Epidemiology of ovarian cancer: a review

Hormonal and reproductive risk factors

Epidemiological research has clearly implicated hormonal and reproductive factors in the pathogenesis of OC. Two predominant hypotheses have emerged to fit the data⁸⁴. The ‘incessant ovulation’ hypothesis posits that the number of ovulatory cycles increases the rate of cellular division associated with the repair of the surface epithelium after each ovulation, thereby increasing spontaneous mutations⁸⁵. The correlation between increasing numbers of lifetime ovulations and higher risk^86-89 are consistent with this hypothesis. The ‘gonadotropin hypothesis’ attributes the impact to gonadotropins, such as luteinizing hormone and follicle-stimulating hormone⁹⁰. Both of these proposed mechanisms provide a framework to interpret the epidemiologic data on both endogenous correlates of reproductive hormone exposure and exogenous sources of hormones. A more detailed review is available by Riman et al.⁹¹.

Age at menarche and age at menopause

According to the incessant ovulation hypothesis, early age at menarche and late age at menopause increases risk by increasing the number of ovulatory cycles. Conversely, according to the gonadotropin hypothesis, a late age at menopause delays the surge of post-menopausal gonadotropin hormones, possibly reducing risk. Results of studies that have examined the age at onset of menses are not terribly consistent^92-102. One study among Chinese women reported lower risk with late age at menarche (after age 18)¹⁰³, while another study observed a slight increased risk with late age at menarche¹⁰⁴. Additional research has failed to clarify the literature^{85,93,105-112} although a meta-analysis yielded an overall inverse association with age at menarche (RR=0.85, 95% CI: 0.75–0.97)¹¹³. Data on age at natural menopause and OC risk are also inconsistent. Case-control studies have reported odds ratios ranging from 1.4 to 4.6 in the highest category of age at menopause^{92,93,95,99,103,104,108}. In the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, age at menopause (>52vs. ≤45 years) was associated with an increased risk (HR=1.57, 95% CI: 1.16–2.13); however after women diagnosed with OC within the first two years of follow-up were excluded the risk was slightly attenuated and marginally statistically significant (HR=1.40, 95% CI: 0.98–2.00)¹⁰⁹. The authors speculated that older women in the sub-clinical stage of OC may mistake bleeding for menses. Other case-control studies^{98,100,106,107,114-116} and several cohort studies^101,105 found no association. The inconsistent findings with ages at menarche and menopause may reflect differences in definitions, recall and misclassification bias, or differences in analysis¹¹⁷. The etiologic heterogeneity of tumor subtypes may also contribute to differential findings. A report from the Nurses’ Health Study (NHS) and NHS II found that age at natural menopause was associated with an increased risk of endometrioid tumors (RR=1.13, 95% CI: 1.04–1.22), but not serous invasive or mucinous tumors²⁹. Studies conducted among populations with different distributions of age at menarche^99,111,118 and age at menopause¹¹⁹ indicate differences in the genetic heritability of these factors across ancestral groups^120-122. Regardless, the available evidence suggests that any magnitude of effect is likely small.

Parity and infertility

The association between pregnancy and OC risk has been studied extensively. Pregnancy causes anovulation and suppresses secretion of pituitary gonadotropins and is thus consistent with both the ‘incessant ovulation’ and the ‘gonadotropin’ hypotheses. Indeed, parous women have a 30%-60% lower risk than nulliparous women^{85,92,99,103-107,115,117,123-126} and each additional full-term pregnancy lowers risk by approximately 15%^98,105,127. Studies in African American¹²⁸ and Asian^129,130 populations have yielded similar results. The protective effect associated with parity is evident across the main histotypes although perhaps slightly weaker for serous carcinomas, with roughly 20% lower risk in parous women, versus other subtypes, particularly clear cell and endometrioid that show 50%–70% reductions in risk^{28-30,131,132}. Comparable to the breast cancer literature, case-control studies with hospital controls have reported elevated risk with late age at first birth (>30 years of age)^{92,97,98,106,108,123,133-136}, but not among studies with population controls^96,98,137. Recent data also suggests that OC risk does not vary by the time interval between the first and last birth¹³⁸.

