Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review

International Journal of Impotence Research volume 21, pages 9–23 (2009)Cite this article

Abstract

This paper provides a systematic review of the literature about prostate cancer risk associated with testosterone therapy for hypogonadism. A comprehensive search of MEDLINE, EMBASE and other resources was conducted to identify articles that highlight occurrences of prostate cancer in men receiving testosterone therapy for hypogonadism treatment. Articles that met study inclusion criteria were assessed for causality between testosterone treatment and prostate cancer, increased prostate-specific antigen or abnormal digital rectal examination findings. Of 197 articles relating to testosterone therapy, 44 met inclusion criteria: 11 placebo-controlled, randomized studies; 29 non-placebo-controlled studies of men with no prostate cancer history; and 4 studies of hypogonadal men with history of prostate cancer. Of studies that met inclusion criteria, none demonstrated that testosterone therapy for hypogonadism increased prostate cancer risk or increased Gleason grade of cancer detected in treated vs untreated men. Testosterone therapy did not have a consistent effect on prostate-specific antigen levels.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Nieschlag E . Testosterone treatment comes of age: new options for hypogonadal men. Clin Endocrinol 2006; 65: 275–281.

    Article  CAS  Google Scholar 

  2. Swyer GI . Male hypogonadism with unexpected response to testosterone therapy. Proc R Soc Med 1951; 44: 157–158.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Hirschhauser C, Hopkinson CR, Sturm G, Coert A . Testosterone undecanoate: a new orally active androgen. Acta Endocrinol (Copenh) 1975; 80: 179–187.

    Article  CAS  Google Scholar 

  4. Seftel A . Testosterone replacement therapy for male hypogonadism, part III: pharmacologic and clinical profiles, monitoring, safety issues, and potential future agents [review]. Int J Impot Res 2007; 19: 2–24.

    Article  CAS  PubMed  Google Scholar 

  5. Tan RS, Salazar JA . Risks of testosterone replacement therapy in ageing men [review]. Expert Opin Drug Saf 2004; 3: 599–606.

    Article  CAS  PubMed  Google Scholar 

  6. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C . Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006; 60: 762–769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Seftel AD . Male hypogonadism, part I: epidemiology of hypogonadism [review]. Int J Impot Res 2006; 18: 115–120.

    Article  CAS  PubMed  Google Scholar 

  8. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 2002; 87: 589–598.

    Article  CAS  PubMed  Google Scholar 

  9. Araujo AB, O'Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2004; 89: 5920–5926.

    Article  CAS  PubMed  Google Scholar 

  10. Cunningham GR . Testosterone replacement therapy for late-onset hypogonadism [review]. Nat Clin Pract Urol 2006; 3: 260–267.

    Article  CAS  PubMed  Google Scholar 

  11. Handelsman DJ . Testosterone: use, misuse and abuse. MJA 2006; 185: 436–439.

    PubMed  Google Scholar 

  12. Seftel A . Male hypogonadism, part II: etiology, pathophysiology, and diagnosis [review]. Int J Impot Res 2006; 18: 223–228.

    Article  CAS  PubMed  Google Scholar 

  13. Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legros JJ et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations [reprint of Int J Androl 2005; 28: 125–127]. J Androl 2006; 27: 135–137.

    Article  CAS  PubMed  Google Scholar 

  14. Tenover JS . Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab 1992; 75: 1092–1098.

    CAS  PubMed  Google Scholar 

  15. Rhoden EL, Morgentaler A . Risks of testosterone-replacement therapy and recommendations for monitoring [review]. N Engl J Med 2004; 350: 482–492.

    Article  CAS  PubMed  Google Scholar 

  16. Huggins C, Hodges CV . Studies on prostatic cancer, I: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate [reprinted by: J Urol 2002; 167: 948–951]. Cancer Res 1941; 1: 293–297.

    CAS  Google Scholar 

  17. Barqawi A, Crawford ED . Testosterone replacement therapy and the risk of prostate cancer: is there a link [review]? Int J Impot Res 2006; 18: 323–328.

    Article  CAS  PubMed  Google Scholar 

  18. Bhasin S, Buckwalter JG . Testosterone supplementation in older men: a rational idea whose time has not yet come. J Androl 2001; 22: 718–731.

