Circulating sex steroids and prostate cancer: introducing the time-dependency theory

We sought whether serum total testosterone (tT), estradiol (E-2), tT/E-2 ratio, and sex hormone-binding globulin (SHBG) significantly fluctuate throughout time in men with prostate cancer (PCa). Circulating hormones were measured in a cohort of 631 candidates for radical prostatectomy. Hormone levels were analyzed according to either patient age, stratified into quartiles, or body mass index (BMI). Linear regression analyses tested the association between sex steroids and continuously coded patient age and BMI values. No significant differences were found among age quartiles regarding serum tT levels and tT/E-2 ratio. Conversely, E-2 and SHBG levels significantly increased throughout time (all, p a parts per thousand currency sign 0.001). Total T did not linearly change according to continuously coded patient age; in contrast, E-2 and SHBG linearly increased (all, p a parts per thousand currency sign 0.001), whereas tT/E-2 decreased (p = 0.016) with aging. Rate of hypogonadism significantly increased with aging (p = 0.04). Total T, T/E-2 ratio, and SHBG linearly decreased along with BMI increases (all p a parts per thousand currency sign 0.02), whereas serum E-2 did not significantly change. Rate of hypogonadism significantly increased with BMI increases (p < 0.001). In contrast with longitudinal studies in the general male population, these data indirectly suggest that serum tT levels could be stable over time in PCa patients. This finding led to formulation of a "time-dependency theory", which postulates that the endocrine biology of prostate tissue is dependent on the exposure time at a given concentration of sex steroid, which, in turn, fluctuates throughout the lifespan of the individual.