Risks of endometrial cancer associated with different hormone replacement therapies in the E3N cohort, 1992-2008

We assessed whether different oral progestogens in hormone replacement therapy may differentially affect the risk of endometrial cancer, using data from the Etude Epidémiologique auprès de femmes de l'Education Nationale (E3N), a French cohort study (1992-2008). Hazard ratios and their confidence intervals were derived from Cox models. Among 65,630 postmenopausal women (mean follow-up: 10.8 years), 301 endometrial cancers occurred. Compared with never use, ever use of estrogen + micronized progesterone was associated with an increased risk of endometrial cancer (hazard ratio (HR) = 1.80, 95% confidence interval (CI): 1.38, 2.34) that was significantly more marked with longer duration of use (for ≤5 years, HR = 1.39 (95% CI: 0.99, 1.97); for >5 years, HR = 2.66 (95% CI: 1.87, 3.77)). Although use of estrogen + dydrogesterone was not associated overall with endometrial cancer risk (HR = 1.05, 95% CI: 0.76, 1.45), there was a significantly increased risk with long-term use compared with never use (for >5 years, HR = 1.69, 95% CI: 1.06, 2.70). Users of preparations containing other progesterone derivatives or a norsteroid derivative were not at significantly increased risk (HR = 0.79 (95% CI: 0.60, 1.05) and HR = 1.30 (95% CI: 0.85, 1.99), respectively). In conclusion, micronized progesterone and, to a lesser extent, dydrogesterone at the doses used in France may not be sufficient to prevent estrogen-induced endometrial cancers.