Abstract
Context:
Estrogen has been suggested as a risk factor for thyroid cancer.
Objective:
The aim of this study is to examine the associations between hysterectomy, bilateral salpingo-oophorectomy (BSO), and incidence of thyroid cancer.
Design:
This was a prospective cohort study.
Setting:
The study was conducted at 40 clinical centers in the United States.
Participants:
A total of 127 566 women aged 50–79 were enrolled in the Women's Health Initiative during 1993–1998.
Main Outcome Measures:
Hysterectomy and BSO were self-reported. Incident thyroid cancer cases were confirmed by medical record review.
Results:
Three hundred forty-four incident thyroid cancer cases were identified during an average of 14.4 years of follow-up. Compared with women without hysterectomy, women with hysterectomy, regardless of ovarian status, had a significantly higher risk of thyroid cancer (hazard ratio 1.46 [95% confidence interval 1.16–1.85]). Hysterectomy with BSO was not associated with a lower risk for thyroid cancer compared with hysterectomy alone. Among women with hysterectomy alone, hormone therapy use was associated with lower risk of thyroid cancer (hazard ratio 0.47 [95% confidence interval 0.28–0.78]). However, we did not observe significant associations between hormone therapy use and thyroid cancer in women without hysterectomy or women with hysterectomy plus BSO.
Conclusion:
Our large prospective study observed that hysterectomy, regardless of oophorectomy status, was associated with increased risk of thyroid cancer among postmenopausal women. In addition, our data did not support the hypotheses that exogenous estrogen is a risk factor or that estrogen deprivation is a protective factor for thyroid cancer. Further research is needed to clarify whether these apparent associations may be due to shared risk factors between indications for hysterectomy and thyroid cancer.
The large prospective study assessed the relationship between hysterectomy and thyroid cancer risk and revealed that hysterectomy regardless of oophorectomy status increased risk of thyroid cancer.
Although a relatively rare cancer, thyroid cancer incidence has been increasing in the past decades and has more than doubled since the early 1990s (1). It is now the fifth most common cancer in women. Although some of this increase may be explained by improved detection of very small papillary tumors, changes in environmental risk factors likely play an important role (2). Apart from a few established risk factors (exposure to ionizing radiation, medical history of benign thyroid disease), little is known about the etiology of thyroid cancer (3). Thyroid cancer is more common in whites than blacks. A recent meta-analysis of 21 observational studies reported that obesity may be associated with an increased risk of thyroid cancer (4). Smoking and alcohol consumption may be associated with a reduced risk of thyroid cancer (5). Given that thyroid cancer is about 3 times more common in women than men, reproductive risk factors may account for the gender disparity. Experimental evidence also suggests a role of estradiol in stimulating cell proliferation and carcinogenesis in human thyroid cancer cells (6, 7). However, epidemiological studies examining reproductive and hormonal factors in relation to risk of thyroid cancer have failed to identify strong or consistent associations (8, 9).
Hysterectomy is one of the most commonly performed surgical procedures in women. Almost 90% of hysterectomy surgeries are for benign gynecological conditions including symptomatic uterine fibroids or abnormal uterine bleeding (10). It is estimated that about 45% of women have bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy to prevent the subsequent development of ovarian cancer, treat medical conditions, or prevent the need for future adnexal surgery (11, 12). There is good evidence to support BSO as a risk-reducing surgery for women at high risk of ovarian cancer and breast cancer (13), but relatively little evidence to support its role in other circumstances. Premenopausal BSO suddenly reduces both estrogen and androgen productions (14). Given the possible promoting role of estrogens in the pathology of both the thyroid gland and the uterus, it is possible that BSO may be associated with a reduced risk of thyroid cancer. However, in contrast to the expected pattern based on experimental evidence, several prospective studies observed that hysterectomy with or without BSO increases thyroid cancer risk (15, 16), although not all studies found this (17, 18). However, most studies either lacked information on oophorectomy or did not discern the effects of oophorectomy from those due to hysterectomy alone (15, 17, 18). Some studies suggest that increased thyroid cancer risk from hysterectomy may be due to earlier detection or surveillance bias (19, 20). It has been reported that a decrease in thyrotropin response to thyroid stimulating hormone after BSO (21) may enhance the growth of thyroid tumors. In summary, the possible harmful or protective effects of hysterectomy and BSO on thyroid cancer risk are poorly understood.
