Hum. Reprod. Advance Access originally published online on December 6, 2007
Human Reproduction 2008 23(2):451-456; doi:10.1093/humrep/dem381
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Risk of thyroid cancer after exposure to fertility drugs: results from a large Danish cohort study
1 Department of Viruses, Hormones and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49,2100 Copenhagen, Denmark 2 The Juliane Marie Centre, Copenhagen University Hospital, Blegdamsvej 9,2100 Copenhagen, Denmark
3 Correspondence address. Tel: +45-3525-7693; Fax: +45-3525-7731; E-mail: allan{at}cancer.dk
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Abstract |
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BACKGROUND: Findings from the few epidemiological studies that have investigated thyroid cancer risk after fertility drugs have been inconclusive. Using data from the largest cohort of infertile women to date, we examined the effects of fertility drugs on thyroid cancer risk.
METHODS: A cohort of 54 362 women with infertility problems referred to Danish fertility clinics in the period 1963–1998 was established. A detailed data collection including information about type and amount of treatment was conducted. Using case-cohort techniques, we calculated rate ratios (RRs) of thyroid cancer associated with different fertility drugs after adjustment for age at first live birth.
RESULTS: A total of 29 thyroid cancers were identified during follow-up through 2000. Use of clomiphene [RR = 2.28; 95% confidence interval (CI): 1.08–4.82] or progesterone (RR = 10.14; 95% CI: 1.93–53.33) was associated with an increased thyroid cancer risk, although the latter estimate was based on few cases. When stratifying for parity status, the risk was primarily associated with clomiphene (RR = 3.09; 95% CI: 1.21–7.88) in parous women. No significantly increased risk was found after use of gonadotrophins, hCG or GnRH. We observed no association with number of cycles of use or years since first use (latency).
CONCLUSIONS: Clomiphene and possibly progesterone may increase thyroid cancer risk, particularly among parous women. Longer follow-up is needed to confirm our findings.
Key words: thyroid cancer/infertility/fertility drugs/clomiphene/gonadotrophins
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Introduction |
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The greater incidence of thyroid cancer in women than men, particularly during the reproductive years may imply that female hormones are involved in the etiology of thyroid cancer. Increased thyroid cancer risk is also related to factors such as high parity (McTiernan et al., 1984
; Preston-Martin et al., 1987, 1993; Kravdal et al., 1991; Negri et al., 1999) and use of exogenous hormones such as oral contraceptives (OC) (McTiernan et al., 1984; Preston-Martin et al., 1987, 1993; La et al., 1999), estrogens (Henderson et al., 1982; Williams, 1990) and hormone replacement therapy (McTiernan et al., 1984). In contrast, the influence of fertility drugs on thyroid cancer risk has not been extensively studied despite the wide use of this group of exogenous hormones over the last 30 years and their recognized effect on ovulation and endogenous hormone production (Fathalla, 1971; Henderson et al., 1985; Wysowski, 1993; Mosgaard et al., 1995; Sovino et al., 2002; Ministry of the Interior and Health, 2006). However, a number of epidemiological studies have indicated that fertility drugs may be a risk factor for the hormone-associated cancers of the ovary (Whittemore et al., 1992; Shushan et al., 1996), endometrium (Modan et al., 1998; Althuis et al., 2005a) and breast (Potashnik et al., 1999; Burkman et al., 2003; Jensen et al., 2007), and it is therefore likely that fertility drugs might also be associated with the potentially hormone-associated cancer of the thyroid. In the few epidemiological studies that have investigated the relationship between fertility drugs and thyroid cancer risk, the findings have been equivocal as most studies found no association (Ron et al., 1987a, b; Brinton et al., 1989; Galanti et al., 1996; Modan et al., 1998; La et al., 1999), whereas two studies observed an increased risk (Kolonel et al., 1990; Althuis et al., 2005b). Most of the previous studies, however, have faced various methodological limitations such as small numbers of study subjects, imprecise information about drug exposures, inability to control for potential confounder variables and short follow-up periods. We have established a cohort of 54 362 women with fertility problems referred to Danish hospitals and private fertility clinics in the period 1963–1998. The infertility cohort includes the largest number of thyroid cancer cases to date and comprises extensive information about fertility drug treatment and patient characteristics such as reproductive factors. Using these data, we performed a case-cohort study to evaluate the effects of different groups of fertility drugs on thyroid cancer risk after adjustment for reproductive factors.
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Materials and Methods |
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The cohort has previously been described in detail (Jensen et al., 2007
). Briefly, the cohort comprised women with infertility problems referred to all Danish hospitals or private fertility clinics in the period 1963–1998. Women were identified from a systematic search of hospital case records, microfilm, index card and outpatient’s records. In addition, we included all women with the infertility diagnoses 628 (ICD-8) and DN97 (ICD-10) recorded in the National Patient Registry, a nationwide registry of virtually all somatic discharges in Danish hospitals since 1977 (National Board of Health, 2007c). A total of 54 449 women were identified and included in the cohort. All data were entered into a single computer database, creating one record for each woman, including initial date of infertility evaluation, name of the hospital or private fertility clinic and the woman’s Civil Registry Number (abbreviated as CPR-number). To verify the CPR-number and to determine any dates of migration or death, record linkage with the population-based Danish Civil Registration System (2007) was undertaken using the CPR-number as key identifier. We found that the CPR-numbers of 87 women were invalid, leaving 54 362 women in the cohort. The investigation was approved by the Danish Data Protection Agency and the Scientific Ethical Committee.
