy for clinically localized prostate cancer. J Urol 193: 1956–1962.CrossRefGoogle Scholar
  36. 36.
    Keating N, Liu P, O’Malley A, Freedland S, Smith M, 2014 Androgen-deprivation therapy and diabetes control among diabetic men with prostate cancer. Eur Urol 65: 816–824.CrossRefGoogle Scholar
  37. 37.
    Morote J, Gomez-Caamano A, Alvarez-Ossorio J, et al, 2015 The metabolic syndrome and its components in patients with prostate cancer on androgen deprivation therapy. J Urol 193: 1963–1969.CrossRefGoogle Scholar
  38. 38.
    American Diabetes Association, 2008 Standards of medical care in diabetes-2008. Diabetes Care 31: Suppl 1: 12–54.CrossRefGoogle Scholar
  39. 39.
    American Diabetes Association, 2009 Diagnosis and classification of diabetes mellitus. Diabetes Care 32: Suppl 1: 62–67.CrossRefGoogle Scholar
  40. 40.
    Shahani S, Braga-Basaria M, Basaria S, 2008 Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. JCEM 93: 2042–2049.Google Scholar
  41. 41.
    Braga-Basaria M, Dobs AS, Muller DC, et al, 2006 Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol 24: 3979–3983.CrossRefGoogle Scholar
  42. 42.
    Prospective Study Collaboration, Lewington S, Whitlock G, Clarke R, et al, 2007 Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 370: 1829–1839.CrossRefGoogle Scholar
  43. 43.
    Rezaei MM, Rezaei MM, Ghoreifi A, Kerigh BF, 2016 Metabolic syndrome in patients with prostate cancer undergoing intermittent androgen-deprivation therapy. Can Urol Assoc J 10: 9–10.CrossRefGoogle Scholar
  44. 44.
    Csongrádi É, Káplár M, Nagy B Jr, 2017 Adipokines as atherothrombotic risk factors in obese subjects: Associations with haemostatic markers and common carotid wall thickness. Nutr Metab Cardiovasc Dis 27: 571–580.CrossRefGoogle Scholar
  45. 45.
    Wilt TJ, Bloomfield HE, MacDonald R, et al, 2004 Effectiveness of statin therapy in adults with coronary heart disease. Arch Intern Med 164: 1427–1436.CrossRefGoogle Scholar
  46. 46.
    Smith MR, Malkowicz SB, Chu F, et al, 2008 Toremifene increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study. J Urol 179: 152–155.CrossRefGoogle Scholar
  47. 47.
    Zarotsky V, Huang MY, Carman W, et al, 2014 Systematic literature review of the risk factors, comorbidities, and consequences of hypogonadism in men. Andrology 2: 819–834.CrossRefGoogle Scholar
  48. 48.
    Smith MR, Lee H, McGovern F, et al, 2008 Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer: Differences from the classic metabolic syndrome. Cancer 112: 2188–2194.CrossRefGoogle Scholar
  49. 49.
    Davis MK, Rajala JL, Tyldesley S, Pickles T, Virani SA, 2015 The prevalence of cardiac risk factors in men with localized prostate cancer undergoing androgen-deprivation therapy in British Columbia, Canada. J Oncol 2015: 820403.CrossRefGoogle Scholar
  50. 50.
    Alberti KG, Zimmet P, Shaw J, 2005 The metabolic syndrome: a new worldwide definition. Lancet 366: 1059–1062.CrossRefGoogle Scholar
  51. 51.
    Samper Ots PM, Muñoz García JL, Ríos Kavadoy Y, et al, 2015 SIMBOSPROST: Prevalence of metabolic syndrome and osteoporosis in prostate cancer patients treated with radiotherapy and androgen deprivation therapy: A multicentre, cross-sectional study. Rep Pract Oncol Radiother 5: 370–376.CrossRefGoogle Scholar
  52. 52.
    Allan CA, McLachlan RI, 2010 Androgens and obesity. Curr Opin Endocrinol Diabetes Obes 17: 224–232.CrossRefGoogle Scholar
  53. 53.
