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Association between fertility drugs and gynecologic cancers, breast cancer, and childhood cancers

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Association between fertility drugs and gynecologic cancers, breast cancer, and childhood cancers
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  ACTA REVIEW Association between fertility drugs andgynecologic cancers, breast cancer, andchildhood cancers A LI  A YHAN 1 , M EHMET  C OSKUN  S ALMAN 1 , H USNU  C ELIK 2 , P OLAT  D URSUN 1 , O ZGUR  O ZYUNCU 1 AND  M URAT  G ULTEKIN 1 From  1 the Department of Obstetrics and Gynecology, Faculty of Medicine, University of Hacettepe, Ankara and  2 theDepartment of Obstetrics and Gynecology, Faculty of Medicine, University of Firat, Elazig, Turkey Acta Obstet Gynecol Scand   2004; 83: 1104–1111. # Acta Obstet Gynecol Scand 83 2004Ovulation-inducing drugs have been widely used for various types of infertility since thebeginning of 1960s and their use increases day by day parallel to the success achieved infertility treatment. However, the researches performed in the last two decades have begunto discuss about the safety of these drugs and the risks associated with their use. Espe-cially, the potential neoplastic effects of these drugs are increasingly questioned. Thestudies have discussed whether there is an association between the exposure to ovula-tion-inducing drugs and the incidence of various cancers. Moreover, several studies havebeen performed to reveal whether there is an increased risk of childhood cancers inchildren conceived after fertility treatment. The point we reached through the availabledata is that the risk of breast, uterine and invasive ovarian cancers is not increased, but therisk of borderline ovarian tumors might increase after such a therapy. The risk of cancerhas been found similar for children conceived after fertility treatment and those conceivednaturally. It should also be kept in mind that cancers are overdiagnosed in infertile womenpopulation because of the close medical surveillance, which may also contribute to theearly detection of cancers. Although it is still early to state the last words on this topic, thepossible association should be addressed when obtaining an informed consent beforestarting treatment. Key words:  breast cancer; cervical cancer; childhood cancers; fertility treatment; infertility;ovarian cancer; ovulation induction; uterine cancer Submitted 6 February, 2004Accepted 18 June, 2004 Ovulation-inducing drugs have been widely usedin various regimes for different types of infertilityfor a period of nearly 40years. However, bothcase reports and retrospective studies performedespecially in the last two decades have begun todiscuss about the safety of these drugs and therisks associated with their use. The main threat-ening result of these studies is that this kind of treatment might be related to a potential increasein risk of some cancers, including ovarian, uterine,and breast cancers. Moreover, several studieshave been performed to reveal whether there isan increased risk of childhood cancers in childrenconceived after fertility treatment. These reportshave caused great concern among both patientsand physicians, because the use of fertility drugsis increasing day by day parallel to the successachieved in conceiving in a population sufferinginfertility for a long time. This review is going todiscuss the relation between the use of various Abbreviations: DNA: deoxyribonucleic acid; OR: odds ratio; SIR:standardized incidence ratio; IVF: in vitro fertilization; HMG:human menopausal gonadotropine; BOT: borderline ovariantumors; CI: confidence interval. #  Acta Obstet Gynecol Scand 83 (2004) Acta Obstet Gynecol Scand 2004: 83: 1104--1111  Copyright  # Acta Obstet Gynecol Scand 2004 Printed in Denmark. All rights reserved   Acta Obstetricia et Gynecologica Scandinavica  regimes of fertility drugs and the risk of somecancers. Ovulation induction and ovarian cancer Ovarian cancer has the highest mortality amongall gynecologic cancers (1). Many factors werereported to play a role in the increased incidenceof ovarian cancer, including genetics, menarcheand menopause age, pregnancy and lactation, useof oral contraceptives, and parity (2,3). Multi-parity and oral contraceptive use are the mostimportant factors decreasing the risk of this cancer.Ovulation-inducing drugs have been thoughtto have carcinogenic and/or promoting effectsbecause of the theory of incessant ovulationraised regarding the etiology of ovarian cancer(4). When the validity of this theory is accepted,it should be expected that