Overview

Note: Separate PDQ summaries on Ovarian Cancer Screening and Ovarian Epithelial Cancer Treatment are also available.

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. Risk may be stronger with estrogen-only therapy compared with combined estrogen-progestin therapy.

Magnitude of Effect: Modest with observed relative risks (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.

Based on solid evidence, perineal application of talc is associated with a small increased risk of ovarian cancer. The International Agency for Research on Cancer has concluded that perineal talc is a possible carcinogen.[1]

Magnitude of Effect: Odds ratio of 1.24 (95% confidence interval [CI], 1.15-1.33).

Study Design: Cohort and case-control studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Based on fair evidence, obesity, weight gain, 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% 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.[2]

Study Design: Cohort and case-control studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Benefits

Based on solid evidence, oral contraceptive use is associated with a decreased risk of developing ovarian cancer.

Magnitude of Effect: The degree of risk reduction varies by duration of oral contraceptive use and time since last use. For 1 to 4 years of oral contraceptive use the RR reduction is 22%, and for 15 or more years of use the RR reduction is 56%. The reduction in risk persisted for over 30 years after use was discontinued but the degree of reduction attenuates over time. The risk reduction per 5 years of use was 29% for women who discontinued use less than 10 years ago and decreased to 15% for women who discontinued use 20 to 29 years ago. Ten years of use reduced cancer incidence before age 75 years from 1.2 to 0.8 per 100 users and mortality from 0.7 to 0.5 per 100 users. The number needed to treat for 5 years was estimated to be about 185 women.

Study Design: Multiple case-control and cohort studies; meta-analyses.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Harms

Based on solid evidence, combined current use of estrogen-progestin oral contraceptive use is associated with an increased risk of venous thromboembolism. Oral contraceptives are not associated with a long-term increased risk of breast cancer but may be associated with a short-term increased risk while a woman is taking oral contraceptives. The risk of breast cancer declines with time since last use.

Magnitude of Effect: The risks may vary by preparation. Overall, the absolute risk of venous thromboembolism is about three events per 10,000 women per year while taking oral contraceptives. The risk is modified by smoking. Breast cancer risk among long-term (>10 years) current users is estimated at one extra case per year per 100,000 women. The risk dissipates with time since last use.

Study Design: Observational studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Benefits

Based on solid evidence, tubal ligation is associated with a decreased risk of ovarian cancer.

Magnitude of Effect: A relative reduction in the odds of developing ovarian cancer, adjusting for other forms of contraception, of about 30% has been observed.

Study Design: Multiple case-control studies and cohort studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Harms

Based on fair evidence, harms include surgical risks, including the following:

• Damage to the bowel, bladder, or major blood vessels requiring unintended surgery (rate of 0.9 per 100 procedures).
• Febrile morbidity (rate of 0.1 per 100 procedures).
• Rehospitalization (rate of 0.6 per 100 procedures) because of complications such as infection, vaginal bleeding, or pain.
• Transfusion (rate of <0.01 per 100 procedures based on one event).
• In one large study of outcomes, one life-threatening event of anaphylaxis was reported (rate of <0.01 per 100 procedures).
• Incomplete ligation may result in pregnancy following the procedure, with a risk from 1 in 100 to 1 in 200 procedures.

Study Design: One prospective cohort study.

Internal Validity: Good.

Consistency: N/A.

External Validity: Fair.

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

Magnitude of Effect: 8% decrease with every 5 months of breast-feeding.

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

Benefits

Based on solid evidence, risk-reducing bilateral salpingo-oophorectomy is associated with a decreased risk of ovarian cancer. Peritoneal carcinomatosis has been reported following surgery. Risk-reducing surgery is generally reserved for women at high risk of developing ovarian cancer, such as women who have an inherited susceptibility to ovarian cancer.

Magnitude of Effect: 90% reduction in risk of ovarian cancer observed among women with a BRCA1 or BRCA2 mutation.

Study Design: Multiple case-control studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Harms

Based on solid evidence, prophylactic oophorectomy among women who are still menstruating at the time of surgery is associated with infertility, vasomotor symptoms, decreased sexual interest, vaginal dryness, urinary frequency, decreased bone mineral density, and increased cardiovascular disease.