    CAS  PubMed  Google Scholar 

  19. Gould DC, Kirby RS . Testosterone replacement therapy for late onset hypogonadism: what is the risk of inducing prostate cancer [review]? Prostate Cancer Prostatic Dis 2006; 9: 14–18.

    Article  CAS  PubMed  Google Scholar 

  20. Gruenewald DA, Matsumoto AM . Testosterone supplementation therapy for older men: potential benefits and risks. J Am Geriatr Soc 2003; 51: 101–115.

    Article  PubMed  Google Scholar 

  21. Kaufman J . A rational approach to androgen therapy for hypogonadal men with prostate cancer [review]. Int J Impot Res 2006; 18: 26–31.

    Article  CAS  PubMed  Google Scholar 

  22. Slater S, Oliver RTD . Testosterone: its role in development of prostate cancer and potential risk from use as hormone replacement therapy. Drugs Aging 2000; 17: 431–439.

    Article  CAS  PubMed  Google Scholar 

  23. Miner MM, Seftel AD . Testosterone and ageing: what have we learned since the institute of medicine report and what lies ahead? Int J Clin Pract 2007; 61: 622–632.

    Article  CAS  PubMed  Google Scholar 

  24. Morgentaler A . Testosterone therapy for men at risk for or with history of prostate cancer. Curr Treat Options Oncol 2006; 7: 363–369.

    Article  PubMed  Google Scholar 

  25. Liverman CT, Blazer DG eds. Testosterone and Aging: Clinical Research Directions. National Academies Press: Washington, DC, 2004.

    Google Scholar 

  26. Amory JK, Watts NB, Easley KA, Sutton PR, Anawalt BD, Matsumoto AM et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 2004; 89: 503–510.

    Article  CAS  PubMed  Google Scholar 

  27. Bhasin S, Storer TW, Asbel-Sethi N, Kilbourne A, Hays R, Sinha-Hikim I et al. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab 1998; 83: 3155–3162.

    CAS  PubMed  Google Scholar 

  28. Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG . Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 2001; 56A: M266–M272.

    Article  CAS  Google Scholar 

  29. Marks LS, Mazer NA, Mostaghel E, Hess DL, Dorey FJ, Epstein JI et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA 2006; 296: 2351–2361.

    Article  CAS  PubMed  Google Scholar 

  30. Okun MS, Fernandez HH, Rodriguez RL, Romrell J, Suelter M, Munson S et al. Testosterone therapy in men with Parkinson disease: results of the TEST-PD Study. Arch Neurol 2006; 63: 729–735.

    Article  PubMed  Google Scholar 

  31. Sih R, Morley JE, Kaiser FE, Perry III HM, Patrick P, Ross C . Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial. J Clin Endocrinol Metab 1997; 82: 1661–1667.

    Article  CAS  PubMed  Google Scholar 

  32. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 1999; 84: 1966–1972.

    CAS  PubMed  Google Scholar 

  33. Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R, the North American AA2500T Gel Study Group. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J Clin Endocrinol Metab 2003; 8: 2673–2681.

    Article  Google Scholar 

  34. Tan RS, Pu SJ . A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer's disease. Aging Male 2003; 6: 13–17.

    Article  CAS  PubMed  Google Scholar 

  35. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE . Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci 2003; 58A: 618–625.

    Article  CAS  Google Scholar 

  36. Gaylis FD, Lin DW, Ignatoff JM, Amling CL, Tutrone RF, Cosgrove DJ . Prostate cancer in men using testosterone supplementation. J Urol 2005; 174: 534–538.

    Article  CAS  PubMed  Google Scholar 

  37. Arver S, Dobs AS, Meikle AW, Caramelli KE, Rajaram L, Sanders SW et al. Long-term efficacy and safety of a permeation-enhanced testosterone transdermal system in hypogonadal men. Clin Endocrinol 1997; 47: 727–737.

    Article  CAS  Google Scholar 

  38. Behre HM, Nieschlag E . Testosterone buciclate (20 Aet-1) in hypogonadal men: pharmacokinetics and pharmacodynamics of the new long-acting androgen ester. J Clin Endocrinol Metab 1992; 75: 1204–1210.

    CAS  PubMed  Google Scholar 

  39. Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA . Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab 1999; 84: 3469–3478.

