1 Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, Denmark
2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
Correspondence: Susanne K Kjaer, Danish Cancer Society, Institute of Cancer Epidemiology, Strandboulevarden 49, DK-2100, Copenhagen Ø, Denmark. E-mail: susanne{at}cancer.dk
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Abstract |
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Methods Using the Danish Hospital Discharge Register we identified 65 232 women who had a tubal sterilization (19771993). The cohort was followed for cancer occurrence, and compared with the expected number based on the national cancer incidence rates.
Results The overall risk of ovarian cancer was decreased (standardized incidence ratio [SIR] = 0.82; 95% CI: 0.6, 1.0), and it was still decreased 10 years after the sterilization (SIR = 0.65; 95% CI: 0.4, 1.0). The rate of endometrial cancer was also decreased (SIR = 0.66; 95% CI: 0.5, 1.0), the risk continued being moderately reduced during follow-up, although it was not statistically significant.
Conclusions In this nationwide, population-based study we find that women with tubal sterilization have a decreased risk of subsequent development of ovarian cancer. As the protective effect is not decreasing with years of follow-up, our data do not support that screening bias can explain the protective effect, but indicate that the sterilization itself may convey a reduction in risk. The same pattern is found for endometrial cancer, the association being less strong.
Accepted 6 October 2003
A history of tubal sterilization has been associated, in some studies, with a reduced risk of ovarian cancer.17 In at least two other studies, however, no such association was seen.8,9 In addition, there has been little consensus with regard to ovarian cancer risk in relation to years of follow-up.
Only a few studies have reported on the risk of other types of cancer. In one case-control study the risk of endometrial cancer was moderately, but non-significantly, decreased,10 while two other case-control studies showed a non-significantly increased risk for this cancer type.11,12 In yet another study, a small, non-significant reduction of invasive cervical cancer was reported, particularly during the first 510 years following the tubal sterilization.13
In relation to both ovarian cancer and endometrial and breast cancer, it has been hypothesized that the decreased risk, if confirmed, could be related to alterations in the levels of endogenous hormones (oestrogen, progesterone), which may occur following tubal sterilization.1416 A possibly decreased risk of cervical cancer has been related to a screening effect as tubal ligation may provide an opportunity for Pap smear screening and thereby secondary prevention of cervical cancer.13
The purpose of the present study was to examine the risk of gynaecological cancer in a cohort of more than 65 000 Danish women who had a tubal sterilization performed during 19771993. In addition, we report on the risk of ovarian borderline tumours and cervical intraepithelial neoplasia grade 3 (CIN3), which to our knowledge has not previously been evaluated in follow-up studies.
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Methods |
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Since 1968, all Danish inhabitants have been assigned a unique personal identification number, comprising information on sex and date of birth, and these identification numbers are registered in the computerized Central Population Register. The number allows correct linkage of information between different registers. The study cohort was linked to the Central Population Register to verify the personal identification number and to obtain information on date of death or date of migration, whenever appropriate. A total of 134 women (0.2%) were excluded because of invalid personal identification number.
To ascertain the cancer occurrence in the cohort, it was linked to the Danish Cancer Registry, which contains information on all cases of cancer in Denmark since 1943, including bladder papillomas and benign brain tumours. With regard to the cervical precancerous lesions, carcinoma in situ and severe dysplasia (CIN 3) may be close to complete registration, the notification of moderate and mild dysplasia is incomplete.19 Since 1987, it has been mandatory to report cancer cases as well as precancerous lesions to the Danish Cancer Registry. The cancers are classified according to a modified version of the Seventh Revision of the International Classification of Diseases (ICD).19
The 65 232 women were followed for cancer occurrence (including borderline ovarian tumours and CIN3) from the date of the hospital discharge for tubal sterilization until the date of emigration, date of death, or 31 December 1995, whichever came first. Additional exit dates were applied when the risk of certain cancers was examined. Thus, follow-up for endometrial cancer was ended at the date of hysterectomy, follow-up for cervical cancer/CIN3 was discontinued at the date of total hysterectomy, and follow-up for ovarian cancer/borderline tumour was ended at the date of bilateral oophorectomy.
