Longitudinal Changes in Sex Hormone Binding Globulin (SHBG) and Risk of Incident Diabetes: The Study of Women's Health Across the Nation (SWAN)

Objective: To investigate the associations of longitudinal changes in sex hormone binding globulin (SHBG) and testosterone (T) over the menopause transition with the risk of diabetes.
Research Design/Methods: We followed 2,952 participants in the Study of Women’s Health Across the Nation (SWAN) who were premenopausal or early peri-menopausal and diabetes-free at baseline. SHBG,T and estradiol (E2) levels were measured at up to 13 follow-up visits (over up to 17 years). We used complementary log-log-based discrete-time survival models anchored at baseline.

Results: 376 women developed diabetes. A 5-unit increase in time-varying SHBG was associated with a 10% reduced risk of diabetes (hazard ratio (HR): 0.91 (95% confidence interval 0.87, 0.95)), adjusting for covariates, baseline SHBG,T and E2 levels. Time-varying T was not associated with diabetes risk. Compared to the lowest quartile for annual rate of change of SHBG since baseline [Q1 (-92.3 to -1.5 nM], all other quartiles were associated with a decreased risk of diabetes adjusting for covariates and baseline SHBG; associations persisted after adjusting for rate of change of T and E2 [Q2 (>-1.5 to -0.2 nM) HR 0.33 (0.23,0.48); Q3 (>-0.2 to 1.3 nM) HR 0.37 (0.25, 0.55); Q4 (>1.3 to 82.0 nM) HR 0.43 (0.30, 0.63)].

Conclusion: Increasing levels of SHBG over the menopause transition were associated with a decreased risk of incident diabetes. Stable to increasing rates of change in SHBG were also independently associated with decreased risk of diabetes compared to decreasing rates of change, suggesting SHBG may affect glucose through a mechanism beyond androgenicity.