Abstract
The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.
Keywords: menarche, menopause, delivery, birth cohort, pooled analysis
Graphical Abstract
Introduction
Gallbladder cancer (GBC) ranks the 25th most common cancer among all types of cancer and the sixth most common malignancy among gastrointestinal cancers, according to GLOBOCAN 2020 1. More than 70% of all GBC cases and deaths occur in Asia, despite Asia accounts for 49.3% of overall cancer cases and 58.3% of overall cancer deaths 1. GBC has a poor prognosis, with five-year relative survival rates ranging from 10% to 30% 2,3.
An interesting epidemiological observation for GBC is its female preponderance in both incidence and mortality, whereas most solid cancers show male predominance, with some exceptions, such as breast cancer and thyroid cancer 4 5. Known risk factors for GBC include a history of gallstones, obesity, and chronic infections such as Salmonella typhi, Salmonella paratyphi, and Helicobacter pylori 4.
The female predominance of GBC has led to the hypothesis that female reproductive factors and hormones may play a role in its development 6,7. Gallbladder tissue expresses oestrogen and progesterone receptors 8, and during pregnancy, elevated oestrogen increases cholesterol secretion, while progesterone reduces bile acid secretion and delays gallbladder emptying, leading to supersaturation of bile and facilitating gallstone formation 9.
A previous report from the Biliary Track Cancers Pooling Project concluded that the risk of GBC increased with an increasing number of live births 7, and a later age at menarche was related to the risk of GBC only among Asian women 7. However, although the pooling project encompassed more than 1.5 million females, only four studies from three Asian countries were included 7. Asian women have been characterized by an earlier age at menopause than European or North American women 10,11 and have experienced a secular transition of reproductive patterns 12,13. Therefore, in the current pooled analysis of data collected by the Asia Cohort Consortium, we aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women.
Materials and Methods
Details for the Asia Cohort Consortium have been described previously 14. The consortium is a collaborative effort involving 44 participating cohorts from 10 Asian countries, aiming to understand the relationship among genetics, environmental exposures, and disease aetiologies, including those for cancer, through the establishment of a cohort of at least one million healthy individuals (https://www.asiacohort.org/index.html). For the current study, 12 cohorts from four countries (China, Japan, Korea, and Singapore) were included. The following exclusions were applied to the participating cohorts: men or missing information on gender, missing information on baseline age, pregnancy history and the number of deliveries, and women with a history of GBC at baseline (Figure 1, Supplementary table 1).
Figure 1.
Inclusion and exclusion criteria of the study population
Data from each cohort that agreed to contribute to the project were collected and harmonized at the Coordinating Centre located at the National Cancer Centre, Japan. Additional data harmonization on reproductive variables was performed by the reproductive factor working group through monthly Zoom meetings (Supplementary material). Reproductive factors included in the current study were age at menarche (<13, 13-14, 15-16, and ≥17 years), parous (no [nulliparous], and yes), parity (no child, 1-2, 3-4, ≥5), age at first delivery or pregnancy (≤20, 21-25, 26-30, and ≥31 years), breastfeeding (never, and ever), age at menopause (among menopausal women; <45, 45-49, 50-54, and ≥55 years), and oral contraceptive (never, and ever) or hormone replacement therapy use (no, and yes).
Cancer incidence was ascertained by linkage to local cancer registries.
