Association between Body Mass Index and Diabetes Mellitus Are Mediated through Endogenous Serum Sex Hormones among Menopause Transition Women: A Longitudinal Cohort Study

Objective: To explore whether and to what extent endogenous sex hormones mediate the association between overweight and diabetes risk in menopausal transition women. Methods: Premenopausal women were from the Study of Women’s Health Across the Nation, with measurements of serum sex hormone including sex hormone binding globulin (SHBG), testosterone (T), estradiol (E2), follicle-stimulating hormone (FSH), and dehydroepiandrosterone sulfate (DHAS) in first postmenopausal follow-up. At the last postmenopausal follow-up, hyperglycemia status was confirmed. The partial least squares (PLS) regression method was used to extract hormonal signals associated with body mass index (BMI). Hyperglycemia was defined as individuals with prediabetes or diabetes; overweight was defined as BMI ≥ 25 kg/m(2). Causal mediation analysis was used to examine the mediation effect on the association between perimenopause overweight and post-menopause hyperglycemia through PLS score and individual sex hormones. Results: The longitudinal study included 1438 normal glucose women with a baseline mean age (SD) of 46.5 (2.6) years and a mean follow-up period of 9.9 years. During the follow-up period, 145 (10.1) cases of hyperglycemia occurred. Compared with normal-weight participants, overweight women were associated with a higher hyperglycemia risk during the transition period (OR = 4.06, 95% CI: 2.52 to 6.80). Overweight women had higher T, E2, and lower SHBG, FSH, and DAHS concentrations (β = 0.26, 0.38, −0.52, −0.52, and −0.13, p < 0.05 for all). After adjusting for overweight and covariates, lower SHBG and FSH levels were associated with higher hyperglycemia risk (OR = 0.70 and 0.69, all p < 0.05). As a linear combination of sex hormones, the PLS score was positively associated with T, E2, and negatively with SHBG, FSH, and DHAS. PLS score interpreted 36.50% (p < 0.001) of the overweight-hyperglycemia association. Considering single-sex hormones, the mediation proportion of SHBG and FSH were 21.38% (p < 0.001) and 24.08% (p < 0.001). Conclusions: Sex hormones mediated the association of overweight and diabetes risk in menopause transition women. SHBG and FSH have the dominant mediation effect.