To determine the development of thyroid cancer after enrolment in the study, we linked the cohort to the nationwide Danish Cancer Registry (National Board of Health, 2007a). The cohort was followed for occurrence of thyroid cancer from initial date of infertility evaluation until date of migration, death or December 31, 2000, whichever date appeared first. A total of 33 women were diagnosed with thyroid cancer [International Classification of Diseases for Oncology, seventh Revision (ICD-7)] during the follow-up period. A subcohort of 1360 women were randomly selected from the cohort in four strata of age at cohort entry (18–26, 27–30, 31–36 and 37–55 years) and in five strata of calendar year of cohort entry (1963–1977, 1978–1984, 1985–1989, 1990–1996 and 1997–1998), equalling 20 strata.
For all infertile women who developed thyroid cancer and for those in the subcohort, we collected hospital files and medical records on all available infertility-associated medical visits. For four cases, the records could not be found, leaving 29 thyroid cancer cases (88%) for analysis. For the subcohort members, 93 records could not be found, the infertility diagnosis of eight women could not be confirmed and the infertility diagnosis of 33 women was previous sterilization, leaving 1226 subcohort members (90%) for analysis. Of the 1226 subcohort members, three women were diagnosed with thyroid cancer during the follow-up period. These women were included both as cases and subcohort members in the analyses.
Information was abstracted on medical interventions for infertility, including the types of fertility drugs prescribed and number of cycles of use. Information about dosage was reviewed, but in many instances this information was not recorded in the medical records; therefore this measure was not analysed in this study. In addition, we intended to abstract information from the medical records about surgical interventions, causes of infertility, BMI, OC use and age at menarche, but this information was not available for a large proportion of women. For example, at the initial data registration, causes of infertility were only accessible for women registered in the National Patient Registry, but not for women registered in inpatients’ or outpatients’ records. In addition, causes of infertility were only registered in some of the collected medical records. Thus, if a woman was identified from inpatients’ or outpatients’ records, she was only registered with an infertility diagnosis if that information was registered in the medical record. In total, we had information about causes of infertility on only 41.4% of the cases and 40.0% of the subcohort members. Trained abstracters entered all data into computers using standardized software.
To obtain information about reproductive history, we linked the cohort to the nationwide Danish Medical Birth Registry since it contains information about all births in Denmark since 1973 (National Board of Health, 2007b). Births before 1973 were identified through the Danish Civil Registration System (2007) as this registry contains ways to link parents and children. However, since it is not possible to identify stillbirths in the Danish Civil Registration System, we included only live births in this study. Information about number of live births and age at live births was obtained for all infertile women with thyroid cancer and for those in the subcohort.
Statistical methods
Cox regression analysis with age as timescale was used to estimate rate ratios (RRs) and 95% confidence intervals (CIs) between thyroid cancer and use of fertility drugs. The analysis was corrected for delayed entry so women were considered at risk only from the age at first date of infertility evaluation. The RRs were calculated so all women in the subcohort contributed to all relevant risk sets until the end of follow-up due to thyroid cancer, migration, death or end of study, whereas cases outside the subcohort only entered their own risk set (Prentice, 1986).
We evaluated the effect of the following fertility drugs: clomiphene, follicle-stimulating hormone (FSH), human menopausal gonadotrophin (hMG), human chorionic gonadotrophin (hCG), gonadotrophin-releasing hormone (GnRH) and progesterone. All fertility drugs were measured as use (never/ever), number of cycles of use (never/1–5 cycles/6+ cycles) and years since first use (never/<5 years/5+ years). In the analyses, we pooled the two gonadotrophins FSH and hMG together in one group (gonadotrophins) since they have identical modes of operation. Potential confounder variables investigated included parity, number of additional live births, age at first live birth and age at last live birth. All variables were entered as time-dependent variables changing values at the specific ages where a new event happened (e.g. live birth or initiation of a new treatment cycle). Since information about causes of infertility, OC use and age at menarche was not available for a large proportion of women, these potential confounders were not included in the final analyses. All statistical data analyses were carried out using the SAS/STAT version 8.2.
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Results |
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A total of 54 362 women were included in the infertility cohort in the period 1963–1998. The distribution of age and calendar year of cohort entry is shown in Table I. The median age and calendar year of the initial clinic evaluation were 30 years and 1989, the median age at the end of follow-up was 40 years and the median length of follow-up was 8.8 years, with 25% followed for >16 years. In total, the 54 362 infertile women contributed 566 122 person-years of observation.
