Key Points
Question
Are reproductive factors and endometrial cancer risk associated among individuals in East Asia?
Findings
In this pooled cohort study of 332 625 women including 1005 endometrial cancer cases from 13 Asian cohort studies, late menarche, early menopause, and a greater number of deliveries were associated with a lower risk of endometrial cancer.
Meaning
The findings from this large pooled analysis in Asia, which are consistent with previous evidence, may have an impact on the understanding of risk factors for endometrial cancer.
This cohort study assesses the association of reproductive factors, such as number of deliveries, age at menarche, and age at menopause, with endometrial cancer risk among East Asian women.
Abstract
Importance
Despite evidence of an association between reproductive factors and endometrial cancer risk, prospective studies have been conducted mainly in non-Asian countries.
Objective
To assess the association between reproductive factors, such as number of deliveries, age at menarche, or menopause, and endometrial cancer risk.
Design, Setting, and Participants
This cohort study used pooled individual data from 13 prospective cohort studies conducted between 1963 and 2014 in the Asia Cohort Consortium. Participants were Asian women. Data analysis was conducted from September 2019 to April 2023.
Exposures
Reproductive factors were assessed using a questionnaire in each cohort.
Main Outcomes and Measures
The main outcome was time to incidence of endometrial cancer. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% CIs.
Results
A total of 1005 endometrial cancer cases were detected among 332 625 women (mean [SD] age, 54.3 [10.4] years) during a mean (SD) of 16.5 (6.4) years of follow-up. Increasing number of deliveries was associated with a decreased endometrial cancer risk in a dose-response manner (≥5 deliveries vs nulliparous [reference]: HR, 0.37; 95% CI, 0.26-0.53; P for trend < .001). Compared with menarche at younger than 13 years, menarche at 17 years or older had an HR of 0.64 (95% CI, 0.48-0.86; P for trend < .001). Late menopause (age ≥55 years) showed an HR of 2.84 (95% CI, 1.78-4.55; P for trend < .001) compared with the youngest age category for menopause (<45 years). Age at first delivery, hormone therapy, and breastfeeding were not associated with endometrial cancer risk.
Conclusions and Relevance
This large pooled study of individual participant data found that late menarche, early menopause, and a higher number of deliveries were significantly associated with a lower risk of endometrial cancer. These convincing results from Asian prospective studies add to the growing body of evidence for the association between reproductive factors and endometrial cancer.
Introduction
Endometrial cancer is the sixth most common cancer among women worldwide and accounted for 2% of new cancer cases and 1% of deaths in 2020.1 The region-specific incidence varies worldwide; the age-standardized rate (per 100 000) was 21.1 in North America and 8.2 in Eastern Asia.2,3 In addition to regional variations, the incidence rate differs according to race. According to the Surveillance, Epidemiology, and End Results Program in the United States, the incidence rate was 28.0 among non-Hispanic White people and 22.6 among Asian and Pacific Islander people.4 Although previous studies have prospectively investigated reproductive factors and the risk of endometrial cancer in the United States and Europe,5,6,7 limited studies in this regard have emanated from Asian countries.8
The endometrium modifies its structure in response to the menstrual cycle, with fluctuations in estrogen and progesterone levels. It has been hypothesized that unopposed estrogen exposure leads to endometrial hyperplasia, which increases the risk of endometrial cancer.9,10 Reproductive factors, such as parity, age at menarche, and menopause, are potentially associated with differences in unopposed estrogen exposure among individuals and might lead to different endometrial cancer risks. Prospective studies have examined these associations,5,6,7 and meta-analyses including case-control and prospective studies have been published.11,12,13,14,15 According to an umbrella review, which included 171 meta-analyses of 1354 individual studies of 53 risk factors, parity, higher age at last birth, and higher age at menarche were associated with a decreased risk of endometrial cancer.16 Moreover, many previous studies have shown that multiparity, higher parity, and early menopause are associated with a decreased risk of endometrial cancer.14,15 However, the association of some factors, such as age at the first pregnancy or breastfeeding, with endometrial cancer risk has been controversial in prospective studies.5,6,7,14
In Asian countries, investigating factors associated with endometrial cancer in a single prospective cohort is likely to be difficult because the incidence rate of endometrial cancer is relatively low.2,3 Therefore, in this study, we pooled 13 Asian prospective cohort studies in the Asia Cohort Consortium (ACC), aiming to investigate the association between reproductive factors and endometrial cancer with a large sample size.
Methods
Study Population
ACC is a consortium of prospective studies conducted in Asia. The details of the ACC have been described elsewhere.17,18,19 Thirteen cohort studies were included in the endometrial cancer project, among which 8 were conducted in Japan,20,21,22,23,24,25,26,27 3 were conducted in Korea,28,29,30 1 in China,31 and 1 in Singapore.32 These cohort studies provided information on reproductive factors, the incidence of endometrial cancer, follow-up duration, and potential confounders, such as age, current smoking status, and alcohol drinking status at the baseline. We excluded participants with the following characteristics: male sex (n = 241 676); missing data regarding sex and age (n = 2422); history of endometrial cancer at the baseline survey (n = 1039); follow-up duration of 0 or less or missing (n = 1858); history of hysterectomy at baseline (n = 10 004); body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) of less than 14 or greater than 45 (n = 7571); and missing data on parity (n = 15 884). A total of 332 625 participants were included in this study.
Ethics Approval and Consent to Participate
The institutional review board of the National Cancer Center Japan approved the protocol for the analysis in the ACC. Each cohort study protocol, including that pertaining to informed consent, was approved by the respective institutional ethics committees. Reporting of this study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Exposure, Outcome, and Other Variables
Our working group in the ACC cleaned the data to harmonize responses to different questions in the participating cohort studies. The detailed process is described in the eAppendix in Supplement 1. For example, given that the response to number of deliveries was categorical in 2 participating studies, we used the categorical values in the analysis and defined the cutoff values included in the original categories. Regarding the question about pregnancy, we focused on the number of deliveries (full-term births) rather than the number of pregnancies because most cohorts asked this. Moreover, we defined the plausible range of the age at first delivery (10-49 years), age at menarche (10-23 years), and menopause (≥20 years), and responses to age beyond this range were treated as missing so as not to include implausible answers in the analyses.
