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Obesity has been recognized as an endometrial cancer risk factor and remains the single most impactful risk factor for the disease.

In a 2010 , every 5 kg/m² increase in body mass index (BMI) was associated with a 60% greater risk of endometrial cancer. Another meta-analysis showed that women with obesity have a than normal-weight women. The link appears to be particularly strong for younger women.

However, obesity is a modifiable risk factor, and the new generation of effective weight-loss injectables like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) are creating hope for counteracting the rising incidence of endometrial cancer and fighting the cancer in those who develop it.

"We know that bariatric surgery can be an effective complementary tool for patients with endometrial cancer," particularly for those interested in maintaining their uterus among the roughly 25% of premenopausal patients, said Leslie R. Boyd, MD, director of the division of gynecologic oncology at NYU Langone's Perlmutter Cancer Center in New York City.

Among these women, those with obesity or morbid obesity are often advised to pursue a combination of hormonal therapy and bariatric surgery, she noted, "the rationale being that medical weight loss tends to be slower and less likely to be maintained. Now that we have all the GLP-1 receptor agonists, it'll be interesting to see how that changes."

Women who aren't interested in bariatric surgery might find medication more appealing, she added. "It is complicated by the fact that progesterone therapy, which is the hormonal therapy that is effective in fighting the cancer, increases appetite and is strongly associated with weight gain. So it's another reason why ... using not just medical or hormonal therapy, but also bariatric therapy or bariatric surgery, is impactful for many of these patients."

The role of estrogen didn't become clear until the 1970s when the "natural experiment" of unopposed estrogen use for menopausal symptoms led to a revealing the key driver of incidence.

Indeed, adding progestin to estrogen for women with an intact uterus, mimicking more closely the natural balance in the body, reduced that risk, though it didn't eliminate it. Decades of follow-up in studies like the showed that postmenopausal women taking estrogen plus progestin had a 2.6-fold increased risk of endometrial cancer, with a higher risk with sequential dosing (rate ratio 3.0, 95% CI 2.0-4.6).

"That was a very good clue into the risk factors associated with endometrial cancer," said Immaculata De Vivo, PhD, of Brigham and Women's Hospital in Boston, who has spent decades researching these risks.

Now it has become clear that the two factors are really interconnected. According to a in the Annals of Oncology, "the combination of hyperestrogenism, inflammation, and insulin resistance that is caused by obesity creates a metabolic state that drives tumorigenesis."

Adipose tissue creates estrogen via peripheral aromatization of fat, and thus obesity creates a non-ovarian source of unopposed estrogen.

And while obesity has classically been thought to be the primary driver for the lower-risk, type 1 endometrial cancers, "actually, you are at higher risk of high-grade endometrial cancers if you are obese as well. So it's certainly impactful for all types of the disease," noted Boyd.

Part of the reason for that discovery has been getting large enough sample sizes to give the statistical power to settle the question, De Vivo said, pointing to the Epidemiology of Endometrial Cancer Consortium (E2C2) that she leads, which now has data for some 45,000 women.

A pooled analysis of E2C2 data showed a modest that is independent of BMI (OR 1.14, 95% CI 1.09-1.19). While diabetes is also associated with endometrial cancer, it is not clear if this is independent of its link to obesity, De Vivo said.

E2C2 is also working to understand potential differences in risk factors for women of color, since most studies had historically only included white women, she added.

Boyd noted that given that endometrial cancer is so hormonally sensitive, it's an open question whether hormone disruptors could be part of the disparities across race and ethnicity.

"Black women get endometrial cancer about as frequently as white women, but they are much more likely to die from it because they are more likely to get high-risk subtypes," she explained. "It's a significant problem. And the overall increase in high-risk subtypes amongst Black and white women, although mostly Black women are driving this, have led to the increase in mortality. And so endometrial cancer is one of the few cancers now in the United States that is increasing in both mortality and incidence, which is why it's such a problem."

A retrospective showed that use of straightening products in the previous 12 months was associated with a higher incidence of uterine cancer, including endometrial cancers (HR 1.80, 95% CI 1.12-2.88). The association was stronger with more frequent use (HR 2.55 for more than four times a year vs never, 95% CI 1.46-4.45).

While use of hair relaxers is more common among women of color, the has cautioned that the low quality of evidence is insufficient to make any conclusions.

Getting to the bottom of mechanisms will likely help more than just women with endometrial cancers, De Vivo said. "What we can learn from this very exquisitely hormonally sensitive cancer, we can apply to more common cancers like breast and ovarian."

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