Cox proportional hazards models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the occurrence of GBC by different reproductive factors. Age was used as a time scale in the analysis, and participants were followed from the date of the baseline survey to the date of GBC incidence, death, or the end of the follow-up period for each cohort, whichever came first. Adjustment for history of smoking (never, ever, and missing), alcohol drinking (never, ever, and missing), and body mass index (BMI) [kg/m2] (<23, ≥23, and missing) was performed in all models. BMI less than 5 kg/m2 or greater than or equal to 40 kg/m2 was treated as an outlier. Cohort-specific HRs were estimated, and we summarized cohort-specific HRs based on a random effect model. We also conducted meta-regression analyses to evaluate the trend of the impact of reproductive factors on GBC risk with an ordinal scale (age at menarche, parity, age at first delivery or pregnancy, and age at menopause). Stratified analysis was conducted by birth cohorts, which were divided into those born before and after 1940, taking into account the median year of birth. The Korean Multi-centre Cancer Cohort (KMCC) and Namwon cohorts were excluded from the stratification analysis due to lack of information on year of birth. For categorical variables with 3 categories, we also performed meta-regression analyses to show trends in GBC risk using the bubble plot (see Supplementary Figures 5–9). The size of the bubbles represents the weights of the study in the meta-analyses. For bubbles that did not include the 95% prediction intervals in the bubble plot, the cohort name was given, which could be considered an outlier.
SAS 9.4 was used for harmonizing and constructing data for analyses, and the “metafor” package was used for pooling cohort-specific effect sizes and conducting meta-regression analyses in R 4.2.2.
Results
A total of 331,323 women from 12 cohorts were included in the analysis (Table 1). Overall, the mean [standard deviation] follow-up was 16.5 [6.6] years. The mean age at study entry was 54.4 [10.3] years, and the mean BMI at study entry was 21.9 [3.3] kg/m2. Seven percent and 19% of the participants had a history of ever smoking and alcohol drinking, respectively. Among the participants, 1,173 GBC cases were ascertained during the follow-up period.
Table 1.
Characteristics of the Asia Cohort Consortium participants
| Country & Cohorts | N | Study period | Follow-up period, years, mean (std) | Age at Enrolment, years, mean (std) | Body mass Index at study entry (kg/m2), mean (std) | % who had ever smoked at study entry | % who had ever drank alcohol at study entry | Number of gallbladder cancer cases |
|---|---|---|---|---|---|---|---|---|
| China | ||||||||
| SWHS | 74,935 | 1996 to 2000 | 15.3 (2.4) | 52.6 (9.1) | 24.0 (3.4) | 2.8 | 2.2 | 163 |
| Japan | ||||||||
| JPHC1 | 21,494 | 1990 to 1992 | 22.0 (3.8) | 49.6 (5.9) | 23.6 (3.1) | 7.5 | 23.0 | 114 |
| JPHC2 | 27,749 | 1993 to 1995 | 18.8 (3.6) | 54.3 (8.8) | 23.4 (3.2) | 7.7 | 21.7 | 175 |
| JACC | 45,659 | 1988 to 1990 | 16.7 (5.7) | 57.4 (9.9) | 22.9 (3.1) | 5.7 | 23.4 | 122 |
| Miyagi | 22,837 | 1990 | 22.8 (5.6) | 52.2 (7.4) | 23.7 (3.1) | 8.2 | 24.3 | 139 |
| Ohsaki | 22,190 | 1996 | 11.2 (4.3) | 60.5 (10.0) | 23.7 (3.2) | 8.4 | 22.8 | 88 |
| LSS | 30,051 | 1963 to 1992 | 24.0 (10.6) | 52.1 (15.1) | 21.9 (3.4) | 14.7 | 26.1 | 210 |
| Miyagi3P | 16,524 | 1984 | 7.9 (2.6) | 57.4 (11.3) | 23.3 (3.4) | 8.7 | 26.0 | 48 |
| Korea | ||||||||
| KMCC | 11,433 | 1993 to 2005 | 14.9 (4.5) | 54.0 (14.2) | 23.9 (3.4) | 8.4 | 20.2 | 55 |
