Pathogenesis
Protective Factors
        Oral contraceptives
        Tubal sterilization
        Prophylactic oophorectomy
Nonhereditary Factors Associated with an Increased Risk of Ovarian Cancer
        Hormone replacement therapy/hormone therapy
        Infertility treatment
        Talc exposure
        Height, weight, and dietary factors

Pathogenesis

The pathogenesis of ovarian carcinoma remains unclear. Several theories have been proposed to explain the epidemiology of ovarian cancer including the theory of "incessant ovulation,"[1,2] gonadotropin stimulation,[3] excess androgenic stimulation,[4] and inflammation.[5] Associated risk factors for ovarian cancer support some or all of these hypotheses. For example, oral contraceptive use is consistently associated with a decreased risk of ovarian cancer and may operate through preventing the trauma from repeated ovulation as well as by lowering exposure to gonadotropins. No one theory, however, explains all the associated risk factors.

Factors associated with a decreased risk of ovarian cancer include: (1) using oral contraceptives, (2) having and breastfeeding children, (3) having a bilateral tubal ligation or hysterectomy, and (4) having a prophylactic oophorectomy.

Multiple studies have consistently demonstrated a decrease in ovarian cancer risk in women who take oral contraceptives.[6,7] The protective association increases with the duration of oral contraceptive use and persists up to 25 years after discontinuing oral contraceptives. A review of the literature demonstrated a 10% to 12% decrease in risk associated with use for 1 year and an approximate 50% decrease after 5 years of use. This reduced risk was present among both nulliparous and parous women.[6] A protective association between oral contraceptives and risk of ovarian cancer has been observed in most studies [8-10] among women who carry a mutation in BRCA1 and BRCA2 genes. A population-based study conducted in Israel did not observe an association between oral contraceptives and ovarian cancer, but parity was protective.[11]

In a prospective study, a 33% decrease in the risk of ovarian cancer among women who underwent tubal sterilization was observed after adjusting the data for oral contraceptive use, parity, and other ovarian cancer risk factors. This study also demonstrated a weaker, although statistically significant, decrease in risk associated with simple hysterectomy.[12]

Prophylactic oophorectomy is a potential option to reduce the risk of developing ovarian cancer for women at high risk. One group for whom this option is considered is women who have an inherited susceptibility to ovarian cancer such as women who have mutations in BRCA1, BRCA2, or hereditary nonpolyposis colon cancer (HNPCC)–associated genes. These women have a lifetime risk much higher than the general population, in the range of 20% to 60%. Evidence of the magnitude of risk reduction associated with bilateral oophorectomy comes primarily from studies of women with an inherited risk of cancer. A family-based study among women with BRCA1 or BRCA2 mutations found that of the 259 women who had undergone bilateral prophylactic oophorectomy, 2 (0.8%) developed subsequent papillary serous peritoneal carcinoma and 6 (2.8%) had stage I ovarian cancer at the time of surgery. Twenty-percent of the 292 matched controls who did not have prophylactic surgery developed ovarian cancer. Prophylactic surgery was associated with a greater than 90% reduction in the risk of ovarian cancer, (relative risk [RR] = 0.04; 95% confidence interval [CI], 0.01–0.16) with an average follow-up of 9 years;[13] however, family-based studies may be associated with biases due to case selection and other factors that may influence the estimate of benefit.[14] A study of 315 women with documented HNPCC–associated germline mutations found no ovarian cancer among 47 women who had bilateral salpingo-oophorectomy and 12 cases (5%) among women with mutations who had not had surgery for a prevented fraction of 100% (95% CI, 62%–100%). Prophylactic surgery, however, is not 100% effective. Case reports and case series have reported the occurrence of peritoneal carcinomatosis following oophorectomy.[15-17]

