Association between the risk of gastrointestinal cancer and hysterectomy from the National Health Insurance Database

doi:10.21203/rs.3.rs-2498211/v1

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Association between the risk of gastrointestinal cancer and hysterectomy from the National Health Insurance Database

https://doi.org/10.21203/rs.3.rs-2498211/v1

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published 29 Sep, 2023

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Background

Thisretrospective cohort study analyzed the risk of gastrointestinal (GI) cancer in patients who underwent hysterectomy due to a benign gynecologic disease in comparison with the no hysterectomy group using Korean health insurance data.

Methods

This population-based retrospective cohort study was conducted using insurance data provided by the Health Insurance Review and Assessment Service (HIRA) from January 1, 2007, to December 31, 2020. The hysterectomy group included 40- to 59-year-old women who underwent hysterectomy with uterine leiomyoma or uterine endometriosis from January 1, 2011, to December 31, 2014. The control group included women aged 40 to 59 years who visited medical institutions for medical examination from January 1, 2011 to December 31, 2014.

Results

The hysterectomy and no hysterectomy groups comprised 66,204 and 89,768 subjects, respectively. The median ages in the no hysterectomy group and hysterectomy group were 48 (range: 43–53) and 46 (range: 44–49) years, respectively. In the unadjusted results of the analysis, all colorectal cancer (CRC) increased in the hysterectomy alone group (HR 1.222, 95% confidence interval (CI) 1.016-1.47, p = 0.033), sigmoid colon cancer increased in the hysterectomy alone group (HR 1.71, 95% CI 1.073-2.724, p = 0.024), and rectal cancer increased in the hysterectomy with adnexal surgery group (HR 1.924, 95% CI 1.073-2.724, p = 0.002). The adjusted results showed that all CRC increased in the hysterectomy alone group (HR 1.406, 95% CI 1.057-1.871, p = 0.019), colon cancer increased in the hysterectomy alone group (HR 1.523, 95% CI 1.068-2.17, p = 0.02), and rectal cancer increased in the hysterectomy with adnexal surgery group (HR 1.933, 95% CI 1.131-3.302, p = 0.016). The all-cause mortality of GI cancer increased in the hysterectomy alone group (HR 3.495, 95% CI 1.347-9.07, p = 0.001).

Conclusions

This study showed that the risk of all CRC increased in women who underwent hysterectomy compared with women who did not. In particular, the risk of rectal cancer was significantly higher in the women who underwent hysterectomy with adnexal surgery than in the controls.

adnexal surgery

colorectal cancer

hysterectomy

gastrointestinal cancer

rectal cancer

Hysterectomy is one of the most frequent gynecological surgeries in developed countries [1]. The majority of hysterectomies are performed because of benign conditions such as symptomatic uterine fibroids, endometriosis, or excessive uterine bleeding [2]. Although many women experience improved quality of life (QoL) after hysterectomy due to elimination of bothersome symptoms [3], hysterectomy is known to cause postoperative physiologic changes that are related to decreased QoL and poor health outcomes, including psychiatric morbidity [4, 5]. Additionally, hysterectomy may cause impaired ovarian function by damaging ovarian tissue or compromising the blood supply [6]. Many studies have shown that premenopausal women who had a hysterectomy with ovarian preservation have lower ovarian sex steroid levels and experience earlier menopause than women who do not have a hysterectomy [7, 8].

Adnexal surgery involves any of the organs that are on the sides of the uterus, such as fallopian tubes and ovaries. Bilateral oophorectomy is most often an elective procedure for the management of benign conditions such as chronic pelvic pain, ovarian cysts or tumors and risk reduction for hereditary ovarian cancer [9]. In contrast to with natural menopause, surgical menopause entails an abrupt withdrawal of estrogen, progesterone, and androgens, which are associated with more severe and prolonged menopausal symptoms, particularly when it is performed before the age of 45 years. Long-term consequences of oophorectomy include not only impaired cognitive and neurologic functions but also increased risks for cardio-metabolic disorder and bone resorption. There is a survival benefit to retention of the ovaries up to the age of 65 years in women at low risk for ovarian cancer [10]. Furthermore, a population-based study from the Swedish patient registry showed that oophorectomy increased the risk of colorectal cancer (CRC) [11]. A prospective cohort study from Denmark showed that oophorectomy was associated with an increased risk of CRC, with the highest rates being among women with bilateral oophorectomy [12].