The observed number of cancer cases was compared with the number of expected cases based on the age- and calendar year-specific cancer incidence rates for women from the Danish Cancer Registry and accumulated person-years. Standardized incidence ratios (SIR) (observed number of cases divided by the expected number) were computed with corresponding 95% CI for each type of cancer, assuming a Poisson distribution of the observed cancer cases.20
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Results |
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A total of 1894 cancers were observed among the 65 232 women who previously had a tubal sterilization. This was slightly less than expected (1981 cases) on the basis of the rates from the general female population (SIR = 0.96; 95% CI: 0.9, 1.00) (Table 1). None of the non-gynaecological cancers contributed in particular to this lower overall cancer rate, except for breast cancer, which occurred less frequently than expected (SIR = 0.9; 95% CI: 0.9, 1.0). In contrast, the group of gynaecological cancers played a role as a total of 277 cases was observed in this population against 328.0 expected (SIR = 0.84: 95% CI: 0.8, 1.0).
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The risk of ovarian cancer of different histological types (serous, mucinous, clear cell/endometrioid, others) was also assessed (Table 2). For both the group of serous invasive tumours as well as for the group of other ovarian cancers, the overall risk was decreased; SIR = 0.72 (95% CI: 0.5, 1.0) and SIR = 0.60 (95% CI: 0.3, 1.0), respectively. In addition, the clear cell/endometrioid group was non-significantly decreased (SIR = 0.86; 95% CI: 0.5, 1.44). In contrast, the mucinous ovarian cancers were more common than expected, SIR = 1.49 (95% CI: 0.9, 2.3). For women with 5 years of follow-up, this risk of mucinous ovarian carcinoma increased to 1.86 (95% CI: 1.1, 3.0)
The rate of endometrial cancer was also decreased in women who had a tubal sterilization (SIR = 0.70; 95% CI: 0.5, 1.0) and except for the first year after the operation. The risk continued being moderately reduced during follow-up, however the associations were not statistically significant (Table 3).
The observed number of cervical cancer cases was only slightly lower than expected, both overall and during follow-up, except for the first year where a non-significantly increased risk was observed (Table 3). In contrast, CIN3 lesions were slightly in excess (SIR = 1.06; 95% CI: 1.0, 1.1), the risk being significantly increased within the first year after sterilization and also in the group with the longest follow-up.
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Discussion |
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Rosenblatt et al.3 reported that the effect of tubal ligation was seen only for clear cell and endometrioid ovarian carcinomas. However, the results were based only on one exposed case in each group. This finding could not be confirmed in the present study. In our study, the overall decrease in ovarian cancer risk seemed to affect the non-mucinous histological types only. It has previously been suggested that mucinous ovarian cancers have a different pattern of risk factors from the non-mucinous types.34 This relates in particular to use of OC and to parity. However, the currently available data on this issue are equivocal. Some studies have found use of OC and increasing parity to decrease the risk of both mucinous and non-mucinous ovarian cancer.3537 In contrast, others observed such a decreased risk only for the non-mucinous tumours, whereas for ovarian cancer of the mucinous type they found no or even an increased risk associated with OC use and parity.34,3840 If the development of mucinous ovarian tumours is less dependent on hormonal/ovulatory factors as indicated by some studies,41 it might be anticipated that a protective effect of sterilization would also be less pronounced for these tumours. Indeed, the results of the present paper may support a different aetiological mechanism for ovarian cancers of the mucinous type, however, due to relatively small numbers when ovarian cancer is divided into histological groups, we cannot exclude the possibility that the findings may be due to chance.