| KNCC | 16,905 | 2007 to 2015 | 9.4 (3.4) | 49.8 (9.0) | 23.1 (3.0) | 7.3 | 45.7 | 23 |
| Namwon | 6,243 | 2004 to 2007 | 13.1 (2.1) | 61.2 (7.8) | 24.6 (3.2) | 5.2 | 34.3 | 8 |
| Singapore | ||||||||
| SCHS | 35,303 | 1993 to 1999 | 14.6 (3.6) | 56.3 (8.0) | 23.2 (3.2) | 8.8 | 9.0 | 28 |
| Total | 331,323 | 16.5 (6.6) | 54.4 (10.3) | 21.9 (3.3) | 7.1 | 18.5 | 1,173 |
SWHS, Shanghai Women’s Health Study; JPHC, Japan Public Health Center-based prospective Study; JPHC2, Japan Public Health Center-based prospective Study; JACC, Japan Collaborative Cohort Study; Miyagi, Miyagi Cohort Study; Ohsaki, Ohsaki National Health Insurance Cohort Study; LSS, Life Span Study Cohort; Miyagi3P, Three Prefecture Cohort Study Miyagi; KMCC, Korean Multi-center Cancer Cohort Study; KNCC, Korean National Cancer Center Cohort; Namwon, The Namwon Study; SCHS, Singapore Chinese Health Study
Std – standard deviation
Table 2 and Figure 2 and 3 show the HRs and 95% CIs for the association between reproductive factors and GBC risk. In general, none of the reproductive factors showed any association with the risk of GBC in the pooled analysis, except for age at menarche. A statistically significant increased risk of GBC was observed in association with a later age at menarche. The HR for an age at menarche of 17 years and older was 1.39 [95% CI 1.14-1.69], indicating higher risk compared to an age at menarche of 13-14 years. No clear trend was observed for an elevated risk among women who experienced their menarche at less than 13 years of age (HR 1.33, 95% CI 0.98-1.80). Parous women had a nonsignificant increased risk of GBC compared with nulliparous women (HR 1.26 [95% CI 0.88-1.81]). Regarding parity, no clear trend of HRs was observed as parity increased, with HRs of 0.93 (95% CI 0.65-1.34) for women with 1-2 children, 1.02 (95% CI 0.72-1.46) for those with 3-4 children, and 1.23 (95% CI 0.84-1.80) for those with 5 or more children (Ptrend= 0.300). Age at first delivery or pregnancy also showed no significant trend (Ptrend=0.699), although women who gave birth or became pregnant for the first time at 31 years of age or older had the highest risk (1.34 [95% CI 0.97-1.86]) compared with those who gave birth or became pregnant at 20 years of age or younger. We did not observe a significant association of breastfeeding, postmenopausal status, age at menopause, oral contraceptive use, and hormone replacement therapy use with GBC risk. The heterogeneity of the association across the cohorts was minimal (Figure 2).
Table 2.
Hazard ratios and corresponding confidence intervals of reproductive factors for gallbladder cancer risk
| Exposure (Number of cohorts that contributed) | N | Person-years | Cases | Crude HRs (95% CIs) | Adjusteda HRs (95% CIs) |
|---|---|---|---|---|---|
| Age at menarche, years (12) | |||||
| <13b | 21,755 | 379,908.1 | 49 | 1.33 (0.98-1.80) | 1.33 (0.98-1.80) |
| 13-14 | 145,678 | 2,365,345.6 | 419 | 1.00 (Reference) | 1.00 (Reference) |
| 15-16 | 108,368 | 1,815,939.5 | 399 | 1.13 (0.98-1.31) | 1.14 (0.98-1.32) |
| ≥17c | 55,120 | 886,840.2 | 306 | 1.38 (1.13-1.69) | 1.39 (1.14-1.69) |
| Parity (9) | |||||
| No (nulliparous) | 21,303 | 352,835.7 | 85 | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 275,439 | 4,688,433.6 | 1,002 | 1.29 (0.90-1.83) | 1.26 (0.88-1.81) |
| Parity (8) | |||||
| No child | 12,504 | 190,221.9 | 34 | 1.00 (Reference) | 1.00 (Reference) |
| 1-2 | 133,634 | 2,184,956.2 | 321 | 0.94 (0.66-1.36) | 0.93 (0.65-1.34) |
| 3-4 | 91,583 | 1,521,256.6 | 362 | 1.05 (0.73-1.50) | 1.02 (0.72-1.46) |
| ≥5 | 28,442 | 412,367.9 | 157 | 1.29 (0.88-1.88) | 1.23 (0.84-1.80) |
| Age at 1st delivery or pregnancy, years (11) | |||||
