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The US Collaborative Review of Sterilization reported reduced menstrual bleeding and pain and increased cycle irregularity after tubal ligation (Peterson et al, 2000). These findings provided evidence against a ‘post-tubal ligation syndrome’ that included dysmenorrhoea and menorrhagia, but could not address long-term outcomes, such as altered menopausal age (Pokoradi et al, 2011), symptoms (Whiteman et al, 2004; Wyshak, 2004; Nelson et al, 2005), or breast cancer risk.

A recent meta-analysis reported no association between tubal ligation and breast cancer (RR=0.97); however, substantial heterogeneity between studies (I2=82.2%, P<0.001) was observed. Effect estimates among eight studies ranged from RR=0.37 (0.19, 0.68) to 1.20 (1.00, 1.30) (Gaudet et al, 2013). This variability may be partly due to incomplete information on subsequent gynaecologic surgeries and tumour subtypes. Women who have a tubal ligation are more likely to undergo hysterectomy (Hillis et al, 1998), which may include bilateral oophorectomy (Lowder et al, 2010), and thereby decrease breast cancer risk. Few studies have evaluated variation by tumours that express oestrogen receptor (ER) or progesterone receptor (PR) and may therefore be more sensitive to hormonal exposures (Eliassen et al, 2006; Press et al, 2011).

We studied tubal ligation in relation to menopausal age, symptoms, and ER/PR-defined breast cancer in the Sister Study.

Materials and Methods

The Sister Study is an ongoing prospective cohort of US women who have a sister who was diagnosed with breast cancer (Godfrey et al, 2013; Xu et al, 2013). During 2003–2009, 50 884 women aged 35–74 years completed baseline telephone interviews including reproductive and medical history. All participants are asked to return brief annual health updates and comprehensive biennial questionnaires. Incident breast cancers are initially self-reported and later confirmed by medical record review. Response rates have been ⩾94% over follow-up. This research was approved by the Institutional Review Boards of the National Institute of Environmental Health Sciences, NIH, and the Copernicus Group. All participants provided informed consent.

Participants reported ever having a tubal ligation and at what age. We excluded 274 women with missing information on tubal ligation or age at tubal ligation, a breast cancer diagnosis preceding enrolment or with unknown date, or who reported tubal ligation after hysterectomy or menopause. Also excluded were 296 women (0.6%) with missing race, education, body mass index, alcohol consumption, oral contraceptive (OC) use, age at menarche, age at first birth, parity, marital status, hysterectomy, or menopausal status. Records from 50 314 women were analysed.

Women reported ever having hot flashes and at what age, and whether they ever had ‘any other symptoms of menopause such as poor sleeping, night sweats, irritability, or depression’ (yes/no) and at what age. Women were considered menopausal after 12 months of amenorrhoea not due to pregnancy or breastfeeding. Age at menopause was defined as a woman’s age at last menstrual period.

Women who reported incident breast cancer were asked to provide diagnosis details and authorise the release of medical records. Approximately 10% declined medical record release or died before providing authorisation. Agreement was high between self-reports and medical records for ER status (95%) and invasiveness (81%) (Kim et al, 2011). When medical records were unavailable, self-reported data were used. At the time of this analysis, medical records were available for 77% of reported breast cancers.

Statistical analyses

Prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated from multivariate log-negative binomial regression. To evaluate tubal ligation in relation to menopausal characteristics, we calculated hazard ratios (HRs) and 95% CIs using Cox proportional hazards models. Women contributed person-time from the age of 30 years to the event of interest (menopause, hot flashes, other menopausal symptoms) or were censored at the age at interview, age at uterine ablation/embolisation, age at hysterectomy, age at oophorectomy, age at tamoxifen (for chemoprevention) initiation, age at ovarian cancer, or at the age of 60 years, whichever occurred first. Model covariates were selected a priori based on known associations with tubal ligation or menopausal characteristics. Final models adjusted for age at interview, race, education, marital status, body mass index (BMI) during ages 30–39 years, and two time-varying covariates: average number of daily cigarettes from the age of 30–60 years and average number of alcoholic drinks per week during each decade (1930s, 1940s, 1950s). In sensitivity analyses, we adjusted for parity and postmenopausal hormone use and stratified by OC use.

For breast cancer analyses, person-time was accrued from the age at study enrolment. In tumour subtype analyses, competing or undefined subtypes were censored at the date of diagnosis. Final models adjusted for the following covariates a priori as potential confounders: age (as the time scale), education, race, age at menarche, parity, OC use, age at first birth, age at last birth, BMI, and alcohol consumption at enrolment. In sensitivity analyses, we controlled for postmenopausal hormone use and stratified by mammography screening.

