Ovulation Induction Treatment and Risk of Borderline Ovarian Tumors

By Cusido, Maite Fabregas, Rafael; S, Pere Barris; Escayola, Cecilia; Barri, Pere Nolsac

Abstract Aim. Research has suggested an association between the use of ovulation induction drugs and the risk of ovarian cancer. It has also been proposed that there may be pre-cancerous alterations in the ovary which themselves are the cause of infertility. The aim of the present study was to evaluate the relationship between the use of ovulation induction drugs and the appearance of borderline ovarian tumors.

Material and methods. This was a case-control study in which the study group comprised 42 women with a borderline ovarian tumor and the control group comprised 257 women with benign ovarian pathology.

Results. No differences were found between the borderline tumor and control groups (14.3% vs. 27.2%, respectively) in terms of infertility history. Nor were there any differences between the groups with respect to the type of drug used, whether clomiphene citrate (9.5% vs. 6.2%, respectively) or gonadotropins (7.1% vs. 10.1%, respectively). Analysis in terms of the number of cycles administered also failed to reveal any differences. The mean number of cycles with clomiphene citrate/gonadotropins was 2.50 +- 1.00 and 3.00 +- 2.64 in the borderline tumor group and 2.44 +- 1.75 and 3.27 +- 2.25 in the control group.

Conclusions. Our series produced no evidence that ovulation induction treatment predisposes women to the development of borderline ovarian tumors.

Keywords: Borderline ovarian tumors, infertility, fertility drugs, ovarian cancer

Introduction

The increased use of ovulation induction drugs and their possible long-term effects, especially their potential to cause cancer, is an issue that has generated much scientific interest. Research has suggested an association between the use of ovulation induction drugs and the risk of ovarian cancer [I]. Two hypotheses have been proposed in this regard: the first is that repeated ovulations alter the ovarian epithelium and increase the risk of occurrence of a malign transformation [2]. If this theory is correct, ovulation induction agents that produce several ovulations in a single cycle could increase the risk of ovarian cancer [3]. The second hypothesis is that persistent ovarian stimulation with pituitary gonadotropins may increase the risk of cancer. Here the use of gonadotropins as ovulation induction agents to stimulate the endogenous production of gonadotropins would heighten the risk of ovarian cancer.

However, this association remains controversial. Research such as that carried out by the Collaborative Ovarian Cancer Group in 1992 showed a relationship between the use of ovulation induction drugs and an increased risk of ovarian cancer, regardless of whether tumors were borderline or infiltrating [4,5]. Other authors found a correlation between the use of clomiphene citrate and borderline ovarian tumors, although only when 12 or more cycles were administered [6]. In contrast, however, several case-control studies have failed to observe this relationship, and argue that the risk factor is not the induction treatment but infertility itself [7,8] . Furthermore, some of the studies in favor of an association, such as that of Whittemore and co-workers [4], have been questioned on the grounds that they report insufficient information about the use of ovulation induction drugs in the group of patients with ovarian cancer [9] . The study by Rossing and collaborators [6] has also been challenged, the argument being that there may be pre-cancerous alterations in the ovary that are themselves the cause of infertility. In addition, it has been suggested that these women were subjected to intense screening and that this produced a bias in the detection of borderline tumors; the small sample size was also criticized [10]. Given the above we aimed to study the relationship between the use of ovulation induction drugs and borderline ovarian tumors in our center. To this end we compared the infertility history and the administration of ovulation induction drugs in women with borderline ovarian tumors and those with benign ovarian pathology. Thus, all the patients in the study presented some form of ovarian pathology. In this way we avoided the bias that may be produced by ovarian alterations themselves and were able to evaluate the impact of ovulation induction drugs.