Regarding reproductive factors, questions pertaining to pregnancy (never and ever), the number of deliveries (0, 1-2, 3-4, and ≥5 times), age at first delivery (≤20, 21-25, 26-30, and ≥31 years or nulliparous), age at menarche (<13, 13-14, 15-16, and ≥17 years), menopausal status (premenopausal and postmenopausal), age at menopause (<45, 45-49, 50-54, and ≥55 years), breastfeeding status (never and ever), and hormone therapy (HT) status (never and ever) were asked in the baseline questionnaire of each prospective study. A limited number of cohorts included questions pertaining to breastfeeding and HT status. Since oral contraceptive (OC) use (never or ever) was asked in 5 cohorts, we did not assess the association of OC use with the risk of endometrial cancer. Also, since the number of deliveries was not assessed in the Life Span Study (LSS), results regarding the number of deliveries were not included. In addition, the Japan Collaborative Cohort Study (JACC) and LSS included questions about age at first pregnancy (not delivery).
The incidence of endometrial cancer was determined in each prospective study via linkage to local cancer registries. The International Classification of Diseases for Oncology, Third Edition, codes for endometrial cancer are C54 and C55.9. First primary cancer was included in this study. Information on whether the endometrial cancer was primary, secondary, or more was collected in each cohort and submitted to the study coordinating center. Because information regarding morphological and histological codes was submitted for a limited number of cohorts, topological codes were used for the definition. Age (continuous), BMI (continuous), current smoking status (yes and no), and current alcohol consumption status at the baseline (yes and no) were considered as possible confounding variables in the model.
Statistical Analysis
This analysis was conducted from September 2019 to April 2023. In the present analysis, we examined the association between reproductive factors and endometrial cancer incidence using hazard ratios (HRs) and 95% CIs in the Cox proportional hazards model. The shared frailty model was applied to pooled individual data, and we used the variable of a cohort in the RANDOM statement of the PHREG procedure in SAS software.33 We created 2 statistical models: age-adjusted and multivariable-adjusted. The age-adjusted model incorporated adjustment for age at the baseline, while the multivariable-adjusted model incorporated adjustment for age at the baseline, current smoking status, current drinking status, and other reproductive factors (age at menarche and menopause were adjusted in the model of parous status, number of deliveries, and age at first delivery; age at menopause and parous status were adjusted in the model of age at menarche; age at menarche and parous status were adjusted in the model for age at menopause; parous status, age at menarche, and menopause were adjusted in the model for HT use and breastfeeding). Regarding missing values for menopausal status, we defined postmenopausal when participants’ menopausal status was missing and their age was 54 years or older and those aged 44 years or younger were defined as premenopausal because the median age at menopause is approximately 50 years among Japanese women, and these statuses were plausible.34 On the other hand, the menopausal status of participants with age 45 to 53 years was left as a missing at the time of this variable cleaning. Next, 5 rounds of multiple imputation were performed on the pooled individual data for missing adjusted variables. Reproductive factors, age at the baseline, BMI, follow-up duration, and diagnosis of endometrial cancer were included in the multiple imputation procedure in SAS, and the Markov chain Monte Carlo method was used. The 5 calculated estimates were combined into the final estimates according to Rubin rule using the SAS MIANALYZE procedure. To calculate the P for trend, we used the mean value of each category when there was a range of values in that category. For example, for age 45 to 49 years in the second category of age at menopause, we applied 47 to calculate P for trend. We performed stratified analyses classified by BMI (greater or less than the median), menopausal status, and parity. In addition, because nulliparous women could not be distinguished from women who did not report age at first pregnancy in LSS, we further examined associations excluding LSS to confirm the consistency of the results. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc), and P < .05 indicated statistical significance.
