Testosterone: its role in development of prostate cancer and potential risk from use as hormone replacement therapy

Evidence from studies in patients with prostate cancer of intermittent hormone therapy combined with results from rechallenge of hormone resistant patients with testosterone demonstrate that the majority of prostate cancers retain a similar degree of dependence on male sex hormone milieu as normal prostate cells. Yet there has so far been no conclusive evidence, despite 34 studies, that levels of circulating testosterone in individuals developing prostate cancer are higher than in controls. The aim of this article was to critically evaluate this evidence and seek clues to other mechanisms whereby sex hormones could influence the development of prostate cancer. Additionally, epidemiological data were examined to investigate the interplay between sex hormone levels and environmental factors to help understand the development of prostate cancer and identify a safe way to provide hormone replacement therapy (HRT). Three overviews provide similar evidence that there is no significant difference in mean testosterone levels between patients and controls. However in the most recent review of studies, though there was no difference in means between cases and controls, there was a significant risk (adjusted odds ratio 2.34) for individuals identified by comparing incidence of prostate cancer in men in the upper and lower quartile of testosterone level. This report, taken with epidemiological data demonstrating that prostate cancer risk is increased by early age of onset of sexual activity and multiple nonspecific sexually transmitted diseases (STDs), has led to the hypothesis that the link between sex hormones and prostate cancer is indirect. Those individuals with high testosterone levels were more at risk of acquisition of multiple nonspecific STDs. This promotes transformation of prostate cells and damage to Leydig cells in the testis leading to there being no difference in testosterone compared with controls by the time the tumour is diagnosed. Because of the observed relationship between testosterone and prostate cancer development there has been anxiety about marketing HRT for men. Two observations support the view that the prostate cancer risks from use of testosterone hormone replacement may not be as great as first feared. Firstly, prostate cancers arising in men with low serum testosterone levels are more malignant and frequently nonresponsive to hormones. Secondly, breast cancers diagnosed in women on HRT though increased in number are less malignant possibly because of enhanced sensitivity to hormone therapy, and the situation may prove to be analogous with prostate cancer and testosterone replacement.