The epidemiology of epithelial ovarian cancer: a review

REVIEW

The epidemiology of epithelial ovarian cancer:a reviewEMILY BANKS, VALERIE BERAL & GILLIAN REEVESImperial Cancer Research Fund-Cancer Epidemiology Unit, Radcliffe Infirmary, Oxford, England, United Kingdom

Abstract. Banks E, Beral V, Reeves G. The epidemiology of epithelialovarian cancer: a review. Int J Gynecol Cancer 1997; 7: 425–438.

This paper presents a review of the scientific literature investigating theepidemiology of epithelial ovarian cancer. Epithelial ovarian cancer is animportant cause of cancer death among women in industrialized coun-tries, and incidence increases with age. It is more common amongwomen of low parity and among those with a family history of thedisease. Oral contraceptive use, hysterectomy, oophorectomy, and ster-ilization have all been shown to protect against epithelial ovarian cancer,while the role of other reproductive and environmental factors, such asinfertility, fertility drugs and hormone replacement therapy, is less clear.The evidence to date is discussed in this review.

Introduction

Ovarian cancer is the most common fatal cancer of thefemale reproductive tract in the western world and isa leading cause of cancer death in North Americanand European women. The lifetime risk of ovariancancer for women in industrialized countries is about2%(1). Although prognosis is strongly related to stageat diagnosis, ovarian cancer tends to present at anadvanced stage, resulting in poor survival overall(2).

The last twenty years have seen increasing researchattention given to the epidemiology of ovarian cancer.Numerous studies have examined ovarian cancer riskfactors, and attempting to reconcile conflicting or in-consistent results has proven difficult. Valuable in-sights into patterns of ovarian cancer occurrence havebeen gained by examining the pooled results of anumber of studies. This has the advantage of provid-ing a cohesive overview, as well as increasing thenumber of women involved, giving greater statisticalreliability.

A large amount of data on epithelial ovarian cancerepidemiology is contained within two pooled analyses

from the United States (US)(3) and Europe(4). The UScollaborative analysis was published in 1992 and com-bined the results of 12 US case-control studies, yield-ing 3,000 cases and 10,000 controls(3). The Europeananalysis combined three case-control studies fromItaly, the United Kingdom (UK), and Greece, involv-ing 1,140 cases and 2,724 controls in total(4). In addi-tion to the studies contained in these overviews, therehave been three large studies of epithelial ovarian can-cer conducted recently in Australia(5), Canada(6), andby the World Health Organization (WHO)(7). This re-view bases much of its discussion and conclusions re-garding reproductive risk factors on these pooledanalyses and recent articles, as they represent the bulkof the epidemiological research done in this area todate. Where appropriate other articles will be cited.

Broadly speaking, ovarian cancer incidence in-creases with age and is more common in women witha family history of the disease. Risk decreases withincreasing parity, oral contraceptive use, hysterec-tomy, and sterilization by tubal ligation. For other fac-tors, such as the use of fertility drugs, the evidence isstill uncertain (Table 1). This paper summarizes theepidemiology of epithelial ovarian cancer. After abrief revision of the pathology of the disease, interna-tional and national variations in ovarian cancer rates

Address for correspondence: Dr. E. Banks, Imperial Cancer Re-search Fund Cancer Epidemiology Unit, Gibson Building, RadcliffeInfirmary, Oxford OX2 6HE, England, UK.

Int J Gynecol Cancer 1997, 7, 425–438

© 1997 IGCS

will be discussed, followed by a description of trendsin the disease over time. Personal characteristics ofwomen contracting ovarian cancer will then be re-viewed in terms of demographic, physical, reproduc-tive, and environmental factors. Particular attentionwill be given to discussion of ovarian cancer risk inrelation to infertility, fertility drug use, and post-menopausal hormone replacement therapy as areas ofcurrent interest and controversy.

Pathology

The large number of histological subtypes and the lackof a universal system of classification represent prob-lems in the investigation of the etiology of ovariancancer(8). This, combined with the relative rarity ofeach specific type, means that epidemiological studiestend to present data in terms of broad tumor groups,with the most common division being into epithelialand non-epithelial tumors.

Non-epithelial tumors are divided into germ celland sex cord stromal tumors. They are relatively rare,tend to affect younger women, and although little isknown about their risk factor profiles, they are gener-ally considered as epidemiologically distinct from ep-ithelial tumors.

The epithelial tumors include serous, mucinous, en-dometrioid, clear cell, Brenner, mixed, and undiffer-entiated subtypes. ‘‘Boarderline’’ epithelial tumors aredistinguished by an absence of ovarian stromal inva-sion and are considered to represent an earlier or less

malignant form of epithelial tumor(9). They appear tohave similar epidemiological characteristics to franklymalignant ovarian tumors but have a better progno-sis(10). Whether these tumors would inevitably pro-gress to overt ovarian cancer is not firmly established.