| ≤ 20 | 34,733 | 563,050.1 | 161 | 1.00 (Reference) | 1.00 (Reference) |
| 21-25 | 145,501 | 2,483,004.1 | 560 | 0.99 (0.79-1.25) | 1.01 (0.80-1.27) |
| 26-30 | 86,424 | 1,457,296.0 | 244 | 1.00 (0.78-1.30) | 1.03 (0.79-1.33) |
| ≥31d | 15,869 | 265,833.4 | 60 | 1.32 (0.95-1.82) | 1.34 (0.97-1.86) |
| Breastfeeding (6) | |||||
| Never | 15,672 | 271,167.3 | 57 | 1.00 (Reference) | 1.00 (Reference) |
| Ever | 97,199 | 1,653,323.8 | 499 | 1.00 (0.74-1.36) | 0.98 (0.72-1.34) |
| Postmenopausal status (12) | |||||
| No | 106,323 | 1,947,670.4 | 175 | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 210,784 | 3,265,358.0 | 976 | 0.68 (0.36-1.29) | 0.67 (0.36-1.28) |
| Age at menopause, years (12) | |||||
| <45 | 29,949 | 471,859.8 | 139 | 1.00 (Reference) | 1.00 (Reference) |
| 45-49 | 67,068 | 1,060,150.9 | 286 | 0.84 (0.68-1.03) | 0.85 (0.68-1.05) |
| 50-54e | 80,508 | 1,265,724.5 | 384 | 0.88 (0.72-1.07) | 0.88 (0.72-1.08) |
| ≥55e | 9,776 | 142,389.8 | 49 | 0.92 (0.66-1.29) | 0.92 (0.66-1.29) |
| Oral contraceptive use (4) | |||||
| Never | 67,221 | 1,090,499.1 | 210 | 1.00 (Reference) | 1.00 (Reference) |
| Ever | 17,100 | 250,151.9 | 30 | 0.94 (0.57-1.54) | 0.92 (0.57-1.50) |
| Hormone replacement therapy (6) | |||||
| No | 124,609 | 1,915,601.7 | 394 | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 10,021 | 140,791.1 | 25 | 0.78 (0.52-1.20) | 0.78 (0.51-1.19) |
Adjusted for the history of smoking (never, ever, and missing) and alcohol drinking (never, ever, and missing), and obesity (body mass index [kg/m2]; <23, ≥23, and missing) Excluded
Excluded Namwon,
KNCC,
Namwon, and SCHS,
Namwon, due to no gallbladder cancer cases
HR – hazard ratio, CI – confidence interval
Figure 2.
Forest plot showing the hazard ratio (HR) and 95% confidence intervals (CIs) of age at menarche (A), parous (B), parity (C), age at 1st delivery or pregnancy (D), and breastfeeding (E) for gallbladder cancer risk
Figure 3.
Forest plot showing the hazard ratio (HR) and 95% confidence intervals (CIs) of postmenopausal status (A), age at menopause (B), oral contraceptive use (C), hormone replacement therapy (D) and reproductive period (E) for gallbladder cancer risk.
Table 3 and Supplementary Figures 1–4 present the association between reproductive factors and GBC risk, stratified by birth cohort: born before 1940 and born in 1940 or later. For age at menarche, there was no significant trend in the adjusted HRs across categories (Ptrend = 0.232) for women born before 1940. There was a significant increasing trend in adjusted HRs with a later age at menarche (Ptrend = 0.029) for women born in 1940 or later. For parous women, although the direction of the associations was opposite between the birth cohorts, there was no significant association with the risk of GBC compared with nulliparous women for either birth cohort (1.17 [0.78-1.76] for women born before 1940 and 0.70 [0.25-1.94] for women born in 1940 or later). Regarding parity, no significant trend was observed with increasing categories of parity for either group (Ptrend=0.297 for women born before 1940 and 0.687 for women born in 1940 or later). In relation to age at first delivery or pregnancy, no significant trend for age at first delivery or pregnancy was observed for either group (Ptrend=0.291 for women born before 1940 and 0.365 for women born in 1940 or later). However, women with an age at first delivery of 31 years or older showed a significantly increased risk of GBC compared to those with an age at first delivery of 20 years or younger (HR [95% CI] 1.56 [1.09-2.25]) in the birth cohort born before 1940.