Material and methods

The research involved a case-control study; cases comprised 42 women with borderline ovarian tumors who were treated and followed up in the Institut Universitari Dexeus, the control group consisted of 257 patients who had undergone ovarian surgery (cystectomy or adnexectomy) due to benign ovarian pathology. Information was obtained from clinical records about the following: a family history of first-degree cancer, distinguishing between ovarian, breast and other cancers; gynecological/obstetric history (menarche, parity); history of hormonal contraceptive use; and, finally, infertility history and the use of ovulation induction drugs, distinguishing between the type of drug used – clomiphene citrate or gonadotropins – and the number of cycles. Data were also collected regarding the surgical intervention performed. It was noted whether, after treatment, the women received ovulation induction treatment or became pregnant.

Statistical analysis

Quantitative variables were compared using either parametric (Student’s t test or analysis of variance) or non-parametric tests (Mann-Whitney U test or Kruskal-Wallis test) depending on the assumptions to be fulfilled in each case. Categorical variables were compared by means of the chi^sup 2^ or Fisher’s exact test. Statistical analysis of the data was carried out using SPSS version 12.0 (SPSS Inc., Chicago, IL, USA). All tests were two-tailed and significance was set at 0.05.

Results

We considered 42 cases of patients diagnosed and treated for borderline ovarian tumor in the Institut Universitari Dexeus during the period 1982-2000; the controls were 257 patients diagnosed and treated for benign ovarian pathology during the same time period. The mean age of patients was 39.5 + 13.6 years for the study group and 37.0 +- 8.2 years for controls.

When analyzing separately the family histories of breast, ovarian and other cancers we found no significant differences between the groups, although ovarian or breast cancers were more common in the borderline group (11.9%) than among controls (8.6%). There were no significant differences in terms of age at menarche, parity (either zero parity or multiple parity, i.e. one or more gestations to term), or in the use of hormonal contraceptives (Table I).

Six patients (14.3%) diagnosed with borderline ovarian tumor and 70 (27.2%) women in the benign ovarian pathology group had a history of infertility. Although the percentage of prior infertility was higher in the control group the difference was not significant. Analysis of those patients who had received ovulation induction treatment, but without taking into account the drug used, revealed that 11.9% (five cases) of patients with borderline ovarian tumor and 13.2% (34 cases) of controls had undergone such treatment. Once again, there were no differences between the groups. When analyzing in more detail the type of drug used, we found that 9.5% (four patients) of the study group and 6.2% (16 patients) of controls had been given ovulation induction treatment with clomiphene citrate. As for induction treatment with gonadotropins, this had been administered to three patients (7.1%) in the study group and to 26 controls (10.1%). Two patients in the borderline ovarian tumor group and eight in the control group had been treated with both drugs. No significant differences were found with respect to the drug used. Finally, we analyzed the mean number of cycles administered to those patients who had received induction treatment. With respect to clomiphene citrate treatment the mean number of cycles for the borderline tumor and control groups was 2.50 +- 1.00 and 2.44 +- 1.75, respectively. When gonadotrophins were administered the mean number of cycles for the two groups was 3.00 +- 2.64 and 3.27 +- 2.25, respectively. Neither of these differences was significant (Table II).

Table 1. Epidemiological data of women with borderline ovarian tumors and control women with benign ovarian pathology.

Table II. Infertility data of women with borderline ovarian tumors and control women with benign ovarian pathology.

Discussion

The meta-analysis conducted by the Collaborative Ovarian Cancer Group [4,5] provides separate information about invasive ovarian tumors and borderline tumors. This analysis found that pregnancy, the use of oral contraceptives and breastfeeding were protective factors against the development of low-malignancy tumors. However, the study has been questioned on the grounds of inadequate data collection, in that causes of infertility that in themselves may increase the risk of ovarian cancer were not evaluated.

In our series neither the use of oral contraceptives nor pregnancy was observed to have a protective effect against borderline ovarian tumors.

