Association of oral contraceptive use with mortality: Findings from NHANES.

Background: Most colorectal cancers (CRC) arise from colorectal adenomas. The influence of reproductive factors on CRC, including oral contraceptive (OC) use, has been examined for a number of years, but less research is available on the role of OC use on adenomas. A better understanding of this association will provide insight into the mechanism through which hormones impact colorectal carcinogenesis. Objective: To examine the association of OC use and colorectal adenomas using detailed data from a large prospective cohort study with 32 yrs of follow-up data. Design: The Nurses' Health Study was established in 1976 when 121,701 female registered nurses 30-55 yrs of age completed a mailed questionnaire on medical history and lifestyle factors. We assessed OC use every 2 yrs between 1976-1982 and categorized this use according to ever (≥2 mo) and never use (reference), duration of use (never, ≤1, >1-<2, ≥2-<5, ≥5-<10, 10+ yrs), and time since last use (never, ≤4, >4-<10, ≥10-<15, 15+ yrs). Participants had to undergo a lower bowel endoscopy during the study period to be eligible for the current analyses. All colorectal adenoma cases identified at endoscopy were included from 1986 (when endoscopies were first accessed) through 2010; cases were stratified by subsite (proximal, distal, rectal), stage/size (small/early, large/advanced), and number of adenomas (1, 2+). Methods: Multivariable logistic regression models for clustered data were used to estimate odds ratios [OR (95% CIs)]. Models were adjusted for age, body mass index, height, physical activity, smoking, processed and red meat, folate, calcium, total energy, alcohol, aspirin use, age at first birth, parity, hormone therapy use/duration, family history of CRC, time period, as well as endoscopy information including reason, number, and yr since most recent. Results: Among 70,164 participants who had a lower bowel endoscopy, 49% (N=34,329) reported never using OCs and 51% (N=35,835) reported ≥2 mo of use. We recorded 2,950 never-users with an adenoma compared to 3,075 ever-users. Ever OC use was associated with a slight increase of small/early stage adenomas [OR=1.12 95% CI (1.03-1.22)] but not with large/advanced stage adenomas or any other category (e.g., number of adenomas). Duration of OC use was not associated with adenomas but longer times since last OC use were associated with increased odds for all of the adenoma outcomes [e.g., compared to never use, 15+ yrs since last use for all adenomas: OR=1.18 (1.08, 1.29)]. Shorter times since last OC use were inversely associated [e.g., ≤4 yrs since last use for all adenomas: OR=0.76 (0.67, 0.86)]. Conclusions: The null association between OC use and colorectal adenomas may be more nuanced than initially described in the literature. We found that OC use was associated with certain stages/sizes of colorectal adenomas (e.g., small/early) and further exploration of the time since last OC use associations are warranted. Support: P01CA87969, T32CA09001, T32HD060454 Citation Format: Brittany M. Charlton, Ed Giovannucci, Charles S. Fuchs, Stacey A. Missmer, Bernard A. Rosner, Kana Wu, Karin B. Michels. A prospective study on oral contraceptive use and risk of colorectal adenomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2166. doi:10.1158/1538-7445.AM2014-2166

Previous studies indicate effects of oral contraceptive (OC) use on spatial and verbal cognition. However, a better understanding of the OC effects is still needed, including the differential effects of androgenic or anti-androgenic OC use and whether the possible impact persists beyond the OC use. We aim to investigate the associations of OC use duration with spatial and verbal cognition, differentiating between androgenic and anti-androgenic OC. Using functional magnetic resonance imaging (MRI), we scanned a group of 94 past and current OC-users in a single session. We grouped current OC users (N=53) and past OC users with a natural cycle (N=41) into androgenic and anti-androgenic user. Effects of OC use duration were observed for current use and after discontinuation. Duration of OC use was reflected only in verbal fluency performance but not navigation: The longer the current OC use, the less words were produced in the verbal fluency task. During navigation, deactivation in the caudate and postcentral gyrus was duration-dependent in current androgenic OC users. Only during the verbal fluency task, duration of previous OC use affects several brain parameters, including activation of the left putamen and connectivity between right-hemispheric language areas (i.e., right inferior frontal gyrus and right angular gyrus). The results regarding performance and brain activation point towards stronger organizational effects of OCs on verbal rather than spatial processing. Irrespective of the task, a duration-dependent connectivity between the hippocampus and various occipital areas was observed. This could suggest a shift in strategy or processing style with long-term contraceptive use during navigation/verbal fluency. The current findings suggest a key role of the progestogenic component of OCs in both tasks. The influence of OC use on verbal fluency remains even after discontinuation which further points out the importance of future studies on OC effects and their reversibility.

