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A causal link between testosterone therapy and prostate cancer has not been established. What are the implications of long-term testosterone treatment for male patients with hypogonadism?
Response by Leonard S. Marks, MD

Testosterone therapy for symptomatic, hypogonadal men can improve libido, muscle mass, bone density, and mood.1-5 Despite these potential benefits, testosterone therapy use has been limited, particularly for older men, by concerns about increasing the risk of new prostate cancer (PCa) and stimulating the growth of occult PCa.2,6-9 Although testosterone therapy is contraindicated for men with existing PCa,1,3,4,10,11 a growing body of evidence demonstrating a lack of association between testosterone therapy and PCa occurrence has provided the basis for a paradigm shift. Testosterone therapy now may be considered for men for whom it was not previously considered: hypogonadal men for whom PCa has been ruled out or cured.6,9,10,12-14 Following are key points from clinical studies in support of this:
  • High endogenous testosterone levels are not associated with PCa15; rather, the opposite is true. PCa prevalence is lower among younger men, in whom endogenous testosterone levels are at their peak6,16
  • Low endogenous testosterone levels may increase risk for higher Gleason scores and poor outcomes for men diagnosed with PCa. Studies have shown that low endogenous testosterone levels are associated with a significantly increased risk of PCa17 and that PCa, when it occurs in this population, is significantly more likely to be a high-grade malignancy18
  • In a prospective study, the relationship between serum total testosterone levels and pathologic end points was evaluated in 455 consecutive patients undergoing radical retropubic prostatectomy for localized PCa. Results suggested that tumors arising in a low-androgen environment are not associated with increased actual or predicted disease progression risk, however, low testosterone may affect PCa grading19
  • A pooled analysis of 18 prospective studies including 3886 men with incident PCa and 6438 control participants demonstrated that serum sex hormone levels (ie, testosterone, free testosterone, dihydrotestosterone, androstanediol glucuronide, dehydroepiandrosterone, androstenedione, estradiol, free estradiol) were not associated with increased risk of subsequent PCa15
  • Testosterone therapy may normalize prostate volume and prostate-specific antigen (PSA) level in hypogonadal men with low PSA5,11,20,21
  • Significant changes in prostate-tissue androgen levels or prostate-related clinical features, histology, biomarkers, or epithelial-cell gene expression were not found after 6 months of testosterone therapy22
  • Studies have not demonstrated a causal relationship between testosterone therapy and the development of new PCa, recurrence in men definitively treated for PCa, or enhanced growth of PCa in noncastrated men2,7,12,16,23
Well-designed, large-scale prospective clinical trials are necessary to demonstrate that prostate health is not affected by testosterone therapy.

Response by E. David Crawford, MD

Testosterone therapy is recommended for symptomatic, hypogonadal men to relieve the symptoms of hypogonadism.3 Efficacy, safety, tolerability, pharmacokinetic profile, and the patient’s lifestyle should be considered when determining which testosterone formulation to prescribe.3 Transdermal patches, buccal tablets, and transdermal gels are intended for daily use, whereas implanted or injectable testosterone formulations have longer durations of effect.1,3,20,24 Each formulation has advantages and disadvantages that may affect patient satisfaction and adherence. To optimize long-term adherence to therapy, long-acting testosterone therapies should be considered for appropriate patients.

Restoring physiologic testosterone levels with little fluctuation over 4 to 6 months can be achieved by treating with subcutaneous testosterone pellet implants. Although they are generally acceptable to patients,25,26 insertion of the pellets requires an outpatient surgical procedure, and implants may be associated with high extrusion rates and infection.26

A novel long-acting injectable formulation of testosterone undecanoate (TU) 750 mg has been approved in more than 80 European and Asian countries and is being evaluated in the United States. TU provides a steady-state pharmacokinetic profile after the third injection, achieving and maintaining serum testosterone levels in the normal range during a 10-week dosing interval.11,27 In a 24-week trial, TU 750 mg depot injection given intramuscularly at 0, 4, and 14 weeks was safe and efficacious, with no PCa noted. European studies of longer than 8 years and a longitudinal study of TU in hypogonadal men further reinforced long-term safety and tolerability.11,27 Thus, the well-established safety and tolerability profile of TU, consistent pharmacokinetic profile, and convenient formulation make it an appropriate treatment option for many symptomatic, hypogonadal men.