    Munoz Garcia J, Samper Ots P, Rios Kavadoy Y, et al, 2013 Cross-section observational study about prevalence of metabolic syndrome and osteoporosis in prostate cancer treated with androgen-deprivation therapy and their impact on quality of life (SIMBOSPROST): Gicor Group. Intl J Rad Onc Bio Phys 87: Suppl: 356.CrossRefGoogle Scholar
  54. 54.
    Valverde J, Planas Morin J, Salvador Lacambra C, et al, 2011 Prevalence of metabolic syndrome in prostatecancer patients under androgen-deprivation therapy: Interim results of a case-control study. Eur Urol Suppl 10: 337.CrossRefGoogle Scholar
  55. 55.
    Bosco C, Bosnyak Z, Malmberg A, Adolfsson J, Keating N, Van Hemelrijck M, 2015 (2015a) Quantifying observational evidence for risk of fatal and nonfatal cardiovascular disease following androgen deprivation therapy for prostate cancer: a meta-analysis. Eur Urol 68: 386–396.CrossRefGoogle Scholar
  56. 56.
    Beilin J, Ball EM, Favaloro JM, Zajac JD, 2000 Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. J Mol Endocrinol 25: 85–96.CrossRefGoogle Scholar
  57. 57.
    Stanworth RD, Kapoor D, Channer KS, Jones TH, 2008 Androgen receptor CAG repeat polymorphism is associated with serum testosterone levels, obesity and serum leptin in men with type 2 diabetes. Eur J Endocrinol 159: 739–746.CrossRefGoogle Scholar
  58. 58.
    Zitzmann M, Gromoll J, von Eckardstein A, Nieschlag E, 2003 The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men. Diabetologia 46: 31–39.CrossRefGoogle Scholar
  59. 59.
    Möhlig M, Arafat AM, Osterhoff MA, et al, 2011 Androgen receptor CAG repeat length polymorphism modifies the impact of testosterone on insulin sensitivity in men. Eur J Endocrinol 164: 1013–1018.CrossRefGoogle Scholar
  60. 60.
    Trujillo ME, Scherer PE, 2005 Adiponectin journey from an adipocyte secretory protein to biomarker of the metabolic syndrome. J Intern Med 257: 167–175.CrossRefGoogle Scholar
  61. 61.
    Hamilton EJ, Gianatti E, Strauss BJ, et al, 2011 Increase in visceral and subcutaneous abdominal fat in men with prostate cancer treated with androgen deprivation therapy. Clin Endocrinol 3: 377–383.CrossRefGoogle Scholar
  62. 62.
    Scailteux LM, Naudet F, Alimi Q, 2016 Mortality, cardiovascular risk, and androgen deprivation therapy for prostate cancer: A systematic review with direct and network meta-analyses of randomized controlled trials and observational studies. Medicine (Baltimore) 95: e3873.CrossRefGoogle Scholar
  63. 63.
    Haffner SM, 2006 The metabolic syndrome: Inflammation, diabetes mellitus and cardiovascular disease. Am J Cardiol 97: 3A–11A.CrossRefGoogle Scholar
  64. 64.
    Berruti L, Dogliotti C, Terrone, et al, 2002 Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. J Urol 167: 2361–2367.CrossRefGoogle Scholar
  65. 65.
    Keating NL, O’Malley AJ, Freedland SJ, Smith MR, 2013 Does comorbidity influence the risk of myocardial infarction or diabetes during androgen-deprivation therapy for prostate cancer? Eur Urol 64: 159–166.CrossRefGoogle Scholar
  66. 66.
    Zareba P, Duivenvoorden W, Leong DP, Pinthus JH, 2016 Androgen deprivation therapy and cardiovascular disease: what is the linking mechanism? Ther Adv Urol 8: 118–129.CrossRefGoogle Scholar
  67. 67.
    Tsai HK, D’Amico AV, Sadetsky N, et al, 2007 Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 99: 1516–1524.CrossRefGoogle Scholar
  68. 68.