Only a few case-control studies and no follow-up studies have focused on the association between tubal ligation and the risk of endometrial cancer.1012,42 In one study, a significantly decreased crude risk was observed; however, after adjustment for confounding factors like age and parity, only a moderately (non-significant) decreased risk remained.10 In the same study, the reduction in risk tended to diminish with time since the sterilization, maybe pointing to some degree of surveillance effect. In another study, based on results from the World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives, it was concluded that the existing findings with regard to the association between endometrial cancer and previous sterilization could most likely be ascribed to random variation.11 This is supported by the most recent study in which no significant association was observed between sterilization and endometrial cancer after adjustment for parity was done.12 In our study, we find an overall decreased risk of endometrial cancer, and we observe no significant tendency that the effect diminishes with length of follow-up. However, as we did not have information on other risk factors, we were unable to make any adjustments for potential confounding factors. Thus, even though it is in theory biologically plausible that sterilization affects endometrial cancer risk, it is still unclear whether a causal association exists.
We find that the occurrence of uterine cervical cancer was slightly lower and the occurrence of CIN3 higher than could be expected from the rates in the general population. Our results for invasive cervical cancer are almost identical to those recently reported by Li et al.13 The association between tubal sterilization and CIN3 has not previously been addressed. The finding of a decrease (although limited) in cancer of the cervix and simultaneously increased detection of CIN3, which is only rarely symptomatic, most likely point to a screening effect i.e. in connection with the surgical procedure, a high proportion of women will also have a Pap smear.
A well-defined study population and a large cohort size strengthen this nationwide, population-based study. Furthermore, information on outcome is nearly complete and there is virtually no loss to follow-up, due to the accuracy and completeness of the Danish Cancer Registry and the Central Population Register. Finally, except for the study by Krieger et al.,7 this is the only study where information on exposure is not dependent on patient recall. It is a limitation of the present study, however, that we had no information on the type of sterilization, and thus were unable to assess whether the cancer risk varied with the different methods of tubal sterilization. In addition, no information on potential confounding factors was available. It is likely that women having a tubal sterilization have more children than other women or at least a lower prevalence of infertility, and consequently an a priori lower risk of ovarian/endometrial cancer. It is also clear that having a tubal ligation, and the age at which this occurs, could influence the total duration of OC use as well as the number of children. Both of these variables constitute important risk determinants for ovarian cancer, and thus our inability to adjust for these factors may well have influenced the results of our study. Nevertheless, it seems less likely that this can account entirely for our findings with regard to ovarian cancer. In none of the recent studies mentioned in Table 4, where information on such factors was collected, neither parity alone nor in combination with other risk determinants could explain the association between tubal sterilization and ovarian cancer (Table 4). Furthermore, if the association could be explained by a reduction in the length of time when a woman could use OC or could have children, one might expect a different magnitude of association in women having their tubal ligation at a young age compared with women sterilized later in life, and we did not observe such a difference (data not shown). Finally, inclusion of women who are actually not at risk (e.g. women with a hysterectomy or bilateral oophorectomy) in the denominator of the standard rate may imply underestimation of the expected number and thus overestimation of the relative rate. As only about 1800 women undergo bilateral oophorectomy and 5500 women have a hysterectomy each year (out of a population of approximately 1.8 million women aged 1569 years),43 the effect on the ovarian cancer SIR estimate is considered limited.
In conclusion, in this nationwide, population-based study we find that women with tubal sterilization have a decreased risk of subsequent development of ovarian cancer, which seems to last for at least 1015 years, and likewise, a slight reduction in the occurrence of ovarian borderline tumours is observed. Our data do not support that screening bias can explain the protective effect against ovarian cancer, but indicate that the sterilization itself may convey a reduction in risk, although the biological mechanism is not entirely clear. The same overall pattern is found for endometrial cancer; however, the association is weaker than for cancer of the ovaries. In contrast, the moderately decreased cervical cancer risk and increased risk of CIN3 observed in our cohort indicate that the effect of tubal sterilization in this case can be explained by an increased cervical cancer screening among sterilized women.
