Long-term risk of malignant neoplasm associated with gestational glucose intolerance

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Long-Term Risk of Malignant Neoplasm Associated with Gestational Glucose Intolerance

Dawson1 reported a significant association between gestational glucose intolerance and risk of breast carcinoma later in life. Although risk estimates were adjusted for body mass index (BMI), anthropometric measures of body fat distribution were, regrettably, not included in the analysis.

Studies indicate that upper-body obesity is an independent risk factor for breast carcinoma in both premenopausal and postmenopausal women.2 The relevance of this confounder arises from observations indicating that a high waist-to-hip ratio is associated with a low level of sex hormone–binding globulin (SHBG), a determinant of the biologically active pool of estradiol. Moreover, for women entering menopause, upper-body obesity also is associated with increased estradiol formation from visceral adipocytes, given the high 17β-hydroxysteroid dehydrogenase–to-aromatase ratio in these cells.3 Therefore, the hormone-sensitive organs of women with upper-body obesity experience enhanced lifetime exposure to endogenous estradiol.

It remains to be determined whether the increased formation and availability of estradiol in women with upper-body obesity play a direct pathogenic role in glucose level disturbances. In this context, we have recently demonstrated that insulin resistance and related glucose and lipid alterations are more closely related to upper-body obesity than to general obesity or BMI.4 The significantly more favorable diabetes profile of obese women with the highest BMIs is attributable to the insulin-sensitizing effect of peripheral fat mass.4

Adiponectin is a fat-derived hormone with putative insulin-sensitizing effects. Emerging evidence suggests that estradiol may have an inhibitory effect on adiponectin secretion. Studies of mice indicated that in parallel with the increases in estradiol levels during pregnancy, levels of adiponectin decreased. Ovariectomy evoked increases in serum levels of adiponectin, which could be reversed by estrogen replacement. Finally, estradiol suppressed adiponectin in cultured adipocytes.5 In addition, excessive exposure of adipocytes to estradiol may also down-regulate the expression of insulin receptor substrate 1, further impairing glucose uptake. A similar inverse association between estradiol and adiponectin was found in postmenopausal women with upper-body obesity.6

These observations provide reasons to believe that the association between gestational glucose disturbances and breast carcinoma is an epiphenomenon. Although the increased exposure of visceral fat mass provokes impaired glucose uptake via release of proinflammatory adipokines (interleukin-6 and tumor necrosis factor alpha), inhibition of adponectin, and impaired insulin receptor metabolism, the excessive lifetime exposure of breast tissue may increase the risk of developing malignant neoplasms. If possible, comparison of endogenous estradiol and SHBG concentrations between women with and without gestational glucose intolerance could provide important information.

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