In the present study, we used the Women's Health Initiative (WHI), a large prospective study in the United States, with detailed information on potential confounders and centrally adjudicated thyroid cancer cases, to investigate the association between hysterectomy, oophorectomy and the risk of thyroid cancer. To further test whether exogenous estrogen is a risk factor for thyroid cancer and whether early loss of endogenous estrogen is a protective factor for thyroid cancer, we compared the risk of thyroid cancer between users and nonusers of hormone therapy (HT) use by hysterectomy/BSO status, and compared the risk of thyroid cancer in women with hysterectomy alone vs hysterectomy plus BSO. Using hysterectomy alone as a reference group helped control for the confounding related to indications for hysterectomy. Furthermore, we examined the impact of hysterectomy and/or oophorectomy on the risk of thyroid cancer by age at time of the surgical procedures and also examined whether these conditions are associated with characteristics of thyroid tumors to assess possible surveillance bias.
Materials and Methods
Women's Health Initiative
The WHI was designed to address the major causes of morbidity and mortality in postmenopausal women (22). It includes both multicenter clinical trials (CT) and an observational study (OS). Details of the scientific rationale, eligibility requirements, and baseline characteristics of the participants in the WHI have been published elsewhere (23–27). Briefly, a total of 161 808 women aged 50–79 years were recruited at 40 clinical centers throughout the United States between September 1, 1993, and December 31, 1998. The WHI CT includes four overlapping components: two hormone therapy trials, a dietary modification trial, and a calcium/vitamin D supplementation trial. Participants in the OS included 93 676 women who were screened for the CT but were ineligible or unwilling to participate or were recruited through a direct invitation for the OS. The study was overseen by institutional review boards at all 40 clinical centers and at the coordinating center as well as by a study-wide data and safety monitoring board. All participants in the WHI gave signed informed consent and were followed prospectively.
Study population
The following participants were excluded from the entire WHI cohort of 161 808 for this analysis: 12 655 women who had a history of cancer (except nonmelanoma skin cancer) at baseline; 636 who joined but provided no follow-up information; 4010 who had no hysterectomy but had oophorectomy, 8261 who had one or partial oophorectomy, 3681 with missing data on hysterectomy or oophorectomy, and 4999 women with missing data on other covariates. After exclusions, 127 566 women remained for further analysis.
Follow-up and ascertainment of cases
All participants were followed up from enrollment to first thyroid cancer diagnosis, date of death, loss to follow-up, or end of CT or OS follow-up (September 30, 2015), whichever occurred first. The study did not perform ultrasound examinations. Incident thyroid cancer cases diagnosed during routine clinical care were identified by self-administered questionnaires (administered every 6 mo in the CT through 2005 and annually in the CT after 2005 and in the OS), with all cases confirmed by medical record review. All primary thyroid cancer cases were then coded centrally in accordance with the Surveillance Epidemiology and End Results coding guidelines.
Measurements
Exposures
Surgical histories of hysterectomy and oophorectomy and age at surgery were collected through the self-reported questionnaires. Hysterectomy status at baseline was determined by asking the following question: “Did you ever have a hysterectomy? (This is a surgery to take out your uterus or womb.)” Oophorectomy status at baseline was based on the question, “Have you ever had an operation to remove one or both of your ovaries?” The response to this question were categorized as no, yes, one was taken out; yes, both were taken out; yes, part of an ovary was taken out; yes, unknown number taken out; and do not know. Age at hysterectomy and age at oophorectomy were also collected at baseline. The validity of self-reported hysterectomy and oophorectomy has been confirmed with sensitivity of 91% and positive predictive value of 97% for hysterectomy status and sensitivity of 64% and positive predictive value of 100% for BSO (28). Hysterectomy status and the date of the operation were also collected during follow-up. The oophorectomy status during follow-up was not collected.
