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1 - Moder n.. trend 5.. ~cl\ll,l'~\'l. E.Wtilltich,. M.. IJ).,AssQclt;l,teEd~tbl' FERTILITY AND Copyright 1996 American Society for Reproductive Medicine VoL 66, No, 4, October 1996 Printed on acid-free paper in U. S. A. Ovulation induction, infertility, and ovarian cancer risk Robert E. Bristow, M.D. Beth Y. Karlan, M.D. * Department of Obstetrics and Gynecology, University of California Los Angeles (UCLA) School of Medicine, and Cedars Sinai Medical Center, Los Angeles, California Objective: To review critically the published data regarding the proposed association of ovulation induction, infertility, and an increased risk of ovarian cancer. Design: A medline search was conducted to identify all case reports, epidemiologic studies, and clinical investigations containing data relevant to infertility, treatment of infertility, and the associated risk of ovarian cancer. Additional sources were obtained from reference lists of original research and review articles. Particular emphasis was placed on the most recently published reports examining these associations. Results: Four case-control studies and three retrospective cohort studies, as well as a large meta-analysis of three additional case-control studies were identified as presenting the most pertinent clinical data. Conclusion: Currently available data in the literature suggest that an association between ovulation induction and ovarian cancer does not indicate necessarily a causal effect. Infertility alone is an independent risk factor for the development of ovarian cancer. Nulliparous women with refractory infertility may harbor a particularly high risk of ovarian cancer, irrespective of their use of fertility drugs. Furthermore, the apparent association between fertility drug use and ovarian cancer may arise because these women are the most likely to have used ovulationstimulating agents as part of their infertility treatment. Close clinical surveillance of patients before, during, and after treatment of infertility is warranted. Fertil Steril 1996;66: Key Words: Infertility, ovulation induction, ovarian cancer Case reports of ovarian carcinoma and tumors of low malignant potential in women undergoing treatment of infertility have raised concern about the potential neoplastic effects of ovulation-inducing agents (1-12). Several recent case-control and cohort studies have attempted to examine this perceived association (13-20). However, analysis of a possible causal relationship between fertility medications and the risk of ovarian cancer often is confounded by the established effects of low parity and infertility on this risk. Low parity consistently has been found to be a positive risk factor for the develop- Received January 9, * Reprint requests: Beth Y. Karlan, M.D., Division of Gynecologic Oncology, Cedars Sinai Medical Center, 8700 Beverly Boulevard, No. 1740, Los Angeles, California (FAX: ). ment of ovarian cancer (21). In contrast, higher parity conveys a protective effect against malignant ovarian neoplasms. It has been theorized that the protection against ovarian cancer afforded by increasing parity is related to suppression of ovulation. Similarly, ovulation suppression also is thought to be the operative mechanism behind the negative association between ovarian cancer risk and oral contraceptive (OC) use (22). Conversely, infertility and "incessant ovulation" have been documented as risk factors for the development of ovarian cancer (23-27). As a result of this consistent association, it has been hypothesized that the hyperstimulatory effects of fertility medications on the ovary may be important etiologically in the genesis of some cases of ovarian cancer. The fundamental question is whether use of these medications independently increases a woman's risk of ovarian cancer over and Vol. 66, No.4, October 1996 Bristow et al. Infertility and ovarian cancer risk 499

2 above that predicated by infertility alone or infertility in conjunction with low parity. This review is a critical analysis of the data currently available in the literature, with particular emphasis on the most recent and pertinent developments. THEORETICAL CONSIDERATIONS In 1971, Fathalla (28) proposed that the etiology of ovarian cancer was related to "incessant ovulation." With each ovulation the ovarian surface (epithelium) was thought to incur minor trauma. The cumulative effect of repetitive surface injury was hypothesized to contribute to the development of ovarian neoplasms. Zajicak (29) postulated that epithelial inclusion cysts of the ovarian surface epithelium, which occur in association with ovulation, may be