Obese men have lower serum prostate-specific antigen (PSA) than comparably aged lean men, but the underlying mechanism remains unclear. The aim of this study was to determine the effect of obesity on PSA and the potential contributing mechanisms. A cohort of 1195 men aged 35 years and over at recruitment, with demographic, anthropometric (BMI, waist circumference (WC)) and serum hormone (serum testosterone, estradiol (E2)) PSA and hematology assessments obtained over two waves was assessed. Men with a history of prostate cancer or missing PSA were excluded, leaving 970 men for the final analysis. Mixed-effects regressions and mediation analyses adjusting for hormonal and volumetric factors explore the potential mechanisms relating obesity to PSA. After adjusting for age, PSA levels were lower in men with greater WC (P = 0.001). In a multivariable model including WC, age, E2/testosterone and PlasV as predictors, no statistically significant associations were observed between with PSA and either WC (P = 0.36) or PlasV (P = 0.49), while strong associations were observed with both E2/testosterone (P < 0.001) and age (P < 0.001). In the mediation analyses with PlasV as the mediator, the average causal mediation effect (ACME) explained roughly 20% of the total effect of WC on PSA (P = 0.31), while when E2/testosterone is a mediator, the ACME explained roughly 50% of the effect (P < 0.001). Our findings indicate that lower PSA levels in obese men, as compared to normal weight men, can be explained both by hormonal changes (elevated E2/testosterone ratio) and hemodilution. Hormonal factors therefore represent a substantial but underappreciated mediating pathway.
Supplementary Table S1: For each variable, the number of men assessed at each wave who had PSA assessments and thereby the data included in the analysis cohort.
Supplementary Table S2: WC and BMI linear mixed-effect regression coefficients after adjustment for age and either plasma volume or hormonal factors.
Supplementary Table S3: Mixed-effect models of log-transformed PSA with exclusion of WC from the model ( SM 1 & SM 2 ) additional (SM 3) SHBG adjustment; (SM 4) DHT instead of E2 & T; (SM 5 & SM 6) BMI instead of WC. Adjusting for SHBG, DHT or replacing WC by BMI does not influence the E2/T association with PSA.
Supplementary Table S4: Multivariable mixed effects models of (log) PSA mass Replacing PSA with PSA mass in multivariable model including WC, E2/T and PlasV showed that there is still significant association detected between PSA mass and E2/T. Of interest, the effect of E2/T is almost the same on both PSA and PSA mass.
Supplementary figure S1: Non-linear mixed effect estimated adiposity levels by age. Adiposity increases with age till approximately the age of 60, then declines in elderly group. This pattern is more significant with the WC. WC: Waist Circumference, PlasV: Plasma volume, E2/T: Estradiol-testosterone ratio.
Supplementary figure S2: Non-linear age-adjusted associations of PSA with BMI, PlasV and hormones (estimated at age = 55). PSA decreases with increasing BMI, plasma volume, and E2/T ratio. BMI: Body mass index, PlasV: Plasma volume, PSA: Prostate specific antigen, T: Testosterone, E2: Estradiol, DHT: Dihydrotestosterone, E2/T: Estradiol-testosterone ratio
Supplementary figure S3: (S3A & S3B) Linear regression model for change of PSA concentration with WC, plasma volume and E2/T ratio at (A) first and (B) second assessment separately. These models showed qualitatively the same conclusion as the mixed effect model. (S3C to F) Causal mediation analyses at the two time points of assessment separately (including average causal mediation effects (ACME), average direct effects (ADE) and the total effects) estimating the contribution of adiposity (WC) to PSA with mediation by either (C & E) Plasma Vol., or (D & F) E2/T. In these models, E2/T ratio shows significant ACME representing with PSA at each time point of assessment. WC: Waist Circumference, PlasV: Plasma volume, E2/T: Estradiol-testosterone ratio. ACME: average causal mediation effect, ADE: average direct effects, WC: Waist Circumference, PlasV: Plasma Volume, E2/T: Estradiol-Testosterone ratio.
Supplementary Figure S4: Single compartment model of the change of PSA mass over time. The steady-state solution indicates that PSA is independent of plasma volume, in contrast to PSA mass which is positively associated with volume.
Supplementary Figure S5: Standardized mixed-effects regression coefficients for log transformed PSA mass. After adjusting for age and the E2/T ratio there were no detectable associations between PSA mass and WC. There was significant positive association between PSA mass and plasma volume (as expected), while the association with E2/T ratio remained negative. WC: Waist Circumference, PlasV: Plasma volume, E2/T: Estradiol-testosterone ratio.