Abstract
Background
Gynecologic surgery is hypothesized to reduce risk of breast cancer; however, associations may be modified by subsequent hormone use. Our objective was to examine the association between gynecologic surgery and breast cancer incidence considering the use of hormone therapy.
Methods
The Sister Study is a prospective cohort of initially breast cancer–free women aged 35-74 years with a sister who had breast cancer. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between gynecologic surgery (no surgery, hysterectomy only, bilateral oophorectomy with or without hysterectomy) and incident breast cancer among 50 701 women.
Results
History of gynecologic surgery was common, with 13.8% reporting hysterectomy only and 18.1% reporting bilateral oophorectomy with or without hysterectomy. During follow-up (median = 11.4 years), 3948 cases were diagnosed. Compared with no surgery, bilateral oophorectomy was inversely associated with breast cancer (HR = 0.91, 95% CI = 0.83 to 1.00), and hysterectomy alone was positively associated (HR = 1.12, 95% CI = 1.02 to 1.23). Compared with no surgery and no hormone therapy, bilateral oophorectomy combined with estrogen only therapy (HR = 0.83, 95% CI = 0.74 to 0.94) was inversely associated with breast cancer, while hysterectomy combined with estrogen plus progestin therapy was positively associated with breast cancer (HR = 1.25, 95% CI = 1.01 to 1.55).
Conclusions
We observed an inverse association between bilateral oophorectomy and breast cancer risk. The positive association between hysterectomy and breast cancer may be due to concomitant estrogen plus progestin therapy.
Gynecologic surgery is hypothesized to reduce risk of breast cancer, the leading cause of cancer death among women worldwide (1). However, epidemiologic findings are mixed and may be complicated by exogenous hormone use. Some prospective studies show that hysterectomy alone (surgical removal of the uterus) without bilateral oophorectomy (surgical removal of the ovaries) or salpingo-oophorectomy (surgical removal of fallopian tubes and ovaries) was not associated with breast cancer risk, even when considering hormone therapy use after surgery (2,3). Yet, other studies conclude gynecologic surgery is associated with reduced breast cancer risk. In 1 study, women with bilateral salpingo-oophorectomy had a 14% lower risk of breast cancer than women with only a hysterectomy (4). Similar findings were reported among women with bilateral oophorectomy compared with women with no surgery (5-7), and a reduced risk of breast cancer was also observed for women with hysterectomy alone (5).
Concerning race and ethnicity, disparities in gynecologic surgery and hormone use are clear. African American women are more likely to receive a hysterectomy compared with non-Hispanic White women, with nearly one-half of hysterectomies concomitant with bilateral oophorectomy (8-10). Hispanic women have lower rates of bilateral oophorectomy compared with non-Hispanic White women (11), but there is conflicting evidence on the odds of hysterectomy compared with White women (12,13). Women are recommended gynecologic surgery by a provider for several reasons, including treatment of fibroids, endometriosis, and uterine prolapse or bleeding (14-16). Some of these conditions are more prevalent in certain groups. For example, fibroids are more common among African American women compared with other racial and ethnic groups (17-19). Following surgery, women may be prescribed hormone therapy to replace hormone levels and manage symptoms, usually estrogen alone or estrogen plus progestin (ie, combination therapy), though prolonged exposure to estrogen alone is contraindicated if a woman still has her uterus (20). Prior research also suggests African American and Hispanic women are less often prescribed hormone therapy (21).
Our primary objective was to examine the association between gynecologic surgery and incident breast cancer. The secondary objective was to evaluate the extent to which this association was modified by menopause status at time of surgery, hormone therapy use, race and ethnicity, family history of breast cancer, body mass index (BMI), and breast cancer estrogen receptor (ER) status or tumor invasiveness.
Methods
Study sample
The Sister Study is a nationwide, prospective cohort of 50 884 participants self-identified as female and aged 35-74 years enrolled between 2003 and 2009 (22). To be eligible, women who never had breast cancer themselves had to have a biological sister who had breast cancer. Given their family history, these women have twice the risk of developing breast cancer, on average, compared with women without a first-degree relative with breast cancer (23). Participants completed a computer-assisted telephone interview and self-completed questionnaires at baseline. An examiner visited participants at home to collect biologic specimens and anthropometric measurements. Detailed follow-up questionnaires are administered every 2-3 years to capture incident breast cancer and changes in medical history. More than 90% of participants remained active through September 2019 (data release 9.0), by which time 4 follow-up questionnaires had been distributed. The Sister Study is approved by the Institutional Review Board of the National Institutes of Health, and written informed consent was obtained from all participants.
We excluded women who withdrew (n = 3), were diagnosed with invasive breast cancer or ductal carcinoma in situ (DCIS) before enrollment (n = 57), or had unclear breast cancer diagnosis or timing of diagnosis before baseline (n = 27). Women were also excluded if they had missing data on gynecologic surgery at baseline (n = 96), which left us with 50 701 eligible women.
Outcome assessment
Participants with self-reported invasive breast cancer or DCIS were considered breast cancer cases. DCIS diagnoses were included as cases because they have similar risk factors and are typically treated even though not all develop into invasive tumors (24,25). Participants with breast cancer were asked for consent to access medical records and pathology reports confirming diagnoses and tumor specimens, including ER status. Medical records were obtained for 82% of known cases, if available, or self-report. Self-reported breast cancer was previously shown to have high agreement with abstracted medical records, with more than 99% positive predictive value (26).
Exposure assessment
Participants reported history of gynecologic surgery (no surgery, hysterectomy only, bilateral oophorectomy with or without hysterectomy) at baseline. Women were also asked about age at each surgery and the reason why they underwent surgery. We defined menopause status at time of gynecologic surgery using self-reported age of surgery and age of last menstrual period. We did not collect data on salpingectomies. Data on gynecologic surgeries were also collected on all follow-up questionnaires, allowing us to update participants’ exposure status over time.
Modifier assessment
Participants were asked about their use of hormones (eg, estrogen, progesterone), including pills or patches, at baseline and each follow-up questionnaire. Participants were also asked to recall the age they initiated hormone therapy, how many years they used hormone therapy, and the extent to which hormone therapy use was inconsistent (ie, periods when the participant stopped for 3 months or longer).