Results
Among 332 625 women (mean [SD] age, 54.3 [10.4] years at baseline) from 13 cohort studies, a total of 1005 endometrial cancer cases were observed. The baseline characteristics of the cohort studies are presented in Table 1. The mean participants’ age at baseline ranged from 49.5 to 61.2 years. More than 90% of the participants experienced pregnancy, except those included in the LSS. A majority of participants reported experiencing menarche at age 13 to 16 years and menopause at age 45 to 54 years.
Table 1. Characteristics of Participants in the Included Cohort Studies.
| Characteristic | Participants, No. (%) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SWHS | JPHC1 | JPHC2 | JACC | Miyagi | Ohsaki | LSS | Takayama | 3P Miyagi | KMCC | KNCC | Namwon | SCHS | Total | |
| No. of women after exclusion | 74 892 | 21 073 | 27 094 | 40 836 | 21 903 | 21 043 | 29 886 | 14 491 | 15 635 | 8640 | 15 586 | 6277 | 35 269 | 332 625 |
| Endometrial cancer cases, No. | 303 | 97 | 67 | 63 | 89 | 47 | 105 | 39 | 25 | 10 | 25 | 6 | 129 | 1005 |
| Baseline year | 1997-2000 | 1990-1992 | 1993-1995 | 1988-1990 | 1990 | 1995 | 1963-1993 | 1992 | 1984 | 1994-2004 | 2002-2014 | 2004-2007 | 1993-1999 | NA |
| Country | China | Japan | Japan | Japan | Japan | Japan | Japan | Japan | Japan | Korea | Korea | Korea | Singapore | NA |
| Duration of follow-up, mean (SD), y | 17.3 (3.1) | 21.5 (3.7) | 18.4 (3.5) | 16.4 (5.5) | 22.2 (5.5) | 11.0 (4.2) | 23.4 (10.3) | 14.0 (3.8) | 7.8 (2.5) | 14.3 (4.2) | 9.1 (3.3) | 12.7 (2.1) | 14.3 (3.5) | 16.5 (6.4) |
| Age, mean (SD), y | 52.6 (9.1) | 49.6 (5.9) | 54.2 (8.8) | 57.3 (10.0) | 52.0 (7.4) | 60.2 (10.0) | 52.0 (15.1) | 55.4 (13.2) | 56.9 (11.2) | 54.3 (13.8) | 49.5 (9.1) | 61.2 (7.9) | 56.3 (8.0) | 54.3 (10.4) |
| BMI, mean (SD) | 24.0 (3.4) | 23.6 (3.1) | 23.4 (3.2) | 22.9 (3.1) | 23.7 (3.1) | 23.7 (3.2) | 22.0 (3.5) | 22.0 (2.9) | 23.3 (3.4) | 24.0 (3.4) | 23.0 (3.0) | 24.6 (3.2) | 23.2 (3.3) | 23.3 (3.3) |
| Current smoker | 1783 (2.4) | 1201 (5.7) | 1719 (6.3) | 1797 (4.4) | 1459 (6.7) | 1372 (6.5) | 3896 (13.0) | 1673 (11.5) | 1018 (6.5) | 590 (6.8) | 674 (4.3) | 288 (4.6) | 2198 (6.2) | 19 668 (5.9) |
| Current alcohol drinker | 1453 (1.9) | 4860 (23.1) | 5405 (19.9) | 8851 (21.7) | 4647 (21.2) | 4086 (19.4) | 7798 (26.1) | 9564 (66.0) | 3727 (23.8) | 1504 (17.4) | 6543 (42.0) | 2151 (34.3) | 3166 (9.0) | 63 755 (19.2) |
| Family history of endometrial cancer | NA | 301 (1.4) | 381 (1.4) | 197 (0.5) | 488 (2.2) | NA | NA | NA | 318 (2.0) | NA | 72 (0.5) | NA | NA | 1757 (0.5) |
| Ever pregnant | 72 392 (96.7) | 19 914 (94.5) | 25 523 (94.2) | 39 314 (96.3) | 21 360 (97.5) | 20 321 (96.6) | 21 149 (70.8) | 13 254 (91.5) | 14 129 (90.4) | 8180 (94.7) | 15 046 (96.5) | 6242 (99.4) | 32 766 (92.9) | 309 590 (93.1) |
| Ever received HT | 2650 (3.5) | NA | NA | NA | 1412 (6.4) | 1578 (7.5) | NA | 219 (1.5) | NA | 270 (1.4) | 2145 (13.8) | 672 (10.7) | 1300 (3.7) | 10 246 (3.1) |
| Ever breastfed | NA | 16 770 (79.6) | 22 017 (81.3) | NA | 16 861 (77.0) | 17 033 (81.0) | NA | NA | NA | 7136 (82.6) | 11 557 (74.1) | 6046 (96.3) | NA | 97 420 (29.3) |
| No. of deliveries | ||||||||||||||
| 0 | 2500 (3.3) | 1159 (5.5) | 1570 (5.8) | 1522 (3.7) | 543 (2.5) | 722 (3.4) | NA | 1237 (8.5) | 1506 (9.6) | 460 (5.3) | 541 (3.5) | 35 (0.6) | 2503 (7.1) | 14 298 (4.3) |
| 1-2 | 56 675 (75.7) | 8794 (41.7) | 10 899 (40.2) | 17 849 (43.7) | 10 690 (48.8) | 8801 (41.8) | NA | 8252 (56.9) | 6233 (39.9) | 1790 (20.7) | 11 308 (72.5) | 840 (13.4) | 9925 (28.1) | 152 056 (45.7) |
| 3-4 | 12 504 (16.7) | 9092 (43.1) | 10 646 (39.3) | 17 996 (44.1) | 9841 (44.9) | 9477 (45.0) | NA | 4232 (29.2) | 5379 (34.4) | 3265 (37.8) | 3449 (22.1) | 2682 (42.7) | 13043 (37.0) | 101 606 (30.5) |
| ≥5 | 3213 (4.3) | 1837 (8.7) | 3661 (13.5) | 3469 (8.5) | 829 (3.8) | 2043 (9.7) | NA | 770 (5.4) | 2517 (16.1) | 3031 (35.1) | 289 (1.9) | 2709 (43.2) | 9798 (27.8) | 34 166 (10.3) |
| Age at first delivery, y | ||||||||||||||
| ≤20 | 8520 (11.4) | 1630 (7.7) | 1832 (6.8) | 1901 (4.7) | 1554 (7.1) | 1739 (8.3) | 4738 (15.9) | 658 (4.5) | 1406 (9.0) | 1664 (19.3) | 330 (2.1) | 1600 (25.5) | 6846 (19.4) | 34 418 (10.3) |
| 21-25 | 22 892 (30.6) | 10 574 (50.2) | 14 271 (52.7) | 21 193 (51.9) | 14 221 (64.9) | 13 863 (65.9) | 11 710 (39.2) | 7376 (50.9) | 8520 (54.5) | 4733 (54.8) | 5341 (34.3) | 3800 (60.5) | 13 522 (38.3) | 152 016 (45.7) |