Magnitude of Effect: Reported prevalence of vasomotor symptoms varies from 41% to 61.4% among women who underwent oophorectomy before natural menopause. Women with bilateral oophorectomy who did not take hormone therapy were twice as likely to have moderate or severe hot flashes compared with women who underwent natural menopause. The RR of cardiovascular disease among women with bilateral oophorectomy and early menopause was 4.55 (95% CI, 2.56–9.01).

Study Design: Cohort and case-control studies.

Internal Validity: Good.

Consistency: Good.

External Validity: Good.

Evidence is poor to determine the association between ovarian hyperstimulation and the risk of ovarian cancer. Risk of borderline ovarian tumors may be increased among subfertile women treated with in vitro fertilization. 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.

1. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans: Carbon black, titanium dioxide, and talc. IARC Monogr Eval Carcinog Risks Hum 93: 1-413, 2010.  [PUBMED Abstract]
   
   
2. Collaborative Group on Epidemiological Studies of Ovarian Cancer: Ovarian cancer and body size: individual participant meta-analysis including 25,157 women with ovarian cancer from 47 epidemiological studies. PLoS Med 9 (4): e1001200, 2012.  [PUBMED Abstract]
   
   

Description of the Evidence

In 2014, it is estimated that 21,980 new cases of ovarian cancer will be diagnosed and 14,270 deaths due to ovarian cancer will occur.[1] Incidence and mortality rates are higher among whites than blacks, but statistically significant decreases in incidence and mortality rates have been observed among both whites and blacks.[2] A statistically significant decrease in delayed adjusted incidence of 0.9% among whites from 1987 to 2010 and 0.4% among blacks from 1997 to 2010 has been observed. A statistically significant decrease in mortality rates of 1.9% per year among whites from 2002 to 2010 and 0.9% per year among blacks from 1992 to 2010 has been observed. The population lifetime risk of ovarian cancer is 1.37%; the population lifetime risk of dying from ovarian cancer is 0.99%.[2]

Underlying ovarian cancer risk can be assessed through accurate pedigrees and/or genetic markers of risk. Because of uncertainties about cancer risks associated with specific gene mutations, genetic information may be difficult to interpret outside of families with a high incidence of ovarian cancer. The following three inherited ovarian cancer susceptibility syndromes have been described: (1) familial site-specific ovarian cancer; (2) familial breast/ovarian cancer; and (3) Lynch II syndrome, which is a combination of breast, ovarian, endometrial, gastrointestinal, and genitourinary cancers.[3,4] Considering family history in the absence of specific information on BRCA1/2 mutation status, unaffected women who have two or three relatives with ovarian cancer have a cumulative ovarian cancer risk of about 7%.[3,5] Women who have a mother or sister with ovarian cancer have a cumulative lifetime risk of ovarian cancer of about 5%.

Ovarian cancer may be of germ cell, stromal, or epithelial origin.[6] Epithelial ovarian cancer, the most common type, is the focus of this summary. The term epithelial ovarian cancer encompasses a heterogeneous group of tumors. Classically, ovarian tumors have been classified as serous, mucinous, endometrioid, and clear cell. However, a dual classification system of type I and type II tumors has been proposed that incorporates molecular profiling of tumors as well as histology and clinical behavior.[7] Type I tumors usually present at a low stage, are associated with an excellent clinical prognosis, and encompass borderline malignant tumors. Type II tumors are more aggressive, usually present in an advanced stage, and have a variety of histologies. Type I tumors tend to be more stable genetically than type II tumors, with type II tumors also having a high prevalence of TP53 mutations. About 75% of epithelial cancers are type II tumors and include ovarian cancer such as serous, endometrioid, and mixed mesodermal tumors. There is increasing evidence that the two types of cancers are different genetically, and thus, may have different molecular pathways of development. Evidence also suggests that both of these types develop outside the ovary and then secondarily involve the ovary, with most type II tumors being of tubal origin.[7] This is hypothesized to be the case for both genetic cancers (BRCA1/2-mutation associated cancers) and most noninherited forms of ovarian cancer.

