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This Month's Question

Response by Abraham Morgentaler, MD, Posted 08/15/07

Testosterone therapy has been successfully used for decades to treat men with hypogonadism. Recent studies show testosterone therapy to be beneficial, restoring sexual function and increasing energy, improving muscle mass and bone density, and promoting an overall sense of well-being.¹ However, a nagging concern for many clinicians and patients has been the fear that raising testosterone concentrations might increase the risk of prostate disease, particularly prostate cancer.¹ The good news is that a wealth of evidence accumulated over several decades establishes this concern is without merit.²

Large, longitudinal studies have failed to show a connection between increasing total testosterone concentrations in men and subsequent risk of prostate cancer.^3-5 In addition, the cancer detection rate in testosterone trials is approximately 1% per year, a rate no higher than that seen in prostate cancer screening programs.¹ In fact, emerging evidence suggests a link between low testosterone levels and prostate cancer. Multiple new studies demonstrate that low testosterone levels are associated with high-grade tumors, advanced stage at diagnosis, and worse prognosis.⁶

That there is no negative effect of testosterone treatment on the prostate is reinforced with a landmark study by Marks et al. In this 6-month study in which men with hypogonadism received injections of testosterone or placebo, intraprostatic concentrations of testosterone and dihydrotestosterone did not change despite a substantial rise in serum testosterone levels.⁷ Thus, it appears that the prostatic hormonal milieu is largely unaffected by substantial increases in serum testosterone. Evidence negating the hypothesis that testosterone supplementation exacerbates voiding symptoms caused by benign prostatic hyperplasia is likewise reassuring. Multiple testosterone trials demonstrated no differences in urine flow rates, post-voiding residual urine volumes, or prostate voiding symptoms.¹

Nonetheless, since androgens have a role in prostatic growth, it remains possible that some individuals might be vulnerable to treatment with testosterone, especially men with severe testosterone deficiency. Also, because prostate disease prevalence rises in men at risk for hypogonadism, it is prudent to monitor prostate health in men receiving treatment for testosterone deficiency.¹

Recommended steps before initiating treatment include^1,8

•  Digital rectal examination (DRE)
•  Prostate specific antigen (PSA) level
•  Assessment of voiding symptoms

• Standard tools for this include the American Urological Association (AUA) symptom score and the International Prostate Symptom Score (IPSS) questionnaires

•  Findings that support a urologic referral or performance of prostate biopsy include^1,8

• PSA >4.0 ng/mL
• Prostatic abnormality detected by DRE
• AUA symptom score or IPSS >19

Follow-up evaluations during testosterone therapy generally include^1,8

•  Monitoring of prostate-related adverse events at 3, 6, and 12 months and annually thereafter through the course of treatment
•  With each evaluation, a serum PSA, DRE, and an AUA symptom score or IPSS
•  Referral to a urologist should be made for ^1,8

• PSA >4.0 ng/mL
• A yearly increase in PSA of >1.0 ng/mL
• Prostatic abnormality detected by DRE

In summary, a wealth of data strongly suggest a reassuring safety profile for the effects of testosterone therapy on the prostate. Nevertheless, assessment of the prostate is essential before initiating testosterone therapy, and regular prostatic monitoring should occur throughout the duration of therapy.

References

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

2. Morgentaler A. Testosterone and prostate cancer: an historical perspective on a modern myth. Eur Urol. 2006;50:935-939.

3. Hsing AW, Reichardt JKV, Stanczyk FZ. Hormones and prostate cancer: current perspectives and future directions. Prostate. 2002;52:213-235.

4. Stattin P, Lumme S, Tenkanen L, et al. High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study. Int J Cancer. 2004;108:418-424.

5. Platz EA, Leitzmann MF, Rifai N, 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 Biomarkers Prev. 2005;14:1262-1269.

6. Morgentaler A. Testosterone deficiency and prostate cancer: emerging recognition of an important and troubling relationship. Eur Urol. 2007;52:623-625.

7. 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;296:2351-2361.

8. 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;91:1995-2010.

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