the source of such neoplasms. In 1979, Casagrande et al. (23) advocated a relationship between ovarian cancer risk and "ovulatory age." This is based on the theory that the number of ovulatory cycles between menarche and menopause is directly proportional to a woman's risk of ovarian cancer. Periods of anovulation due to pregnancy or OC use are considered "protected time" and are subtracted from the menarche to menopause time interval to yield a woman's "ovulatory age." As ovarian tissue is responsive to gonadotropins, a hypergonadotropic state also has been implicated as a contributing factor to the development of ovarian cancer (30, 31). Cramer and Welch (32) synthesized these theories to propose a model in which epithelial inclusion cysts are thought to be stimulated by elevated gonadotropins either directly or indirectly through their effect on steroidogenesis, to induce malignant transformation. If this hypothesis is true, then ovulation-stimulating agents, which promote multiple ovulations in a single cycle, theoretically could increase the risk of ovarian cancer. CASE REPORTS Because ovarian cancer is a relatively rare disease and ovarian cancer associated with fertility drug use even more rare, the methodology used to investigate this association is limited largely to case reports and retrospective case-control studies. The first case of invasive epithelial ovarian cancer associated with ovulation induction was described by Bamford and Steele (1) in Since that time 14 additional reports have been published describing an association between invasive epithelial ovarian cancer or ovarian tumors oflow malignant potential and infertility medications (2-12) (Table 1). Eleven additional cases of epithelial ovarian malignancies have been reported to the Food and Drug Administration (FDA) (33). The frequency of reported cases appears to be 500 Bristow et al. Infertility and ovarian cancer risk related temporally to an increasing awareness of the possible association between ovulation induction and ovarian cancer by the medical community. The most commonly used fertility medications did not gain widespread use until the late 1960s and early 1970s. Considering the probable lag time following any potential carcinogenic effect of these agents, it is noteworthy that the population of early infertility drug users is just now reaching the age of greatest ovarian cancer incidence (50 to 60 years). OVULATION INDUCTION AND RISK OF OVARIAN CANCER One of the earliest studies concerning treatment for infertility and carcinoma of the ovary was published by Ron et al. in 1987 (34). The study cohort consisted of 2,632 Israeli women treated for infertility between 1964 and The authors found no evidence of an association between ovulation-inducing drugs and cancer ofthe ovary among women with "hormonal" infertility. However, the wide variety of therapeutic regimens used did not allow these investigators to distinguish independent effects of specific medications. This was followed by a case-control study examining 229 cases of ovarian cancer from 1984 to 1986 in Shanghai, China (19). An equal number of population-based controls were selected for comparison. Among their findings, Shu et al. (19) reported that women who had used "hormones to help become pregnant" had an adjusted odds ratio for developing ovarian cancer of 2.1 (95% confidence interval [Cl] = 0.2 to 22.7). Concern about the risk of ovarian cancer and the use of fertility medications was heightened recently by a series ofthree publications by Whittemore et al. (13, 14) and Harris et al. (15), from the Collaborative Ovarian Cancer Group, which reported findings from a combined analysis of 12 United States casecontrol studies of ovarian cancer (13-15). These authors found that infertile women using fertility drugs had almost three times the risk (relative risk [RR] = 2.8, 95%CI = 1.3 to 6.1) for invasive epithelial ovarian cancer as women without a history of infertility; conversely, infertile women not using fertility drugs were found to have no increased risk (RR = 0.9, 95%CI = 0.66 to 1.3). Parity was protective in that infertile women who used fertility drugs and became pregnant did not have a significantly increased risk of ovarian cancer (RR = 1.4, 95%CI = 0.52 to 3.6). However, infertile women using fertility drugs and remaining nulliparous experienced a 27-fold increased risk of ovarian cancer (RR = 27.0, 95%CI = 2.3 to 315.6) compared with nulligravid controls. Critics of this report have cited selection bias, wide confidence intervals, lack of a uniform Fertility and Sterility

