Causal Link Between Vitamin D and Total Testosterone in Men: A Mendelian Randomization Analysis

Context: Low circulating vitamin D levels have been associated with lower total testosterone levels. These epidemiological associations, if true, would have public health importance because vitamin D deficiency is common and correctable. We tested whether genetically lowered vitamin D levels were associated with lower total testosterone (T), using Mendelian randomization (MR) methodology.

Design And Setting: A total of 4254 men were enrolled from the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China) study, which was performed at 23 sites in eastern China during 2014 to 2016. Using four single-nucleotide polymorphisms strongly associated with 25-hydroxyvitamin D [25(OH)D] levels, we created a genetic risk score (GRS) as an instrumental variable to estimate the effect of genetically lowered 25(OH)D on total T.

Main Outcome Measure: Total T was detected by chemiluminescence assay.

Results: Lower 25(OH)D levels were associated with lower total T (β, 0.40; 95% CI, 0.23 to 0.58) after multivariable adjustment. Per-SD increase in the vitamin D GRS (VD_GRS) was significantly associated with 25(OH)D (β, -1.64; 95% CI, -2.04 to -1.24) and with total T (β, -0.19; 95% CI, -0.37 to -0.02). Using VD_GRS as the instrumental variable in the MR analysis, the causal regression coefficient of genetically determined per-SD increase for 25(OH)D on total T was 0.12 (95% CI, 0.02 to 0.22).

Conclusion: We provide evidence for the biologically plausible causal effects of 25(OH)D on total T using MR analysis. Whether vitamin D supplementation can raise androgen levels merits further investigation in long-term, randomized controlled trials.