Factors that affect cumulative exposure to ovarian hormones have repeatedly been associated with breast cancer risk. Late age at natural menopause, for example, is an important reproductive risk factor for breast cancer (24
). Bilateral ovariectomy also reduces breast cancer risk, presumably by artificially lowering a woman's age at menopause and by causing an immediate halt to the production of ovarian hormones (2
). The present study supports the role of lifetime exposure to ovarian hormones as a predictor of breast cancer risk. Women who underwent bilateral ovariectomy at earlier ages experienced successively reduced risks, with an approximate 69% risk reduction among women with bilateral ovariectomy before 30 years of age. Odds ratios for bilateral ovariectomy after 45 years of age approached unity, likely because these ages coincided with ages at natural menopause, resulting in similar exposure to ovarian hormones for women who had surgical menopause and for those who had natural menopause. These findings are consistent with other studies that reported a protective effect of bilateral ovariectomy performed before, but not after, 50 years of age (2
A protective effect of hysterectomy on breast cancer risk was observed previously in some studies (6
) but not in a recent prospective study (15
). The latter study cited unpublished results from the Collaborative Group on Hormonal Factors in Breast Cancer (26
), which estimated an approximate 10% breast cancer risk reduction due to the effect of hysterectomy (OR = 0.90, 95% CI: 0.87, 0.93). Hysterectomy with ovarian conservation in premenopausal women was associated with premature ovarian failure in some (27
) but not all (35
) studies. A decrease in ovarian blood supply has been observed immediately after hysterectomy (34
), and it has been suggested that this phenomenon is a mechanism by which both tubal sterilization and hysterectomy may protect against ovarian cancer (40
). Some (29
) but not all (35
) studies using concentrations of follicle-stimulating hormone as a clinical marker of ovarian function have reported high concentrations of this hormone, which indicates a decline in ovarian function (41
), in women who had hysterectomy with ovarian conservation. Other findings for women who had hysterectomy with ovarian conservation included an increase in complaints about climacteric symptoms (42
), bone loss (43
), and increased risk of hypertension (44
), which may also indicate hormonal sequelae after hysterectomy. Our data indicate that hysterectomy in the absence of bilateral ovariectomy is associated with a moderate reduction in breast cancer risk after >10 years.
A prior report from this Women's CARE Study population found that continuous combined HT use was associated with increased breast cancer risk among current HT users (17
). Another Women's CARE Study report indicated that the association with HT use was limited to invasive lobular breast carcinoma (45
). The effect of HT use on breast cancer risk, as well as its possible interaction with ovariectomy and hysterectomy, indicates that studies investigating the effects of hysterectomy, partial ovariectomy, or HT use on breast cancer risk should account for all 3 of these potential risk factors in their analyses. Among studies investigating hysterectomy with ovarian conservation and premature ovarian failure, none considered HT use in their analyses. Several studies excluded hysterectomized women with a history of HT use (27
One study (9
) examined the effect of tubal sterilization as the only reproductive surgery. Results showed a reduction in breast cancer risk among all women and among those who had tubal sterilization at 15–34 years of age. Studies that have examined the impact of tubal sterilization with no consideration of other reproductive surgeries have provided inconsistent results (10
). Tubal sterilization techniques have varied over time, and there is speculation that disparate procedures may have differential effects on blood flow and tissue damage and thus hormone levels and ovarian function (46
). Studies assessing risk in relation to calendar year of tubal sterilization have also been inconsistent (11
). When we considered tubal sterilization irrespective of other reproductive surgeries, a protective effect was observed for tubal sterilization before age 28 years (OR = 0.79, 95% CI: 0.66, 0.96) and before calendar year 1980 (OR = 0.84, 95% CI: 0.74, 0.96). However, it is likely that the cumulative impact of other reproductive surgeries dominated this effect, because among women having only tubal sterilization, breast cancer risk was not reduced within any age grouping (), calendar-year grouping (), or duration since tubal sterilization (data not shown).