Other covariates
We obtained covariate information at baseline and updated information during follow-up. We selected the following a priori confounders based on assumed causal relationships. We considered self-reported race and ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic or Latina, other), attained education (high school or less, some college or technical degree, bachelor’s degree, graduate degree), family history of breast cancer (1 sister or half-sister, ≥2 first-degree relatives), current alcohol consumption (non-drinker, drinker <7 drinks per week, drinker ≥7 drinks per week), smoking status (never, former, current), self-reported BMI (continuous), hormonal birth control (never or ever), age at menarche (≤11 years, 12-13 years, ≥14 years), parity (nulliparous, 1 birth, 2 births, ≥3 births), age at first pregnancy (nulligravid, ≤20 years, 21-29 years, ≥30 years), breastfeeding (nulliparous, parous never, parous ever), menopause status (premenopausal, postmenopausal), and hormone therapy (never, estrogen only, estrogen plus progestin). If a participant had a hysterectomy without a bilateral oophorectomy, we continued to classify her as premenopausal given that her body still had the capacity to produce hormones (though at a lower level) despite ceased menstruation. These women were considered postmenopausal at age 55 years or at age of bilateral oophorectomy, whichever occurred first. Women in the “other” race and ethnicity category identified as non-Hispanic for ethnicity and Asian, Native Hawaiian or other Pacific Islander, American Indian or Alaskan Native, or had no specified race.
Statistical analysis
We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between time-varying gynecologic surgery (ie, changing exposure status) and incident breast cancer. Using age as the time scale, models were adjusted for sociodemographic and lifestyle factors, reproductive history, and hormone therapy. Women were censored for age at end of follow-up, death, or loss to follow-up. We also considered sensitivity analyses 1) limiting to postmenopausal person-time, and 2) limiting the outcome to invasive breast cancer. In addition, we evaluated the association between menopausal status at time of first gynecologic surgery with incidence of breast cancer. We tested the proportional hazards assumption via a Wald test of the gynecologic surgery-by-age interaction term. Thereafter, we investigated the combined effects of time-varying gynecologic surgery and time-varying hormone therapy use. To evaluate the joint effects of gynecologic surgery and hormone therapy, we measured the additive interaction as relative excess risk due to interdependence (RERI) (27,28). We also examined effect measure modification on the relative scale by race and ethnicity, family history of breast cancer, and BMI (≥30 kg/m2 vs <30 kg/m2), testing for heterogeneity using Wald tests of gynecologic surgery-by-modifier interaction terms. We estimated outcome-specific hazard ratios using a data augmentation approach for breast cancer subtypes (ER+ and ER−, then invasive and DCIS). This approach allowed us to simultaneously estimate stratum-specific effects, where cases of the opposite subtype were censored at the time of diagnosis (ie, ER+ was censored in the ER− strata), and directly compare those estimates using Wald tests of gynecologic surgery-by-subtype interaction terms (29). Given that less than 2.0% of women had missing data for key variables, analyses were conducted using complete cases (final n = 50 003) in SAS version 9.4.
Results
At baseline, 13.8% of women reported hysterectomy only and 18.1% reported bilateral oophorectomy with or without hysterectomy (Table 1). Of note, 97.2% of women with bilateral oophorectomy also had a hysterectomy. Most women were non-Hispanic White (83.7%), had only 1 sister or half-sister with a history of breast cancer (73.2%), and had some level of educational attainment beyond high school (84.7%). Compared with women with hysterectomy only, women with bilateral oophorectomy were more likely to be nulligravid (12.1% vs 8.4%), users of estrogen only therapy (60.1% vs 44.7%), and users of estrogen plus progestin therapy (20.1% vs 9.2%) but less likely to be non-Hispanic Black (9.2% vs 13.6%).
Table 1.
Sample characteristics at baseline stratified by gynecologic surgery, Sister Study (2003-2009)
| All, No. (%) | No surgery, No. (%) | Hysterectomy only, No. (%) | Bilateral oophorectomya, No. (%) | |
|---|---|---|---|---|
| N = 50 701 | n = 34 560 (68.2) | n = 6980 (13.8) | n = 9161 (18.1) | |
| Mean age (SD), y | 55.6 (9.0) | 54.1 (8.9) | 58.5 (8.3) | 59.2 (7.9) |
| Mean body mass index (SD), kg/m2 | 27.8 (6.3) | 27.3 (6.2) | 28.9 (6.3) | 28.9 (6.4) |
| Race and ethnicity, No. (%) | ||||
| Hispanic/Latina | 2503 (4.9) | 1694 (4.9) | 380 (5.4) | 429 (4.7) |
| Non-Hispanic Black | 4448 (8.8) | 2651 (7.7) | 951 (13.6) | 846 (9.2) |
| Non-Hispanic White | 42 407 (83.7) | 29 329 (84.9) | 5454 (78.2) | 7624 (83.2) |
| Other | 1328 (2.6) | 877 (2.5) | 191 (2.7) | 260 (2.8) |
| Attained education, No. (%) | ||||
| High school or less | 7768 (15.3) | 4593 (13.3) | 1410 (20.2) | 1765 (19.3) |
| Some college/technical degree | 17 121 (33.8) | 10 739 (31.1) | 2835 (40.6) | 3547 (38.7) |
| Bachelor’s degree | 13 671 (27.0) | 10 137 (29.3) | 1457 (20.9) | 2077 (22.7) |
| Graduate degree | 12 129 (23.9) | 9083 (26.3) | 1276 (18.3) | 1770 (19.3) |
| Family history of breast cancer, No. (%) | ||||
| 1 sister/half-sister | 37 110 (73.2) | 25 594 (74.1) | 5069 (72.6) | 6447 (70.4) |
| ≥2 first-degree relatives | 13 590 (26.8) | 8965 (25.9) | 1911 (27.4) | 2714 (29.6) |
| Alcohol consumption, No. (%) | ||||
| Nondrinker | 9616 (19.0) | 5721 (16.6) | 1673 (24.0) | 2222 (24.3) |