Although the relationship between oral contraceptive (OC) use and colorectal cancer (CRC) risk has been studied extensively, the results of epidemiological studies are controversial. Therefore, we carried out a meta-analysis of epidemiological studies to summarize the available evidence and to quantify the potential dose-response relation. We searched PubMed database for studies of OC use and CRC risk that were published until the end of March 2014. Random- and fixed-effects models were applied to estimate summary relative risks (RRs) and 95 % confidence intervals (CIs). Twelve cohorts and seventeen case-control studies with a total of 15,790 CRC cases were included in the final analysis. The summary RR for the ever versus never category of OC use was 0.82 (95 % CI 0.76-0.88). Similar result was observed when we compared the longest duration of OC use with the shortest duration (RR = 0.86, 95 % CI 0.76-0.96). Furthermore, the results of stratified analysis were comparable to those of overall meta-analysis. In dose-response analysis, significant inverse associations emerged in nonlinear models for the duration of OC use and CRC (P nonlinearity = 0.001). The greatest risk reduction was observed when the duration of OC use was approximately 42 months. There was moderate heterogeneity in the analysis, and no evidence of small-study bias was observed. Based on the findings of this meta-analysis, ever use of OC is associated with lower risk of CRC. Additionally, there is a statistically significant nonlinear inverse association between the duration of OC use and CRC risk.

Objective To assess the cross-sectional association between oral contraceptive (OC) use and type 2 diabetes mellitus (T2DM) risk among US women. Methods The data was obtained from the National Health and Nutrition Examination Survey (NHANES 2007–2018). OC use was assessed by questionnaires and the diagnosis of T2DM was confirmed by the glycosylated hemoglobin, fasting blood glucose, and self-report. Binary logistic regression models and the restricted cubic spline model were adopted to evaluate whether OC use was associated with T2DM. Results Compared with non-users, the odds ratio (OR) with 95% confidence interval (CI) of T2DM risk for the OC users was 0.71 (0.57–0.89) in unadjusted Model. The association remained significant in fully adjusted models, and the OR with 95%CI was 0.78 (0.62–0.99). In the stratified analyses, there was an inverse association of OC use with T2DM risk when women were overweight. Dose-response analysis also revealed an inversely nonlinear relationship between the duration of OC use and T2DM (p-value for linearity = .589). Conclusions Our findings suggested that OC use may be inversely associated with T2DM risk.

Association of oral contraceptive use with suicidal behavior among representative Korean population: Results from Korea National Health and Nutrition Examination Survey (2007–2016)

Oral contraceptive use and breast cancer in Indonesia

Eileen Rillamas-Sun1, Laura Ichikawa1, Andrea LaCroix1, Susan Ott2, Rebecca Hubbard1, Leslie Spangler1 and Delia Scholes1 1Group Health Cooperative; 2University of Washington

