Prolactin increasing antipsychotics and reduced prostate cancer risk in cohort and nested case control studies

Abstract Background Prostate cancer is one of the most diagnosed cancers among men worldwide. Prolactin is a pituitary hormone that can influence androgen regulation, and antipsychotics that increase prolactin may suppress testosterone levels. Because lower free testosterone has been associated with lower prostate cancer risk, prolactin-increasing antipsychotics may have a potential protective effect. However, this association has not been well characterized in real-world comparative studies. Methods Using territory-wide electronic health records from Hong Kong covering the period from 1 January 2004 to 31 December 2023, we conducted a retrospective cohort study and nested case-control analysis among adults prescribed antipsychotics. We excluded individuals with a history of cancer, organ transplantation, or sexually transmitted infections. Baseline characteristics included demographics, comorbidities, and co-medications. The outcome was incident prostate cancer. Cohort incidence rate ratios (IRRs) were estimated using Poisson regression incorporating inverse probability of treatment weighting (IPTW) and multivariable adjustment. Based on biological hypotheses of cellular adaptation, the prespecified primary exposure window was 1–5 years. Conditional logistic regression estimated odds ratios (ORs) for longer-term prolactin-increasing antipsychotic use versus short-term use or non-use in the nested case-control analysis. Results The primary cohort analysis included 81,177 individuals. During the prespecified 1–5-year exposure window, prolactin-increasing antipsychotic users had lower observed prostate cancer incidence than prolactin-sparing antipsychotic users (adjusted IRR 0.410, 95% CI 0.237–0.710). The nested case-control analysis identified 291 cases and showed a similar association for 1–5 years of use (adjusted OR 0.569, 95% CI 0.356–0.909). The association was directionally consistent across age groups and appeared stronger among individuals older than 75 years, but estimates varied in magnitude by age. Conclusion Prolactin-increasing antipsychotics were associated with lower observed prostate cancer risk during 1–5 years of exposure. These findings are consistent with hypothesized mechanisms of androgen deprivation and subsequent cellular adaptation, although residual confounding cannot be excluded.