It is unclear whether spontaneous or induced abortions impact OC risk. About half of the published studies found that an increased number of incomplete pregnancies may slightly decrease risk^{85,92,97,98,104,105,139-141} while others have reported risk to be increased^107,126, or not affected^{96,99,100,102,106,115,123,125,142}. Induced abortions have been associated with lower risk in several studies^105,140,141, but not others^96,108,139. With regard to spontaneous abortions, positive^100,123,139, inverse¹⁰², and null associations^103,125,140 with risk have been reported. Interpretation of this literature is difficult because of the recognized potential for recall bias Should be 'abortions' here not pregnancies but better to end at recall bias.¹⁴³.

Infertility is a term that is used to describe a heterogeneous group of biologically distinct conditions ranging from genital tract infections and tubal disturbances to medical conditions such as endometriosis and polycystic ovarian syndrome (PCOS)^144,145. Infertility appears to be a risk factor in most studies^{92,98,102,106,115,123,125,126,136,144}, but not all^105,146. The inconsistent results may reflect the failure to examine the various types of infertility separately. It is yet to be determined whether nulliparity and low parityper se, rather than difficulty becoming pregnant due to female infertility, is the relevant factor. Infertility seems to pose the greatest risk among women who remain nulliparous, while periods of temporary infertility among parous women are of little concern^{92,98,102,106,125}. For example, in a large Canadian case-control study in which most nulliparous women were so by choice, infertility was not associated with risk among parous women but there was a trend towards elevated risk among a small group of infertile nulliparous women (OR=2.5, 95% CI: 0.6–4.1)¹⁰². A particular challenge is trying to distinguish an influence of infertility from an adverse effect of fertility drug exposure. Although some studies report that women with a prior history of fertility drug use who remain nulliparous are at an elevated risk for ovarian tumors, particularly tumors of LMP^98,147, the results are not consistent^{144-146,148-150}. Early detection bias may explain the discrepant findings, as early-stage cancers may be over-diagnosed in infertile women due to the close medical surveillance¹⁵¹. Further muddying of the water is caused by factors that may influence both infertility and OC risk such as a personal history of endometriosis^152-154, PCOS¹⁵⁵, and BRCA1 mutations¹⁵⁶.

Lactation

Lactation suppresses secretion of pituitary gonadotropins and leads to anovulation, particularly in the initial months after delivery¹⁵⁷. Both the incessant ovulation and gonadotropin hypotheses would predict lactation reduces the risk of OC. In fact, most studies indicate a slight protective effect from breastfeeding, with odds ratios approximating 0.6–0.7^{98,99,102,124-126,158-161}, although some have not^96,100,115. Few studies have explored the association by tumor subtype, with one report of the greatest risk reduction for endometrioid tumors¹⁶² while another observed the strongest reduction among mucinous cancers³⁰. A recent meta-analysis indicates a significant protective effect (summary RR=0.68, 95% CI: 0.61–0.76) for breastfeeding that increased with longer duration (summary RR=0.85, 0.73, and 0.64 for <6 months, 6–12 months, and >12 months of total breastfeeding duration)¹⁶³. Thus, lactation protects against epithelial OC, especially for long-term duration.

Benign gynecologic conditions and gynecologic surgery

Several gynecologic conditions have been examined as risk factors for OC, including PCOS, endometriosis, and pelvic inflammatory disease (PID). PCOS is a multi-factorial disease often characterized by obesity, hirsutism, infertility, and menstrual abnormalities. Due to unopposed endogenous estrogen and/or elevated androgens, women with PCOS have an increased risk for endometrial cancer. The association between PCOS and OC risk was investigated using data from the Cancer and Steroid Hormone Study, a population-based case-control study¹⁵⁵. Among 476 histologically confirmed epithelial OC cases and 4,081 controls, 7 cases (1.5%) and 24 controls (0.06%) reported a history of PCOS (OR=2.5, 95% CI: 1.1–5.9)¹⁵⁵. The limited data was insufficient for a consensus statement that PCOS is a risk factor¹⁶⁴. Larger studies that adjust for potential confounders are clearly needed.

Endometriosis is one of the most common gynecological disorders, affecting 10%–15% of women in reproductive years¹⁶⁵. Despite being considered a benign condition, endometriosis has been linked with OC in the medical literature since 1925. Sayasneh and colleagues¹⁶⁵ conducted a systematic review of eight studies; seven reported an increased risk of OC, with effect sizes ranging from 1.3 to 1.9. The strongest associations with endometriosis are evident among endometrioid and clear cell histologies^30,165,166, consistent with molecular data that supports endometrial epithelium as the origin of these subtypes⁸. In addition, Pearce and colleagues¹⁶⁷ identified an increased risk of low-grade serous OC (OR=2.11, 95% CI: 1.39–3.20) among women with endometriosis as well as for endometrioid (OR=2.04, 95% CI: 1.67–2.48) and clear cell cancers (OR=3.05, 95% CI: 2.43–3.84). The authors speculated that the processes of endometriosis and endosalpingiosis may result from a similar underlying host susceptibility to implantation of exfoliated Müllerian epithelial cells from both the endometrium and fallopian tube. The association between endometriosis and endometrioid and clear cell ovarian carcinomas may represent shared risk factors¹⁶⁵, genetic susceptibility¹⁶⁸, and/or pathogenesis¹⁶⁹ rather than a causal association.

