As compared to other studies, we neither found an increased [1
] nor a decreased [2
] risk of breast cancer in relation to simple hysterectomy status. In agreement with other studies, we did not find an association with age at surgery [1
]. Given these null findings, inclusion of women with hysterectomy in the analysis of the association between ethnicity and breast cancer risk did not materially change the conclusions about this association despite large variation in hysterectomy prevalence by ethnic group.
The balance of several phenomena, including measurement error and biological mechanisms that may be weak or counteract one another, could have resulted in the null association that was estimated between hysterectomy and breast cancer risk in this study. A biological mechanism that could increase risk is that conditions leading to hysterectomy may share a hormonal etiology with breast cancer. Indications for hysterectomy include leiomyomas (uterine fibroids), endometriosis, uterine prolapse, and menstrual disorders [12
]. Risk factors for some of these conditions are also known breast cancer risk factors: early age at menarche, low parity, BMI, and low physical activity [10
]. There are exceptions. Alcohol intake and BMI decrease the risk for endometriosis [30
] but increase the risk for postmenopausal breast cancer. Parity and early age at first birth increase the risk of prolapse [33
] but decrease the risk of breast cancer. Further, the conditions themselves should be associated with breast cancer but studies of endometriosis show no overall association [1
] or a slightly increased risk [40
] and the one study of hysterectomy for leiomyomas reported only a slight increased risk [1
Another biological mechanism, but which could reduce the risk associated with hysterectomy, is that simple hysterectomy seems to reduce blood flow to the ovaries [41
] and consequently, lessens the production of estrogens and hastens menopause. Simple hysterectomy is associated with changes in ovarian histology [42
], differential expression of menopausal symptoms [43
], and increases in follicle-stimulating hormone [46
]. Women with a simple hysterectomy have an average age at menopause as determined by follicle-stimulating hormone levels > 40 IU/L that is 3.7 years younger than women who have a natural menopause [47
]. Given that each year of earlier age at menopause reduces breast cancer risk by 2 to 3% [5
], 3.7 years earlier would translate into a risk reduction of 7% to 11%. The reduction in risk could be larger because hysterectomy may have effects on hormone levels even after menopause; levels of testosterone and estrone are slightly lower in women who had a simple hysterectomy than women who had a natural menopause [49
The null association that was estimated between hysterectomy and breast cancer risk could also be influenced by the possibility that women may have taken pharmacological treatments for the indications for which they had a hysterectomy prior to having the surgery and these treatments could have affected breast cancer risk. For example, treatments given for leiomyomas and endometriosis, two of the main indications for hysterectomy, may include danazol (an androgenic medication), oral contraceptives, and gonatropin releasing hormone agonists [50
Finally, possible measurement error in hysterectomy status could influence the association that was estimated as null. Although one study showed excellent concordance between hospital records and self-reported hysterectomy and oophorectomy [53
], other studies have shown less concordance between self-report and information from physicians [54
], hospital records [55
], a second self-report up to ten years later [59
], or a second self-report within a short period of time [56
]. The study with excellent concordance was among nurses, who are likely more medically informed than the general population [53
]. Because bilateral oophorectomy reduces breast cancer risk (in the current study, relative to women having natural menopause, RR=0.81; 95% CI=0.69-0.94), if women with bilateral oophorectomy were included in the simple hysterectomy group, the risk associated with hysterectomy would be biased toward a reduction in risk. This bias may be more apparent in studies using self-report than in studies using medical records. Although slightly reduced risks were observed in two case-control studies using self-reported data [3
], reduced risks were also observed in one of the two retrospective studies using medical records [2
]. Conversely, women who were premenopausal at the time of entry into the cohort study could subsequently have had a simple hysterectomy in the follow-up time. The person-years incorrectly classified should be minimal, however, because few women were premenopausal at baseline and those women who were premenopausal were over 45 years of age.
The balance of these biological mechanisms and potential biases could be different among different populations such that some studies estimate an increased risk, some estimate a decreased risk, and some show no risk difference with hysterectomy. On the other hand, no real association may exist between hysterectomy and breast cancer risk.
As in other studies [12
], we found that the prevalence of simple hysterectomy differed by ethnicity; it was relatively high in African American women and low in Japanese American women. This difference in prevalence could be due to ethnic differences in the incidence and severity of uterine pathologies, prevalence of early treatment to prevent hysterectomy, or medical practice [12
]. We had been concerned that if hysterectomy was associated with breast cancer risk and also associated with ethnicity, then the exclusion of women with simple hysterectomies would affect the association between ethnicity and breast cancer risk. Their exclusion, however, did not substantially change the association and supports the generalizability of this observation. Furthermore, the association was remarkably similar to results presented previously for the MEC [6
] despite two to three years additional follow-up and a sample with premenopausal women, women with a simple hysterectomy and naturally postmenopausal women as compared to using a sample with naturally postmenopausal women and women with bilateral oophorectomy.
Although we did not have specific data to disentangle the effects of differing age at menopause, indication for hysterectomy, or possible misreporting of hysterectomy and oophorectomy status, this study and others have not shown an increased risk of breast cancer associated with simple hysterectomy. Despite the considerable variation in hysterectomy prevalence by ethnicity, because of the lack of association between hysterectomy and breast cancer risk, exclusion of women with simple hysterectomies did not substantially change the observed differences in breast cancer risk by ethnicity.