Results

Overall, 14 802 women (29.4%) reported having a tubal ligation (mean age=32.7 years; s.d.=5.5); prevalence was highest among women who reported lower education, African-American race, overweight to obese BMI, current cigarette smoking, ever OC use, younger age at first birth, and having ⩾2 births. Tubal ligation was also more prevalent among women who reported hysterectomy, postmenopausal hormone use, and mammography screening (Table 1).

Table 1 PRs and 95% CIs for tubal ligation
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Menopause

Women who had a tubal ligation were 9% more likely to report hot flashes (95% CI: 1.06–1.12) and 10% more likely to have other symptoms of menopause (e.g., poor sleeping, night sweats, irritability, depression) (95% CI: 1.07–1.13) compared with women who did not have a tubal ligation (Table 2). Among those reporting symptoms, 71% had both hot flashes and other symptoms. Risk of hot flashes did not vary by age at tubal ligation, although other menopausal symptoms appeared more frequent at older ages (HR 1.15: 95% CI: 1.11–1.20 for tubal ligation ⩾35 years vs HR 1.07; 95% CI: 1.03–1.11 for <35; Table 2). In analyses among women who never used OCs or additionally adjusted for parity or postmenopausal hormone use, the results were virtually unchanged (data not shown).

Table 2 HRs and 95% CIs for menopausal symptoms and menopause
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Breast cancer

During 203 141 person-years (mean=4.0 years), 1646 incident breast cancers were reported (1079 invasive, 422 in situ, 145 undefined). We observed no overall association between breast cancer and tubal ligation (HR 0.95; 95% CI: 0.85–1.06), or by timing of tubal ligation or subsequent gynaecologic surgery (Table 3).

Table 3 HRs and 95% CIs for breast cancer
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Oestrogen receptor/PR status was available for 95% of invasive breast tumours. The HR for ER+/PR+ invasive disease after tubal ligation was 0.84 (95% CI: 0.70–1.01). Compared with women who reported no tubal ligation, hysterectomy, or bilateral oophorectomy, those who reported tubal ligation and hysterectomy with bilateral oophorectomy had a 42% decreased risk of ER+/PR+ invasive breast cancer (HR=0.58; 95% CI: 0.38–0.89). Associations with ER+/PR+ invasive tumours were unchanged by adjustment for postmenopausal hormones (data not shown). Tubal ligation was not associated with ER−/PR− invasive breast cancer.

We observed an increased risk of in situ breast cancer associated with tubal ligation within the past 10 years (HR 2.12; 95% CI: 1.20–3.73). Among women who reported having a screening mammogram within 12 months of enrolment, this association was no longer statistically significant (HR 1.87; 95% CI: 0.96–3.62; Supplementary Table).

Discussion

Women who had a tubal ligation were ∼10% more likely to report menopausal symptoms. Tubal ligation did not alter menopausal age or overall breast cancer risk. We observed a decreased risk of ER+/PR+ invasive breast cancer associated with tubal ligation among women who also had a hysterectomy with bilateral oophorectomy.

In controlled studies, the majority report a higher prevalence of hot flashes among women with prior tubal ligation (Visvanathan and Wyshak, 2000; Whiteman et al, 2004; Wyshak, 2004). A study of 3650 postmenopausal women in the United Kingdom reported a 38% increase (95% CI: 1.02–1.87) in the odds of menopause before the age of 49 years among women who reported tubal ligation (Pokoradi et al, 2011); we did not observe an association between tubal ligation and menopausal age.

Our analysis is one of few to evaluate breast cancer risk according to ER/PR status (Eliassen et al, 2006; Press et al, 2011) or in situ disease. Previous studies were often unable to account for subsequent hysterectomy, which probably contributes to heterogeneity between reports (Gaudet et al, 2013). In our data, decreased breast cancer risk after tubal ligation appeared largely limited to women who also underwent bilateral oophorectomy and to hormonally responsive disease.

Strengths include our large sample and detailed reproductive and lifestyle information. We reconstructed life events from the age of 30 years to interview and used time-varying exposures. Limitations include potential misclassification based on self-reported information. However, in previous studies, hysterectomy and oophorectomy status have been reliably reported (Colditz et al, 1987; Phipps and Buist, 2009; Nichols et al, 2011). All exposure information was reported before diagnosis and was therefore unlikely to bias our results. Subgroup analyses of incident breast cancers were constrained by small numbers, and diagnoses not reported by participants would not have been captured. Our results were robust to covariate selection; however, we cannot exclude the possibility of residual confounding.

In our study, women who had a tubal ligation were more likely to report menopausal symptoms; however, tubal ligation alone did not influence menopausal age or breast cancer risk.