| 26-30 | 33 168 (44.3) | 6013 (28.5) | 7079 (26.1) | 11 903 (29.1) | 4711 (21.5) | 3497 (16.6) | 3708 (12.4) | 4034 (27.8) | 3139 (20.1) | 1268 (14.7) | 7552 (48.4) | 684 (10.9) | 8878 (25.2) | 95 634 (28.8) |
| ≥31 | 7807 (10.4) | 1253 (5.9) | 1337 (4.9) | 1787 (4.4) | 746 (3.4) | 570 (2.7) | 993 (3.3) | 786 (5.4) | 734 (4.7) | 211 (2.4) | 1345 (8.6) | 104 (1.7) | 3496 (9.9) | 21 169 (6.4) |
| Nulliparous or missing | 2505 (3.3) | 1603 (7.6) | 2575 (9.5) | 4052 (9.9) | 671 (3.1) | 1374 (6.5) | 8737 (29.2) | 1636 (11.3) | 1836 (11.7) | 764 (8.8) | 1019 (6.5) | 89 (1.4) | 2527 (7.2) | 29 388 (8.8) |
| Age at menarche, y | ||||||||||||||
| <13 | 4691 (6.3) | 1873 (8.9) | 2445 (9.0) | 2537 (6.2) | 1733 (7.9) | 472 (2.2) | 1321 (4.4) | 1862 (12.9) | 881 (5.6) | 102 (1.2) | 544 (3.5) | 247 (3.9) | 5043 (14.3) | 23 751 (7.1) |
| 13-14 | 27 327 (36.5) | 8610 (40.9) | 10 620 (39.2) | 14 264 (34.9) | 8260 (37.7) | 3222 (15.3) | 8603 (28.8) | 5287 (36.5) | 5175 (33.1) | 1031 (11.9) | 2713 (17.4) | 1293 (20.6) | 13 545 (38.4) | 109 950 (33.1) |
| 15-16 | 29 532 (39.4) | 7378 (35.0) | 8845 (32.6) | 14 867 (36.4) | 6883 (31.4) | 4825 (22.9) | 8193 (27.4) | 4952 (34.2) | 6036 (38.6) | 2824 (32.7) | 2644 (17.0) | 1417 (22.6) | 12 164 (34.5) | 11 0560 (33.2) |
| ≥17 | 13 317 (17.8) | 2948 (14.0) | 4928 (18.2) | 7441 (18.2) | 2960 (13.5) | 2413 (11.5) | 3606 (12.1) | 2035 (14.0) | 2808 (18.0) | 4378 (50.7) | 1181 (7.6) | 828 (13.2) | 4510 (12.8) | 53 353 (16.0) |
| Missing | 25 (<0.1) | 264 (1.3) | 256 (0.9) | 1727 (4.2) | 2067 (9.4) | 10111 (48.0) | 8163 (27.4) | 355 (2.5) | 735 (4.7) | 305 (3.5) | 8504 (54.6) | 2492 (39.7) | 7 (<0.1) | 35 011 (10.5) |
| Age at menopause, y | ||||||||||||||
| Premenopausal | 37 093 (49.5) | 9538 (45.3) | 8900 (32.9) | 5116 (12.5) | 8598 (39.3) | 3773 (17.9) | 11 897 (39 8) | 6156 (42.5) | 4340 (27.8) | 285 (3.3) | 5934 (38.1) | 752 (12.0) | 9388 (26.6) | 111 770 (33.6) |
| <45 | 6266 (8.4) | 1724 (8.2) | 2449 (9.0) | 2719 (6.7) | 1959 (8.9) | 1820 (8.7) | 2416 (8.1) | 751 (5.2) | 1133 (7.2) | 1065 (12.2) | 709 (4.5) | 1353 (21.6) | 3125 (8.9) | 27 479 (8.3) |
| 45-49 | 16 394 (21. 9) | 4153 (19.7) | 5800 (21.4) | 8993 (22.0) | 3518 (16.1) | 4189 (19.9) | 5036 (16.9) | 2226 (15.4) | 2582 (16.5) | 1494 (17.3) | 2240 (14.4) | 1755 (28.0) | 7944 (22.5) | 66 324 (19.9) |
| 50-54 | 13 218 (17.6) | 4993 (23.7) | 8396 (31.0) | 13 901 (34.0) | 4512 (20.6) | 6312 (30.0) | 5382 (18.0) | 4431 (30.6) | 3039 (19.4) | 1901 (22.0) | 3732 (23.9) | 1893 (30.2) | 12511 (35.5) | 84 221 (25.3) |
| ≥55 | 1439 (1.9) | 296 (1.4) | 929 (3.4) | 1561 (3.8) | 423 (1.9) | 820 (3.9) | 557 (1.9) | 441 (3.0) | 314 (2.0) | 417 (4.8) | 723 (4.6) | 393 (6.3) | 1936 (5.5) | 10 249 (3.1) |
| Missing | 482 (0.6) | 369 (1.8) | 620 (2.3) | 8546 (20.9) | 2893 (13.2) | 4129 (19.6) | 4598 (15.4) | 486 (3.3) | 4227 (27.0) | 3488 (40.4) | 2248 (14.4) | 131 (2.1) | 365 (1.0) | 32 582 (9.8) |
Abbreviations: 3P, 3-Prefecture; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared; HT, hormone therapy; JACC, Japan Collaborative Cohort Study; JPHC, Japan Public Health Center-Based Prospective Study; KMCC, Korean Multicenter Cancer Cohort Study; KNCC, Korean National Cancer Center Cohort Study; LSS, Life Span Study; NA, not applicable; SCHS, Singapore Chinese Health Study; SWHS, Shanghai Women’s Health Study.
The results pertaining to associations between reproductive factors and the risk of endometrial cancer are shown in Table 2. Participants who reported ever being pregnant showed a significantly lower risk of endometrial cancer than the nulliparous group (HR, 0.54; 95% CI, 0.48-0.67). An increased number of deliveries was associated with a decreased risk of endometrial cancer. Compared with nulliparous women, the HRs for women with 1 to 2, 3 to 4, and 5 or more deliveries were 0.54 (95% CI, 0.42-0.70), 0.50 (95% CI, 0.38-0.64), and 0.31 (95% CI, 0.22-0.45), respectively (P for trend < .001). Among parous women, when the lowest category of number of deliveries (1-2) was set as a reference, the HRs for the highest category (≥5 deliveries) was 0.57 (95% CI, 0.42-0.78) (P for trend = .003). The results adjusted for age as a categorical variable were similar and are shown in eTable 1 in Supplement 1.
Table 2. Association Between Reproductive Factors and Endometrial Cancer Risk Among Prospective Cohorts in the Asia Cohort Consortium.
