Skip to main content

Advertisement

SpringerLink
Log in

The Role of Testosterone Therapy in the Setting of Prostate Cancer

  • Andrology and Infertility (L Lipshultz, Section Editor)
  • Published:
Current Urology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The role of testosterone in the development of prostate cancer and the safety of testosterone therapy (TTh) after prostate cancer treatment, or in the setting of active surveillance, remains controversial. There are many concerns about using TTh in men, particularly those with a history of prostate cancer, ranging from a possible increased risk of cardiovascular disease to cancer progression or recurrence. With many prostate cancer patients living longer, and hypogonadism having significant morbidity, much care must go into the decision to treat. Here, we review the literature investigating the effects of testosterone on the prostate as well as the efficacy and safety of exogenous testosterone in men with a history of prostate cancer.

Recent Findings

The improvement in quality of life with TTh is well studied and understood, while the argument for significantly increased risk of cancer or other adverse effects is much less robust. Neither increased rates of prostate cancer, cancer recurrence, or cardiovascular risk have been well established. In men with high-risk prostate cancer, evidence in the setting of TTh is very limited, and TTh should be used with caution.

Summary

The fears of TTh causing or worsening prostate cancer do not appear to be well supported by available data. Though more studies are needed to definitively determine the safety of TTh in men with prostate cancer, consideration should be given to treatment of hypogonadal men with a history of CaP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

AR:

Androgen receptor

DRE:

Digital rectal examination

CaP:

Prostate cancer

PSA:

Prostate-specific antigen

TTh:

Testosterone therapy

AS:

Active surveillance

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Pastuszak AW, Gomez LP, Scovell JM, Khera M, Lamb DJ, Lipshultz LI. Comparison of the effects of testosterone gels, injections, and pellets on serum hormones, erythrocytosis, lipids, and prostate-specific antigen. Sex Med. 2015;3(3):165–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. 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(7):762–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Araujo AB, Esche GR, Kupelian V, O’Donnell AB, Travison TG, Williams RE, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92(11):4241–7.

    Article  PubMed  CAS  Google Scholar 

  4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30.

    Article  PubMed  Google Scholar 

  5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.

    Article  PubMed  Google Scholar 

  6. Brawley OW. Prostate cancer epidemiology in the United States. World J Urol. 2012;30(2):195–200.

    Article  PubMed  Google Scholar 

  7. Cunningham GR, et al. Testosterone replacement therapy and sleep-related erections in hypogonadal men. J Clin Endocrinol Metab. 1990;70(3):792–7.

    Article  PubMed  CAS  Google Scholar 

  8. Pastuszak AW, Pearlman AM, Lai WS, Godoy G, Sathyamoorthy K, Liu JS, et al. Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy. J Urol. 2013;190(2):639–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Storer TW, Woodhouse L, Magliano L, Singh AB, Dzekov C, Dzekov J, et al. Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men. J Am Geriatr Soc. 2008;56(11):1991–9.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Corona G, Isidori AM, Buvat J, Aversa A, Rastrelli G, Hackett G, et al. Testosterone supplementation and sexual function: a meta-analysis study. J Sex Med. 2014;11(6):1577–92.

    Article  PubMed  CAS  Google Scholar 

  11. Isidori AM, Balercia G, Calogero AE, Corona G, Ferlin A, Francavilla S, et al. Outcomes of androgen replacement therapy in adult male hypogonadism: recommendations from the Italian society of endocrinology. J Endocrinol Investig. 2015;38(1):103–12.

    Article  CAS  Google Scholar 

  12. Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med. 2013;173(15):1465–6.

    Article  PubMed  PubMed Central  Google Scholar 

  13. •• Boyle P, et al. Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate-specific antigen (PSA) level: a meta-analysis. BJU Int. 2016 A well-done meta-analysis including available literature to 2016. Includes both increase in occult CaP and PSA increase.