3 Table 1 Published Cases of Ovarian Cancer Associated With Ovulation Induction Patient FIGO* Author Year agey stage Histology Ovulation induction regimen Bamford and Steele (1) lia Endometrioid HMG 11 cycles Atlas and Menczer (2) IC Serous low malignant potential Clomiphene citrate "repeatedly" Ben-Hur et al. (3) IIIB Serous low malignant potential Clomiphene citrate "repeatedly" IIIC Serous Clomiphene citrate three cycles Carter and Joyce (4) IIIC Serous Clomiphene citrate + hmg (IVF three cycles) Kulkarni and McGarry (5) It Serous Clomiphene citrate three cycles, cyclofenil Dietl (6) IIIB Serous Clomiphene citrate "1 year", HMG one cycle Goldberg and Runowicz (7) IC Serous low malignant potential HMG (IVF two cycles) IA Serous low malignant potential HMG (IVF three cycles) IA Serous low malignant potential HMG two cycles Nijman et al. (8) IIIA Serous low malignant potential HMG (IVF two cycles) Lopes and Mensier (9) lib Serous low malignant potential Clomiphene citrate:j:, hmg (IVF five cycles) Balasch and Barri (10) lic Serous low malignant potential Clomiphene citrate six cycles Karlan et al. (11) IIIC Serous Clomiphene citrate five cycles Grimbizis et al. (12) IBt Serous low malignant potential Clomiphene citrate one cycle, hmg seven cycles (IVF one cycle) * FIGO, International Federation of Gynecology and Obstetrics. t Complete surgical staging not performed. :j: Duration of treatment not stated. etiology of infertility, and temporal incompatibility between treatment for infertility and licensing of modern fertility drugs in the subjects reported (35). Because of these limitations, the conclusion of a causal link between fertility medications and ovarian cancer cannot be drawn confidently from these data. Rossing et al. (16) recently published a large casecohort study containing important data pertaining to this issue. These investigators examined the risk of ovarian tumors in a cohort of 3,837 women evaluated for infertility in the Seattle area between 1974 and All subjects had attempted unsuccessfully conception for?: 1 year. The 11 cases of ovarian tumors identified consisted of 4 invasive epithelial carcinomas, 5 tumors of low malignant potential, and 2 granulosa-cell tumors. The expected incidence of ovarian tumors for the population at risk was 4.4. A "subcohort," 135 subjects randomly selected from the larger "infertile" cohort, was used for statistical comparison. The risk of ovarian tumors associated with exposure to fertility medications was assessed through age standardized comparison with rates of ovarian tumors in the general population. The RR of developing any ovarian tumor was 2.5 times higher among the cohort of infertile women compared with the general population in the Seattle area (95%CI = 1.3 to 4.5). Stratifying the tumors by subtype revealed that the risk of invasive epithelial ovarian cancer in the cohort of infertile women was "somewhat increased" over that in the general population, though not statistically significant (incidence ratio [SIR] = 1.5, 95%CI = 0.4 to 3.7). Analysis of tumors of low malignant potential showed a "substantially higher" risk among the infertile cohort compared Vol. 66, No.4, October 1996 with the general population (SIR = 3.3, 95%CI = 1.1 to 7.8). Nine of 11 women developing ovarian tumors had used clomiphene citrate (CC). When compared with the general population, infertile women using CC had a threefold increased risk of developing any ovarian neoplasm (SIR = 3.1, 95%CI = 1.4 to 5.9). However, when infertile CC users were compared with infertile non-cc users in the 135 subject subcohort, no statistically significant increased risk was found (RR = 2.3, 95%CI = 0.5 to 11.4). Comparisons within the cohort revealed that the use of CC for?: 12 ovulatory cycles was associated with an increased risk of developing an ovarian neoplasm. The association was evident both in women with ovulatory abnormalities and those without apparent abnormalities and in both gravid and nulligravid women. In contrast, no excess risk was associated with the use of CC for 1 to 11 ovulatory cycles or with the use of hcg for any length of time. This was a well-designed and executed study avoiding many of the limitations that have plagued previous investigations. Information was provided on the various types of infertility, the individual fertility medications used, and the number of induced ovulatory cycles for each patient. Recall bias was minimized by gathering this information before diagnosis of an ovarian tumor. Although no statistically significant increased risk could be demonstrated for the development of invasive ovarian cancer in infertile women, the finding of a significant increased risk for ovarian tumors of low malignant potential is in agreement with other investigators and resulted in an overall increased risk of any ovarian tumor in the infertile cohort compared with the general population (15, 36). Bristow et al. Infertility and ovarian cancer risk 501