While most investigations refer to epithelial ovariancancer specifically, national incidence and registrydata tend to pool all types, irrespective of histology.Since epithelial ovarian cancer is much more commonthan other types, representing 80 to 90% of tumors(11),it tends to dominate these data. This review will dis-cuss the epidemiology of epithelial ovarian cancer, ex-cept in the section relating to national and interna-tional trends, where all types of ovarian cancer will beconsidered.

International and national variations

Figure 1 presents the age-adjusted annual incidencerates of ovarian cancer from a broad geographicalrange of cancer registries and shows the considerableinternational variation in ovarian cancer incidence(1).Generally speaking, ovarian cancer is more commonin industrialized countries where women tend to havefewer children, particularly in Europe and the US. InAsia and Africa incidence and mortality rates are up toten times lower than in Euorpe and North America,although variations in diagnosis and registrationshould be borne in mind. Notable exceptions to thisare the relatively low (but increasing) rates seen inJapan, Italy, and Spain(11).

Rates of ovarian cancer vary among different ethnicgroups within a particular country. For instance, Jew-ish women is Israel have an ovarian cancer rate eighttimes that of their non-Jewish counterparts, and inNew Zealand the ovarian cancer rate among Maoris isapproximately half that of non-Maoris. In Los Angelescounty in the United States, women belonging to Japa-nese, Chinese, Hispanic, and Black ethnic groups haveincidence rates of 13.5, 9.0, 8.2 and 8.9 per 100,000women, respectively, compared to the rate of 20.4 per100,000 among white women(1).

A more detailed analysis of racial variation in ovar-ian cancer in the US shows that the main discrepanciesare in rates of epithelial ovarian cancer, and that non-epithelial ovarian cancer rates tend to be similar be-tween different ethnic groups(12). Migration studieshave shown that ovarian cancer rates tend to approachthose of the country of adoption rather than the coun-try of origin(13–15), suggesting variations within coun-tries are unlikely to be fully explained by racial orgenetic differences.

Table 1. Risk factors for ovarian cancer

Established protective factorsIncreasing parityOral contraceptive useHysterectomySterilizationOophorectomy

Established risk conferring factorsIncreasing ageFamily historyBRCA1 and BRCA2

Equivocal factorsAge at menarche/menopauseAge at birth of first childHormone replacement therapyInfertilityFertility drug useBreast feedingSocio-economic statusWeightDietTalcSmokingChildhood virusesIonizing radiation

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© 1997 IGCS, International Journal of Gynecological Cancer 7, 425–438

Time trends

Until recently ovarian cancer incidence in industrial-ized countries has been increasing(11). This has stabi-lized and in some more affluent countries ovarian can-cer risk is currently on the decline (Finland, Denmark,New Zealand, US). This trend is seen particularly incountries with high rates of oral contraceptive use(11).Rates in Hungary and Spain appear to be on the in-crease. Asia and Oceania show generally increasingrates of ovarian cancer (Japan, Hong Kong, Singapore)apart from Australia and New Zealand, where theyare decreasing(11). There is evidence of a cohort effect(see below) in the latter two nations.

In their analysis of ovarian cancer incidence andmortality rates in England and Wales, Dos SantosSilva and Swerdlow(16) noted increases in ovarian can-cer over the years 1962–1987, amounting to 0.76% perannum, with incidence trends differing by age. Olderwomen (45 years and over) experienced a marked in-crease in ovarian cancer while younger women (44years and under) showed a small decrease in rates.This decline is now reaching older women.

Different birth cohorts of women in Britain, Swedenand the US show varying rates of ovarian cancer. In-cidence rises among successive cohorts born during

the late nineteenth century, with peaks among thoseborn in 1906 (in Britian) and 1925–1929 (in Britain,Sweden and the US) and declining thereafter(16–18).Similar incidence patterns have also been observed inDenmark, although the peak in the earlier part of thiscentury was not apparent(19). These differing rateshave been attributed to changes in average family size,with those women of reproductive age during the1930s depression having a comparatively low averagefamily size and correspondingly high rates of ovariancancer and those giving birth later having a higheraverage family size and lower ovarian cancer rates. Incontrast, some cohorts born after the 1920s show de-clines in cancer of the ovary accompanying decreasingparity. Some authors have proposed that this phenom-enon relates to oral contraceptive use(11,16,17,20).

Personal characteristics

Age

Epithelial ovarian cancer is rare among young womenand increases exponentially with age(17). There is aplateau in incidence around age 50 to 55, with ratesincreasing more slowly in later life(8,19) (Fig. 2).

Fig. 1. Age-adjusted annual incidence of ovarian cancer at selected cancer registries.