| Drinker, <7 drinks/wk | 34 167 (67.5) | 23 815 (69) | 4502 (64.6) | 5850 (64.0) |
| Drinker, ≥7 drinks/wk | 6831 (13.5) | 4968 (14.4) | 792 (11.4) | 1071 (11.7) |
| Smoking status, No. (%) | ||||
| Never smoker | 28 453 (56.1) | 19 714 (57.1) | 3800 (54.5) | 4939 (53.9) |
| Former smoker | 18 078 (35.7) | 12 102 (35) | 2528 (36.2) | 3448 (37.7) |
| Current smoker | 4154 (8.2) | 2733 (7.9) | 650 (9.3) | 771 (8.4) |
| Hormonal birth control, No. (%) | ||||
| Never user | 7454 (14.8) | 4851 (14.1) | 1090 (15.7) | 1513 (16.6) |
| Ever user | 42 974 (85.2) | 29 540 (85.9) | 5853 (84.3) | 7581 (83.4) |
| Age at menarche, No. (%) | ||||
| ≤11 y | 10 356 (20.4) | 6474 (18.7) | 1691 (24.2) | 2191 (23.9) |
| 12-13 y | 28 433 (56.1) | 19 735 (57.1) | 3697 (53.0) | 5001 (54.7) |
| ≥14 y | 11 867 (23.4) | 8323 (24.1) | 1587 (22.8) | 1957 (21.4) |
| Parity, No. (%) | ||||
| Nulliparous | 9177 (18.1) | 6863 (19.9) | 810 (11.6) | 1504 (16.4) |
| 1 birth | 7327 (14.5) | 5134 (14.9) | 877 (12.6) | 1316 (14.4) |
| 2 births | 18 628 (36.8) | 12 708 (36.8) | 2627 (37.7) | 3293 (36.0) |
| ≥3 births | 15 536 (30.7) | 9832 (28.5) | 2663 (38.2) | 3041 (33.2) |
| Age at first pregnancy, No. (%) | ||||
| Nulligravid | 6352 (12.6) | 4661 (13.5) | 588 (8.4) | 1103 (12.1) |
| ≤20 y | 13 299 (26.3) | 7644 (22.2) | 2708 (38.9) | 2947 (32.2) |
| 21-29 y | 24 831 (49.1) | 16 983 (49.2) | 3348 (48.0) | 4500 (49.2) |
| ≥30 y | 6126 (12.1) | 5205 (15.1) | 324 (4.6) | 597 (6.5) |
| Breastfeeding, No. (%) | ||||
| Nulliparous | 9177 (18.1) | 6863 (19.9) | 810 (11.6) | 1504 (16.4) |
| Parous, never | 12 641 (25.0) | 7197 (20.9) | 2465 (35.4) | 2979 (32.6) |
| Parous, ever | 28 813 (56.9) | 20 455 (59.3) | 3696 (53.0) | 4662 (51.0) |
| Menopausal status, No. (%) | ||||
| Premenopausal | 16 974 (33.5) | 14 588 (42.2) | 2386 (34.2) | 0 (0.0) |
| Postmenopausal | 33 712 (66.5) | 19 962 (57.8) | 4592 (65.8) | 9158 (100.0) |
| Hormone therapy, No. (%) | ||||
| Never user | 29 086 (57.5) | 24 077 (69.8) | 3209 (46.1) | 1800 (19.7) |
| Estrogen only user | 10 011 (19.8) | 1414 (4.1) | 3108 (44.7) | 5489 (60.1) |
| Estrogen plus progestin user | 11 463 (22.7) | 8986 (26.1) | 638 (9.2) | 1839 (20.1) |
Includes women with hysterectomy (n = 8903) or without hysterectomy (n = 258); missing: body mass index (10 no surgery, 1 hysterectomy only, 5 bilateral oophorectomy), race and ethnicity (9 no surgery, 4 hysterectomy only, 2 bilateral oophorectomy), education (8 no surgery, 2 hysterectomy only, 2 bilateral oophorectomy), family history of breast cancer (1 no surgery), alcohol consumption (56 no surgery, 13 hysterectomy only, 18 bilateral oophorectomy), smoking status (11 no surgery, 2 hysterectomy only, 3 bilateral oophorectomy), hormonal birth control (169 no surgery, 37 hysterectomy only, 67 bilateral oophorectomy), age at menarche (28 no surgery, 5 hysterectomy only, 12 bilateral oophorectomy), parity (23 no surgery, 3 hysterectomy only, 7 bilateral oophorectomy), age at first pregnancy (67 no surgery, 12 hysterectomy only, 14 bilateral oophorectomy), breastfeeding (45 no surgery, 9 hysterectomy only, 16 bilateral oophorectomy), menopausal status (10 no surgery, 2 hysterectomy only, 3 bilateral oophorectomy), and hormone therapy (83 no surgery, 25 hysterectomy only, 33 bilateral oophorectomy).
Baseline characteristics by incident breast cancer are shown in Supplementary Table 1 (available online), and race- and ethnicity-stratified comparisons are presented in Supplementary Table 2 (available online). Non-Hispanic White women were more likely to have received combination therapy, and women categorized as “Other” race and ethnicity were more likely to have received estrogen only therapy. Hispanic or Latina women and Non-Hispanic Black women were more likely to receive hysterectomy only compared with non-Hispanic White women. We also explored characteristics by select gynecologic surgery and hormone therapy combinations considered atypical or contraindicated to obtain a better sense of participant profiles (Supplementary Table 3, available online). For example, we do not see strong differences by race and ethnicity among women reporting no surgery and estrogen only therapy.
Regarding the timing of hormone therapy initiation at baseline, many women in our sample (47.6%) started hormone therapy at the same age of gynecologic surgery (hysterectomy only or bilateral oophorectomy). Of the remaining women, 31.9% initiated hormone therapy after surgery and 20.5% initiated hormone therapy before surgery. Among women with bilateral oophorectomy and estrogen only therapy, 71.1% initiated hormone therapy at the same age of surgery. For women with hysterectomy only and estrogen plus progestin, 31.8% initiated hormone therapy before surgery.
After excluding participants with missing covariate data among the eligible sample (n = 698), there were 3948 diagnoses of invasive breast cancer or DCIS over 541 711 person-years during follow-up (median = 11.4 years) (Table 2). In adjusted models with no surgery as the referent, having a bilateral oophorectomy was inversely associated with breast cancer incidence (HR = 0.91, 95% CI = 0.83 to 1.00) while having a hysterectomy only was positively associated with disease (HR = 1.12, 95% CI = 1.02 to 1.23). When considering menopause status at time of surgery, women with postmenopausal hysterectomy had increased breast cancer rates compared with women with no surgery (HR = 1.32, 95% CI = 0.97 to 1.80). The hazard ratio was elevated for women with premenopausal hysterectomy but was attenuated (HR = 1.09, 95% CI = 0.99 to 1.20). Risks associated with bilateral oophorectomy did not vary by menopausal status at time of surgery. There were no violations of the proportional hazards assumption.
Table 2.