the events that increaseovulation would also increase the risk of ovariancancer. The trauma of the ovarian surface epithe-lial cells caused by ovulation renders the ovariessensitive to this process. In animals, DNAdamage was detected in the ovarian surfaceepithelial cells of the ovulation site and cancermay develop unless DNA repair or apoptosistakes place (5). A 1-year increase in ovulationmay cause a 6% increase in the risk of ovariancancer (6). Nieto et al. (7) found an associationbetween ovulation induction therapy and ovarianepithelial dysplasia. In that study, the mean dys-plasia score was significantly higher in women, whohad undergone ovulation induction, compared tothat in fertile controls; however, the difference indysplasia score between nulliparous women andfertile controls was not detected. This dysplasiacould be a precursor of invasive neoplastic diseaseof the ovary. The mechanism for this effect is notknown, but may be related to the mechanicaltrauma associated with ovulation (8) or increasedlevels of vascular endothelial growth factor inwomen undergoing ovulation induction (9).A well-established risk factor for ovarianmalignancies is parity; the risk of ovarian cancerdecreases with the increasing number of births(10). It was reported that each birth reduced therisk of ovarian cancer (11). The increased risk of ovarian cancer among infertile women has alsobeen demonstrated in epidemiological studieswith odds ratio (OR) ranging between 1.5 and2.5 (12,13).The relationship between ovulation-inducingdrugs and ovarian cancer may not be causal,but some other factors can give rise to both infer-tility and ovarian cancer (14). These factorsinclude genital tract infections, mutations of some genes, and polycystic ovarian syndrome.The infection agents causing infertility may alsoaffect the ovarian surface epithelium. Thefirst-degree relatives of infertile women werelikely to develop ovarian cancer two times more,compared to the relatives of fertile women; thismay reflect a genetic association. In polycysticovarian syndrome, the most common cause of anovulatory infertility, a high frequency of hyper-plasia and metaplasia in the surface epithelium of ovaries was reported (15). In a case-control study,Schildkraut et al. (16) reported a 2.5-fold increasedrisk of ovarian cancer in women previously diag-nosedwithpolycysticovariansyndrome.Therefore,it is not clear whether the risks are attached toinfertility or its treatment.Infertility itself has been regarded as a riskfactor for ovarian cancer (17). On the otherhand, the ovarian stimulation with ovulation-inducing drugs and other factors, such as oocyteaspiration by ovarian puncture, may acceleratethe growth of an existing tumor (18).According to a pooled interview data fromeight case-control studies, Ness et al. reportedthat any fertility drug use was not significantlyassociated with increased ovarian cancer risk(19).Whittemore et al. (20) found that infertilewomen, who had been treated with fertilitydrugs, had a 2.8 times increased risk of ovariancancer, compared to women without infertility.Rossing et al. (21) found a non-significantincreased risk of ovarian cancer among womentreated with fertility drugs, compared to thatamong infertile women without treatment andthey suggested that there could be an increase inovarian tumors with the use of clomiphene for 12cyclesormore.Mosgaardetal.(10)andVennetal.(22) showed that the treatment with fertility drugsdid not increase the risk of ovarian cancer, com-pared to non-treated infertile women (TableI).Parazzini et al. (23) reported that treatment withfertility drugs was not significantly associated withan increased risk of invasive ovarian cancer. Inaddition, Lerner-Geva et al. (24) reported anincreased incidence of ovarian cancer ininfertile patients treated with fertility drugs, butthey suggested that the higher than expected can-cer rate could not be attributed to that therapy.These different results from different studiesmight result from the methodological concerns,such as defining infertility, ascertainment of exposures to various fertility drugs, and types of infertility.In a prospective control study with a meanfollow-up time of 17.9years, Potashnik et al. (25)could not detect an increased incidence of ovariancancers among 1197 infertile women or treatedand untreated groups, compared to the general Association between fertility drugs and various cancers  1105 #  Acta Obstet Gynecol Scand 83 (2004)  population with standardized incidence ratio(SIR) of 0.91, 0.68, and 1.35, respectively (TableI).In one of the largest case series world-wide,Venn et al. (26) investigated cancer