Parity has been linked to gallbladder cancer and gallstones, but the effects of other reproductive factors are less clear.
We examined 361 incident biliary tract cancer cases, 647 biliary stone cases, and 586 healthy women in a population-based study in Shanghai.
The effects of parity (odds ratios, OR⩾3 vs 1 child=2.0, 95% confidence interval (CI) 0.7–5.1), younger age at first birth (ORper 1-year decrease=1.2, 95% CI 0.99–1.6), and older age at menarche (ORper 1-year increase=1.4, 95% CI 1.1–1.8) on gallbladder cancer risk were more pronounced among women with stones, but the interactions were not significant.
Our results provide support for high parity, younger age at first birth, and late age at menarche in the development of gallbladder cancer, particularly among women with biliary stones.
Biliary tract cancers, encompassing tumours of the gallbladder, extrahepatic bile ducts, and ampulla of Vater, are uncommon but highly fatal (Hsing et al, 2006). Apart from a strong association with gallstones, little is known about the aetiology of these cancers (Lowenfels et al, 1989; Hsing et al, 1998, 2006). The incidence rates for gallbladder cancer and gallstones are two-fold higher in women, whereas bile duct and ampulla of Vater cancers are 50% more common in men (Hsing et al, 2006), suggesting that reproductive and/or hormonal factors have a role in their pathogenesis (Sama et al, 1990; Vitetta et al, 2000).
High parity is considered as a risk factor for gallstones (Thijs et al, 1991; Stampfer et al, 1992). During pregnancy, gallbladder volume increases and the flow of bile decreases, which are precursors to gallstone formation (Everson et al, 1982, 1991). Moreover, elevated oestrogen levels during pregnancy increase cholesterol content in the bile, contributing to biliary stasis (Braverman et al, 1980; Kern et al, 1982; Everson et al, 1982, 1991; Novacek, 2006). Pregnancy has also been associated with gallbladder cancer (Lambe et al, 1993; LaVecchia et al, 1993; Moerman et al, 1994; Tavani et al, 1996), but the modifying effect of gallstones and the role of other reproductive factors are not clear. We examined the risks of biliary tract cancers and stones associated with several reproductive factors among women in a population-based case–control study in Shanghai, China, where the rates of these conditions have rapidly increased in recent decades (Hsing et al, 2006, 1998).
Material and methods
Details of the study have been described previously (Hsing et al, 2007a, 2007b, 2007c, 2007d; Andreotti et al, 2008; Hsing et al, 2008). A total of 361 women with biliary tract cancer (269 gallbladder, 92 bile duct) between 35 and 74 years of age were included. Ampulla of Vater cancer cases were excluded because of small numbers (n=31). In all, 70% of cancer cases were confirmed by histopathology, whereas the remaining were confirmed with medical records. We included 647 female patients with stones (511 gallstones, 136 bile duct stones) but without cancer; stone cases were confirmed with medical records. A total of 586 healthy women without cancer or stones were randomly selected from the Shanghai population. Stone status was assessed in nearly all cancer cases and controls using self-reported history and medical records.
Information on demographic, lifestyle, and reproductive factors was obtained through in-person interviews. Cancer and stone cases were interviewed within 3 weeks after diagnosis. Response rates were 95% among cases and 82% among controls. A second interview was conducted 3 months later among 5% of the subjects; the concordance of responses was 90%.
We compared gallbladder cancers with controls without a cholecystectomy (n=545), bile duct cancers with all controls (n=586), and stones with controls without stones (n=422). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusted for age, education, and body mass index. Continuous variables were categorised into quartiles or tertiles on the basis of distributions within controls and those reported among Chinese women (Gao et al, 2000; Wernli et al, 2006). The likelihood ratio test was used to test for multiplicative interactions.