KEY MESSAGES
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Acknowledgments |
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References |
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2 Hankinson SE, Hunter DJ, Colditz GA et al. Tubal ligation, hysterectomy and risk of ovarian cancer. JAMA 1993;270:281318.[Abstract]
3 Rosenblatt KA, Thomas DB and The World Health Organization Collaborative Study of Neoplasia and Steroid Contraception (1996). Reduced risk of ovarian cancer in women with a tubal ligation or hysterectomy. Cancer Epidemiol Biomark Prev 1996;5:93335.[Abstract]
4 Cornelison TL, Natarajan N, Piver MS, Mettlin CJ. Tubal ligation and the risk of ovarian carcinoma. Cancer Detect Prev 1997;21:16.[ISI][Medline]
5 Green A, Purdie D, Bain C et al. Tubal sterilization, hysterectomy and decreased risk of ovarian cancer. Int J Cancer 1997;71:94851.[CrossRef][ISI][Medline]
6 Miracle-McMahill HL, Calle EE, Kosinski AS et al. Tubal ligation and fatal ovarian cancer in a large prospective study. Am J Epidemiol 1997;145:34957.[Abstract]
7 Krieger N, Sloan M, Cotterchio M, Parsons P. Surgical procedures associated with risk of ovarian cancer. Int J Epidemiol 1997;26:71015.[Abstract]
8 McGowan L, Parent L, Lednar W et al. The woman at risk for developing ovarian cancer. Gynecol Oncol 1979;7:32544.[ISI][Medline]
9 Koch M, Starreveld AA, Hill GB et al. The effect of tubal ligation on the incidence of epithelial cancer of the ovary. Cancer Detect Prev 1984;7:24145.[ISI][Medline]
10 Castelsagué X, Thompson WD, Dubrow R. Tubal sterilization and the risk of endometrial cancer. Int J Cancer 1996;65:60712.[CrossRef][ISI][Medline]
11 Rosenblatt K, Thomas D. Association between tubal ligation and endometrial cancer. Int J Cancer 1997;71:12930.[CrossRef][ISI][Medline]
12 Lacey JV, Brinton LA, Mortel R et al. Tubal sterilization and the risk of cancer of the endometrium. Gynecol Oncol 2001;79:48284.[CrossRef][ISI]
13 Li H, Thomas DB. Tubal ligation and risk of cervical cancer. Contraception 2000;61:32328.[CrossRef][ISI][Medline]
14 Sørensen T, Ladehoff P, Lindholm P, Quist K. Follicular stimulating hormone, luteinizing hormone and estrogen levels before and after female sterilization. Acta Obstet Gynecol Scand 1981;50:55961.
15 Cattanach JF, Milne BJ. Post-tubal ovulatory problems correlated with ovarian steroidogenesis. Contraception 1988;38:54150.[ISI][Medline]
16 Hakverdi AU, Taner CE, Esden AC, Satici O. Changes in ovarian function after sterilization. Adv Contracept 1994;10:5156.
17 Danish National Board of Health. Activity in the Hospital Care System 1979. Copenhagen: Danish National Board of Health, 1981.
18 Danish National Board of Health. Classification of Surgical Procedures and Therapies. 1st, 2nd and 3rd Edns. Copenhagen: Danish National Board of Health 1973, 1980, 1988.
