Association of Sex Hormone-Binding Globulin with Glycated Hemoglobin and Multidimensional Biomarker Structure in Reproductive-Age Women: An Analysis Based on NHANES 2021--2023

Abstract

Background: Sex hormone-binding globulin (SHBG) is linked to adiposity, insulin resistance and type 2 diabetes, but nationally representative evidence on the shape of the continuous SHBG-HbA1c association in reproductive-age women remains limited. Methods: We analyzed NHANES August 2021-August 2023 data for nonpregnant women aged 20-44 years (n=843). Survey-weighted linear regression related log-transformed SHBG to continuous HbA1c, with quadratic and spline tests for nonlinearity and tests for age modification. Forty biomarkers in hormone, biochemical, hematologic and inflammation/lipid blocks were analyzed by multiple factor analysis, sparse PLS and LASSO with bootstrap stability selection, with nested cross-validation. Results: After adjustment for age, race/ethnicity, poverty-income ratio and BMI, ln(SHBG) was inversely associated with HbA1c (beta=-0.1454, P=0.00083). Quadratic (P=0.00386) and spline (P=0.00236) tests supported nonlinearity, with a steeper slope at lower SHBG. The ln(SHBG)-by-age interaction was significant (P=0.0169). Adjustment for BMI, waist circumference and HOMA-IR attenuated the coefficient by 43.7%, 48.1% and about 55%. SHBG remained associated with HbA1c after conditioning on leading biomarker axes (beta=-0.1062, P=0.00342) and was selected in 98.8% of 500 LASSO bootstrap resamples. Nested cross-validation gave out-of-fold R^2 of 0.1298, 0.2136 and 0.2392 for clinical, biomarker and combined models. Conclusions: Higher SHBG was associated with lower HbA1c in a nonlinear pattern among reproductive-age women. The association overlapped with adiposity and insulin resistance but persisted after adjustment. The cross-sectional design and limited fasting subsample preclude causal or clinical interpretation.