The heterogeneity of ovarian cancer and the suggestion of different molecular pathways of origin for cancer subtypes present challenges and opportunities for the conduct and interpretation of etiologic factors associated with the development of ovarian cancer. Etiologic association may vary by the mix of subtypes in the populations included in the epidemiologic studies. Ovarian cancer is a rare cancer, thus sample size and power of studies to detect moderate association by subtype of cancer are limited. However, clearer subtyping of cancers may assist is improving our understanding of the etiology of ovarian malignancies in future studies.

Some women are at an increased risk because of an inherited susceptibility to ovarian cancer, with the magnitude of that risk depending 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 specific gene mutations, genetic information may be difficult to interpret outside of families with a high incidence of ovarian cancer. The following three inherited ovarian cancer susceptibility syndromes have been described: (1) familial site-specific ovarian cancer; (2) familial breast/ovarian cancer; and (3) Lynch II syndrome, which is a combination of breast, ovarian, endometrial, gastrointestinal, and genitourinary cancers.[3,4] Considering family history in the absence of specific information on BRCA1/2 mutation status, unaffected women who have two or three relatives with ovarian cancer have a cumulative ovarian cancer risk of about 7%.[3,5] Women who have a mother or sister with ovarian cancer have a cumulative lifetime risk of ovarian cancer of about 5%.

Multiple genetic syndromes are not addressed in this summary. This summary also does not address women who are at high risk because of inherited genetic factors. (Refer to the Oral contraceptives section in the PDQ summary on Genetics of Breast and Ovarian Cancer and the PDQ summary on Genetics of Colorectal Cancer for specific information related to ovarian cancer risk associated with multiple genetic syndromes and ovarian cancer in BRCA1/2 mutation carriers.)

A modest association between current, but not past, postmenopausal hormone therapy use and incident ovarian cancer was observed in the Million Women Study.[8] The Million Women Study reported on 2,273 incident cases of ovarian cancer observed among women followed for an average of 5.3 years. The relative risk (RR) among current users of hormone therapy compared with women who never used hormone therapy was 1.20 (95% confidence interval [CI], 10.9–1.32). A dose-response relationship was observed with increasing risk, noted with increasing duration of use. The observed RRs were higher for estrogen-only therapy than for combined estrogen-progestogen therapy (RR, 1.34; 95% CI, 1.13–1.60 vs. RR, 1.14; 95% CI, 1.01–1.28, respectively). No excess risk of ovarian cancer was observed among past users.

As in the Million Women Study, a population-based case-control study conducted in Washington State observed an association between ovarian cancer and current or recent use (within the last 3 years) of exclusively estrogen-only therapy for at least 5 years (current use: odds ratio [OR], 1.6; 95% CI, 1.1–2.5; recent use: OR, 1.8; 95% CI, 0.8–3.7). However, no increased risk was observed among users of combined estrogen-progestogen therapy.[9]

The Women’s Health Initiative estrogen-progestin randomized trial observed a nonstatistically significant excess risk of ovarian cancer, based on 32 cases of ovarian cancer at the 5.6-year follow-up (hazard ratio, 1.58; 95% CI, 0.77–3.24).[10] An accelerated decline in ovarian cancer incidence rates after 2002—following the report of the Women’s Health Initiative and subsequent decline in the use of hormone therapy—supports, but does not prove, a causal association between hormone therapy and ovarian cancer risk.[11]

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).[12] 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, there was no evidence of a dose response. A pooled analysis from the Ovarian Cancer Association Consortium that included 8,525 cases and 9,859 controls observed a modest increased risk of epithelial ovarian cancer associated with genital powder use (OR, 1.24; 95% CI, 1.15–1.33). Risks assessed across quartiles of lifetime number of applications, compared with women who never used talc, was 1.18 (1.02–1.36), 1.22 (1.06–1.41), 1.22 (1.06–1.41), and 1.37 (1.19–1.58) (P _trend = .17). Perineal application of talc is associated with a small increased risk of ovarian cancer. The International Agency for Research on Cancer (IARC) has concluded that perineal talc is a possible carcinogen.[13,14]

Obesity is associated with increased mortality from ovarian cancer.[15] In cohort studies, height and body mass index (BMI),[16,17] including high BMI during adolescence,[17] were associated with an increased risk of ovarian cancer, suggesting a role for diet and nutrition during the adolescent period. The California Teachers Study Cohort (277 cases of ovarian cancer) observed an increased risk of ovarian cancer associated with a weight gain of more than 40 pounds (but not BMI) (RR, 1.8; 95% CI, 1.0–3.0) compared with women who had a stable adult weight and who never used hormone therapy.[18]

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. [19] 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, with no 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.[20] 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 Ovarian Cancer for specific information related to ovarian cancer risk among BRCA1/2 mutation carriers.)