In South Korea, CRC is the third most commonly diagnosed cancer in both sexes, following breast cancer and thyroid cancer in females and gastric cancer and lung cancer in males [13]. The incidence of CRC has recently increased dramatically in Korea. Globally, South Korea had the second highest CRC incidence in 2018, with an estimated 44.5 cases per 100,000 people per year [14]. The incidence of CRC is lower in women than in men at all ages, and estrogen exposure is known to have preventive effects, more so in women than in men [15].

The Women's Health Initiative (WHI) clinical trial reported that relatively short-term use of estrogen plus progestin was associated with a decreased risk of CRC but that CRCs in women who took estrogen plus progestin were diagnosed at a more advanced stage than those in women who took placebo [16]. However, in the long-term treatment and follow-up of women for over 7 to 8 years, the hazard ratio (HR) patterns in the WHI clinical trial and observational study did not provide strong evidence of a clinically important CRC benefit with either estrogen alone or estrogen plus progestin [17]. Numerous epidemiological studies have shown that users of high-dose oral contraceptives and of MHT have a 20 to 40% lower incidence of CRC than nonusers [18–20]. Observational and experimental studies have revealed that exposure to oral contraceptives and MHT lowers the risk of CRC [21]. However, several cohort and case control studies have shown conflicting results regarding the risk of CRC and endogenous levels of sex steroids in postmenopausal women [22, 23].

As mentioned above, hysterectomy could affect the decrease in the endogenous levels of estrogen and progesterone and eventually increase the risk of CRC [7, 8]. Abundant previous studies have suggested that female sex hormones are associated with the risk of CRC [16, 18–21]. Therefore, we designed this study to evaluate the impact of hysterectomy or hysterectomy with adnexal surgery, which may cause early menopause or impairment of ovarian function, on the risk of gastrointestinal (GI) cancer using Korean health insurance data. The primary purpose of this study was to analyze the risk of CRC in women who underwent hysterectomy due to a nonmalignant disease, and the secondary purpose was to determine the risk of each GI cancer according to specific sites, such as the stomach, small bowel, and colon.

The majority of South Koreans are obliged to take national health insurance [24]. The National Health Insurance Service (NHIS) manages the medical record information (age, sex, prescribed drug name, diagnosis, type of medical insurance, operation name, hospitalization and outpatient care) of Koreans (approximately 51 million people) who are subscribed to the program. The Health Insurance Review and Assessment Service (HIRA) is an arbitration agency that evaluates the appropriateness of medical care to prevent disputes over the payment of premiums between the Health Insurance Corporation and medical institutions. Therefore, the HIRA shares most of the medical record information of the National Health Insurance Corporation. This population-based retrospective cohort study was conducted using the database provided by HIRA from January 1st, 2007, to December 31st, 2020.

Selection Of Participants

We used the International Classification of Diseases, 10th revision (ICD-10) and Korea Health Insurance Medical Care Exposes (2016, 2019 version) for the selection and analysis of subjects. From January 1st, 2011, to December 31st, 2014, women aged 40 to 59 who underwent hysterectomy with uterine myoma or endometrial disease were selected as the hysterectomy group. Adnexal surgery was performed by extirpation of the adnexal tumor (unilateral or bilateral oophorectomy, unilateral or bilateral salpingo-oophorectomy, unilateral or bilateral salpingectomy, unilateral or bilateral ovarian cystectomy, incision and drainage of the ovarian cyst, ovarian wedge resection, and adhesional adnexectomy, and hysterectomy and adnexal surgery were performed on the same day. The day of hysterectomy was determined as the inclusion day. The no hysterectomy group included women aged 40–59 years who visited a medical institution for health checkups from January 1, 2011, to December 31, 2014, and those who underwent hysterectomy were excluded for the group. The first visit to the health examination was designated the inclusion day.

We excluded subjects who had any of the following cancer diagnosis codes (any Cxx) or gastrointestinal disease codes within 180 days before enrollment: K25 (gastric ulcer), K26 (duodenal ulcer), K27 (peptic ulcer), K28 (gastrojejunal ulcer), K31.7 (polyp of stomach and duodenum), K50 (Crohn’s disease), K51 (ulcerative colitis), K63.5 (polyposis of colon), or D51.0 (pernicious anemia).

Outcomes

Individuals were classified into the GI cancer group if they visited medical institutions more than 3 times with GI cancer diagnostic codes C15 (esophageal cancer), C16 (gastric cancer), C17 (cancer of small intestine), C18 (colon cancer; ascending, transverse, and descending colon), C19 (cancer of rectosigmoid junction; sigmoid cancer), or C20 (rectal cancer).