Association between time-varying gynecologic surgery and incident breast cancer
| Gynecologic Surgerya | Noncases, No. (%)b | Cases, No. (%)b | Person-time (years)c | HR (95% CI) |
|---|---|---|---|---|
| Overall | ||||
| No surgery | 31 420 (68.2) | 2703 (68.5) | 356 236 | 1.00 |
| Hysterectomy only | 6276 (13.6) | 601 (15.2) | 77 400 | 1.12 (1.02 to 1.23) |
| Bilateral oophorectomyd | 8359 (18.2) | 644 (16.3) | 108 075 | 0.91 (0.83 to 1.00) |
| Menopause status at time of surgerye | ||||
| No surgery | 31 420 (68.3) | 2703 (68.6) | 358 709 | 1.00 |
| Premenopausal, hysterectomy only | 6048 (13.2) | 571 (14.5) | 70 952 | 1.09 (0.99 to 1.20) |
| Postmenopausal, hysterectomy only | 209 (0.5) | 26 (0.7) | 3884 | 1.32 (0.97 to 1.80) |
| Premenopausal, bilateral oophorectomyd | 7194 (15.6) | 545 (13.8) | 88 416 | 0.90 (0.81 to 1.01) |
| Postmenopausal, bilateral oophorectomyd | 1115 (2.4) | 95 (2.4) | 19 007 | 0.92 (0.77 to 1.09) |
| Hormone therapy stratified estimates | ||||
| No hormone therapy | ||||
| No surgery | 22 065 (47.9) | 1776 (45.0) | 216 876 | 1.00 |
| Hysterectomy only | 2924 (6.3) | 250 (6.3) | 31 366 | 1.08 (0.94 to 1.23) |
| Bilateral oophorectomyd | 1649 (3.6) | 122 (3.1) | 19 454 | 0.95 (0.80 to 1.14) |
| Estrogen only hormone therapy | ||||
| No surgery | 1290 (2.8) | 109 (2.8) | 36 058 | 0.89 (0.77 to 1.02) |
| Hysterectomy only | 2791 (6.1) | 283 (7.2) | 37 127 | 1.03 (0.90 to 1.17) |
| Bilateral oophorectomyd | 5046 (11.0) | 374 (9.5) | 62 895 | 0.83 (0.74 to 0.94) |
| Estrogen plus progestin hormone therapy | ||||
| No surgery | 8065 (17.5) | 818 (20.7) | 103 302 | 1.03 (0.94 to 1.13) |
| Hysterectomy only | 561 (1.2) | 68 (1.7) | 8907 | 1.25 (1.01 to 1.55) |
| Bilateral oophorectomyd | 1664 (3.6) | 148 (3.7) | 25 726 | 0.89 (0.76 to 1.05) |
CI = confidence interval; HR = hazard ratio. Adjusted for race and ethnicity (Non-Hispanic White, Non-Hispanic Black, Hispanic or Latina, Other), education (high school or less, some college or technical degree, bachelor’s degree, graduate degree), family history of breast cancer (1 sister or half-sister, ≥2 first-degree relatives), alcohol consumption (time-varying; nondrinker, drinker <7 drinks per week, drinker ≥7 drinks per week), smoking status (time-varying; never, former, current), body mass index (time-varying; continuous), hormonal birth control (time-varying; never or ever), age at menarche (≤11 years, 12-13 years, ≥14 years), parity (time-varying; nulliparous, 1 birth, 2 births, ≥3 births), age at first pregnancy (time-varying; nulligravid, ≤20 years, 21-29 years, ≥30 years), breastfeeding (time-varying; nulliparous, parous never, parous ever), menopause status (time-varying; premenopausal, postmenopausal), and hormone therapy (time-varying; never, estrogen only, estrogen plus progestin).
Based on gynecologic surgery and hormone therapy at baseline.
Incorporates time-varying gynecologic surgery, menopause status, and hormone therapy status.
Includes women with or without hysterectomy; missing menopause status at time of surgery for 77 women.
Defined based on self-reported age of first gynecologic surgery (hysterectomy only vs bilateral oophorectomy) and age of last menstrual period.
We also investigated how incident breast cancer was associated with combinations of gynecologic surgery and hormone therapy, comparing everyone with the common referent group of no surgery and no hormone therapy (Table 2). The inverse association between bilateral oophorectomy and breast cancer was comparable for women taking estrogen only therapy (HR = 0.83, 95% CI = 0.74 to 0.94) and women with estrogen plus progestin therapy (HR = 0.89, CI = 0.76 to 1.05). When we explored additive interaction, there was no clear joint effect of bilateral oophorectomy and estrogen only therapy on breast cancer incidence (RERI = 0.00, 95% CI = −0.21 to 0.22).
In an analysis stratified by hormone use, compared with a common referent of no surgery and no hormone therapy, an association between hysterectomy and breast cancer was most apparent among women who also reported use of combined estrogen plus progestin therapy (HR = 1.25, 95% CI = 1.01 to 1.55; Table 2). The hazard ratio for hysterectomy was 1.08 (95% CI = 0.94 to 1.23) for those who did not use hormones and 1.03 (95% CI = 0.90 to 1.17) among those who also used estrogen only therapy. The estimated joint effect on the additive scale of having a hysterectomy and receiving combination therapy was larger than the estimated effects of no hysterectomy and no combination therapy (RERI = 0.12, 95% CI = −0.20 to 0.43).
Similar results were observed when the sample was restricted to postmenopausal person-time only (Supplementary Table 4, available online) and when cases excluded DCIS (Supplementary Table 5, available online). We also saw no evidence of heterogeneity in the stratified analyses by race and ethnicity, family history, or BMI (Table 3). Bilateral oophorectomy was possibly associated with increased risk of ER+ breast cancer (Pheterogeneity = .10). We observed no differences by tumor invasiveness.
Table 3.