    CAS  PubMed  Google Scholar 

  40. Douglas TH, Connelly RR, McLeod DG, Erickson SJ, Barren III R, Murphy GP . Effect of exogenous testosterone replacement on prostate-specific antigen and prostate-specific membrane antigen levels in hypogonadal men. J Surg Oncol 1995; 59: 246–250.

    Article  CAS  PubMed  Google Scholar 

  41. El-Sakka AI, Hassoba HM, Elbakry AM, Hassan HA . Prostatic specific antigen in patients with hypogonadism: effect of testosterone replacement. J Sex Med 2005; 2: 235–240.

    Article  CAS  PubMed  Google Scholar 

  42. Gooren LJG . A ten-year safety study of the oral androgen testosterone undecanoate. J Androl 1994; 15: 212–215.

    CAS  PubMed  Google Scholar 

  43. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A . Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 1996; 81: 4358–4365.

    CAS  PubMed  Google Scholar 

  44. McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA . A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU Int 2003; 91: 69–74.

    Article  CAS  PubMed  Google Scholar 

  45. Meikle AW, Arver S, Dobs AS, Adolfsson J, Sanders SW, Middleton RG et al. Prostate size in hypogonadal men treated with a nonscrotal permeation-enhanced testosterone transdermal system. Urology 1997; 49: 191–196.

    Article  CAS  PubMed  Google Scholar 

  46. Pechersky AV, Mazurov VI, Semiglazov VF, Karpischenko AI, Mikhailichenko VV, Udintsev AV . Androgen administration in middle-aged and ageing men: effects of oral testosterone undecanoate on dihydrotestosterone, oestradiol and prostate volume. Int J Androl 2002; 25: 119–125.

    Article  CAS  PubMed  Google Scholar 

  47. Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 2000; 85: 2670–2677.

    CAS  PubMed  Google Scholar 

  48. Von Eckardstein S, Nieschlag E . Treatment of male hypogonadism with testosterone undecanoate injected at extended intervals of 12 weeks: a phase II study. J Androl 2002; 23: 419–425.

    CAS  PubMed  Google Scholar 

  49. Wang C, Swerdloff RS, Iranmanesh A, Dobs A, Snyder PJ, Cunningham G et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 2000; 85: 2839–2853.

    CAS  PubMed  Google Scholar 

  50. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab 2004; 89: 2085–2098.

    Article  CAS  PubMed  Google Scholar 

  51. Swerdloff RS, Wang C . Three-year follow-up of androgen treatment in hypogonadal men: preliminary report with testosterone gel. Aging Male 2003; 6: 207–211.

    Article  CAS  PubMed  Google Scholar 

  52. Guay AT, Perez JB, Fitaihi WA, Vereb M . Testosterone treatment in hypogonadal men: prostate-specific antigen level and risk of prostate cancer. Endocr Pract 2000; 6: 132–138.

    Article  CAS  PubMed  Google Scholar 

  53. Hajjar RR, Kaiser FE, Morley JE . Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab 1997; 82: 3793–3796.

    Article  CAS  PubMed  Google Scholar 

  54. Rhoden EL, Morgentaler A . Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J Urol 2003; 170: 2348–2351.

    Article  CAS  PubMed  Google Scholar 

  55. Rhoden EL, Morgentaler A . Influence of demographic factors and biochemical characteristics on the prostate-specific antigen (PSA) response to testosterone replacement therapy. Int J Impot Res 2006; 18: 201–205.

    Article  CAS  PubMed  Google Scholar 

  56. Gerstenbluth RE, Maniam PN, Corty EW, Seftel AD . Prostate-specific antigen changes in hypogonadal men treated with testosterone replacement. J Androl 2002; 23: 922–926.

    PubMed  Google Scholar 

  57. Bydder SA, Joseph DJ, Weinstein S, Stuckey BGA . Prostate cancer following testosterone replacement in Klinefelter syndrome [case report]. ANZ J Surg 2007; 77: 93–94.

    Article  PubMed  Google Scholar 

  58. Hwang JJ, Dharmawardana PG, Uchio EM, Wynberg J, Phillips JL . Prostate cancer in Klinefelter syndrome during hormonal replacement therapy. Urology 2003; 62: 941iv–941vi.

    Article  Google Scholar 

  59. Curran MJ, Bihrle III W . Dramatic rise in prostate-specific antigen after androgen replacement in a hypogonadal man with occult adenocarcinoma of the prostate. Urology 1999; 53: 423–424.

