Ovarian, Fallopian Tube, and Primary Peritoneal Cancers Prevention (PDQ®)–Health Professional Version

Factors With Adequate Evidence of an Increased Risk of Ovarian, Fallopian Tube, and Primary Peritoneal Cancers

Factors With Adequate Evidence of a Decreased Risk of Ovarian, Fallopian Tube, and Primary Peritoneal Cancers

Areas of Uncertainty

Family History and Inherited Susceptibility to Ovarian, Fallopian Tube, and Primary Peritoneal Cancers

Some women are at an increased risk of these cancers because of an inherited mutation, with the magnitude of that risk dependent on the affected gene and specific mutation. Underlying ovarian cancer risk can be assessed through accurate pedigrees and/or genetic markers of risk. Because of uncertainties about cancer risks associated with certain specific gene mutations, genetic information may be difficult to interpret outside of families with a high incidence of ovarian cancer.

This summary does not address multiple genetic syndromes or women who are at high risk because of inherited genetic factors. For specific information related to ovarian cancer risk associated with multiple genetic syndromes and ovarian cancer in BRCA1/BRCA2 mutation carriers, see Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer.

Endometriosis

Endometriosis has been associated with a modestly increased risk of ovarian cancer. The association is stronger with nonserous histological subtypes, specifically endometrioid and clear cell carcinomas. In one analysis, data were pooled from 13 ovarian cancer case-control studies, including 13,226 controls and 7,911 women with invasive ovarian cancer who were part of the Ovarian Cancer Association Consortium. Logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Self-reported endometriosis was associated with a significantly increased risk of clear cell (odds ratio [OR], 3.05; 95% confidence interval [CI], 2.43–3.84; P < .0001), low-grade serous (OR, 2.11; 95% CI, 1.39–3.20; P < .0001), and endometrioid invasive ovarian cancers (OR, 2.04; 95% CI, 1.67–2.48; P < .0001). No association was noted between endometriosis and risk of mucinous (OR, 1.02; 95% CI, 0.69–1.50; P = .93) or high-grade serous invasive ovarian cancer (OR, 1.13; 95% CI, 0.97–1.32; P = .13), or borderline tumors of either subtype (OR, 1.20; 95% CI, 0.95–1.52; P = .12 for serous and OR, 1.12; 95% CI, 0.84–1.48; P = .45 for mucinous).[1] Considering that the clear cell and endometrioid ovarian cancers represented approximately 15% of all ovarian cancers, the lifetime risk of these histological subtypes is approximately 0.2%, which, on the basis of these data, would increase to approximately 0.4% to 0.6% in the presence of self-reported endometriosis.

A cohort study from the Danish National Patient Register identified 45,790 women with a clinical diagnosis of endometriosis between 1977 and 2012. Data were linked to the Danish Cancer Register, which identified 186 women with a diagnosis of ovarian cancer. Endometriosis was associated with modestly increased risks of ovarian cancer overall (standardized incidence ratio [SIR], 1.34; 95% CI, 1.16–1.55). This was primarily caused by increases in endometrioid (SIR, 1.64; 95% CI, 1.09–2.37) and clear cell subtypes (SIR, 3.64; 95% CI, 2.36–5.38). No increased risk of serous or mucinous histological subtypes was reported.[2]

Using data from the Nurses’ Health Study II, 228 ovarian cancers were identified from among 102,025 eligible women. Cox proportional hazards regression models were used to assess associations between endometriosis and cancer risk, evaluating the impacts of self-reported versus laparoscopically confirmed endometriosis, delayed diagnosis, and postendometriosis diagnosis changes in risk-factor exposures. Self-reported endometriosis was associated with ovarian cancer (relative risk [RR], 1.81; 95% CI, 1.26–2.58), which was stronger for laparoscopically confirmed endometriosis diagnoses (RR, 2.14; 95% CI, 1.45–3.15). Diagnosis delays or postendometriosis diagnosis changes in risk factors had little impact on risk. Although this study had limited power to detect differences in risk on the basis of histological subtype, nonserous cases were shown to have an increased risk (RR, 2.44; 95% CI, 1.48–4.01), and serous cases were not (RR, 1.69; 95% CI, 0.92–3.11).[3] A large case-control study in African American women found similar associations with a history of endometriosis and ovarian cancer (OR, 1.78; 95% CI, 1.09–2.90), suggesting that findings from populations of predominantly White women are also observed in Black women.[4]

