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A Systematic Review and Meta-analysis

Eric L. Ding, BA; Yiqing Song, MD, ScD; Vasanti S. Malik, MSc; Simin Liu, MD, ScD

JAMA. 2006;295:1288-1299.

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) (P<.001 for sex difference). Similarly, prospective studies showed that men with higher testosterone levels (range, 449.6-605.2 ng/dL) had a 42% lower risk of type 2 diabetes (RR, 0.58; 95% CI, 0.39 to 0.87), while there was suggestion that testosterone increased risk in women (P = .06 for sex difference). Cross-sectional and prospective studies both found that SHBG was more protective in women than in men (P.01 for sex difference for both), with prospective studies indicating that women with higher SHBG levels (>60 vs 60 nmol/L) had an 80% lower risk of type 2 diabetes (RR, 0.20; 95% CI, 0.12 to 0.30), while men with higher SHBG levels (>28.3 vs 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.

Author Affiliations: Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass (Drs Song and Liu and Mr Ding); Departments of Epidemiology (Dr Liu and Mr Ding) and Nutrition (Mssrs Ding and Malik), Harvard School of Public Health, Boston; and Program on Genomics and Nutrition, Department of Epidemiology, UCLA School of Public Health, Los Angeles, Calif (Dr Liu).

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