Over the last 2 decades, there has been growing awareness of the impact of testosterone deficiency (TD) on men’s health. This includes body composition (reduced muscle mass and increased body fat), bone density, mood, and quality of life. New evidence suggests that TD may be related to several key medical conditions such as diabetes, obesity, and metabolic syndrome, and may even be associated with reduced longevity. These new data make it more important than ever to be aware of TD, to diagnose it when suggestive symptoms are present, and to initiate testosterone replacement therapy (TRT) when indicated.
Until recently, physicians have been taught that TRT could cause prostate cancer (Pca) or exacerbate the progression of the disease. The origin of the fear that higher testosterone levels will stimulate more rapid Pca growth arose in 1941 with the work of Huggins et. al., who demonstrated that castration caused PCa to regress. However, recent longitudinal studies have consistently failed to show any relationship between TRT and PCa risk. In 2008, a landmark article (Natl Cancer Inst. 2008; 110:170:183) was published that represented a collaborative global analysis of pooled data from 18 longitudinal studies involving more than 3000 men with PCa. No relationship between PCa and serum concentrations of testosterone was found. Men with the highest testosterone concentrations turned out to have no greater risk of developing Pca than men with the lowest concentrations.
In a similar fashion to PCa, recent studies have failed to demonstrate a relationship between TRT and urinary symptoms and function. A theoretical concern is that TRT would increase prostate size, thereby leading to or exacerbating urinary symptoms. Ultrasound studies of prostate volume in patients with TD on TRT did demonstrate an initial “catch-up” growth in the first 3 to 6 months of therapy; however, there was little or no change in urine flow rates, episodes of urinary retention, post-void residuals (volume left behind after voiding) or voiding symptoms. Furthermore, most human studies have shown just small increases in PSA in patients on TRT. Although the PSA may increase slightly during the first 3-6 months of therapy, it has been recommended to perform a prostate biopsy if the PSA increases by > 0.5 ng/ml in the first 6 months. This is based on the concept that TRT does not cause PCa, rather, it can increase PSA expression by prostate cells. As a result, it has been stated that TRT could act like a provocative test to diagnose prostate cancer; however, this concept is still theoretical. It should be noted that biopsy guidelines for patients on TRT are currently being studied and to date there is no general consensus.
Several publications over the last few years have challenged the mainstream by failing to demonstrate any negative outcomes in men who received TRT despite a prior history of PCa. There are now several reports of TRT after radical prostatectomy (surgery) or brachytherapy (seed implantation) without any signs of PSA elevations, and a recent report noted a decline in PSA after 2 years of TRT in a man with untreated PCa undergoing “active surveillance” (observation only). Although the number of treated men in these studies is small, the results do suggest that higher testosterone cannot be nearly as risky as once believed.
On the other hand, several studies have shown a troublesome association between PCa and low testosterone levels. One such study reveals that the lower the testosterone level, the greater the risk of a positive biopsy. Furthermore, other studies seem to indicate that low testosterone levels may predispose a patient to higher grade (more aggressive) PCa, greater risk for recurrence after surgery, and lower survival rates. Lastly, it is very important to consider a patient’s testosterone level when interpreting PSA for prostate cancer screening. It has been shown that men with low testosterone levels and normal PSA have higher prostate cancer detection rates than would be expected. In other words, a normal PSA level in the setting of a low testosterone level must be interpreted with caution.
Overall, new data support the concept that the risks of TRT are not as worrisome as once believed, especially with PCa. Clearly, more research will need to be done to be conclusive. At the current time, TRT is safe with appropriate medical monitoring. Laboratory monitoring of patients on TRT should include Total Testosterone, PSA, and Hematocrit. Testosterone levels should be monitored 2-3 months after initiation of TRT with a goal towards a therapeutic level about mid-normal or high normal. PSA and digital rectal exam (DRE) should be checked every 3 months for the first year and then annually thereafter. Any increase in PSA >0.5ng/ml in the first 6 months of TRT or abnormality on DRE deserves further evaluation. Finally, a hemoglobin or hematocrit level should be checked at baseline, at 3months into therapy, and annually thereafter.