Table 3.
Hazard ratios and corresponding confidence intervals of reproductive factors for gallbladder cancer risk by birth year
| <1940 |
≥1940 |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| N | Person-years | Cases | Crude HRs (95% CIs) | Adjusted HRs (95% CIs) | N | Person-years | Cases | Crude HRs (95% CIs) | Adjusted HRs (95% CIs) | |
| Age at menarche, years | ||||||||||
| <13 | 7,090 | 119,162.9 | 29 | 1.39 (0.94-2.04) | 1.40 (0.95-2.06) | 10,232 | 190,339.0 | 19 | 1.48 (0.89-2.49) | 1.48 (0.88-2.48) |
| 13-14 | 65,856 | 1,106,140.1 | 324 | 1.00 (Reference) | 1.00 (Reference) | 67,504 | 1074446.1 | 80 | 1.00 (Reference) | 1.00 (Reference) |
| 15-16 | 63,815 | 1,075,459.8 | 326 | 1.08 (0.91-1.29) | 1.09 (0.92-1.30) | 36,926 | 625746.9 | 54 | 1.43 (0.98-2.11) | 1.43 (0.97-2.09) |
| ≥17 | 35,649 | 588,269.6 | 251 | 1.34 (1.10-1.63) | 1.35 (1.11-1.64) | 10,044 | 163673 | 22 | 2.58 (1.52-4.38) | 2.56 (1.50-4.35) |
| Parity | ||||||||||
| No (nulliparous) | 13,910 | 224,834.4 | 81 | 1.00 (Reference) | 1.00 (Reference) | 3,449 | 53,822.9 | 4 | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 145,242 | 2,366,858.4 | 740 | 1.19 (0.80-1.77) | 1.17 (0.78-1.76) | 75,415 | 1,240,702.8 | 89 | 0.69 (0.25-1.92) | 0.70 (0.25-1.94) |
| No child | 6,776 | 94,612.1 | 30 | 1.00 (Reference) | 1.00 (Reference) | 3,449 | 53,822.9 | 4 | 1.00 (Reference) | 1.00 (Reference) |
| 1-2 | 45,668 | 689,706.1 | 173 | 0.81 (0.54-1.20) | 0.80 (0.53-1.19) | 61,114 | 989,509.7 | 74 | 0.85 (0.30-2.37) | 0.85 (0.30-2.39) |
| 3-4 | 56,168 | 849,963.4 | 263 | 0.94 (0.64-1.38) | 0.92 (0.63-1.35) | 12,636 | 224,321.9 | 15 | 0.61 (0.18-2.01) | 0.62 (0.19-2.04) |
| ≥5 | 24,556 | 340,543.0 | 142 | 1.11 (0.74-1.66) | 1.08 (0.72-1.61) | 3,369 | 58,120.1 | 0 | - | - |
| Age at 1st delivery or pregnancy, years | ||||||||||
| ≤ 20 | 24,026 | 391,551.1 | 124 | 1.00 (Reference) | 1.00 (Reference) | 4,226 | 75,359.1 | 14 | 1.00 (Reference) | 1.00 (Reference) |
| 21-25 | 84,985 | 1,428,235.0 | 455 | 1.14 (0.92-1.41) | 1.15 (0.93-1.44) | 35,515 | 648,101.2 | 67 | 0.51 (0.22-1.20) | 0.52 (0.22-1.22) |
| 26-30 | 36,553 | 628,341.6 | 186 | 1.10 (0.83-1.46) | 1.13 (0.84-1.50) | 38,127 | 637,976.7 | 44 | 0.61 (0.32-1.17) | 0.63 (0.33-1.20) |
| ≥31 | 6,581 | 112,732.5 | 48 | 1.54 (1.07-2.20) | 1.56 (1.09-2.25) | 7,889 | 129,046.6 | 10 | 0.84 (0.30-2.38) | 0.86 (0.30-2.43) |
