Menopausal Hormone Therapy and Ovarian Cancer Risk in the National Institutes of Health–AARP Diet and Health Study Cohort

JNCI Journal of the National Cancer Institute, Oct 2006

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 97 638 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 100 000 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, 51 698 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 100 000 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 100 000 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.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://jnci.oxfordjournals.org/content/98/19/1397.full.pdf

Menopausal Hormone Therapy and Ovarian Cancer Risk in the National Institutes of Health–AARP Diet and Health Study Cohort

James V. Lacey Jr. ) 0 1 Louise A. Brinton 0 1 Michael F. Leitzmann 0 1 Traci Mouw 0 1 Albert Hollenbeck 0 1 Arthur Schatzkin 0 1 Patricia Hartge 0 1 0 Affiliations of authors: Hormonal and Reproductive Epidemiology Branch (JVL , LAB), Nutritional Epidemiology Branch (MFL , TM, AS), and Epidemi- ology and Biostatistics Program (PH), Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health , Rockville, MD ; AARP, Washington DC (AH). 5030, Rockville, MD 20852-7234 ( 1 Journal of the National Cancer Institute , Vol. 98, No. 19, October 4, 2006 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 97 638 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 100 000 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, 51 698 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 100 000 personyears) or continuous (progestin for 15 days per cycle; RR = 1.82, 95% CI = 1.03 to 3.23; P = .02; 49 versus 66 per 100 000 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. [J Natl Cancer Inst 2006;98:1397-405] - Many of the reports of higher ovarian cancer risks in women who used hormone therapy arose from study populations in which women with intact uteri had used unopposed estrogen (5 7,911). This exposure combination, although etiologically and historically intriguing, is of less relevance today because, since the early 1990s, clinical guidelines (1517) have recommended use of estrogen plus progestin formulations for women with intact uteri and use of unopposed estrogen formulations for women with hysterectomy. Data on ovarian cancer risk associated with use according to those guidelines are sparse. Long-duration unopposed estrogen use among women with hysterectomy was associated with statistically significantly increased ovarian cancer risk in two studies (5,7), statistically nonsignificantly increased risk in another (14), and no increased risk in a fourth (13). Much of the limited data on exposure to estrogen plus progestin and risk of ovarian cancer came from studies of women who previously used unopposed estrogen (11,14) or from studies that did not evaluate individual estrogen plus progestin regimens (10,13,14). In one Swedish casecontrol study (7), use of sequential estrogen plus progestin regimens (i.e., daily estrogen and progestin taken for 15 days per cycle) was associated with increased ovarian cancer risk but use of continuous regimens (i.e., daily estrogen and progestin taken for 19 days per cycle) was not. Menopausal hormone therapies used in Sweden contain different estrogens and progestins than those used in the United States (7). The difference in formulations may be particularly important for ovarian cancer risk (18). The most detailed US data on continuous combined estrogen plus progestin come from the Womens Health Initiative (WHI), a randomized clinical trial in which this regimen was associated with a statistically nonsignificantly increased ovarian cancer risk, based on 32 participants who developed ovarian cancer (19). The studies to date do not provide clear evidence on ovarian cancer risk associated with the common patterns of menopausal hormone use in the United States since the early 1990 (...truncated)


This is a preview of a remote PDF: https://jnci.oxfordjournals.org/content/98/19/1397.full.pdf

James V. Lacey Jr., Louise A. Brinton, Michael F. Leitzmann, Traci Mouw, Albert Hollenbeck, Arthur Schatzkin, Patricia Hartge. Menopausal Hormone Therapy and Ovarian Cancer Risk in the National Institutes of Health–AARP Diet and Health Study Cohort, JNCI Journal of the National Cancer Institute, 2006, pp. 1397-1405, 98/19, DOI: 10.1093/jnci/djj375