Large epidemiologic studies that have looked at different risk factors for the development of endometrial cancer have found that insulin resistance, in the context of diabetes or prediabetes, is consistently associated with increased risk. There is probably also some overlap in risk due to comorbidities since obesity is the strongest risk factor for endometrial cancer, and, of course, it is also a risk factor for type 2 diabetes and metabolic syndrome. So, there is likely a matrix of conditions and comorbidities that combine to increase the risk for endometrial cancer.

One of the factors that may explain the relationship between insulin resistance and endometrial cancer risk is the effect of hyperinsulinemia on the endometrium. We know that there are insulin receptors in the endometrial lining, and the hyperinsulinemia in those with insulin resistance or diabetes can promote abnormal growth. The promotion of growth in the endometrial lining, together with the lack of physiologic progesterone surges in patients who may be anovulatory, can increase overall growth, leading to hyperplasia and then, ultimately, endometrial cancer if left untreated or unrecognized. That is the major link that has been identified to date.

Several studies have attempted to quantify the risk that diabetes poses for developing endometrial cancer. I would say that it is roughly a 2-fold higher risk, perhaps even higher. A meta-analysis of 22 cohort and case-control studies found that the risk of endometrial cancer is 72% higher in patients with diabetes versus in those without it.

Moreover, patients with endometrial cancer and diabetes may also have poorer outcomes compared with patients who do not have diabetes. Again, several factors may account for this observation. A more recent meta-analysis reported a 15% increased risk of cancer-specific mortality and a 42% increased risk of all-cause mortality in patients with endometrial cancer who had preexisting diabetes compared with patients who did not. Many studies looking into these questions have been retrospective. It is not entirely clear what accounts for these differences and whether the differences in outcomes might be related to differences in the type of endometrial cancer that these women develop or to other factors, including comorbidities.