| Factor | No. of cases | No. of participants | Age-adjusted HR (95% CI)a | Multivariable-adjusted (with LSS)b | Multivariable-adjusted (excluding LSS)b |
|---|---|---|---|---|---|
| Pregnancy | |||||
| Never | 103 | 23 035 | 1 [Reference] | 1 [Reference] | 1 [Reference] |
| Ever | 902 | 309 590 | 0.58 (0.47-0.71) | 0.54 (0.48-0.67) | 0.51 (0.40-0.65) |
| No. of deliveries | |||||
| 0 | 72 | 14 298 | 1 [Reference] | NA | 1 [Reference] |
| 1-2 | 496 | 152 056 | 0.58 (0.45-0.75) | NA | 0.54 (0.42-0.70) |
| 3-4 | 276 | 101 606 | 0.56 (0.43-0.72) | NA | 0.50 (0.38-0.64) |
| ≥5 | 54 | 34 166 | 0.37 (0.26-0.53) | NA | 0.31 (0.22-0.45) |
| P for trend | NA | NA | <.001 | NA | <.001 |
| No. of deliveries among parous women | |||||
| 1-2 | 496 | 152 056 | 11 [Reference] | NA | 1 [Reference] |
| 3-4 | 276 | 101 606 | 0.94 (0.80-1.10) | NA | 0.90 (0.76-1.06) |
| ≥5 | 54 | 34 166 | 0.61 (0.45-0.83) | NA | 0.57 (0.42-0.78) |
| P for trend | NA | NA | .01 | NA | .003 |
| Age at first delivery among parous women, yc | |||||
| ≤20 | 97 | 34 418 | 1 [Reference] | 1 [Reference] | 1 [Reference] |
| 21-25 | 451 | 152 016 | 1.05 (0.84-1.31) | 1.11 (0.89-1.39) | 1.05 (0.82-1.33) |
| 26-30 | 278 | 95 634 | 0.91 (0.71-1.16) | 0.99 (0.77-1.26) | 0.94 (0.73-1.21) |
| ≥31 | 63 | 21 169 | 0.91 (0.66-1.26) | 0.99 (0.72-1.37) | 0.91 (0.65-1.28) |
| P for trend | NA | NA | .12 | .20 | .20 |
| Age at menarche, y | |||||
| <13 | 93 | 23 751 | 1 [Reference] | 1 [Reference] | 1 [Reference] |
| 13-14 | 402 | 109 950 | 0.95 (0.76-1.20) | 0.99 (0.79-1.24) | 0.99 (0.78-1.25) |
| 15-16 | 336 | 110 560 | 0.84 (0.67-1.07) | 0.89 (0.70-1.13) | 0.91 (0.71-1.16) |
| ≥17 | 105 | 53 353 | 0.60 (0.45-0.80) | 0.64 (0.48-0.86) | 0.66 (0.49-0.89) |
| P for trend | NA | NA | <.001 | <.001 | .002 |
| Age at menopause among postmenopausal women, y | |||||
| <45 | 39 | 27 479 | 1 [Reference] | 1 [Reference] | 1 [Reference] |
| 45-49 | 122 | 66 324 | 1.32 (0.92-1.89) | 1.33 (0.92-1.91) | 1.36 (0.93-2.00) |
| 50-54 | 235 | 84 221 | 2.15 (1.52-3.04) | 2.14 (1.51-3.02) | 2.12 (1.46-3.06) |
| ≥55 | 35 | 10 249 | 2.92 (1.82-4.67) | 2.84 (1.78-4.55) | 2.90 (1.77-4.75) |
| P for trend | NA | NA | <.001 | <.001 | <.001 |
| HT used | |||||
| Never | 586 | 169 003 | 1 [Reference] | NA | 1 [Reference] |
| Ever | 17 | 10 246 | 0.57 (0.35-0.93) | NA | 0.62 (0.38-1.01) |
| Breastfeedingd | |||||
| Never | 55 | 15 189 | 1 [Reference] | NA | 1 [Reference] |
| Ever | 246 | 97 195 | 0.77 (0.57-1.04) | NA | 0.76 (0.56-1.02) |
Abbreviations: HR, hazard ratio; HT, hormone therapy; LSS, Life Span Study; NA, not applicable.
Adjusted for age at baseline. HRs were calculated using the Cox proportional hazard frailty model (with random effects).
Adjusted for age at baseline, body mass index, age at menarche, age at menopause (including premenopausal), current smoking, current drinking, parity, HT use, and breastfeeding. HRs were calculated using the Cox proportional hazard frailty model (with random effects).
Japan Collaborative Cohort Study and LSS included questions about the age at first pregnancy (not delivery).
Model for HT use included 8 cohorts and that for breastfeeding included 7 cohorts.
Older age at menarche and younger age at menopause were significantly associated with a lower risk of endometrial cancer. When the youngest categories of age at menarche (<13 years) and menopause (<45 years) were defined as references, the HR of the highest age at menarche (≥17 years) was 0.64 (95% CI, 0.48-0.86; P for trend = .004) and that of menopause (≥55 years) was 2.84 (95% CI, 1.78-4.55; P for trend < .001). Age at first delivery, HT use, and breastfeeding were not associated with endometrial cancer risk, although point estimates of the HR for HT use and ever breastfeeding were less than 1.0. We examined the influence of one study by excluding each study, but the results did not change largely (eTable 2 in Supplement 1). Moreover, the results did not change significantly when missing values were treated as a single category.
The Figure shows the results stratified by BMI, menopausal status, and parity, and the detailed results are shown in eTable 3 in Supplement 1. Most results were similar to those obtained in the main analyses. Because the number of cancer cases became small due to stratification, the associations of pregnancy among postmenopausal women and the number of deliveries among parous women with lower BMI in the premenopausal group were not statistically significant. In addition, because the number of deliveries was not asked in LSS, we examined the association excluding LSS (eTable 4 in Supplement 1). Although the results were not largely changed, the results for age at menarche were no longer statistically significant.
Figure. Stratified Analyses Between Reproductive Factors and Endometrial Cancer Risk by Body Mass Index (BMI), Menopausal Status, and Parous Status.
The model for hormone therapy (HT) use included 8 cohorts and that for breastfeeding included 7 cohorts. Detailed results are in eTable 3 in Supplement 1. Models were adjusted for age at baseline, BMI, age at menarche, age at menopause (including premenopause), current smoking, current drinking, parity, HT use, and breastfeeding, except for the stratification variable. Japan Collaborative Cohort Study and Life Span Study included a question about the age at first pregnancy (not delivery).
aSignificant (P < .05) trend of categories of each reproductive factor.
Discussion
In this pooled analysis comprising 332 625 participants from 13 cohort studies, parity, a greater number of deliveries, late menarche, and early menopause were associated with a lower risk of endometrial cancer among Asian women. Because there are a limited number of prospective reports owing to the low incidence of endometrial cancer, this report provides evidence regarding reproductive factors and endometrial cancer in Asian countries.
The results regarding multiparity, age at menarche, and age at menopause in this study were consistent with previously published evidence. In an umbrella review,16 parity showed strong evidence, delay in achieving menarche showed suggestive evidence, and prolonged breastfeeding showed weak evidence of a lower risk of endometrial cancer. Although that review included 171 meta-analyses, only 6 focused on the reproductive factors investigated in this study. Among more than 100 individual studies included in these 6 meta-analyses, 7 were from Asian countries, and only 2 were prospective. Regarding other reproductive factors investigated in other meta-analyses, an increase in parity and early menopause showed an association with a lower risk of endometrial cancer, similar to the results of our study.14,15 One systematic review35 showed that breastfeeding was significantly associated with a reduced relative risk (RR) of endometrial cancer, particularly in North America (6 studies; RR, 0.87; 95% CI, 0.79-0.95) but not in Asia (4 studies; RR, 0.58; 95% CI, 0.31-1.07).35 Consistent with these results, we did not find a significant association between breastfeeding and endometrial cancer. Breastfeeding, which suppresses ovulation, may reduce the risk of endometrial cancer. Although our pooled results can be regarded as including the maximum number of cases possible from Asian prospective studies, further studies including information on the duration of breastfeeding and a larger number of cancer cases might be required to establish evidence for the association between breastfeeding and endometrial cancer.
