Lifetime Number Of Ovulatory Cycles Research Articles

An empirical evaluation of approximate and exact regression-based causal mediation approaches for a binary outcome and a continuous or a binary mediator for case-control study designs

BackgroundIn the causal mediation analysis framework, several parametric regression-based approaches have been introduced in past years for decomposing the total effect of an exposure on a binary outcome into a direct effect and an indirect effect through a target mediator. In this context, a well-known strategy involves specifying a logistic model for the outcome and invoking the rare outcome assumption (ROA) to simplify estimation. Recently, exact estimators for natural direct and indirect effects have been introduced to circumvent the challenges prompted by the ROA. As for the approximate approaches relying on the ROA, these exact approaches cannot be used as is on case-control data where the sampling mechanism depends on the outcome.MethodsConsidering a continuous or a binary mediator, we empirically compare the approximate and exact approaches using simulated data under various case-control scenarios. An illustration of these approaches on case-control data is provided, where the natural mediation effects of long-term use of oral contraceptives on ovarian cancer, with lifetime number of ovulatory cycles as the mediator, are estimated.ResultsIn the simulations, we found few differences between the performances of the approximate and exact approaches when the outcome was rare, both marginally and conditionally on variables. However, the performance of the approximate approaches degraded as the prevalence of the outcome increased in at least one stratum of variables. Differences in behavior were also observed among the approximate approaches. In the data analysis, all studied approaches were in agreement with respect to the natural direct and indirect effects estimates.ConclusionsIn the case where a violation of the ROA applies or is expected, approximate mediation approaches should be avoided or used with caution, and exact estimators favored.

The Risk of Ovarian Cancer Increases with an Increase in the Lifetime Number of Ovulatory Cycles: An Analysis from the Ovarian Cancer Cohort Consortium (OC3).

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. SIGNIFICANCE: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.

Invited Commentary: Women's Reproductive Life Spans and Subsequent Inflammatory Profiles-How to Best Measure Reproductive Life Span and the Need for Baseline Assessments.

Inflammatory processes are known to drive the pathogenesis of several chronic diseases, including cardiovascular disease and Alzheimer disease, as well as all-cause mortality. Emerging research indicates that women who have a longer reproductive life span-roughly determined as the period from menarche to menopause or lifetime number of ovulatory cycles after accounting for anovulatory time spans-are at lower risk for these inflammation-related chronic diseases. The paradox is that ovulation is known to induce acute inflammation. Given the limited research assessing the relationship between reproductive life span and later inflammatory profiles, Huang et al. (Am J Epidemiol. 2020;189(7):660-670) set out to investigate this relationship within 2 of the most robust longitudinal cohort studies of women, the Nurses' Health studies. They found that after adjustment for other inflammation-related factors, including adiposity, exercise, and diet, lifetime ovulatory years was associated with lower C-reactive protein levels in both premenopausal and postmenopausal women. Huang et al. call attention to several challenges in research on women's reproductive life spans, including how to appropriately capture lifetime ovulatory cycles and the need for repeated measurements of inflammatory biomarkers across the life course if we wish to understand pathogenic processes linking reproductive factors to subsequent chronic disease.

Lifetime number of ovulatory cycles and epithelial ovarian cancer risk in African American women.

Incessant ovulation has been consistently linked to epithelial ovarian cancer (EOC). Although reproductive characteristics differ substantially by race, the association between incessant ovulation and EOC has been evaluated only in populations of predominantly white women. In the present study, we examined the association between lifetime number of ovulatory cycles (LOCs) and EOC risk among African American (AA) women. We used data from 534 cases and 722 controls enrolled in the African American Cancer Epidemiology Study. LOCs were determined using the standard method, with modifications to include episodes of irregular or missed periods. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between LOCs and EOC risk overall and by age, while adjusting for appropriate confounders. The mean number of LOCs was 378.2 ± 105.8 for cases and 346.4 ± 117.3 for controls. Women in the highest tertile of LOCs had 59% higher odds of EOC compared to women in the lowest tertile (OR = 1.59; 95% CI = 1.15-2.20). When examining this relationship by age, the positive association with EOC was stronger among women <50years of age (OR for highest vs. lowest tertile = 2.61; 95% CI = 1.15-5.94), followed by women aged 50-60years (OR = 2.27; 95% CI = 1.30-3.94). Yet, no association was present among women aged >60years (OR = 0.79; 95% CI = 0.45-1.40). In a population of AA women, we observed a positive association between LOCs and EOC risk, providing further support for the hypothesis that incessant ovulation contributes to the etiology of EOC.