The degree of risk of ovarian cancer, potential morbidity and mortality of surgery, and the risks associated with early menopause, should be taken into account when considering prophylactic oophorectomy for high-risk women. Adverse effects of bilateral oophorectomy and premature menopause include infertility, vasomotor symptoms, decline in sexual interest and activity, cardiovascular disease, and osteoporosis. Among women who have not taken hormone therapy, women undergoing bilateral oophorecotmy were twice as likely to have moderate or severe hot flashes than women who underwent natural menopause (odds ratio [OR] = 2.44; 95% CI, 1.03–5.77).[18] Women at increased hereditary risk of ovarian cancer who underwent oophorectomy without hormone therapy reported statistically significantly more vasomotor symptoms than women choosing screening or those using hormone replacement therapy (HRT).[19] These women also reported lower sexual function scores but the difference was not statistically significant.[19] A meta-analysis of early menopause as a risk factor for cardiovascular disease observed a pooled risk of 4.55 (95% CI, 2.56–8.01) among women with bilateral oophorectomy and early menopause (defined as younger than 50 years).[20] Early menopause is also associated with an increased risk of fracture (OR = 1.5; 95% CI, 1.2–1.8).[21]

Postmenopausal use of HRT, also called hormone therapy (HT), is associated with an increased risk of developing ovarian cancer.[22-24] The risk may vary by use of estrogen replacement therapy (ERT), also called estrogen therapy (ET), or estrogen-progestin replacement therapy (EPRT). A cohort study of women who participated in the Breast Cancer Detection Demonstration Project showed an increased risk of ovarian cancer associated with use of ERT/ET and ERT/ET followed by EPRT. An RR of 3.2 (95% CI, 1.7–5.7) was associated with 20 or more years use of ERT/ET only, with a statistically significant trend of increasing risk with increasing duration of use. Although no risk of ovarian cancer associated with EPRT use alone was observed, the number of women in this subgroup was small and an associated risk cannot be ruled out.[23] A case-control study of ovarian cancer also did not find an association between combined estrogen and progestin, but use of estrogen-only therapy for more than 10 years was associated with an increased risk.[25] An association between postmenopausal estrogen use and ovarian cancer mortality also has been shown. Vital status of 211,581 postmenopausal women, all of whom completed a baseline questionnaire in 1982 documenting no history of cancer, hysterectomy, or ovarian surgery was assessed through December 31, 1996. Women who were using estrogen at baseline had a significantly higher risk of ovarian cancer death than women who never used estrogen (RR = 1.51; 95% CI, 1.16–1.96). The risk increased with longer duration of use; women using estrogen at baseline and those who had used estrogen for at least 10 years had a higher risk of ovarian cancer death than did women who had never used estrogen, respectively (RR = 2.20; 95% CI, 1.53–3.17).[26]

The largest double-blind randomized controlled trial of combined HRT/HT was the Women’s Health Initiative (N = 16,608). This study found that, after an average follow-up of 5.6 years, women taking combined HRT/HT (compared with women randomly assigned to placebo) had a nonstatistically significant increased risk of invasive ovarian cancer (hazard ratio [HR] = 1.58; 0.77–3.24), with a wide confidence interval.[27]

A collaborative analysis of case-control studies, analyzing data from 2,200 women with ovarian cancer and 8,900 control women from 12 U.S. studies, reported an association between fertility, drug use, and invasive ovarian cancer.[28] The use of fertility drugs was associated with an increased risk of ovarian cancer, primarily in women who did not have a subsequent pregnancy. Two case-control studies published subsequent to the collaborative analysis did not find an association between fertility drug use and risk of ovarian cancer.[29,30]

A retrospective cohort study of women evaluated for infertility observed an increased risk of invasive or borderline malignant ovarian tumors associated with prolonged use of clomiphene.[31] Another retrospective cohort of more than 12,000 women evaluated for infertility found an increased risk of ovarian cancer compared with the general population (standardized incidence ratio 1.98; 95% CI, 1.4–2.6). There was no excess risk with the use of clomiphene or gonadotropins. Although the risks of ovarian cancer were slightly higher among women with 15 or more years from first exposure, the number of exposed cases were small (five exposed cases and three exposed cases, respectively) and observed rate ratios were not statistically significant.

Several other cohort studies of women undergoing infertility treatment have not observed an excess risk of ovarian cancer.[32-34] In one study, women with unexplained infertility who were not exposed to fertility drugs had an excess risk of ovarian and uterine cancers.[34]

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).[35] 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.

Obesity is associated with an increased mortality from ovarian cancer.[36] In cohort studies, height and body mass index (BMI),[37,38] including high BMI during adolescence,[38] were associated with an increased risk of ovarian cancer, suggesting a role for diet and nutrition during the adolescent period.

Associations with specific dietary factors and ovarian cancer are not consistent among observational studies.[39-47]

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