The epidemiology of epithelial ovarian cancer 427


Socio-economic status

Studies in Britain and China have found an elevatedrisk of ovarian cancer among women of higher socio-economic status(21–23). This relationship is believed tobe the result of lower fertility rates among these moreeducated and affluent groups(18). However, few stud-ies have investigated the effect of social class whileaccounting for the effects of parity. In Canada, Rischand colleagues(6) found no difference in the educationlevel between cases and controls, while in Australiaresearchers found that higher education was associ-ated with a 31% reduction in ovarian cancer risk afteradjusting for parity(5).

Weight/body mass index

It is difficult to compare studies relating body massindex (BMI = weight/height2), weight, and ovariancancer, as different studies report measurements forvarying periods in a woman’s life. Some obtain infor-mation regarding ‘‘usual weight,’’ others ‘‘heaviestweight,’’ others specify weight at a particular age,while some do not specify a period and so presumablyrefer to current weight or BMI. Since the disease pro-cess affects weight, information regarding body sizeclose to diagnosis may not be representative of a wom-an’s lifetime body size.

While most authors report no association betweenweight or BMI and ovarian cancer(23–29), there aresome population based studies that show an increas-ing risk of ovarian cancer with increasing weight(30),‘‘obesity’’(31) or increasing BMI(5). In a collaborativeanalysis of US case-control studies, Whittemore et al.(3)

found that results varied by choice of control group, inthat high BMI was associated with an increased risk ofovarian cancer when population controls were used,whereas high BMI was associated with a reduced riskof ovarian cancer when hospital based controls wereused. The implications of this are unclear.

Genetic/familial factors

Familial clustering of ovarian cancer has been re-ported for over 100 years, with cases in these familiesnoted to have their onset at younger ages than cases inthe general population(32–35). Breast and ovarian can-cer have also been found to be associated with oneanother, both within families(36) and within individu-als(37). A review of observational studies reports thatwomen with a family history of ovarian cancer arethree to four times more likely to develop ovarian can-cer than those without such a history(38). Recent ad-vances in molecular biology have identified the onco-genes BRCA1 and BRCA2 which appear to beassociated with inherited breast and inherited ovariancancer(39–41). Although these findings are of scientificand etiological importance, familial ovarian cancer ac-counts for only a small proportion of those contractingthe disease, with the vast majority of cases occurringamong women with no family history of ovarian can-cer(39,42).

Genetic factors are also important in the etiology ofsporadic ovarian cancer, and although the specific ge-netic defects involved are less well-delineated, theyinclude growth factor, kinase and tumor supressorgene abnormalities(40). ABO blood group A has beenfound to be associated with ovarian cancer in a num-ber of studies(27,39,43,44). Ovarian cancers have beenknown to have altered expression of group A antigensand, since individuals of blood group A do not recog-nize group A antigens, they may be less likely to reactimmunologically to ovarian neoplasms(38).

Reproductive factors

Menarche and menopause

The exact nature of the relationship between menar-che, menopause, and ovarian cancer is by no meansclear. Most studies have found no significant effect ofage at menarche on ovarian cancer risk(5,6,10,22,28,45–48).The pooled analysis of US case control studies(3) re-ported a weak trend of decreasing ovarian cancer riskwith increasing age at menarche, and the AmericanCancer Society prospective study(49) shows a statisti-cally significant decrease in risk of fatal ovarian cancer

Fig. 2. Annual incidence of ovarian cancer by age in England andWales, 1983–1987.

428 E. Banks et al.


(all histological types combined) with menarche aftertwelve years old, compared to menarche at a youngerage.

The age-specific incidence curve for ovarian cancer(Fig. 2) suggests a lessening of the rate of increase inovarian cancer around the age of menopause, but thisfinding is not always apparent in observational stud-ies. The pooled European studies(45) report of dou-bling in the relative risk associated with an age atmenopause of 53 or greater compared with meno-pause at under 45 years old and note a significanttrend of increasing risk of ovarian cancer with laterage at menopause. However, the pooled US case con-trol studies found no trend in ovarian cancer risk withincreasing time since last menses(3). In their study ofover 800 ovarian cancer cases, Purdie et al.(5) found nosignificant effect of age at menopause on ovarian can-cer risk in Australia.

Parity and gravidity

Interest in this area started with the observation ofhigh rates of ovarian cancer among nuns(50) and lowrates among groups with generally high parity, in-cluding Mormons(51) and Seventh-Day Adventists(52).

The association of increasing parity with de-creasing ovarian cancer risk is now well-establish-ed(6,10,21,24,26,46,48,53–57) and applies to populations inNorth America(3,6), Europe(4,53), and Asia(22,23,27). Fur-thermore, national and international trends in ovariancancer tend to reflect fertility rates, in that those coun-tries and population subgroups with lower fertilityrates tend to have higher rates of ovarian cancer whencompared with higher fertility groups(18). In general,published results tend to show a 40% reduction inovarian cancer risk associated with the first term preg-nancy and overall trends consistent with a 10–15%average reduction in risk with each term pregnancy(3).Only one study has closely analyzed the temporal re-lationship between childbirth and ovarian cancerrisk(53). It was based on population cancer and fertilityregister information from Sweden and found that riskof ovarian cancer is reduced soon after childbirth andthis protective effect appears to diminish with time.