Lifetime Number of Ovulatory Cycles and Risks of Ovarian and Endometrial Cancer Among Postmenopausal Women.

Previous studies have shown that a greater number of ovulatory cycles, cumulatively summed as lifetime number of ovulatory cycles (LOC), increases ovarian cancer risk, but there is no uniform algorithm with which to compute LOC. The association between LOC and endometrial cancer is less certain. Accordingly, we identified 14 different LOC algorithms in a literature review and calculated LOCs in the Polish Cancer Study (2001-2003). We evaluated the associations of LOC with ovarian and endometrial cancer risks using unconditional logistic regression, with and without adjustment for individual risk factors used in the LOC computations. Our analysis included 302 ovarian cancer cases with 1,356 controls and 532 endometrial cancer cases with 1,286 controls. We found a high correlation between LOC values among the combined controls (r ≥ 0.88) and identified 5 groups of similar LOC algorithms. A LOC value in the highest quartile was associated with ovarian cancer risk as computed by 2 algorithms (odds ratio (OR) = 2.22 (95% confidence interval (CI): 1.07, 4.62) and OR = 2.44 (95% CI: 1.22, 4.87)) and with endometrial cancer risk as computed by 1 algorithm (OR = 1.95, 95% CI: 1.11, 3.44). LOC algorithms using a core set of variables widely available in epidemiologic studies may be independently associated with risk of gynecological cancers beyond the contribution of the individual risk factors, such as ages at menopause and menarche.

Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

The role of the lifetime number of ovulatory cycles has not been evaluated in the context of BRCA-associated ovarian cancer. Thus, we conducted a matched case-control study to evaluate the relationship between the cumulative number of ovulatory cycles (and contributing components) and risk of developing ovarian cancer in BRCA mutation carriers (1,329 cases and 5,267 controls). Information regarding reproductive and hormonal factors was collected from a routinely administered questionnaire. Conditional logistic regression was used to evaluate all associations. We observed a 45% reduction in the risk of developing ovarian cancer among women in the lowest vs. highest quartile of ovulatory cycles (OR = 0.55; 95% CI 0.41-0.75, p = 0.0001). Breastfeeding for more than 12 months was associated with a 38% (95% CI 0.48-0.79) and 50% (95% CI 0.29-0.84) reduction in risk among BRCA1 and BRCA2 mutation carriers, respectively. For oral contraceptive use, maximum benefit was seen with five or more years of use among BRCA1 mutation carriers (OR = 0.50; 95% CI 0.40-0.63) and three or more years for BRCA2 mutation carriers (OR = 0.42; 95% CI 0.22-0.83). Increasing parity was associated with a significant inverse trend among BRCA1 (OR = 0.87; 95% CI 0.79-0.96; p-trend = 0.005) but not BRCA2 mutation carriers (OR 0.98; 95% CI 0.81-1.19; p-trend = 0.85). A later age at menopause was associated with an increased risk in women with a BRCA1 mutation (OR trend = 1.18; 95% CI 1.03-1.35; p = 0.02). These findings support an important role of breastfeeding and oral contraceptive use for the primary prevention of ovarian cancer among women carrying BRCA mutations.

Benign breast and gynecologic conditions, reproductive and hormonal factors, and risk of thyroid cancer.