Variables

The medical insurance type was defined as low socioeconomic status (SES) when it was medical protection; the residential area was defined as rural area if it was nonmetropolitan. The Charlson Comorbidity Index (CCI) was obtained using the diagnostic code from the selection date of the study to the year before [25]. Parity was analyzed only for delivery in the entire cohort. We classified women who had a history of more than one adnexal surgery before hysterectomy as women with a history of adnexal surgery. We defined women who visited medical institutions more than once with a menopause-related diagnostic code before hysterectomy as menopause. The menopause-related diagnostic codes include N95.x (menopausal and other perimenopausal disorders), M80.0 (postmenopausal osteoporosis with pathological fracture), M81.0 (postmenopausal osteoporosis), and E28.3 (premature menopause), among others. Individuals who were prescribed their first MHT (menopausal hormone therapy) more than 180 days before the study were classified as having MHT before inclusion. Those who were prescribed their first MHT after inclusion were classified as having MHT after inclusion if the prescription date was 180 days or more after inclusion. MHT included tibolone, estradiol valerate, estradiol hemihydrate, dydrogesterone, norethisterone acetate, medroxyprogesterone acetate, drospirenone, and cyproterone, among others. Patients who visited medical institutions more than 3 times with gallbladder (GB) and biliary disease were defined as having gallbladder and biliary disease. The GB and biliary disease codes include K80 (Cholelithiasis), K81 (Cholecystitis), K82 (Other Diseases of gallbladder), K83 (Other Diseases of biliary tract), and K87 (Disorders of gallbladder, biliary tract and pancreas in diseases classification ed elsewhere), among others. The patients who visited medical institutions more than three times with uterine myoma (D25.x) or endometriosis (N80.x) were defined as having each of the relevant diseases. Death was defined as all cases of death during hospitalization.

Statistics

SAS Enterprise Guide 7.15 (SAS Institute Inc) and R 3.5.1 (The R Foundation for Statistical Computing) were used for statistical analysis. All statistical analyses were two-sided, and the results were defined as statistically significant if the p value was 0.05 or less. The analysis of categorical variables was carried out by Pearson’s chi-squared test or Fisher’s exact test, and t tests and Mann‒Whitney U tests were used for the analysis of continuous variables. We performed Cox regression analysis to correct the bias caused by confounding factors in the effect of hysterectomy on the risk of GI cancer. The first day for Cox analysis was set as the inclusion day of each group, and the last day was set as any GI cancer, the death date, or December 31st, 2020. We applied the listwise deletion method when the proportion of missing values for a statistical variable was less than 10% and the regression imputation method when the proportion of missing values was more than 10%. To confirm the robustness of our study, Cox regression analysis was performed on the risk of GI cancer in the laparotomic hysterectomy group (versus no hysterectomy group).

Ethics

This study was approved by the IRB of Sanggye Paik Hospital (Approval number: SGPAIK 2021-12-005). In this study, the identifying variables of individuals were removed (deidentification). In addition, the analysis of this study was conducted only on closed servers provided by HIRA, and results data (e.g., tables, statistical values) can only be taken out of the server. Therefore, there is no harm to the participants who participated in this study because the individual cannot be specified. Additionally, raw data cannot be offered. Accordingly, it is not necessary to provide informed content according to the Bioethics and Safety Act of South Korea. This study uses data provided by HIRA, but HIRA has no interest in this study.

Among a total of 155,972 subjects included, 66,204 and 89,768 subjects were classified into the hysterectomy and no hysterectomy groups, respectively (Fig. 1). The baseline characteristics of participants with or without hysterectomy are shown in Table 1. The median age was 48 (range: 43–53) years in the no hysterectomy group and 46 (range: 44–49) years in the hysterectomy group. The incidence of GI cancer among participants with/without hysterectomy according to specific sites of the GI tract is shown in Table 2. The number of subjects with any GI cancer was 533 (0.6%) in the no hysterectomy group and 419 (0.6%) in the hysterectomy group. GI cancers were classified as esophageal cancer, stomach cancer, small bowel cancer, colon cancer (ascending, transverse, descending), sigmoid cancer, or rectal cancer. Esophageal cancer occurred in 8 subjects (0.009%) in the hysterectomy group and 9 subjects (0.009%) in the no hysterectomy group (p = 0.975). There were 247 (0.3%) subjects with stomach cancer in the no hysterectomy group and 158 (0.2%) in the hysterectomy group (p = 0.162). There were 15 (0.0%) subjects with small bowel cancer in the no hysterectomy group and 10 (0.0%) in the hysterectomy group (p = 0.806). The number of subjects with colon cancer (ascending, transverse, descending) was 174 (0.2%) in the no hysterectomy group and 162 (0.2%) in the hysterectomy group (p = 0.032). There were 35 (0.0%) subjects with sigmoid colon cancer in the no hysterectomy group and 43 (0.1%) in the hysterectomy group (p = 0.023). There were 94 (0.1%) subjects with rectal cancer in the no hysterectomy group and 94 (0.1%) in the hysterectomy group (p = 0.036). The number of subjects with total CRC was 265 (0.3%) in the no hysterectomy group and 251 (0.4%) in the hysterectomy group (p = 0.004) (Table 2).

