Family history and inherited susceptibility to ovarian, fallopian tube, and primary peritoneal cancer

Based on solid evidence, women with a family history of ovarian cancer, especially in a first-degree relative, and those with an inherited predisposition to ovarian cancer, such as a BRCA1 or BRCA2 mutation, have an increased risk of developing ovarian cancer (refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information).

Endometriosis

Based on fair evidence, self-reported and laparoscopically confirmed endometriosis is associated with an increased risk of ovarian cancer.[1,2] The association is stronger with nonserous histologic subtypes, specifically endometrioid and clear cell carcinomas.[2,3]

Magnitude of Effect: Modest with observed relative risks (RRs) of 1.8 to 2.4.

• Study Design: Cohort and case-control studies.
• Internal Validity: Good.
• Consistency: Fair.
• External Validity: Good.

Hormone replacement therapy

Based on fair evidence, current or recent hormone therapy is associated with a small increased risk of ovarian cancer. Risks attenuate after hormone therapy is discontinued. Risks did not differ by preparation type (estrogen only vs. combined estrogen/progestin).[4,5]

Magnitude of Effect: Modest with observed RRs of 1.20 to 1.8.

• Study Design: One randomized clinical trial, cohort and case-control studies.
• Internal Validity: Good.
• Consistency: Fair.
• External Validity: Good.

Obesity and height

Based on fair evidence, obesity and height are associated with a modest increased risk of ovarian cancer.

Magnitude of Effect: Based on an overview analysis of 25,157 women with ovarian cancer and 81,211 women without ovarian cancer from 47 epidemiological studies, the RR of ovarian cancer per 5 cm increase in height is 1.07 (95% confidence interval [CI], 1.05–1.09). The RR of ovarian cancer per 5 kg/m² increase in body mass index is 1.10 (95% CI, 1.07–1.13) among never-users of hormone therapy and 0.95 (95% CI, 0.92–0.99) among ever-users of hormone therapy.[6]

• Study Design: Cohort and case-control studies.
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

Oral contraceptives

Tubal ligation

Multiparity

Based on good evidence, multiparity is associated with a decreased risk of ovarian cancer.

Magnitude of Effect: Based on good evidence from multiple observational epidemiological studies, parous women have appropriately 30% lower ovarian cancer risk than nulliparous women.[6,8,9]

• Study Design: Observational epidemiologic studies.
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

Salpingectomy

Based on limited data, salpingectomy is associated with a decrease in risk of ovarian cancer.

Magnitude of Effect: Approximately 50% decrease for bilateral salpingectomy, less protection for unilateral salpingectomy.

• Study Design: Observational epidemiologic studies from several different countries.
• Internal validity: Good.
• Consistency: Good.
• External validity: Good.

Breast-feeding

Based on solid evidence, breast-feeding is associated with a decreased risk of ovarian cancer.

Magnitude of Effect: 2% decrease with every month of breast-feeding.[10]

• Study Design: Multiple case-control and cohort studies; meta-analysis.
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

Risk-reducing bilateral salpingo-oophorectomy

Ovarian hyperstimulation for infertility treatment

Evidence is poor to determine the association between ovarian hyperstimulation and the risk of ovarian cancer. Risk of ovarian cancer may be increased among women who remain nulligravid after being treated with ovarian stimulating medications.

Magnitude of Effect: Uncertain—risk of invasive ovarian cancer may be increased among women who remain nulligravid after treatment; risk of borderline ovarian tumors may be increased among women treated with infertility drugs.

• Study Design: Cohort and case-control studies; systematic review.
• Internal Validity: Fair.
• Consistency: Poor.
• External Validity: Fair.

Incidence and mortality

In 2017, it is estimated that 22,440 new cases of ovarian cancer will be diagnosed and 14,080 deaths due to ovarian cancer will occur.[1] Incidence and mortality rates are higher among whites than among blacks, but statistically significant decreases in incidence and mortality rates have been observed among both whites and blacks.[2] Given that the Surveillance, Epidemiology, and End Results Program does not adjust for oophorectomy or salpingectomy, racial differences in the prevalence of women who had undergone these procedures could bias racial rate comparisons. A statistically significant decrease in delayed adjusted incidence of 0.9% among whites from 1987 to 2012 and 0.2% among blacks from 1992 to 2012 was observed. A statistically significant decrease in mortality rates of 2.0% per year among whites from 2002 to 2012 and 1.3% per year among blacks from 1992 to 2012 was observed. The population lifetime risk of ovarian cancer is 1.3%; the population lifetime risk of dying from ovarian cancer is 0.97%.[2]

Family history and inherited susceptibility to ovarian, fallopian tube, and primary peritoneal cancer

Some women are at an increased risk 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. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer for specific information related to ovarian cancer risk associated with multiple genetic syndromes and ovarian cancer in BRCA1/BRCA2 mutation carriers.)