PID causes inflammation of the endometrium, fallopian tubes, and ovaries. Studies evaluating the association between PID and OC risk have yielded inconsistent results^103,170-172. Lin and colleagues¹⁷³ evaluated this association in a large nationwide cohort from Chinese Taiwan that included 67,936 women with PID (42 of whom later developed OC) and 135,872 women without a history of PID (48 of whom developed OC). A history of PID was a significant risk factor (adjusted HR=1.92, 95% CI: 1.27–2.92), especially among subjects diagnosed with PID before the age of 35 and women who had at least 5 episodes of PID. Other studies found no association^171,172. In the Danish MALOVA (MALignant OVArian tumor) case-control study of 2,300 women, PID history was associated with increased risk of ovarian borderline tumors but not with invasive OC¹⁷⁴. Rasmussen et al.¹⁷⁵ further evaluated borderline ovarian tumors in a cohort of over 1.3 million Danish women and found that history of PID was associated with an 85% increased risk of serous borderline tumors but not those of the mucinous subtype. In previous studies of PID and OC risk, some only considered invasive tumors^103,108,173 whereas others included both invasive and borderline tumors¹⁷² perhaps contributing to the inconsistent findings. There is no evidence that risk associated with PID history varies by histotype of invasive ovarian carcinomas^172,174.

Several gynecologic procedures appear to influence the risk for OC. It is well established that among high risk women, bilateral prophylactic oophorectomy decreases risk by at least 90%¹⁷⁶. Numerous studies have identified a reduced risk associated with either a hysterectomy or tubal ligation ranging from 30%–40%^{92,102,177-183} with the highest risk reductions observed among endometrioid and clear cell histotypes^{30,181,184-187}. Furthermore, the risk reduction from these procedures appears to last for at least 10–15 years, which argues against screening bias (due to selective removal of subclinical ovarian tumors)^{116,178,188,189}. Although it is unknown how these procedures reduce the risk of OC, it has been proposed that through retrograde menstruation (i.e. menstrual fluid flows backwards into the fallopian tubes instead of leaving the body through the vagina) endometrial tissue implants on peritoneal and ovarian surfaces (endometriosis) and becomes invasive, developing into endometrioid or clear cell ovarian carcinomas^13,190. Indeed, this hypothesis is supported by epidemiological studies that show the strongest associations with tubal ligation and endometriosis for ENOC and CCOC.

Oral contraceptives and other forms of contraception

The epidemiological literature over the past several decades has consistently reported that use of oral contraceptives is inversely associated with the risk of OC. The protective effect increases with longer duration of use^{98,102,191-195} with about a 20% decreased risk for each 5 years of use that persists decades after use has ceased^{115,124,193,196-200}. Moreover, the risk reduction does not appear to be specific to any particular oral contraceptive formulation^195,201 or OC histotype, although oral contraceptive use appears less effective for mucinous cancers in some studies^{23,27,28,30,118,131,200}. Oral contraceptive use corresponds to the prevention of approximately 30,000 OC cases every year and has already prevented an estimated 200,000 OC cases and 100,000 deaths over the last 50 years²⁰⁰. Progestin-only contraceptives have been less studied, mostly due to the low prevalence of use, but the available data suggest they may also lower risk of OC^124,193,202.