Of the biliary diseases examined, the strongest associations were for gallbladder cancer after adjustment for age, education, and body mass index (Table 1). Parity was positively associated with gallbladder cancer (P-trend=0.04). Compared with women who had one child, those having three or more children had a 2.1-fold risk (95% CI 1.0–4.2) of gallbladder cancer. Among parous women (97% of subjects), those who had their first child before 27 years of age had higher risks of gallbladder cancer relative to those who had their first child at 27 years or after, although the trend test was not significant (P-trend=0.15). Women who began menstruating after the age of 17 years had a 1.8-fold risk (95% CI 1.03–3.24) of gallbladder cancer, compared with those with menarche at age 13 years or younger, but the trend test was borderline significant (P-trend=0.05). Breastfeeding was associated with a reduced risk of bile duct cancer (OR=0.40, 95% CI 0.20–0.81), but the association became borderline significant after adjustment for parity (OR=0.90, 95% CI 0.74–1.00). Parity was not associated with biliary stones, regardless of their location in the biliary tree, age at stone diagnosis (<50 years, ⩾50 years), or duration between diagnosis and interview (<1 year, 1–4 years, 5–9 years, ⩾10 years). None of the other reproductive factors were associated with biliary stones, and there was no effect of menopausal status, age at menopause, or menstruation duration on the risk of biliary tract cancer.
The effects of parity, age at first birth, and age at menarche on gallbladder cancer risk were more pronounced among women with stones, but the interactions were not statistically significant (Table 2). Among women with stones, parity (⩾3 vs 1 child) was associated with a 1.9-fold risk (95% CI 0.74–5.09), whereas those without stones had a 1.2-fold risk (95% CI 0.25–5.84) (P-interaction=0.09). Among women with stones, the effect of parity was attenuated after further adjustment for age at first birth and age at menarche (OR⩾3 vs 1 child=1.47, 95% CI 0.51–4.23). Younger age at first birth (<27 vs ⩾27) was associated with a two-fold risk, but the estimates did not increase monotonically (P-trend=0.06) among those with stones; the association was weaker among those without stones (P-trend=0.39) (P-interaction=0.07). Among women with stones, the association between age at first birth and gallbladder cancer was not considerably changed when further adjusted for parity and age at menarche. Older age at menarche was significantly associated with gallbladder cancer among women with stones (ORper 1-year increase=1.37, 95% CI 1.06–1.77, P-trend=0.02), but nonsignificantly among women without stones (ORper 1-year increase=1.32, 95% CI 0.89–1.96, P-trend=0.17) (P-interaction=0.86). The association between age at menarche and gallbladder cancer remained significant after further adjustment for parity and age at first birth, although the estimates did not increase monotonically.
Given the strong inverse correlation between parity and age at first birth among controls (r=−0.66, P<0.0001), we examined their joint effect on gallbladder cancer among women with stones (Table 2). The risk of gallbladder cancer increased monotonically with increasing parity, regardless of age at first birth, but was highest for women having four or more children, with the first birth before the age of 23 years (OR=3.26, 95% CI 1.06–10.03). Gallbladder cancer risk also increased monotonically with increasing parity regardless of age at menarche, but the highest risk was seen for women having four or more children, with age at menarche being 16 years or older (OR=4.01, 95% CI 1.19–13.58).
We observed that high parity, early age at first birth, and late age at menarche contributed to gallbladder cancer risk. It is unclear why we did not find an association between parity and biliary stones, as previous studies have shown positive associations (Scragg et al, 1984; Basso et al, 1992), but some have been null (Maclure et al, 1989; Chen et al, 1999; Walcher et al, 2005). We lacked information on modifying factors, such as pre-pregnancy body mass index, which may have obscured an association (Basso et al, 1992; Lindseth and Bird-Baker, 2004; Ko et al, 2005). Of the 230 parous women with gallbladder cancer and biliary stones, 98% had their stones diagnosed after giving birth, and 50% >30 years after giving birth. It is likely that asymptomatic gallstones were present for many years before diagnosis, as it has been estimated that 20% of stones become symptomatic after 20 years (Diehl, 1991; Wada et al, 1993). The mechanism underlying the interaction between parity and stones in the development of gallbladder cancer is unclear, but may involve combined or sequential hormonal and inflammatory effects (Bartlett, 2000; Pandey and Shukla, 2000; Tazuma and Kajiyama, 2001).
