Testosterone Replacement Therapy and the Risk of Prostate Cancer. Is There a Link?

A. Barqawi; E. D. Crawford


Int J Impot Res. 2006;18(4):323-328. 

In This Article

The Effect of Testosterone Level on Prostate Cancer Risk

Since the landmark publication by Huggins and Hodges[6] in 1941 showing the potential benefit of androgen deprivation for controlling prostate cancer growth, several long-term studies have failed to establish that the use of testosterone suppression provides a clear disease-specific survival advantage in men with early organ-confined prostate cancer and the current indications for hormonal therapy is preserved for patients with recurrent or metastatic disease. In fact, the inevitable occurrence of androgen-refractory prostate cancer after hormonal therapy suggests that androgens play a rather 'permissive' role in prostate cancer growth.[7] This concept is supported by evidence that dependence on the androgen-AR binding process persists regardless of the oncogenic pathways triggered by the genetic instability of prostate cells, which is thought to be linked to the initiation of prostate cancer.[8] Furthermore, an increase in prostate cancer incidence coincides with a gradual decrease in testosterone levels with advancing age, that is, the development of AMS.[9] However, a causal relationship between hypogonadism and the risk of prostate cancer has not been established in controlled studies. Similarly, a definite correlation has not been shown between adjusted testosterone levels in hypogonadal men due to TRT and the initiation and/or acceleration of latent prostate cancer. Designing such studies would be difficult, due to a lack of consensus on what constitute a normal range of testosterone levels, the well-known inaccuracy of measuring serum bioavailable testosterone levels, and the considerable interindividual variation in the degree of testosterone decline associated with age. The decrease in bioavailable testosterone (i.e., a combination of free testosterone and the fraction weakly bound to albumin) with aging is reported to be considerably greater than the total testosterone decline.[10] The Massachusetts Male Aging Study found declines of 0.8% in total testosterone and 2-3% in bioavailable testosterone and an increase of 1.6% in sex hormone binding globulin (SHBG) per year.[11] Roberts et al.[12] reported a significant decline in bioavailable testosterone levels with increasing cross-sectional age, which was associated with a significant increase in the ratio of estradiol to bioavailable testosterone. When these variations are coupled with the potential effects of cofactors such as obesity, diabetes, race, and family history, assessment of the potential role of testosterone in prostate cancer risk becomes increasingly complex.

Several other observations are worth consideration in assessing the risk of TRT on prostate cancer. Since concentrations of testosterone, SHBG, and DHT are substantially higher in prostate tissue than in serum, the modest increase in androgens in the peripheral circulation resulting from TRT supplementation may not accurately reflect the androgenic environment within the prostate. The effect of exogenous supplementation on the ratio of testosterone to DHT within the prostate is still unknown. DHT, which is the most potent intraprostatic androgen, appears to play a significant role in the initiation of prostate cancer. Based on the 24% decrease in the risk of prostate cancer observed in men treated with a selective 5α-reductase inhibitor in the Prostate Cancer Prevention Trial (PCPT),[13] it can be postulated that a reduction in tissue DHT level may prevent cancerous transformation in the prostate or delay its clinical manifestations. However, other factors may play a role, taking into account that men in the 5α-reductase inhibitor arm had a statistically significant proportion (37%) of men with high Gleason score (7, 8, 9, or 10), when compared to the placebo group (22.2%). The clinical significance, of which, is still debatable.[13]


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