Relatively few studies have examined methods of contraception other than oral contraceptives. The use of an intrauterine device (IUD) has been associated with reduced OC risk in several studies^182,203,204 while the NHS cohort observed increased risks²⁰⁵, however, there was a low prevalence of IUD use in that population which occurred prior to the newer IUD formulations. Similar to oral contraceptives, any protective effect associated with IUD use may be dependent upon duration of use. Huang and colleagues²⁰³ evaluated IUD use and OC risk in the Shanghai Women’s Health Study cohort and found long-term IUD use of at least 20 years was associated with a 38% reduction in risk. IUD use is the most common contraceptive method in China with a prevalence rate of about 50% among women of reproductive age²⁰⁶. The authors propose that the high prevalence of long-term IUD use and the associated strong protective effect may contribute to the low incidence of OC observed in China²⁰³. Vasectomy has been evaluated in association with OC risk and findings have been inconclusive²⁰⁵, although Ness and colleagues¹⁸² reported that vasectomy may confer a small reduction in risk (adjusted OR=0.77, 95% CI: 0.61–0.99), perhaps due to reduced exposure to sperm. Given that contraceptive methods are modifiable, further research to replicate these findings is needed. Additionally, research is needed to elucidate how different types of contraception influence OC risk, especially by histotype.

Hormone replacement therapy (HRT)

Unlike oral contraceptive use that has a well-established benefit on OC risk, the association with HRT is less clear. HRT reduces the secretion of gonadotropins and should therefore decrease risk, but the reduced levels are still higher than pre-menopausal women²⁰⁷. Conversely, postmenopausal HRT may enhance estrogen-induced proliferation of ovarian cells and therefore increase risk²⁰⁸. Initial studies on the topic have focused on unopposed estrogen therapy (ET) among postmenopausal women. Several case-control^98,209,210, cohort²¹¹ and meta-analysis^212,213 studies have found no association with duration of use, although two have observed either a significant or suggestive trend in increased risk^23,214. More recent studies indicate that OC risk is increased in ever users of HRT^215-218 and larger increases are seen for longer durations of use^219-223. For example, in the NHS cohort both current and past HRT users of five or more years had a significantly higher risk than never users (RR=1.41, 95% CI: 1.07–1.86 and RR=1.52, 95% CI: 1.01–2.27, respectively), but no association with risk was seen for users of less than five years for either current or past users (RR=1.01, 95% CI: 0.70–1.44 and RR=0.88, 95% CI: 0.64–1.19, respectively)²¹⁹. The authors concluded that the elevated risk appeared to be driven largely by duration rather than by status of use. Conversely, a collaborative re-analysis of 52 epidemiological studies found OC risk was increased in current HRT users, even those with less than 5 years of use²²⁴. Furthermore, risk decreased over time after cessation of use, although a small excess in risk was still observed even 10 years after stopping long duration HRT.

Combined estrogen and progestin use and OC risk have only recently been evaluated in studies with sufficient statistical power. It has been hypothesized that progestin promotes apoptosis while estrogen promotes proliferation of ovarian epithelial cells²²⁵ thus the effects of unopposed ET are thought to be more detrimental to the ovaries than estrogen plus progestin (EPT)²²⁵. Most studies that investigated EPT use and OC risk have found no association or a weak protective association^{118,215,216,218,219,222,225-227}. A few prospective studies^215,221,228 and meta-analysis²¹⁷ have reported a small increased risk for EPT users compared to ET only users. For example, a recent meta-analysis of 14 population-based studies concluded that ET is associated with a 22% increased risk of OC per 5-year increment of use; however, the risk among women who used EPT was attenuated to only a 10% increase²¹⁶. The authors suggest that the addition of progestin mitigates the effect of estrogen, because the increased risk among EPT users was statistically significantly lower than the risk among ET users (P=0.004)²¹⁶. However, several prospective cohort studies observed similar increased risks for both ET and EPT users^224,228. The basis for the inconsistent literature is not readily apparent.

Some studies have indicated that any HRT-associated risk is limited to specific histologic subtypes. For example, in the NHS the increased risk was slightly stronger for endometrioid tumors and was not present for mucinous tumors, consistent with other studies^{29,30,131,210,229}. Endometrioid tumors are histologically similar to endometrial tissue²³⁰ and ET use increases the risk of endometrial cancer²⁰⁸, enhancing plausibility.

The available data indicates that HRT is a risk factor for OC. The magnitude may be moderate, but women should be counseled about the potential dangers of long-term use, particularly for unopposed ET. Although large-scale reductions in hormone therapy have occurred since reports of negative health effects from the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI)²³¹, approximately 12% of women over 40 still take HRT for menopausal symptoms^232,233 totaling some 6 million women in the USA and UK alone²²⁴. Given the prevalence of HRT and that many women take HRT several years before the peak age-specific incidence of OC, even a small change in risk may have a significant impact on OC rates at the population level.