Hormone Replacement Therapy/Hormone Therapy

A meta-analysis of 52 studies (17 prospective and 35 retrospective) including 21,488 ovarian cancers found increased risks with current or recent hormone replacement use in prospective studies (RR, 1.37; 95% CI, 1.29–1.46), with similar results for retrospective designs. Significant relationships were found for serous and endometrioid subtypes.[5] Recent use was strongly related to risk even among women who had used hormone replacement therapy for less than 5 years (RR, 1.41; 95% CI, 1.32–1.50). Risk declined among women who had discontinued use, with greater effects for longer periods of cessation. Risks did not differ by preparation types (estrogen only vs. combined estrogen/progestin). Risks also did not differ by age at use.[6,7] Cutaneous hormone therapy may have a lower risk than oral hormone therapy.[8]

Tibolone, a synthetic steroid with estrogenic, progestogenic, and androgenic properties, has been associated with an increased incidence rate ratio of 3.56 (95% CI, 3.08–4.69) for endometrial cancer for current users compared with never-users. Tibolone is approved for use to manage menopausal symptoms or to prevent osteoporosis in many countries. However, it is not approved for use in Canada or the United States. Other combined therapy with estrogen and progestin may also increase the risk of breast cancer, so the risks and benefits must be considered.[9]

Obesity and Height

Ovarian cancer risk increases with increasing height and weight (body mass index [BMI]).[10] The Collaborative Group on Epidemiological Studies of Ovarian Cancer compiled individual data, both published and unpublished, from 47 epidemiological studies including 12,157 women with ovarian cancer and 81,311 controls. RR increased significantly with increasing height (1.07 per 5 cm of height) and with increasing BMI (1.10 per 5 kg/m2). These findings were unaffected by other factors known to be associated with ovarian cancer risk, with the exception that ever-users of hormone therapy had no increased risk with increasing BMI. Given that height, weight, and BMI are thought to be strongly correlated, separating out the individual effects can be difficult.[11,12] Ovarian cancer mortality has also been shown to be increased in women with obesity.[13,14]

Multiparity

Compared with nulliparous women, the risk of ovarian cancer was reduced by 30% to 60% among parous women, with additive protection for each additional birth.[1] The risk of developing ovarian cancer was lower for parous women (relative risk [RR], 0.69; 95% CI, 0.64–0.74) than for women who never had children, with increased risk reduction with increasing number of children for one child (RR, 0.82; 95% CI, 0.43–0.91) to four or more children (RR, 0.58; 95% CI, 0.53–0.64).[7]

Oral Contraceptives

A collaborative analysis was performed of individual data from 23,257 women with ovarian cancer and 87,303 women without ovarian cancer from 45 studies in 21 countries.[8] Oral contraceptive use was associated with a dose-response effect by duration of use, without observed changes in risk reduction by decade of use from the 1960s to 1980s, over which time the amount of estrogen in oral contraceptives was approximately halved. No risk reduction was observed for women who used oral contraceptives for less than 1 year. The risk reduction associated with use from 1 to 4 years, 5 to 9 years, 10 to 14 years, and 15 years or more was 0.78 (99% CI, 0.73–0.893), 0.64 (99% CI, 0.59–0.69), 0.56 (99% CI, 0.50–0.62), and 0.42 (99% CI, 0.36–0.49), respectively. The observed risk reduction persisted after cessation of oral contraceptive therapy but attenuated over time since last use. The proportional reduction in risk per 5 years of use was 29% (95% CI, 23%–34%) for women who had discontinued use within the last 10 years. The reduction in risk was 15% (95% CI, 9%–21%) for women who discontinued use 20 to 29 years ago.[9]

