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Abstract

Adverse effects have been related to infertility treatments. Infertility in general, and female infertility in particular, is a well established risk factor for cancer development, especially ovarian, breast and endometrial cancer. This article addresses the possible association between infertility and cancer development, with an emphasis on the influence of infertility treatments, through a meticulous search of the literature published thus far. While results regarding the possible association of infertility, ovulation induction medications and invasive ovarian cancer show no increased risk and are reassuring, results for increased risk for breast cancer and endometrial cancer following exposure to ovarian stimulation medications are inconclusive. Larger population studies with longer periods of follow-up and better adjustment for confounding factors are needed.

Keywords

borderline tumors of the ovary breast cancer endometrial cancer ovarian cancer ovarian stimulation ovulation induction

More than 15% of couples will face infertility problems during their reproductive years, and will seek treatment [1]. Adverse effects have been related to infertility treatments, many of which are short term, (i.e., multiple pregnancies [2,3], ectopic pregnancies [4] and hyperstimulation syndrome [5 –7]). However, long-term adverse effects of infertility treatments are still controversial. While infertility in general, and female infertility in particular, is a well established risk factor for cancer development, with special emphasis on ovarian, breast and endometrial cancer [8 –10], the role of infertility treatments as a possible risk factor for cancer development is less clear. Therefore, it is important to evaluate the possible additional risks associated with infertility medications, that could by themselves modify the hormonal environment and be cofactors towards cancer development [10].

Part of the problem in evaluating the possible association between infertility treatments and cancer development is to conduct a well-designed epidemiological investigation. Cohort studies are usually conducted for relatively rare exposures and frequent outcomes. The incidence of the investigated outcome will be compared between a group of exposed individuals and a group of unexposed individuals after a sufficient follow-up period and the relative risk (RR) for the outcome between these two groups will be calculated as the ratio between the incidences. This is the most direct method to calculate the risk. However, in the case of exposure to infertility treatments the recruitment of exposed individuals could be biased by the inclusion of only the patients who that approached infertility clinics. It will be even more difficult to assemble the group of unexposed individuals (i.e., infertile women that were not exposed to infertility treatments) and, therefore, some of the studies use the general population rates for comparison of cancer incidence. This compromise, while easier to investigate, only allows the calculation of a standardized incidence ratio (SIR), which is an underestimation of the actual risk, since the general population rates reflect both the infertile and the fertile population. In addition, comparison with the general population data, usually through linkage to registries, does not allow for complete control of a wide range of potential confounding factors, such as parity, menstrual factors, family history of cancer, oral contraceptive use, and other hormone use, that will be available from medical records. Moreover, due to the long latency period for cancer development, most cohort studies will be conducted as a historical cohort in order to avoid very long follow-up periods. Therefore, some of the individuals will have been exposed to treatment protocols that are no longer relevant. However, the most profound limitation of the cohort study design in evaluating cancer incidence following infertility treatments would be the fact that some of the investigated cancers are rare, such as ovarian and endometrial cancers, and therefore even a substantial sized cohort will yield only few cancer cases at the end of follow-up, which will not be enough to control for possible confounding factors. The insufficient number of cancer cases could be overcome by using a case–control designed study. While case–control studies are usually conducted for rare outcomes, such as cancer development, they may suffer from a recall bias on the information about infertility and infertility treatments. Since infertility treatments, especially in past decades, were relatively infrequent, only a few cases will actually report exposure. Moreover, owing to the fact that it is not possible to evaluate the true incidence for cancer development in a case–control design, only an estimation of the risk could be calculated as the odds ratio (OR).

This article addresses the possible association between infertility and cancer development with an emphasis on the influence of infertility treatments as presented by the various studies published thus far.

Ovarian cancer

Nulliparity represents a known risk factor for epithelial ovarian cancer. Therefore, the differentiation between the effect of infertility per se and the possible effect of ovulation-induction treatments is difficult to assess. During the past decades, many case reports described women who were treated for infertility and were diagnosed with ovarian cancer [11 –25].