We analyzed the hazard ratios (HRs) of GI cancer with/without hysterectomy. The HRs were adjusted for hysterectomy, age, SES, region, CCI, parity, menopause before inclusion, MHT before inclusion, adnexal surgery before inclusion, diseases of the gallbladder and biliary tract before inclusion, uterine leiomyoma, and endometriosis. Among the adjusted results of the analysis, the risk of esophageal cancer did not significantly change in the hysterectomy group (HR 0.558, 95% CI 0.104–3.001, p = 0.497) compared to the no hysterectomy group. The risk of gastric cancer also did not significantly change in the hysterectomy group (HR 0.959, 95% CI 0.689–1.334, p = 0.805) compared to the no hysterectomy group. All CRC increased in the hysterectomy-alone group (HR 1.406, 95% CI 1.057–1.871, p = 0.019), colon cancer increased in the hysterectomy-alone group (HR 1.523, 95% CI 1.068–2.17, p = 0.02), and rectal cancer increased in the hysterectomy with adnexal surgery group (HR 1.933, 95% CI 1.131–3.302, p = 0.016) (Table 3). The forest plot of the HRs associated with GI cancers in hysterectomy with or without adnexal surgery is shown in Fig. 2.

The HRs of all-cause mortality among participants with GI cancer are shown in Table 4. Among the adjusted results, the mortality of GI cancer increased in the hysterectomy alone group (HR 3.495, 95% CI 1.347–9.07, p = 0.001).

This study showed that the risk of all CRC was higher in women who underwent hysterectomy than in women who did not. In particular, the risk of rectal cancer was significantly higher in the women who underwent hysterectomy with adnexal surgery than in the no hysterectomy group. This result is consistent with a systematic review suggesting that oophorectomy or hysterectomy increases the subsequent risk of CRC and should not be recommended for women who are not at high risk except for those with susceptibility genes for ovarian cancer [26]. Many studies have reported that hysterectomy itself, regardless of adnexal surgery, causes impairment mostly of ovarian function, which may decrease the protective effect of endogenous estrogen against CRC [6–8]. This prior evidence supports our observation that the risk of CRC, particularly rectal cancer, was higher in women with a hysterectomy than in those without a hysterectomy.

The risk factors for CRC include red and processed meat, body fat composition, alcohol consumption, smoking, and male sex [27, 28]. Sex disparities in not only the risk of CRC but also the prognosis of metastatic CRC have led to controversies regarding the role of sex hormones [29]. Estrogen, especially estradiol, is known to affect the onset of CRC in various laboratory and clinical studies [30, 31]. The morbidity and mortality of CRC are higher in men than in women because estrogen is associated with various growth factors affecting cell proliferation and microscopic changes in the cell immune response by binding ERβ in the colon [32]. Furthermore, both estrogen and progestin reduce the serum levels of fasting blood sugar and insulin, which explains why hyperglycemia and hyperinsulinemia increase the risk of CRC [33, 34].

On the other hand, one study showed that colonic tumorigenesis is promoted by male hormones rather than decreased by female hormones [35]. Taken together, these findings suggest that estrogen in women and testosterone in men underlie a notably large sex disparity in the risk of CRC. There is a growing body of evidence supporting the notion that both female and male sex hormones can influence the onset of CRC. However, the ovaries of postmenopausal women do not produce female sex hormones but still produce substantial amounts of androgens [36, 37]. The postmenopausal ovary remains a critical source of androgen throughout the lifespan of older women within the 50–89 year age range [38]. The persistent secretion of androgens together with decreased levels of sex hormone binding globulin (SHBG) in the circulation during menopause provides an increased biological availability of androgens [39]. Long-term androgen deprivation therapy for prostate cancer is associated with an increased risk of CRC [40]. While the physiological effects of androgens are maintained in postmenopausal women with an intact uterus and ovaries, these protective effects of androgens cannot be maintained in women who have undergone surgical removal of the uterus and ovaries. These protective effects of androgen support the results of our study that hysterectomy with or without adnexal surgery is associated with an increased risk of CRC regardless of the use of MHT in postmenopausal women. After menopause, the absolute amount of androgen decreases, but it is assumed to play a role in the risk reduction of CRC because it is secreted continuously until the age of 90 in postmenopausal women with an intact uterus and ovaries. However, in our study, there was no difference in the risk of CRC when adnexal surgery was performed. Therefore, further study is needed to identify more clearly the physiological role of the ovaries after menopause.