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), observed no association between DMPA and ovarian cancer (RR, 1.07; 95% CI, 0.6–1.8).[21] 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 (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.[22]

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).[23] 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.[24] 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.[24]

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, 2,215 borderline tumors, and 13,904 controls.[25] 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. No significant association was observed between tubal ligation and risk of borderline ovarian tumors.

The United States Collaborative Review of Sterilization includes data from 15 participating institutions collected from nine cities from 1978 to 1987.[26] The rate of unintended major surgery was 0.9 per 100 procedures. Other reported complications included rehospitalization (0.6 per 100 procedures), febrile morbidity (0.1 per 100 procedures), and transfusion (<0.01 per 100 procedures). No deaths were reported among 9,475 women who had laparoscopic surgery. One life-threatening event of anaphylaxis, presumed to be caused by anesthesia, was reported. Overall rates did not statistically significantly vary by type of methods (silicone rubber band application, spring clip, or unipolar or bipolar coagulation).

A meta-analysis [27] 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).

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 Ovarian Cancer for more information on this as a risk-reducing intervention.)

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.[28]

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.[29] A systematic review of the role of diet in ovarian cancer included only prospective studies, with at least 200 reported cases in the publications.[30] Twenty-four publications from ten cohort studies were reviewed and no dietary factors were consistently associated with the risk of ovarian cancer. Tea consumption was not specifically addressed in that review, but another systematic review included 16 articles, with nine articles reporting no association with tea consumption, five reporting a decreased risk, and one each reporting a borderline decreased and increased risk associated with tea consumption.[31] A case-control study conducted in southern China (500 cases and 500 controls), published subsequent to the review, reported a protective association between regular drinking of green tea, black tea, and/or oolong tea, with an OR of 0.29 (95% CI, 0.22–0.39).[32]

Circulating vitamin D levels and the association with ovarian cancer was examined in a nested case-control study (516 cases and 770 matched controls) conducted among seven prospective cohorts.[33] No association was observed between circulating 25-hydroxyvitamin D [25(OH)D] levels and the development of ovarian cancer. A nested case-control study in Finland (172 ovarian cancer cases and 172 matched controls) observed a decreased risk of ovarian cancer among women who had 25(OH)D levels of more than 75 nmol/L (considered sufficient) compared with women who had lower levels (OR, 0.32; 95% CI, 0.12–0.91).[34]

The Australian Ovarian Cancer Study (1,366 cases and 1,414 population controls) [35] found no association between intake of omega-3 fatty acids and ovarian cancer risk. High intake of omega-6 fatty acids that came from avocados, vegetables, or nuts, but not other sources, was associated with a modest decreased risk (OR, 0.78; 95% CI, 0.60–1.00). Overall, the authors concluded that the benefit from omega-6 fatty acids was from the general properties of the food source rather than from the omega-6 fatty acid per se.

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).[36] 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).[37] A population-based case-control study [38] 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).

An individual participant meta-analysis from 51 studies that included 28,114 women with ovarian cancer found a very small increased risk of ovarian cancer among current smokers compared with women who never smoked (RR, 1.06; 95% CI, 1.01–1.11).[39] Smoking risk varied by subtype, with no association observed for serous ovarian cancer (RR, 0.99; 95% CI, 0.93–1.06), an excess risk for mucinous cancers (RR, 1.79; 95% CI, 1.60–2.00), and a decreased risk for endometrioid (RR, 0.81; 95% CI, 0.72–0.92) and clear-cell ovarian cancer (RR, 0.80; 95% CI, 0.65–0.97).

Controversy persists concerning the association between ovarian hyperstimulation and ovarian cancer. 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.[40] 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 included 11 case-control studies and 14 cohort studies, for a total of 186,972 women; however, 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, but there may be an increased risk of borderline ovarian tumors.[41]

A follow-up study of an infertility cohort [42] 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.

1. American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014. 
   
   
2. Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. Bethesda, Md: National Cancer Institute, based on November 2012 SEER data submission, posted to the SEER web site, April 2013. Also available online. Last accessed June 13, 2014. 
   
