Sex Differences of Endogenous Sex Hormones and Risk of Type 2 Diabetes

CONTEXT: Inconsistent data suggest that endogenous sex hormones may have a role in sex-dependent etiologies of type 2 diabetes, such that hyperandrogenism may increase risk in women while decreasing risk in men. OBJECTIVE: To systematically assess studies evaluating the association of plasma levels of testosterone, sex hormone-binding globulin (SHBG), and estradiol with risk of type 2 diabetes. DATA SOURCES: Systematic search of EMBASE and MEDLINE (1966-June 2005) for English-language articles using the keywords diabetes, testosterone, sex-hormone-binding-globulin, and estradiol; references of retrieved articles; and direct author contact. STUDY SELECTION: From 80 retrieved articles, 43 prospective and cross-sectional studies were identified, comprising 6974 women and 6427 men and presenting relative risks (RRs) or hormone levels for cases and controls. DATA EXTRACTION: Information on study design, participant characteristics, hormone levels, and risk estimates were independently extracted by 2 investigators using a standardized protocol. DATA SYNTHESIS: Results were pooled using random effects and meta-regressions. Cross-sectional studies indicated that testosterone level was significantly lower in men with type 2 diabetes (mean difference, -76.6 ng/dL; 95% confidence interval CI, -99.4 to -53.6) and higher in women with type 2 diabetes compared with controls (mean difference, 6.1 ng/dL; 95% CI, 2.3 to 10.1) (P60 vs 28.3 vs < or =28.3 nmol/L) had a 52% lower risk (RR, 0.48; 95% CI, 0.33 to 0.69). Estradiol levels were elevated among men and postmenopausal women with diabetes compared with controls (P = .007). CONCLUSIONS: This systematic review indicates that endogenous sex hormones may differentially modulate glycemic status and risk of type 2 diabetes in men and women. High testosterone levels are associated with higher risk of type 2 diabetes in women but with lower risk in men; the inverse association of SHBG with risk was stronger in women than in men.