However, most of these reports were related to women who were diagnosed with ovarian cancer during the infertility treatments or shortly after and, therefore, may be regarded as coincidental findings that are not related to the infertility treatments themselves. The possible link between exposure to ovulation-induction drugs and ovarian cancer development has biological credibility, given that ‘incessant ovulation’ and associated alternation in endogenous hormones during reproductive years are plausible explanations for several factors that alter ovarian cancer risk [26 –28].

The association between infertility, ovulation-induction treatments and ovarian cancer development has been investigated in numerous case–control and cohort studies. As for invasive ovarian cancer development, all but one case–control study failed to demonstrate a significant excess risk of invasive ovarian cancer following treatments for infertility (Table 1) [29].

Table 1.

Summary of case–control studies regarding ovarian stimulation and the risk for ovarian cancer.

Study (year)	OR	95% CI	Ref.
Shu et al. (1989)	2.1	0.2–22.7	[73]
Whittemore et al. (1992)	2.8	1.3–6.1	[29]
Franceschi et al. (1994)	0.73	0.2–3.3	[74]
Shushan et al. (1996)	1.3	0.6–2.7	[75]
Mosgaard et al. (1997)	0.8	0.4–2.0	[76]
Parazzini et al. (1997)	1.1	0.4–3.3	[44]
Parazzini et al. (2001)	1.3	0.7–2.5	[77]
Nees et al. (2002)	0.97	0.8–1.3	[31]

OR: Odds ratio.

Whittemore et al. in a pooled analysis of 12 case–control studies from the USA, including 2197 ovarian cancer cases and 4144 controls, observed a significant excess risk related to infertility and infertility medications of 2.8 excess risk (95% CI: 1.3–6.1) [29]. These findings gained extensive criticism mainly owing to the fact that only a small proportion of the cases and controls actually suffered from infertility and that some of the older women in the study were exposed to fertility medications that are no longer in use [30]. A more recently published pooled analysis of case–control studies by Ness et al., failed to confirm these findings [31]. Numerous cohort studies (Table 2) have compared ovarian cancer rates in infertile women with those of the general population. Although cohort sizes were sufficient, most studies failed to present a significant association between exposure to infertility and infertility medication, and invasive ovarian cancer development. Tworoger et al. observed a significant excess risk for ovarian cancer development in women with female factor infertility (adjusted RR: 1.36; 95%CI:1.07–1.75) but not in male factor infertility [32]. The potential limitation of most of these cohort studies is the small number of ovarian cancers. Since most of these studies involve historical cohorts and are based on the abstraction of medical records, significant confounding factors, such as use of oral contraceptives or family history of ovarian and breast cancer, are not available for adjustment. In addition, information regarding infertility medications, including dose and duration of use, are not precise. Some of the cohort studies included an internal comparison between infertile women who were treated with infertility medications and those who were not, with similar results [33 –36]. In a meta-analysis published by Kashyap et al. no excess risk for ovarian cancer was evident between treated and untreated infertile patients in both cohort and case–control study designs (RR: 0.67; 95% CI: 0.32–1.41 and OR: 0.99; 95% CI: 0.67–1.45, respectively) [37].

Table 2.

Summary of cohort studies regarding ovarian stimulation and the risk for ovarian cancer.

Study (year)	Cohort size (n)	RR/SIR	95% CI	Ref.
Ron et al. (1987)	2632	3.2	0.3–32.9	[41]
Rossing et al. (1994)	3837	2.3	0.5–11.4	[33]
Venn et al. (1995)	10,358	1.45	0.3–7.6	[59]
Modan et al. (1998)	2498	1.6	0.8–2.9	[34]
Venn et al. (1999)	29,700	0.88	0.4–1.8	[60]
Potashnik et al. (1999)	1197	0.68	0.01–3.8	[55]
Doyle et al. (2002)	5556	0.59	0.1–3.0	[35]
Dor et al. (2002)	5026	0.57	0.01–3.2	[61]
Lerner-Geva et al. (2003)	1082	1.67	0.02–9.3	[78]
Brinton et al. (2004)	12,193	0.8	0.4–1.5	[36]
Tworoger et al. (2007)	107,900	1.36	1.07–1.75	[32]
Calderon-Margalit et al. (2009)	15,030	0.61	0.08–4.42	[57]
Sanner et al. (2009)	2768	5.89	1.91–13.75	[38]
Jensen et al. (2009)	54,362	0.83	0.50–1.37	[39]

RR: Relative risk; SIR: Standardized incidence ratio.