Stratified adjusteda hazard ratios of association between time-varying gynecologic surgeryb and breast cancer risk
| Hysterectomy only |
Bilateral oophorectomyc |
|||
|---|---|---|---|---|
| Cases (n = 601)d | HR (95% CI) | Cases (n = 644)d | HR (95% CI) | |
| Race and ethnicitye | ||||
| Non-Hispanic White | 478 | 1.12 (1.00 to 1.24) | 547 | 0.91 (0.83 to 1.01) |
| Non-Hispanic Black | 79 | 1.22 (0.92 to 1.61) | 54 | 0.94 (0.67 to 1.33) |
| Hispanic/Latina | 28 | 1.23 (0.80 to 1.88) | 24 | 1.02 (0.64 to 1.62) |
| Pheterogeneityf | .96 | |||
| Family history of breast cancer | ||||
| 1 sister/half sister | 394 | 1.17 (1.04 to 1.32) | 407 | 0.98 (0.87 to 1.10) |
| ≥2 first-degree relatives | 207 | 1.04 (0.88 to 1.22) | 237 | 0.81 (0.69 to 0.94) |
| Pheterogeneityf | .10 | |||
| Body mass index, kg/m2 | ||||
| >30 | 389 | 1.16 (1.04 to 1.31) | 395 | 0.92 (0.82 to 1.03) |
| <30 | 212 | 1.04 (0.88 to 1.22) | 249 | 0.87 (0.74 to 1.02) |
| Pheterogeneityf | .46 | |||
| ER status | ||||
| ER+ | 428 | 1.01 (0.91 to 1.12) | 447 | 1.07 (0.96 to 1.18) |
| ER− | 78 | 0.94 (0.72 to 1.22) | 104 | 0.90 (0.72 to 1.14) |
| Pheterogeneityf | .10 | |||
| Invasiveness | ||||
| Invasive | 471 | 0.96 (0.87 to 1.06) | 502 | 1.07 (0.97 to 1.18) |
| DCIS | 130 | 1.10 (0.91 to 1.33) | 142 | 0.99 (0.82 to 1.19) |
| Pheterogeneityf | .69 | |||
CI = confidence interval; DCIS = ductal carcinoma in situ; ER = estrogen receptor; HR = hazard ratio. Adjusted for race and ethnicity (Non-Hispanic White, Non-Hispanic Black, Hispanic and Latina, Other), attained education (high school or less, some college or technical degree, bachelor’s degree, graduate degree), family history of breast cancer (1 sister or half-sister, ≥2 first-degree relatives), alcohol consumption (time-varying; nondrinker, drinker <7 drinks per week, drinker ≥7 drinks per week), smoking status (time-varying; never, former, current), body mass index (time-varying; continuous), hormonal birth control (time-varying; never/ever), age at menarche (≤11 years, 12-13 years, ≥14 years), parity (time-varying; nulliparous, 1 birth, 2 births, ≥3 births), age at first pregnancy (time-varying; nulligravid, ≤20 years, 21-29 years, ≥30 years), breastfeeding (time-varying; nulliparous, parous never, parous ever), menopause status (time-varying; premenopausal, postmenopausal), and hormone therapy (time-varying; never, estrogen only, estrogen plus progestin).
Reference group is no surgery (ie, no hysterectomy only or bilateral oophorectomy).
Includes women with or without hysterectomy.
Based on gynecologic surgery and hormone therapy at baseline.
Women reporting a race and ethnicity other than Non-Hispanic White, Non-Hispanic Black, or Hispanic and Latina not included.
Heterogeneity P values are from Wald tests of the gynecologic surgery-by covariate interaction term(s), where the covariate is the stratification factor (race and ethnicity, family history of breast cancer, body mass index) or the breast cancer subtype (ER+/−, invasive or DCIS) of interest.
Discussion
We observed an inverse association between bilateral oophorectomy (with or without hysterectomy) and incident breast cancer, especially with estrogen only therapy. The association of hysterectomy with breast cancer incidence was more apparent among women reporting combination therapy. Although non-Hispanic Black women were more likely to have hysterectomy and less likely to take hormone therapy compared with non-Hispanic White women, stratum-specific analyses did not reveal racial and ethnic differences with breast cancer incidence. We also did not see clear evidence of heterogeneity by breast cancer family history or BMI.
Our finding that bilateral oophorectomy is inversely associated with breast cancer is consistent with several studies (5-7,30-32). However, some studies have reported that incident breast cancer and bilateral oophorectomy have no association (33-35). These studies often examine bilateral oophorectomy in accompaniment with another surgery (eg, salpingo-oophorectomy), denote hysterectomy alone as the referent instead of no surgery, and/or exclusively investigate these associations among special populations such as BRCA mutation carriers or postmenopausal women. A potential explanation for our finding is that women who undergo a bilateral oophorectomy have reduced levels of estrogen (36,37). Because estrogen stimulates breast cell growth and can increase breast cancer risk over time (38), high levels are considered an established risk factor for breast cancer. Therefore, a surgery that greatly reduces estrogen could plausibly reduce risk. However, there are also known health consequences of abrupt hormone withdrawal and estrogen deficiency (36,37,39). Women having a bilateral oophorectomy followed by estrogen only therapy may retain some of the protective effects of surgery while also safely replacing some of the lost estrogen critical for other biological functions. Other considerations involve differences in dosage and the type of estrogen used in hormone therapy compared with major estrogens released by ovaries (eg, estradiol, estrone, estriol) or other hormones. In addition, less than 1.0% of all Sister Study participants and only 1.1% of women with bilateral oophorectomy report prophylactic mastectomy, which is important because women with strong family history of breast cancer and BRCA mutations may decide to undergo prophylactic oophorectomy.
We observed positive associations between breast cancer risk and having hysterectomy only, though conflicting evidence of no association or an inverse association has been observed in other studies (2,5,6,31,40). Hysterectomy alone, leaving at least some ovarian tissue intact, allows the continued production of estrogen and progesterone. Women who undergo a hysterectomy before menopause may experience fluctuations in hormone levels, which have previously been linked to early ovarian failure, reduced ovarian blood flow, modified ovulation, and differential menopausal symptoms (41-44) and could plausibly affect breast cancer risk. Comorbid conditions that precede a hysterectomy could also cause hormonal imbalances that affect breast cancer risk.
Although there was a small risk of breast cancer associated with hysterectomy among those with no hormone therapy, this risk was more apparent among those with estrogen plus progestin therapy. This observation is consistent with the well-supported hypothesis that combination therapy is a risk factor for breast cancer (24,45-49). Progestin could be a driving factor, including through its potential interaction with other hormones (eg, androgens, prolactin), the procarcinogenic and anticarcinogenic effects of progestin metabolites, or the signaling actions of the progesterone receptor (50). Because progestin is usually not recommended after hysterectomy (when unopposed estrogen can be prescribed), this coexposure is rare (1.3% of our sample) and therefore not widely studied.
Our focus was the impact of gynecologic surgeries on breast cancer risk, which cannot be fully evaluated without additional exploration of hormone therapy use. Although this study primarily evaluates hormone therapy as an effect modifier, our findings are mostly compatible with prior observational studies (51,52) that report estrogen only therapy may be protective while combination therapy is associated with increased breast cancer risk. Furthermore, the magnitude of the association between hormone therapy (when operationalized as an exposure) and breast cancer may vary by age at initiation and duration of use (6,45,52,53), with some studies reporting estrogen only therapy does not remain protective with long-term use (eg, 15 years, ≥20 years) with and without adjustment for gynecologic surgery (51-53).
A major strength of this study was that we considered type of gynecologic surgery, menopause status at time of surgery, surgery modified by hormone therapy, and the joint effects of surgery and hormone therapy. Because data were collected at baseline and across 4 follow-up questionnaires, we were also able to account for changes in surgery and other covariates over time. Another strength is the prospective design, meaning women were asked about surgery and other factors before their diagnosis of breast cancer. Though a small proportion of the cohort, we included a large sample of non-Hispanic Black and Hispanic or Latina women, which enabled exploration by race and ethnicity. Overall, the Sister Study cohort is large, has high retention, and has accurate self-reported data on breast cancer, ensuring high internal validity.
