Serum testosterone and prostate cancer in men with germline BRCA1/2 pathogenic variants

Abstract

Objectives: The relation of serum androgens and the development of prostate cancer (PCa) is subject of debate. Lower total testosterone (TT) levels have been associated with increased PCa detection and worse pathological features after treatment. However, data from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) and Prostate Cancer Prevention (PCPT) trial groups indicate no association. The aim of this study is to investigate the association of serum androgen levels and PCa detection in a prospective screening study of men at higher genetic risk of aggressive PCa due to BRCA1/2 pathogenic variants (PVs), the IMPACT study.Methods: Men enrolled in the IMPACT study provided serum samples during regular visits. Hormonal levels were calculated using immunoassays. Free testosterone (FT) was calculated from TT and sex hormone binding globulin (SHBG) using the Sodergard mass equation. Age, body mass index (BMI), prostate-specific antigen (PSA) and hormonal concentrations were compared between genetic cohorts. We also explored associations between age and TT, SHBG, FT and PCa, in the whole subset and stratified by BRCA1/2 PVs status.Results: A total of 777 participants in the IMPACT study had TT and SHBG measurements in serum samples at annual visits, giving 3940 prospective androgen levels, from 266 BRCA1 PVs carriers, 313 BRCA2 PVs carriers and 198 non-carriers. The median number of visits per patient was 5. There was no difference in TT, SHBG and FT between carriers and non-carriers. In a univariate analysis, androgen levels were not associated with PCa. In the analysis stratified by carrier status, no significant Please see Appendix A for full list of The IMPACT Study Collaborators and Steering Committee.

Oncogenic BRCA1,2 Mutations in the Human Lineage—A By-Product of Sexual Selection?

“…This suggests that the aggressive phenotype of PCa observed in BRCA2 PV carriers may not be linked to variations in circulating hormone levels. It is also noteworthy that the average hormone levels for both carrier and non-carrier groups fell within the normal physiological range [77].…”

“…This could manifest as a reduced female lifespan versus enhanced male fitness, perhaps together with a sexual conflict, exemplified here with increased male fitness and increased BC incidence in females. Unfortunately, this intriguing hypothesis lacks broader support, as more recent studies on larger cohorts indicate that male hormone levels remain relatively consistent [77]. Nonetheless, this hypothesis might still hold merit when specifically examining the Jewish population, despite the ready explanation that BRCA1 and BRCA2 frequencies in Ashkenazi Jews can be adequately explained via a historical bottleneck event, rendering it unnecessary to invoke positive selection [39].…”

BRCA Mutations and Fertility Preservation

“…A small cohort study assessed the impact of the mutation on hormone levels and reported increasing levels of total testosterone and free androgen index in BRCA mutation carriers [ 135 ]. However, a recent study on a larger cohort of men at increased genetic risk of PCa did not show any difference in testosterone levels (total and free) nor in sex hormone binding globulin levels in BRCA -mutated carriers compared to non-carriers [ 136 ].…”