   
3. Trimble EL, Karlan BY, Lagasse LD, et al.: Diagnosing the correct ovarian cancer syndrome. Obstet Gynecol 78 (6): 1023-6, 1991.  [PUBMED Abstract]
   
   
4. Genetic risk and screening techniques for epithelial ovarian cancer. ACOG Committee Opinion: Committee on Gynecologic Practice. Number 117--December 1992. Int J Gynaecol Obstet 41 (3): 321-3, 1993.  [PUBMED Abstract]
   
   
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8. Beral V, Bull D, Green J, et al.: Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet 369 (9574): 1703-10, 2007.  [PUBMED Abstract]
   
   
9. Rossing MA, Cushing-Haugen KL, Wicklund KG, et al.: Menopausal hormone therapy and risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 16 (12): 2548-56, 2007.  [PUBMED Abstract]
   
   
10. Anderson GL, Judd HL, Kaunitz AM, et al.: Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 290 (13): 1739-48, 2003.  [PUBMED Abstract]
    
    
11. Yang HP, Anderson WF, Rosenberg PS, et al.: Ovarian cancer incidence trends in relation to changing patterns of menopausal hormone therapy use in the United States. J Clin Oncol 31 (17): 2146-51, 2013.  [PUBMED Abstract]
    
    
12. Gertig DM, Hunter DJ, Cramer DW, et al.: Prospective study of talc use and ovarian cancer. J Natl Cancer Inst 92 (3): 249-52, 2000.  [PUBMED Abstract]
    
    
13. Terry KL, Karageorgi S, Shvetsov YB, et al.: Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls. Cancer Prev Res (Phila) 6 (8): 811-21, 2013.  [PUBMED Abstract]
    
    
14. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans: Carbon black, titanium dioxide, and talc. IARC Monogr Eval Carcinog Risks Hum 93: 1-413, 2010.  [PUBMED Abstract]
    
    
15. Calle EE, Rodriguez C, Walker-Thurmond K, et al.: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348 (17): 1625-38, 2003.  [PUBMED Abstract]
    
    
16. Schouten LJ, Goldbohm RA, van den Brandt PA: Height, weight, weight change, and ovarian cancer risk in the Netherlands cohort study on diet and cancer. Am J Epidemiol 157 (5): 424-33, 2003.  [PUBMED Abstract]
    
    
17. Engeland A, Tretli S, Bjørge T: Height, body mass index, and ovarian cancer: a follow-up of 1.1 million Norwegian women. J Natl Cancer Inst 95 (16): 1244-8, 2003.  [PUBMED Abstract]
    
    
18. Canchola AJ, Chang ET, Bernstein L, et al.: Body size and the risk of ovarian cancer by hormone therapy use in the California Teachers Study cohort. Cancer Causes Control 21 (12): 2241-8, 2010.  [PUBMED Abstract]
    
    
19. Collaborative Group on Epidemiological Studies of Ovarian Cancer, Beral V, Doll R, et al.: Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 371 (9609): 303-14, 2008.  [PUBMED Abstract]
    
    
20. Havrilesky LJ, Moorman PG, Lowery WJ, et al.: Oral contraceptive pills as primary prevention for ovarian cancer: a systematic review and meta-analysis. Obstet Gynecol 122 (1): 139-47, 2013.  [PUBMED Abstract]
    
    
21. Depot-medroxyprogesterone acetate (DMPA) and risk of epithelial ovarian cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Cancer 49 (2): 191-5, 1991.  [PUBMED Abstract]
    
    
22. Wilailak S, Vipupinyo C, Suraseranivong V, et al.: Depot medroxyprogesterone acetate and epithelial ovarian cancer: a multicentre case-control study. BJOG 119 (6): 672-7, 2012.  [PUBMED Abstract]
    
    
23. Cibula D, Widschwendter M, Májek O, et al.: Tubal ligation and the risk of ovarian cancer: review and meta-analysis. Hum Reprod Update 17 (1): 55-67, 2011 Jan-Feb.  [PUBMED Abstract]
    
    
24. Ness RB, Dodge RC, Edwards RP, et al.: Contraception methods, beyond oral contraceptives and tubal ligation, and risk of ovarian cancer. Ann Epidemiol 21 (3): 188-96, 2011.  [PUBMED Abstract]
    
