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Review | Clinician's Corner

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
JAMA. 2006;295(11):1288-1299. doi:10.1001/jama.295.11.1288.
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Published online

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.

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Figures

Figure 1. Summary of Article Selection Process
Graphic Jump Location

*Sum of specific excluded studies greater than total due to overlapping classifications of excluded studies.

Figure 2. Random-Effects Pooled Mean Difference of Testosterone Levels Between Type 2 Diabetes Cases and Controls, Men and Women
Graphic Jump Location

Negative values represent lower levels among type 2 diabetes cases. Sizes of data markers represent the statistical weight that each study contributed to the overall random-effects estimate. To convert nmol/L to ng/dL, divide by 0.0347. CI indicates confidence interval.
*European population.
†Melanesian population.
‡Independent population of type 2 diabetes cases and controls among women with acanthosis nigricans.

Figure 3. Random-Effects Pooled Relative Risks of Testosterone and Type 2 Diabetes from Prospective Studies in Men
Graphic Jump Location

Relative risks reported for upper dichotomy (449.6-605.2 ng/dL [15.6-21.0 nmol/L]) vs lower dichotomy (213.2-449.5 ng/dL [7.4-15.5 nmol/L]). Sizes of data markers represent the statistical weight that each study contributed to the overall random-effects estimate. Only 1 prospective study among women (P = .06 for sex dimorphism). CI indicates confidence interval.

Figure 4. Random-Effects Pooled Mean Difference of Sex Hormone–Binding Globulin Levels Between Type 2 Diabetes Cases and Controls, Men and Women
Graphic Jump Location

Sizes of data markers represent the statistical weight that each study contributed to the overall random-effects estimate. Significant sex dimorphism (P<.001 for effect modification by sex). CI indicates confidence interval.
*Melanesian population.

Figure 5. Random-Effects Pooled Relative Risks of Sex Hormone–Binding Globulin (SHBG) and Type 2 Diabetes from Prospective Studies
Graphic Jump Location

Relative risks reported for upper dichotomy (>60 nmol/L for women and >28.3 nmol/L for men) vs lower dichotomy. Sizes of data markers represent the statistical weight that each study contributed to the overall random-effects estimate. Significant sex difference (P = .003 for interaction). CI indicates confidence interval.

Figure 6. Random-Effects Pooled Mean Difference of Estradiol Levels Between Type 2 Diabetes Cases and Controls, Men and Postmenopausal Women
Graphic Jump Location

Sizes of data markers represent the statistical weight that each study contributed to the overall random-effects estimate. P = .87 for sex difference. To convert pmol/L to pg/mL, divide by 3.671. CI indicates confidence interval.

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