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Candidates for testosterone therapy and indications

Although controversy surrounds the concept of male andropause or late-onset hypogonadism, there is growing evidence that age- related decreases in testosterone and associated symptomatology may respond to treatment with testosterone therapy.24 Testosterone therapy is also used as a second-line therapy in hypogonadal patients with ED and only when there is deficiency.23,31 There is also debate over the potential risks of testosterone therapy to prostate health. General guidelines exist; however, it is important that therapy be individualized to each patient’s unique medical profile and current condition.32,33

Goals and benefits of testosterone therapy

The goals of testosterone therapy for hypogonadism are to restore serum testosterone levels to normal and minimize the signs and symptoms. The Institute of Medicine recommends that the goal of therapy should be to restore testosterone levels to those seen in young adult males aged 20 to 40 years (ie, 21.8 nmol/L [627 ng/dL]).34 Supraphysiologic levels should be avoided and are not necessary to maintain the physiologic circadian rhythm of testosterone levels.31

Treatment of low testosterone with testosterone therapy may provide patients with significant improvements in other areas. Benefits of testosterone therapy include improvements in bone density, muscle mass, body composition, mood, erythropoiesis, energy, and sexual desire and performance.1,22,35

A long-term (12 months) study of 371 hypogonadal men reported that testosterone therapy resulted in a significant increase in lean body mass and significant decrease in fat mass from baseline (P<.001 for both); there was no significant change in total body mass.35 Sexual function, as measured by sexual desire, performance, motivation, satisfaction with duration of erection, percentage of full erection, and ability to have spontaneous erections, showed significant improvement from baseline at all time points of the extension study (P<.001). Improvements in mood were also observed and were maintained over the course of the study. There was also a significant (P<.001) change in BMD of the lumbar spine as measured by DEXA scan.

Another area of interest is the potential beneficial effect of testosterone on metabolic syndrome and its components. Kapoor and colleagues looked at the effect of testosterone on insulin resistance and glycemic control in 24 hypogonadal men with type 2 diabetes who were older than age 30 years.36 Testosterone improved fasting insulin sensitivity (-1.73, P=.02) as measured by the homeostasis model assessment index, which is the ratio of insulin levels to fasting glucose control. Glycosylated hemoglobin and fasting blood glucose were reduced (-0.37 and -1.58 mmol/L, respectively; P=.03 for both). Visceral adiposity as measured by waist circumference was reduced (-1.63 cm, P=.03), as was waist:hip ratio (-0.30, P=.01). There was also a decrease in total cholesterol (-0.4 mmol/L, P=.03), but there was no effect on blood pressure. Taken together, the improvements in insulin resistance and glycemic control represent a potential overall reduction in associated cardiovascular risk. However, other studies have failed to observe a beneficial effect on diabetes control.



As with any pharmacotherapy, there are some potential risks associated with treatment. Table 4 lists potential adverse events associated with testosterone therapy.1,22

With regard to sleep apnea, the true association with testosterone therapy is not clear. Many hypogonadal men are at an increased risk for sleep apnea as a result of obesity.13,37 Also, clinicians should be aware that the studies correlating sleep apnea to testosterone treatment used supraphysiologic levels and do not necessarily indicate that testosterone treatment with physiologic levels will cause sleep apnea.

A meta-analysis of randomized, placebo-controlled trials by Calof and colleagues revealed that testosterone therapy in older men was associated with a significantly higher risk of hematocrit >50%, confirming the need to carefully monitor hematocrit in this population.38

Testosterone therapy: risk to the prostate

There is a long-standing belief held by the medical community that low testosterone levels are protective against prostate cancer and that, conversely, normal or elevated testosterone levels may cause cancers to grow. This simplistic belief is mostly historical and contrary to a growing body of evidence. However, this concept is perhaps the single greatest barrier to initiating testosterone therapy.

Initially, prostate cancer is androgen-dependent: The cancer regresses when testosterone levels are lowered to castrate levels, and allowing testosterone to return to normal levels may cause prostate cancer to recur.39 However, the testosterone-prostate relationship is not as simple as an on/off switch or a 1:1 ratio. When testosterone levels rise above the near-castration range, there is little detectable effect: PSA does not change, nor does prostate volume. This important, key distinction suggests a saturation curve, whereby at near-castration range, testosterone levels are important, and profound effect is seen on prostate cancer growth. However, there has been no evidence of such effect beyond these ranges.40

Paradoxically, low testosterone levels have been associated with higher Gleason scores and more advanced stage at presentation.41 A paradox also exists in the percentage of age-matched men with prostate cancer in the general population compared with those in testosterone therapy trials. About 15% of men with a PSA

Testosterone does not cause prostate cancer but may cause a cancer to become clinically apparent

Glenn R. Cunningham, MD


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