the inhibition of testosterone's conversion to DHT by dutasteride had no significant effect on the ability of testosterone to exert its effects on muscle mass and strength, sexual function, erythropoiesis, plasma lipid levels, prostate volume, and sebum production. Instead, over the range of testosterone concentrations that were achieved (and which spanned the entire physiological male range and extended well into the subphysiological and supraphysiological range for men), testosterone was able to subserve all androgen-dependent functions that were studied herein, including maintenance of prostate volumes, PSA levels, and sebum production.
The net androgen effect in any tissue can be viewed as a function of the prevalent intratissue testosterone and DHT concentrations and their relative androgenic potencies (eFigure 6). In tissues with low steroid 5α-reductase activity such as muscle and bone, intratissue DHT concentration is very low relative to testosterone and can be discounted, and the androgen effect attributed largely to testosterone. In tissues with high 5α-reuctase activity such as the prostate, intratissue DHT concentrations are higher than those of testosterone.
22,
23,
36,
37 Administration of 0.5 mg/d of dutasteride suppresses nearly completely intraprostatic DHT formation (approximately 94%)
22,
23; therefore, we assume that intraprostatic DHT concentrations in men who received 2.5 mg/d of dutasteride were suppressed to very low levels. Even under these conditions of suppressed circulating and intraprostatic DHT concentrations induced by a high-dose dutasteride regimen, prostate volumes and PSA levels were maintained by testosterone doses administered in this trial.
How can we reconcile these findings with those from trials in which dutasteride has been reported to decrease prostate volume and PSA in men with benign prostatic hyperplasia?
10,
11 The suppression of prostate volume by dutasteride in older men with benign prostatic hyperplasia, when viewed together with the findings from our trial, suggests that DHT formation is important for amplifying testosterone's effect in this tissue at concentrations lower than those achieved in our trial. Indeed, our model predicts that administration of a 5α-reductase inhibitor in men who have low testosterone levels below the activation threshold of the prostate should attenuate androgen effects in this tissue.
This argument is supported by the finding that in older men with benign prostatic hyperplasia, the largest reduction in prostate volume with dutasteride is observed in men with low serum testosterone levels.38 However, as circulating testosterone concentrations are increased from physiological to supraphysiological, testosterone alone can maintain prostate volumes even when 5α-reductase activity is suppressed effectively.