4 The data provided on fertility medications, while suggestive of a causal effect of ovulation induction on the risk of ovarian cancer, demonstrate several inconsistencies. Infertile gravid women using CC for > 12 cycles had a RR = 17.0 (95%CI = 1.22 to 242.8) for developing an ovarian tumor, whereas infertile nulligravid CC users only had a RR = 10.8 (95%CI = 1.5 to 77.9). The greater relative risk in the gravid infertile population is curious given the known protective effect of parity. Additionally, an effect was seen only with prolonged use of CC and not with use for < 12 cycles. In fact, those infertile women using CC for 1 to 11 cycles had a RR = 0.8 (95%CI = 0.1 to 5.7). If this relationship was truly causal, one would expect a more consistent dose-dependent relationship. Additionally, the small number of ovarian tumors overall (n = 11), and particularly in those cases using CC for 2': 12 cycles (n = 5), limits the precision of the risk estimates for these groups. It is entirely possible that those subjects receiving 2': 12 cycles of CC may represent a subgroup of women with particularly refractory infertility and this alone may predispose them to a higher risk of ovarian neoplasms. The possibility of a relationship between infertility secondary to underlying ovarian pathology and ovarian cancer is suggested by Rossing et al.'s (16) data on infertility diagnosis. When the cohort of infertile women were stratified by subtype of infertility, subjects with ovarian ("ovulatory") abnormalities demonstrated the greatest risk of ovarian cancer. These ovarian abnormalities may have been the underlying cause of the increased risk of ovarian cancer observed in these patients. Shapiro (37) has suggested that precancerous ovarian conditions may have "caused" CC therapy rather than the reverse. The inclusion of granulosa-cell tumors in this database is an additional confounding factor. Epithelial ovarian carcinoma and granulosa-cell tumors should not be considered as a single outcome as they have different embryologic, pathologic, and epidemiologic features. When patients with granulosa-cell tumors were eliminated from Rossing et al.'s (38) analysis, the RR of ovarian cancer associated with CC use for> 12 cycles was reduced to 6.7, with a statistically insignificant CI (95%CI = 0.8 to 58.8). Del Priore et al. (39) have pointed out that the presence of surveillance bias and the absence of analysis of major confounding variables such as OC use and family history of breast and ovarian cancers may compromise further the validity ofthese results. The authors also suggest that ovarian tumors oflow malignant potential are precursor lesions to invasive neoplasms and that treatment for infertility results in diagnosis at an earlier stage of tumor development. The concept of borderline tumors being preinvasive epithelial carcinomas is as yet unproven. 502 Bristow et al. Infertility and ovarian cancer risk Preliminary results of an ongoing case-control study in Italy were published recently and did not suggest a role for ovulation stimulation in the etiology of ovarian cancer (17). One hundred ninety-five cases of ovarian cancer were examined and compared with 1,339 controls, identified by hospitalization diagnosis other than malignant or gynecologic conditions. Comparisons between diagnosis and type of infertility, number of months of unprotected intercourse before first pregnancy, and use of fertility drugs were made. These investigators found no increased risk of ovarian cancer associated with the use offertility drugs (odds ratio [OR] = 0.73, 95%CI = 0.16 to 3.30). However, only 2 of 195 cases and 15 of 1,339 controls ever had used fertility drugs. In fact, both cases using fertility drugs were treated before the early 1960s when CC use was rare. Although these preliminary results may seem encouraging, because of the small numbers of patients actually undergoing ovulation induction, this study has thus far failed to adequately assess the population most at risk. Additional clinical evidence for a possible link, though not necessarily causal, between gonadotropins and ovarian cancer was described in a case reported by Bandera et al. (40). These authors describe the case of a 31-year-old nulliparous patient diagnosed and treated for stage IC grade 1 mucinous cystadenocarcinoma of the ovary before beginning ovulation induction treatment for infertility. Shortly after follicular stimulation therapy, she