One limitation is the possibility of nondifferential exposure misclassification with respect to the outcome because women were asked to recall their gynecologic surgery type and age from potentially many years prior. Women eligible for the cohort have family history of breast cancer, which may decrease its generalizability. However, we did not observe strong heterogeneity in risks by degree of family history. Participants were also predominantly non-Hispanic White and well educated. Low statistical power in the stratum-specific analyses should also be considered a limitation.
Future research should investigate the association of breast cancer risk with type and timing of other gynecologic surgeries not yet widely studied, including salpingectomies, which are becoming more common. As documented by 1 study, salpingectomies increased by 77.0% in 2013 compared with 2000, while other gynecologic surgery types trended downwards (54). This paradigm shift can be partially explained by the Society of Gynecologic Oncology’s recognition of salpingectomies as a feasible strategy for reducing ovarian cancer risk, especially if completed at the same time as another abdominal or pelvic surgery (55-59).
Additional studies may also consider further exploring the impact of hormone use in relation to duration and start of use since surgery to better assess the “timing hypothesis” because there is growing evidence to suggest the time between menopause and the start of hormone therapy is important (6,60). Other considerations involve the prescribing of hormone therapy postsurgery for women already using exogenous hormones for the prevention or treatment of chronic conditions. Clinical changes in hormone therapy prescribing that follow reports from the Women’s Health Initiative citing increased breast cancer risk with certain treatments (46-49,61,62) may also be worth further exploration. Lastly, more studies should examine racial and ethnic differences in gynecologic surgery and hormone therapy use to understand the full impacts of such disparities.
Bilateral oophorectomy with or without estrogen only therapy was associated with reduced breast cancer risk, but hysterectomy alone was associated with increased risk, especially when estrogen plus progestin was used. Though we saw descriptive differences in gynecologic surgery by race and ethnicity, there was limited evidence of heterogeneity in the estimated associations. Findings from this study provide insight into how providers and patients might approach decision-making about gynecologic surgery in light of differing risk of breast cancer as well as how they might consider the pros and cons of subsequent hormone therapy. Future research is needed to address more specific questions about how different types of gynecologic surgeries and hormone therapy use patterns may affect breast cancer risk.
Supplementary Material
Acknowledgements
We thank Dr. Quaker Harmon and Jordan Zeldin (National Institute of Environmental Health Sciences) for their comments on an earlier draft of this manuscript.
The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; writing of the manuscript; preparation of the manuscript; and decision to submit the manuscript for publication.
Findings related to this manuscript were presented at the 2022 Society for Epidemiologic Research (SER) Conference in Chicago, IL via poster presentation.
Contributor Information
Sharonda M Lovett, Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
Dale P Sandler, Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Katie M O’Brien, Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Data availability
Data used in this manuscript are available as described on the Sister Study website (The Sister Study: Collaborations and Data Requests, nih.gov) or by request via the Sister Study tracking and review system (www.sisterstudystars.org; registration required). Computing code can be requested from the corresponding author.
Author contributions
Sharonda M. Lovett, MPH (Conceptualization; Formal analysis; Investigation; Methodology; Writing – original draft; Writing – review & editing), Dale P. Sandler, PhD, MPH (Conceptualization; Data curation; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Writing – review & editing), Katie M. O’Brien, PhD, MSPH (Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Supervision; Writing – review & editing). All authors approved the final manuscript and agreed to be accountable for all aspects of the work.
Funding
This work was funded by the Intramural Research Program at the National Institutes of Health, National Institute of Environmental Health Sciences (Z01-ES044005 to DPS).
Conflicts of interest
The authors (SML, DPS, KMO) have no conflicts to disclose.
References
- 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A.. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi: 10.3322/caac.21492. [DOI] [PubMed] [Google Scholar]
- 2. Woolcott CG, Maskarinec G, Pike MC, Henderson BE, Wilkens LR, Kolonel LN.. Breast cancer risk and hysterectomy status: the Multiethnic Cohort Study. Cancer Causes Control. 2009;20(5):539-547. doi: 10.1007/s10552-008-9262-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Terry MB, Daly MB, Phillips KA, et al. Risk-reducing oophorectomy and breast cancer risk across the spectrum of familial risk. J Natl Cancer Inst. 2019;111(3):331-334. doi: 10.1093/jnci/djy182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Chow S, Raine-Bennett T, Samant ND, Postlethwaite DA, Holzapfel M.. Breast cancer risk after hysterectomy with and without Salpingo-oophorectomy for benign indications. Am J Obstet Gynecol. 2020;223(6):900e1-900e7. doi: 10.1016/j.ajog.2020.06.040. [DOI] [PubMed] [Google Scholar]
- 5. Robinson WR, Nichols HB, Tse CK, Olshan AF, Troester MA.. Associations of premenopausal hysterectomy and oophorectomy with breast cancer among black and white women: The Carolina Breast Cancer Study, 1993-2001. Am J Epidemiol. 2016;184(5):388-399. doi: 10.1093/aje/kwv448. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Nichols HB, Trentham-Dietz A, Newcomb PA, et al. Postoophorectomy estrogen use and breast cancer risk. Obstet Gynecol. 2012;120(1):27-36. doi: 10.1097/AOG.0b013e31825a717b. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Boggs DA, Palmer JR, Rosenberg L.. Bilateral oophorectomy and risk of cancer in African American women. Cancer Causes Control. 2014;25(4):507-513. doi: 10.1007/s10552-014-0353-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Bower JK, Schreiner PJ, Sternfeld B, Lewis CE.. Black-White differences in hysterectomy prevalence: the CARDIA study. Am J Public Health. 2009;99(2):300-307. doi: 10.2105/AJPH.2008.133702. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Mikhail E, Salemi JL, Mogos MF, Hart S, Salihu HM, Imudia AN.. National trends of adnexal surgeries at the time of hysterectomy for benign indication, United States, 1998-2011. Am J Obstet Gynecol. 2015;213(5):713.e1-713.e13. doi: 10.1016/j.ajog.2015.04.031. [DOI] [PubMed] [Google Scholar]
- 10. Wright MA, Doll KM, Myers E, Carpenter WR, Gartner DR, Robinson WR.. Changing trends in Black-White racial differences in surgical menopause: a population-based study. Am J Obstet Gynecol. 2021;225(5):502.e1-502.e13. doi: 10.1016/j.ajog.2021.05.045. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Moore BJ, Steiner CA, Davis PH, Stocks C, Barrett ML. Trends in hysterectomies and oophorectomies in hospital inpatient and ambulatory settings. 2005-2013: statistical brief #214. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. 2006. https://hcup-us.ahrq.gov/reports/statbriefs/sb214-Hysterectomy-Oophorectomy-Trends.jsp. Accessed July 25, 2022.
