Sex differences of endogenous sex hormones and risk of type 2 diabetes: A systematic review and meta-analysis

Eric L. Ding, Yiqing Song, Vasanti S. Malik, Simin Liu

Research output: Contribution to journalReview article

833 Citations (Scopus)

Abstract

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 ofEMBASEand 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.

Original languageEnglish (US)
Pages (from-to)1288-1299
Number of pages12
JournalJournal of the American Medical Association
Volume295
Issue number11
DOIs
StatePublished - Mar 15 2006
Externally publishedYes

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Gonadal Steroid Hormones
Sex Characteristics
Type 2 Diabetes Mellitus
Meta-Analysis
Sex Hormone-Binding Globulin
Testosterone
Confidence Intervals
Estradiol
Information Storage and Retrieval
Cross-Sectional Studies
Hormones
Hyperandrogenism
MEDLINE
Language
Research Personnel

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sex differences of endogenous sex hormones and risk of type 2 diabetes : A systematic review and meta-analysis. / Ding, Eric L.; Song, Yiqing; Malik, Vasanti S.; Liu, Simin.

In: Journal of the American Medical Association, Vol. 295, No. 11, 15.03.2006, p. 1288-1299.

Research output: Contribution to journalReview article

@article{9221902717f84e55bd3df54a51f65ec5,
title = "Sex differences of endogenous sex hormones and risk of type 2 diabetes: A systematic review and meta-analysis",
abstract = "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 ofEMBASEand 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 = "Ding, {Eric L.} and Yiqing Song and Malik, {Vasanti S.} and Simin Liu",
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T1 - Sex differences of endogenous sex hormones and risk of type 2 diabetes

T2 - A systematic review and meta-analysis

AU - Ding, Eric L.

AU - Song, Yiqing

AU - Malik, Vasanti S.

AU - Liu, Simin

PY - 2006/3/15

Y1 - 2006/3/15

N2 - 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 ofEMBASEand 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.

AB - 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 ofEMBASEand 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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