  14. Huggins C, Hodges CV. Studies on prostatic cancer. J Urol. 2002;167(2):948–51.

    Article  PubMed  CAS  Google Scholar 

  15. Prout GR, Brewer WR. Response of men with advanced prostatic carcinoma to exogenous administration of testosterone. Cancer. 1967;20(11):1871–8.

    Article  PubMed  Google Scholar 

  16. Fowler Jr J, Whitmore Jr W. The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol. 1981;126(3):372–5.

    Article  CAS  Google Scholar 

  17. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2006;91(6):1995–2010.

    Article  PubMed  CAS  Google Scholar 

  18. Morgentaler A, Bruning CO 3rd, DeWolf WC. Occult prostate cancer in men with low serum testosterone levels. Jama. 1996;276(23):1904–6.

    Article  PubMed  CAS  Google Scholar 

  19. Klap J, Schmid M, Loughlin KR. The relationship between total testosterone levels and prostate cancer: a review of the continuing controversy. J Urol. 2015;193(2):403–14.

    Article  PubMed  CAS  Google Scholar 

  20. 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(6):1263–7.

    Article  PubMed  Google Scholar 

  21. Shin BS, Hwang EC, Im CM, Kim SO, Jung SI, Kang TW, et al. Is a decreased serum testosterone level a risk factor for prostate cancer? A cohort study of Korean men. Korean J Urol. 2010;51(12):819–23.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mearini L, Zucchi A, Nunzi E, Villirillo T, Bini V, Porena M. Low serum testosterone levels are predictive of prostate cancer. World J Urol. 2013;31(2):247–52.

    Article  PubMed  CAS  Google Scholar 

  23. Bayar G, Sirin H, Aydin M, Ozagari A, Tanriverdi O, Kadihasanoglu M, et al. Low free and bioavailable testosterone levels may predict pathologically-proven high-risk prostate cancer: a prospective, clinical trial. Turk J Urol. 2017;43(3):289–96.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Garcia-Cruz E, et al. Low testosterone levels are related to poor prognosis factors in men with prostate cancer prior to treatment. BJU Int. 2012;110(11 Pt B):E541–6.

    Article  PubMed  CAS  Google Scholar 

  25. Albuquerque G, et al. Low serum testosterone is a predictor of high-grade disease in patients with prostate cancer. Rev Assoc Med Bras (1992). 2017;63(8):704–10.

    Article  Google Scholar 

  26. Izumi K, Shigehara K, Nohara T, Narimoto K, Kadono Y, Mizokami A. Both high and low serum total testosterone levels indicate poor prognosis in patients with prostate cancer. Anticancer Res. 2017;37(10):5559–64.

    PubMed  Google Scholar 

  27. Salonia A, Abdollah F, Capitanio U, Suardi N, Briganti A, Gallina A, et al. Serum sex steroids depict a nonlinear u-shaped association with high-risk prostate cancer at radical prostatectomy. Clin Cancer Res. 2012;18(13):3648–57.

    Article  PubMed  CAS  Google Scholar 

  28. Gann PH, Hennekens CH, Ma J, Longcope C, Stampfer MJ. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst. 1996;88(16):1118–26.

    Article  PubMed  CAS  Google Scholar 

  29. Shaneyfelt T, Husein R, Bubley G, Mantzoros CS. Hormonal predictors of prostate cancer: a meta-analysis. J Clin Oncol. 2000;18(4):847–53.

    Article  PubMed  CAS  Google Scholar 

  30. Yano M, Imamoto T, Suzuki H, Fukasawa S, Kojima S, Komiya A, et al. The clinical potential of pretreatment serum testosterone level to improve the efficiency of prostate cancer screening. Eur Urol. 2007;51(2):375–80.

    Article  PubMed  CAS  Google Scholar 

  31. Muller RL, Gerber L, Moreira DM, Andriole G, Castro-Santamaria R, Freedland SJ. Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial. Eur Urol. 2012;62(5):757–64.