Hypogonadal men receiving testosterone therapy should be routinely monitored for clinical response at 3 months, for side effects, and for prostate health every 3 to 4 months for the first year and every 6 to 12 months thereafter.1-4,11,24 Prostate health should be evaluated by measurement of PSA levels and digital rectal examination.1-4,11,24 Urinary symptoms should be assessed, and careful monitoring of serum testosterone, hematocrit, and hemoglobin levels is also recommended.11,24

  1. AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients—2002 update. Endocr Pract. 2002;8(6):439-456.
  2. Bhasin S, Buckwater JG. Testosterone supplementation in older men: a rational idea whose time has not yet come [review]. J Androl. 2001;22(5):718-731.
  3. Bhasin S, Cunningham GR, Hayes FJ, 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.
  4. Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males ISA, ISSAM, and EAU recommendations. Eur Urol. 2005;48(1):3-4.
  5. Wang C, Cunningham G, Dobs A, 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(5):2085-2098.
  6. Morgentaler A. Testosterone therapy for men at risk for or with history of prostate cancer. Curr Treat Options Oncol. 2006;7(5):363-369.
  7. Barqawi A, Crawford ED. Testosterone replacement therapy and the risk of prostate cancer: is there a link [review]? Int J Impot Res. 2006;18(4):323-328.
  8. Dobs AS, Morgentaler A. Does testosterone therapy increase the risk of prostate cancer [review]? Endocr Pract. 2008;14(7):904-911.
  9. Shabsigh R, Crawford ED, Nehra A, Slawin KM. Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review [review]. Int J Impot Res. 2009;21(1):9-23.
  10. 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;102(1):62-64.
  11. Morales A, Nieschlag E, Schubert M, Yassin AA, Zitzmann M, Oettel M. Clinical experience with the new long-acting injectable testosterone undecanoate: report on the educational symposium on the occasion of the 5th World Congress on the Aging Male, 9–12 February 2006, Salzburg, Austria. Aging Male. 2006;9(4):221–227.
  12. Kaufman JM, Graydon JR. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men [review]. J Urol. 2004;172(3):920-922.
  13. Holyoak JD, Crawford ED, Meacham RB. Testosterone and the prostate: implications for the treatment of hypogonadal men. Curr Urol Rep. 2008;9(6):500-505.
  14. Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer. 2007;109(3):536-541.
  15. Endogenous Hormones and Prostate Cancer Collaborative Group. Endogenous hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst. 2008;100(3):170-183.
  16. Morgentaler A. Testosterone replacement therapy and prostate cancer. Urol Clin North Am. 2007;34(4):555-563.
  17. 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):1263-1267.
  18. Schatzl G, Madersbacher S, Thurridl T, et al. High-grade prostate cancer is associated with low serum testosterone levels. Prostate. 2001;47(1):52-58.
  19. Lane BR, Stephenson AJ, Magi-Galluzzi C, Lakin MM, Klein EA. Low testosterone and risk of biochemical recurrence and poorly differentiated prostate cancer at radical prostatectomy. Urology. 2008;72(6):1240-1245.
  20. Bhasin S, Bremner WJ. Emerging issues in androgen replacement therapy. J Clin Endocrinol Metab. 1997;82(1):3-8.
  21. Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in comparison to age-matched normal controls. Clin Endocrinol. 1994;40(3):341-349.
  22. Marks LS, Mazer NA, Mostaghel E, et al. Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA. 2006;296(19):2351-2361.
  23. Morgentaler A, Schulman C. Testosterone and prostate safety. Front Horm Res. 2009;37:197-203.
  24. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring [review]. N Engl J Med. 2004;350(5):482-492.
  25. Harle L, Basaria S, Dobs AS. Nebido: a long-acting injectable testosterone for the treatment of male hypogonadism. Expert Opin Pharmacother. 2005;6(10):1751-1759.
  26. Korbonits M, Slawik M, Cullen D, et al. A comparison of a novel testosterone bioadhesive buccal system, striant, with a testosterone adhesive patch in hypogonadal males. J Clin Endocrinol Metab. 2004;89(5):2039-2043.
  27. Morgentaler A, Dobs AS, Kaufman JM, et al. Long acting testosterone undecanoate therapy in men with hypogonadism: results of a pharmacokinetic clinical study. J Urol. 2008;180(6):2307-2313.

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