Is Weight Gain a Risk Factor for Uterine Cancer?
Yes, weight gain and obesity are among the strongest established risk factors for endometrial cancer (the most common type of uterine cancer), with severe obesity increasing risk by up to 4.7-fold compared to normal-weight women. 1, 2
Magnitude of Risk by Body Mass Index
The relationship between obesity and endometrial cancer demonstrates a clear dose-response pattern:
- BMI 22-27.2 (overweight): 21% increased incidence 1
- BMI 27.5-29.5 (mild obesity): 43% increased incidence 1
- BMI >30 (obesity): 173% increased incidence (2.73-fold increase) 1
- BMI >35 (severe obesity): 370% increased incidence (4.7-fold increase) 2, 3
The ESMO Clinical Practice Guidelines (2022) explicitly identify BMI as a major risk factor, with obesity representing one of the strongest associations with endometrial cancer development. 1
Weight Gain Specifically
Beyond static obesity measurements, weight gain itself increases endometrial cancer risk, while weight loss may provide protective effects. 3 The American Cancer Society guidelines note that rising mortality rates from endometrial cancer are primarily attributed to increasing obesity prevalence. 1
Biological Mechanisms
The cancer-promoting effects of obesity operate through multiple pathways:
In postmenopausal women: Adipose tissue converts androstenedione to estrone, creating elevated circulating bioavailable estrogens without progesterone opposition—the primary driver of endometrial hyperplasia and malignant transformation. 2
In premenopausal women: Obesity causes insulin resistance, elevated ovarian androgens, chronic anovulation, and progesterone deficiency, all contributing to unopposed estrogen stimulation of the endometrium. 2
Additional mechanisms include hyperinsulinemia, chronic inflammation, and adipokine dysregulation. 3
Clinical Context and Trends
The incidence of endometrial cancer is increasing by 0.7-0.82% annually in the United States, with mortality rising 1.1-1.9% per year—trends directly linked to rising obesity rates. 1, 4, 5 During 1999-2017, obesity prevalence increased from 19.5% to 27.5%, paralleling the rise in uterine cancer cases. 5
Importantly, recent data challenge the traditional assumption that obesity primarily affects low-grade (Type I) endometrial cancers. High-risk Type II endometrial cancers (serous, clear cell, carcinosarcoma) have increased by 63% since 2001, with serous carcinoma rising 4.88% annually—suggesting obesity may impact all histologic subtypes through molecular mechanisms beyond simple estrogen exposure. 5
Other Obesity-Related Risk Factors
The NCCN Guidelines identify additional obesity-associated risk factors that compound endometrial cancer risk: 1
- Diabetes and hyperinsulinemia 1
- Hypertension 1
- High-fat diet 1
- Polycystic ovarian syndrome (PCOS), which confers a 2.79-2.89-fold increased risk through chronic anovulation 6
Impact on Prognosis
Among women already diagnosed with endometrial cancer, obesity at diagnosis is associated with 20% higher all-cause mortality and roughly twofold increased endometrial cancer-specific mortality. 1, 3 A 10% increase in BMI correlates with 9% higher odds of all-cause mortality among endometrial cancer survivors. 1
Clinical Pitfalls
Do not dismiss obesity as a risk factor in younger women or those with high-grade histologies—molecular evidence suggests obesity creates a proinflammatory microenvironment affecting tumor biology across all endometrial cancer subtypes. 5 Additionally, central adiposity (measured by waist circumference or waist-to-hip ratio) increases risk 1.5- to 2-fold independent of BMI. 3