one therapy in addition to any new prostate findings suspicious for cancer on physical exam or an absolute PSA level greater than 4 ng/mL.

In addition, both the baseline PSA and its rate of change over time can be used to predict risk of complications of BPH. In an analysis of the Baltimore Longitudinal Study of Aging, risk stratification based on PSA identified men at greatest risk for adverse events over time due to BPH (Wright et al., 2002). These data are in concert with the PLESS analysis previously discussed.

Therefore, in order to monitor prostate status closely, men enrolled in studies of testosterone therapy should have a DRE and PSA test every six months during the course of the study. Urologic evaluation (including transrectal ultrasound) is indicated if the AUA symptom score is greater than 21; urologic evaluation (including transrectal ultrasound and biopsy of the prostate) is indicated if:

• DRE reveals changes suspicious for prostate cancer; or

• PSA >4 ng/mL; or

• PSA velocity greater than 0.75 ng/mL/year measured over 12 months for men whose PSA levels rise above 4 ng/mL and over 18 months for men with PSA levels less than 4 ng/mL.

Follow-up. There are still many unknowns regarding the effect of testosterone treatment on prostate histopathology. It is known that testosterone or its metabolite, DHT, is required for the development of the prostate since males with 5-α-reductase deficiency do not develop a prostate. In addition, DHT plays a role in sustaining BPH, as is evident through the action of finasteride (a synthetic compound that inhibits the type II 5-reductase enzyme from converting testosterone to DHT), which reduces prostate size by 20 percent to 30 percent. However, the fact that significant glandular BPH persists following finasteride treatment shows that other factors are operative. In addition, the effect of testosterone administration on occult or incidental prostate cancer is unknown, although current studies suggest minimal risk (Brawer, 2003).

Thus, there is a great deal of information that could be obtained if histopathologic studies were conducted at the termination of any future long-term clinical trials of testosterone therapy. Biopsies at the termination of study were used in the Prostate Cancer Prevention Trial and revealed a 24.4 percent detection rate in the control group (Thompson et al., 2003). The use of an end-of-study biopsy would also eliminate the effect of verification bias, an issue of concern (Punglia et al., 2003; Schroder and Kranse, 2003).