Does testosterone mediate the relationship between vitamin D and prostate cancer progression? A systematic review and meta-analysis

PURPOSE: Observational studies and randomized controlled trials (RCTs) have shown an association between vitamin D levels and prostate cancer progression. However, evidence of direct causality is sparse and studies have not examined biological mechanisms, which can provide information on plausibility and strengthen the evidence for causality. METHODS: We used the World Cancer Research Fund International/University of Bristol two-stage framework for mechanistic systematic reviews. In stage one, both text mining of published literature and expert opinion identified testosterone as a plausible biological mechanism. In stage two, we performed a systematic review and meta-analysis to assess the evidence from both human and animal studies examining the effect of vitamin D on testosterone, and testosterone on advanced prostate cancer (diagnostic Gleason score of ≥ 8, development of metastasis) or prostate cancer-specific mortality. RESULTS: A meta-analysis of ten human RCTs showed evidence of an effect of vitamin D on total testosterone (standardised mean difference (SMD) = 0.133, 95% CI = − 0.003–0.269, I(2) = 0.0%, p = 0.056). Five human RCTs showed evidence of an effect of vitamin D on free testosterone (SMD = 0.173, 95% CI = − 0.104–0.450, I(2) = 52.4%, p = 0.220). Three human cohort studies of testosterone on advanced prostate cancer or prostate cancer-specific mortality provided inconsistent results. In one study, higher levels of calculated free testosterone were positively associated with advanced prostate cancer or prostate cancer-specific mortality. In contrast, higher levels of dihydrotestosterone were associated with lowering prostate cancer-specific mortality in another study. No animal studies met the study eligibility criteria. CONCLUSION: There is some evidence that vitamin D increases levels of total and free testosterone, although the effect of testosterone levels within the normal range on prostate cancer progression is unclear. The role of testosterone as a mechanism between vitamin D and prostate cancer progression remains inconclusive. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10552-022-01591-w.