    Article  PubMed  CAS  Google Scholar 

  32. Platz EA, et al. Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era. Cancer Epidemiol Biomark Prev. 2005;14(5):1262–9.

    Article  CAS  Google Scholar 

  33. Roddam AW, et al. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst. 2008;100(3):170–83.

    Article  PubMed  CAS  Google Scholar 

  34. Stattin P, et al. High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study. Int J Cancer. 2004;108(3):418–24.

    Article  PubMed  CAS  Google Scholar 

  35. Mearini L, Costantini E, Zucchi A, Mearini E, Bini V, Cottini E, et al. Testosterone levels in benign prostatic hypertrophy and prostate cancer. Urol Int. 2008;80(2):134–40.

    Article  PubMed  CAS  Google Scholar 

  36. Ahmadi H, Allameh F, Baradaran N, Montaser-Kouhsari L, Bazargan-Hejazi S, Salem S, et al. Circulating sex hormones play no role in the association between sexual activity and the risk of prostate cancer. J Sex Med. 2011;8(3):905–13.

    Article  PubMed  CAS  Google Scholar 

  37. Porcaro AB, Petrozziello A, Ghimenton C, Migliorini F, Sava T, Caruso B, et al. Associations of pretreatment serum total testosterone measurements with pathology-detected Gleason score cancer. Urol Int. 2014;93(3):269–78.

    Article  PubMed  CAS  Google Scholar 

  38. Porcaro AB, Petroziello A, Brunelli M, de Luyk N, Cacciamani G, Corsi P, et al. High testosterone preoperative plasma levels independently predict biopsy Gleason score upgrading in men with prostate cancer undergoing radical prostatectomy. Urol Int. 2016;96(4):470–8.

    Article  PubMed  CAS  Google Scholar 

  39. Salonia A, Abdollah F, Capitanio U, Gallina A, Suardi N, Briganti A, et al. Preoperative sex steroids are significant predictors of early biochemical recurrence after radical prostatectomy. World J Urol. 2013;31(2):275–80.

    Article  PubMed  CAS  Google Scholar 

  40. Roder MA, et al. Serum testosterone level as a predictor of biochemical failure after radical prostatectomy for localized prostate cancer. BJU Int. 2012;109(4):520–4.

    Article  PubMed  CAS  Google Scholar 

  41. Yamamoto S, Yonese J, Kawakami S, Ohkubo Y, Tatokoro M, Komai Y, et al. Preoperative serum testosterone level as an independent predictor of treatment failure following radical prostatectomy. Eur Urol. 2007;52(3):696–701.

    Article  PubMed  CAS  Google Scholar 

  42. Imamoto T, et al. Pretreatment serum level of testosterone as a prognostic factor in Japanese men with hormonally treated stage D2 prostate cancer. Endocr J. 2001;48(5):573–8.

    Article  PubMed  CAS  Google Scholar 

  43. • Cooper CS, Perry PJ, Sparks AET, MacIndoe JH, Yates WR, Williams RD. Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men. J Urol. 1998;159(2):441–3. One of the early studies that set the stage for the set point theory.–3.

  44. •• Dupree, J.M., et al., The safety of testosterone supplementation therapy in prostate cancer. Nat Rev Urol, 2014. 11(9): p. 526–30. A comprehensive and well-written review from 2014.

  45. • Song W, Khera M. Physiological normal levels of androgen inhibit proliferation of prostate cancer cells in vitro. Asian J Androl. 2014;16(6):864–8. In vitro data that adds to the understanding of the relationship between CaP and testosterone.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. •• Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol. 2006;50(5):935–9. An interesting review put into the context of historial concerns and modern literature.

    Article  PubMed  CAS  Google Scholar 

  47. Morgentaler A, Benesh JA, Denes BS, Kan-Dobrosky N, Harb D, Miller MG. Factors influencing prostate-specific antigen response among men treated with testosterone therapy for 6 months. J Sex Med. 2014;11(11):2818–25.