incidence in29700 women, who had been referred for  in vitro fertilization (IVF) treatment. This cohort con-sisted of 20656 treated and 9044 untreatedwomen. The incidence of ovarian cancer wasnot higher than expected, compared to the gen-eral population in the whole group with an SIRof 0.99; the SIR for ovarian cancer in the treatedand untreated group was 0.88 and 1.16, respect-ively (TableI). They found no associationbetween the number of treatment cycles andtype of ovarian stimulation regime and theincidence of ovarian cancers, but they showed asignificant increase in ovarian cancer risk inwomen with unexplained infertility (TableII).The development of cancer may be provokedby the hormonal changes caused by ovulationinduction. In addition, a cohort of IVF patientsis unique in that every patient is closely followedbefore, during, and after each cycle of ovulationinduction. Therefore, the close medical surveil-lance may contribute to the early detection of gynecological cancers, especially ovarian and cer-vical cancers, by using routine ultrasonographyand Papanicolaou’s smears (18). In a cohort of 5026 infertile women, no increased risk of anycancers was found in women undergoing IVFtreatment, compared to that in the general popu-lation (TableI). It was suggested that careful fol-low-up of these women may allow us to haveearlier diagnosis of already existing cancers, espe-cially the cancers of the genital organs (18).In a meta-analysis, the available data did notsupport an increased risk of ovarian cancer as aresult of ovulation induction. Although the ORfor ovarian cancer was found to be 1.52 wheninfertile treated women were compared with gen-eral population, it was found to be 1.00 wheninfertile treated women were compared withinfertile untreated women (27).A large number of epidemiological studies haveshown inconsistent findings on the incidence of ovarian cancer after treatment with fertilitydrugs. While some of these studies showedincreased risk of ovarian cancer, others couldnot find such a result (28). However, on thebasis of available evidence, the risk of ovariancancer appears to be restricted to those women,who remain childless despite the infertility TableI. The standardized incidence ratios (SIR) with 95% confidence interval for breast, ovarian, and uterine cancers infertility-drug-exposed and fertility-drug-unexposed womenDrug exposed Drug unexposedAuthor  n   Ovarian Breast Uterine  n   Ovarian Breast UterineDor et al., 2002 (18) 5026 0.57 0.69 2.25 – – – –(0.01–3.20) (0.46–1.66) (0.25–8.11)Venn et al., 1999 (26) 20656 0.88 0.91 1.09 9044 1.16 0.95 2.47(0.42–1.84) (0.74–1.13) (0.45–2.61) (0.52–2.59) (0.73–1.23) (1.18–5.18)*Potashnik et al., 1999 (25) 780 0.68 1.65 3.00 417 1.35 0.80 –(0.01–3.80) (0.94–2.69) (0.34–10.85) (0.02–7.49) (0.21–2.04)Venn et al., 1995 (22) 5564 1.70 0.89 – 4794 1.62 0.98 –(0.55–5.27) (0.55–1.46) (0.52–5.02) (0.62–1.56)* P  < 0.05TableII. The standardized incidence ratios (SIR) with 95% confidence interval for breast, ovarian, and uterine cancers by the type of infertility and the ovarianstimulation regime (modified from Venn etal (26))Breast Ovarian UterineType of infertilityMale 1.26 (0.94–1.70) 0.68 (0.17–2.71) 1.29 (0.32–5.15)Tubal 0.60 (0.44–0.80)* 0.96 (0.43–2.14) 1.09 (0.41–2.89)Ovarian 0.52 (0.17–1.62) – 3.57 (0.50–25.3)Unexplained 1.26 (0.87–1.82) 2.64 (1.10–6.35)* 4.59 (1.91–11.0)*Endometriosis 1.04 (0.71–1.54) 1.48 (0.48–4.59) 0.91 (0.13–6.49)Type of ovarian stimulation regimeClomiphene 0.85 (0.32–2.26) 2.46 (0.35–17.5) –HMG 0.99 (0.55–1.79) 1.14 (0.16–8.10) –Clomiphene plus HMG 1.17 (0.85–1.62) 0.77 (0.19–3.07) 1.29 (0.32–5.18)HMG plus GnRH agonist 0.94 (0.63–1.40) 0.48 (0.07–3.38) 1.74 (0.44–6.96)* P  < 0.05 1106  M. C. Salman et al. #  Acta Obstet Gynecol Scand 83 (2004)  treatment (14). Such patients may be prescribedoral contraceptives against the risk of ovariancancer. Nevertheless, an informed consentobtained before infertility treatment is increasingin light of published reports, suggesting a possibleassociation between ovulation induction andsome cancers (29). It is reasonable to limit thelength of treatment and address the risk of ovarian cancer before starting treatment. Ovulation induction and borderline ovariantumors There are several similarities between borderlineand invasive ovarian cancers with respect topatients’ characteristics (30). However, contrary toinvasive ovarian cancer, there is some evidence tosuggest an association between induction of ovula-tion and borderline ovarian tumors (BOT). TheBOT may be associated with hormonal factorsrather than genetic mutations (4) – for instance,estrogen receptor expression was shown to be acommon feature of borderline tumors (31). Thesereceptors may lead to tumor promotion in patientswith superovulation and excessively high estrogenlevels, who were treated with fertility drugs. Thisidea was supported by the studies of Rossing et al.