Most previous studies with MHT have reported that the decreased risk of CRC is related to the use of estrogen and/or progestin in women without hysterectomy but not to estrogen alone in women with hysterectomy [18–21]. A logical explanation for the role of progestins in the protection of CRC is that progestins can increase the estrogenic effects of conjugated estrogens, making them more biologically active in the colon in women without hysterectomy than estrogen alone in women with hysterectomy. Meijer et al. reported that CRC prevention by progestin medroxyprogesterone acetate (MPA) is critically dependent on postmenopausal status. They found that MPA reduces tumorigenesis in postmenopausal mice but not in fertile mice [41]. Zhang et al. demonstrated that progesterone suppressed proliferation in CRC cells by arresting the cell cycle and inducing apoptosis. Moreover, progesterone-induced inhibition of CRC progression was regulated by GADD45α/JNK/c-Jun signaling [42].

Since the discovery of two types of estrogen receptor, namely, ERα [43, 44] and ERβ [45, 46], it has become clear that estrogen has diverse and complex effects in various tissues. ERα and ERβ have different biological functions in both nuclear and extranuclear signaling. ERα promotes proliferative signaling through differential expression of pro- and antiapoptotic proteins [47]. However, ERβ plays a role as a dominant regulator reducing ERα-mediated gene expression, which results in a consequent negative effect on cell proliferation [48]. On the other hand, ERβ has antiproliferative effects in the absence of ERα by activating proapoptotic signaling [49]. Numerous studies have suggested that ERβ is essential for the maintenance of cellular homeostasis and for driving cellular differentiation in the colon [50]. In vitro and in vivo studies showing that ERβ is more highly expressed in colonic epithelial cells than ERα strongly suggest a functional implication for ERβ in mediating the effects of estrogens on colonic epithelial cancer cells [51] and in the protective effects of MHT against CRC [52].

Additionally, estrogen is emerging as an important regulator of bile acid (BA) production and, through critical hepatic feedback mechanisms, serum cholesterol levels [53]. BAs could act as tumor promoters in the colon. Approximately 90 ~ 95% of the BA pool is reabsorbed in the ileum, transported back to the liver via the hepatic portal vein and ready for new enterohepatic circulation. Approximately 5 ~ 10% of the total BA pool escapes from ileum reabsorption and flows to the colon, where some of it is deconjugated by bacterial bile salt hydrolases to become free BA and converted to secondary BAs. Less than 10% of these BAs are lost via feces [54]. Bacterial conversion of BAs in the colon has a significant impact on their tumorigenic activity through its effects on colonic microbial metabolism [55]. While hydrophilic, less cytotoxic BAs play a protective role in GI and liver cells, hydrophobic BAs can be cytotoxic and can generate oxidative stress and DNA damage, which affects the development of cancer in various digestive and extra-digestive organs by affecting epigenetic factors and changes in intestinal microbes [56]. Women have fewer BAs excreted in the stool and less cholesterol through bile production than men [57]. Therefore, a decrease in estrogen in women who undergo hysterectomy may contribute to the risk of developing CRC by increasing the proportion of BAs in the intestine.

One of the notable findings of our study is that the risk of rectal cancer had the highest HR of 1.933 in women who underwent hysterectomy and adnexal surgery among all CRC patients. However, we cannot explain this finding because we had difficulty finding previous studies with differential analysis for each colon cancer and rectal cancer. Further studies must be performed to determine the real impact of hysterectomy with adnexal surgery on the risk of rectal cancer in the future. The overall risk of GI cancer was not different between the groups with or without hysterectomy, but the risk of CRC increased in women who had hysterectomy. When we divided all GI cancers into upper GI (UGI) and lower GI (LGI) cancers, the risk of UGI cancer did not increase, but the risk of LGI cancer increased in women who underwent hysterectomy. These results are consistent with many epidemiologic studies showing that carcinogenesis of the UGI tract, especially esophageal and gastric cancer, is highly dependent on several medical conditions, such as gastroesophageal reflux disease (GERD), Barrett's esophagus, use of acid-suppressive medication or nonsteroidal anti-inflammatory drugs, and major environmental factors, such as tobacco use, diet, alcohol drinking, and Helicobacter pylori infection [58]. However, unlike the risk factors for UGI cancer, the risk factors for LGI cancer include female hormones in addition to environmental factors.