Obesity

In postmenopausal women the predominant source of circulating estrogens is aromatization of androgens in adipose tissue^84,234. The compelling role of obesity in the pathogenesis of hormone-related cancers, such as endometrial and post-menopausal breast cancers²³⁵, has prompted research on the potential association with OC²³⁶. One measure of great interest is body mass index (BMI), calculated as weight in kilograms divided by height in meters squared. A 2007 meta-analysis of 28 population studies reported an increased risk of OC for overweight women (BMI of 25–29.9 kg/m²) and obese women (BMI ≥ 30 kg/m²) compared with normal weight (BMI of 18.5–24.9 kg/m²), pooled RR=1.2 and 1.3, respectively²³⁷. In a 2008 analysis of 12 prospective cohort studies, an increased risk was seen among pre-menopausal obese women compared to normal weight women (RR=1.72; 95% CI: 1.02–2.89); however, this increased risk was not apparent among post-menopausal women (RR=1.07; 95% CI: 0.87–1.33)²³⁸. A more recent analysis of 12 case-control studies by the Ovarian Cancer Association Consortium (OCAC) also found that the positive association with BMI was stronger among pre-menopausal women²³⁹. Conversely, the EPIC cohort study observed the strongest risk associations for measures of adiposity (BMI and weight) among post-menopausal women²⁴⁰. In the NHS, greater hip circumference, a measure of fat distribution, was a risk factor among post-menopausal women, but waist-to-hip ratio, waist circumference and BMI were not²⁴¹.

Several studies have evaluated obesity and OC risk stratified by HRT use^239-244. The results for BMI did not differ by HRT use in the OCAC analysis, NHS, or EPIC study. In contrast, three studies observed an increased risk only for obese women that have never used HRT [RR 1.8 (95% CI: 1.2–2.8)²⁴² and RR=1.10 (95% CI: 1.07–1.13)²⁴⁴] and for never HRT users with greater weight gain since age 18 (RR=1.8; 95% CI: 1.0–3.0 for ≥40 lbs.vs. stable weight), a larger waist circumference (RR=1.8; 95% CI: 1.1.–3.0 for ≥35vs. <35 inches) and a larger waist-to-height ratio (RR=1.8; 95% CI: 1.1.–3.1 for ≥35vs. <35 inches)²⁴³.

The risk associated with obesity may be specific to non-serous and low-grade serous subtypes. Two large-scale pooled analyses, one performed by OCAC²³⁹ and another by the Collaborative Group on Epidemiological Studies of Ovarian Cancer²⁴⁴, observed the strongest risk increases for borderline serous tumors (OR/RR=1.24 and 1.29 per 5 kg/m², respectively) and somewhat lower increases for clear cell (OR/RR=1.06 and 1.05 per 5 kg/m²), mucinous (OR/RR=1.19 and 1.15 per 5 kg/m²), and endometrioid (OR/RR=1.17 and 1.08 per 5 kg/m²) tumors. Overall, serous tumors were not associated with an increased risk in either study, however, the OCAC analysis included stratification by tumor grade and found an increased risk for low-grade serous tumors only (OR=1.13 per 5 kg/m²). OCAC confirmed these findings in a later Mendelian randomization study where genetically predicted BMI was associated with an increased risk for non-high-grade serous subtypes only (OR=1.29; 95% CI: 1.03–1.61 per 5 BMI units) and the strongest increase was observed for low-grade serous tumors (OR=1.93; 95% CI: 1.33–2.81)²⁴⁵. An increased risk for OC has been observed between waist-to-hip ratio and risk of mucinous tumors (HR per 0.05 unit increment=1.19; 95% CI: 1.02–1.38), but not with serous, endometrioid, or clear cell tumors²⁴⁰. The large prospective NIH-AARP Diet and Health Study reported obese women had elevated risk of endometrioid OC (RR=1.64; 95% CI: 1.00–2.70), but not for serous¹³¹. Similarly, in the NHS, obesity was associated with increased endometrioid risk²⁹; however, in a systematic review only the pooled analysis and one case-control study found BMI to be associated with an increased risk of endometrioid OC²³⁷.

In summary, elevated BMI appears to increase risk of OC. Since adiposity is a modifiable risk factor for OC, other cancers and other chronic diseases, weight control is prudent.

