Is estrogen plus progestin menopausal hormone therapy safe with respect to endometrial cancer risk?

Abstract

Given the strong link between use of unopposed estrogens and development of endometrial cancers, estrogens are usually prescribed with a progestin, particularly for women with intact uteri. Some studies suggest that sequential use of progestins may increase risk; however, the moderating effects of usage patterns or patient characteristics, including body mass index (BMI), are unknown. We evaluated menopausal hormone use and incident endometrial cancer (n = 885) in 68,419 postmenopausal women with intact uteri enrolled in the National Institutes of Health-American Association of Retired Persons Diet and Health study. Participants completed a risk factor questionnaire in 1996-1997 and were followed up through 2006. Hazard rate ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox regression. Among 19,131 women reporting exclusive estrogen plus progestin use, 176 developed endometrial cancer (RR = 0.88; 95% CI = 0.74-1.06). Long-duration (≥ 10 years) sequential (<15 days progestin per month) estrogen plus progestin use was positively associated with risk (RR = 1.88; 95% CI = 1.36-2.60], whereas continuous (>25 days progestin per month) estrogen plus progestin use was associated with a decreased risk (RR = 0.64; 95% CI = 0.49-0.83). Increased risk for sequential estrogen plus progestin was seen only among thin-to-normal weight women (BMI < 25 kg/m(2); RR = 2.53). Our findings support that specific categories of estrogen plus progestin use increases endometrial cancer risk, specifically long durations of sequential progestins, whereas decreased endometrial cancer risk was observed for users of short-duration continuous progestins. Risks were highest among thin-to-normal weight women, presumably reflecting their lower endogenous estrogen levels, suggesting that menopausal hormones and obesity increase endometrial cancer through common etiologic pathways.

Figure 1

Age-standardized incidence of endometrial cancer by menopausal hormone therapy use and body mass index (BMI) groups (in kg/m²), NIH-AARP Diet and Health Study, 1995–2006. Error bars indicate 95% confidence interval on the age-standardized incidence rate. Abbreviations: CEPT = continuous estrogen plus progestin therapy, SEPT = sequential estrogen plus progestin therapy, ET = unopposed estrogen therapy, MHT = Menopausal hormone therapy, BMI = body mass index