(21), Shushan et al. (32), and Harris et al. (33), inwhich the OR of BOT in patients treated withfertilitydrugswasfound3.30,3.52,and4.0,respec-tively (TableIII). Such studies reporting statistic-ally significant increase in the risk of BOT afterfertility treatment have been criticized because of their confounding influence of infertility itself.No convincing evidence of an increased risk of invasive ovarian cancer after treatment with fer-tility drugs has emerged with available data. Onthe other hand, the risk of BOT may be increasedafter such a therapy. Mosgaard et al. (34)reported an increased risk of BOT in nulliparouswomen, compared to that in parous women (OR:1.64). However, nulliparity without infertility wasnot found to increase the risk. The risk in infertilewomen was greater than that in fertile women(OR: 1.70). The duration of infertility had nosignificant influence. They also showed that infer-tile nulliparous women treated with fertility drugsdid not have an increased risk of BOT, comparedto untreated women. Any regimen of ovulationinduction was not associated with a significantlyincreased risk of these tumors.As a result, there seems to be an increased riskof BOT after infertility treatment, but the con-founding influence of infertility itself should alsobe kept in mind. Ovulation induction and uterine cancer Endometrial cancer is the most common gyneco-logic cancer in many countries. The establishedrisk factors for endometrial carcinoma are nulli-parity or low parity, history of infertility,increased body mass index, early menarche, latemenopause, and unopposed estrogen replace-ment therapy. Almost all of these etiological fac-tors put forward in relation to endometrial cancercan be explained by means of the hypothesis of ‘exposure to unopposed estrogen’. When endo-metrium is exposed to unopposed estrogen mito-tic activity increases, DNA replication errors,somatic mutations, and lastly malignancy maydevelop (35). The source of estrogen may be exo-genous, as well as endogenous, as in anovulatorycases. This is the case in polycystic ovarian syn-drome characterized by chronic anovulation, inwhich an increased risk of endometrial cancerwas reported in retrospective studies (36,37).Therefore, the highly increased levels of estrogensachieved in ovulation induction cycles may causefears about the risk of endometrial cancer.Endometrial biopsy is, sometimes, performedin the evaluation of infertile patients before IVF.During treatment cycles, ultrasound evaluationof endometrium with ovaries is performed.Therefore, it is expected that IVF patients wouldhave increased ascertainment of pre-existingcancers before and during the treatment (28).Venn et al. (26) observed that the incidence of uterine cancers within the first year of exposure tofertility drugs was higher than that expected. Over-all uterine cancers were not found more commonthan those expected in the whole group (SIR: 1.61)and in the treated group (SIR: 1.09), but morecommon in the untreated group (SIR: 2.47)(TableI). They found no association among thenumber of treatment cycles, the type of ovarianstimulation regime, and the incidence of uterinecancers, but they suggested an increased risk in thesubgroup of unexplained infertility (TableII).Similarly, in a study of 1197 infertile women,the incidence of uterine cancers was not foundhigher in infertile women or treated anduntreated groups, compared to that in the generalpopulation (25) (TableI). TableIII. Therelationshipbetweenovulationinductionandborderlineovariantumors (BOT)Author Patients OR (95% CI)Shushan et al., 1996 (32) 36 patients with BOT 3.52 (1.23–10.09)*Rossing et al., 1994 (21) 3837 infertile women 3.30 (1.1–7.8)*Harris et al., 1992 (33) 112 patients with BOT 4.00 (1.1–13.9)** P  < 0.05 Association between fertility drugs and various cancers  1107 #  Acta Obstet Gynecol Scand 83 (2004)  Clomiphene citrate is a commonly used ovula-tion-inducing agent and its pharmacokinetics andstructure are very similar to tamoxifen (38). Itwas shown that it stimulates the growth of endo-metrial carcinoma in animal model (39). More-over, the estrogenic activity of tamoxifen and itsassociation with endometrial cancer are wellestablished in clinical studies (40). However,unlike the treatment for breast cancer withtamoxifen, clomiphene is not used for a longperiod of time for ovulation induction. Neverthe-less, Ron et