Covariates
In the multivariable models, we considered potential confounders, including age at enrollment (<55, 55 to <60, 60 to <65, 65 to <70, 70 to <75, 75+ y); race/ethnicity (American Indian or Alaska Native, Asian or Pacific Islander, black or African-American, Hispanic/Latino, non-Hispanic white, and other); education (high school or less, some college/technical training, college or some postcollege, and master or higher); body mass index (BMI; kilograms per square meter, continuous); smoking (never, former, current); alcohol intake (nondrinker, past drinker, current and less than seven drinks per week, current and seven or more drinks per week); physical activity (metabolic equivalent [MET] hours per week, <5, 5 to <10, 10 to <20, 20 to <30, 30+); history of HT use (none, estrogen alone, estrogen and progestin, mixed); family history of cancer (no, yes); and history of previous thyroid disease (no, yes).
Statistical analysis
Our primary analysis focused on the impact of hysterectomy and BSO at baseline. Hysterectomy/oophorectomy status was categorized as no hysterectomy and no BSO, hysterectomy alone, or hysterectomy with BSO.
Baseline characteristics were described using percentages for categorical variables and means (SD) for continuous variables. Comparisons among three categories of hysterectomy or BSO were made using the χ2 test for categorical variables and an ANOVA test for continuous variables. In addition, we compared tumor characteristics among the three categories of hysterectomy and BSO.
Multivariable Cox proportional hazard modeling was used to assess the association between hysterectomy or BSO status and thyroid cancer risk. In all multivariable models, potential confounders included variables listed in Table 1. Furthermore, we analyzed exposure (hysterectomy status) as the time-varying variable using time-dependent covariate Cox models as a sensitivity analysis.
Table 1.
Characteristics of Study Participants by Hysterectomy/Oophorectomy Status Among 127 566 Participants in Women's Health Initiative
| No Hysterectomy/Oophorectomy | Hysterectomy Only | Hysterectomy With BSO | P Valuea | |
|---|---|---|---|---|
| Total number of women | 43 139 | 10 695 | 13 880 | |
| Age at baseline (mean), y | 62.9 (7.2) | 63.0 (7.2) | 63.4 (7.1) | <.0001 |
| White, non-Hispanic-ethnicity, % | 68 596 (85.0) | 16 897 (80.9) | 21 273 (81.9) | <.0001 |
| College or above education, % | 35 617 (44.1) | 6866 (32.9) | 9270 (35.7) | <.0001 |
| BMI (mean), kg/m2 | 27.6 (5.9) | 28.4 (5.8) | 28.4 (6.0) | <.0001 |
| Physical activity, MET h/wk | 13.1 (14.0) | 11.8 (13.4) | 11.7 (13.1) | <.0001 |
| Smoking status | <.0001 | |||
| Never-smokers | 40 987 (50.8) | 11 056 (53.0) | 13 521 (52.1) | |
| Former smokers | 34 164 (42.3) | 8393 (40.2) | 10 850 (41.8) | |
| Current smokers | 5563 (6.9) | 1428 (6.8) | 1604 (6.2) | |
| Alcohol intake | <.0001 | |||
| Nondrinker | 8237 (10.2) | 2560 (12.3) | 3027 (11.7) | |
| Past drinker | 13 403 (16.6) | 4418 (21.2) | 5242 (20.2) | |
| <7 drinks per week | 48 752 (60.4) | 11 816 (56.6) | 15 036 (57.9) | |
| 7+ drinks per week | 10 322 (12.8) | 2083 (10.0) | 2670 (10.3) | |
| History of hormone therapy use | <.0001 | |||
| None | 43 830 (54.3) | 6843 (32.8) | 4845 (18.7) | |
| Estrogen alone | 5448 (6.8) | 12 433 (59.6) | 18 016 (69.4) | |
| Estrogen and progestin | 27 609 (34.2) | 485 (2.3) | 736 (2.8) | |
| Mixed | 3827 (4.7) | 1116 (5.4) | 2378 (9.2) | |
| Duration of hormone therapy (mean), y | 6.2 (5.7) | 10.5 (8.8) | 12.5 (9.1) | <.0001 |
| Family history of cancer (yes) | 50 630 (62.7) | 13 357 (64.0) | 16 998 (65.4) | <.0001 |
| History of thyroid disease | 17 790 (22.0) | 5487 (26.3) | 6871 (26.5) | |
| Age at hysterectomy, y | <.0001 | |||
| <40 | 8674 (41.6) | 5838 (22.5) | ||
| 40 to < 50 | 8712 (41.7) | 12 268 (47.2) | ||
| 50+ | 3491 (16.7) | 7869 (30.3) |
P values were results of difference in tests of baseline characteristics among three categories of hysterectomy or BSO. A χ2 test was used to evaluate differences for categorical covariates, and a t test was used for continuous variables.