A meta-analysis, in which the primary analysis was restricted to 24 case-control and cohort studies published since 2000 to reflect more recent types of oral contraceptive preparations, also observed a dose-response by duration of use.[2] The authors estimated that 185 women needed to be treated for 5 years to prevent one case of ovarian cancer. Based on an estimated lifetime risk of 1.38% and prevalence of ever-use of oral contraceptives of 83%, the authors estimated a lifetime relative reduction of ovarian cancer attributable to oral contraceptives of 0.54%. A prospective cohort study from Denmark, which represented nearly 1.9 million women, also examined contemporary oral contraceptive formulations and found that current oral contraceptive formulation users had an RR reduction of 0.58 (95% CI, 0.49–0.68), and former oral contraceptive formulation users had a RR reduction of 0.77 (95% CI, 0.66–0.91). The benefits were strengthened by longer duration of use and weakened by more time since last use. No benefit was found for progesterone-only birth control products. This study was limited by only including incident ovarian cancers that occurred in women younger than 50 years.[10]

For specific information related to ovarian cancer risk among BRCA1/BRCA2 mutation carriers, see Genetics of Breast and Gynecologic Cancers.

Depot-Medroxyprogesterone Acetate

Limited information is available on the use of injectable progestational contraceptives (depot-medroxyprogesterone acetate [DMPA]) and the risk of ovarian cancer. Studies are confounded by the use of other contraceptive methods, particularly oral contraceptives. A hospital-based study conducted in Mexico and Thailand, with 224 cases and 1,781 controls (the World Health Organization Collaborative Study of Neoplasia and Steroid Contraceptives), did not observe an association between DMPA and ovarian cancer (RR, 1.07; 95% CI, 0.6–1.8).[11] However, only 22 of the participants had ever used DMPA, and nine of them had used it for 6 months or less.

A subsequent multicenter study conducted in 12 hospitals in Thailand, including 330 cases and 982 matched controls, observed a statistically significant decreased risk of ovarian cancer associated with DMPA use, controlling for oral contraceptive use and other associated factors (OR, 0.52; 95% CI, 0.33–0.88). A dose-response association was observed, but the sample size was limited in longer-term use categories.[12]

Tubal Ligation

A meta-analysis of 16 case-control studies, three retrospective studies, and two prospective cohort studies observed a decreased risk of ovarian cancer associated with tubal ligation (RR, 0.66; 95% CI, 0.60–0.73).[4] The reduced risk was observed up to 14 years after tubal ligation. A population-based case-control study of 902 cases and 1,802 controls published subsequent to the meta-analysis observed an adjusted OR of 0.62 (95% CI, 0.51–0.75) associated with a history of a tubal ligation.[13] The association was adjusted for oral contraceptive use, which was also associated with a lower risk of ovarian cancer (OR, 0.62; 95% CI, 0.47–0.85) and other risk factors.[13] Salpingectomy has also been discussed as a preferred means of sterilization.[14,15] For more information, see the Salpingectomy section.

Another pooling project with primary data from 13 population-based case-control studies examined the association between tubal ligation and ovarian cancer risk. It included 7,942 individuals with epithelial ovarian cancers and 13,904 controls.[16] Overall, tubal ligation was associated with a 29% reduction in risk (OR, 0.71; 95% CI, 0.66–0.77). The observed risk reduction varied by subtype of invasive cancers and was 52% (OR, 0.48; 95% CI, 0.40–49) for endometrioid cancer; 48% (OR, 0.52; 95% CI, 0.40–0.67) for clear cell cancer; 32% (OR, 0.68; 95% CI, 0.52–89) for mucinous cancer; and 19% (OR, 0.81; 95% CI, 0.74–0,89) for serous cancer.

A pooled analysis from 21 prospective cohort studies examined 14 hormonal, reproductive, and lifestyle factors by histological subtype among 5,584 women with invasive ovarian cancer within a total sample of 1.3 million participants. Overall, tubal ligation was associated with an 18% reduction in risk (OR, 0.82; 95% CI, 0.73–0.93). The observed risk reduction varied by subtype of invasive cancer and was 40% (OR, 0.60; 95% CI, 0.41–88) for endometrioid cancer; 65% (OR, 0.35; 95% CI, 0.18–0.69) for clear cell cancer; and 9% (OR, 0.91; 95% CI, 0.79–1.06) for serous cancer. There was a nonsignificant increase in risk of 1% (OR, 1.01; 95% CI, 0.60–1.71) for mucinous cancer.[7]