Given that the age at menarche is likely to be higher in Asian populations than in European and US populations,36 a different category of menarche age was used in Asian studies. We included cohorts in which data pertaining to age were acquired categorically, with the lowest and highest categories being the ages of 13 years or younger and 17 years or older, respectively, whereas studies conducted in Europe and the United States applied the lowest and highest age categories of 11 years and 14 or 15 years, respectively.5,6,11 On the other hand, the category of age at menopause was similar, although natural menopause has been shown to occur at a later age among Japanese Americans than in other ethnic groups.37 Some Western studies applied the lowest age category of 50 years6,38; however, an age category of 45 years or younger was used overall, regardless of the country.5,7,37 Although the categories varied slightly among studies and countries, the associations between age at menarche and menopause and endometrial cancer were consistent.
Moreover, age at menarche and menopause are influenced by BMI.39 The consistent results from Asian countries with lower BMI (mean BMI, 22.0-24.6 in our analysis) are worth reporting to broaden the evidence. In a dose-response meta-analysis of BMI,40 the risk of endometrial cancer increased more obviously when BMI was 25 or greater. In our analysis, the P value for the interaction between the higher and lower BMI groups was not significant, and the trend of age at menopause in the low BMI group was significant (median BMI, approximately 23). While some reproductive factors, such as the number of deliveries, did not show significant associations in the low-BMI group, it is possible that protective effects of these factors may occur in higher-BMI groups. However, the limited number of cases in the low-BMI group indicates the need for further studies with larger numbers of participants from lower-BMI populations. The presence of unopposed estrogen underlies the association between selected reproductive factors and the risk of endometrial cancer.9,10,41 Excess estrogen causes endometrial cell proliferation and is a risk factor for endometrial cancer.42 Parity, menarche, and menopause cause changes in estrogen and progesterone levels. For example, parous women have lower estrogen levels than nulliparous women.43 In line with this, higher age at last birth has been proposed to be associated with a lower risk of endometrial cancer because decreased estrogen levels accompanying pregnancy among women approaching menopause may have a protective effect against cancer. Moreover, OC use might reduce the cancer risk, and HT (especially estrogen therapy) is a potential risk factor for endometrial cancer.44,45 However, in the present study, age at last birth, OC use, and type of HT could not be investigated as exposure or confounding factors because the age at last birth and type of HT were not included in the questionnaires, and OC and HT use were uncommon in Asian countries, particularly in the 1990s. According to data from the United Nations in 2019, the estimated prevalence rates of OC use were 2.9% in Japan and 3.3% in Korea, compared with 15.1% in North America and 19.1% in European countries.46 Regarding HT use, the total prevalence reported in surveys of nurses in Japan was 13.8%, which was lower than that in non-Asian countries.47 Although most of the participating cohorts did not include information on the type of HT, a Korean study48 found that the proportion of HT use among women older than 40 years was 7.8%, and the rate of estrogen therapy was 3 times higher than that of estrogen-plus-progesterone therapy in 2002.48 In the future, such a study including HT type may be required because the lifestyle in Asian countries may be westernized.
Strengths and Limitations
This study has strengths. To our knowledge, it is the largest pooled analysis of Asian prospective studies with a large number of cases and long follow-up durations. Although generalizability of results was limited to Asians, individual data from multiple sites in Asia were collected and analyzed.
However, our study also has several limitations. First, each cohort used a different questionnaire, and questions regarding reproductive factors differed slightly among the participating cohorts. Although we checked each questionnaire, and data cleaning was performed by a working group, JACC and LSS included questions about the age at first pregnancy, and categorical variables were applied to include all possible cohorts. Second, not all cohorts were asked about all reproductive factors investigated in this study, such as a history of hysterectomy, duration of breastfeeding, type of HT, and number of deliveries in LSS. Histological cancer types or types I and II classifications were not considered in this study because morphological information was obtained in 5 cohorts. As obesity and reproductive factors might be influenced more by type II tumors,49 further studies including endometrial cancer types are essential. Moreover, we did not collect information on the history of cancer other than endometrial cancer in this study, and participants with a history of cancer other than endometrial cancer were not excluded from analyses. Third, confounding factors other than age, country, smoking status, and drinking status were not included in the model. Physical activity, family history of endometrial cancer, and education level might be important confounding factors but could not be adjusted for in this study due to lack of data. Although further studies with full adjustment are ideal, we observed an HR trend that is consistent with the existing evidence, and these confounding factors may not have changed the results. Fourth, because we collected the data on reproductive factors at baseline, misclassification may have occurred, especially for factors such as menopausal status that change with time. Harmonization of time-varying data should be considered in future studies.
Conclusions
In conclusion, among 1005 endometrial cancer cases recorded in 13 Asian cohort studies comprising 332 625 women, late menarche, early menopause, and a higher number of deliveries were significantly associated with a lower risk of endometrial cancer. These results are consistent with previous evidence emanating mainly from non-Asian countries. Breastfeeding was not significantly associated with endometrial cancer in this study. Since Asian countries are characterized by a low incidence of endometrial cancer, this study contributes to expanding the generalizability of evidence on the risk and protective factors for endometrial cancer.