| Breastfeeding | ||||||||||
| Never | 5,343 | 96,871.0 | 34 | 1.00 (Reference) | 1.00 (Reference) | 8,394 | 151,424.7 | 22 | 1.00 (Reference) | 1.00 (Reference) |
| Ever | 47,193 | 845,533.3 | 372 | 1.05 (0.73-1.49) | 1.02 (0.72-1.46) | 36,184 | 620,746.3 | 70 | 0.70 (0.42-1.15) | 0.70 (0.42-1.15) |
| Postmenopausal status | ||||||||||
| No | 12,916 | 332,422.1 | 56 | 1.00 (Reference) | 1.00 (Reference) | 87,205 | 1,485,459.7 | 116 | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 49,888 | 887,624.2 | 392 | 0.59 (0.12-2.91) | 0.60 (0.12-2.95) | 40,778 | 596,589.4 | 58 | 0.68 (0.45-1.03) | 0.65 (0.43-0.98) |
| Age at menopause, years | ||||||||||
| <45 | 17,399 | 279,160.7 | 108 | 1.00 (Reference) | 1.00 (Reference) | 3,635 | 59,070.9 | 10 | 1.00 (Reference) | 1.00 (Reference) |
| 45-49 | 47,211 | 765,553.3 | 257 | 0.87 (0.69-1.09) | 0.88 (0.69-1.12) | 4,770 | 67,485.5 | 9 | 0.67 (0.26-1.68) | 0.68 (0.27-1.71) |
| 50-54 | 64,713 | 1,052,183.4 | 347 | 0.84 (0.68-1.04) | 0.85 (0.68-1.05) | 4,653 | 49,136.8 | 9 | 0.52 (0.16-1.69) | 0.52 (0.15-1.79) |
| ≥55 | 8,199 | 124,668.0 | 39 | 0.82 (0.56-1.19) | 0.82 (0.56-1.20) | 702 | 5,908.6 | 3 | 1.14 (0.22-5.89) | 1.18 (0.23-6.11) |
| Oral contraceptive use | ||||||||||
| Never | 27,837 | 498,135.3 | 122 | 1.00 (Reference) | 1.00 (Reference) | 31,705 | 481,333.4 | 48 | 1.00 (Reference) | 1.00 (Reference) |
| Ever | 3,811 | 59,860.8 | 10 | 1.55 (0.73-3.26) | 1.50 (0.70-3.24) | 9,650 | 132,055.9 | 8 | 0.89 (0.38-2.06) | 0.87 (0.36-2.10) |
| Hormone replacement therapy | ||||||||||
| No | 46,275 | 714,227.1 | 259 | 1.00 (Reference) | 1.00 (Reference) | 55,195 | 823,276.9 | 62 | 1.00 (Reference) | 1.00 (Reference) |
| Yes | 2,291 | 35,688.3 | 13 | 1.01 (0.57-1.77) | 0.98 (0.56-1.73) | 4,754 | 57,357.8 | 8 | 1.08 (0.48-2.44) | 1.09 (0.48-2.48) |
For breastfeeding, postmenopausal status, age at menopause, the use of oral contraceptives, and the use of hormone replacement therapy, there was no significant heterogeneity in the risk estimates by birth cohort.
Discussion
In this pooled analysis of 12 cohorts from Asia, we found that a later age at menarche was associated with an increased risk of GBC, especially among the birth cohort born in 1940 and later. Additionally, among the birth cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC. Other reproductive factors did not show a clear association with GBC risk.