The strength of our study is that we analyzed the risk of cancer according to each portion of the GI track from the stomach to rectum in women who had a hysterectomy with/without adnexal surgery using big data from the national health care system of South Korea. Our study has some limitations. First, although adjustments were made for the numerous factors related to the risk of CRC, we must be careful in the interpretation of our results because this study has the inborn limitation of retrospective cohort studies. Second, our study is a one-sided sex analysis, which means that this study could ignore the complex effects sex-related hormones on the risk of CRC.

BAs, bile acids; BC, breast cancer; BMI, body mass index; BPA, bisphenol A; BWHS, black women’s health study; CCI, Charlson comorbidity index; CI, confidence interval; CIS, carcinoma in situ; CRC, colorectal cancer; DM, diabetes mellitus; E2, 17b-estradiol; P4, progesterone; GERD, gastroesophageal reflux disease; GI, gastrointestinal: HIRA, health insurance review and assessment service; HR, hazard ratio; HTN, hypertension; ICD-10, international classification of diseases, 10th revision; IRB, institutional review board; LGI, lower gastrointestinal; MHT, menopausal hormone therapy; MPA, medroxyprogesterone acetate; NHIS, national health insurance service; QoL, quality of life; RCT, randomized clinical trial; SES, socioeconomic status; SHBG, sex hormone binding globulin; UGI, upper gastrointestinal; WHI, Women’s Health Initiative

a. Ethical approval and consent to participate

This study was approved by the IRB of Sanggye Paik Hospital (Approval number: SGPAIK-2021-02-005). The need for written informed consents was waived by the IRB of Sanggye Paik Hospital due to data extraction for this study can be done only with NHIS servers according to NHIS's personal information protection policy. The NHIS provided the data to the investigators after removing the variables that can identify individuals. Therefore, the individual included in the data cannot be specified, so it does not cause any damage to the individual included in the data. All experiments were performed in accordance with relevant guidelines and regulations of the Declaration of Helsinki.

b. Consent for publication

Not applicable

c. Availability of data and materials

Data supporting the findings of this study are available upon request from the corresponding author.

d. Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

e. Funding

The authors declare that they have received no funding for this study.

f. Author contributions

Jin-Sung Yuk: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Resources, Supervision, Writing - review and editing.

Seung-Woo Yang: Writing - review and editing.

Sang-Hee Yoon: Writing - review and editing.

Myoung Hwan Kim: Writing - review and editing.

Yong-Soo Seo: Writing - review and editing.

Yujin Lee: Writing - review and editing.

Jungbin Kim: Writing - review and editing.

Keunho Yang: Writing - review and editing.

Geumhee Gwak: Supervision, Formal analysis, Investigation, Writing - original draft, Writing - review and editing.

Hyunjin Cho: Supervision, Project administration, Formal analysis, Investigation, Writing - review and editing.

g. Acknowledgement

We would like to thank Dr. Won I Park of the Korean Ministry of Food & Drug Safety for reviewing our manuscript.

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Table 1. Baseline characteristics of participants with/without hysterectomy from the Korea National Health Insurance Database, 2007-2020.


