Obesity is the Most Significant Risk Factor for Endometrial Cancer
Among the options provided, obesity (Option C) is the most significant risk factor for endometrial cancer, with the strongest evidence showing a 2.5-fold increased risk for obesity and up to 4.7-fold for severe obesity. 1, 2
Evidence-Based Risk Stratification
Obesity: The Dominant Risk Factor
- Obesity (BMI ≥30) confers the greatest relative risk of 2.21-2.54 among individual metabolic syndrome components for developing endometrial cancer 1
- Severe obesity (BMI >35) increases risk by 4.7-fold compared to normal-weight women 2
- The strength of association increases progressively with BMI: overweight (BMI 25-30) has RR 1.32, while obesity has RR 2.54 1
- This represents convincing evidence that greater body fatness is a cause of endometrial cancer 1
Why the Other Options Are Less Significant
Early Menopause (Option B) - PROTECTIVE, Not a Risk Factor:
- This is a common pitfall: late menopause (≥55 years), not early menopause, increases risk with RR 1.8 compared to menopause <50 years 1
- Early menopause would actually reduce lifetime estrogen exposure and be protective
Multiparity (Option D) - PROTECTIVE, Not a Risk Factor:
- Nulliparity, not multiparity, is the classical risk factor for endometrial cancer 1
- Multiple pregnancies provide progesterone exposure that protects the endometrium
DES Exposure (Option A) - Not Established:
- DES exposure is not mentioned as a risk factor in major endometrial cancer guidelines 1
- The established hormonal risk factors relate to unopposed estrogen from other sources
Mechanistic Understanding
How Obesity Drives Endometrial Cancer Risk
- In postmenopausal women: Adipose tissue converts androstenedione to estrone, creating higher circulating bioavailable estrogens without progesterone opposition 1
- In premenopausal women: Obesity causes insulin resistance, elevated ovarian androgens, anovulation, and chronic progesterone deficiency 1
- Hyperinsulinemia independently increases risk 2.33-fold (and 4.30-fold in overweight/obese women), separate from estrogen effects 3
Clinical Implications
- Weight gain of every 5 kg increases endometrial cancer risk by 20% (OR 1.2) 4
- Weight loss shows protective effects: sustained weight loss reduces risk (OR 0.7) 4
- Bariatric surgery demonstrates reversal of endometrial proliferation markers and oncogenic signaling within 2-12 months 5
Answer: C. Obesity
The correct answer is unequivocally obesity, which has the strongest epidemiologic evidence with relative risks exceeding all other listed options by substantial margins 1, 2.