    
25. Sieh W, Salvador S, McGuire V, et al.: Tubal ligation and risk of ovarian cancer subtypes: a pooled analysis of case-control studies. Int J Epidemiol 42 (2): 579-89, 2013.  [PUBMED Abstract]
    
    
26. Jamieson DJ, Hillis SD, Duerr A, et al.: Complications of interval laparoscopic tubal sterilization: findings from the United States Collaborative Review of Sterilization. Obstet Gynecol 96 (6): 997-1002, 2000.  [PUBMED Abstract]
    
    
27. Luan NN, Wu QJ, Gong TT, et al.: Breastfeeding and ovarian cancer risk: a meta-analysis of epidemiologic studies. Am J Clin Nutr 98 (4): 1020-31, 2013.  [PUBMED Abstract]
    
    
28. Rota M, Pasquali E, Scotti L, et al.: Alcohol drinking and epithelial ovarian cancer risk. a systematic review and meta-analysis. Gynecol Oncol 125 (3): 758-63, 2012.  [PUBMED Abstract]
    
    
29. Chandran U, Bandera EV, Williams-King MG, et al.: Healthy eating index and ovarian cancer risk. Cancer Causes Control 22 (4): 563-71, 2011.  [PUBMED Abstract]
    
    
30. Crane TE, Khulpateea BR, Alberts DS, et al.: Dietary intake and ovarian cancer risk: a systematic review. Cancer Epidemiol Biomarkers Prev 23 (2): 255-73, 2014.  [PUBMED Abstract]
    
    
31. Oppeneer SJ, Robien K: Tea consumption and epithelial ovarian cancer risk: a systematic review of observational studies. Nutr Cancer 63 (6): 817-26, 2011.  [PUBMED Abstract]
    
    
32. Lee AH, Su D, Pasalich M, et al.: Tea consumption reduces ovarian cancer risk. Cancer Epidemiol 37 (1): 54-9, 2013.  [PUBMED Abstract]
    
    
33. Zheng W, Danforth KN, Tworoger SS, et al.: Circulating 25-hydroxyvitamin D and risk of epithelial ovarian cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol 172 (1): 70-80, 2010.  [PUBMED Abstract]
    
    
34. Toriola AT, Surcel HM, Calypse A, et al.: Independent and joint effects of serum 25-hydroxyvitamin D and calcium on ovarian cancer risk: a prospective nested case-control study. Eur J Cancer 46 (15): 2799-805, 2010.  [PUBMED Abstract]
    
    
35. Ibiebele TI, Nagle CM, Bain CJ, et al.: Intake of omega-3 and omega-6 fatty acids and risk of ovarian cancer. Cancer Causes Control 23 (11): 1775-83, 2012.  [PUBMED Abstract]
    
    
36. Baandrup L, Faber MT, Christensen J, et al.: Nonsteroidal anti-inflammatory drugs and risk of ovarian cancer: systematic review and meta-analysis of observational studies. Acta Obstet Gynecol Scand 92 (3): 245-55, 2013.  [PUBMED Abstract]
    
    
37. Murphy MA, Trabert B, Yang HP, et al.: Non-steroidal anti-inflammatory drug use and ovarian cancer risk: findings from the NIH-AARP Diet and Health Study and systematic review. Cancer Causes Control 23 (11): 1839-52, 2012.  [PUBMED Abstract]
    
    
38. Lo-Ciganic WH, Zgibor JC, Bunker CH, et al.: Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, or acetaminophen and risk of ovarian cancer. Epidemiology 23 (2): 311-9, 2012.  [PUBMED Abstract]
    
    
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41. Rizzuto I, Behrens RF, Smith LA: Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility. Cochrane Database Syst Rev 8: CD008215, 2013.  [PUBMED Abstract]
    
    
42. Trabert B, Lamb EJ, Scoccia B, et al.: Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large United States infertility cohort. Fertil Steril 100 (6): 1660-6, 2013.  [PUBMED Abstract]
    
    

Changes to This Summary (06/20/2014)

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

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National Cancer Institute: PDQ® Ovarian Cancer Prevention. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/prevention/ovarian/HealthProfessional. Accessed <MM/DD/YYYY>.

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