Sanner et al. observed no overall risk of invasive ovarian cancer in a cohort of infertile women compared with the general population [38]. However, the risk was elevated for women with human menopausal gonadotropin (hMG) treatment for nonovulatory disorders based on only five observed cases of ovarian cancer (SIR: 5.89; 95%CI: 1.95–13.75). In a large cohort of over 54,000 infertile women, Jensen et al. observed no excess risk for invasive ovarian cancer in any of the groups exposed to fertility drugs [39].

In a recent update for cancer development in a cohort of infertile women with more than 84,000 women and over 30 years follow-up, 18 ovarian cancer cases were observed compared with 18.1 expected with no excess risk for ovarian cancer that was evident (SIR: 1.0; 95% CI: 0.6–1.6) [40]. This cohort of infertile women, which was previously investigated by Ron et al. [41] and Modan et al. [34], is currently the cohort with the longest period of follow-up consisting of infertile women who reached the peak age for cancer development (mean age at the end of follow-up: 62.7 years).

In contradiction to the results for invasive ovarian cancer, the risk for borderline tumors of the ovary in infertile women was found to be significantly increased in both case–control and cohort studies (Table 3). In the cohort analysis by Rossing et al., a significantly higher risk for borderline tumors and even higher risk in infertile women with prolonged use (12 or more cycles) of clomiphene citrate (adjusted RR: 11.1; 95% CI: 1.5–82.3) were observed [33]. In another cohort analysis, by Sanner et al., similar findings were observed with a more than threefold increase for borderline tumors and an even higher risk in women exposed to clomiphene (SIR: 3.61; 95% CI: 1.45–7.44 and SIR: 7.47; 95% CI: 1.54–21.83, respectively) [38]. Harris et al. were the first to analyze the risk for borderline tumors separately in a meta-analysis of 12 case–control studies, and observed a fourfold increased risk (95% CI: 1.1–13.9) [42]. In another case–control study conducted by Shushan et al., an excess risk of borderline tumors was observed in infertile women who were treated with hMG [43]. Parazzini et al. also observed that treatment with ovulation-induction was a statistically significant risk factor for borderline tumors of the ovary [44]. Similar risk was also reported by Ness et al. in a pooled analysis of eight case–control studies [36]. Borderline tumors of the ovary present a unique entity of ovarian malignancy with less family history, less detection of breast cancer mutations [45], higher incidence of estrogen receptors [46], more diagnosis before the age of 50 years and significantly higher 5-year survival rates [47], as compared with invasive ovarian cancer. Therefore, the possible association of these tumors to exposure to ovulation-induction could be feasible. In addition, the excess risk of borderline tumors of the ovary may be a result of diagnosis due to surveillance bias, especially in women with longstanding infertility and resistance to infertility treatments, which undergo repeated ultrasonographic examinations.

Table 3.

Summary of studies regarding ovarian stimulation and the risk for borderline tumors of the ovary.

Author	Design	OR/SIR	95% CI	Ref.
Harris et al. (1992)	Meta-analysis case–control	4.0	1.1–13.9	[42]
Rossing et al. (1994)	Cohort	3.3	1.1–7.8	[33]
Shushan et al. (1996)	Case–control	3.5	1.1–10.1	[43]
Parazzini et al. (1998)	Case–control	–	p = 0.004	[44]
Ness et al. (2002)	Pooled analysis case–control	2.43	1.01–5.88	[31]
Sanner et al.(2009)	Cohort	3.61	1.45–7.44	[38]

OR: Odds ratio; SIR: Standardized incidence ratio.