The data regarding incomplete pregnancies areless convincing. Some studies report significantdecreases in ovarian cancer with incomplete preg-nancy(4,28,47,56,58) while many have failed to find anyeffect(5,6,25,27,55). The 1991 pooled European analysis(4)

showed a significant 30% decrease in risk for thosewomen having had two or more abortions comparedto those women who had never had an abortion. Intheir collaborative analysis Whittemore et al.(3) found a

non-significant decreasing risk of ovarian cancer withincreasing numbers of ‘‘failed’’ pregnancies. On fur-ther analysis the researchers found similar rates ofovarian cancer protection per month of pregnancy, re-gardless of outcome, and attribute the lesser protec-tion of incomplete pregnancy to its shorter duration.

Debate continues as to whether the increase in ovar-ian cancer risk is a consequence of voluntary limita-tion of family size or subfertility, with evidence sug-gesting that both may play an important role. Earlierthis century in Britain, changing fertility patternstended to be the consequence of voluntary limitationof family size, with the proportion of childless womenremaining relatively constant(18). Changes in ovariancancer rates have followed these therefore voluntarychanges in fertility. In addition to this, subfertility it-self appears to affect risk, albeit mainly among nullip-arous women (this is discussed in detail below).

Age at first birth

To date, there are inconsistent findings as to how theage of a woman at the birth of her first child affectsovarian cancer risk. A study from Sweden(53) and apooled analysis from the United States(3) have dem-onstrated a significant trend of decreasing ovariancancer risk with increasing age at first birth. In thelatter this trend was present even after controlling fornumber of births and oral contraceptive use. How-ever, these findings are contradicted by those of thepooled European studies which found a significantlyincreased risk in those women having their first child atages greater than 35 years compared with those firstgiving birth at age 25 or younger(4). Indeed, the riskamong those with a first birth at ages over 35 years didnot differ significantly from the nulliparous women.Studies in Canada(6), the US(59), Australia(5) and Nor-way(46) report no significant association between ageat first birth and ovarian cancer in either direction.

Breast feeding

The evidence regarding the effect of breast feeding onovarian cancer risk is inconclusive, if anything sug-gesting some level of protection. In an analysis basedon six US case control studies, Whittemore et al.(3)

found a reduced risk of ovarian cancer in women whobreast fed compared to those who had not, after con-trolling for parity and oral contraceptive use. Thetrend for this was significant only in the populationbased studies and suggested a 1% reduction in risk foreach month of breast feeding. Studies outside the US(UK, China, Japan, Canada, WHO, Australia) do not



support these findings(5–7,21,22,27). Although some re-port non-significantly reduced relative risks, no sig-nificant trend with breast feeding was seen and twostudies found an increase in risk of ovarian cancerwith prolonged breast feeding(21,27).

Oral contraceptive use

Evidence has been steadily accumulating that the useof oral contraceptives results in a reduced risk of ovar-ian cancer. Studies over the last twenty years showconsistently lowered relative risks of ovarian cancerfor ever- versus never-use of oral contracep-tives(21,28,49,54,60–66). Collaborative analyses of both Eu-ropean and US case control studies estimate an ap-proximately 40% reduction in risk of ovarian cancerwith ever-use, and a 5–10% decrease in risk with eachyear of use(3,67). The protective effect appears to lastfor at least 10 to 20 years after cessation of use(3,60,64,67)

and applies to parous as well as nulliparous women.Based on sparse data, Rosenberg et al.(64) found thatpreparations containing 50 mg or more of estrogenconferred marginally greater protection than formula-tions containing lesser amounts. A 1989 multicenterstudy by the World Health Organization(7) suggeststhat protection against ovarian cancer with use of oralcontraceptives is also seen among women in less af-fluent countries, although possibly to a lesser extent.

The inverse relationship between oral contraceptiveuse and ovarian cancer incidence is borne out by com-parison of their respective temporal trends in Britain.Increases in oral contraceptive use over the past 30years have been paralleled by decreases in ovariancancer incidence(16).

Hormone replacement therapy

The relationship between hormone replacementtherapy (HRT) and ovarian cancer is controversial.The slowing of the increase in incidence rates of ovar-ian cancer after the menopause is consistent with ahormonal influence on the development of ovariancancer and means that post-menopausal exposure tohormones could plausibly increase ovarian cancerrisk. Of the 13 larger case-control studies (that is, thosebased on more than 20 cases) investigating ovariancancer and HRT, one found a significantly lower riskof ovarian cancer with ever-use of HRT(68), sevenfound risks close to unity(5,10,24,25,47,54,57), and fivefound non-significantly elevated risks(21,29,69–71). Notsurprisingly, a collaborative analysis of US case con-trol studies did not find any alteration in ovarian can-cer risk for women who had ever used HRT(3). How-

ever, a significantly decreased risk of ovarian canceramong current users of HRT was seen in the combinedanalysis of the population based case control studies.

