Exploring the link between sex hormone-binding globulin levels and prostate cancer risk: a comprehensive systematic review and meta-analysis

Background Sex hormone-binding globulin (SHBG) plays a critical role in regulating androgen bioavailability and has been hypothesized to influence prostate cancer risk, though existing evidence is inconsistent. This systematic review and meta-analysis aimed to evaluate the association between SHBG levels and prostate cancer risk. Methods A comprehensive search was conducted across PubMed, Embase, and Web of Science for studies published up to December 1, 2024. Observational studies assessing SHBG levels and prostate cancer risk were included. Effect sizes were pooled using random-effects meta-analysis. Heterogeneity was evaluated using the I2 statistic, and quality assessment was performed using the Newcastle-Ottawa Scale. Statistical analysis was performed using R software version 4.4. Results Sixteen studies, including 720,298 participants and 90,799 prostate cancer cases, were analyzed. The pooled odds ratio (OR) for prostate cancer risk per unit increase in SHBG was 0.907 (95% CI 0.799-1.030), indicating no statistically significant association. Substantial heterogeneity was observed among the included studies (I2 = 79%; P < 0.0001). Subgroup analyses showed no significant variation in effect sizes by study design. However, a Mendelian randomization analysis conducted in 140,254 European-descent males, including 79,148 prostate cancer cases, suggested a modest protective effect of higher SHBG levels, with an OR of 0.944 (95% CI 0.897-0.993). Sensitivity analyses confirmed the robustness of the pooled findings. Conclusion This meta-analysis showed a complex relationship between SHBG levels and prostate cancer risk. While overall findings do not support a statistically significant association, higher SHBG levels may confer a protective role in specific contexts. Further research is needed to elucidate mechanisms, reduce heterogeneity, and validate SHBG as a biomarker for risk stratification.