A long-held belief is that testosterone causes prostate cancer or accelerates its growth. This so called “androgen hypothesis” arose from a small study in the 1940s. Medical students and doctors have been taught ever since that high testosterone levels promote the development of prostate cancer, that low testosterone is protective, and that the administration of testosterone to a man with existing prostate cancer is like ‘‘pouring gasoline on a fire.’’ This fear is also the most common reason for doctor’s reluctance to prescribing testosterone replacement therapy, even in hypogonadal men.[2, 3]
The Androgen Hypothesis
It is critical to note that the androgen hypothesis was accepted prior to the discovery of the androgen receptor and PSA (prostate specific antigen), and before the availability of reliable serum testosterone assays. It should therefore not be surprising that some predictions of the androgen hypothesis would prove false when submitted to scientific investigation. Although the dramatic effects of androgen deprivation therapy (ADT) in PCa are indisputable , a wealth of current evidence fails to support the concept that increasingly high levels of testosterone or DHT lead to ever-greater growth of benign or malignant prostate tissue. For example, multiple studies show no correlation between endogenous testosterone and PSA or prostate volume.[5-7] In healthy men, administration of supra-physiologic doses of testosterone (weekly injections of 500-600 mg of testosterone enanthate to healthy volunteers for up to 16 weeks) resulted in no increase in PSA nor prostate volume.[5, 7] The Androgen Hypothesis has therefore been replaced by the Saturation Model.
The Saturation Model
The Saturation Model explains the paradoxical observations that prostate tissue is exquisitely sensitive to changes in testosterone levels at low concentrations, but becomes insensitive to changes in androgen concentrations at higher levels. This response is consistent with the observation that testosterone exerts its prostatic effects primarily via binding to the androgen receptor (AR), and that maximal testosterone-AR binding is achieved at testosterone levels well below the physiologic range.
Changes in testosterone levels below the point of maximal testosterone -AR binding can elicit substantial changes in prostate cancer growth, as seen with castration, or with testosterone administration to castrated men. In contrast, once maximal testosterone -AR binding is reached, further increasing testosterone levels results in little further effect.
Thus, there is a threshold where increasing testosterone levels reach a limit (the saturation point) beyond which there is no further induction of androgen-driven changes in prostate tissue growth, as illustrated in the graph.
Maximal testosterone–AR binding (ie, saturation) occurs at fairly low androgen concentrations. In clinical practice, the saturation point appears to be approximately 230 ng/dL (8 nmol/L). However, there is inter-individual variation in the saturation point. Other physiologic mechanisms may contribute, as well. For example, in aging men with low testosterone levels, 6 months of TRT (testosterone replacement therapy) normalized serum testosterone levels but had little effect on prostate tissue androgen levels, suggesting the presence of local regulatory mechanisms. It should be noted that different tissues likely have different saturation points.
This explains why dramatic changes in PSA are noted when testosterone levels are manipulated into or out of the castration range, whereas minimal or no PSA changes occur when supra-physiologic testosterone doses are administered to most men.
The long-held belief that prostate cancer risk is related to high testosterone levels, aka the Androgen Hypothesis, is not supported by clinical data. The Saturation Model and paradigm change that it brings to old inaccurate reasoning is that testosterone has a finite ability to stimulate prostate cancer growth.
The saturation model explains the paradoxical observations that prostate tissue is sensitive to changes in testosterone levels at low concentrations, but becomes insensitive to changes in testosterone levels at higher levels. Men with high testosterone levels are not at increased risk of developing prostate cancer, low testosterone levels provide no protection against the development of prostate cancer, and some men with untreated prostate cancer have received testosterone therapy without evidence of prostate cancer progression. Current evidence shows that maximal testosterone-stimulated prostate cancer growth is achieved at low sub-optimal testosterone levels.
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10. Morgentaler, A., et al., Testosterone therapy in men with untreated prostate cancer. J Urol, 2011. 185(4): p. 1256-60.