al. (41) reported an excess of endo-metrial cancer among 2575 infertile women; thismay be related to the increased serum estradiollevels during the cycles of induced ovulation.Benshushan et al. (40) found that clomipheneand other ovulation-inducing agents are not asso-ciated with a higher risk of endometrial carcin-oma, although their cohort consisted of arelatively small number of cases.The epidemiology of uterine sarcomas is lesswell described than that of endometrial carcin-omas. Similar risk factors are seen in both tumors.In a case-control study, including 29 cases, inferti-lity was not found a risk factor for uterine sarco-mas (42). However, Venn et al. (26) reported anincreased incidence of sarcomas in women with ahistory of infertility. They found four uterine sar-comas, all among untreated infertile women, withan SIR of 8.56 (95% CI: 3.21–22.8).When the clinical observations are interpretedtogether, the concern of expected increase in therisk of uterine cancer because of high levels of estrogen reached in induced cycles should notworry infertile patients and their physicians. Ovulation induction and cervical cancer The close surveillance of infertile women beforeand during treatment may give rise to the earlydetection of cervical cancers by using routinePapanicolaou’s smears (18). Moreover, cervicalcancer may share the same infectious etiologywith tubal infertility caused by pelvic adhesions.In a study with a mean follow-up time of 17.9years, no evidence of increased incidence of cer-vical cancers was found among a cohort of infer-tile women or treated or untreated subgroups,compared to the general population (25). TheSIR in treated group was found to be 1.08. Ovulation induction and breast cancer Breast cancer is the most frequent cancer seenin women. It is of multifactorial etiology likeovarian cancer. The risk factors include familyhistory, early menarche, late menopause, anddietary factors. In addition to many etiologicalfactors, there is a close relation between breastcancer and ovarian hormones. It was demon-strated in both epidemiological and experimentalstudies that ovarian hormones were effective inthe development of breast cancer (43). In light of this information, the effect of ovulation-inducingdrugs on the risk of breast cancer has been a topicof intense research in recent years. Theoretically,the extreme increases in estrogen and progester-one caused by the stimulation of ovaries by fertil-ity drugs may lead to the development of breastcancer by affecting the proliferation of the cells of breast epithelium. Besides, infertility was shownone of the factors increasing the risk of breastcancer (41,44).Brzezinski et al. (44) reported 16 cases of breastcancer in 950 infertile women treated with fertil-ity drugs, suggesting an incidence of 2.2 timeshigher than that in general population. However,in four of 16 patients, the period of time betweenthe ovulation induction and the diagnosis of can-cer was quite short to mention about a causalassociation.In a recent study, including a large number of cases and controls, it was reported that the use of fertility drugs was not associated with an overallincrease in the risk of breast cancer amongwomen, who had been diagnosed with infertility(OR: 1.2; 95% CI: 0.8–1.7). On the other hand, thestudy suggested that women, who had used HMGfor  6months or for at least six treatment cycles,had an increased risk of breast cancer (OR: 2.8;95% CI: 1.1–6.8 for   6months of use and OR:3.8; 95% CI: 1.2–11.8 for  6 cycles of use) (45).Two retrospective studies have shown that theincidence of breast cancer in infertile women trea-ted with ovulation-inducing drugs is not differentfrom that in untreated infertile patients or that inthe general population (22,46).These reports are consistent with previous stud-ies, in which an elevated, but non-significant, riskof breast cancer was found associated with infer-tility; however, there was no additional risk afterthe use of fertility drugs (41,47). In addition, in alarge case-control study, Braga et al. (48) sug-gested that there were no statistically significantdifferences between women, who were exposed tofertility drugs, and women, who were not exposedto fertility drugs. Therefore, the use of fertilitydrugs among infertile women does not seem to besignificantly associated with an increased risk of breast cancer. Furthermore, it has been reportedthat the risk of breast cancer among women, whohad taken clomiphene for ovulation induction,was reduced, compared to that among infertile1108  M. C. Salman et al. #  Acta Obstet Gynecol Scand 83 (2004)
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