Testosterone and prostate cancer - a paradigm shift
16 July 2014
"Bye-bye Androgen Hypothesis, Welcome Saturation Model"
A new era of testosterone and prostate cancer: from physiology to clinical implications. Khera M, Crawford D, Morales A, et al., Eur Urol 2014; 65(1): 115-23.
A long-held belief is that testosterone stimulates development of prostate cancer (PCa) and/or accelerates its growth. This summary gives an overview of an in-depth review of current literature regarding the relationship of serum testosterone and PCa and the effect of testosterone therapy on PCa progression and recurrence. Key studies which have refuted the old belief that testosterone has harmful effects on the prostate are presented, along the new testosterone-prostate paradigm known as the saturation model.
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. Notably, these observations were made in a special population (castrated men) and are therefore not relevant to testosterone therapy in hypogonadal men.
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." This fear is also the most common reason for doctors' reluctance to prescribe testosterone therapy, even in hypogonadal men, which unnecessarily deprives many hypogonadal men of clinical benefits.
Although the dramatic effects of androgen deprivation therapy (ADT) in PCa are indisputable, 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).
What this study adds - The Saturation Model
It has been conclusively demonstrated that PCa risk is unrelated to testosterone levels, and several studies show no correlation between testosterone levels and PSA or prostate volume. Thus, men with higher testosterone levels are at no greater risk for PCa than men with lower serum testosterone.
The incidence of PCa during long-term (up to 20 years) testosterone therapy has been demonstrated to be equivalent to that expected in the general population. In hypogonadal men treated with testosterone, levels of PSA typically rise up to levels of eugonadal men, but stay within the normal range. This elevation in PSA and prostate volume commonly occurs during the initial 3-6 months after initiation of testosterone therapy, and then stabilize, even with continued testosterone therapy.
To explain these finding, the androgen hypothesis has been replaced by the saturation model. The saturation model explains the paradoxical observations that prostate tissue is very sensitive to changes in testosterone levels when levels are low, but becomes insensitive to testosterone at higher levels. The reason for this is that maximal binding of testosterone to the androgen receptors is achieved already at very low testosterone levels.
Thus, there is a threshold where increasing testosterone levels reach a limit (the saturation point) beyond which there is no further induction of testosterone-driven changes in prostate tissue growth, see figure 1. This threshold, a.k.a. saturation point, appears to be around 8 nmol/L (230 ng/dL). This is below the commonly used threshold for diagnosis of hypogonadim, which is around 300-350 ng/dL (the exact diagnostic thresholds vary among laboratories).
Figure 1: The saturation model. Increasing testosterone (androgen) levels produce increasing prostate tissue growth (as reflected by PSA elevation) until a limit is reached (the saturation point). Beyond the saturation point, which occurs at very low testosterone levels, there is no further ability of testosterone to induce prostate changes.
This explains why elevations in PSA occur when hypogonadal men start testosterone therapy treatment, whereas minimal or no PSA changes occur when higher doses are administered to men who are not testosterone deficient. Thus, according to the saturation model, the initial modest PSA elevation and prostate growth within the reference range is a normal physiologic response to testosterone therapy in hypogonadal men. Therefore, testosterone-induced prostate growth and modest PSA elevations should not preclude hypogonadal men from testosterone substitution therapy.
The long-held belief that prostate cancer risk is related to high testosterone levels (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 indicates that maximal testosterone-stimulated prostate cancer growth is achieved already at low sub-optimal testosterone levels. Provocative new research suggests that it is not high serum T that is problematic for PCa, but to the contrary that it is low serum T that is associated with worrisome cancer features and outcomes, in that androgens promote less aggressive PCa phenotypes and inhibit metastasis of established PCa.