Given the high correlation between parity and age at first birth, it is difficult to tease apart their individual effects. Among women with stones, a strong joint effect was evident for parity and early age at first birth. This finding is biologically plausible, as younger age at first birth may reflect higher levels and longer exposure to oestrogen and progesterone (Moerman et al, 1994). Although not statistically significant, there was a positive correlation between age at first birth and age of first stone diagnosis among controls, with mean ages of first stone diagnosis of 50 and 58 years for women who gave birth before the age of 21 and after 26 years, respectively.
The association between late age at menarche and gallbladder cancer is consistent with the results of some previous studies (Pandey and Shukla, 2003), but not with all (Chow et al, 1994; Moerman et al, 1994; Tavani et al, 1996; Zatonski et al, 1997). In our study, the association was independent of stones, parity, and age at first birth. It is unclear why older age at menarche was associated with higher gallbladder cancer risk, as younger age at menarche has been linked to longer exposure to oestrogen and progesterone (Moerman et al, 1994). As the risk estimates did not increase monotonically with increasing age at menarche, these findings should be interpreted with caution.
Breastfeeding was associated with a reduced risk of bile duct cancer, independent of stones, parity, and age at menarche, but was not associated with gallbladder cancer. Breastfeeding was related to a higher risk of gallbladder cancer in a South-American study (Strom et al, 1995), but not to gallbladder or bile duct cancer in a Japanese study (Kato et al, 1989). Although breastfeeding may have an effect through hormonal mechanisms (Bonnar et al, 1975; Braverman et al, 1980; Kern et al, 1982; Tazuma and Kajiyama, 2001; Novacek, 2006), our finding could be due to chance.
The null effect of menopausal status is consistent with the results of previous studies (Pandey and Shukla, 2003; Pagliarulo et al, 2004); however, as the majority of our population was postmenopausal (92.5% controls), we had limited statistical power to assess risk among premenopausal women. In addition, the null effect of oral contraceptive (OC) use is consistent with the results of previous studies on biliary stones (Pagliarulo et al, 2004; Dhiman and Chawla, 2006) and biliary tract cancers (Milne and Vessey, 1991; Chow et al, 1994; Moerman et al, 1994), but the prevalence of OC use in the population is low (20% controls) and we lacked information on duration, composition, dose, and age of use. Furthermore, few subjects received hormone replacement therapy (2.4% controls), which has been associated with gallstones (Uhler et al, 2000; Simon et al, 2001; Chen et al, 2006) and gallbladder cancer (Gallus et al, 2002; Fernandez et al, 2003).
In this study, selection bias was minimal because of the population-based design, high case ascertainment, and high response rates. Misclassification of cases was minimal because of the review of diagnostic data. The assessment of stone status allowed us to evaluate cancer risk while controlling for stones. The limited exposure to OCs and hormone-replacement therapy allowed us to assess reproductive factors independently of exogenous hormones. Despite being the largest population-based study on biliary tract cancers to date, we had limited statistical power to test for interactions. In addition, our findings may have limited generalisability because of the homogeneous Shanghai population.
This study revealed increased risks of gallbladder cancer associated with higher parity, younger age of first birth, and late age at menarche, primarily among those with stones, whereas there was no effect for menopausal status or OC use. The joint effects of reproductive risk factors and stones suggest the need for further study into the hormonal and inflammatory mechanisms underpinning the development of gallbladder cancer.
