1 Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
2 Department of Social and Preventive Medicine, The University of Queensland, Brisbane, Queensland, Australia.
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ABSTRACT |
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contraceptives; oral; histology; ovarian neoplasms; parity
Abbreviations: CI, confidence interval
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INTRODUCTION |
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MATERIALS AND METHODS |
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Controls were selected from the electoral roll by a random procedure designed to yield an age and regional distribution similar to that of the cases; enrollment to vote is compulsory in Australia. Women with a history of ovarian cancer or bilateral oophorectomy, or who were incapable of completing the questionnaire, were ineligible for inclusion in the control series. Two cases and two controls whose calendars contained insufficient information on contraceptive practices were excluded, as were those cases known to be not on the electoral roll. Ethical approval for the study was obtained from all participating hospitals and institutions, and all women in the study, as well as all treating doctors, provided informed consent.
Trained interviewers administered a standard questionnaire in person either in the clinic (cases) or in the woman's home (some cases, all controls). The topics covered included demography, medical and surgical history, and family history of cancer. We collected details of each woman's reproductive experience by means of a pregnancy and lactation record, including the time to return of menses following pregnancy, and a month-by-month calendar dealing with contraception and attempts to become pregnant during the reproductive years. The questionnaire used is available from the study's web site: http://www.qimr.edu.au/research/labs/davidp/swh.
This procedure yielded 791 cases of epithelial ovarian cancer and 853 controls with data suitable for analysis, reflecting response rates of 90 percent and 73 percent, respectively. Based on histologic review, cases were classified into the following subtypes: 114 (14.4 percent) as mucinous, 415 (52.5 percent) as serous, 99 (12.5 percent) as endometrioid, and 57 (7.2 percent) as clear cell. The remainder (n = 106, 13.4 percent) were mainly of mixed or undifferentiated histologic type, two being transitional cell (Brenner) tumors.
The factors examined were duration of oral contraceptive use, parity, breastfeeding, tubal sterilization, hysterectomy, history of breast or ovarian cancer in a first-degree relative, and infertility as measured by self-reported difficulty in conceiving (7). For each woman we also calculated her ovulatory life within each decade of life between the age at menarche and the age at menopause (8
), diagnosis, or interview, as appropriate. From the length of each full or partial decade we subtracted the total reported anovulatory period in that decade due to pregnancy, postpartum amenorrhea, oral contraceptive use, and/or amenorrhea due to illness, underweight, or other causes. We then weighted the results from each decade by the intensity of ovulation in that decade of life applicable to this population (9
) and summed. We adjusted the total number of ovulations upward or downward depending on the extent to which each participant's reported average menstrual interval was proportionately lower or higher, respectively, than a standard 4 weeks. The total number of ovulations was then divided by 13, the average number of menstrual cycles per year, to create the variable "ovulation years."
Age, years of oral contraceptive use (among users), and ovulation years were all approximately normally distributed, so mean differences were assessed using Student's t test. Differences in the prevalence of exposure between cases with mucinous and nonmucinous ovarian tumors were tested using Pearson's chi-square statistic.
Multivariate analysis was by means of polytomous logistic regression in which the response categories were mucinous cancers, nonmucinous cancers, and controls. We conducted two analyses that differed only in that the factor ovulatory years was omitted in the first model but included in the second. Additional covariates were age in years and its square, body mass index (split at the 65th and 85th percentiles), smoking (current; past; never), alcohol consumption (none; 0.12.5 g/day; >2.5 g/day; unknown), and hormone replacement therapy, all of which have previously been found to be associated with disease status in these data (6, 7
, 10
). Age-squared was included to allow for residual confounding inadequately accounted for by the linear age term. This had the same effect as adjusting for age in 5-year bands with greater statistical efficiency. The net effect of ovulation years on the risk of mucinous and nonmucinous tumors was assessed in a model not including factors from which it was constructed, namely, duration of oral contraceptive use, parity, and breastfeeding. Significance levels for the comparisons between mucinous and nonmucinous forms of ovarian cancer were derived from a similar logistic model comparing mucinous with nonmucinous cancers in the absence of the control group. The statistical software packages SAS (11
) and SUDAAN (12
) were used to conduct all analyses.
