Human Reproduction, Vol. 16, No. 7, 1372-1375,
July 2001
© 2001 European Society of Human Reproduction and Embryology
Use of fertility drugs and risk of ovarian cancer
1 Istituto di Ricerche Farmacologiche `Mario Negri', Milano, Italy, 2 Prima Clinica Ostetrico Ginecologica, Università degli Studi di Milano, Milano, Italy, 3 International Agency for Research on Cancer, Lyon, France, 4 Centro di Riferimento Oncologico, Aviano (PN), 5 Istituto Tumori `Fondazione Pascale', Napoli and 6 Istituto di Statistica Medica e Biometria, Università di Milano, Milano, Italy
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Abstract |
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BACKGROUND: The potential association between fertility drugs and risk of ovarian cancer has been analysed using data from a case–control study conducted between January 1992 and September 1999 in four Italian areas. METHODS: Cases were 1031 women (median age 56, range 18–79 years) with incident, histologically confirmed epithelial ovarian cancer. Controls were 2411 women (median age 57, range 17–79 years) residing in the same geographical areas and admitted to the same network of hospitals for cases for a wide spectrum of acute, non neoplastic, non hormone-related conditions. RESULTS: A total of 15 cases and 26 controls reported use of fertility drugs. The corresponding odds ratio (OR) was 1.3 (95% confidence interval 0.7–2.5). The OR was 1.2 for women reporting last use <25 years before interview and 1.3 for >25 years. CONCLUSIONS: Considering calendar year at use, the OR was non-significantly above unity for women reporting fertility drug use after 1970. The OR was 0.6 among nulliparous women and 1.9 among parous ones.
Key words: fertility drugs/gonadotrophins/ovarian cancer
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Introduction |
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Following the suggestion from a meta-analysis of five American case–control studies showing an increased risk of ovarian cancer among fertility drug users, particularly for nulligravidae, (Whittemore et al., 1992
) several studies have analysed the potential association between medical treatment for infertility and the risk of ovarian carcinoma (Ron et al., 1987; Shu et al., 1989; Rossing et al., 1994; Venn et al., 1995; Shushan et al., 1996; Mosgaard et al., 1997; Parazzini et al., 1997; Glud et al., 1998; Modan et al., 1998; Nugent et al., 1998; Potashnik et al., 1999; Venn et al., 1999; Klip et al., 2000). For invasive epithelial ovarian cancer, most studies gave relative risk around unity, but elevated risks were in some studies reported for selected groups of women (i.e. nulligravidae) or types of treatment (Nugent et al., 1998; Klip et al., 2000). Consequently, the issue is still open to debate. Further, an open question is whether the observed association between fertility drugs and ovarian cancer is due to the effect of the drug itself, which may vary by type of drug, or potential confounding by multiparity or by the underlying cause of infertility itself.
In general, however, a potential role for fertility drugs as risk factors for ovarian cancer is plausible, particularly in the light of the incessant ovulation hypothesis for ovarian carcinogenesis (La Vecchia et al., 1983).
In order to provide further data on the issue, the results of a large, multicentric case–control study conducted in Italy are presented. An interim analysis including 195 cases and controls has been published (Franceschi et al., 1994). The present analysis does not include information from a previous case–control study conducted in the 1980's, whose results have been published elsewhere (Parazzini et al., 1997).
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Materials and methods |
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The data were derived from a case–control study of ovarian cancer, conducted between January 1992 and September 1999 in four Italian areas: greater Milan, the provinces of Pordenone, Padua and Gorizia (North-eastern Italy); the province of Latina (Central Italy); and the urban area of Naples (southern Italy). The interviewers were centrally trained. Less than 4% of cases and controls approached refused the interview, and the response rates did not vary across hospitals and geographic areas.
Cases were 1031 women (median age 56, range 18–79 years) with incident, histologically confirmed ovarian cancer, admitted to the major teaching and general hospitals in the areas under surveillance. Borderline tumours were not included in the study.
Controls were 2411 women (median age 57, range 17–79 years) residing in the same geographical areas and admitted to the same network of hospitals of cases for a wide spectrum of acute, non-neoplastic conditions. Women were specifically excluded if admitted for hormonal and gynaecological diseases, and if they had bilateral oophorectomy. Among controls, 26% had traumatic conditions (mostly fractures and sprains), 28% non-traumatic orthopaedic disorders (mostly low back pain and disc disorders), 15% acute surgical conditions (mostly abdominal, such as acute appendicitis or strangulated hernia), and 31% miscellaneous other illnesses (such as eye, ear, nose, throat and dental disease).
Information was obtained on general characteristics and habits, gynaecological and obstetric data, infertility-related variables: history of infertility leading to medical consultation and/or treatment, parity, use of contraceptive methods and use of fertility drugs. All information was obtained through a structured interviewer-administered questionnaire. The women were asked: Did you ever use any drug for infertility? If yes, when did you start the treatment and how long did you use it? Information on the type of fertility drugs, duration of drug use and the cause of infertility was not available. Information obtained was checked with medical records, whenever required.
