Beyond ovulation: oral contraceptives and epithelial ovarian cancer

In a case-control study in three Australian states that included 794 women with epithelial ovarian cancer and 853 community controls for whom we had adequate contraceptive and reproductive histories, we examined the effects of oral contraceptive use after controlling for estimated number of ovulatory cycles. Other covariates included in the multiple logistic regression analysis were parity, smoking, and history of pelvic surgery. The protective effect of duration of oral contraceptive use appeared to be multiplicative, with a 7% decrease in relative risk per year [95% confidence interval (CI) = 4-9%], persisting beyond 15 years of exposure. Use for up to 1 year may have a greater effect than predicted (odds ratio = 0.57; 95% CI = 0.40-0.82), whereas use before the first pregnancy may be additionally beneficial (odds ratio = 0.95; 95% CI = 0.87-1.03, adjusted for overall duration of use). Better control for ovulatory life might attenuate these estimates somewhat. There was little evidence of waning protection with time since last exposure or of extra benefit with early commencement of oral contraceptive use. We found no convincing evidence of effect modification in any factor examined or differences in effect among the three main histologic cancer types or between borderline and malignant tumors. Oral contraceptives may act by both suppressing ovulation and altering the tumor-promoting milieu.     

The risk of epithelial ovarian cancer in short-term users of oral contraceptives.

Short-term use (less than 1 year) or oral contraceptives has been associated with increased to slightly decreased risks of epithelial ovarian cancer in several studies. To determine what might account for a statistically significant 40% reduction in risk associated with as little as 3 to 6 months of use, a finding previously reported from the Cancer and Steroid Hormone Study, and to consider the implications for mechanisms of pathogenesis, the authors compared numerous characteristics of short-term users of oral contraceptives (41 cases, 412 controls) with those of never users (242 cases, 1,517 controls). The reduced risk among short-term users was consistently restricted to women who stopped using oral contraceptives for medical reasons, which were essentially side effects; there was little evidence of a protective effect among women who stopped for nonmedical reasons. Factors such as age, parity, family history of ovarian cancer, estrogen dose, history of sterilization, and latency (interval from first use) could not account for the finding. These analyses suggest that short-term use of oral contraceptives has little to no effect per se on reducing the risk of epithelial ovarian cancer and that side effects resulting in cessation of oral contraceptive use shortly after it was begun may be indicative of factors that are protective against the disease.     

Short-term oral contraceptive use and the risk of epithelial ovarian cancer

Oral contraceptive (OC) use has been consistently linked to a reduction in ovarian cancer in a dose-dependent fashion. Whether short-term OC use is protective remains controversial. In 1994-1998 in the Delaware Valley of Pennsylvania, the authors examined the association between short-term OC use and ovarian cancer in a population-based case-control study comparing 608 incident epithelial ovarian cancer cases with 926 community controls. Using unconditional logistic regression and adjusting for known confounders, they found a significant reduction in ovarian cancer risk for women who had used OCs for < or =6 months (odds ratio = 0.73, 95% confidence interval: 0.54, 0.99). This protective effect was observed in only that group who had used OCs for < or =6 months and stopped because of side effects (odds ratio = 0.59, 95% confidence interval: 0.40, 0.87 for side effects and odds ratio = 0.91, 95% confidence interval: 0.60, 1.37 for non-side-effects). Women who used OCs for >6 months were at a reduced risk independent of their reason for stopping. Results were similar when stratifying by parity and hormone therapy use. Thus, OC use for as little as 6 months provides significant protection against ovarian cancer risk, protection that appears limited to those women who stop using OCs because of side effects. Mediating factors may reflect endogenous hormone levels, OC metabolism, or OC bioactivity.     

Oral contraceptives and breast cancer risk

Because of the continuing controversy on the breast cancer risks associated with the use of combined oral contraceptives (OCs), the medical literature was reviewed to assess the risks of this cancer to OC users. This review found that the medical literature supports the view that OC use is associated with small increased risks of premenopausal breast cancer. There is no consensus as to which subgroups of women might be at an increased risk.     