eTable 1. Association Between Reproductive Factors and Endometrial Cancer Risk Including Models Adjusted for Age as Categorical Variable
eTable 2. Association Between Reproductive Factors and Endometrial Cancer Risk Excluding One Cohort Study
eTable 3. Subgroup Analyses of the Association Between Reproductive Factors and Endometrial Cancer Risk
eTable 4. Subgroup Analyses of the Association Between Reproductive Factors and Endometrial Cancer Risk Excluding LSS
eAppendix. Supplemental Material
Data Sharing Statement
References
- 1.World Cancer Research Fund . Endometrial cancer statistics. Accessed September 27, 2022. https://www.wcrf.org/cancer-trends/endometrial-cancer-statistics/
- 2.Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660 [DOI] [PubMed] [Google Scholar]
- 3.Khazaei Z, Hasanpour Dehkordi A, Amiri M, et al. The incidence and mortality of endometrial cancer and its association with body mass index and human development index in Asian population. World Cancer Res. 2018;5(4):e1174. doi: 10.32113/wcrj_201812_1174 [DOI] [Google Scholar]
- 4.The Surveillance, Epidemiology, and End Results Program. Cancer stat facts: uterine cancer. Accessed September 27, 2022. https://seer.cancer.gov/statfacts/html/corp.html
- 5.McPherson CP, Sellers TA, Potter JD, Bostick RM, Folsom AR. Reproductive factors and risk of endometrial cancer. The Iowa Women’s Health Study. Am J Epidemiol. 1996;143(12):1195-1202. doi: 10.1093/oxfordjournals.aje.a008707 [DOI] [PubMed] [Google Scholar]
- 6.Karageorgi S, Hankinson SE, Kraft P, De Vivo I. Reproductive factors and postmenopausal hormone use in relation to endometrial cancer risk in the Nurses’ Health Study cohort 1976-2004. Int J Cancer. 2010;126(1):208-216. doi: 10.1002/ijc.24672 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Dossus L, Allen N, Kaaks R, et al. Reproductive risk factors and endometrial cancer: the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 2010;127(2):442-451. doi: 10.1002/ijc.25050 [DOI] [PubMed] [Google Scholar]
- 8.Wernli KJ, Ray RM, Gao DL, De Roos AJ, Checkoway H, Thomas DB. Menstrual and reproductive factors in relation to risk of endometrial cancer in Chinese women. Cancer Causes Control. 2006;17(7):949-955. doi: 10.1007/s10552-006-0034-6 [DOI] [PubMed] [Google Scholar]
- 9.Akhmedkhanov A, Zeleniuch-Jacquotte A, Toniolo P. Role of exogenous and endogenous hormones in endometrial cancer: review of the evidence and research perspectives. Ann N Y Acad Sci. 2001;943:296-315. doi: 10.1111/j.1749-6632.2001.tb03811.x [DOI] [PubMed] [Google Scholar]
- 10.Key TJ, Pike MC. The dose-effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. Br J Cancer. 1988;57(2):205-212. doi: 10.1038/bjc.1988.44 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Setiawan VW, Pike MC, Karageorgi S, et al. ; Australian National Endometrial Cancer Study Group . Age at last birth in relation to risk of endometrial cancer: pooled analysis in the epidemiology of endometrial cancer consortium. Am J Epidemiol. 2012;176(4):269-278. doi: 10.1093/aje/kws129 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Gong TT, Wang YL, Ma XX. Age at menarche and endometrial cancer risk: a dose-response meta-analysis of prospective studies. Sci Rep. 2015;5:14051. doi: 10.1038/srep14051 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Jordan SJ, Na R, Johnatty SE, et al. Breastfeeding and endometrial cancer risk: an analysis from the epidemiology of endometrial cancer consortium. Obstet Gynecol. 2017;129(6):1059-1067. doi: 10.1097/AOG.0000000000002057 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Wu QJ, Li YY, Tu C, et al. Parity and endometrial cancer risk: a meta-analysis of epidemiological studies. Sci Rep. 2015;5:14243. doi: 10.1038/srep14243 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Wu Y, Sun W, Liu H, Zhang D. Age at menopause and risk of developing endometrial cancer: a meta-analysis. Biomed Res Int. 2019;2019:8584130. doi: 10.1155/2019/8584130 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Raglan O, Kalliala I, Markozannes G, et al. Risk factors for endometrial cancer: an umbrella review of the literature. Int J Cancer. 2019;145(7):1719-1730. doi: 10.1002/ijc.31961 [DOI] [PubMed] [Google Scholar]
- 17.Rolland B, Smith BR, Potter JD. Coordinating centers in cancer epidemiology research: the Asia Cohort Consortium coordinating center. Cancer Epidemiol Biomarkers Prev. 2011;20(10):2115-2119. doi: 10.1158/1055-9965.EPI-11-0391 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Zheng W, McLerran DF, Rolland B, et al. Association between body-mass index and risk of death in more than 1 million Asians. N Engl J Med. 2011;364(8):719-729. doi: 10.1056/NEJMoa1010679 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Chen Y, Copeland WK, Vedanthan R, et al. Association between body mass index and cardiovascular disease mortality in east Asians and south Asians: pooled analysis of prospective data from the Asia Cohort Consortium. BMJ. 2013;347:f5446. doi: 10.1136/bmj.f5446 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Watanabe S, Tsugane S, Sobue T, Konishi M, Baba S; Japan Public Health Center-based Prospective Study on Cancer and Cardiovascular Diseases . Study design and organization of the JPHC study. J Epidemiol. 2001;11(6)(suppl):S3-S7. doi: 10.2188/jea.11.6sup_3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Tsugane S, Sawada N. The JPHC study: design and some findings on the typical Japanese diet. Jpn J Clin Oncol. 2014;44(9):777-782. doi: 10.1093/jjco/hyu096 [DOI] [PubMed] [Google Scholar]
- 22.Tamakoshi A, Ozasa K, Fujino Y, et al. ; JACC Study Group . Cohort profile of the Japan Collaborative Cohort Study at final follow-up. J Epidemiol. 2013;23(3):227-232. doi: 10.2188/jea.JE20120161 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Fukao A, Tsubono Y, Komatsu S, et al. A cohort study on the relation of lifestyle, personality and biologic markers to cancer in Miyagi, Japan: study design, response rate and profiles of the cohort subjects. J Epidemiol. 1995;5(3):153-157. doi: 10.2188/jea.5.153 [DOI] [Google Scholar]