    Article  PubMed  CAS  Google Scholar 

  48. Khera M, Bhattacharya RK, Blick G, Kushner H, Nguyen D, Miner MM. Changes in prostate specific antigen in hypogonadal men after 12 months of testosterone replacement therapy: support for the prostate saturation theory. J Urol. 2011;186(3):1005–11.

    Article  PubMed  CAS  Google Scholar 

  49. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci. 2005;60(11):1451–7.

    Article  PubMed  Google Scholar 

  50. Yassin A, Salman M, Talib RA, Yassin DJ. Is there a protective role of testosterone against high-grade prostate cancer? Incidence and severity of prostate cancer in 553 patients who underwent prostate biopsy: a prospective data register. Aging Male. 2017;20(2):125–33.

    Article  PubMed  CAS  Google Scholar 

  51. Wallis CJ, et al. Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study. Lancet Diabetes Endocrinol. 2016;4(6):498–506.

    Article  PubMed  CAS  Google Scholar 

  52. Debruyne FM, et al. Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men. BJU Int. 2017;119(2):216–24.

    Article  PubMed  CAS  Google Scholar 

  53. Loeb S, Folkvaljon Y, Damber JE, Alukal J, Lambe M, Stattin P. Testosterone replacement therapy and risk of favorable and aggressive prostate cancer. J Clin Oncol. 2017;35(13):1430–6.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol. 2004;172(3):920–2.

    Article  PubMed  CAS  Google Scholar 

  55. Khera M, Grober ED, Najari B, Colen JS, Mohamed O, Lamb DJ, et al. Testosterone replacement therapy following radical prostatectomy. J Sex Med. 2009;6(4):1165–70.

    Article  PubMed  CAS  Google Scholar 

  56. Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer. 2007;109(3):536–41.

    Article  PubMed  CAS  Google Scholar 

  57. Morales A, Black AM, Emerson LE. Testosterone administration to men with testosterone deficiency syndrome after external beam radiotherapy for localized prostate cancer: preliminary observations. BJU Int. 2009;103(1):62–4.

    Article  PubMed  CAS  Google Scholar 

  58. Pastuszak AW, Pearlman AM, Godoy G, Miles BJ, Lipshultz LI, Khera M. Testosterone replacement therapy in the setting of prostate cancer treated with radiation. Int J Impot Res. 2013;25(1):24–8.

    Article  PubMed  CAS  Google Scholar 

  59. Balbontin FG, Moreno SA, Bley E, Chacon R, Silva A, Morgentaler A. Long-acting testosterone injections for treatment of testosterone deficiency after brachytherapy for prostate cancer. BJU Int. 2014;114(1):125–30.

    Article  PubMed  CAS  Google Scholar 

  60. Ory J, Flannigan R, Lundeen C, Huang JG, Pommerville P, Goldenberg SL. Testosterone therapy in patients with treated and untreated prostate cancer: impact on oncologic outcomes. J Urol. 2016;196:1082–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Morgentaler A, Lipshultz LI, Bennett R, Sweeney M, Avila D Jr, Khera M. Testosterone therapy in men with untreated prostate cancer. J Urol. 2011;185(4):1256–60.

    Article  PubMed  CAS  Google Scholar 

  62. Kacker R, Hult M, San Francisco IF, Conners WP, Rojas PA, Dewolf WC, et al. Can testosterone therapy be offered to men on active surveillance for prostate cancer? Preliminary results. Asian J Androl. 2016;18(1):16–20.

    Article  PubMed  CAS  Google Scholar 

  63. Pastuszak AW, Khanna A, Badhiwala N, Morgentaler A, Hult M, Conners WP, et al. Testosterone therapy after radiation therapy for low, intermediate and high risk prostate cancer. J Urol. 2015;194(5):1271–6.