In conclusion, results regarding the possible association of infertility, ovulation-induction medications and invasive ovarian cancer demonstrate no increased risk and are reassuring. The possible excess risk of borderline tumors of the ovary may be due to intrinsic characteristics of these tumors or surveillance bias.

Breast cancer

Breast cancer is the leading cause of malignancy in women in developed nations with peak incidence at the age of 60–65 years [48]. Nulliparity, younger age of menarche, older age at menopause and late age at first birth and infertility are traditionally considered to be potential risk factors for breast cancer development [49]. However, the issue of the potential risk associated with exposure to infertility treatments is less clear. Specific concerns regarding the effects of fertility drugs have been raised by the recognized effects on breast cancer risk of ovulation and hormonal patterns related to estrogen levels, and, more recently, progesterone [28,50]. Several case–control studies (Table 4) investigated the potential risk factors for breast cancer development. All but one failed to observe an association between exposure to ovulation induction and breast cancer [51]. Buckman et al. reported a significant excess risk of breast cancer in women who were treated with hMG for more than 6 months or more than six cycles (OR: 2.1 and 2.7, respectively) [52]. Numerous large cohort studies (Table 5) that have been published over the last 30 years have failed to reach a definite conclusion regarding the possible association between infertility, ovulation-induction exposure and breast cancer risk. While a significant body of scientific literature failed to observe such association, others reported an excess risk of breast cancer in specific subgroups of women. Cowan et al. compared the risk for breast cancer in women with hormonal infertility to women with non-hormonal infertility and observed an excess risk in premenopausal women with hormonal infertility [53]. Coulam et al. observed similar excess risks only in postmenopausal women [54]. Only a few cohort studies reported data regarding specific ovulation-induction drugs. Potashnik et al. reported an excess risk for breast cancer in women who were treated with relatively smaller doses of clomiphene citrate (i.e., 1–2 cycles and cumulative dose of <1000 mg), but not in women who were exposed to higher doses [55]. Brinton et al. observed a significant association to exposure to clomiphene citrate, but only after 20 or more years of follow-up (RR: 1.60; 95% CI: 1.0–2.5). Our group also observed a significant association to exposure to clomiphene citrate [56]. Recently, Calderon-Margalit et al. reported a significant excess risk for breast cancer following any fertility treatment use and an insignificant risk following exposure to clomiphene citrate [57]. However, in a recent update for cancer development in one of the cohorts of infertile women with a follow-up of over 30 years and more than 84,000 women-years of follow-up, the excess risk related to ovulation-induction treatments (and especially clomiphene citrate) that was previously reported with a shorter follow-up [56], disappeared (hazard ratio: 0.9; 95% CI: 0.6–1.5) [40]. Possible explanations could be either that clomiphene citrate exposure decreases the latency period for breast cancer development and enhances the proliferation of already existing tumors, or that surveillance bias occurs in women who attend infertility clinics. Another recent cohort study observed an excess risk for breast cancer in users of high-dose clomiphene citrate (SIR: 1.90; 95% CI: 1.08–3.35) [58]. This association was more pronounced among women referred for nonovulatory factors (SIR: 3.00; 95% CI: 1.35–6.67).

Table 4.

Summary of case–control studies regarding ovarian stimulation and the risk for breast cancer.

Study (year)	Number of cases/controls	OR/SIR	95% CI	Comments	Ref.
Gammon et al. (1990)	4730/4688	–	–	No association	[79]
Braga et al. (1996)	2569/2588	–	–	No association	[51]
Ricci et al. (1996)	3415/2916	–	–	No association	[80]
Burkman et al. (2003)	4575/4682	2.1	1.0–4.4	hMG
>6 months	[52]
		2.7	1.0–6.9	hMG >6 cycles

hMG: Human menopausal gonadotropin; OR: Odds Ratio; SIR: Standardized incidence ratio.

Table 5.

Summary of cohort studies regarding ovarian stimulation and the risk for breast cancer.