19 Storm HH, Mandres T, Friis S, Bang S. Cancer Incidence in Denmark in 1988. Copenhagen: Danish Cancer Society, 1991.
20 Bailar JC, Ederer F. Significance factors for the ratio of a Poisson variable to its expectation. Biometrics 1964;20:63943.[ISI]
21 Fatalla MF. Incessant ovulationa factor in ovarian neoplasia? Lancet 1971;ii:163.[CrossRef]
22 Purdie D, Green A, Bain C et al. Reproductive and other factors and risk of epithelian ovarian cancer: an Australian case-control study. Int J Cancer 1995;62:67884.[ISI][Medline]
23 Risch HA, Marrett LD, Howe GR. Parity, contraception, infertility and the risk of epithelial ovarian cancer. Am J Epidemiol 1994;140:58597.[Abstract]
24 Stadel BV. The etiology and prevention of ovarian cancer. Am J Obstet Gynecol 1975;123:77274.[Medline]
25 Cramer DW, Welch WR. Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst 1983;71:71721.[ISI][Medline]
26 Rilman T, Persson I, Nilsson S. Hormonal aspects of epithelial ovarian cancer: review of epidemilogic evidence. Clin Endocrinol 1998;49:66570.[CrossRef][ISI][Medline]
27 Cramer DW, Xu H. Epidemiologic evidence for growth factors in the pathogenesis of ovarian cancer. Ann Epidemiol 1995;5:31014.[CrossRef][Medline]
28 Henderson BE, Ross RK, Pike MC, Casagrande JT. Endogenous hormones as a major factor in human cancer. Cancer Res 1982;42:323239.[Abstract]
29 Henderson BE, Feigelson HS. Hormonal carcinogenesis. Carcinogenesis 2000;21:42733.
30 Radwanska E, Headley SK, Dmowski P. Evaluation of ovarian function after tubal sterilization. J Reprod Med 1982;27:37684.[ISI][Medline]
31 Cattanach JF. Oestrogen deficiency after tubal ligation. Lancet 1985;i:84749.[CrossRef]
32 Garza-Flores J, Vázquez-Estrada L, Reyes A et al. Assessment of luteal function after surgical tubal sterilization. Adv Contracept 1991;7:37177.[Medline]
33 Erruo W, Bilian X, Weigian Y, Hui L, Beisheng I. Hormonal profile of the menstrual cycle in Chinese women after tubal sterilization. Contraception 1992;45:58393.[CrossRef][ISI][Medline]
34 Risch AR, Marret LD, Howe JM. Differences in risk factors for epithelial ovarian cancer by histology. Am J Epidemiol 1996;144:36372.[Abstract]
35 Wittenberg L, Cook LS, Rossing MA, Weiss NS. Reproductive risk factors for mucinous and non-mucinous epithelial ovarian cancer. Epidemiology 1999;10:76163.[ISI][Medline]
36 Weis NS, Lyon JL, Liff JM, Vollmer WM, Daling JR. Incidence of ovarian cancer in relation to the use of oral contraceptives. Int J Cancer 1981;28:66971.[ISI][Medline]
37 Cramer DW, Hutchison GB, Welch WR, Scully RE, Ryan RE. Determinants of ovarian cancer risk. I. Reproductive experience and family history. J Natl Cancer Inst 1982;71:71116.[ISI]
38 Kvåle G, Heuch I, Nilsen S, Beral V. Reproductive factors and risk of ovarian cancer: a prospective study. Int J Cancer 1988;42:24651.[ISI][Medline]
39 World Health Organization Collaborative Study of Neoplasia and Steriod Contraceptives. Epithelial ovarian cancer and combined oral contraceptives. Int J Epidemiol 1989;18:53845.[Abstract]
40 Cramer DW, Hutchison GB, Welch WR, Beral V. Factors affecting the association of oral contraceptives and ovarian cancer. N Engl J Med 1982;307:104751.[Abstract]
41 Purdie DM, Siskind V, Bain CJ, Webb PM, Green A. Reproduction-related risk factors for mucinous and nonmucinous epithelial ovarian cancer. Am J Epidemiol 2001;153:86064.
42 Kelsey JL, Livolsi VA, Holford TR et al. A case-control study of the endometrium. Am J Epidemiol 1982;116:33342.[Abstract]
43 Danish National Board of Health. Surgical Activity in Danish Hospitals 1992. Copenhagen: Danish National Board of Health, 1992.
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