- 24.Tsuji I, Nishino Y, Ohkubo T, et al. A prospective cohort study on National Health Insurance beneficiaries in Ohsaki, Miyagi Prefecture, Japan: study design, profiles of the subjects and medical cost during the first year. J Epidemiol. 1998;8(5):258-263. doi: 10.2188/jea.8.258 [DOI] [PubMed] [Google Scholar]
- 25.Ozasa K, Shimizu Y, Suyama A, et al. Studies of the mortality of atomic bomb survivors, Report 14, 1950-2003: an overview of cancer and noncancer diseases. Radiat Res. 2012;177(3):229-243. doi: 10.1667/RR2629.1 [DOI] [PubMed] [Google Scholar]
- 26.Shimizu H. The Basic Report on Takayama Study. Gifu University; 1996. [Google Scholar]
- 27.Sado J, Kitamura T, Kitamura Y, et al. ; Three-Prefecture Cohort Study Group . Rationale, design, and profile of the Three-Prefecture Cohort in Japan: a 15-year follow-up. J Epidemiol. 2017;27(4):193-199. doi: 10.1016/j.je.2016.05.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Yoo KY, Shin HR, Chang SH, et al. Korean Multi-center Cancer Cohort Study including a Biological Materials Bank (KMCC-I). Asian Pac J Cancer Prev. 2002;3(1):85-92. [PubMed] [Google Scholar]
- 29.Kim J. Cancer screenee cohort study of the National Cancer Center in South Korea. Epidemiol Health. 2014;36:e2014013. doi: 10.4178/epih/e2014013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Kweon SS, Shin MH, Jeong SK, et al. Cohort profile: the Namwon study and the Dong-gu study. Int J Epidemiol. 2014;43(2):558-567. doi: 10.1093/ije/dys244 [DOI] [PubMed] [Google Scholar]
- 31.Zheng W, Chow WH, Yang G, et al. The Shanghai Women’s Health Study: rationale, study design, and baseline characteristics. Am J Epidemiol. 2005;162(11):1123-1131. doi: 10.1093/aje/kwi322 [DOI] [PubMed] [Google Scholar]
- 32.Hankin JH, Stram DO, Arakawa K, et al. Singapore Chinese Health Study: development, validation, and calibration of the quantitative food frequency questionnaire. Nutr Cancer. 2001;39(2):187-195. doi: 10.1207/S15327914nc392_5 [DOI] [PubMed] [Google Scholar]
- 33.Amrhein J. Introduction to frailty models. Proceedings of the SAS Global Forum Conference, 2014. Accessed August 3, 2023. https://support.sas.com/resources/papers/proceedings14/1492-2014.pdf
- 34.Tamada T, Iwasaki H. Age at natural menopause in Japanese women. Article in Japanese. Nihon Sanka Fujinka Gakkai Zasshi. 1995;47(9):947-952. [PubMed] [Google Scholar]
- 35.Wang L, Li J, Shi Z. Association between breastfeeding and endometrial cancer risk: evidence from a systematic review and meta-analysis. Nutrients. 2015;7(7):5697-5711. doi: 10.3390/nu7075248 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Morabia A, Costanza MC; World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives . International variability in ages at menarche, first livebirth, and menopause. Am J Epidemiol. 1998;148(12):1195-1205. doi: 10.1093/oxfordjournals.aje.a009609 [DOI] [PubMed] [Google Scholar]
- 37.Setiawan VW, Pike MC, Kolonel LN, Nomura AM, Goodman MT, Henderson BE. Racial/ethnic differences in endometrial cancer risk: the multiethnic cohort study. Am J Epidemiol. 2007;165(3):262-270. doi: 10.1093/aje/kwk010 [DOI] [PubMed] [Google Scholar]
- 38.Trentham-Dietz A, Nichols HB, Hampton JM, Newcomb PA. Weight change and risk of endometrial cancer. Int J Epidemiol. 2006;35(1):151-158. doi: 10.1093/ije/dyi226 [DOI] [PubMed] [Google Scholar]
- 39.Zhu D, Chung HF, Pandeya N, et al. Body mass index and age at natural menopause: an international pooled analysis of 11 prospective studies. Eur J Epidemiol. 2018;33(8):699-710. doi: 10.1007/s10654-018-0367-y [DOI] [PubMed] [Google Scholar]
- 40.Aune D, Navarro Rosenblatt DA, Chan DS, et al. Anthropometric factors and endometrial cancer risk: a systematic review and dose-response meta-analysis of prospective studies. Ann Oncol. 2015;26(8):1635-1648. doi: 10.1093/annonc/mdv142 [DOI] [PubMed] [Google Scholar]
- 41.Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev. 2002;11(12):1531-1543. [PubMed] [Google Scholar]
- 42.Yang S, Thiel KW, Leslie KK. Progesterone: the ultimate endometrial tumor suppressor. Trends Endocrinol Metab. 2011;22(4):145-152. doi: 10.1016/j.tem.2011.01.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Bernstein L, Pike MC, Ross RK, Judd HL, Brown JB, Henderson BE. Estrogen and sex hormone-binding globulin levels in nulliparous and parous women. J Natl Cancer Inst. 1985;74(4):741-745. [PubMed] [Google Scholar]
- 44.Gierisch JM, Coeytaux RR, Urrutia RP, et al. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev. 2013;22(11):1931-1943. doi: 10.1158/1055-9965.EPI-13-0298 [DOI] [PubMed] [Google Scholar]
- 45.Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol. 1995;85(2):304-313. doi: 10.1016/0029-7844(94)00383-O [DOI] [PubMed] [Google Scholar]
- 46.United Nations, Department of Economic and Social Affairs, Population Division . Contraceptive use by method 2019: data booklet. Accessed August 3, 2023. https://digitallibrary.un.org/record/3849735?ln=en
- 47.Collaborative Group on Hormonal Factors in Breast Cancer . Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019;394(10204):1159-1168. doi: 10.1016/S0140-6736(19)31709-X [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Park CY, Lim JY, Kim WH, Kim SY, Park HY. Evaluation of menopausal hormone therapy use in Korea (2002-2013): A nationwide cohort study. Maturitas. 2021;146:57-62. doi: 10.1016/j.maturitas.2021.02.003 [DOI] [PubMed] [Google Scholar]
- 49.Setiawan VW, Yang HP, Pike MC, et al. ; Australian National Endometrial Cancer Study Group . Type I and II endometrial cancers: have they different risk factors? J Clin Oncol. 2013;31(20):2607-2618. doi: 10.1200/JCO.2012.48.2596 [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
eTable 1. Association Between Reproductive Factors and Endometrial Cancer Risk Including Models Adjusted for Age as Categorical Variable
eTable 2. Association Between Reproductive Factors and Endometrial Cancer Risk Excluding One Cohort Study
eTable 3. Subgroup Analyses of the Association Between Reproductive Factors and Endometrial Cancer Risk
eTable 4. Subgroup Analyses of the Association Between Reproductive Factors and Endometrial Cancer Risk Excluding LSS
eAppendix. Supplemental Material
Data Sharing Statement