- 12. Brett KM, Higgins JA.. Hysterectomy prevalence by Hispanic ethnicity: evidence from a national survey. Am J Public Health. 2003;93(2):307-312. doi: 10.2105/ajph.93.2.307. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Powell LH, Meyer P, Weiss G, et al. Ethnic differences in past hysterectomy for benign conditions. Womens Health Issues. 2005;15(4):179-186. doi: 10.1016/j.whi.2005.05.002. [DOI] [PubMed] [Google Scholar]
- 14. Jacoby VL, Fujimoto VY, Giudice LC, Kuppermann M, Washington AE.. Racial and ethnic disparities in benign gynecologic conditions and associated surgeries. Am J Obstet Gynecol. 2010;202(6):514-521. doi: 10.1016/j.ajog.2010.02.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Lewis CE, Groff JY, Herman CJ, McKeown RE, Wilcox LS.. Overview of women's decision making regarding elective hysterectomy, oophorectomy, and hormone replacement therapy. J Womens Health Gend Based Med. 2000;9(Suppl 2):S5-S14. doi: 10.1089/152460900318722 [DOI] [PubMed] [Google Scholar]
- 16. Bhavnani V, Clarke A.. Women awaiting hysterectomy: a qualitative study of issues involved in decisions about oophorectomy. BJOG Int J Obs Gyn. 2003;110(2):168-174. [PubMed] [Google Scholar]
- 17. Baird DD, Patchel SA, Saldana TM, et al. Uterine fibroid incidence and growth in an ultrasound-based, prospective study of young African Americans. Am J Obstet Gynecol. 2020;223(3):402.e1-402.e18. doi: 10.1016/j.ajog.2020.02.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM.. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003;188(1):100-107. doi: 10.1067/mob.2003.99. [DOI] [PubMed] [Google Scholar]
- 19. Eltoukhi HM, Modi MN, Weston M, Armstrong AY, Stewart EA.. The health disparities of uterine fibroid tumors for African American women: a public health issue. Am J Obstet Gynecol. 2014;210(3):194-199. doi: 10.1016/j.ajog.2013.08.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Practice Bulletin No. 149: endometrial cancer. Obstet Gynecol. 2015;125(4):1006-1026. doi: 10.1097/01.AOG.0000462977.61229.de. [DOI] [PubMed] [Google Scholar]
- 21. Brown AF, Perez-Stable EJ, Whitaker EE, et al. Ethnic differences in hormone replacement prescribing patterns. J Gen Intern Med. 1999;14(11):663-669. doi: 10.1046/j.1525-1497.1999.10118.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Sandler DP, Hodgson ME, Deming-Halverson SL, et al. ; Sister Study Research Team. The Sister Study cohort: baseline methods and participant characteristics. Environ Health Perspect. 2017;125(12):127003. doi: 10.1289/EHP1923. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Collaborative Group on Hormonal Factors in Breast Cancer. Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet. 2001;358(9291):1389-1399. doi: 10.1016/S0140-6736(01)06524-2 [DOI] [PubMed] [Google Scholar]
- 24. Reeves GK, Pirie K, Green J, Bull D, Beral V; Million Women Study Collaborators. Comparison of the effects of genetic and environmental risk factors on in situ and invasive ductal breast cancer. Int J Cancer. 2012;131(4):930-937. doi: 10.1002/ijc.26460. [DOI] [PubMed] [Google Scholar]
- 25. Virnig BA, Tuttle TM, Shamliyan T, Kane RL.. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 2010;102(3):170-178. doi: 10.1093/jnci/djp482. [DOI] [PubMed] [Google Scholar]
- 26. D’Aloisio AA, Nichols HB, Hodgson ME, Deming-Halverson SL, Sandler DP.. Validity of self-reported breast cancer characteristics in a nationwide cohort of women with a family history of breast cancer. BMC Cancer. 2017;17(1):692. doi: 10.1186/s12885-017-3686-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Li R, Chambless L.. Test for additive interaction in proportional hazards models. Ann Epidemiol. 2007;17(3):227-236. doi: 10.1016/j.annepidem.2006.10.009. [DOI] [PubMed] [Google Scholar]
- 28. Knol MJ, VanderWeele TJ.. Recommendations for presenting analyses of effect modification and interaction. Int J Epidemiol. 2012;41(2):514-520. doi: 10.1093/ije/dyr218. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Xue X, Kim MY, Gaudet MM, et al. A comparison of the polytomous logistic regression and joint Cox proportional hazards models for evaluating multiple disease subtypes in prospective cohort studies. Cancer Epidemiol Biomarkers Prev. 2013;22(2):275-285. doi: 10.1158/1055-9965.EPI-12-1050. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Parker WH, Broder MS, Chang E, et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses' Health Study. Obstet Gynecol. 2009;113(5):1027-1037. doi: 10.1097/AOG.0b013e3181a11c64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Parazzini F, Braga C, La Vecchia C, Negri E, Acerboni S, Franceschi S.. Hysterectomy, oophorectomy in premenopause, and risk of breast cancer. Obstet Gynecol. 1997;90(3):453-456. doi: 10.1016/s0029-7844(97)00295-0. [DOI] [PubMed] [Google Scholar]
- 32. Schairer C, Persson I, Falkeborn M, Naessen T, Troisi R, Brinton LA.. Breast cancer risk associated with gynecologic surgery and indications for such surgery. Int J Cancer. 1997;70(2):150-154. doi:. [DOI] [PubMed] [Google Scholar]
- 33. Jacoby VL, Grady D, Wactawski-Wende J, et al. Oophorectomy vs ovarian conservation with hysterectomy: cardiovascular disease, hip fracture, and cancer in the Women's Health Initiative Observational Study. Arch Intern Med. 2011;171(8):760-768. doi: 10.1001/archinternmed.2011.121. [DOI] [PubMed] [Google Scholar]
- 34. Kotsopoulos J, Huzarski T, Gronwald J, et al. ; The Hereditary Breast Cancer Clinical Study Group. Bilateral oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2017;109(1):djw177. doi: 10.1093/jnci/djw177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Mavaddat N, Antoniou AC, Mooij TM, et al. ; BCFR. Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. 2020;22(1):8. doi: 10.1186/s13058-020-1247-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Shuster LT, Gostout BS, Grossardt BR, Rocca WA.. Prophylactic oophorectomy in premenopausal women and long-term health. Menopause Int. 2008;14(3):111-116. doi: 10.1258/mi.2008.008016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Sarrel PM, Sullivan SD, Nelson LM.. Hormone replacement therapy in young women with surgical primary ovarian insufficiency. Fertil Steril. 2016;106(7):1580-1587. doi: 10.1016/j.fertnstert.2016.09.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Simoes BM, Vivanco MD.. Cancer stem cells in the human mammary gland and regulation of their differentiation by estrogen. Future Oncol. 2011;7(8):995-1006. doi: 10.2217/fon.11.80. [DOI] [PubMed] [Google Scholar]