Background: Oral contraceptive (OCP) use might increase the risk of stroke in women. We examined a possible dose–response relation between OCP use and the risk of stroke in young and middle-aged women.Methods: A retrieval of PubMed and EMBASE databases was performed. We selected observational studies that reported odds ratios (ORs) with 95% confidence intervals (CIs) for the risk of stroke in OCP users. A two-stage dose–response analysis was conducted using the random-effects model and the restricted spline model.Results: A total of 6 cohort studies and 12 case–control studies were included, which involved 2,143,174 participants and 11,661 cases of stroke including ischemic stroke (IS), hemorrhagic stroke (HS), and stroke of unknown origin. The pooled ORs of total stroke were 1.19 (95% CI, 1.16–1.23) for every 10-μg increment in estrogen dosage, 1.20 (95% CI, 1.05–1.37) for every 5-years increment in duration of OCP use, and 0.82 (95% CI, 0.68–0.98) for every 5-years increment in duration of OCP cessation. The ORs of IS were 1.20 (95% CI, 1.17–1.22) in estrogen dosage, 1.24 (95% CI, 1.04–1.49) in duration of OCP use, and 0.78 (95% CI, 0.67–0.92) in duration of OCP cessation. The ORs of HS were 1.10 (95% CI, 1.04–1.16) in estrogen dosage, 1.13 (95% CI, 0.93–1.36) in duration of OCPs, and 0.71 (95% CI, 0.55–0.92) in duration of OCP cessation. The pooled ORs of total stroke from prospective studies (1.12; 95% CI, 1.01–1.24) were lower than those from retrospective studies (1.30; 95% CI, 1.01–1.67).Conclusions: The higher estrogen dosage significantly increased the risks of total stroke, IS, and HS, respectively. The longer duration of OCP use significantly increased the risks of total stroke and IS, but its effects on HS risk were marginal. The longer duration of OCP cessation significantly decreased the risks of total stroke, IS, and HS, respectively. These findings affirm the contribution of estrogen dose and duration of OCP use to the increased risk of stroke, which may be critical for the instruction of OCP use and the prevention and management of cerebrovascular diseases.

Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study

We designed a study to assess the association of oral contraceptive use and the development of breast cancer for women in the following groups: (1) ever oral contraceptive users, (2) long-term oral contraceptive users, and (3) oral contraceptive users before a first full-term pregnancy. A MEDLINE search of studies published in English from 1966 to 1990 was conducted using the following key words: "oral contraceptive and breast carcinoma." Eligible studies included all published case-control reports of nonduplicated data on a population (hospital or community-based). The following data were extracted from each report: country, age of subjects, number of cases and controls, whether it was a hospital or community-based study, and results. Two evaluators using a quality-assessment instrument independently and blindly reviewed the methods and data analysis section from each eligible study. In the category of "ever oral contraceptive users," an estimate of the pooled relative risk with 95 percent confidence intervals (CIs) was calculated. In the categories of "duration of oral contraceptive use" and "duration of oral contraceptive use before a first full-term pregnancy," Spearman's rank correlation coefficient (rs) was calculated. For the categories of "ever oral contraceptive users" and "long-term oral contraceptive users," no association between the use of oral contraceptives and the development of breast cancer could be detected (pooled relative risk "ever oral contraceptive users" = 1.07, 95 percent CI 0.78 to 1.36, rs "duration of use" -0.153, P = 0.189). For the category of "oral contraceptive use before a first full-term pregnancy," a significant correlation was found (rs = +0.497, P = 0.011). Many reports failed to demonstrate adequate protection against the biases most relevant to case-control methods (namely, recall bias, interviewer bias, surveillance bias, and nonresponse bias) and therefore received low-quality scores. This meta-analysis suggests a possible increased risk for breast cancer in women who use oral contraceptives before a first full-term pregnancy. The data, however, are confounded by studies that are generally of low quality. Further studies addressing the risk for breast cancer in oral contraceptive users need to be designed with methods that limit the biases inherent in case-control studies.

Ovarian cancer incidence has declined in recent decades, due in part to oral contraceptive (OC) use and tubal ligation. However, intrauterine device (IUD) use has increasingly replaced OC use. As ovarian cancer is an inflammation-related disease, we examined the association of OC use, IUD use, and tubal ligation with plasma levels of C-reactive protein (CRP), interleukin 6, and soluble tumor necrosis factor α receptor 2 in the Nurses' Health Study (NHS) and NHSII. After adjusting for reproductive, hormonal, and lifestyle factors and mutual adjustment for other methods of contraception, there were no differences in inflammatory markers between ever and never use of each method. However, CRP levels decreased from an average of 30.4% (95% CI, -53.6 to 4.4) with every 5years since initial IUD use (P-trend=.03), while CRP increased an average of 9.9% (95% CI, 5.7, 14.3) with every 5years of use of OC (P-trend < .0001) as well as differences by body mass index and menopausal status. Our results suggest IUD use and tubal ligation are not associated with higher circulating inflammatory markers long term, although long duration of OC use may increase generalized inflammation, which may in part explain why its protective effect wanes over time. This article is part of a Special Collection on Gynecological Cancer.