Andreotti G, Chen J, Gao YT, Rashid A, Chen BE, Rosenberg P, Sakoda LC, Deng J, Shen MC, Wang BS, Han TQ, Zhang BH, Yeager M, Welch R, Chanock S, Fraumeni Jr JF, Hsing AW (2008) Polymorphisms of genes in the lipid metabolism pathway and risk of biliary tract cancers and stones: a population-based case-control study in Shanghai, China. Cancer Epidemiol Biomarkers Prev 17: 525–534
Bartlett DL (2000) Gallbladder cancer. Semin Surg Oncol 19: 145–155
Basso L, McCollum PT, Darling MR, Tocchi A, Tanner WA (1992) A study of cholelithiasis during pregnancy and its relationship with age, parity, menarche, breast-feeding, dysmenorrhea, oral contraception and a maternal history of cholelithiasis. Surg Gynecol Obstet 175: 41–46
Bonnar J, Franklin M, Nott PN, McNeilly AS (1975) Effect of breast-feeding on pituitary-ovarian function after childbirth. Br Med J 4: 82–84
Braverman DZ, Johnson ML, Kern Jr F (1980) Effects of pregnancy and contraceptive steroids on gallbladder function. N Engl J Med 302: 362–364
Chen CY, Lu CL, Lee PC, Wang SS, Chang FY, Lee SD (1999) The risk factors for gallstone disease among senior citizens: an Oriental study. Hepatogastroenterology 46: 1607–1612
Chen CH, Huang MH, Yang JC, Nien CK, Etheredge GD, Yang CC, Yeh YH, Wu HS, Chou DA, Yueh SK (2006) Prevalence and risk factors of gallstone disease in an adult population of Taiwan: an epidemiological survey. J Gastroenterol Hepatol 21: 1737–1743
Chow WH, McLaughlin JK, Menck HR, Mack TM (1994) Risk factors for extrahepatic bile duct cancers: Los Angeles County, California (USA). Cancer Causes Control 5: 267–272
Dhiman RK, Chawla YK (2006) Is there a link between oestrogen therapy and gallbladder disease? Expert Opin Drug Saf 5: 117–129
Diehl AK (1991) Epidemiology and natural history of gallstone disease. Gastroenterol Clin North Am 20: 1–19
Everson GT, McKinley C, Kern Jr F (1991) Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism. J Clin Invest 87: 237–246
Everson GT, McKinley C, Lawson M, Johnson M, Kern Jr F (1982) Gallbladder function in the human female: effect of the ovulatory cycle, pregnancy, and contraceptive steroids. Gastroenterology 82: 711–719
Fernandez E, Gallus S, Bosetti C, Franceschi S, Negri E, La Vecchia C (2003) Hormone replacement therapy and cancer risk: a systematic analysis from a network of case-control studies. Int J Cancer 105: 408–412
Gallus S, Negri E, Chatenoud L, Bosetti C, Franceschi S, La Vecchia C (2002) Post-menopausal hormonal therapy and gallbladder cancer risk. Int J Cancer 99: 762–763
Gao YT, Shu XO, Dai Q, Potter JD, Brinton LA, Wen W, Sellers TA, Kushi LH, Ruan Z, Bostick RM, Jin F, Zheng W (2000) Association of menstrual and reproductive factors with breast cancer risk: results from the Shanghai Breast Cancer Study. Int J Cancer 87: 295–300
Hsing AW, Bai Y, Andreotti G, Rashid A, Deng J, Chen J, Goldstein AM, Han TQ, Shen MC, Fraumeni Jr JF, Gao YT (2007b) Family history of gallstones and the risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China. Int J Cancer 121: 832–838
Hsing AW, Gao YT, Devesa SS, Jin F, Fraumeni Jr JF (1998) Rising incidence of biliary tract cancers in Shanghai, China. Int J Cancer 75: 368–370
Hsing AW, Gao YT, McGlynn KA, Niwa S, Zhang M, Han TQ, Wang BS, Chen J, Sakoda LC, Shen MC, Zhang BH, Deng J, Rashid A (2007a) Biliary tract cancer and stones in relation to chronic liver conditions: a population-based study in Shanghai, China. Int J Cancer 120: 1981–1985