- 39. Challberg J, Ashcroft L, Lalloo F, et al. Menopausal symptoms and bone health in women undertaking risk reducing bilateral salpingo-oophorectomy: significant bone health issues in those not taking HRT. Br J Cancer. 2011;105(1):22-27. doi: 10.1038/bjc.2011.202. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Irwin KL, Lee NC, Peterson HB, Rubin GL, Wingo PA, Mandel MG.. Hysterectomy, tubal sterilization, and the risk of breast cancer. Am J Epidemiol. 1988;127(6):1192-1201. doi: 10.1093/oxfordjournals.aje.a114912. [DOI] [PubMed] [Google Scholar]
- 41. Chan CC, Ng EH, Ho PC.. Ovarian changes after abdominal hysterectomy for benign conditions. J Soc Gynecol Investig. 2005;12(1):54-57. doi: 10.1016/j.jsgi.2004.07.004. [DOI] [PubMed] [Google Scholar]
- 42. Souza AZ, Fonseca AM, Izzo VM, Clauzet RM, Salvatore CA.. Ovarian histology and function after total abdominal hysterectomy. Obstet Gynecol. 1986;68(6):847-849. [PubMed] [Google Scholar]
- 43. Hartmann BW, Kirchengast S, Albrecht A, Metka M, Huber JC.. Hysterectomy increases the symptomatology of postmenopausal syndrome. Gynecol Endocrinol. 1995;9(3):247-252. doi: 10.3109/09513599509160453. [DOI] [PubMed] [Google Scholar]
- 44. Janson PO, Jansson I.. The acute effect of hysterectomy on ovarian blood flow. Am J Obstet Gynecol. 1977;127(4):349-352. doi: 10.1016/0002-9378(77)90488-4. [DOI] [PubMed] [Google Scholar]
- 45. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997;350(9084):1047-1059. [PubMed] [Google Scholar]
- 46. Rossouw JE, Anderson GL, Prentice RL, et al. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333. doi: 10.1001/jama.288.3.321. [DOI] [PubMed] [Google Scholar]
- 47. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women's Health Initiative randomized clinical trials. JAMA. 2020;324(4):369-380. doi: 10.1001/jama.2020.9482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48. Chlebowski RT, Hendrix SL, Langer RD, et al. ; WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA. 2003;289(24):3243-3253. doi: 10.1001/jama.289.24.3243 [DOI] [PubMed] [Google Scholar]
- 49. Chlebowski RT, Rohan TE, Manson JE, et al. Breast cancer after use of estrogen plus progestin and estrogen alone: analyses of data from two Women's Health Initiative randomized clinical trials. JAMA Oncol. 2015;1(3):296-305. doi: 10.1001/jamaoncol.2015.0494. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50. Trabert B, Sherman ME, Kannan N, Stanczyk FZ.. Progesterone and breast cancer. Endocr Rev. 2020;41(2):320-344. doi: 10.1210/endrev/bnz001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R.. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA. 2000;283(4):485-491. doi: 10.1001/jama.283.4.485. [DOI] [PubMed] [Google Scholar]
- 52. Ross RK, Paganini-Hill A, Wan PC, Pike MC.. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst. 2000;92(4):328-332. doi: 10.1093/jnci/92.4.328. [DOI] [PubMed] [Google Scholar]
- 53. Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med. 2006;166(9):1027-1032. doi: 10.1001/archinte.166.9.1027. [DOI] [PubMed] [Google Scholar]
- 54. Hicks-Courant KD. Growth in salpingectomy rates in the United States since 2000. Am J Obstet Gynecol. 2016;215(5):666-667. doi: 10.1016/j.ajog.2016.07.055. [DOI] [PubMed] [Google Scholar]
- 55. ACOG Committee Opinion No. 774. Opportunistic salpingectomy as a strategy for epithelial ovarian cancer prevention. Obstet Gynecol. 2019;133(4):e279-e284. doi: 10.1097/AOG.0000000000003164 [DOI] [PubMed] [Google Scholar]
- 56. Walker JL, Powell CB, Chen LM, et al. Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer. Cancer. 2015;121(13):2108-2120. doi: 10.1002/cncr.29321 [DOI] [PubMed] [Google Scholar]
- 57. Society of Gynecologic Oncology. SGO Clinical Practice Statement: salpingectomy for ovarian cancer prevention. https://www.sgo.org/resources/sgo-clinical-practice-statement-salpingectomy-for-ovarian-cancer-prevention/. Accessed July 25, 2022.
- 58. Mandelbaum RS, Adams CL, Yoshihara K, et al. The rapid adoption of opportunistic salpingectomy at the time of hysterectomy for benign gynecologic disease in the United States. Am J Obstet Gynecol. 2020;223(5):721.e1-721.e18. doi: 10.1016/j.ajog.2020.04.028. [DOI] [PubMed] [Google Scholar]
- 59. Mandelbaum RS, Matsuzaki S, Sangara RN, et al. Paradigm shift from tubal ligation to opportunistic salpingectomy at cesarean delivery in the United States. Am J Obstet Gynecol. 2021;225(4):399.e1-399.e32. doi: 10.1016/j.ajog.2021.06.074. [DOI] [PubMed] [Google Scholar]
- 60. Hodis HN, Mack WJ.. The timing hypothesis and hormone replacement therapy: a paradigm shift in the primary prevention of coronary heart disease in women. Part 2: comparative risks. J Am Geriatr Soc. 2013;61(6):1011-1018. doi: 10.1111/jgs.12281. [DOI] [PubMed] [Google Scholar]
- 61. Chlebowski RT, Anderson GL.. Changing concepts: menopausal hormone therapy and breast cancer. J Natl Cancer Inst. 2012;104(7):517-527. doi: 10.1093/jnci/djs014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62. Chlebowski RT, Anderson G, Manson JE, et al. Estrogen alone in postmenopausal women and breast cancer detection by means of mammography and breast biopsy. J Clin Oncol. 2010;28(16):2690-2697. doi:10.1200/J Clin Oncol.2009.24.8799. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data used in this manuscript are available as described on the Sister Study website (The Sister Study: Collaborations and Data Requests, nih.gov) or by request via the Sister Study tracking and review system (www.sisterstudystars.org; registration required). Computing code can be requested from the corresponding author.