Evidence from epidemiologic studies suggests a possible role of exogenous and endogenous hormones in colorectal carcinogenesis in women. However, with respect to exogenous hormones, in contrast to hormone replacement therapy, few cohort studies have examined oral contraceptive use in relation to colorectal cancer risk. We used data from a large cohort study of Canadian women enrolled in a randomized controlled trial of breast cancer screening to assess the association of oral contraceptive use, hormone replacement therapy and reproductive factors with risk of colorectal cancer, overall and by subsite within the colorectum. Cancer incidence and mortality were ascertained by linkage to national databases. Among 89,835 women aged 40-59 at enrollment and followed for an average of 16.4 years, we identified 1,142 incident colorectal cancer cases. Proportional hazards models were used to estimate the associations between the exposures of interest and risk of colorectal cancer. Ever use of oral contraceptives at baseline was associated with a modest reduction in the risk of colorectal cancer (hazard ratio 0.83, 95% confidence interval 0.73-0.94), with similar effects for different subsites within the colorectum. No trend was seen in the hazard ratios with increasing duration of oral contraceptive use. No associations were seen with use of hormone replacement therapy (ever use or duration of use) or reproductive factors. Our results are suggestive of an inverse association between oral contraceptive use and colorectal carcinogenesis. However, given the lack of a dose-response relationship and the potential for confounding, studies with more complete assessment of exogenous hormone use throughout the life course are needed to clarify this association.

Objectives: While oral contraceptives (OC) use is associated with lower risk of ovarian cancer compared to non-users, its role in the etiology of aggressive and highly fatal disease has not been determined. Thus, we utilized data from the Ovarian Cancer Association Consortium (OCAC) to evaluate the association between pre-diagnostic OC use and highly fatal ovarian cancer. Methods: Data were pooled from 20 case-control studies participating in OCAC to examine the association between oral contraceptive use and risk of highly fatal ovarian cancer; defined as dying within 12 or 18-months of diagnosis. Controls were frequency matched to cases (4:1) on five-year age categories, race, and study site. The study samples included 579 patients who died within 12 months of their diagnosis, matched to 2279 controls as well as 1294 patients who died within 18-months, matched to 5095 controls. Analyses were performed using unconditional logistic regression, and separate models were run for any use of OC and duration of OC use per five year increase. Race, education, prior hysterectomy or tubal ligation, parity, age at menarche, menopausal status, and smoking status were assessed as potential confounders of the association. Results: After adjusting for age, site, and parity, any OC use was associated with a 46% reduction in the odds of death within 12-months after adjusting for age, site, and parity (OR=0.54, 95% CI: 0.43-0.68). There was also a significant trend of decreased odds with increased duration of OC use. Among those who used OC for over 10 years, a 66% reduction in the odds of death within 12-months was observed (OR=0.34, 95% CI: 0.23-0.49) while there was no significant benefit from use of OC for 1 year or less (OR=0.83, 95% CI: 0.60-1.14). Similar trends were observed among those who died within 18-months, although OC use appeared to be more protective among highly fatal cases. Use of OC was most protective for endometrioid subtypes among both those who died within 12-months (OR=0.43, 95% CI: 0.20-0.93) and 18-months (OR=0.39, 95% CI: 0.23-0.65). Conclusions: To our knowledge, this is the first large, multi-center study to investigate the association between OC use and risk of highly fatal ovarian cancer. These results are in line with current evidence that has demonstrated a substantial decrease in risk of ovarian cancer with OC use for five or more years. Future research should aim at understanding the mechanisms behind this association and identifying specific subpopulations that may benefit most from this chemopreventive strategy. Citation Format: Jennifer M. Mongiovi, Janine M. Joseph, Albina N. Minlikeeva, Ahmad AlSulimani, Hani Almohanna, Kirsten B. Moysich. Oral contraceptive use and risk of highly fatal ovarian cancer: Evidence from the Ovarian Cancer Association Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 641.