The higher incidence of thyroid cancer in women compared with men suggests an influence of sex steroid hormones in the etiology of this malignancy. We investigated a comprehensive set of potential indicators of lifetime sex steroid hormone exposure in relation to thyroid cancer risk. Using data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, which enrolled 70,047 women, 50 to 78 years old, we prospectively examined associations of self-reported history of benign breast and gynecologic conditions, reproductive factors, and exogenous sex hormone use with thyroid cancer risk. Multivariable-adjusted HRs and 95% confidence intervals (CI) were calculated in models using age as the time metric. During follow-up (median, 11 years), 127 women were diagnosed with first primary thyroid cancer. Older age at natural menopause (≥55 vs. <50 years; HR, 2.24; 95% CI, 1.20-4.18), greater estimated lifetime number of ovulatory cycles (≥490 vs. <415 cycles; HR, 2.40; 95% CI, 1.33-4.30), greater number of live births (≥5 vs. 1-2; HR, 1.72; 95% CI, 1.05-2.82), and history of uterine fibroids (HR, 1.72; 95% CI, 1.18-2.50) were associated with an increased risk of thyroid cancer. Earlier age at menarche, greater number of reproductive years, history of a tubal ligation, and history of ovarian cysts were nonsignificantly associated with increased thyroid cancer risk. No associations were observed for oral contraceptive use, menopausal hormone therapy, or history of benign breast disease or endometriosis. In general, we found that factors reflecting a greater length of exposure to endogenous hormones, particularly during the reproductive years, were associated with risk of postmenopausal thyroid cancer.

Breastfeeding and its Relationship with Reduction of Breast Cancer: A Review

In this review, we describe the patterns of known immunological components in breast milk and examine the relationship between breastfeeding and reduced risk of breast cancer. The top risk factors for breast cancer are a woman's age and family history, specifically having a first-degree relative with breast cancer. Women that have a history of breastfeeding have been shown to have reduced rates of breast cancer. Although the specific cause has not been elucidated, previous studies have suggested that breastfeeding reduces the risk of breast cancer primarily through two mechanisms: the differentiation of breast tissue and reduction in the lifetime number of ovulatory cycles. In this context, one of the primary components of human milk that is postulated to affect cancer risk is alpha-lactalbumin. Tumour cell death can be induced by HAMLET (a human milk complex of alpha-lactalbumin and oleic acid). HAMLET induces apoptosis only in tumour cells, while normal differentiated cells are resistant to its effects. Therefore, HAMLET may provide safe and effective protection against the development of breast cancer. Mothers should be encouraged to breastfeed their babies because the complex components of human milk secretion make it an ideal food source for babies and clinical evidence has shown that there is a lower risk of breast cancer in women who breastfed their babies.

Abstract A65: Does the lifetime number of ovulatory cycles predict the risk of breast cancer in BRCA1 and BRCA2 mutation carriers?

Abstract Background: In the general population, various reproductive factors are believed to influence breast cancer risk via their effects on the number of ovulatory cycles and subsequently on cumulative endogenous hormonal exposure. It is not clear to what extent this is true for women with a BRCA1 or BRCA2 mutation. We undertook a case-control study to evaluate the effect of the cumulative number of ovulatory cycles and each of the contributing components) on the risk of developing breast cancer among BRCA mutation carriers. Methods: A matched case-control study was conducted in 2,632 pairs of women with a deleterious mutation in either BRCA1 (n = 1,915 pairs) or BRCA2 (n = 717 pairs). Women diagnosed with breast cancer were matched to unaffected control subjects by year of birth, mutation status, and country of residence. Information about reproductive factors, hormonal exposures and menopausal status was collected from a routinely administered questionnaire and was used to estimate the cumulative number of ovulatory cycles. Conditional logistic regression was used to estimate the association between various exposures and the risk of breast cancer. Results: The risk of breast cancer decreased with the number of ovulatory cycles (ρ = −0.69;P = 0.03). Age at menarche and breastfeeding were inversely related with risk of breast cancer among BRCA1 (P-trend &amp;lt; 0.0001) but not BRCA2 (P-trend ≥ 0.36) mutation carriers. Parity, oral contraceptive use, and the number of ovulatory cycles, were not associated with risk (P-trend ≥ 0.21). The reduction in breast cancer risk associated with surgical menopause (OR = 0.49; 95%CI 0.37–0.64; P-trend &amp;lt; 0.001) was stronger than that conferred by natural menopause (OR = 0.78; 95%CI 0.58–1.06; P-trend = 0.11). There was a significant reduction in breast cancer risk among women who had an oophorectomy after natural menopause (OR = 0.13; 95%CI 0.02–0.54; P = 0.006). Conclusions: These data challenge the prevailing hypothesis that the risk of breast cancer in a woman can be predicted by her lifetime number of ovulatory cycles in women with a BRCA1 or BRCA2 mutation. Reproductive risk factors, such as age at menarche and breastfeeding are important in BRCA1, but not BRCA2 carriers. The observation that a postmenopausal oophorectomy protects against breast cancer is consistent with either a direct carcinogenic activity of ovarian androgens or through aromatization of androgen to estrogen. It is important to distinguish between these two possibilities because of the different implications for chemoprevention. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A65.

