Incessant ovulation has been proposed as one of the primary causes of epithelial ovarian cancer. The ovarian epithelial cells proliferate after ovulation, which may propagate mutations or promote carcinogenesis.8 Ovulation itself has been implicated in malignant transformation of the epithelium. Various epidemiologic studies have attempted to estimate women's total duration of ovulatory life based on reproductive and contraceptive histories. Purdie and associates9 considered the effects of age-specific ovulation on ovarian cancer risk and found the highest risk for ovulations in the 20- to 29-year age group (odds ratio [OR] = 1.20 for each ovulatory year in this age group). For age groups 30 to 39 and 40 to 49 years, the odds ratios were 1.06
and 1.04, respectively. Therefore, suppression of ovulation in the 20- to 29-year age group would provide maximal reduction in risk of developing ovarian cancer.
Nulliparity is a known risk factor for ovarian cancer. Women who have ever been pregnant have a 30% to 60% reduction in ovarian cancer risk compared with nullipa-rous women.10 Ovarian cancer risk is inversely related to parity (OR = 0.59 for four or more pregnancies compared with nulliparous women).11 No significant association between ovarian cancer risk and young age at menarche has been seen in recent studies. However late menopause may be associated with a trend toward higher risk for ovarian cancer risk.11,12
There is a strong protective association between oral contraceptives and ovarian cancer. The decline in incidence and mortality rates in ovarian cancer among younger women in the United States has been associated with increased oral contraceptive use. The overall estimated protection from cohort and case-control studies is approximately 40% in women who have ever used oral contraceptives and increases with duration of use to more than 50% for users of 5 years or longer. The favorable effect of oral contraceptives against ovarian cancer risk persists for at least 10 to 15 years after use has ceased, and it is not confined to any particular type of oral contraceptive formulation.13 The risks in ever-users is appreciably lower in women who reported their first oral contraceptive use before 25 years of age (relative risk [RR] = 0.3 for first use before age 25, 0.8 for first use at age 25 to 34, and 0.7 at 35 years or after).14 The Cancer and Steroid Hormone Study suggested that 10 years of oral contraceptive use by women with a family history of ovarian cancer appeared to reduce their risk to levels lower than those of women with no family history of ovarian cancer who never used oral contraceptives. Similarly, 5 years of oral contraceptives by nulliparous women was projected to reduce their risk to the levels seen for parous women who never use oral contraceptives.15 Lactation has been associated with a slight additional reduction in risk of ovarian cancer.16 Women who breastfeed only 1 to 2 months have a relative risk of ovarian cancer of 0.6 compared with that of women who never breastfed, with this effect being most prominent with the first exposure.17
Infertility alone is an independent risk factor for ovarian cancer. The possible link between fertility drugs and ovarian cancer remains controversial. Various studies have focused on the risk of ovarian cancer after use of fertility agents. A meta-analysis of eight case-control studies showed that neither longer duration of fertility drug use nor unsuccessful fertility drug use was independently associated with significant elevations in adjusted cancer risk. Women who did not achieve a pregnancy after prolonged use of infertility drugs had a higher risk of developing borderline serous tumors, but not invasive tumors.18 No association between fertility drugs, ovulation-inducing agents, and clomiphene citrate and ovarian cancer has been observed when comparing parous with nulliparous women.19
Few studies have examined the association of ovarian cancer after in vitro fertilization (IVF). During in vitro fertilization, multiple folliculogenesis is achieved by intensive ovulation induction. Both ovulation induction and ovarian puncture have been associated in the past with ovarian cancer.20 However, more recent studies show no excessive risk of ovarian cancer in patients after completion of IVF when compared with the general population.21,22
Data from earlier epidemiologic studies did not show a clear association between hormone replacement therapy and ovarian cancer.23 However, more recent studies suggest an association between long duration of use of unopposed estrogen and ovarian cancer.24-26 The Women's Health Initiative Randomized Trial provided additional support regarding the effects of estrogen and progesterone on risks of ovarian cancer. The hazard ratio (HR) for invasive ovarian cancer in women assigned to estrogen plus progestin compared with placebo was 1.58 (95% confidence interval [CI] =
0.77 to 3.24).27 The National Institutes of Health-AARP Diet and Health Study Cohort included 97,638 women age 50 to 71 years. Use of unopposed estrogen for fewer than 10 years was not associated with ovarian cancer. Compared with no hormone therapy, use of unopposed estrogen for 10 or more years was statistically significantly associated with ovarian cancer among all women (RR = 1.89, 95% CI = 1.22 to 2.95; P = .004; 56 versus 72 ovarian cancers per 100,000 person-years, respectively) and, though not statistically significant, among women with hysterectomy (N = 19,359, RR = 1.70, 95% CI = 0.87 to 3.31; P = .06). Compared with women with intact uteri who never used hormone therapy, women who used estrogen and progestin had a statistically significant increased risk of ovarian cancer. (RR = 1.50, 95% CI = 1.03 to 2.19; P = .04). Risks of ovarian cancer were higher for women taking sequential (RR = 1.94, 95% CI = 1.17 to 3.22; P =.01) than continuous (RR = 1.41, 95% CI = .90 to 2.22; P = .14) regimens28 (Table 1-3). Given the data, women who take hormone replacement therapy for more than 10 years should consider the potential increased risk for ovarian cancer when deciding to discontinue.
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