Breastfeeding

A meta-analysis [3] that included five prospective studies and 30 case-control studies examined the association between breastfeeding and the risk of ovarian cancer. Any breastfeeding was associated with a decreased risk of ovarian cancer (RR, 0.76; 95% CI, 0.69–0.83). The risk of ovarian cancer decreased 8% for every 5-month increase in duration of breastfeeding (95% CI, 0.90–0.95). Another meta-analysis that included five prospective studies and 35 case-control studies found that any breastfeeding was associated with a decreased risk of ovarian cancer (RR, 0.70; 95% CI, 0.64–0.76). These results are consistent with a previous meta-analysis and further support the prior finding of a suggested association between increased duration of breastfeeding and greater levels of protection.[17] Another meta-analysis of 19 studies, including four cohort and 15 case-control studies, found an overall decreased risk of ovarian cancer with an OR of 0.66 (95% CI, 0.57–0.76) and an association with duration (2% decrease per month). The benefit of breastfeeding was greatest for the first 8 to 10 months.[18]

Risk-Reducing Salpingo-Oophorectomy

Risk-reducing surgery is an option considered by women who are at high risk of ovarian cancer, such as those with an inherited susceptibility to cancer. For more information on this as a risk-reducing intervention, see the Oral contraceptives section in Genetics of Breast and Gynecologic Cancers. Among women in the general population, opportunistic salpingectomy, oophorectomy, or salpingo-oophorectomy have been considered as possible interventions at the time of surgery for other benign indications.

Dietary Factors

No consistent association has been observed between a variety of dietary factors and the risk of ovarian cancer.

A systematic review and meta-analysis that included 23 case-control studies and three cohort studies found no evidence of an association between alcohol use and epithelial ovarian cancer.[1]

A case-control study of the Healthy Eating Index (HEI), based on current U.S. Department of Agriculture dietary guidelines, found no association between the highest HEI score and ovarian cancer risk for any specific food group.[2] A systematic review of the role of diet in ovarian cancer included only prospective studies, with at least 200 reported cases in the publications.[3] Twenty-four publications from ten cohort studies were reviewed, and no dietary factors were consistently associated with the risk of ovarian cancer.

Aspirin and Nonsteroidal Anti-Inflammatory Drugs

A systematic review and meta-analysis of 21 observational studies found a decreased risk of invasive ovarian cancer associated with aspirin use (relative risk [RR], 0.88; 95% confidence interval [CI], 0.79–0.98), but no statistically significant association with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).[4] A study published after that review examined NSAID use and ovarian cancer risk in the National Institutes of Health–AARP Diet and Health Study. No association was observed between the development of ovarian cancer and regular aspirin use (RR, 1.06; 95% CI, 0.87–1.29) or NSAID use (RR, 0.93; 95% CI, 0.74–1.15).[5] A population-based case-control study [6] of 902 incident cases and 1,802 population controls observed a decreased risk of ovarian cancer associated with continual use (0.71; 95% CI, 0.53–0.97) or low-dose daily use (0.72; 95% CI, 0.53–0.97). In that study, selective cyclooxygenase-2 NSAIDs, but not nonselective NSAIDs, were associated with a decreased risk of ovarian cancer (odds ratio [OR], 0.60; 95% CI, 0.39–0.94). A cohort analysis of about 200,000 women in the Nurses' Health Studies, which used detailed data about the intensity and duration of aspirin use over time, showed a reduced hazard ratio (HR) for ovarian cancer of 0.77 (95% CI, 0.61–0.96) for low-dose aspirin use (≤100 mg/d) but no reduction for standard-dose aspirin use (HR, 1.17; 95% CI, 0.92–1.49).[7]

Perineal Talc Exposure

Results from case-control and cohort studies are inconsistent, so the data are inadequate to support an association between perineal talc exposure and an increased risk of ovarian cancer.

