Menopausal hormone therapy and ovarian cancer risk in the National Institutes of Health-AARP Diet and Health Study Cohort

Background. Recent studies offer conflicting data on risks of ovarian cancer in users of menopausal hormone therapy. Some findings of increased risks associated with unopposed estrogen use are based on older studies of women with intact uteri, and small sample size and incomplete exposure information have limited the data on estrogen plus progestin associations. Methods: The National Institutes of Health-AARP Diet and Health Study Cohort included 97638 women aged 50-71 years at baseline who completed two questionnaires (1995-1996 and 1996-1997). We identified 214 incident ovarian cancers among these women through the year 2000 using data from state cancer registries and mortality indexes. We estimated relative risks (RRs) of ovarian cancer for detailed hormone therapy exposures using multivariable proportional hazards regression models. All statistical tests were two-sided. Results: Use of unopposed estrogen for fewer than 10 years was not associated with ovarian cancer. Compared with use of no hormone therapy, use of unopposed estrogen for 10 or more years was statistically significantly associated with ovarian cancer among all women (RR = 1.89,95% confidence interval [CI] = 1.22 to 2.95; P =.004; 56 versus 72 ovarian cancers per 100000 person-years, respectively) and, albeit not statistically significantly, among women with hysterectomy (n = 19 359, RR = 1.70, 95% CI = 0.87 to 3.31; P =.06). Among the 73 483 women with intact uteri, 51698 had used no hormone therapy or only estrogen plus progestin. Compared with no hormone therapy use, 5 or more years of use of sequential (progestin for < 15 days per cycle; RR = 3.09, 95% CI = 1.68 to 5.68; P <.001; 49 versus 108 per 100000 person-years) or continuous (progestin for >= 15 days per cycle; RR = 1.82, 95% CI = 1.03 to 3.23; P = .02; 49 versus 66 per 100000 person-years) estrogen plus progestin regimens were statistically significantly associated with ovarian cancer. Conclusions: Long durations of use of unopposed estrogen and of estrogen plus progestin, especially sequential regimens, are associated with increased ovarian cancer risk. These data expand the range of possible risks associated with menopausal hormone therapy.