Study (year)	Cohort size (n)	RR/SIR	95% CI	Comments	Ref.
Cowan et al. (1981)	1083	5.4	1.1–49.0	Premenopausal	[53]
Coulam et al. (1983)	1270	3.6	1.2–8.3	Postmenopausal	[54]
Ron et al. (1987)	2575	–	–	No association	[41]
Brinton et al. (1989)	2335	–	–	No association	[81]
Rossing et al. (1996)	3837	–	–	No association	[82]
Modan et al. (1998)	2496	–	–	No association	[34]
Potashnik et al. (1999)	1197	2.6	1.2–5.0	CC 1–2 cycles	[55]
		2.6	1.2–4.6	CC ≤1000 mg (cumulative dose)
Doyle et al. (2002)	5556	–	–	No association	[35]
Ganthier et al. (2004)	6602	1.37	0.99–1.87	Treated with family history	[83]
Brinton et al. (2004)	12,193	1.60	1.0–2.5	CC ≥20 years of follow-up	[56]
Terry et al. (2006)	5798	–	–	No association	[84]
Lerner-Geva et al. (2006)	5877	1.5	1.0–2.2	Treatment with CC	[85]
Jensen et al. (2007)	54,362	–	–	No association	[86]
Calderon-Margalit et al. (2009)		HR: 1.65	1.15–2.36	Any treatment	[57]
		HR: 1.48	0.93–2.37	Treatment with CC
Orgéas et al. (2010)	1135	1.90	1.08–3.35	Treatment with CC	[58]
		3.00	1.35–6.67	Nonovulation and CC

CC: Clomiphene citrate; HR: Hazard ratio; RR: Relative ratio; SIR: Standardized incidence ratio.

In vitro fertilization (IVF) treatments pose an even greater dilemma. This technology was established only at the beginning of the 1980s and follow-up time for cancer development may not be sufficient. In addition, differences in effects between fertility treatments used in the 1960s and 1970s, and later IVF protocols, focus on the fact that the latter involve exposure to higher doses of ovulation-inducing drugs. However, generally there are different drugs involved, with IVF protocols involving much more exposure to gonatropines. Australian [59,60], Israeli [61 –63] and Danish [64] cohorts of women who underwent IVF treatments were investigated (Table 6). Most cohorts did not observe an excess risk for breast cancer development. An insignificant excess risk was observed only by Brzezinski et al. [62] for all IVF patients and by Pappo et al. [63] for women who were treated with four or more IVF cycles. In a meta-analysis presented by Kashyap et al., no excess risk for breast cancer was evident in both cohort and case–control study designs [65]. Moreover, for cohort studies the results for exposure to infertility treatments were actually protective against breast cancer development (OR: 0.74; 95% CI: 0.67–0.97).

Table 6.

Summary of studies regarding IVF and the risk for breast cancer.

Study (year)	Cohort size (n)	RR/SIR	95% CI	Comments	Ref.
Brzezinski et al. (1994)	950	2.2	–	Significance reported	[62]
Venn et al. (1995)	10,358	–	–	No association	[59]
Venn et al. (1999)	29,700	–	–	No association	[60]
Dor et al. (2002)	5026	–	–	No association	[61]
Kristiansson et al. (2007)	8716	–	–	No association	[64]
Pappo et al. (2008)	3375	HR: 1.9	0.95–3.81	≥4 IVF cycles	[63]

HR: Hazard ratio; RR: Relative risk; SIR: Standardized incidence ratio.

In a recent meta-analysis by Zreik et al., which included most of the aforementioned case–control as well as cohort studies, the risk of breast cancer was not significantly associated with fertility drug treatment [66].

In conclusion, numerous studies regarding the possible association between infertility, ovulation-induction exposure and breast cancer have been conducted. Although these studies include significant sample sizes and sufficient follow-up for cancer development, results regarding effects of fertility drugs on breast cancer risk are still conflicting. Given that breast cancer is widely recognized as having a hormonal etiology, further assessment of the effects of ovulation-induction drugs should be undertaken [67].