Do oral contraceptives cause breast cancer?

This critique of the research study on oral contraceptives and breast cancer by Weinstein, et al., published in the journal Epidemiology, September 1991, points out several design faults, then notes some of the findings that nevertheless agree with other large, well conceived studies. Some of the difficulties of the study were the lack of disaggregation by race, fewer low socioeconomic group controls, more high socioeconomic group users, and lack of data on pill formulation used. The results agree with those of the large CASH study, which found that there was no overall dose response of pill use with risk of breast cancer, even taking into account use before or after the 1st birth. The results also agree with the finding in the CASH study that relative risk was higher, here 1.8, for women using the pill 4 or more years in the 20-49 age group, while lower, 0.7, for those aged 50-70. This suggests that the pill may have accelerated onset of breast cancer in some young women, but not affected cumulative lifetime risk. Since the question of oral contraceptive use and breast cancer still remains unsettled, women over 30 who have taken the pill for 4 or more years should have mammagraphy and self and clinical breast exams regularly.     

IPPF statement on oral contraceptives and cancer of the breast

The 1989 statement issued by the International Medical Advisory Panel (IMAP) concluded that no overall effect of oral contraceptives (OCs) on breast cancer is demonstrable from the studies conducted since 1980. However, some studies have suggested an adverse association in women whose breast cancer was diagnosed before the age of 45, who used OCs for a long period of time, or who started them before the age of 25 and/or before their 1st full-term pregnancy. 3 recent publications have received much publicity. Kay and Hannaford suggest an increased risk among women aged 30-34, and Stadel et al., suggest an increased risk among nulliparous women who experienced menarche before age 13 and who used OCs for 8 or more years. Neither of these studies showed an overall effect of OCs on breast cancer. However, Miller et al. suggest a 2-fold rise in the risk of breast cancer among previous users of combined OCs who are under 45 years. The diversity of such results renders them inconclusive. Furthermore, the studies which have been done so far mainly included women who began using OCs in the 1960s and 1970s when larger doses of estrogen and progestagen were common. Continued research is needed to resolve the contradictory findings of previous studies, to study the new formulations now in use, and to achieve a better understanding of the biological factors underlying the development of breast cancer. While acknowledging concern about continued controversy, IMAP does not presently recommend any changes in OC use. When counselling women, service providers should present the risks of OCs, as well as the benefits (such as, prevention of pregnancy, endometrial and ovarian cancer, ectopic pregnancy, and acute pelvic inflammatory disease). IMAP will continue to closely monitor developments surrounding this issue.     

Combined oral contraceptive use and epithelial ovarian cancer risk: time-related effects

BACKGROUND: Although the protective effect of oral contraceptives (OCs) use against epithelial ovarian cancer is well-established, there remain gaps in our understanding of the contributions of time-related characteristics of OC use to risk. METHODS: This population-based case-control study, carried out in Hawaii and Los Angeles 1993-2006, included 813 cases of epithelial ovarian cancer and 992 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. RESULTS: Epithelial ovarian cancer risk was reduced 5 or more years after initiation of OC use (OR = 0.18; CI = 0.08-0.39). Each year of use provided a 5% reduction (CI = 2%-8%) in risk. A positive gradient in risk with time since first OC use was independent of duration of OC use. The inverse association of OCs with risk was attenuated decades after last use, but was not affected by age at first or last use. OC use for <1 year was associated with decreased ovarian cancer risk (OR = 0.45; CI = 0.26-0.79) only among recent users (< or =20 years from diagnosis/interview). Women who used OCs for a year or more were protected for at least 3 decades after they stopped use. CONCLUSIONS: Reduction in epithelial ovarian cancer risk associated with OC use became apparent after a short latency period and short duration of use, and was long-lasting. Time since first use and time since last use seem to modify the association of OCs with ovarian cancer risk independently of duration of use.     