	Non-Hysterectomy	Hysterectomy	Total	P-value
Nunber of participants	89,768	66,204	155,972
Adnexal surgery during hysterectomy
Hysterectomy		51,439 (77.7)	51,439 (77.7)
Hysterectomy + adnexal surgery		14,765 (22.3)	14,765 (22.3)
Median age (years)	48 [43-53]	46 [44-49]	47 [44-52]	<0.001
Age at inclusion (years)				<0.001
40~44	27,736 (30.9)	21,616 (32.7)	49,352 (31.6)
45~49	21,731 (24.2)	28,908 (43.7)	50,639 (32.5)
50~54	22,535 (25.1)	13,274 (20.1)	35,809 (23)
55~59	17,766 (19.8)	2,406 (3.6)	20,172 (12.9)
Year at inclusion				<0.001
2011	19,076 (21.3)	19,267 (29.1)	38,343 (24.6)
2012	20,296 (22.6)	17,096 (25.8)	37,392 (24)
2013	24,478 (27.3)	15,369 (23.2)	39,847 (25.5)
2014	25,918 (28.9)	14,472 (21.9)	40,390 (25.9)
SES				<0.001
Mid~high SES	86,920 (96.8)	64,714 (97.7)	151,634 (97.2)
Low SES	2,848 (3.2)	1,490 (2.3)	4,338 (2.8)
Region				<0.001
Urban area	47,904 (53.4)	42,379 (64)	90,283 (57.9)
Rural area	41,864 (46.6)	23,825 (36)	65,689 (42.1)
CCI				<0.001
0	66,666 (74.3)	50,902 (76.9)	117,568 (75.4)
1	13,125 (14.6)	8,758 (13.2)	21,883 (14)
≥2	9,977 (11.1)	6,544 (9.9)	16,521 (10.6)
Parity in cohort				<0.001
0	86,181 (96)	65,316 (98.7)	151,497 (97.1)
1	2,278 (2.5)	626 (0.9)	2,904 (1.9)
≥2	1,309 (1.5)	262 (0.4)	1,571 (1)
Menopause before inclusion				<0.001
Absent	71,234 (79.4)	60,747 (91.8)	131,981 (84.6)
Present	18,534 (20.6)	5,457 (8.2)	23,991 (15.4)
MHT before inclusion				<0.001
Absent	86,244 (96.1)	65,277 (98.6)	151,521 (97.1)
Present	3,524 (3.9)	927 (1.4)	4,451 (2.9)
Adnexal surgery before inclusion				<0.001
Absent	88,076 (98.1)	65,481 (98.9)	153,557 (98.5)
Present	1,692 (1.9)	723 (1.1)	2,415 (1.5)
Diseases of the gallbladder and biliary tract before inclusion				<0.001
Absent	88,280 (98.3)	65,330 (98.7)	153,610 (98.5)
Present	1,488 (1.7)	874 (1.3)	2,362 (1.5)
Uterine leiomyoma				<0.001
Absent	81,590 (90.9)	13,870 (21)	95,460 (61.2)
Present	8,178 (9.1)	52,334 (79)	60,512 (38.8)
Endometriosis				<0.001
Absent	87,904 (97.9)	48,535 (73.3)	136,439 (87.5)
Present	1,864 (2.1)	17,669 (26.7)	19,533 (12.5)
MHT after inclusion				<0.001
Absent	83,456 (93)	56,757 (85.7)	140,213 (89.9)
Present	6,312 (7)	9,447 (14.3)	15,759 (10.1)

CCI, Charlson comorbidity index; MHT, menopausal hormone therapy; SES, socioeconomic status
Data are expressed as the number (%) or median [25 percentile, 75 percentile].

Table 2. The incidence of gastrointestinal cancer in participants with/without hysterectomy from the Korea National Health Insurance Database, 2007-2020.


	Non-Hysterectomy	Hysterectomy	Total	P-value
Nunber of participants	89,768	66,204	155,972
Esophageal cancer				0.975
Absent	89,760 (100)	66,198 (100)	155,958 (100)
Present	8 (0.008)	6 (0.009)	14 (0.009)
Stomach cancer				0.162
Absent	89,521 (99.7)	66,046 (99.8)	155,567 (99.7)
Present	247 (0.275)	158 (0.238)	405 (0.260)
Small bowel cancer				0.805
Absent	89,753 (100)	66,194 (100)	155,947 (100)
Present	15 (0.017)	10 (0.015)	25 (0.016)
Colon cancer				0.032
Absent	89,594 (99.8)	66,042 (99.8)	155,636 (99.8)
Present	174 (0.194)	162 (0.225)	336 (0.215)
Sigmoid cancer				0.023
Absent	89,733 (100)	66,161 (99.9)	155,894 (99.9)
Present	35 (0.039)	43 (0.065)	78 (0.050)
Rectal cancer				0.036
Absent	89,674 (99.9)	66,110 (99.9)	155,784 (99.9)
Present	94 (0.105)	94 (0.142)	188 (0.121)
Colorectal cancer				0.004
Absent	89,503 (99.7)	65,953 (99.6)	155,456 (99.7)
Present	265 (0.295)	251 (0.379)	516 (0.331)
Gastrointestinal cancer				0.327
Absent	89,235 (99.4)	65,785 (99.4)	155,020 (99.4)
Present	533 (0.594)	419 (0.633)	952 (0.610)

Data are expressed as the number (%).