    Article  CAS  PubMed  Google Scholar 

  60. Ferri M, Norman RW . Prostate cancer in a hypogonadal male receiving androgen supplementation [case report]. Can J Urol 2000; 7: 1055–1056.

    CAS  PubMed  Google Scholar 

  61. Halland A, Jønler M, Pedersen KV . Prostate cancer after exogenous testosterone replacement therapy in a patient with pituitary insufficiency [case report]. Scand J Urol Nephrol 2005; 39: 87–88.

    Article  PubMed  Google Scholar 

  62. Jackson JA, Waxman J, Spiekerman AM . Prostatic complications of testosterone replacement therapy. Arch Intern Med 1989; 149: 2365–2366.

    Article  CAS  PubMed  Google Scholar 

  63. Loughlin KR, Richie JP . Prostate cancer after exogenous testosterone treatment for impotence. J Urol 1997; 157: 1845.

    Article  CAS  PubMed  Google Scholar 

  64. Sandeman TF . Impotence, androgens and prostate cancer [letter]. Med J Aust 1998; 169: 400.

    Article  CAS  PubMed  Google Scholar 

  65. Ferreira U, Leitao VA, Denardi F, Matheus WE, Stopiglia RM, Netto Jr NR . Intermittent androgen replacement for intense hypogonadism symptoms in castrated patients. Prostate Cancer Prostatic Dis 2006; 9: 39–41.

    Article  CAS  PubMed  Google Scholar 

  66. Sarosdy MF . Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer 2007; 109: 536–541.

    Article  CAS  PubMed  Google Scholar 

  67. Agarwal PK, Oefelein MG . Testosterone replacement therapy after primary treatment for prostate cancer. J Urol 2005; 173: 533–536.

    Article  CAS  PubMed  Google Scholar 

  68. Kaufman JM, Graydon RJ . Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol 2004; 172: 920–922.

    Article  CAS  PubMed  Google Scholar 

  69. Morgentaler A, Rhoden EL . Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4.0 ng/mL or less. Urology 2006; 68: 1263–1267.

    Article  PubMed  Google Scholar 

  70. Pacelli A, Bostwick DG . Clinical significance of high-grade prostatic intraepithelial neoplasia in transurethral resection specimens. Urology 1997; 50: 355–359.

    Article  CAS  PubMed  Google Scholar 

  71. Lefkowitz GK, Taneja SS, Brown J, Melamed J, Lepor H . Followup interval prostate biopsy 3 years after diagnosis of high grade prostatic intraepithelial neoplasia is associated with high likelihood of prostate cancer, independent of change in prostate specific antigen levels. J Urol 2002; 168: 1415–1418.

    Article  PubMed  Google Scholar 

  72. Gore JL, Shariat SF, Miles BJ, Kadmon D, Jiang N, Wheeler TM et al. Optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate cancer. J Urol 2001; 165: 1554–1559.

    Article  CAS  PubMed  Google Scholar 

  73. Shariat SF, Lamb DJ, Iyengar RG, Roehrborn CG, Slawin KM . A herbal/hormonal dietary supplement: an association with prostate cancer progression? Clin Cancer Res 2008; 14: 607–611.

    Article  CAS  PubMed  Google Scholar 

  74. Endogenous Hormones and Prostate Cancer Collaborative Group. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst 2008; 100: 170–183.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Urology, Maimonides Medical Center, Brooklyn, College of Physicians & Surgeons of Columbia University, New York, NY, USA

    R Shabsigh

  2. Division of Urologic Oncology, University of Colorado Health Sciences Center, Aurora, CO, USA

    E D Crawford

  3. Department of Urology, Mayo Medical School, Mayo Clinic, Rochester, MN, USA

    A Nehra

  4. Department of Urology, Baylor College of Medicine, Memorial Hermann Hospital—TMC, Vanguard Urologic Institute and Texas Prostate Center, Houston, TX, USA

    K M Slawin

Authors
  1. R Shabsigh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E D Crawford
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Nehra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K M Slawin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R Shabsigh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shabsigh, R., Crawford, E., Nehra, A. et al. Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review. Int J Impot Res 21, 9–23 (2009). https://doi.org/10.1038/ijir.2008.31

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijir.2008.31

Keywords

This article is cited by

Search

Advanced search

Quick links