Hsing AW, Rashid A, Devesa SS, Fraumeni Jr JF (2006) Biliary tract cancer. In: Schottenfeld D and Fraumeni JF Jr (eds). Cancer Epidemiology and Prevention (edition III). Oxford University Press: New York, New York, pp 787–800
Hsing AW, Rashid A, Sakoda LC, Deng J, Han TQ, Wang BS, Shen MC, Fraumeni Jr JF, Gao YT (2007c) Gallstones and the risk of biliary tract cancer: a population-based study. Br J Cancer 97: 1577–1582
Hsing AW, Sakoda LC, Chen J, Rashid A, Chu L, Deng J, Wang BS, Shen MC, Chen E, Rosenberg P, Zhang M, Andreotti G, Welch R, Yeager M, Fraumeni Jr JF, Gao YT, Chanock S (2008) Variants of inflammation-related genes and the risk of gallstones and biliary tract cancer: a population-based study in China. Cancer Res 68: 6442–6452
Hsing AW, Zhang M, Rashid A, Gao YT, McGlynn KA, Wang B, Shen M, Zhang B, Deng J, Fraumeni Jr JF, O’Brien T (2007d) Hepatitis B and C infection in relation to biliary stones and cancer: a population-based study. Int J Cancer 122: 1849–1853
Kato K, Akai S, Tominaga S, Kato I (1989) Case-control study of biliary tract cancer in Niigata Prefecture, Japan. Jpn J Cancer Res 80: 932–938
Kern Jr F, Everson GT, DeMark B, McKinley C, Showalter R, Braverman DZ, Szczepanik-Van Leeuwen P, Klein PD (1982) Biliary lipids, bile acids, and gallbladder function in the human female: effects of contraceptive steroids. J Lab Clin Med 99: 798–805
Ko CW, Beresford SA, Schulte SJ, Matsumoto AM, Lee SP (2005) Incidence, natural history, and risk factors for biliary sludge and stones during pregnancy. Hepatology 41: 359–365
Lambe M, Trichopoulos D, Hsieh CC, Ekbom A, Adami HO, Pavia M (1993) Parity and cancers of the gall bladder and the extrahepatic bile ducts. Int J Cancer 54: 941–944
LaVecchia C, Negri E, Franceschi S, Parazzini F (1993) Long-term impact of reproductive factors on cancer risk. Int J Cancer 53: 215–219
Lindseth G, Bird-Baker MY (2004) Risk factors for cholelithiasis in pregnancy. Res Nurs Health 27: 382–391
Lowenfels AB, Walker AM, Althaus DP, Townsend G, Domellöf L (1989) Gallstone growth, size, and risk of gallbladder cancer: an interracial study. Int J Epidemiol 18: 50–54
Maclure KM, Hayes KC, Colditz GA, Stampfer MJ, Speizer FE, Willett WC (1989) Weight, diet, and the risk of symptomatic gallstones in middle-aged women. N Engl J Med 321: 563–569
Milne R, Vessey M (1991) The association of oral contraception with kidney cancer, colon cancer, gallbladder cancer (including extrahepatic bile duct cancer) and pituitary tumours. Contraception 43: 667–693
Moerman CJ, Berns MP, Bueno de Mesquita HB, Runia S (1994) Reproductive history and cancer of the biliary tract in women. Int J Cancer 57: 146–153
Novacek G (2006) Gender and gallstone disease. Wien Med Wochenschr 156: 527–533
Pagliarulo M, Fornari F, Fraquelli M, Zoli M, Giangregorio F, Grigolon A, Peracchi M, Conte D (2004) Gallstone disease and related risk factors in a large cohort of diabetic patients. Dig Liver Dis 36: 130–134
Pandey M, Shukla VK (2000) Fatty acids, biliary bile acids, lipid peroxidation products and gallbladder carcinogenesis. Eur J Cancer Prev 9: 165–171
Pandey M, Shukla VK (2003) Lifestyle, parity, menstrual and reproductive factors and risk of gallbladder cancer. Eur J Cancer Prev 12: 269–272
Sama C, Labate AM, Taroni F, Barbara L (1990) Epidemiology and natural history of gallstone disease. Semin Liver Dis 10: 149–158
