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medingenuityThe Use of Testosterone in Men With Prostate Cancer

Doctors, trained between 1960 and 1995, were of the opinion that using testosterone in men with prostate cancer was like "adding gasoline to a fire". This was the admonition and categorical contraindication to the use of androgens in men with prostate cancer because androgen replacement therapy was thought to hasten the recurrence of the disease. There were even physicians who were fearful of using androgens in clinically hypogonadal men because they were concerned about increasing the risk of prostate cancer by using exogenous androgens. Using evidenced based medicine, it is now considered safe to use testosterone in some men who are symptomatic for hypoandrogenism, who have documented decrease in their serum testosterone level, and who have been treated for localized prostate cancer. It has also been proven that supplemental androgens in men without prostate cancer is safe and does not lead to prostate cancer. HOWEVER, IT SHOULD BE NOTED, ACCORDING TO THE FDA, THE USE OF TESTOSTERONE THERAPY IN MEN WITH A HISTORY OF PROSTATE CANCER IS CONTRAINDICATED.

Several decades ago it was the "party line" that androgens promoted or accelerated the growth of prostate cancer and that decreasing the androgens, for example by orchiectomy, would cause regression of prostate cancer. Thus the dictum for men with prostate cancer was "no supplemental androgens to feed a hungry tumor"!

A major turning point came in the early 1990's through the work of Dr. Abraham Morgentaler at Harvard Medical School, whom I know personally, have spent time with, and greatly respect. He, too, had been trained in the era of testosterone was "adding gasoline on a fire" and cautioned about the dangers of using androgens in clinically hypogonadal men without prostate cancer: The prevailing attitude was that high testosterone might lead to prostate cancer and low testosterone would be protective against the disease. However, Dr. Morgentaler chose to use supplemental androgens in hypogonadal men whose PSA levels were below 4.0 ng/mL and who had been biopsied prior to initiation of androgen therapy. He discovered that 11 of 77 (14%) of testosterone deficient men with a normal PSA and digital rectal exam had prostate cancer. This finding of prostate cancer in clinically documented hypogonadal men was far greater than the normal population of eugonadal men. (1) A subsequent paper by Dr. Morgentaler and his colleagues demonstrated that men with a greater decrease in androgen levels, 250 ng/dL or less, had twice the risk of prostate cancer than men with testosterone levels over 250 ng/dL. (2) Now, for the first time, it was suggested that low testosterone levels may not protect against prostate cancer, but may even increase the risk of developing the disease. Additional research by Dr. Morgentaler and associates confirmed that hypogonadal men who received androgen replacement therapy were not at an increased risk of prostate cancer as compared to men in the general population.

Side effects include headaches, facial flushing, nasal congestion, and back pain. In looking at the percentages it appears that the side effect profile is probably similar to Cialis or maybe slightly better.

What is the explanation?

Dr. Morgantaler proposed a saturation model for androgens and growth of prostate cancer. This model suggests that prostate tissue requires androgens for optimal growth. However, once optimal growth has been satisfied, additional androgen has little, if any, further effect on growth of the prostate tissue. Prostate cancer cell lines demonstrate a dose-response growth curve with increasing concentrations of testosterone. However, this cancer cell growth eventually plateaus after androgen receptor saturation is reached, and no further growth occurs, even with increased androgen concentrations. (4) Accordingly, there is exquisite sensitivity to androgens at very low testosterone concentrations and indifference to androgens at higher concentrations. Dr. Morgentaler explains the saturation model as follows: An androgen receptor is maximally bound to androgens at 120 ng/dL. When the concentration of androgen exceeds 120 ng/dL there is no further increase in cellular proliferation of the prostatic epithelium. Thus, when castration levels of testosterone are achieved either by orchiectomy or LHRH agonists, then exogenous testosterone will cause growth of the prostatic tissue. However, once the androgen receptor is maximally bound or saturated, additional androgens do not influence the proliferation of prostatic tissue.

Clinical application of testosterone replacement therapy in men with prostate cancer

So what is the clinician to do when confronted with a man who was treated for localized prostate cancer, either by radical prostatectomy or radiation therapy, and has both symptoms of hypogonadism and a documented low level of serum testosterone?

Clinically, hypogonadal men who have been treated for prostate cancer and have nadired their PSA level for 6-12 months after treatment would be candidates for supplemental androgen replacement therapy with either injections or gels. As a condition of their treatment, these men must agree to more frequent monitoring of their PSA levels, either on a monthly or bimonthly basis. If there is a consistent and persistent increase in the PSA level above a PSA nadir, then testosterone treatment should be discontinued. Some expertise, close follow-up, and significant time discussing the issue with men with a history of prostate cancer, we feel it would be optimal for a urologist to review, discuss and follow these patients. We at Texas Urology are happy to do so for your patients.

Summary

There has been a dramatic change in thinking regarding testosterone levels and prostate cancer. At present, there is no evidence based data that supports a causal linkage between high testosterone levels and the initiation of prostate cancer. On the contrary, there is evidence that a low testosterone level may increase the incidence of prostate cancer. Therefore, it is important to remember to follow all men on testosterone replacement therapy with regular PSAs and digital rectal examinations. Perhaps, then, we need to shift our concern to the effects of low levels of testosterone as related to prostate cancer rather than focusing so intently on elevated testosterone levels. Finally, after treatment for prostate cancer, men experiencing symptoms of hypogonadism need to be treated on an individual basis and monitored very carefully.

Bottom Line: For decades testosterone was considered verboten in men with prostate cancer. Now, in selected patients treated for localized prostate cancer who have nadired PSA levels and documented hypogonadism, testosterone replacement therapy is indicated providing there is close follow-up. So the old adage about gasoline on the fire does not apply prostate cancer.

REFERENCES

Morgentaler A., Bruning CO, III, DeWolf WC. Incidence of occult prostate cancer among men with low total or free serum testostereone. JAMA 1996; 276:1904-6.

Morgentaler A., Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen of 4.0 ng/mL or less. Urology 2006; 68:1263-7.

Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004; 350:482-92.

Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the Saturation Model and the limits of androgen stimulation of prostate cancer. Eur Urol 2009; 55:310-21.

Other Resources

Agarwal PK, Oefelein MG. Testosterone replacement therapy after primary treatment for prostate cancer. J Urol 2005; 173:533-6.

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

Khere M, Grober ED, Najari B, et al. Testosterone replacement therapy following radical prostatectomy. J Sex Med 2009; 6:1165-70.

Sarosdy MF. Testosterone replacement for hypogonadism after treatment of early prostate cancer with brachytherapy. Cancer 2007; 109:536-41.

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