Abstract
Abstract | The controversies surrounding testosterone replacement therapy (TRT) have been addressed in the past few years. Although the androgenic effects of TRT on normal and malignant prostate cells have been studied for over 70 years, little clinical prospective research exists on the physiological responses of prostate tissues to a wide range of serum testosterone levels. The prostate is both an androgen-dependent and an androgen-sensitive organ; active processes are triggered at a 'threshold' or 'saturation' level of testosterone. Despite decades of research, no compelling evidence exists that increasing testosterone beyond this threshold level has a causative role in prostate cancer, or indeed changes the biology of the prostate. Testosterone deficiency has marked physiological and clinical effects on men in middle age and beyond. With subnormal testosterone levels, the potential positive benefits of TRT on factors such as muscle mass, libido or erectile function are likely a dose–response phenomenon, and should be considered differently than the threshold influence on the prostate. This Review will re-examine classic androgen research and reflect on whether testosterone actually stimulates prostatic cellular growth and progression in a 'threshold' or a 'dose–response' (or both) manner, as well as discuss the influence of testosterone on prostate cells in the hypogonadal and eugonadal states.
Key Points
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The risks and benefits of testosterone replacement therapy (TRT) need to be considered through the physiological mechanisms of proliferation, differentiation, and apoptosis studied in in vivo experiments over the past 70 years
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The etiology of prostate cancer reflects a complex interplay between the domains of genetic determinants, endocrine milieu and environmental exposure—anecdotal cases of cancer in men on TRT demonstrate association, not causation
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Multiple studies all conclude that testosterone level does not correlate with prostate cancer incidence; low (not absent) testosterone levels may actually be a marker of more-aggressive prostate cancer
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It is likely that occult cancers or premalignant cells in hypogonadal men have adequate testosterone levels for healthy homeostasis and TRT does not provide any additional stimulus to growth
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Maintaining a normal testosterone level throughout life may be beneficial from a survival point of view
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To determine whether TRT increases de novo tumors, an appropriately powered prospective study would require 10,000 men randomized for 13 years, questions remain as to whether this type of study would be feasible
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S. L. Goldenberg, A. Koupparis and M. E. Robinson contributed equally to researching, discussing, writing, reviewing and editing this article.
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Goldenberg, S., Koupparis, A. & Robinson, M. Differing levels of testosterone and the prostate: a physiological interplay. Nat Rev Urol 8, 365–377 (2011). https://doi.org/10.1038/nrurol.2011.79
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