Abstract
<title>Abstract</title> <p>Background Benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) are prevalent in aging men and substantially impair quality of life. Although obesity and metabolic syndrome have been implicated as risk factors, whether excess adiposity independently drives BPH/LUTS beyond its metabolic consequences remains controversial. Crucially, prior studies have not isolated the effect of obesity from metabolic dysregulation using definitions that avoid collinearity, nor have they formally tested the mediating pathway via systemic inflammation. Therefore, we investigated the associations of combined BMI-metabolic phenotypes with incident BPH/LUTS and examined the mediating role of hs-CRP in Chinese middle-aged and older men. Methods This prospective cohort study included 2,893 male participants aged ≥ 45 years from the China Health and Retirement Longitudinal Study (CHARLS) who were free of BPH/LUTS at baseline (2011). Participants were categorized into four BMI-metabolic phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight/obesity (MHOO), and metabolically unhealthy overweight/obesity (MUOO). The primary outcome was incident BPH/LUTS during 2011–2015. Cox proportional hazards models, ROC analyses at the 2- and 4-year follow-ups, and counterfactual-based mediation analyses were performed. Results During follow-up, 329 incident BPH/LUTS cases were documented. Compared with the MHNW group, the MHOO group (HR = 1.91, 95% CI: 1.28–2.86) and MUOO group (HR = 1.49, 95% CI: 1.12–2.01) exhibited significantly elevated risks, whereas the MUNW group did not (HR = 1.10, 95% CI: 0.83–1.51). Decomposing the combined phenotype revealed that overweight/obesity was independently associated with a 49% higher risk (HR = 1.49, 95% CI: 1.19–1.86), while metabolically unhealthy status was not (HR = 1.07, 95% CI: 0.85–1.35). Mediation analyses indicated that hs-CRP did not significantly mediate these associations. Subgroup analyses showed that the obesity risks were more pronounced in younger (aged 45–60 years) and rural populations. Sensitivity analyses confirmed the robustness of these findings. Conclusions MHOO and MUOO groups are independently associated with an increased risk of BPH/LUTS in Chinese middle-aged and older men, and this association is not mediated by systemic inflammation. Excess body weight, rather than metabolic dysregulation alone, appears to be the predominant modifiable risk factor. These findings support prioritizing weight management strategies, particularly for younger and rural populations, as a key component of BPH/LUTS prevention.</p>