Although oral contraceptive (OC) use is common, the influence of OC use on carcinogenesis is not fully understood. A recent Agency for Healthcare Research and Quality report identified a need to understand the consistency of OC use and cancer associations across subpopulations, including smokers and obese women. To determine whether associations between duration of OC use and risk of specific cancers were modified by lifestyle characteristics. The prospective NIH-AARP Diet and Health Study (enrolled 1995-1996, followed until 2011), with population-based recruitment of AARP members in 6 states and 2 metropolitan areas. All analyses included at least 100 000 women who reported OC use at enrollment. We identified 1241 ovarian, 2337 endometrial, 11 114 breast, and 3507 colorectal cancer cases during follow-up. Data analysis was performed between September 2016 and April 2017. Duration of OC use (never or <1 year [reference], 1-4, 5-9, or ≥10 years). Development of ovarian, endometrial, breast, and colorectal cancers. We examined effect modification by modifiable lifestyle characteristics: cigarette smoking, alcohol consumption, body mass index (BMI), and physical activity. We used Cox models adjusted for age, race, age at menarche, and the modifiers of interest. The analytic population was aged 50 to 71 years (median, 62 years) at enrollment and largely white (91%) and postmenopausal (96%). For ovarian cancer, OC use-associated risk reductions strengthened with duration of use (long-term OC use [≥10 years] HR, 0.60; 95% CI, 0.47-0.76; P < .001 for trend) and were similar across modifiable lifestyle factors. Risk reductions for endometrial cancer strengthened with duration of use (long-term OC use HR, 0.66; 95% CI, 0.56-0.78; P < .001 for trend); the most pronounced reductions were among long-term OC users who were smokers (HR, 0.47; 95% CI, 0.25-0.88), had obese BMIs (0.36; 95% CI, 0.25-0.52), and who exercised rarely (HR, 0.40; 95% CI, 0.29-0.56). Associations between OC use and breast and colorectal cancers were predominantly null. Long-term OC use is consistently associated with reduced ovarian cancer risk across lifestyle factors. We observed the greatest risk reductions for endometrial cancer among women at risk for chronic diseases (ie, smokers, obese BMI). Oral contraceptive use may be beneficial for chemoprevention for a range of women with differing baseline cancer risks.

Background: Although oral contraceptive (OC) use is ubiquitous in the United States, the influence of OCs on the development of cancers is not fully understood. In 2013, an Agency for Healthcare Research and Quality Evidence Report identified several data gaps with regard to OC use and its associations with cancer, including a need to understand if associations are consistent across subpopulations of users, including smokers and obese women. Methods: To address this data gap, we used Cox proportional hazards models to examine duration of OC use (never/less than 1 year [reference], 1 to 4, 5 to 9, 10+ years) and subsequent development of incident ovarian or endometrial cancer among participants in the NIH-AARP Diet and Health Study. We further examined effect modification by a variety of modifiable risk factors, including body mass index (BMI), cigarette smoking, alcohol consumption, and physical activity, via interaction terms and a likelihood ratio test. Models were adjusted for age, race, age at menarche and the modifiers of interest. Results: For ovarian cancer (n=1,241 cases, 149,502 non-cases), a reduction in risk was conferred by OC use that linearly decreased with duration of use (hazard ratios [HR] ranging from 0.83 to 0.60 across categories of duration). We also identified linear, inverse associations between increasing duration of OC use and ovarian cancer risk across most potential modifiers. Some of the most pronounced reductions were observed among long-term OC users (10+ years) who were current smokers (HR compared to non-users of 0.44, 95% confidence interval [CI] 0.20, 0.97) or who engaged in moderate physical activity (0.44, CI 0.23, 0.85). For endometrial cancer (n=2,337 cases, n=112,132 non-cases), we observed pronounced reductions in risk associated with long-term OC use among women with obese BMIs (0.36, CI 0.25, 0.52) and those who exercised rarely (0.40, CI 0.29, 0.56) or moderately (0.50, CI 0.33, 0.75). However, long-term use was not associated with risk reductions among women with BMIs of less than 25 or among women who exercised at least three times per week. Conclusions: OC use is consistently associated with reduced risks of ovarian cancer across most strata of modifiable risk factors. For endometrial cancer risk, OC use seems to offer the greatest risk reduction among women in previously identified high-risk categories (i.e., overweight/obese BMI, physically inactive), findings which merit further discussion as these women may be more likely to have comorbid conditions that would contraindicate OC use (e.g., hypertension, diabetes). Citation Format: Kara A. Michels, Louise A. Brinton, Ruth M. Pfeiffer, Britton Trabert. Duration of oral contraceptive use and the prevention of gynecologic cancers: Modification by modifiable factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3013. doi:10.1158/1538-7445.AM2017-3013