Scragg RK, McMichael AJ, Seamark RF (1984) Oral contraceptives, pregnancy, and endogenous oestrogen in gall stone disease – a case-control study. Br Med J (Clin Res Ed) 288: 1795–1799
Simon JA, Hunninghake DB, Agarwal SK, Lin F, Cauley JA, Ireland CC, Pickar JH (2001) Effect of estrogen plus progestin on risk for biliary tract surgery in postmenopausal women with coronary artery disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 135: 493–501
Stampfer MJ, Maclure KM, Colditz GA, Manson JE, Willett WC (1992) Risk of symptomatic gallstones in women with severe obesity. Am J Clin Nutr 55: 652–658
Strom BL, Soloway RD, Rios-Dalenz JL, Rodriguez-Martinez HA, West SL, Kinman JL, Polansky M, Berlin JA (1995) Risk factors for gallbladder cancer. An international collaborative case-control study. Cancer 76: 1747–1756
Tavani A, Negri E, La Vecchia C (1996) Menstrual and reproductive factors and biliary tract cancers. Eur J Cancer Prev 5: 241–247
Tazuma S, Kajiyama G (2001) Carcinogenesis of malignant lesions of the gall bladder. The impact of chronic inflammation and gallstones. Langenbecks Arch Surg 386: 224–229
Thijs C, Knipschild P, Leffers P (1991) Pregnancy and gallstone disease: an empiric demonstration of the importance of specification of risk periods. Am J Epidemiol 134: 186–195
Uhler ML, Marks JW, Judd HL (2000) Estrogen replacement therapy and gallbladder disease in postmenopausal women. Menopause 7: 162–167
Vitetta L, Best SP, Sali A (2000) Single and multiple cholesterol gallstones and the influence of bacteria. Med Hypotheses 55: 502–506
Wada K, Wada K, Imamura T (1993) Natural course of asymptomatic gallstone disease. Nippon Rinsho 51: 1737–1743
Walcher T, Haenle MM, Kron M, Hay B, Mason RA, von Schmiesing AF, Imhof A, Koenig W, Kern P, Boehm BO, Kratzer W (2005) Pregnancy is not a risk factor for gallstone disease: results of a randomly selected population sample. World J Gastroenterol 11: 6800–6806
Wernli KJ, Ray RM, Gao DL, De Roos AJ, Checkoway H, Thomas DB (2006) Menstrual and reproductive factors in relation to risk of endometrial cancer in Chinese women. Cancer Causes Control 17: 949–955
Zatonski WA, Lowenfels AB, Boyle P, Maisonneuve P, Bueno de Mesquita HB, Ghadirian P, Jain M, Przewozniak K, Baghurst P, Moerman CJ, Simard A, Howe GR, McMichael AJ, Hsieh CC, Walker AM (1997) Epidemiologic aspects of gallbladder cancer: a case-control study of the SEARCH Program of the International Agency for Research on Cancer. J Natl Cancer Inst 89: 1132–1138
We thank Jiarong Cheng, Lu Sun, Kai Wu, Enju Liu, and Xuehong Zhang, as well as the staff at the Shanghai Cancer Institute, for data collection, specimen collection, and processing; the surgeons at the collaborating hospitals for data collection; the local pathologists for pathology review; and Hope Webb-Cohen and Shelley Niwa of Westat for data preparation and management. This research was supported by the Intramural Research Programme of the National Institutes of Health, National Cancer Institute.
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Andreotti, G., Hou, L., Gao, Y. et al. Reproductive factors and risks of biliary tract cancers and stones: a population-based study in Shanghai, China. Br J Cancer 102, 1185–1189 (2010). https://doi.org/10.1038/sj.bjc.6605597
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