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 (relative risk [RR], 1.37; 95% confidence interval [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 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]

Obesity and height

Obesity is associated with increased mortality from ovarian cancer.[8] In cohort studies, height and body mass index (BMI),[9,10] including high BMI during adolescence,[10] were associated with an increased risk of ovarian cancer, suggesting a role for diet and nutrition interventions during adolescence to prevent excessive weight gain.

A meta-analysis found that a five-unit increase in BMI was associated with an RR of 1.07 (95% CI, 1.03–1.11), with a nonlinear increase indicating an association mainly for women with a BMI of 28 kg/m² and greater. For every 10 cm increase in height, the RR was 1.16 (95% CI, 1.11–1.21). Other anthropometric measurements, such as weight gain, hip circumference, and waist-to-hip ratio were not associated with risk, on the basis of few studies.[11,12]

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.[13] The studies included 13 prospective studies, 19 population-based case-control studies, and 12 hospital-based case-control studies. 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.

A meta-analysis that was restricted to 24 case-control and cohort studies published since 2000 for the primary analysis—in order to reflect more recent types of oral contraceptive preparations—also observed a dose-response by duration of use.[14] The risk reduction among women using oral contraceptives for more than 1 year but less than 5 years was 0.77 (95% CI, 0.66–0.89), and for women using oral contraceptives for more than 10 years, the risk reduction was 0.43 (95% CI, 0.37–0.51). 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 reduction of ovarian cancer attributable to oral contraceptives of 0.54%.

(Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for specific information related to ovarian cancer risk among BRCA1/2 mutation carriers.)

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).[15] However, only 22 of the cases had ever used DMPA and nine of these 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 (odds ratio [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.[16]

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).[17] 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.[18] 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.[18]

Another pooling project with primary data from 13 population-based case-control studies examined the association between tubal ligation and ovarian cancer risk and included 7,942 epithelial ovarian cancers, and 13,904 controls.[19] 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 histologic subtype among 5,584 invasive ovarian cancers within a total sample of 1.3 million women. 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.[20]

Breast-feeding

A meta-analysis [21] that included five prospective studies and 30 case-control studies examined the association between breast-feeding and the risk of ovarian cancer. Any breast-feeding 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 breast-feeding (95% CI, 0.90–0.95). Another meta-analysis that included five prospective studies and 35 case-control studies found that any breast-feeding 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 breast-feeding and greater levels of protection.[22] 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 breast-feeding was greatest for the first 8 to 10 months.[23]

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. (Refer to the Oral contraceptives section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information on this as a risk-reducing intervention.) 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. Salpingectomy has also been discussed as a preferred means of sterilization.[24,25]

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.[36]

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.[37] A systematic review of the role of diet in ovarian cancer included only prospective studies, with at least 200 reported cases in the publications.[38] 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 (RR, 0.88; 95% CI, 0.79–0.98), but no statistically significant association with nonsteroidal anti-inflammatory drugs (NSAIDs).[39] A study published subsequent to that review examined NSAIDs 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 NSAIDs use (RR, 0.93; 95% CI, 0.74–1.15).[40] A population-based case-control study [41] 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 cyclo-oxygenase-2 NSAIDs but not nonselective NSAIDs were associated with a decreased risk of ovarian cancer (OR, 0.60; 95% CI, 0.39–0.94).

Perineal talc exposure

The weight of evidence does not support an association between perineal talc exposure and an increased risk of ovarian cancer. Results from case-control and cohort studies are inconsistent. 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.[42] A pooled analysis from the Ovarian Cancer Association Consortium, composed of multiple case-control studies, included 8,525 cases and 9,859 controls 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).[43] 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 increased risk with increasing frequency of use.[44] 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 (hazard ratio) 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.[45]

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.[46] An increased risk of ovarian cancer was observed when the comparison group was the general population (RR, 1.50; 95% 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.[47]

A follow-up study of an infertility cohort [48] was published subsequent to the aforementioned Cochrane review. 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.