A Systematic Review of the Association between Breastfeeding and Breast Cancer

Breastfeeding is hypothesized to reduce the risk of breast cancer primarily through two mechanisms, differentiation of breast tissue and reduction of the lifetime number of ovulatory cycles, but previous reviews of the association between breastfeeding and breast cancer have not consistently found that breastfeeding reduces risk of breast cancer. Our systematic review yielded 30 case-control studies and 1 cohort study published between 1999 and 2007. Of the 27 studies that assessed the effect of ever breastfeeding compared with never breastfeeding, only 11 found significant protection against breast cancer. Of the 24 studies of the effect of breastfeeding duration, only 13 found a reduced risk of breast cancer with extended lactation. We conclude that no consensus about the relationship between breastfeeding and breast cancer is emerging. Expanded consideration of possible confounders for this relationship is required to determine if breastfeeding is protective and how protection might be conferred.

Cyclin E Overexpression Relates to Ovarian Cancer Histology but not to Risk Factors

To the Editors: Schildkraut et al. ([1][1]) report that the relationship between calculated lifetime number of ovulatory cycles (LOC) and risk of epithelial ovarian cancer is significantly stronger among cancer cases overexpressing cyclin E than those not overexpressing it. They conclude that this

Incessant Ovulation, Mucin 1 Immunity, and Risk for Ovarian Cancer

Risk for ovarian cancer correlates directly with "ovulatory years or cycles" estimated from time not pregnant, breast-feeding, or using oral contraceptives. Recently, we reported that several factors known to reduce ovarian cancer risk may operate by inducing antibodies against mucin 1 (MUC1), a glycoprotein overexpressed in ovarian cancer. Conversely, other events might increase risk by interfering with the development of protective immunity. In this study, we examined whether the total number of ovulatory cycles decreases the likelihood of anti-MUC1 antibodies and provides an immune basis for the association between "incessant ovulation" and ovarian cancer risk. From 1998 to 2003, we enrolled 668 epithelial ovarian cancer cases and 721 controls residing in eastern Massachusetts or New Hampshire, collected information on menstrual and reproductive events, and obtained blood samples from controls to measure anti-MUC1 antibodies. Using logistic regression, we calculated odds ratios to evaluate the influence of reproductive factors, including the estimated lifetime number of ovulatory cycles on ovarian cancer risk and on the presence of MUC1 antibodies in controls. Overall, we observed that early age at first birth, cycle lengths >or=30 days, and oral contraceptive use increased the likelihood of having anti-MUC1 antibodies. Estimated ovulatory cycles were correlated positively with ovarian cancer risk and inversely with the presence of anti-MUC1 antibodies among controls ages 46 to 60 years. These data suggest that suppression of MUC1-specific immunity should be considered as an additional explanation for the observation that ovarian cancer risk increases with the lifetime number of ovulatory cycles.

Ovarian cancer: epidemiology, biology, and prognostic factors.

