Sex‐Specific and Nonlinear Associations Between Serum 25‐Hydroxyvitamin D and Sex Hormones in US Adults
Yi Han, Simin GaoObjective
This population‐based study sought to characterize sex‐specific linear and nonlinear associations between serum 25‐hydroxyvitamin D [25(OH)D] and four circulating sex hormone markers—total testosterone, estradiol, sex hormone–binding globulin (SHBG), and free testosterone index (FTI)—in the noninstitutionalized US adult population.
Methods
We analyzed data from the 2021–2023 National Health and Nutrition Examination Survey (NHANES), including 4801 eligible participants aged 20 years and older (2169 men, 2632 women). A tiered analytical strategy was applied: weighted Spearman rank correlation for crude associations, multivariable weighted linear regression for adjusted effect estimates, restricted cubic spline (RCS) modeling for nonlinear dose–response characterization, and bootstrap resampling (500 replicates) for robustness validation.
Results
In men, crude weak positive correlations of 25(OH)D with total testosterone ( r = 0.07) and SHBG ( r = 0.23) were fully attenuated to nonsignificance after adjustment for BMI and waist circumference; no robust nonlinear associations were identified via RCS. In women, 25(OH)D was moderately positively correlated with SHBG ( r = 0.21), and this association remained significant after full adjustment ( β = 0.148, p = 0.028), corresponding to a 10.8% increase in SHBG per doubling of 25(OH)D. RCS revealed a robust J‐shaped nonlinear relationship between 25(OH)D and SHBG ( p for nonlinearity < 0.001), a decline‐then‐plateau pattern for FTI ( p for nonlinearity = 0.015), an approximately linear negative trend for estradiol, and only a borderline nonlinear trend for total testosterone. Bootstrap analyses confirmed the robustness of SHBG, estradiol, and FTI associations in women.
Conclusions
The association between vitamin D status and sex hormone profiles exhibits pronounced sex dimorphism. In women, SHBG most consistently correlates with 25(OH)D, showing a BMI‐independent positive association and a J‐shaped, nonlinear dose–response pattern. In men, adiposity indices (BMI and waist circumference) fully account for the crude associations of 25(OH)D with testosterone, estradiol, and SHBG.