According to Shushan and associates [11] a history of infertility increases the risk of tumors of low malignancy potential (odds ratio (OR) =1.9), while the use of ovulation induction drugs increases the risk of developing a low-malignancy tumor fourfold in patients with or without a history of infertility. Similar results were reported in an American cohort study of infertile women, where the OR for borderline ovarian tumors was 2.5 in women who had received ovulation stimulation drugs [12]. Goldberg and Runowicz reported three cases of tumors of low malignancy potential associated with infertility and ovulation induction [13]. In the series of Parazzini and co-workers there was also a correlation between the use of ovulation induction drugs and a risk of borderline ovarian tumors [14]. In the review by Saygili and colleagues, however, only one case among 21 (4.7%) had a history of clomiphene citrate treatment, in this case for five cycles [12]. Moreover, other authors such as Ness and collaborators [8] failed to corroborate the positive results. In their analysis of eight case-control studies with 7705 controls and 5207 cases, they found no increased risk associated with the use of ovulation induction drugs, although there was a relationship between infertility and ovarian cancer (OR= 1.26). Women with at least a 2-year history of infertility (regardless of whether this was due to endometriosis or of unknown origin) had the same risk of ovarian cancer (0.97) both with and without treatment. Furthermore, those infertile women who had sought to become pregnant for more than 5 years were at greater risk than those who had been attempting pregnancy for less than a year. Similarly, zero-parity women presented 2.42 times more ovarian cancer than did multiple- parity women (four or more pregnancies). This finding may be due to the relationship between zero parity and a longer period of attempting pregnancy. Another possible explanation for why infertile women are more at risk for developing a borderline ovarian tumor is the fact that these women have been more widely studied, therefore increasing the detection of such tumors [15]. These alarming data have not, however, been confirmed by other authors such as Mosgaard and associates [16], who argue that the risk factor for the development of borderline tumors is infertility itself rather than the use of ovulation induction drugs. These authors found a reduced risk of ovarian cancer among multiple-parity women (OR = 0.56) compared with zero-parity women. Their analysis of infertility revealed an OR for ovarian cancer of 1.54, and when they analyzed infertile zero-parity women and infertile women who had received ovulation induction treatment the OR rose to 2.71 and 2.26, respectively. They concluded, therefore, that the risk factor was infertility rather than the ovulation induction treatment. Our data reveal no increased risk of borderline ovarian tumors associated with either infertility or the use of ovulation induction drugs, whether clomiphene citrate or gonadotropins, and independent of the dose used. Moreover, in our series parity was not found to be a risk factor, the rate of zero parity overlapping between the two groups. We compared groups with ovarian pathology (benign vs. borderline tumors) with the aim of correcting the possible bias resulting from the presence of an ovarian lesion as an infertility risk factor. It can be seen that there were no significant differences with respect to a history of sterility or infertility; likewise, once this potentially confounding factor was eliminated no differences were observed in terms of the use of ovulation induction drugs, whether clomiphene citrate or gonadotropins.

In a previous study we conducted of 45 patients, 11 (24.4%) had a history of infertility and seven cases (15.6%) had received ovulation induction treatment [17]. In the current series five of 42 patients with a borderline tumor had undergone ovulation induction treatment, two with clomiphene citrate and gonadotropins.

Although the number of patients with a borderline tumor is low, our data corroborate those obtained by other authors. We therefore conclude that our results provide no evidence that ovulation induction treatment predisposes women to the development of borderline ovarian tumors.

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MAITE CUSIDO, RAFAEL FABREGAS, PERE BARRIS S, CECILIA ESCAYOLA, & PERE NOLSAC BARRI

Departament d’Obstetricia i Ginecologia, Institut Universitari Dexeus, Catedra d’Investigacio en Ginecologia,

Barcelona, Spain

(Received 14 March 2007; revised 18 March 2007; accepted 19 March 2007)

Correspondence: M. Cusido, Pso. Bonanova 67, E-08017 Barcelona, Spain. Tel: OO 34 32274700. Fax: OO 34 34187832. E-mail: maicus@dexeus.com

Copyright Taylor & Francis Ltd. Jul 2007

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