Table 3. Hazard ratios of gastrointestinal cancer in participants with/without hysterectomy from the Korea National Health Insurance Database, 2007-2020.

	Unadjusted		Adjusted ^a
	HR (95% CI) ^a	P-value	HR (95% CI) ^a	P-value
Esophageal cancer
Reference (no hysterectomy)	1 (reference)		1 (reference)
Hysterectomy alone	1.031 (0.337-3.156)	0.957	0.558 (0.104-3.001)	0.497
Hysterectomy + adnexal surgery	0.726 (0.091-5.803)	0.763	0.355 (0.032-3.975)	0.401
Stomach cancer
Reference (no hysterectomy)	1 (reference)		1 (reference)
Hysterectomy alone	0.842 (0.679-1.045)	0.118	0.959 (0.689-1.334)	0.805
Hysterectomy + adnexal surgery	0.781 (0.543-1.124)	0.183	0.854 (0.55-1.324)	0.48
Small bowel cancer
Reference (no hysterectomy)	1 (reference)		1 (reference)
Hysterectomy alone	1.069 (0.479-2.382)	0.871	0.724 (0.2-2.62)	0.622
Hysterectomy + adnexal surgery	1 (0-Infinite)	0.984	1 (0-Infinite)	0.99
Colon cancer
Reference (no hysterectomy)	1 (reference)		1 (reference)
Hysterectomy alone	1.249 (0.996-1.566)	0.055	1.523 (1.068-2.17)	0.02
Hysterectomy + adnexal surgery	0.999 (0.678-1.471)	0.994	1.138 (0.712-1.82)	0.589
Sigmoid cancer
Reference (no hysterectomy)	1 (reference)		1 (reference)
Hysterectomy alone	1.71 (1.073-2.724)	0.024	1.647 (0.808-3.359)	0.17
Hysterectomy + adnexal surgery	1.168 (0.519-2.63)	0.708	1.045 (0.397-2.755)	0.929
Rectal cancer
Reference (no hysterectomy)	1 (reference)		1 (reference)
Hysterectomy alone	1.113 (0.808-1.531)	0.513	1.128 (0.7-1.818)	0.62
Hysterectomy + adnexal surgery	1.924 (1.282-2.888)	0.002	1.933 (1.131-3.302)	0.016
Colorectal cancer
Reference (no hysterectomy)	1 (reference)		1 (reference)
Hysterectomy alone	1.222 (1.016-1.47)	0.033	1.406 (1.057-1.871)	0.019
Hysterectomy + adnexal surgery	1.206 (0.902-1.613)	0.206	1.315 (0.917-1.884)	0.136
Gastrointestinal cancer
Reference (no hysterectomy)	1 (reference)		1 (reference)
Hysterectomy alone	1.029 (0.897-1.181)	0.68	1.169 (0.946-1.446)	0.149
Hysterectomy + adnexal surgery	0.963 (0.768-1.206)	0.741	1.042 (0.791-1.372)	0.772

CCI, Charlson comorbidity index; CI, confidence interval; HR, hazard ratio; MHT, menopausal hormone therapy; SES, socioeconomic status

^a HRs were adjusted for hysterectomy, age, SES, regrion, CCI, parity, menopause before inclusion, MHT before inclusion, adnexal surgery before inclusion, diseases of the gallbladder and biliary tract before inclusion, uterine leiomyoma, endometriosis.

Table 4. Hazard ratios of all-cause mortality in participants with Gastrointestinal cancer from the Korea National Health Insurance Database, 2007-2020.


	Adjusted ^a
	HR (95% CI) ^a	P-value
Colon cancer
Reference (no hysterectomy)	1 (reference)
Hysterectomy alone	2.405 (0.385-15.018)	0.348
Hysterectomy + adnexal surgery	1 (0-Infinite)	0.993
Colorectal cancer
Reference (no hysterectomy)	1 (reference)
Hysterectomy alone	3.369 (0.641-17.719)	0.152
Hysterectomy + adnexal surgery	1 (0-Infinite)	0.991
Gastrointestinal cancer
Reference (no hysterectomy)	1 (reference)
Hysterectomy alone	3.495 (1.347-9.07)	0.001
Hysterectomy + adnexal surgery	1.913 (0.535-6.844)	0.319

CCI, Charlson comorbidity index; CI, confidence interval; HR, hazard ratio; MHT, menopausal hormone therapy; SES, socioeconomic status

No competing interests reported.

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Association between the risk of gastrointestinal cancer and hysterectomy from the National Health Insurance Database

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