The only prospective study in this area was pub-lished recently and has rekindled concerns over theeffects of HRT. In an analysis based on 436 fatal ovar-ian cancer cases (combining all histological subtypes)from a cohort of 240,073 women, the researchersfound a significantly raised relative risk of 1.71 withgreater than 11 years of HRT use prior to study entryand a relative risk of 1.72 for those who were currentusers with greater than or equal to six years of HRTuse at study entry(49). There was no significant differ-ence in ovarian cancer risk when HRT ever-users werecompared to never-users. These results were not af-fected by controlling for other risk factors.

Results of the association between ever-use of HRTand the risk of epithelial ovarian cancer from pub-lished studies with the necessary information are sum-marized in Figure 3. Studies included in the Whitte-more collaboration(3) are not shown individually. TheEuropean studies are shown separately as the collabo-rative analysis did not report on HRT use(4). AlthoughRodriguez et al. reported on fatal ovarian cancer andcombined all subtypes, their result is included forcomparison(49). The overall relative risk of 1.06 (95%confidence interval 0.96 to 1.17) represents a weightedaverage of the individual study relative risks andshows no significant elevation in risk. However, itwould be of interest to investigate further the effects ofHRT looking at different aspects of use, including thespecific effect of current use and that of combined es-trogen and progesterone preparations.

Fig. 3. Relative risk of epithelial ovarian cancer in ever-users ofHRT compared to never-users.

430 E. Banks et al.


An important concern with studies of ovarian can-cer and HRT is that the vast majority of them have notaccounted for the effect of hysterectomy in their analy-ses. Since hysterectomy appears to protect againstovarian cancer (see below) and is strongly associatedwith HRT use(72,73), not adjusting for hysterectomymay have compromised the studies’ ability to detectany increase in risk of ovarian cancer with HRT use.

Other hormonal preparations, such as diethylstil-boestrol and depotmedroxyprogesterone acetate, weresubject to initial concerns(23,74), but larger studies in-vestigating them have shown that they are unlikely tosignificantly affect ovarian cancer risk(69,75–77).

Infertility

Investigating the effects of infertility on ovarian can-cer, above and beyond the elevated risk conferred bylow parity and other factors, has proven problematic,and its role in the epidemiology of ovarian cancer re-mains unclear. Although infertility has long been con-sidered as a risk factor for ovarian cancer, a recentcollaborative analysis of 12 US case control studies(three with information on fertility drug treatment)suggests that risks within ‘‘infertile’’ subgroups areheterogeneous and vary according to factors such asfertility drug treatment and parity(3). Indeed, thisstudy found no significantly increased risk of ovariancancer once the drug treated subgroup has been ex-cluded (see ‘‘Fertility treatment’’ below) and alsofound the risk associated with infertility to be confinedto nulliparous women.

Earlier reports suggested elevated risks of ovariancancer in those with surrogate markers of infer-tility (ever-married nulligravid or nulliparouswomen) compared with never-married nulliparouswomen(56,78); however, more recent studies and col-laborative analyses have failed to confirm this associa-tion(3,4,46,61). Indirect numerical measures of fertilitystatus, such as years of contraceptive free intercourseor pregnancies per year of unprotected intercourse,show increased ovarian cancer with decreasing fertil-ity(3,22,26,56,79). In particular, a recent British studyshows a significant trend for increasing duration ofunprotected intercourse in nulliparous women(21),while a collaborative analysis of three US case controlstudies show a significantly raised relative risk of 1.6for greater than 15 years of unprotected intercourse(adjusted for parity, breast feeding and oral contracep-tive use)(3).

Studies questioning women directly about their dif-ficulty in conceiving have generally found increasedrelative risks of ovarian cancer(10,22,47,55,78), however,

few have achieved statistical significance(47,55). Manyhave not controlled for parity in their analyses(47,69,78)

and, in those studies that have, it appears to diminishthe effect of infertility on ovarian cancer risk(3,5,6).The 1992 U.S. collaborative study(3) found non-significantly elevated relative risks of ovarian cancerwith infertility defined by unsuccessful attempts toconceive, physician diagnosed infertility (not attribut-able to the male partner), and personal doubts aboutability to conceive, but only among nulliparouswomen. Similarly, a 1995 study(5) shows a nonsignif-icant 20% increase in risk for women having unsuc-cessfuly tried to become pregnant compared to thosewith no such difficulties, having controlled for parity,oral contraceptive use, and other reproductive factors.Risch et al.(6) found the risk of ovarian cancer to beunaffected by infertility, after controlling for parity.

