CLINICIAN’S CORNER REVIEW Sex Differences of Endogenous Sex Hormones and Risk of Type 2 Diabetes A Systematic Review and Meta-analysis Eric L. Ding, BA Yiqing Song, MD, ScD Vasanti S. Malik, MSc Simin Liu, MD, ScD D IABETES MELLITUS CUR - rently afflicts approximately 21 million Americans, 90% to 95% of whom have type 2 diabetes. 1 An important sex difference is recognized in which type 2 diabetes is a more powerful risk factor for coro- nary heart disease mortality in women than in men, ie, diabetes increases the risk of coronary heart disease mortality by approximately 3.5-fold in women but only 2-fold in men (P = .008 for sex dif- ference). 2 Furthermore, evidence sug- gests a sex difference such that the posi- tive association between adiposity and risk of type 2 diabetes is stronger for women compared with men. 3 Previous studies have suggested the role of endogenous sex hormones in the development of type 2 diabetes. 4 Hy- perandrogenic conditions, such as poly- cystic ovarian syndrome (PCOS), have been strongly associated with glucose intolerance and insulin resistance in women, 5-14 while hypoandrogenism has been linked with insulin resis- tance 13-26 and adiposity 14,15,18,23,25,27-31 in men. Sex-dependent relationships may also exist for estradiol and risk of dia- betes. Several studies have observed positive associations between estra- See also Patient Page. CME available online at www.jama.com Author Affiliations: Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hos- pital and Harvard Medical School, Boston, Mass (Drs Song and Liu and Mr Ding); Departments of Epide- miology (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). Corresponding Author: Simin Liu, MD, ScD, Pro- gram on Genomics and Nutrition, Department of Epi- demiology, UCLA School of Public Health, CHS 73- 265, Box 951772, 650 Charles E Young Dr S, Los Angeles, CA 90095-1772 (siminliu@ucla.edu). Context Inconsistent data suggest that endogenous sex hormones may have a role in sex-dependent etiologies of type 2 diabetes, such that hyperandrogenism may in- crease risk in women while decreasing risk in men. Objective To systematically assess studies evaluating the association of plasma lev- els 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 stud- ies 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 stan- dardized 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). Simi- larly, 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 pro- spective 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 postmeno- pausal 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. JAMA. 2006;295:1288-1299 wwww.jama.com 1288 JAMA, March 15, 2006—Vol 295, No. 11 (Reprinted) ©2006 American Medical Association. All rights reserved. at Johns Hopkins University, on March 14, 2006 www.jama.com Downloaded from