Sex-specific associations of serum estradiol and the testosterone-to-estradiol ratio with handgrip strength and appendicular lean soft tissue in US adults aged 40-59 years

Background: Sex steroids play a key role in skeletal muscle regulation, yet sex-specific links between estradiol, testosterone-estrogen balance, and muscle health in midlife remain sparse. In this study we evaluated associations between circulating estradiol and testosterone-to-estradiol (T/E) ratio with handgrip strength (HGS) and appendicular lean soft tissue index (ALSTI) in men and women aged 40-59 years. Methods: We analyzed data from 1350 adults [48.8 (5.7) years, 693 women] participating in NHANES 2013-2014. HGS was assessed using a handheld dynamometer, and ALSTI by dual-energy X-ray absorptiometry. Sex-specific linear and logistic regression models examined associations of estradiol and T/E with continuous and categorical muscle outcomes. Complementary analyses examined log10-transformed estradiol, T/E ratio, and total testosterone, with SHBG included in sensitivity analyses. Results: In unadjusted analyses, higher estradiol was associated with greater ALSTI in men (b = 0.43, 95% CI 0.25 to 0.61) and higher HGS in women (b = 1.56, 95% CI 0.92 to 2.20), while higher T/E was associated with lower HGS and ALSTI in men (b = -1.87, 95% CI -3.19 to -0.55, and b = -0.74, 95% CI -1.02 to -0.46, respectively) and lower HGS in women (b = -1.84, 95% CI -2.69 to -0.99). However, these associations were largely attenuated after multivariable adjustment. In logistic models, women with lower estradiol concentrations had significantly higher odds of low HGS compared with those with higher estradiol in Model 2 (OR = 2.44, 95% CI 1.01 to 5.88), while the association with moderate estradiol levels did not reach statistical significance (OR = 2.27, 95% CI 0.98 to 5.26). These associations were attenuated after additional adjustment for SHBG. No corresponding associations were observed in men. The T/E ratio was not independently associated with low HGS after adjustment in either sex. Conclusions: Circulating estradiol and T/E show sex-specific associations with muscle health. Lower estradiol was associated with higher odds of low HGS in women in the primary adjusted analysis, whereas most other hormone-muscle associations were attenuated after adjustment. These findings support further longitudinal studies to clarify sex-specific hormone-muscle trajectories across midlife.