Results
Among 127 566 women, 46 852 women (36.7%) had a hysterectomy at baseline. Among these, 25 975 (55.4%) had BSO. Over a mean of 14.4 years of follow-up, 344 women developed thyroid cancer.
Baseline characteristics by hysterectomy and oophorectomy status at enrollment are shown in Table 1. Compared with women with no hysterectomy, women with hysterectomy alone or with BSO were more likely to be older, nonwhite (non-Hispanic), less educated, and have a higher BMI. They were less physically active and were more likely to be a nonsmoker, a never- or past drinker, have a history of hormone use of estrogen alone, a longer duration of HT use, and report a family history of cancer and history of thyroid disease. Compared with women with hysterectomy alone, women with hysterectomy plus BSO were more likely to be older, white (non-Hispanic), and more educated. They were more likely to be a former smoker, a current drinker, have a history of hormone use of estrogen alone, report a family history of cancer, and have surgery at later age. There were no significant differences in BMI, physical activity, and history of thyroid disease between women with hysterectomy alone and women with hysterectomy and bilateral oophorectomy (Table 1).
There were no significant differences in tumor size, stage, or histological types among women with different hysterectomy/oophorectomy status (Table 2).
Table 2.
Tumor Characteristics by Hysterectomy and Oophorectomy Status Among Women With Thyroid Cancer
| No Hysterectomy/Oophorectomy | Hysterectomy Alone | Hysterectomy With BSO | P Value | |
|---|---|---|---|---|
| Cases, n | 189 | 67 | 88 | .71 |
| Tumor size, mm (mean, SD) | 17.8 (14.9) | 17.6 (14.9) | 16.2 (13.8) | |
| SEER stage | .50 | |||
| Localized | 147 (77.8) | 51 (76.1) | 61 (69.3) | |
| Regional | 26 (13.8) | 11 (16.4) | 21 (23.9) | |
| Distant | 10 (5.3) | 2 (3.0) | 3 (3.4) | |
| Missing | 6 (3.2) | 3 (4.5) | 3 (3.4) | |
| Histological types | .46 | |||
| Papillary carcinoma | 159 (84.1) | 57 (85.1) | 70 (79.6) | |
| Follicular carcinoma | 16 (8.5) | 3 (4.5) | 11 (12.5) | |
| Others | 14 (7.4) | 7 (10.5) | 7 (8.0) |
Abbreviation: SEER, Surveillance Epidemiology and End Results.
In the multivariable-adjusted model (Table 3), hysterectomy, regardless of ovarian status, was associated with an increased risk of thyroid cancer (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.16–1.85). Compared with women without hysterectomy, women with hysterectomy alone and women with hysterectomy plus BSO had similar significant increased risk of thyroid cancer, with little difference between the simple age-adjusted and multivariable-adjusted models. Hysterectomy at all ages appeared associated with risk of thyroid cancer, with no differences in risk by age (Table 3). After stratification by HT use, the associations between risk of thyroid cancer and all exposures of interest became stronger than the overall findings among women who had never used HT, whereas the strength of associations attenuated among women who had ever used HT (Table 4).
