Testosterone and prostate cancer - a paradigm shift

What is known - the androgen hypothesis

The idea that testosterone has detrimental effects on the prostate, the so called "androgen hypothesis" arose from two small studies in the 1940s in which men with metastatic PCa demonstrated clinical and biochemical improvement with androgen deprivation via castration or estrogen treatment, and conversely rapid PCa progression with testosterone administration.^2, 3 Rather than concluding that exogenous testosterone attenuates the effects of surgical castration, the authors concluded that prostate cancer is activated by testosterone.¹⁸ Notably, these observations were made in a special population (castrated men) and are therefore not relevant to TRT in hypogonadal men.⁴

Medical students and doctors have since been taught 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."¹ This fear is also the most common reason for doctors' reluctance to prescribe testosterone replacement therapy, even in hypogonadal men^19, 20, which unnecessarily deprives many hypogonadal men of clinical benefits.

Although the dramatic effects of androgen deprivation therapy (ADT) in PCa are indisputable²¹, a large body 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 (see below). 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 turn out to be false when submitted to rigorous scientific investigation.

What this study adds - the saturation model

It has been conclusively demonstrated that PCa risk is unrelated to endogenous serum androgen concentrations⁵, and several studies show no correlation between endogenous testosterone and PSA or prostate volume.^22, 23 Thus, men with higher endogenous testosterone are at no greater risk for PCa than men with lower serum testosterone.

The incidence of PCa during long-term (up to 20 years) TRT has been demonstrated to be equivalent to that expected in the general population.⁸ 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.^24, 25 In hypogonadal men treated with testosterone, levels of PSA typically rise up to levels of eugonadal men, but stay within the normal range.²⁶ This elevation in PSA and prostate volume commonly occurs during the initial 3-6 months after initiation of TRT, and then stabilize, even with continued TRT.^27-30

In line with these findings, two meta-analyses of TRT intervention studies, which focused on analyzing potential adverse effects of testosterone therapy, did not find any significant differences in prostate outcomes between TRT vs. placebo treated men.^6, 7 Specifically, the most recent meta-analysis published in 2010 demonstrated no difference in the rates of prostate cancer, the need for prostate biopsy, international prostate symptom score (IPSS), increase in PSA, or total number of prostate-related adverse events when comparing the testosterone group with the placebo group.⁷

To explain these finding, the androgen hypothesis has been replaced by the saturation model.³¹ 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.³¹ This response is consistent with the observation that testosterone exerts its prostatic effects primarily via binding to the AR, and that maximal testosterone-AR binding is achieved at testosterone levels well below the physiologic range.³¹

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 or hypogonadal 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, see figure 1.