Dietary antioxidants, supplements, and risk of epithelial ovarian cancer

Several studies of dietary and serum antioxidant micronutrients (vitamins A, C, and E and beta-carotene) suggest that higher levels may be protective for ovarian cancer. None of these has examined supplements. We used a food frequency questionnaire and additional questions on supplements to study 168 histologically confirmed epithelial ovarian cancer cases, 159 community controls, and 92 hospital-based controls. Antioxidant consumption from diet or supplements was calculated in milligrams or international units per day. In multivariate analyses using only community controls, the highest levels of intake of vitamins C and E from supplements were protective: odds ratio (OR) = 0.40 [95% confidence interval (CI) = 0.21-0.78] and OR = 0.33 (95% CI = 0.18-0.60), respectively. Consumption of antioxidants from diet was unrelated to risk. In analyses combining antioxidant intake from diet and supplements, vitamins C (> 363 mg/day) and E (> 75 mg/day) were associated with reduced risks: OR = 0.45 (95% CI = 0.22-0.91) and OR = 0.44 (95% CI = 0.21-0.94), respectively. Results were similar, with some attenuation toward the null, in analyses combining both control groups. The levels of vitamins C and E associated with the protective effect were well above the current US Recommended Dietary Allowances. These findings support the hypothesis that antioxidant vitamins C and E from supplements are related to a reduced risk of ovarian cancer.     

Oral contraceptives, other methods of contraception, and risk reduction for ovarian cancer

Oral contraceptives reduce the risk of ovarian cancer, but the impact of other methods of contraception has not been fully explored. This population-based, case-control study involved women 20-69 years of age who had ever had intercourse. We compared cases with a recent diagnosis of ovarian cancer (N = 727) with community controls (N = 1,360). All methods of contraception evaluated were associated with a reduced risk for ovarian cancer. After adjustment for age, race, pregnancies, and family history of ovarian cancer, the odds ratios for ever-use of each method as compared with never-use were: oral contraceptives for contraception, 0.6 (95% confidence interval = 0.5-0.8); intrauterine device, 0.8 (95% confidence interval = 0.6-1.0); barrier methods, 0.8 (95% confidence interval = 0.6-0.9); tubal ligation, 0.5 (95% confidence interval 0.4-0.7); and vasectomy, 0.8 (95% confidence interval = 0.6-1.1). Nulligravid women were not protected by any of these contraceptive methods. Multigravid women, however, were protected by all methods. We conclude that various methods of contraception reduce ovarian cancer risk. This effect does not appear to result from contraceptive use being a nonspecific marker of fertility. The results imply mechanisms other than hormonal or ovulatory by which ovarian cancer risk is reduced.     

Cigarette smoking and the risk of epithelial ovarian cancer

Cigarette smoking may affect each of the currently proposed mechanisms of ovarian carcinogenesis. Whether cigarette smoking has any effect on the development of ovarian cancer has not been adequately evaluated. To study this issue, the authors examined data from the Cancer and Steroid Hormone Study, a multicenter, case-control study of gynecologic cancers conducted between December 1, 1980, and December 31, 1982, in eight geographic areas of the United States. This analysis utilized data on 494 women with newly diagnosed epithelial ovarian cancer and 4,238 population-based control women 20-54 years of age. There was no association of epithelial ovarian cancer with dose of cigarette smoking, age smoking started, time since smoking started, or time since smoking last occurred. Simultaneous adjustment for age, parity, history of oral contraceptive use, and other potentially confounding factors did not alter these results.     