Table 3.
HRs) and 95% CIs for the Association Between Hysterectomy, Oophorectomy, and Risk of Thyroid Cancer in the WHIa
| Cases | Age-Adjusted HR (95% CI) | Multivariable-Adjusted HR (95% CI)a | |
|---|---|---|---|
| Hysterectomy | |||
| No | 189 | 1 | 1 |
| Yes | 155 | 1.47 (1.19 1.82) | 1.46 (1.16–1.85) |
| Hysterectomy/oophorectomy status | |||
| None | 189 | 1 | 1 |
| Hysterectomy alone | 67 | 1.42 (1.08 1.88) | 1.45 (1.08 1.94) |
| Hysterectomy with BSO | 88 | 1.51 (1.17 1.94) | 1.48 (1.13 1.93) |
| Age of hysterectomy, y | |||
| <40 | 52 | 1.54 (1.13 2.09) | 1.57 (1.13 2.17) |
| 40 to <50 | 72 | 1.50 (1.14 1.97) | 1.50 (1.12 1.99) |
| ≥50 | 31 | 1.31 (0.89 1.92) | 1.27 (0.86 1.88) |
| P for trendb | 0.78 | 0.70 | |
| Women with hysterectomy | |||
| Hysterectomy alone | 67 | 1 | 1 |
| Hysterectomy with BSO | 88 | 1.07 (0.78 1.47) | 1.04 (0.75 1.34) |
In the multivariable-adjusted models, we adjusted for age at enrollment (<55, 55–59, 60–64, 65–69, 70–74, > 75 y); ethnicity (American Indian or Alaska Native, Asian or Pacific Islander, Black or African-American, Hispanic/Latino, non-Hispanic white, and other); education (high school or less, some college/technical training, college or higher); smoking status (never, former, current); BMI (continuous); recreational physical activity (<5, 5 to < 10, 10 to < 20, 20 to < 30, 30+ METs/wk); alcohol intake (nondrinker, past drinker, less than one drink per month, and current drinker including frequency: less than one drink per month, one drink per month to less than one drink per week, one to less than seven drinks per week, more than seven drinks per week); and previous thyroid disease.
The second P value was for tends test in model without including reference group.
Table 4.
HRs and 95% 95% CIs for the Association Between Hysterectomy, Oophorectomy, and Risk of Thyroid Cancer Stratified by HT Use in the WHIa
| Never-Hormone Therapy Users |
Ever-Hormone Therapy Users |
P for Interaction | |||
|---|---|---|---|---|---|
| Cases | Multivariable-Adjusted HR (95% CI)a | Cases | Multivariable-Adjusted HR (95% CI)a | ||
| Hysterectomy | .02 | ||||
| No | 93 | 1 | 96 | 1 | |
| Yes | 47 | 2.55 (1.73 3.76) | 108 | 1.26 (0.93–1.70) | |
| Hysterectomy/oophorectomy status | .046 | ||||
| None | 93 | 1 | 96 | 1 | |
| Hysterectomy alone | 28 | 2.63 (1.66 4.15) | 39 | 1.14 (0.77 1.68) | |
| Hysterectomy with BSO | 19 | 2.45 (1.46 4.12) | 69 | 1.34 (0.96 1.87) | |
| Age of hysterectomy, y | .01 | ||||
| <40 | 20 | 3.31 (1.96 5.59) | 32 | 1.18 (0.77 1.80) | |
| 40 to < 50 | 15 | 1.89 (1.07 3.34) | 57 | 1.44 (1.01 2.04) | |
| ≥50 | 12 | 2.76 (1.48 5.14) | 19 | 1.00 (0.60 1.66) | |
| P for trendb | 0.66 | 0.96 | |||
| Women with hysterectomy | .09 | ||||
| Hysterectomy alone | 28 | 1 | 39 | 1 | |
| Hysterectomy with BSO | 19 | 0.97 (0.54 1.75) | 69 | 1.17 (0.79 1.74) | |
In the multivariable-adjusted models, we adjusted for age at enrollment (<55, 55–59, 60–64, 65–69, 70–74, > 75 y); ethnicity (American Indian or Alaska Native, Asian or Pacific Islander, black or African-American, Hispanic/Latino, non-Hispanic white, and other); education (high school or less, some college/technical training, college or higher); smoking status (never, former, current); BMI (continuous); recreational physical activity (<5, 5 to <10, 10 to < 20, 20 to < 30, 30+ METs/wk); alcohol intake (nondrinker, past drinker, less than one drink per month, and current drinker including frequency: less than one drink per month, one drink per month to less than one drink per week, one to less than seven drinks per week, more than seven drinks per week); and previous thyroid disease.