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RESULTS |
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The odds ratios (and 95 percent confidence intervals) of mucinous and nonmucinous tumors versus controls for the factors included in the polytomous logistic regression models are presented in table 2, along with the significance level of the mucinous versus nonmucinous comparison (i.e., without controls). The duration of oral contraceptive use had a lesser protective effect, at a marginally significant level, among cases with mucinous cancer than among other cases. The protective effects for parity were also smaller in the mucinous group, albeit not significantly so. Differences between the mucinous and nonmucinous groups with respect to hysterectomy, tubal sterilization, and breastfeeding were not significant. A history of self-reported infertility was positively associated with the occurrence of nonmucinous tumors only. The difference between mucinous and nonmucinous tumors, however, was not significant. A history of breast or ovarian cancer in a first-degree relative showed a significant positive association with nonmucinous tumors only.
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Once ovulation years were taken into consideration, there was no longer a meaningful difference between the two histologic groups in their odds ratios for the duration of oral contraceptive use, and there was less difference between the coefficients for parity. The odds ratios for hysterectomy, tubal sterilization, breastfeeding, self-reported infertility, and history of breast or ovarian cancer in a first-degree relative were not materially affected by the inclusion of ovulation years (table 2).
Because ovulatory life is closely associated with age in premenopausal women, but not in postmenopausal women, and because women with mucinous tumors were considerably younger on average than were women with nonmucinous tumors, the analysis was repeated for pre- and postmenopausal women separately. The differences between mucinous and nonmucinous tumors seen overall did not appear to differ within the two menopausal groups. In addition, because of the excess of borderline tumors among those of mucinous histology, we repeated the analysis separately for borderline (n = 139) and frankly malignant (n = 652) tumors. Nearly identical effects were seen for mucinous and nonmucinous tumors among the borderline and malignant tumor groups. For instance, the odds ratio associated with each year's ovulation in borderline tumors was 1.01 for mucinous (95 percent CI: 0.98, 1.05) and 1.07 for nonmucinous (95 percent CI: 1.03, 1.10) tumors, while among frankly malignant tumors, the risks were 1.01 for the mucinous subtype (95 percent CI: 0.97, 1.04) and 1.05 for nonmucinous subtypes (95 percent CI: 1.04, 1.07).
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DISCUSSION |
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Our findings (unadjusted for ovulation years) are consistent with those reported previously in that the effects of parity and oral contraceptive use were less marked in mucinous than in nonmucinous tumors. However, both increasing parity and longer duration of use of oral contraceptives were negatively associated with the occurrence of both tumor groups. We took the analysis a step further and observed that the differences between them appeared to be driven by a significant difference in the effect of ovulation. The increasing number of lifetime ovulations appeared to increase the risk of nonmucinous tumors only and, once this was taken into account, the differences between the risks of mucinous and nonmucinous tumors associated with the duration of oral contraceptive use and pregnancy diminished. Mucinous ovarian tumors are histologically and clinically similar to adenocarcinomas of the uterine cervix (13), and these tumors may also share some risk factors. The risk of cervical adenocarcinoma is not reduced by oral contraceptive usage (14
) or by parity (15
).
Previous studies have also shown a low occurrence of mucinous tumors among women with a family history of ovarian cancer (1, 16
19
). This finding was supported in our data, with a positive association being seen between a family history of breast or ovarian cancer and nonmucinous tumors only.
There was a nonsignificant difference seen between the effect of a reported history of infertility and the two tumor classes, with a positive association seen in nonmucinous tumors only. This finding is in contrast to that reported by Wittenberg et al. (5) who found that the risk associated with infertility was restricted to mucinous tumors only. It should be noted here that women's self reported difficulty in conceiving is subject to variable interpretation. Infertility is a heterogeneous combination of disorders, which may have very different etiologies.
No significant differences were observed between the risks of mucinous and nonmucinous tumors for tubal sterilization, hysterectomy, and breastfeeding. Wittenberg et al. (5) found an inverse association with hysterectomy among women with mucinous tumors only; however, in our data the protective effect of hysterectomy, if anything, was greater in nonmucinous tumors. Differences in the effect of these factors on the occurrence of mucinous and nonmucinous ovarian tumors have never been seen consistently, and any observed differences seem quite likely to be due to random variation.
In conclusion, this study has provided evidence to support the conclusions reached by Risch et al. (1) that ovarian cancer is an etiologically heterogeneous collection of tumors, and important risk factors such as ovulation and genetic susceptibility may apply only to a subset of ovarian cancers, namely, the nonmucinous subtypes. Data we have presented elsewhere (10
), with respect to the effects of exposure to hormone replacement therapy, also fit with this interpretation.
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ACKNOWLEDGMENTS |
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The contribution made by other members of the Survey of Women's Health Study Group has been acknowledged previously (7).
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NOTES |
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REFERENCES |
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