The findings regarding the associations between age at menarche and GBC risk were generally consistent across cohorts, except for the KMCC cohort, which showed a nonsignificant decrease in GBC risk among women with a later age at menarche. This is in line with a previous pooled analysis 7, which showed an increased risk for GBC among Asian women with later age at menarche, as well as with a Korean study based on health insurance data that included 443,909 women 15. Although not statistically significant, women who experienced menarche very early, i.e., at younger than 13 years old, also showed an elevated risk of GBC. The birth cohort born in 1940 and later experienced menarche earlier than the birth cohort born before 1940 in our study population, which is consistent with reports from China 16, Japan 17, and Korea 18.
The association between age at menarche and GBC risk was more prominent among the later birth cohort. Age at menarche reflects nutritional status during childhood and puberty as well as genetic predisposition 19. Considering that excess body weight leads to early menarche, the observed association may be better explained by the cumulative effect of female hormonal exposure throughout a woman’s lifetime than by nutritional status during childhood. Although not statistically significant, women with an early age at menopause also tended toward a higher risk of GBC. Together, these results are consistent with a case‒control study from China 9, suggesting that a later age at menarche and a consequent shorter lifetime duration of menstruation were related to a higher risk of GBC.
The birth cohort born in 1940 and later in our study had a later age at first delivery or pregnancy and lower parity than the birth cohort born before 1940. Serum sex hormones such as oestrogen, sex hormone-binding globulin, androstenedione, and testosterone increase throughout pregnancy and reach their peak at birth in pregnant women 20. It is possible that the transition in reproductive patterns among Asian women has led to lower lifetime exposure to sex hormones. Although not reaching statistical significance the direction of the association between parity and GBC risk was consistent with a previous pooled analysis 7 and meta-analysis 6, indicating an increased risk of GBC with increasing parity. Similarly, the direction of the association between age at first delivery or pregnancy and GBC risk was in line with a previous pooled analysis 7.
The use of exogenous hormones has been suggested to increase the risk of GBC 21. In the current study, four studies provided information on oral contraceptive use, and six studies provided information on hormone replacement therapy use, and our study did not find a significant association between exogenous hormone therapy and gallbladder cancer, in contrast to previous studies. This may be due to differences in the treatment of menopausal symptoms between Western and Eastern women, with reports of more herbal treatments in the Eastern women 22,23 and less use of HRT in the East compared with Caucasians 24.
The risk factors for GBC have been observed to show variation between Asian and Western populations, demonstrating a complex interplay of genetic, environmental, lifestyle, and metabolic factors. Notably, in East Asia, particularly within Chinese provinces, there is considerable concern regarding the liver fluke Clonorchis sinensis 25. Identified as a Group I carcinogen, 26 this parasite is linked to cholangiocarcinoma 27. South Korea has also observed an increasing trend in cholangiocarcinoma, with approximately 10% attributed to C. sinensis 28. Additionally, East Asia experiences a higher incidence of choledochal cysts and anomalous pancreaticobiliary duct junctions, which significantly increase the risk of GBC 29. Furthermore, GBC can develop even after surgeries like radical biliary cyst removal, suggesting potential influences of additional factors such as bile duct abnormalities and the presence of gallbladder polyps 30. Genetic factors may also play a role in Asian populations, with certain genetic predispositions increasing the risk of GBC 31.
The study has some limitations, including the lack of information on gallstones, which are on the causal pathway between hormonal factors and GBC 7. However, results from a previous study have shown that additional adjustment for gallstones or sensitivity analysis restricted to the cohorts with information on gallstones did not change the results 7. Therefore, we assume that the residual confounding by the presence of gallstones would be minimal. Another limitation is the heterogeneity in the questionnaires on reproductive factors in each cohort, leading to some loss of information when combining into common categories. In addition, although our study included 12 prospective cohorts, only four cohorts were included in the analysis for OC use and six for breastfeeding and HRT, which may have been insufficient to observe statistically significant associations.