The second P value was for tends test in model without including reference group.
HT use was not associated with a risk of thyroid cancer in women without hysterectomy and in women with hysterectomy plus BSO. However, among women with hysterectomy alone, HT use was associated with a significant lower risk (HR 0.47, 95% CI 0.28–0.78), especially in women with a duration of hormone use of 10 years or longer (HR 0.24, 95% CI 0.11–0.52) (Table 5).
Table 5.
HRs and 95% 95% CIs for the Association Between HT Use and Risk of Thyroid Cancer for Women With Hysterectomy Alone or Women With Hysterectomy Plus BSO Overall and Stratified by Age of Hysterectomy and Duration of Hormone in the WHIa
| Cases | HR (95% CI) | |
|---|---|---|
| No hysterectomy | ||
| Never HT use | 93 | 1 |
| Ever HT use | 96 | 1.07 (0.79–1.44) |
| Duration < 10 y | 74 | 1.06 (0.77–1.47) |
| Duration ≥ 10 y | 22 | 1.08 (0.67–1.74) |
| Hysterectomy alone | ||
| Never HT use | 28 | 1 |
| Ever HT use | 39 | 0.47 (0.28–0.78) |
| Duration < 10 y | 30 | 0.65 (0.38–1.11) |
| Duration ≥ 10 y | 9 | 0.24 (0.11–0.52) |
| Hysterectomy with BSO | ||
| Never HT use | 19 | 1 |
| Ever HT use | 69 | 0.69 (0.40–1.17) |
| Duration < 10 y | 38 | 0.82 (0.46–1.46) |
| Duration ≥ 10 y | 31 | 0.57 (0.31–1.04) |
In the multivariable-adjusted models, we adjusted for age at enrollment (<55, 55–59, 60–64, 65–69, 70–74, > 75 y); ethnicity (American Indian or Alaska Native, Asian or Pacific Islander, black or African-American, Hispanic/Latino, non-Hispanic white, and other); education (high school or less, some college/technical training, college or higher); smoking status (never, former, current); BMI (continuous); recreational physical activity (<5, 5 to <10, 10 to < 20, 20 to < 30, 30+ METs/wk); alcohol intake (nondrinker, past drinker, less than one drink per month, and current drinker including frequency: less than one drink per month, one drink per month to less than one drink per week, one to less than seven drinks per week, more than seven drinks per week); and previous thyroid disease.
To further test whether early loss of endogenous ovarian estrogen is a protective factor for thyroid cancer, we also compared hysterectomy plus BSO with hysterectomy alone on the risk of thyroid cancer overall (Table 3) and stratified by HT use (never, ever) (Table 4). Compared with women with hysterectomy alone, women with hysterectomy plus BSO did not have lower risk for thyroid cancer irrespective of HT use.
When hysterectomy status was analyzed as a time-varying variable using time-dependent covariate Cox models, an increased risk of thyroid cancer was observed in women with hysterectomy compared with women without hysterectomy (HR 1.78, 95% CI 1.33–2.37). Finally, we performed analyses confined to papillary carcinoma; results were similar to the overall findings when using all types of thyroid cancers.