experienced aggressive tumor recurrence. The temporal relationship noted suggests that follicular stimulation somehow aggravated or accelerated the progression of her disease. Although not providing evidence for a direct causal link between fertility drugs and ovarian cancer, this report does illustrate two important points. First, the apparent link between fertility drugs and ovarian cancer may not be a causal one, but rather one of hastening or stimulating tumor growth. Gonadotropins are thought to have a direct growthstimulating effect on ovarian epithelium (31). It also is possible that follicular hyperstimulation may drive an already existing epithelial ovarian neoplasm to become clinically apparent. This distinction between mitogenic and mutagenic effects is an important one. Evidence against this hypothesis, however, is provided by several studies that have shown epithelial ovarian carcinomas to be insensitive to gonadotropins (41, 42). Second, this case illustrates the theory that there may be a group of women with particularly refractory infertility who are predisposed to an unusually high risk of developing ovarian cancer irrespective of their use of fertility medications. Two case reports by Karlan et al. (11) reinforce Fertility and Sterility

5 these points. Both patients were of relatively young age (38 and 39 years), had a history of "incessant ovulation," and had rather limited exposure to fertility medications. Both patients presented with advanced stage epithelial ovarian cancer, one during infertility evaluation and the other early in the course of ovulation induction treatment. Because of their limited exposure to ovarian hyperstimulation, these patients may be more indicative of a small but particularly high-risk group of infertility patients prone to developing ovarian cancer rather than a causal effect offertility drugs. The association offertility drug use in this group of patients may be merely coincident to their pre-existing risk factor of refractory infertility. INFERTILITY AS AN INDEPENDENT RISK FACTOR FOR OVARIAN CANCER In multiple studies investigating the relationship between reproductive factors and ovarian cancer, infertility has been found to be an independent ovarian cancer risk factor, separate from the nulliparity effect (24-27, 36). One difficulty in ascribing an unconditional risk to infertility is that there are many possible causes for a patient's inability to conceive. In 1974, Joly et al. (24) concluded that "women who developed ovarian cancer had a gonadal status that predisposed to both the ovarian cancer and the low fertility." In 1984, Nasca et al. (25) found that "infertility plays an important role in determining the relationship between reduced parity and gravidity and increased ovarian cancer risk." In 1989, Booth et al. (26) found that women who had not conceived after > 10 years of unprotected intercourse had 6.5 times the risk (95%CI = 2.1 to 20.4) of developing ovarian cancer as nulligravid women reporting <3 months of unprotected intercourse. Additionally, in 1989, Whittemore et al. (27) found that the ovarian cancer risk to women having 2:10 years of unprotected intercourse was 1.8 times that of women reporting fewer years' worth. These investigators concluded that "some abnormality of ovulation that reduces the likelihood of conception plays a role in epithelial cancer." In a recent comprehensive review ofthe epidemiology of ovarian cancer, Shoham (43) reached a similar conclusion: that a common factor, probably gonadal in nature, is responsible for both ovarian carcinogenesis and decreased fertility, at least in a subset of patients. A large case-control study by Risch et al. (18) was designed to examine the relationship of infertility and reproductive factors to cancer of the ovary. These investigators reviewed 450 cases of primary, malignant, or borderline epithelial ovarian tumors and 564 age-matched controls in the Ontario, Can- Vol. 66, No.4, October 1996 ada area between 1989 and The number of ovarian tumors of low malignant potential (borderline) was not specified. A distinction was made between "voluntary and involuntary infertility" in an attempt to separate infertility risk from the nulliparity effect. True or involuntary infertility was measured as time without contraception during which pregnancy was attempted without success. Only two controls and no cases reported having used CC for treatment oftheir infertility, which effectively nullified the ability of this study to assess risk associated with follicular stimulation. In accordance with previous data, the authors found that, relative to nulliparae, parous women had a 61% lower risk of