Menstrual factors and the risk of epithelial ovarian cancer

The relationship between menstrual factors and the risk of ovarian cancer was evaluated in the framework of a hospital-based case-control study conducted in the greater Milan area on a total of 634 cases of ovarian cancer and 1626 control subjects with a spectrum of acute conditions unrelated to any of the established or potential risk factors for ovarian cancer. Compared with women whose menarche occurred at age 13 or later, the risk of ovarian cancer was moderately (and not significantly) elevated for earlier menarche (multivariate relative risk, RR = 1.13, 95% confidence interval, CI = 0.97-1.37). There was a positive association with age at menopause, the multivariate relative risk, compared with women aged 45 years or less at menopause, being 1.25 for those aged 45-49 years, 1.40 for 50-53 and 1.58 for 54 or over (chi 2(1) trend = 8.86, p = 0.003). A lifelong irregular menstrual pattern (defined as frequent menstrual-like episodes of bleeding less than 21 or more than 35 days apart) was negatively associated with the risk of ovarian cancer (multivariate RR = 0.45, 95% CI = 0.31-0.65). The effect of age at menopause and lifelong menstrual pattern was similar in different strata of age, whereas there was a positive association with early menarche among younger women which disappeared with advancing age. The present findings confirm the influence of various menstrual factors on the risk of epithelial ovarian cancer.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pregnancy weight gain and breast cancer risk

Background  

Elevated pregnancy estrogen levels are associated with increased risk of developing breast cancer in mothers. We studied whether pregnancy weight gain that has been linked to high circulating estrogen levels, affects a mother's breast cancer risk.     

Combined oral contraceptives, smoking, and cardiovascular risk

STUDY OBJECTIVE: To assess age specific incidence and mortality of stroke, acute myocardial infarction (AMI), and idiopathic venous thromboembolism (VTE) associated with use of modern low dose combined oral contraceptives (OCs) and the interaction with smoking. DESIGN: Hospital-based case-control study. SETTING: Hospitals in Oxford region in the United Kingdom, which covered a defined population, during the period 1989-1993. METHODS: Relative risk estimates from the WHO Collaborative Study and observed incidence rates from the Oxford region were used to estimate age specific incidence of each disease among women without cardiovascular risk factors and model total cardiovascular incidence and mortality. RESULTS: Among women who did not use OCs, smoke nor had any other cardiovascular risk factors, total incidence of stroke and AMI were less than 2 events per 100,000 woman years in those aged 20-24 years and rose exponentially with age to 8 events per 100,000 among women aged 40-44 years. Incidence of idiopathic VTE among women who did not use OCs rose linearly with age (from 3.3 per 100,000 at ages 20-24 years to 5.8 per 100,000 at ages 40-44 years). The increased risk of idiopathic VTE associated with OC use among non-smokers constituted over 90% of all cardiovascular events for women aged 20-24 years and more than 60% in those aged 40-44 years. Fatal cardiovascular events were dominated by haemorrhagic stroke and AMI, and among OC users who smoked these two diseases accounted for 80% of cardiovascular deaths among women aged 20-24 years, rising to 97% among those aged 40-44 years. Cardiovascular mortality associated with smoking was greater than that associated with OC use at all ages. Attributable risk associated with OC use was 1 death per 370,000 users annually among women aged 20-24 years, 1 per 170,000 at ages 30-34 years, and 1 per 37,000 at ages 40-44 years. Among smokers, the cardiovascular mortality attributable to OC use was estimated to be about 1 per 100,000 users annually among women aged less than 35 years, and about 1 per 10,000 users annually among those above the age of 35 years. CONCLUSION: The incidence of fatal cardiovascular events among women aged less than 35 years is low. The VTE risk associated with OC use is the largest contributor to OC induced adverse effects. The potentially avoidable excess VTE risk associated with the newer progestogens desogestrel and gestodene would account for a substantial proportion of total cardiovascular morbidity in this age group. For women over age 35 years the absolute risks associated with OC use and smoking are greater because of the steeply rising incidence of arterial diseases. The combination of smoking and OC use among such women is associated with particularly increased risks. Any potential reduction in AMI or stroke risk with use of third generation OCs would be a more important consideration among older compared with younger women, particularly if they smoke. However, the mortality associated with smoking is far greater than that associated with OC use (of any type) at all ages.     