Odds ratios (OR), and the corresponding 95% confidence intervals (CI) of ovarian cancer, were computed using unconditional multiple logistic regression, fitted by the method of maximum likelihood (Breslow and Day, 1980). Included in the regression equations were age and terms significantly associated with the risk of ovarian cancer in the data-set: education, parity, family history of ovarian cancer and oral contraceptive use.
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Results |
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Table I
shows the distribution of cases and controls according to age and selected factors. Cases were more educated, nulliparous and reported more frequently a family history of ovarian cancer in first degree relatives and a history of difficulties in conception.
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Fertility drug use is considered in Table II
. A total of 15 cases and 26 controls reported using fertility drugs: the corresponding OR was 1.3 (95% CI 0.7–2.5). The OR was 1.2 for women reporting last use <25 years before interview, and 1.3 for those reporting last use >25 years. The OR of ovarian cancer was above unity for women reporting the last fertility drug use after 1970, but the finding was based on only nine cases, and not statistically significant. The OR was 0.6 among nulliparous women and 1.9 among parous ones.
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Discussion |
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The results of this study, while providing further reassuring evidence on the relation between fertility treatment and ovarian cancer risk, cannot exclude a moderate association between fertility drugs and ovarian cancer risk, particularly among parous women.
Among potential limitations of this study is the relatively low statistical power, despite a uniquely large dataset. This is because frequency of fertility drug use was low, reflecting the pattern of use among Italian women in the past, as most of the cases with a history of infertility (see Materials and methods) were reported as arising before efficacious infertility treatments became available. In general, the frequency of use of fertility drugs in the period 1970–1990 was lower than in other European countries, thus reducing the statistical power of the results. One specific interest of this analysis is to analyse the association between ovarian cancer and fertility drugs use with a population with a low frequency of fertility drug use.
The choice of hospital controls has potential weaknesses. However, all diagnoses potentially related to hormonal factors, fertility problems and any known or likely risk factor for ovarian cancer were excluded from the control group. More importantly, hospital controls are preferable to population ones for any aspect concerning recall of drug use or medical treatments, since they are more comparable with the studied cases for recalling their medical history (Kelly et al., 1990; van Leeuwen et al., 1992; Nischan et al., 1993). Furthermore, the same catchment areas, the identical interview setting for cases and controls, and the almost complete participation are reassuring, particularly with regard to possible selection bias and recall of infertility treatments. Infertility has been associated with the risk of ovarian cancer. However, the OR did not markedly change when the analysis was stratified by or adjusted for difficulties in conception, as well as for other major identified potential confounding factors.
There is still debate on the effects of fertility treatments on the risk of invasive epithelial ovarian cancer. In particular large uncertainties are still present on the role of various drugs since limited information is available on potential different effects of various drugs. No information about type of drugs or duration of use was available in a combined analysis of three American case–control studies (Whittemore et al., 1992). In an American cohort of infertile women, the risk of ovarian cancer was higher among women using clomiphene citrate (CC) for 12 cycles or more, but not among those who had used human chorionic gonadotrophin (HCG) (Rossing et al., 1994). An increased risk for CC use emerged also in two cohort studies conducted in Israel (Modan et al., 1998; Potashnik et al., 1999). However, no excess risk was evident among CC users in a large case–control study from Denmark (Mosgaard et al., 1997) and in another Israelian study (Shu et al., 1989). With regard to HCG use, an increased risk of borderline significance was observed in a case–control study from Israel (Shushan et al., 1996), but not in other studies (Ron et al., 1987; Rossing et al., 1994; Mosgaard et al., 1997; Venn et al., 1999).
In the current study, no information was available on the type of drugs used. In order to understand the potentially different effects of various drugs, the data were analysed separately according to calendar year of use. The OR was below unity before 1970, but above unity after 1970, when CC was introduced into clinical practice in Italy, suggesting that the increased risk of ovarian cancer associated with fertility treatment, if any, should be observed only in women using recent, more powerful drugs.
Finally, an apparently stronger association, although not significant, was found between fertility drug use and ovarian cancer risk in parous women, but caution is required for any inference on subgroups, in the absence of consistent findings in the overall dataset as well as across various studies. In fact most previous studies found a stronger association between fertility drug use and ovarian cancer risk in nulliparous women. It is difficult to explain these differences, but chance and potential selective mechanisms or a different effect of fertility drugs on ovarian carcinogenesis in responders (i.e. parous women) or non responders can be suggested.
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Acknowledgements |
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This work was conducted with the contribution of the Italian Association for Cancer Research, Milan. The authors thank Mrs Ivana Garimoldi for editorial assistance.
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Notes |
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7 To whom correspondence should be addressed at: Istituto di Ricerche Farmacologiche `Mario Negri',Via Eritrea, 62–20157 Milano, Italy. E-mail: parazzini{at}irfmn.mnegri.it
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Submitted on July 27, 2000; accepted on March 9, 2001.
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