ovarian cancer overall, with a stepwise decrease in risk with each successive full-term pregnancy. The relatively lower parity amongst cases compared with controls largely was due to voluntary behavioral choices. Of 105 nulliparous cases, 87 were voluntarily nulliparous (i.e., only 18 had a history of involuntary nulliparity). The protective effect of parity was apparent among those women reporting a history of infertility. Among parous women, an interval of involuntary infertility was not associated with an increased risk of ovarian cancer. However, among involuntarily infertile and nulliparous women (n = 18), the risk of ovarian cancer was increased 50% over age-matched controls (n = 7), though due to small numbers this did not reach statistical significance (OR = 1.54, 95%CI = 0.59 to 4.06). The authors summarized that they were unable to confirm a significant role for infertility over and above that for low parity, but that there was a possible increase in risk for involuntarily infertile nulliparae. If involuntarily infertile women are considered to be a high-risk group, then the relative paucity of such women in this study may account for the failure of this risk assessment to achieve statistical significance. These data suggest that, among parous women, infertility may have little to do with their risk of ovarian cancer. However, women who do not remain nulliparous by choice may constitute a high-risk group in which infertility is a manifestation of some underlying factor predisposing them to both decreased fertility and ovarian cancer. Venn and co-workers (20) recently published results of a retrospective study examining the risk of ovarian cancer associated with infertility and IVF. The cohort consisted of 10,358 women referred for IVF in Victoria, Australia between 1978 and Women who had undergone one or more IVF treatment cycles with ovarian stimulation to induce multiple folliculogenesis, including those who had started but not completed a stimulated IVF cycle, comprised the "exposed" population (n = 5,564). The "unexposed" group (n = 4,794) consisted of women Bristow et al. Infertility and ovarian cancer risk 503

6 who had registered for IVF but had not received treatment (93.4%) or who had "natural cycle" treatment only, without ovarian stimulation. Data collection included information on patient age, date of registration into the IVF program, and number of stimulated cycles in the exposed group. Infertility was stratified by type to include male factor, tubal factor, endometriosis, ovarian disorders, unexplained, or others (such as cervical factors and uterine abnormalities). Record linkage with a population-based regional cancer registry was used to ascertain the number of ovarian cancer cases in the study cohort. The expected incidence of ovarian cancer was calculated from age-specific rates for the Victorian female population during 1982 to Median length of follow-up was somewhat shorter for the exposed group (5.2 years) than for the unexposed group (7.6 years). During this period, six cases of invasive epithelial ovarian cancer were identified within the entire cohort, and these were distributed evenly between the exposed and unexposed groups (three each). No cases of ovarian tumors oflow malignant potential were detected. Standardized incidence ratios (SIR) showed a modest but statistically insignificant increase for both the exposed group (SIR = 1.70, 95%CI = 0.55 to 5.27) and the unexposed group (SIR = 1.62, 95%CI = 0.52 to 5.02). Comparison between the exposed and unexposed groups revealed no significant increase in risk of ovarian cancer associated with follicular stimulation (RR = 1.45, 95%CI = 0.28 to 7.55). In addition, within the exposed group there was no evidence of a dose-dependent relationship between number of IVF cycles and ovarian cancer risk. When the entire cohort was stratified by type of infertility, a significant association was detected between a diagnosis of unexplained infertility (18.7% of subjects) and invasive epithelial ovarian cancer (RR = 19.19, 95%CI = 2.23 to 165). This effect was independent of IVF exposure status, in other words, patients with unexplained infertility had a markedly increased risk of developing ovarian cancer irrespective of their exposure to ovulation induction medications. This study provides important information in addressing the proposed association between ovulation induction treatment of infertility and ovarian cancer risk. Selection of subjects based on treatment with or referral for IVF allowed these investigators to examine a large at-risk population. Documentation of the number if IVF cycles received by subjects in the exposed