Why Women with PCOS Have Threefold Risk of Endometrial Cancer
The correct answer is D: estrogen regularly stimulates the endometrium. Women with PCOS experience chronic anovulation, which results in continuous estrogen stimulation of the endometrium unopposed by progesterone, leading to a nearly threefold increased risk of endometrial cancer (OR 2.79-2.89). 1
The Mechanism: Unopposed Estrogen Exposure
The fundamental pathophysiology centers on hormonal imbalance:
Chronic anovulation in PCOS prevents cyclic progesterone production, leaving estrogen to continuously stimulate the endometrium without the protective effects of progesterone. 2, 3
This unopposed estrogen exposure is the primary driver of endometrial hyperplasia and subsequent malignant transformation, similar to the mechanism seen with exogenous unopposed estrogen therapy (which increases endometrial cancer risk 10-30 fold with 5+ years of use). 1, 4, 5
The prolonged anovulation with consequent continued secretion of estrogen unopposed by progesterone enhances the development and growth of endometrial malignancy, particularly in young women with PCOS. 2
Why the Other Options Are Incorrect
Option A is backwards: PCOS does not cause reduction of estrogen with excess progesterone buildup. In fact, the opposite occurs—estrogen levels remain elevated while progesterone is deficient due to lack of ovulation. 2, 3
Option B is a symptom, not the mechanism: While menstrual irregularity is a clinical manifestation of PCOS, it is not the mechanistic explanation for cancer risk. The irregular bleeding reflects the underlying hormonal dysfunction rather than causing the cancer risk itself. 1
Option C contributes but is not the primary mechanism: While insulin resistance and hyperandrogenism are features of PCOS and may contribute to cancer risk through multiple pathways, the direct mechanism linking PCOS to endometrial cancer is the unopposed estrogen stimulation of the endometrium. 2, 6, 7
Additional Contributing Factors
Beyond unopposed estrogen, other PCOS-related factors may amplify risk:
Obesity is a major confounding factor, with the BMI-adjusted odds ratio for endometrial cancer in PCOS dropping from 2.79-2.89 to 2.2 (95% CI 0.9-5.7), suggesting obesity independently contributes to risk. 1
Hyperinsulinemia and elevated IGF-I levels may represent additional risk factors for endometrial cancer development in PCOS patients. 2, 7
Chronic inflammation and dyslipidemia associated with PCOS may also contribute to the overall cancer risk. 6
Clinical Implications
Hormonal treatment to provide cyclic progesterone exposure is commonly prescribed to reduce the perceived endometrial cancer risk in PCOS patients, though consensus on which PCOS subgroups require this intervention remains unclear. 3