Obesity and Endometrial Cancer: Another Piece in the Puzzle

Abstract & Commentary

By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston. Dr. Coleman is on the speaker's bureau for GlaxoSmithKline, Merck, and Ortho Biotech.

Synopsis: Adiponectin level was found to be independently and inversely associated with endometrial cancer.

Source: Soliman PT, et al. Association between adiponectin, insulin resistance and endometrial cancer. Cancer. 2006;106:2376-2381.

One of the most recognized risk factors for the development of endometrial cancer is obesity. However, recent studies have suggested that this factor alone cannot fully account for all the risk associated with obesity.1,2 Insulin resistance has been suspected as a potential mechanism for carcinogenesis in these patients. Soliman and colleagues examined this issue by conducting a case-control, retrospective study of 117 women diagnosed with endometrial cancer (cases) and 238 women without endometrial cancer (controls) in whom adiponectin, a protein secreted by adipocytes, could be measured. Adiponectin has been shown to be a surrogate marker for insulin resistance, with low levels correlated with hyperinsulinemia and degree of insulin resistance.

The authors found that mean serum adiponectin levels were significantly lower among endometrial cancer cases than among non-cancer controls. This effect remained significant even after controlling for age, body mass index, diabetes, and hypertension. Cases were significantly more likely to have serum adiponectin levels in the lowest and intermediate tertiles when compared with controls. For instance, women with endometrial cancer were 10.5 times more likely to have adiponectin levels in the lowest tertile compared with controls. Based on a multivariate analysis, adiponectin level was found to be independently and inversely associated with endometrial cancer, even after controlling for body mass index. The authors concluded that insulin resistance, as measured by adiponectin levels is independently associated with endometrial cancer.

Commentary

Endometrial cancer is the most common gynecologic malignancy and is among the few gynecologic sites increasing in annual incidence. Most patients, fortunately, are diagnosed with disease limited to the corpus where surgical extirpation is curative. Recent clinical investigative focus in this disease has been rooted in refining the nuances of surgical management and defining appropriate adjuvant therapy strategies. However, accelerating rates of obesity, a recognized national health care issue, is thought to be a dominant contributing force to disease prevalence in the US population. Our understanding as to how obesity is linked to the development of endometrial cancer is mechanistically hypothesized to occur through mitogenic endogenous estrogen exposure leading to prolonged growth signals at the target organ. The relationship is predicated on heightened peripheral conversion of androstenedione to estrone from adipose tissue. However, a well recognized cohort of patients, normal in weight is also known to develop the disease. Conversely, high body mass index has been correlated to endometrial cancer risk independent of endogenous estrogen levels. This suggests other factors associated with obesity may contribute to carcinogenesis. The authors of the current report hypothesized insulin resistance may be one of these factors.

A clear indicator of how insulin resistance is associated with this disease has been difficult to find. For instance, while hyperinsulinemia is associated with an increased risk of endometrial cancer and women who are insulin resistant and obese have the highest risk of endometrial cancer, hyperinsulinemia alone does not explain the association of obesity and cancer development. Soliman and colleagues examine the association of adiponectin, a unique protein correlated with insulin resistance, in endometrial cancer. Low levels of adiponectin have been associated with the hyperinsulinemia and the degree of insulin resistance, independent of body mass index. Their observation that low levels of adiponectin, and therefore insulin resistance, is associated with an increased risk of endometrial cancer, independent of obesity, corroborates previously reported retrospective studies and helps to understand the phenomena of diabetes and disease development. Further validation in prospective studies will help to assign individual risk on the basis of serial determinations offering a surrogate measure through which intervention may be levied to modulate acquired cancer potential.

References

1. Dal Maso L, et al. Circulating adiponectin and endometrial cancer risk. J Clin Endocrinol Metab. 2004;89:1160-1163.

2. Petridou E, et al. Plasma adiponectin concentrations in relation to endometrial cancer: a case-control study in Greece. J Clin Endocrinol Metab. 2003;88:993-997.