group facilitated assessment of any dosedependent association, if present, between ovulation induction agents and ovarian cancer. However, this study also has significant limitations that must be taken into consideration when interpreting the results presented. Information on parity, gravidity, 504 Bristow et al. Infertility and ovarian cancer risk history of breast feeding, and OC use was not collected, any of which may have had an interaction with ovarian cancer risk depending on the relative distribution between exposed and unexposed groups. Statistically, this study required a RR of 5.05 for ovarian cancer associated with IVF treatment in order to be detected with 80% power at the 0.05 level of significance. The small overall number of cases somewhat limits the precision of the risk estimates as evidenced by the wide confidence interval around the relative risk of ovarian cancer for subjects with unexplained infertility. Additionally, the relatively short follow-up period may not reflect accurately the true latency period between a potential carcinogenic insult and the clinical detection of a neoplasm. Despite these limitations, these data do indicate that ovulation induction treatment in a population of infertility patients is not associated with an increased risk of ovarian cancer. Furthermore, the increased risk associated with unexplained infertility is concordant with the findings of Risch et al. (18). There appears to be select population of infertile women that carry a significant risk for the development of ovarian cancer, regardless of fertility drug use. TUMORS OF LOW MALIGNANT POTENTIAL Ovarian tumors of low malignant potential have epidemiologic risk factors similar to their more malignant counterparts, yet they are distinctly different with respect to biologic and clinical behavior. Approximately 80% of borderline tumors will present as stage I and II disease, in contrast to approximately 40% of invasive ovarian neoplasms (44, 45). Survival is also significantly better for tumors of low malignant potential: 7 year survival of 99% for stage I and 92% for stages II and III (44). Among white populations, tumors of low malignant potential comprise 4% to 14% of all ovarian malignancies (44). However, of the 15 published reports of ovarian carcinoma associated with fertility drug use, 9 have been of borderline histology. Inclusion of the cases reported to the FDA reveals that tumors of low malignant potential represent 42% (11/26) of malignant ovarian neoplasms associated with infertility treatment and ovulation induction. It is possible, but unlikely that some carcinogenic effect of fertility medications leads to the preferential development of low malignant potential tumors rather than more invasive lesions. A more plausible explanation is suggested by the finding that the mean age of diagnosis for borderline tumors is 40 years (44). It also is important to recognize that infertility is a risk factor for both invasive and low malignant potential tumors and that no patient in the published reports of ovarian cancer in association with Fertility and Sterility

7 fertility drug use was older than 39 years (Table 1). Considering these facts, it is not surprising that tumors oflow malignant potential would contribute a higher background frequency of cases than the 4% to 14% in a more typical population of ovarian cancer patients. Despite the significant number of patients treated for infertility and subsequently developing borderline ovarian tumors, there are relatively little data examining this group of women in particular. This probably is due to problems inherent in diagnosing and reporting these tumors as well as confusion over various histologic classification schemes. Harlow et al. (36) retrospectively reviewed 116 cases of serous and mucinous borderline ovarian tumors between 1980 and 1985 and compared them with 158 randomly selected controls. The authors found that patients with borderline tumors displayed similar epidemiologic patterns with regard to reproductive events as more invasive ovarian tumors. Specifically, increasing parity and OC use were associated with a lower risk of developing a low malignant potential tumor. In contrast, in nulliparous women, a history of infertility was associated with an increased risk, though this did not reach statistical significance (RR = 6.0, 95%CI = 0.6 to 57.1). No association between infertility and borderline tumors was detected for parous women. Use of fertility medications was not analyzed in this study. In 1992, Harris and co-workers (15) from the Collaborative Ovarian Cancer Group examined epithelial ovarian tumors of low malignant potential