    Efstathiou JA, Bae K, Shipley WU, et al, 2009 Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85-31. J Clin Oncol 27: 92–99.CrossRefGoogle Scholar
  69. 69.
    Roach III M, Bae K, Speight J, et al, 2008 Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 86-10. J Clin Oncol 26: 585–591.CrossRefGoogle Scholar
  70. 70.
    Efstathiou JA, Bae K, Shipley WU, et al, 2008 Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: analysis of RTOG 92-02. Eur Urol 54: 816–824.CrossRefGoogle Scholar
  71. 71.
    Nguyen PL, Je Y, Schutz FA, et al, 2011 Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 306: 2359–2366.CrossRefGoogle Scholar
  72. 72.
    Bolla M, de Reijke TM, Van Tienhoven G, et al, 2009 Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 360: 2516–2527.CrossRefGoogle Scholar
  73. 73.
    Piccirillo JF, Tierney RM, Costas I, et al, 2004 Prognostic importance of comorbidity in a hospital-based cancer registry. JAMA 291: 2441–2447.CrossRefGoogle Scholar
  74. 74.
    Smith MR, Klotz L, van der Meulen E, et al, 2011 Gonadotropin-releasing hormone blockers and cardiovascular disease risk: analysis of prospective clinical trials of degarelix. J Urol 186: 1835–1842.CrossRefGoogle Scholar
  75. 75.
    Albertsen PC, Klotz L, Tombal B, et al, 2014 Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol 65: 565–573.CrossRefGoogle Scholar
  76. 76.
    Stamler J, Stamler R, Neaton JD, et al, 1999 Low risk-factor profile and long-term cardiovascular and non-cardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women. JAMA 282: 2012–2018.CrossRefGoogle Scholar
  77. 77.
    Lim TH, Orija IB, Pearlman BL, 2014 American College of Cardiology; American College of Cardiology. The new cholesterol treatment guidelines from the American College of Cardiology/American Heart Association, 2013: what clinicians need to know. Postgrad Med 126: 35–44.CrossRefGoogle Scholar
  78. 78.
    Wall BA, 2016 Androgen deprivation therapy and cardiovascular disease risk — The role of exercise in prostate cancer treatment. Frontiers in Oncology 6: 200.CrossRefGoogle Scholar
  79. 79.
    Galvão DA, Taaffe DR, Spry N, 2010 Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial. J Clin Oncol 28: 340–347.CrossRefGoogle Scholar
  80. 80.
    Taaffe DR, Newton RU, Spry N, 2017 Effects of different exercise modalities on fatigue in prostate cancer patients undergoing androgen deprivation therapy: A year-long randomised controlled trial. Eur Urol [Epub ahead of Print].Google Scholar
  81. 81.
    Gaskin CJ, Fraser SF, Owen PJ, Craike M, Orellana L, Livingston PM, 2016 Fitness outcomes from a randomised controlled trial of exercise training for men with prostate cancer: the ENGAGE study. J Cancer Surviv 10: 972–980.CrossRefGoogle Scholar
  82. 82.
    Teleni L, Chan RJ, Chan A, 2016 Exercise improves quality of life in androgen deprivation therapy-treated prostate cancer: systematic review of randomised controlled trials. Endocr Relat Cancer 23: 101–112.CrossRefGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2017

Authors and Affiliations

  • Vasileios Tzortzis
    • 1
  • Michael Samarinas
    • 1
  • Ioannis Zachos
    • 1
  • Athanasios Oeconomou
    • 1
  • Louis L. Pisters
    • 2
  • Alexandra Bargiota
    • 3
  1. 1.Department of Urology, Faculty of Medicine, School of Health SciencesUniversity of ThessalyLarissaGreece
  2. 2.Department of Urology, Division of SurgeryThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of Endocrinology and Metabolic Diseases, Faculty of Medicine, School of Health SciencesUniversity of ThessalyLarissaGreece

Personalised recommendations