A previous Women's CARE Study report found multiparity and early age at first birth to be associated with reduced risk of ER+/PR+ tumors but not ER−/PR− tumors (16
). ER/PR status mediated the associations between breast cancer and reproductive and lifestyle risk factors in a case-control study of Vietnamese and Chinese women eligible for a clinical trial of ovariectomy and tamoxifen as breast cancer treatment (47
). However, neither report considered ER/PR status as a possible mediator in the protective effect of bilateral ovariectomy. In the current analysis, bilateral ovariectomy was associated with reduced risk of ER+/PR+ tumors but not ER−/PR− tumors, although the direction was the same. The finding that the protective effect of bilateral ovariectomy, which terminates exposure to ovarian hormones, is limited to receptor-positive tumors is consistent with the proposal that ER+ and PR+ breast cancers are influenced by exposure to estrogen and progesterone, whereas ER− and PR− breast cancers are not (48
Among this study's strengths are the study size, population-based sampling, geographic diversity, and inclusion of both black and white women. The large number of women who underwent reproductive surgery in each subsample provides sufficient statistical power to detect moderate associations.
A potential limitation of case-control studies is that selection bias or recall bias may influence results. Here, RDD screening rates and interview completion rates were acceptably high (76.5% of eligible cases; 78.6% of eligible controls at households successfully screened), falling within ranges reported in the literature (19
). Recall bias was minimized by assessing reproductive and contraceptive histories in conjunction with completion of a calendar of life events to facilitate recall.
It was not possible to compare reported reproductive surgeries with medical records. Self-reporting of hysterectomy and tubal sterilization was shown to be reliable and valid in an Australian study (49
). A validation study of self-reported hysterectomy and ovariectomy in a group setting in Washington State reported high accuracy for hysterectomy but not for ovariectomy (22
). The accuracy of self-reporting for ovariectomy is a potential limitation in our study, especially when reproductive surgeries were performed concurrently. This may have been a particular problem for self-reporting of the number of ovaries remaining after all reproductive surgeries. It is possible that women may not always know the extent of a hysterectomy operation (i.e., unilateral, partial, or bilaterateral ovariectomy performed in addition to a hysterectomy). Of women classified as having had a hysterectomy and partial ovariectomy in our study, 128 reported having both ovaries intact after all ovarian surgeries. Excluding these women from analyses did not alter our results. It is unclear whether previous studies assessing the relation between breast cancer risk and unilateral ovariectomy (2
) included only women with 1 total ovary removed, excluding those with partial ovariectomy. An additional potential limitation is that we did not collect data on indications for reproductive surgeries. Hysterectomy rates have considerable geographic, patient-related, and physician-related variation (50). This may help explain discrepant findings in studies investigating hysterectomy and breast cancer risk. Another potential limitation is our inability to control for age at menopause among women having a hysterectomy before natural menopause; for these women, age at menopause is unknown.
ER/PR status was not available for all cases. A previous study conducted within SEER registries (51) reported a frequency of 18% unknown ER/PR status and 5% not carried out, which is comparable to the 17.6% frequency of unknown receptor status in our study. The Women's CARE Study cases with no ER/PR status were more likely to be multiparous, have earlier first births, and have breastfed for shorter periods of time; however, it is unlikely that information on ER/PR status for these women would have altered findings (16
). An additional limitation was that we used ER/PR status as reported in the pathology report. It is possible that the cutoff for positive receptor status and assay quality varied between laboratories. A recent Women's CARE Study publication, which compared ER/PR status obtained from SEER registries to that obtained from a single expert laboratory (for Los Angeles and Detroit cases), showed that registry results for ER+/PR+ and ER−/PR− tumors are reasonably reliable and that risk estimates for tumors classified using the SEER results and using the expert laboratory classification differed minimally for standard reproductive breast cancer risk factors (52).
In summary, our findings support the association between bilateral ovariectomy and lower breast cancer risk. Hysterectomy with or without partial ovary removal was also protective. Breast cancer risk was not reduced among women who had only tubal sterilization or partial ovariectomy without hysterectomy. Because reproductive surgeries can alter ovarian hormone production, such alterations are likely to mediate the association between these surgeries and breast cancer risk.