Discussion
In this large prospective study of postmenopausal women, we observed that women with hysterectomy, regardless of oophorectomy status, had an increased risk for thyroid cancer compared with women without hysterectomy among women who had never used HT. Hysterectomy with BSO was not associated with a lower risk for thyroid cancer compared with hysterectomy alone. Contrary to our original hypothesis, we found no evidence that exogenous estrogen increased the risk for thyroid cancer. In fact, HT use was associated with a lower risk of thyroid cancer in women who had hysterectomy alone, especially for women with a long duration use of HT.
A number of previous studies have reported that hysterectomy increased significantly the risk of thyroid cancer (15, 16, 19, 29), although not all studies have observed this (17, 18, 30). Of these, four were prospective studies (15–18). Among studies (16, 19, 29, 30) that attempted to distinguish the effects of BSO from those due to hysterectomy alone, two (16, 30) reported that hysterectomy with BSO was associated with a similar increase of thyroid cancer incidence as with hysterectomy alone; one small case-control study (29) observed that hysterectomy with BSO (14 cases and three controls) but not hysterectomy alone (18 cases and 15 controls) was associated with elevated risk of thyroid cancer, whereas another case-control study (19) reported that a history of hysterectomy was associated with an increased risk of thyroid cancer in women 45 years of age or older, and the association was not attributable to concurrent BSO or to a variety of studied medical indications for hysterectomy.
A possible hormonal etiology of thyroid cancer is hypothesized, given the substantially higher incidence rates of this cancer among women compared with men and the proliferative effect of estrogen on thyroid cells (6). Experimental studies have demonstrated that estradiol, the main female sex hormone, is a potent stimulator of both human benign and malignant thyroid cells (6, 7, 31). However, findings from epidemiological studies on the role of estrogen in the thyroid cancer are conflicting (17, 19, 32, 33), and our data do not support the hypotheses that exogenous estrogen is a risk factor for thyroid cancer or that early loss of ovarian estrogens is a protective factor for thyroid cancer.
First, our data show that women with hysterectomy, regardless of oophorectomy status, had an increased risk for thyroid cancer compared with women without hysterectomy, especially among women who had never used HT. If a high estrogen level is a risk factor for thyroid cancer, we would expect to observe that hysterectomy, especially hysterectomy plus BSO, would be associated with a lower risk of thyroid cancer because hysterectomy and especially BSO abruptly reduces the production of estrogens (14, 34).
Second, we observed that the magnitude of associations for hysterectomy alone or hysterectomy plus BSO in women without HT use was stronger than women who had ever had HT. Further direct examination of the impact of HT use on the risk of thyroid cancer stratifying by hysterectomy or BSO status showed that HT use had a lower or similar risk of thyroid cancer compared with HT nonusers. These findings further support that estrogen is not a risk factor for thyroid cancer.
Third, our data revealed that compared with hysterectomy alone, concomitant BSO does not confer a lower risk for thyroid cancer. This finding suggests that early loss of ovarian estrogens may not be a protective factor for thyroid cancer for postmenopausal women. BSO abruptly decreases the production of estrogens for premenopausal women, whereas hysterectomy with ovarian conservation causes similar but less dramatic hormone changes (14, 34). It is possible that the absolute difference in hormone levels between women who undergo hysterectomy with or without BSO may not be sufficient to demonstrate a significant effect on risk of thyroid cancer in older women. Among postmenopausal women, circulating estrone and estradiol levels are derived primarily from peripheral aromatization of androstenedione and T. Studies have shown that oophorectomy does not seen to influence peripheral estrogen production in older women (35).