A meta-analysis of 16 studies observed an increased risk with the use of talc (RR, 1.33; 95% CI, 1.16–1.45); however, a dose-response relationship was not found.[8] A pooled analysis from the Ovarian Cancer Association Consortium, composed of multiple case-control studies, included 8,525 cases and 9,859 controls. The analysis found a modest increased risk of epithelial ovarian cancer associated with genital powder use (OR, 1.24; 95% CI, 1.15–1.33), but the trend across increasing lifetime number of applications was not statistically significant (P trend = .17).[9] A meta-analysis of ten case-control studies and a highly selected subset analysis of one prospective cohort study found an association (OR, 1.47; 95% CI, 1.31–1.65) among women who used perineal talc at least twice a week.[10] The subset analysis of the prospective study was inconsistent with the main findings of the original report.[11] However, because of the structure of this analysis, the results should be interpreted with care.[10] A population-based case-control study of African American women in the United States found an association between genital powder use and risk of epithelial ovarian cancer (OR, 1.44; 95% CI, 1.11–1.86).[12] In this study of 584 cases and 745 controls, a dose-response relationship for any genital powder use was reported. Specifically, among any genital powder use, daily powder use was associated with increased adjusted OR of developing ovarian cancer (OR, 1.71; 95% CI, 1.26–2.33) compared with less than daily use (OR, 1.12; 95% CI, 0.80–1.58).

A cohort study among nurses did not observe a risk of ovarian cancer associated with perineal talc use (RR, 1.09; 95% CI, 0.86–1.37), and there was no evidence of increasing risk with increasing frequency of use.[13] Another prospective study, the Women’s Health Initiative, examined the association between perineal powder use and the development of ovarian cancer among 61,576 women without a history of cancer at enrollment and who provided exposure information. Among this group, 429 cases of ovarian cancer occurred. Powder use on genitals, sanitary napkins, and diaphragms was examined individually and as a combined exposure. Women were followed for a mean of 12.4 years. An association of ovarian cancer with ever-use was not found when analyzed either by individual method of exposure or by overall combined exposure. The observed risk (HR) for combined exposure to perineal powder was 1.06 (95% CI, 0.87–1.28), and there was no increased risk observed for increasing duration of use.[14] The cohort study cited above,[11] which included 250,000 women enrolled in four long-term studies of women’s health, was consistent with other cited cohort studies, as the risk of ovarian cancer in perineal talc exposure never-users was similar to that in ever-users, with an HR of 1.08 (95 % CI, 0.99–1.17).[11]

Ovarian Hyperstimulation Due to Infertility Treatment

Controversy persists concerning the association between ovarian hyperstimulation and ovarian cancer. Results of a systematic review and meta-analysis of nine cohort studies comprised 109,969 women who were exposed to ovarian hyperstimulation for infertility treatment (i.e., in vitro fertilization [IVF]), with 76 incident ovarian cancer cases observed, provided inconclusive evidence for an association.[1] An increased risk of ovarian cancer was observed when the comparison group was the general population (relative risk [RR], 1.50; 95% confidence interval [CI], 1.17–1.92), but no statistically significant increased risk was observed when the reference group was unexposed infertile women (RR, 1.26; 95% CI, 0.62–2.55). A major limitation was that only one of the cohort studies included in the meta-analysis had a follow-up period longer than 10 years for those exposed to IVF.

A Cochrane systematic review that included 11 case-control studies and 14 cohort studies, for a total of 186,972 women, was also indeterminate for an association. Summary statistics were not calculated because of methodological and clinical heterogeneity. Among seven cohort studies that compared treated women with untreated subfertile women, no excess risk was noted in association with hyperstimulation medications. Two cohorts noted an increased risk of twofold to fivefold when treated women were compared with the general population. An increased risk of borderline ovarian tumors was noted in three case-control studies and two cohort studies. Overall, the authors concluded there was no convincing evidence that an increased risk of invasive ovarian tumors was associated with fertility drug treatments.[2]

After the Cochrane review, a follow-up study of an infertility cohort [3] was published. A retrospective cohort of 9,825 women enrolled between 1965 and 1988 was followed through 2010. Ovarian cancer occurred in 85 women. Overall, there was no association between ovarian cancer and clomiphene citrate (RR, 1.34; 95% CI, 0.86–2.07) or gonadotropins (RR, 1.00; 95% CI, 0.48–2.08). Among the subgroup of women who remained nulligravid after treatment, an increased risk of ovarian cancer was associated with clomiphene citrate (RR, 3.63; 95% CI, 1.36–9.72). No increased risk was observed among women who successfully conceived after being treated, compared with women who were not treated.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about ovarian, fallopian tube, and primary peritoneal cancers prevention. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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PDQ® Screening and Prevention Editorial Board. PDQ Ovarian, Fallopian Tube, and Primary Peritoneal Cancers Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/ovarian/hp/ovarian-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389359]

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