Studies following women diagnosed with infertilityand comparing their rate of ovarian cancer with thatexpected in the general population have shown in-creased rates of cancer of the ovary among infertilewomen(80–82). However, these studies are unable toaccount for the fact that infertile women are generallyof low parity. A recently published Australian cohortstudy shows a significantly increased risk of ovariancancer among those women with unexplained infer-tility compared to those cohort members with infer-tility of known cause, regardless of treatment re-ceived(83).

Figure 4 presents a summary of the results frompublished studies with information regarding infertil-ity and ovarian cancer and shows the relative risk (and

Fig. 4. Relative risk of ovarian cancer according to history of infer-tility.



95% confidence interval) of ovarian cancer for womenwho are relatively ‘‘infertile’’ compared to womenwho are relatively ‘‘fertile.’’ Summary relative risksare shown separately for nulliparous women and par-ous women. Because the risks are derived only frompublished data, measures of infertility differ betweenstudies: for Booth et al.(21) and Chen et al.(22) ‘‘infertile’’is defined as self-reported difficulty becoming preg-nant; for Whittemore et al.(3) a total duration of unpro-tected intercourse of greater than or equal to two yearswas considered relatively ‘‘infertile,’’ compared with aduration of less than two years; for Risch et al.(6) aninfertile interval of greater than or equal to two yearswas considered relatively infertile compared withwomen with a shorter interval or women who hadnever reported an infertile interval; and for Franceschiet al.(79) a length of time of first pregnancy attempt ofgreater than or equal to two years was defined as ‘‘in-fertile’’ compared to a shorter interval. It was not pos-sible to adjust for confounding variables in all ofthe results as the appropriate statistics were not avail-able for all studies, nor was it possible to account fullyfor the effects of parity, beyond a crude division into‘‘gravidae/parous’’ and ‘‘nulligravidae/nulliparous.’’

From this figure it can be seen that no single studyreported a significantly elevated relative risk of ovar-ian cancer for ‘‘infertile’’ women. However, the sum-mary relative risk of 1.49 (95% confidence interval 0.97to 2.28) suggests that there may be an increased risk ofovarian cancer associated with infertility in nulli-gravid/nulliparous women.

Fertility treatment

The possible association between the use of fertilitydrugs and ovarian cancer represents a pressing issuein contemporary gynecology. All findings to datemust be regarded with extreme caution, as they arebased on very small numbers and it is difficult to sepa-rate out the effects of infertility from its treatment.Many women treated with ovulation induction agentsfor infertility are likely to have pre-existing ovulatorydysfunction and may be predisposed to ovarian can-cer for reasons other than the treatment they havereceived. They may also be more readily diagnosedwith ‘‘borderline’’ tumors due to increased medicalsurveillance. Attempts to address confounding andbias by subgroup analysis result in even smaller num-bers and statistically unstable results. There are simi-lar difficulties in investigating specific drug treat-ments.

A proposed influence of fertility drugs on ovariancancer was first raised in case reports(84–86). In their

1992 collaborative analysis of three case control stud-ies with information on infertility treatments, Whitte-more et al.(3) found an odds ratio for all women with ahistory of infertility treated with fertility drugs versusthose without a history of infertility of 2.8 (95% con-fidence interval 1.3–6.1). When attention was re-stricted to women treated with fertility drugs whonever became pregnant, the analysis reported an oddsratio of 27.0 (95% confidence interval 2.3–315.6) com-pared with nulligravid women with no history of in-fertility. Franceschi et al.(79) did not find any associa-tion between fertility drug use and ovarian cancer intheir Italian case-control study.

Rossing and co-workers(82) followed a cohort ofwomen treated for infertility and report 11 cases ofovarian cancer (4 invasive epithelial, 5 borderline and2 granulosa cell) after 18 years of follow-up. Althoughthese numbers are too small to reach any firm conclu-sions, and the relative risk of 2.3 in those womentreated with clomiphene citrate was non-significant,and significantly elevated risk was seen in women tak-ing the drug for more than a year (based on 5 cases).The inclusion of borderline and non-epithelial tumorsin the analysis means that the results of this studycannot be directly compared with others. A similarcohort study in Australia(83) reported six cases of in-vasive ovarian cancer among its subjects. The risk ofovarian cancer was not significantly raised amongthose treated with fertility drugs when compared withcohort members not receiving drug treatment (relativerisk 1.45) or with population expected rates (standard-ized incidence ratio 1.70), although this study also hadlow power. A case-control study in Israel(87) showedsome increase in risk of invasive ovarian cancer withfertility drug use, and human menopausal gonadotro-phin in particular, but findings were generally non-significant.

