Magnesium depletion score and erectile dysfunction: A cross-sectional and Mendelian randomization study

Erectile dysfunction (ED) is closely linked to vascular and metabolic disorders. Magnesium plays a crucial role in endothelial function, inflammation, and metabolism, but the relevance of chronic magnesium depletion to ED remains unclear. The magnesium depletion score (MDS) is a practical marker of long-term magnesium loss. This study examined the association between MDS and ED in United States adults and explored genetic evidence for magnesium metabolism using Mendelian randomization (MR). This cross-sectional study included 3692 men aged ≥ 20 years from National Health and Nutrition Examination Survey 2001 to 2004. MDS was calculated from renal function, diuretic and proton-pump inhibitor use, and alcohol consumption. Survey-weighted logistic regression, subgroup analysis, and restricted cubic splines were used to evaluate the association between MDS and ED, adjusting for demographic, lifestyle, and metabolic factors. Two-sample and multivariable MR analyses assessed genetic evidence for the relationship between magnesium metabolism disorders and ED, with adjustment for body mass index (BMI), type 2 diabetes, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. Higher MDS was associated with increased odds of ED (fully adjusted odds ratio = 1.40; 95% confidence interval, 1.22-1.61; P = .002). Men with MDS ≥ 2 had more than twice the odds of ED compared with those with MDS < 2. Restricted cubic spline analysis demonstrated a nonlinear relationship, with the risk beginning to rise at approximately an MDS of 1 and increasing sharply when the MDS exceeded 3. Two-sample MR found no direct causal effect of magnesium metabolism disorders on ED. In multivariable MR, magnesium metabolism disorders showed a modest positive association with ED after adjustment for BMI, diabetes, and lipid traits (odds ratio = 1.01; 95% confidence interval, 1.00-1.02; P = .028). Genetically predicted higher BMI and diabetes were also associated with ED. Higher MDS was associated with increased odds of ED in United States adult men. MR findings provided limited but supportive evidence for a role of magnesium metabolism within a broader cardiometabolic context. Overall, MDS may serve as a potential risk marker for ED, but further prospective and interventional studies are needed to confirm its clinical relevance.