Oral contraceptives and breast cancer risk: a case-control study

The association between breast cancer risk and oral contraceptive use was examined in 401 breast cancer patients and 519 hospital controls interviewed in New York City during 1979-1981. Control subjects were ascertained utilizing variable ratio matching to the cases (2:1 or 1:1) by sex, age, hospital, and time of diagnosis. No evidence of a positive association was found between cancer risk and the duration of use in either parous or nulliparous women. The odds ratios obtained by comparing users to non-users in women under 50 years of age after adjusting for other risk factors were 0.8 (95% CI = 0.4-1.4) for less than five years duration and 0.4 (95% CI = 0.2-0.8) for five or more years duration (P less than 0.05 when tested for decreasing trend). There was also no evidence of effect modification between oral contraceptive use and other breast cancer risk factors (viz. family history, nulliparity, late age at first pregnancy, or abstention from breastfeeding). Our results do not indicate that the use of oral contraceptives increases the risk of breast cancer.     

Analgesic drug use and risk of epithelial ovarian cancer

Analgesic use may reduce ovarian cancer risk, possibly through antiinflammatory or antigonadotropic effects. The authors conducted a population-based, case-control study in Washington State that included 812 women aged 35-74 years who were diagnosed with epithelial ovarian cancer between 2002 and 2005 and 1,313 controls. Use of analgesics, excluding use within the previous year, was assessed via in-person interviews. Logistic regression was used to calculate odds ratios and 95% confidence intervals. Overall, acetaminophen and aspirin were associated with weakly increased risks of ovarian cancer. These associations were stronger after more than 10 years of use (acetaminophen: odds ratio (OR) = 1.8, 95% confidence interval (CI): 1.3, 2.6; aspirin: OR = 1.6, 95% CI: 1.1, 2.2) and were present for indications of headache, menstrual pain, and other pain/injury. Reduced risk was observed among aspirin users who began regular use within the previous 5 years (OR = 0.6, 95% CI: 0.4, 1.0) or used this drug for prevention of heart disease (OR = 0.7, 95% CI: 0.5, 1.0). These results, in the context of prior findings, do not provide compelling evidence of a true increase in risk of ovarian cancer among women who use these drugs. However, they add to the weight of evidence that, in the aggregate, provides little support for the use of analgesic drugs as chemoprevention for this disease.     

Intake of specific carotenoids and the risk of epithelial ovarian cancer

There has been considerable interest in the role of carotenoids in the chemoprevention of cancer. However, few studies have examined the association between intake of specific carotenoids and the risk of epithelial ovarian cancer and the results for carotenoids have been inconclusive. To investigate whether the intake of alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein and zeaxanthin, and lycopene is inversely associated with ovarian cancer risk, a case-control study was conducted in China during 1999-2000. The cases were 254 patients with histologically confirmed epithelial ovarian cancer and 652 age-matched controls were randomly recruited during the same period. Habitual dietary intake and lifestyle were collected by face-to-face interview using a validated and reliable FFQ. The US Department of Agriculture nutrient composition database was used to calculate the intake of specific carotenoids. Unconditional logistic regression analyses were used to estimate OR and 95 % CI, accounting for age, locality, education, BMI, smoking, tea drinking, parity, oral contraceptive use, hormone replacement therapy, menopausal status, family history of ovarian cancer, physical activity and energy intake. Compared with the highest v. the lowest quartile of intake, the adjusted OR were 0.39 (95 % CI 0.23, 0.66) for alpha-carotene, 0.51 (95 % CI 0.31, 0.84) for beta-carotene, 0.51 (95 % CI 0.31, 0.83) for beta-cryptoxanthin, 0.45 (0.27, 0.76) for lutein and zeaxanthin, and 0.33 (95 % CI 0.20, 0.56) for total carotenoids, with statistically significant tests for trend. It is concluded that a higher intake of carotenoids can reduce the risk of epithelial ovarian cancer.