Ovarian cancer and menopausal hormone therapy: more data and new questions.

The key message on the use of unopposed estrogen and estrogen plus progestin after menopause is clear: increased risks of stroke, coronary heart disease, pulmonary embolism, and breast cancer outweigh reduced risks of fractures and colorectal cancer. Individual riskbenefit profiles will, of course, vary, but current clinical guidelines emphasize use for symptom relief only, at low doses and for short durations. After the 2002 announcement of the main findings from the Women’s Health Initiative estrogen-plus-progestin trial (1), which clarified those risks, use of menopausal hormone therapy decreased by f50% (2). Today, however, symptom relief apparently trumps potential risks: many postmenopausal women are continuing to use hormone therapy or are having difficulty discontinuing use (3). The increased risks associated with unopposed estrogen therapy use now include ovarian cancer, based largely on recent evidence indicating that current or long-duration use increases risk by 50% to 100%. Fortunately, ovarian cancer is rare. A 2-fold higher relative risk only increases a woman’s absolute lifetime risk of developing ovarian cancer from f1.5% to 3.0%. Unfortunately, ovarian cancer is often lethal because it typically evades early detection. A 3.0% absolute risk means more women will face grim prognoses, difficult treatments, and low survival odds. Whether the ovarian cancer risks will influence decision-making about unopposed estrogen is uncertain because women and their physicians presumably will heavily weight elevated risks of common conditions, such as coronary heart disease or stroke, and discount even quantitatively similar increased risks of rare outcomes such as ovarian cancer. The association between ovarian cancer and estrogen plus progestin is less clear. Ovarian cancer studies published through 2002 included too few exposed women to provide reliable measures of association. The new case-control data from Rossing et al. (4), published in this issue of Cancer Epidemiology, Biomarkers & Prevention , are therefore especially informative. Its large case group, appropriate controls, and extensive risk-factor data from a population with substantial menopausal hormone therapy use offer an opportunity to directly compare associations between ovarian cancer and both unopposed estrogen and estrogen plus progestin. Compared with no menopausal hormone therapy use, unopposed-estrogen use for z10 years was statistically significantly associated with increased risk of ovarian cancer. Use for z5 years was associated with increased risk among both former and current users, but that increase disappeared 3 years after cessation of use. These data generally match most of the recently published results and nicely expand the available data on risk among former users. In contrast, estrogen-plus-progestin use was inversely associated with ovarian cancer. Most of the odds ratios for specific exposures were close to the null, but short-duration (<5 years) and former use were both associated with a statistically significant 50% reduction in risk, which persisted among women whose last use occurred at least 3 years before their diagnosis or interview. Rossing et al. succinctly summarized the relevant published literature, offering reasonable explanations of the inconsistent results. However, important consistencies went unnoticed. The largest cohort study to date (5) replicated recent findings from a U.S. cohort (6) and the Women’s Health Initiative estrogen-plus-progestin clinical trial (7). Together, these three prospective studies suggest an increased risk among current, long-duration estrogen-plus-progestin users that is similar to that among long-duration unopposed-estrogen users. Almost all of the case-control studies, however, observed null associations. Rossing et al.’s study is the third (8, 9) to report inverse associations with estrogen plus progestin use, but the first in which the association is statistically significant. In each of these studies, reduced risk seen among short-duration or former users was absent among long-duration and current users. Inconsistent findings typically resolve themselves over time, even when firstpass explanations, like chance or small sample size, do not fit. Contradictory findings that are each separately replicated are more puzzling. Rossing et al. propose that estrogen and progesterone play opposing mechanistic roles in ovarian carcinogenesis, the former as a promoter and the latter encouraging apoptosis. For estrogen plus progestin to be truly protective, progestin should both negate estrogenassociated (risk-increasing) proliferation and leave the ovaries better off than they were before menopausal hormone therapywas used (because users’ risk was lower than nonusers’ risk). By extension, progestin-only hormone therapy would offer the best possible protection. The few studies with data on this uncommon exposure did not observe reduced risks among progestin-only