    Article  PubMed  CAS  Google Scholar 

  64. Golla V, Kaplan AL. Testosterone therapy on active surveillance and following definitive treatment for prostate cancer. Curr Urol Rep. 2017;18(7):49.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Cooperberg MR, Carroll PR. Trends in management for patients with localized prostate cancer, 1990–2013. Jama. 2015;314(1):80–2.

    Article  PubMed  CAS  Google Scholar 

  66. Fowler, J.E., Jr. and W.F. Whitmore, Jr., Considerations for the use of testosterone with systemic chemotherapy in prostatic cancer. Cancer, 1982. 49(7): p. 1373–7.

  67. • Mohammad OS, et al. Supraphysiologic testosterone therapy in the treatment of prostate cancer: models mechanisms, and questions. Cancers (Basel). 2017;9(12). Interesting paper supporting the emerging bipolar androgen therapy hypothesis.

  68. Geck P, Maffini MV, Szelei J, Sonnenschein C, Soto AM. Androgen-induced proliferative quiescence in prostate cancer cells: the role of AS3 as its mediator. Proc Natl Acad Sci U S A. 2000;97(18):10185–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Soto AM, Sonnenschein C. The two faces of Janus: sex steroids as mediators of both cell proliferation and cell death. J Natl Cancer Inst. 2001;93(22):1673–5.

    Article  PubMed  CAS  Google Scholar 

  70. Umekita Y, Hiipakka RA, Kokontis JM, Liao S. Human prostate tumor growth in athymic mice: inhibition by androgens and stimulation by finasteride. Proc Natl Acad Sci. 1996;93(21):11802–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  71. Liao S, Umekita Y, Guo J, Kokontis JM, Hiipakka RA. Growth inhibition and regression of human prostate and breast tumors in athymic mice by tea epigallocatechin gallate. Cancer Lett. 1995;96(2):239–43.

    Article  PubMed  CAS  Google Scholar 

  72. Morris MJ, Huang D, Kelly WK, Slovin SF, Stephenson RD, Eicher C, et al. Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer. Eur Urol. 2009;56(2):237–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Szmulewitz R, Mohile S, Posadas E, Kunnavakkam R, Karrison T, Manchen E, et al. A randomized phase 1 study of testosterone replacement for patients with low-risk castration-resistant prostate cancer. Eur Urol. 2009;56(1):97–103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Denmeade SR, Isaacs JT. Bipolar androgen therapy: the rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer. Prostate. 2010;70(14):1600–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Mohammad OS, et al. Supraphysiologic testosterone therapy in the treatment of prostate cancer: models, mechanisms and questions. Cancers. 2017;9(12):166.

    Article  PubMed Central  Google Scholar 

  76. Schweizer, M.T., et al., Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study. Sci Transl Med, 2015. 7(269): p. 269ra2.

  77. Schweizer MT, Wang H, Luber B, Nadal R, Spitz A, Rosen DM, et al. Bipolar androgen therapy for men with androgen ablation naive prostate cancer: results from the phase II BATMAN study. Prostate. 2016;76(13):1218–26.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Baylor College of Medicine, Houston, TX, USA

    Katherine M. Rodriguez

  2. Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, USA

    Alexander W. Pastuszak

  3. Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA

    Alexander W. Pastuszak & Mohit Khera

Authors
  1. Katherine M. Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander W. Pastuszak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohit Khera
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohit Khera.

Ethics declarations

Conflict of Interest

Katherine Rodriguez, Alexander W. Pastuszak, and Mohit Khera each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

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

Additional information

This article is part of the Topical Collection on Andrology and Infertility

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rodriguez, K.M., Pastuszak, A.W. & Khera, M. The Role of Testosterone Therapy in the Setting of Prostate Cancer. Curr Urol Rep 19, 67 (2018). https://doi.org/10.1007/s11934-018-0812-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11934-018-0812-1

Keywords

Search

Navigation