Ovarian cancer varies widely in frequency among different geographic regions and ethnic groups, with a high incidence in Northern Europe and the United States, and a low incidence in Japan. The majority of cases are sporadic, and only 5% to 10% of ovarian cancers are familial. The etiology of ovarian cancer is poorly understood. Models of ovarian carcinogenesis include the theory of incessant ovulation, in which a person's age at ovulation, i.e., lifetime number of ovulatory cycles, is an index of her ovarian cancer risk. Excessive gonadotropin and androgen stimulation of the ovary have been postulated as contributing factors. Exposure of the ovaries to pelvic contaminants and carcinogens may play a role in the pathogenesis of ovarian cancer. Epidemiologic and molecular-genetic studies identify numerous risk and protective factors. The most significant risk factor is a family history of the disease. Recent advances in molecular genetics have found mutations in the BRCA1 and BRCA2 tumor suppressor genes responsible for the majority of hereditary ovarian cancer. Additional risk factors include nulliparity and refractory infertility. Protective factors include multiparity, oral contraceptives, and tubal ligation or hysterectomy. With five years of oral contraceptive use, women can cut their risk of ovarian cancer approximately in half; this also holds true for individuals with a family history. Stage at diagnosis, maximum residual disease following cytoreductive surgery, and performance status are the three major prognostic factors. Using a multimodality approach to treatment, including aggressive cytoreductive surgery and combination chemotherapy, five-year survival rates are as follows: Stage I (93%), Stage II (70%), Stage III (37%), and Stage IV (25%).

Relationship between lifetime ovulatory cycles and overexpression of mutant p53 in epithelial ovarian cancer.

Several lines of evidence have suggested a relationship between a woman's number of ovulatory cycles and the development of ovarian epithelial cancer. Repair of the ovarian surface after ovulation requires cellular proliferation, and spontaneous mutations arising during the DNA synthesis that accompanies this proliferation may play a role in carcinogenesis. We conducted a molecular epidemiologic study to test the hypothesis that a greater number of ovulatory cycles increases the risk of ovarian cancer by inducing proliferation-associated DNA damage. In particular, we examined the association between the lifetime number of ovulatory cycles and mutation of the p53 tumor-suppressor gene (also known as TP53) in ovarian tumors. Case-case and case-control analyses involving participants in the Cancer and Steroid Hormone study were used to examine the association between p53 gene mutation in ovarian tumors and the lifetime number of ovulatory cycles. The women in our study were 20-54 years of age and included 197 case patients with invasive ovarian epithelial cancer and 3363 control subjects. Mutation of the p53 gene was indicated by overexpression of p53 protein (i.e., cellular accumulation of mutant p53 protein) in paraffin-embedded ovarian cancer tissue blocks; the mutant protein was detected by means of standard immunohistochemical techniques. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by employing multivariate analyses, with the use of logistic regression. Reported P values are two-sided. Women whose cancers overexpressed p53 protein (p53 positive) had a greater mean number of lifetime ovulatory cycles (388 +/- 77.4 cycles [mean +/- standard deviation]) than women whose cancers did not overexpress p53 protein (p53 negative) (342 +/- 119.0 cycles) (P = .0025). Furthermore, women with p53-positive tumors were more likely to have had moderate (i.e., 235-375) or high (i.e., 376-533) numbers of ovulatory cycles than women with p53-negative tumors (age-adjusted ORs = 7.0 [95% CI = 1.6-30.5] and 7.7 [95% CI = 1.4-41.2], respectively) (< or = 234 cycles was the referent category). After controlling for age, menopausal status, and nulliparity, women with p53-positive tumors were found to be significantly more likely to have had moderate or high numbers of ovulatory cycles than control subjects (ORs = 4.3 [95% CI = 1.4-13.0] and 9.1 [95% CI = 2.7-30.9], respectively); the corresponding ORs for women with p53-negative tumors compared with control subjects were 0.6 (95% CI = 0.3-1.4) and 1.3 (95% CI = 0.5-3.2), respectively. A higher number of ovulatory cycles may be associated with increased amounts of proliferation-associated DNA damage and increased risk of developing p53-positive but not p53-negative epithelial ovarian cancer. Our results are consistent with more than one developmental pathway in the pathogenesis of this type of cancer.