Alternatively, the association of thyroid cancer with hysterectomy may reflect either increased detection of thyroid cancers at the time of hysterectomy or confounding by indication for hysterectomy. Our data do not suggest surveillance bias because we compared tumor characteristics between women with and without hysterectomy and did not observe significant differences in tumor size, stage, and histological types. It is also possible that the association may be due to confounding by indications or risk factors for hysterectomy. Abnormal uterine bleeding, the most common benign indication for hysterectomy, is often correlated to thyroid dysfunction (36). For example, studies have observed a higher thyroid-stimulating hormone in patients with abnormal uterine bleeding compared with women with regular menstruation (37). Also, uterine fibroids, another common indication for hysterectomy, is associated with thyroid modules (38). Therefore, hysterectomy can be considered as an indicator of prolonged menstrual disorders or uterine fibroids that share a common etiology with thyroid cancer, rather than a causal factor for thyroid cancer. A final possibility is unmeasured confounding, such as ionizing radiation exposure, especially during women's childhood. If women with hysterectomy were more likely to have ionizing radiation exposure during their childhood than women without hysterectomy, it would overestimate the effect of hysterectomy on the risk of thyroid cancer.
Strengths of our study include the prospective design with detailed potential confounders, large sample size, and long-term follow-up. However, several limitations deserve mention. First, hysterectomy and oophorectomy status were self-reported, although other studies have reported reasonable validity for self-report of hysterectomy. The misclassification of exposures would tend to attenuate the associations. Second, our analyses may also be affected by survival bias because WHI participants began follow-up many years after they underwent hysterectomy. Third, we do not know the risk factor status of these women before hysterectomy or the reason for the surgery. Fourth, we were unable to adjust for ionizing radiation exposure because we did not ask this question.
In conclusion, our large prospective study observed that hysterectomy, regardless of oophorectomy status, was associated with an increased risk of thyroid cancer among postmenopausal women. HT use was associated with a lower or no risk of thyroid cancer. These findings did not support that exogenous estrogen is a risk factor and estrogen deprivation is a protective factor for thyroid cancer. Our study suggests that when deciding to remove the uterus for benign conditions, a possible increased risk of thyroid cancer should be considered. Further research is needed to identify whether higher thyroid cancer risk associated with hysterectomy is the result of indication variables or reflects true physiological consequences of hysterectomy and oophorectomy.
Acknowledgments
The short list of Women's Health Initiative investigators is also available online at http://press.endocrine.org/doi/suppl/10.1210/jc.2016-2011/suppl_file/jc-16-2011.pdf.
The Women's Health Initiative program is supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, through Contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.
Disclosure Summary: The authors have nothing to disclose.
Appendix
Short list of WHI investigators
Program Office
National Heart, Lung, and Blood Institute, Bethesda, Maryland: Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller.
Clinical coordinating center
Fred Hutchinson Cancer Research Center, Seattle, Washington: Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg.
Investigators and academic centers
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts: JoAnn E. Manson; MedStar Health Research Institute/Howard University, Washington, DC: Barbara V. Howard; Stanford Prevention Research Center, Stanford, California: Marcia L. Stefanick; The Ohio State University, Columbus, Ohio: Rebecca Jackson; University of Arizona, Tucson/Phoenix, Arizona: Cynthia A. Thomson; University at Buffalo, Buffalo, New York: Jean Wactawski-Wende; University of Florida, Gainesville/Jacksonville, Florida: Marian Limacher; University of Iowa, Iowa City/Davenport, Iowa: Robert Wallace; University of Pittsburgh, Pittsburgh, Pennsylvania: Lewis Kuller; Wake Forest University School of Medicine, Winston-Salem, North Carolina: Sally Shumaker.
Women's Health initiative memory study
Wake Forest University School of Medicine, Winston-Salem, North Carolina: Sally Shumaker.
For a list of all the investigators who have contributed to WHI science, please visit https://www.whi.org/researchers/documents%20%20write%20a%20paper/whi%20investigator%20long%20list.pdf.
Footnotes
- BMI
- body mass index
- BSO
- bilateral salpingo-oophorectomy
- CI
- confidence interval
- CT
- clinical trials
- HR
- hazard ratio
- HT
- hormone therapy
- MET
- metabolic equivalent
- OS
- observational study
- WHI
- Women's Health Initiative.
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