Diet and nutrition

Despite numerous analytical epidemiological studies, whether diet affects risk of OC is largely unresolved. The notable exception is intake of vegetables, for which the evidence that higher intakes are associated with lower risk is emerging²⁴⁶ and to a certain extent also for consumption of whole grain foods and low-fat milk. Associations with specific fats and oils, fish and meats and certain milk products are inconsistent and no firm conclusions can be made. Recently, the EPIC cohort study and Netherlands Cohort Study performed a nutrient-wide association analysis evaluating 28 foods/food groups and 29 nutrients by dietary questionnaires from 430,476 women including 1,522 incident OC cases. Meta-analysis of the two cohort studies found that women with a high intake of saturated fats had elevated risks (HR=1.21, 95% CI: 1.04–1.41). Studies on meat consumption are not consistent^247-249. A large prospective study found that women in the highest intake quartile of dietary nitrate had an increased risk of OC (HR=1.31, 95% CI: 1.01–1.68, andP=0.02). Similarly, the association between coffee and tea intake is inconclusive^{104,108,250-256}.

Although the majority of vitamin D is produced in the skin from UV-B exposure²⁵⁷, it is also partly obtained from our diet or dietary supplements. Vitamin D is converted to 25-hydroxyvitamin [25(OH)D] in the liver and metabolized to the active form in the kidney. 1, 25-dihydroxyvitamin D [1, 25(OH)₂D₃] is involved in bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation^257,258. Experimental studies have shown that 1, 25(OH)₂D₃ inhibits cell proliferation in OC cell lines and induces apoptosis²⁵⁹. However, epidemiological evidence that vitamin D status influences OC risk is inconsistent. One systemic review concluded that there is no strong evidence that vitamin D decreases risk²⁶⁰ and a meta-analysis of ten longitudinal studies²⁶¹ as well as other cohort studies²⁶² reached a similar conclusion. In the meta-analysis the protective effect was evident in seven of the ten studies and the pooled estimate was a 17% reduced risk with increasing 25(OH)D levels; however, the pooled estimate was not statistically significant (RR = 0.83, 95% CI: 0.63–1.08)²⁶¹. To address the conflicting findings from observational studies, a recent Mendelian randomization study²⁶³ of almost 32,000 European women was conducted and found single nucleotide polymorphisms (SNPs) associated with circulating vitamin D levels were associated with an increased risk of OC (OR=1.27; 95% CI: 1.06–1.54). The beneficial effect of vitamin D may be more pronounced among overweight or obese women^259,264 perhaps reflecting differential bioavailability of circulating 25(OH)D levels²⁵⁹.

A complementary approach has been to examine SNPs in the vitamin D receptor, which mediates the biological activity of the active form of vitamin D and interacts with other cell-signaling pathways^258,265,266. The vitamin D receptor polymorphism FokI is among the most extensively studied and several studies have observed an increased OC risk among carriers^267,268. Associations with other common vitamin D receptor variants, BsmI, ApaI, and TaqI, and OC risk remain controversial²⁶⁹. Prescott and colleagues²⁷⁰ investigated all vitamin D receptor variants genotyped as part of a GWAS stratified by predicted 25(OD)D scores (highvs. low) derived from known determinants of serum 25(OH)D²⁷⁰. There was evidence that OC risk was increased for minor allele carriers of rs731236 (OR=1.31) and rs7975232 (OR=1.83) among women with high predicted 25(OH)D but these findings require replication.

Exercise and physical activity

The general health benefits of exercise are well established and a specific effect on OC might be expected, at least indirectly, through the resulting reduction of adipose tissue (and therefore estrogen levels), lower ovulation frequency, and reduced chronic inflammation²⁷¹. To date, 29 epidemiological studies have investigated physical activity and OC risk, including fourteen prospective cohort studies^272-285, two historical cohort studies^286,287, ten population-based case-control studies^252,288-296 and three hospital-based case-control studies^297-299. Results are not entirely consistent, but a 2007 meta-analysis estimated a nearly 20% lower risk for the most active women compared to the least active (pooled relative risk=0.81, 95% CI: 0.72–0.92)²⁹². Most studies that measured physical activity across the lifespan reported consistent null findings^{278,279,282,290,292} or risk reductions^{252,289,291,297} in each age period. Similarly, prolonged sedentary behavior²⁷⁸, high levels of total sitting duration^283,285,300, and chronic recreational physical inactivity²⁹⁵ have all been noted to increase risk. The benefit of physical activity does not appear to vary by histological type^285,295 but there are insufficient data to draw firm conclusions^291,294. Although further research can refine the picture, when considering the additional benefits of exercise on weight control, bone density, and heart disease, the promotion of regular activity should be encouraged.

Other lifestyle and environmental factors