Figure 5 summarizes the results of the publishedstudies with data on fertility drug treatment and ovar-ian cancer, using the same format as Figures 3 and 4.Since infertility itself may influence the risk of ovariancancer, the studies are divided into those investigatingthe effect of fertility drugs among infertile womenonly and those investigating it among all women com-bined. The numbers of women involved in theseanalyses, particularly in comparisons among infertilewomen only, were extremely small. When womenwho had taken fertility drugs were compared withother infertile women who had not taken infertilitydrugs, the summary relative risk of ovarian cancerwas 1.26 (95% confidence interval 0.41–3.83), which isnot statistically significant. In studies where women

432 E. Banks et al.


who had taken fertility drugs were compared withwomen who had not taken these drugs (regardless offertility status) the summary relative risk was 1.69(95% confidence interval 1.02–2.13). This suggests thatpart of the effect of fertility drugs may be due to therelative infertility of the women taking them. Divisionof the data into nulliparous and parous women wasnot possible.

Oophorectomy, hysterectomy and sterilization

As expected, previous unilateral oophorectomy isassociated with a decrease in risk of ovarian can-cer(8,54,64,68). The majority of studies show a signifi-cant and substantial (30–40%) reduction in the riskof ovarian cancer with simple hysterectomy (withbilateral ovarian conservation) which is presentafter controlling for parity and oral contraceptiveuse(3,5,6,8,54,64,71,88–90). There is evidence to suggest thatthis protective effect is lasting(88), with no apparenttrend in risk with time since hysterectomy(3), althoughsome authors dispute this(91).

Tubal ligation has been noted to protect againstovarian cancer in a number of studies(5,21,27,64,88,92)

with reported reductions in risk ranging from 40%(64)

to 80%(21). Other studies show non-significant reduc-tions in risk(6,23), while some fail to find any effect atall(22,26,49,65). The pooled analysis of Whittemore et al.(3)

found relative risks of ovarian cancer with tubal liga-tion of 0.59 and 0.87 in hospital and population basedstudies, respectively, significant only in the hospitalbased studies.

A number of possible explanations for the protec-tive effect of simple hysterectomy are offered in the

literature. It has been suggested that this associationmay be the result of misclassification bias, wherewomen reporting hysterectomy only may have hadan accompanying oophorectomy of which there werenot aware(21). Hartge et al.(68) obtained confirmatoryoperative reports in 86% of controls reporting hyster-ectomy with ovarian preservation and in all cases re-porting the same procedure. They report a non-significant reduction in ovarian cancer risk of 30%.The Boston Nurses Heath Study(88) found completeconcordance between a sample of their (admittedlymedically minded) subjects’ reports of hysterectomyonly and medical records. Other researchers have hy-pothesized that hysterectomy and tubal ligation allowvisualization and removal of ovaries noted to have adiseased appearance at surgery(3). This argument is tosome extent countered by the finding of a sustainedbenefit of simple hysterectomy for many years follow-ing the operation. On an etiological level, hysterec-tomy and tubal ligation may both act by impairingovarian blood supply and inducing anovulation(90).Alternatively, they may prevent passage of carcino-gens from the vagina to the ovary, via the uterus(93).

Environmental factors

Diet

Dietary factors may explain aspects of risk variationbetween different ethnic groups and nations andchanges in ovarian cancer incidence with migration(8).While the nutritional epidemiology of ovarian canceris by no means resolved, it would appear that a highintake of saturated fat and a low intake of vegetablesand/or vegetable fiber are associated with an elevatedrisk of ovarian cancer(94–98). The effect of meat and fishconsumption is unclear. Earlier findings of associa-tions between milk and lactose intakes, galactose, andovarian cancer(99,100) have not been sustained(101–104).Evidence to date suggests that neither coffee nor alco-hol intake is consistently related to ovarian cancerrisk(27,55,95,98,105–108).

Smoking

The British doctors study found an increased rate ofovarian cancer among female smokers compared totheir non-smoking counterparts(109). After controllingfor parity and oral contraceptive use Purdie et al.(5)

report a significantly raised relative risk of 1.38 amongsmokers compared to non-smokers. Other studies inthis area show no association(21–23,26–28,108,110,111).

Fig. 5. Relative risk of ovarian cancer according to use of fertilitydrugs.



Talc

Investigation of the relationship between ovarian can-cer and talc was prompted by the chemical similarityof talc and asbestos (a known carcinogen), the findingthat particulate matter can migrate from the lower tothe upper genital tract(112), and the presence of talcparticles in both normal and cancerous ovaries(113).Many studies have shown significantly increasedovarian cancer risk with use of talc on the perineum orsanitary napkins(5,21,22,93,114,115). Others have notfound a significant association(108,116,117). Whether thisassociation is causal or of public health importance isnot clear(118) and has been the source of considerablecontroversy(119,120).