Endometrial cancer

Endometrial cancer has been significantly associated with infertility in most studies published to date [10]. Compared with the general population rates of endometrial cancer, the risk was significantly increased by ninefold in infertile patients with normal estrogen levels and progesterone deficiency [41,34]. Venn et al. observed an increased risk for endometrial cancer for untreated IVF clinic patients (SIR: 2.47; 95% CI: 1.18–5.18) [42]. This is also the case for patients diagnosed with polycystic ovary disease and has been associated with the ‘unopposed’ estrogen effect [34,68 –70]. Moreover, infertile patients treated with ovulation-induction drugs, regardless of their infertility diagnosis, could also be exposed to an unopposed estrogen environment [28,71].

However, the association between exposure to ovulation induction and endometrial cancer development, independent of the infertility problem, is less clear.

Benshushan et al. in a case–control study of 128 endometrial cancer patients, observed that the use of fertility hormones was more prevalent in cancer patients, although not significantly (5.5 vs 3.9% among cases vs controls, respectively) [72].

Most studies (Table 7) failed to observe an association between treatment with ovulation induction and endometrial cancer. The study by Venn et al. that observed an increased risk for endometrial cancer in untreated infertile patients (compared with the general population), did not find an increased risk in treated compared with untreated patients [60]. Althuis et al. suggested an increased risk of endometrial cancer following treatment with clomiphene citrate. Interestingly, the risk was more strongly associated with clomiphene citrate among nulligravid (RR: 3.49; 95% CI: 1.3–9.3) and obese (RR: 6.02; 95% CI: 1.2–30.0) patients [68]. In a recent update for cancer development in a cohort of infertile women with over 30 years of follow-up, no excess risk for endometrial cancer in association to ovulation-induction drugs was observed [40]. As previously reported, for the same cohort with shorter follow-up periods [34,41], the risk for endometrial cancer in infertile women is elevated, especially in women with normal estrogen levels and progesterone deficiency independent from the exposure to ovulation-induction drugs.

Table 7.

Summary of cohort studies regarding ovarian stimulation and the risk for endometrial cancer.

Author	Cohort size (n)	RR/SIR	95% CI	Ref.
Ron et al. (1987)	2575	4.8	1.7–10.6	[41]
Brinton et al. (1989)	2335	0.9		[81]
Modan et al. (1998)	2496	4.8	3.0–7.4	[34]
Venn et al. (1999)	20656	1.09	0.4–1.8	[60]
Potashnik et al. (1999)	1197	0.68	0.01–3.8	[55]
Doyle et al. (2002)	5556	0.59	0.1–3.0	[35]
Dor et al. (2002)	5026	0.57	0.01–3.2	[61]
Lerner-Geva et al. (2003)	1082	1.67	0.02–9.3	[78]
Brinton et al. (2004)	12,193	0.8	0.4–1.5	[36]
Althuis et al. (2005)	8401	1.6	1.1–2.1	[68]
Calderon-Margalit et al. (2008)	14,463	3.3	1.3–8.4	[57]

RR: Relative risk; SIR: Standardized incidence ratio.

In conclusion, the risk for endometrial cancer development in infertile women, and especially in women with unopposed estrogen state, is well established. However, data regarding the possible association to exposure of ovulation-induction drugs to endometrial cancer development is inconclusive.

Executive summary

Infertility in general, and female infertility in particular, is a well established risk factor for cancer development, especially ovarian, breast and endometrial cancer.

Results regarding the possible association of infertility, ovulation induction medications and invasive ovarian cancer show no increased risk and are reassuring.

The possible excess risk of borderline tumors of the ovary may be due to intrinsic characteristics of these tumors or surveillance bias.

Results regarding the effects of fertility drugs on breast cancer risk are still conflicting.

Increased risk for endometrial cancer following exposure to ovulation-induction medication is inconclusive.

Larger population studies with longer periods of follow-up and better adjustment for confounding factors are needed.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Ovarian Stimulation: Is There a Long-Term Risk for Ovarian,Breast and Endometrial Cancer?

Abstract

Keywords

Ovarian cancer

Breast cancer

Endometrial cancer

Footnotes

References