and their relationship to infertility as part of a larger meta-analysis of ovarian cancer. Data from nine case-control studies conducted between 1974 and 1986 were combined to yield a total of 327 cases of borderline tumors and 4,144 controls. Increasing parity, breast feeding, and OC use were found to be protective against the development oflow malignant potential tumors. Women with a history of infertility were at increased risk (OR = 1.9, 95%CI = 1.3 to 2.7), with nulliparous infertile women having a higher risk than their parous counterparts. Although use of fertility medications was associated with a fourfold risk elevation (RR = 4.0, 95%CI = 1.1 to 13.9), this analysis was based on only 13 patients from the three case-control studies that provided such information. It is noteworthy that this risk analysis examined infertile women using fertility drugs versus a comparison population of women with no history of infertility. In a recent review, Kaufman et al. (33) recalculated the crude OR for this association using infertile women as the reference group. Analysis of the data in this fashion rendered the original finding statistically insignificant. Thus, the available data suggest that infertile Vol. 66, No.4, October 1996 women who remain nulliparous carry a risk for ovarian tumors oflow malignant potential similar to that of invasive carcinoma. However, a causal association between use of fertility medications and this increased risk has not been demonstrated conclusively. FUTURE DIRECTIONS The National Institute of Child Health and Human Development currently is funding a project that will enable Rossing and co-workers to enlarge their cohort from 3,837 women to at least 12,000 and expand the surveillance period through 1993 (46). In addition to ovarian cancer risk, the investigators will examine other potential hazardous effects of follicular hyperstimulation, including breast cancer risk and possible teratogenic effects on the offspring of women undergoing such treatment. Sponsorship for extended follow-up of the cohort of Israeli women originally reported by Ron et al. (34) has been provided by the National Cancer Institute. This will permit an additional 10 years of observation to ascertain cases that may have escaped earlier detection because of a significant latency period between exposure and clinical appearance. A second project funded by the National Cancer Institute will examine retrospectively fertility drug exposure in a cohort of 10,000 women evaluated and treated for infertility between 1965 and 1984 (47). Several different geographic regions of the United States will be investigated with a maximum follow-up period of 30 years. These projects should provide valuable information regarding the long-term effects of pharmacologic treatment for infertility. CONCLUSIONS The etiology of ovarian cancer is probably multifactorial with genetic, environmental, and endocrinologic factors directly or indirectly related to carcinogenesis (48). The recent observation that infertile women who use fertility drugs might experience an increased risk for the development of ovarian cancer has been difficult to assess because of the relatively low incidence of ovarian cancer and multiple confounding factors. If an association is proven to exist, it must be put into appropriate perspective. Whittemore (49) stated in a recent editorial that use of fertility medications would amount to an overall lifetime risk of a woman developing ovarian cancer of 4% to 5%, which can be contrasted with the 12% lifetime risk of breast cancer for the average U.s. woman. Currently available data in the literature suggest that an association between ovulation induction and ovarian cancer do not necessarily indicate Bristow et al. Infertility and ovarian cancer risk 505

8 a causal effect. Small numbers of cases, variable treatment regimens, and duration oftreatment have precluded attempts to implicate specific agents with any certainty. Further controversy comes from the lack of a consistent dose-dependent relationship between the number of stimulated cycles and risk of ovarian cancer. Similarly, the latency period between exposure and detection of a neoplasm has been highly variable, which raises questions about the biologic plausibility of a cause and effect relationship. An alternative explanation is that infertility and ovarian cancer may be related indirectly because both are associated with a common, as yet undiscovered, third factor. The data do suggest that women with particularly refractory infertility may constitute a high risk population for developing ovarian cancer. 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