Viruses

Some of the earliest case-control studies showed thatwomen with ovarian cancer reported a past historyof mumps significantly less frequently than con-trols(28,121,122). This was considered of etiological im-portance because mumps virus is known to affect thegonads. Six further studies did not find any significantdifference between cases and controls with respect tomumps history(22,29,47,55,58,123), although one foundthat cases were significantly more likely to report ahistory of measles(29) and another found significantlymore cases than controls reported a history of ru-bella(47). Three groups investigated mumps antibodystatus as well as history; two found no difference intiter(121,123) while a Chinese study found significantlyhigher antibody titers among cases(22). Explanationsoffered for some of the above findings are: a higherrate of subclinical infection among cases(121); that ovar-ian cases are generally of lower parity and may comefrom smaller sibships than controls, resulting in re-duced exposure to childhood infections(8); that anti-body titers may be affected by immunomodulationsecondary to cancer; or, indeed, that these viral infec-tions are not related to ovarian cancer risk at all.

Ionizing radiation

While ionizing radiation is clearly linked with leuke-mia and other cancers, it is unlikely to play a substan-tial role in the epidemiology of ovarian cancer. Studiesinvestigating cancer risk in women with irradiationtreated menorrhagia or radiation induced menopausedid not find them to have elevated rates of ovariancancer, although rates of pelvic cancer in general wereincreased(124–126). Case control studies in this areahave not found any association between diagnostic or

therapeutic radiation exposure and ovarian can-cer(21,23,26,28,54).

Mechanism

Two main hypotheses about the mechanism of ovari-an cancer induction have arisen in response to experi-mental and epidemiological data. The most commonlycited was first proposed by Fathalla in 1971(127) and isusually termed the ‘‘incessant ovulation’’ hypothesis.It relates the risk of ovarian cancer to a woman’s life-time frequency of ovulation. Humans ovulate far morefrequently than other mammals and appear to have amuch higher incidence of epithelial ovarian malig-nancy. In addition, epithelial ovarian cancer can beinduced in chickens by artifical stimulation of egg pro-duction(127). Fathalla proposed that ovulation causestrauma to the ovarian epithelium and stimulation ofmitoses by exposure to estrogen rich follicular fluid,which could result in neoplastic transformation. Thishypothesis is in keeping with findings of high rates ofovarian cancer among nulliparous women, with fewinterruptions to ovulation, and predated the discoveryof the protection conferred by use of the oral contra-ceptive pill.

More recent studies have used age at menarche, ageat menopause, parity, breast feeding, and oral contra-ceptive use to estimate and evaluate the effect of totalduration of ovulation (or ‘‘ovulatory age’’) on ovariancancer incidence. While these studies have generallyfound that the longer a woman’s duration of ovula-tion, the more likely she is to develop ovarian can-cer(21,24,30,57), the degrees of protection conferred bythe relevant factors are not fully explained by the re-sultant duration of anovulation(128–130). Wu et al.(57)

report a 56% increase in ovarian cancer risk with eachadditional five years of ovulation (P < 0.001).

The second ‘‘gonadotrophin’’ hypothesis hasproved less popular and robust. It proposes that highlevels of circulating gonadotrophins enhance thetransformation of ovarian epithelial cells either di-rectly or by stimulation of estrogen production whichin turn enhances transformation(131). The protective ef-fects of pregnancy and the oral contraceptive pill areexplained by their effect on gonadotrophin secretionby the pituitary. Some authors argue that this hypoth-esis is not consistent with age specific patterns of ovar-ian cancer incidence and the fact that hormone re-placement therapy tends to decrease gonadotrophinlevels but does not appear to protect against ovariancancer(132). The only prospective study in this areafound ovarian cancer to be associated with lower se-rum gonadotrophin levels or higher androgen lev-

434 E. Banks et al.


els(133). Neither theory accounts for the apparentlyminimal effect of age at menarche and age at meno-pause(134).

Other postulated mechanisms of ovarian carcino-genesis include the direct effects of proposed environ-mental carcinogens (e.g. talc), gaining access to theovary via the lower genital tract(93), and a recentspeculation that pregnancy is capable of ‘‘clearing’’transformed cells from the ovary(53).

Conclusions

Over the past two decades enormous progress hasbeen made in the understanding of ovarian cancerand its epidemiology. Many of the more firmly estab-lished risk factors represent major life decisions or arenot amenable to modification, and prospects for pre-vention concerning these remain limited. In contrast,the effects of hormone replacement therapy, breastfeeding, and fertility drug treatment are not well-understood, and larger studies are needed to addressthe issues surrounding them. A pooled analysis of allavailable studies to date is likely to clarify some cur-rent points of contention.

Acknowledgments

The authors would like to thank Paul Appleby for hisstatistical and graphical assistance.

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Accepted for publication August 19, 1997

438 E. Banks et al.


The epidemiology of epithelial ovarian cancer: a review

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