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Association of Endogenous Sex Hormones and Insulin Resistance among Postmenopausal Women: Results from the Postmenopausal Estrogen/Progestin Intervention Trial

Yale University School of Medicine (G.M.K., B.I.G.), New Haven, Connecticut 06510-8046; and Department of Family and Preventive Medicine (E.B.-C., G.A.L.), University of California-San Diego, La Jolla, California 92093-0607

Address all correspondence and requests for reprints to: Elizabeth Barrett-Connor, M.D., Department of Family and Preventive Medicine, School of Medicine, Mail Code 0607, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0607. E-mail: ebarrettconnor{at}ucsd.edu.

Most studies of sex hormones and insulin resistance (IR) have focused on androgens; few have examined the association of endogenous estrogens and IR. We determined the cross-sectional association of endogenous levels of total and bioavailable testosterone and estradiol and SHBG with IR among 845 healthy, postmenopausal women aged 45–65 yr. Women were within 10 yr of menopause and not using hormone replacement therapy. Total adiposity was estimated by body mass index, visceral adiposity by waist to hip ratio (WHR), and IR by the homeostasis model assessment. We defined homeostasis model assessment-IR as the highest quartile (cutpoint, 2.1) of the distribution in this cohort. In logistic regression analyses, the odds for IR were significant and increased in a dose-response fashion across each quartile of total estradiol, bioavailable estradiol, and bioavailable testosterone (all P < 0.001 for linear trend). These associations remained significant after adjusting for WHR; adjusted odds ratios were 4.0, 6.1, and 2.7 for total estradiol, bioavailable estradiol, and bioavailable testosterone, respectively, comparing the highest to the lowest quartile (all P < 0.001). Adjusting for body mass index and WHR together eliminated the linear association of IR with total estradiol and bioavailable testosterone, but the association with bioavailable estradiol remained (adjusted odds ratio, 2.7; P < 0.001, comparing the highest to the lowest quartile). IR was not associated with total testosterone before or after adjusting for adiposity. Lower SHBG levels were associated with higher odds of IR, independent of adiposity. These results suggest that estrogen may be equally or more important than testosterone in the pathway to IR in healthy, young postmenopausal women, with differences not entirely explained by body size.

This work was supported by National Heart, Lung, and Blood Institute/National Institutes of Health Grant 1 R03 HL70311-01.

Abbreviations: BMI, Body mass index; FPG, fasting plasma glucose; HOMA, homeostasis model assessment; IR, insulin resistance; PCOS, polycystic ovary syndrome; WHR, waist to hip ratio.

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