Nevertheless, this study represents the largest pooled analysis on this topic among Asian women, including 12 individual cohorts with a mean follow-up of 16.5 years.
In conclusion, the current study, which included 331,323 women from the Asia Cohort Consortium, suggests that later ages at menarche and at first delivery are associated with a higher risk of GBC. The increased risk associated with a later age at menarche was more prominent in the birth cohort born in 1940 and later, while the increased risk associated with a later age at first delivery was significant in the birth cohort born before 1940. The secular transition in reproductive factors may have an impact on the risk of GBC among Asian women.
Supplementary Material
Novelty and Impact:
In this pooled analysis of 12 cohort studies, later ages at menarche and first delivery were associated with a higher gallbladder cancer risk. The increased risk associated with later menarche was more prominent in birth cohorts born after 1940, while the increased risk associated with later age at first delivery was significant in birth cohorts born before 1940. The secular transition in reproductive factors among Asian women may have an impact on gallbladder cancer risk.
Funding
The cohorts participating in the pooled analysis were supported by the following grants: Shanghai Women’s Health Study, US National Cancer Institute (R37 CA070867 and UM1 CA182910, Principal Investigator: Wei Zheng); Japan Public Health Center-Based Prospective Study 1 and 2, National Cancer Center Research and Development Fund (23-A-31[toku], 26-A-4 and 2020-A-4, since 2011) and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010); Japan Collaborative Cohort Study, National Cancer Center Research and Development Fund (a grant-in-aid for cancer research), Ministry of Health, Labour and Welfare, Japan (grant for health services and grant for comprehensive research on cardiovascular and lifestyle-related diseases), and Ministry of Education, Culture, Sports, Science and Technology, Japan (grant for the scientific research); Miyagi Cohort Study, National Cancer Center Research and Development Fund; Ohsaki National Health Insurance Cohort Study, National Cancer Center Research and Development Fund; Life Span Study Cohort–Radiation Effects Research Foundation, The Japanese Ministry of Health, Labour and Welfare and the US Department of Energy; 3 Prefecture Miyagi Study, National Cancer Center Research and Development Fund; Korea Multi-Center Cancer Cohort Study, National Research Foundation of Korea, funded by the Ministry of Science, ICT & Future Planning (2016R1A2B4014552); Korea National Cancer Center Cohort, National Cancer Center Research Grant (1510040, 1810090, and 1910330); Namwon Study, Chonnam National University Hwasun Hospital Research grant (HCRI21019, HCRI18007-1, HCRI16911-1) and Singapore Chinese Health Study, The US National Cancer Institutes (R01CA144034 and UM1CA182876). This work was supported by the grant from the National Research Foundation of Korea (NRF) (No: 2022R1A2C1004608).
Abbreviations:
- ACC
Asia Cohort Consortium
- BMI
Body mass index
- CIs
Confidence intervals
- GBC
Gallbladder cancer
- HRs
Hazard ratios
- KMCC
Korean Multi-centre Cancer Cohort
Footnotes
Ethics statement
Each cohort received approval from its respective institutional review board. Informed consent was obtained from all participants in each study cohort (either written or verbal, depending on the cohort). The pooling project was approved by the executive committee of the Asia Cohort Consortium and by the ethical committee of the National Cancer Centre Japan (number 2014-041).
Conflict of Interest
None declared.
Data availability statement
The data underlying this article were obtained from the Asia Cohort Consortium (ACC). Researchers can apply for access to these data through the ACC Coordinating Center (https://www.asiacohort.org/CC/index.html) after obtaining ethics approval from an Institutional Review Board. Further information is available from the corresponding author upon request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data underlying this article were obtained from the Asia Cohort Consortium (ACC). Researchers can apply for access to these data through the ACC Coordinating Center (https://www.asiacohort.org/CC/index.html) after obtaining ethics approval from an Institutional Review Board. Further information is available from the corresponding author upon request.