Insulin resistance is associated with elevated circulating androgens in postmenopausal women: A potential pathway for breast cancer etiology

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Background: We recently found an association between elevated fasting glucose and the risk of breast cancer among heavier postmenopausal women in the ORDET cohort study (Varese, Italy). The present cross-sectional analysis has been done to explore the association between insulin resistance and levels of circulating hormones that have been implicated in breast cancer pathogenesis. Methods: Study participants were 86 healthy women, aged 42-69 years, enrolled in the ORDET cohort and subsequently selected as controls in a nested case-control study of the roles of hormones and diet in breast cancer etiology. Women reporting a diabetes diagnosis were excluded from analysis. Sex-steroid hormones were measured in serum and urine using radioimmunoassay. The General Linear Model was used to compare levels of hormones and binding proteins in women with and without evidence of insulin resistance (fasting glucose > 100 ng/ml or waist circumference > 35 inches) while adjusting for age. Results: Participants classified as insulin resistant had higher levels of circulating testosterone (p<0.01) and free testosterone (p<0.01). In contrast, levels of two androgen metabolites excreted in urine were lower in women with insulin resistance (etiocolanone: p=0.05, androsterone: p=0.09). There were no significant differences between groups in levels of 17-Beta Estradiol, or Sex-Hormone Binding Globulin (SHBG). Conclusions: Our findings suggest that insulin resistance may affect the risk of breast cancer in postmenopausal women by increasing levels of available circulating androgens. The effect of insulin resistance on testosterone levels observed in these healthy subjects was independent of any association between insulin resistance and measured SHBG levels, and may be a result of altered metabolism or excretion of these hormones.