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A total of 29 women diagnosed with thyroid cancer during the follow-up period were included in the study. The median age at diagnosis was 38 years, ranging from 28 to 55 years. The median time from initial clinic evaluation until diagnosis was 7.2 years, ranging from 1 to 29 years. Of the 29 thyroid cancer cases, 11 cases were papillary carcinomas not otherwise specified (NOS), nine cases were papillary adenocarcinomas (NOS), five cases were follicular adenocarcinomas (NOS), two cases were mixed papillary, follicular adenocarcinomas, one case was Hurthle cell carcinoma and one case was medullary carcinoma (NOS) (DeLellis et al., 2004
). Among the 29 women with thyroid cancer, 17 women (59%) had used fertility drugs and of the 1226 subcohort members, 598 (49%) had used fertility drugs. Clomiphene was the most frequently used fertility drug and was used by 16 cases (94%) and 406 subcohort members (68%), followed by hCG (cases: 76%; subcohort members: 66%), gonadotrophins (cases: 35%; subcohort members: 28%), GnRH (cases: 24%; subcohort members: 16%) and progesterone (cases: 12%; subcohort members: 2%).
Parity status, number of live births and age at first and last live birth did not affect the risk of thyroid cancer significantly (Table II), although the risk appeared to be lower among parous women compared with nulliparous women (RR = 0.75; 95% CI: 0.35–1.62) and seemed to increase with later ages at first live birth (RR = 1.07; 95% CI: 0.85–1.36 per additional 5 years). However, in the final analyses we adjusted for age at first live birth (linear) since this variable has been associated with thyroid cancer risk in previous epidemiological studies (Preston-Martin et al., 1993; Negri et al., 1999; Neale et al., 2005).
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After adjustment, we found that women who used clomiphene (RR = 2.28; 95% CI: 1.08–4.82) or progesterone (RR = 10.14; 95% CI: 1.93–53.33) had a significantly increased thyroid cancer risk compared with women who never used clomiphene or progesterone, respectively (Table III). However, the risk estimate for progesterone was based on only few exposed cases (two cases). In contrast, the risk of thyroid cancer was not significantly increased after use of gonadotrophins (RR = 1.43; 95% CI: 0.54–3.83), hCG (RR = 1.67; 95% CI: 0.79–3.54) or GnRH (RR = 1.82; 95% CI: 0.47–7.02). For all groups of fertility drugs, we found no substantial differences in thyroid cancer risk according to number of cycles of use. Years since first use (latency) of the different fertility drugs did not markedly affect the risk of thyroid cancer among infertile women. However, a small, but statistically non-significant, increased thyroid cancer risk was found for users of gonadotrophins, hCG and GnRH who were followed for five years or longer.
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To estimate whether the risk of thyroid cancer associated with use of fertility drugs differed according to parity status at end of follow-up, we estimated separate effects of the fertility drugs for parous and nulliparous women as defined at the end of follow-up (Table IV). Except for GnRH, the risk of thyroid cancer associated with drug use was more increased among parous women than among nulliparous women. For both clomiphene and progesterone, a significantly increased thyroid cancer risk was observed among parous women (clomiphene: RR = 3.76; CI: 1.48–9.58; progesterone: RR = 14.95; CI: 1.59–140.70), whereas the risk in nulliparous women was not significantly increased. However, none of the interaction terms were statistically significant (clomiphene: P = 0.12; gonadotrophins: P = 0.39; hCG: P = 0.62; GnRH: P = 0.48 and progesterone: P = 0.62).
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Finally, to evaluate the effect of OC use as a potential confounder variable, we adjusted all the above analyses for use of OC in that subset of women with information about this variable (cases: 69%; subcohort members: 56%). However, none of the above-mentioned risk estimates changed markedly after adjustment for OC use (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionFundingAcknowledgementReferences |
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Our results indicate that clomiphene and progesterone may increase the risk of thyroid cancer, with the risk being primarily increased among parous women. In contrast, there was no significantly increased risk after use of gonadotrophins, hCG or GnRH. For all groups of fertility drugs, we found no association with number of cycles of use and no marked association with years since first use (latency).
The majority of previous epidemiological studies have had limited capability to assess the association between a diagnosis of infertility, use of fertility drugs and thyroid cancer risk. Three previous cohort studies have only assessed the risk in populations of infertile women compared with the risk of the general population, and none of the studies found a significantly increased risk (Ron et al., 1987b; Brinton et al., 1989; Modan et al., 1998). However, using data from the present infertility cohort, we recently observed a 33% borderline significantly increased risk of thyroid cancer among infertile women compared with women in the general Danish population (unpublished data). Four case–control studies have assessed the association between use of fertility drugs and thyroid cancer risk, but were not able to differentiate between the different types of fertility drugs (Ron et al., 1987a; Kolonel et al., 1990; Galanti et al., 1996; La et al., 1999). None of the case–control studies found a significantly increased risk with the exception of Kolonel et al. (1990) who reported a 4-fold increased risk. Only a recent cohort study by Althuis et al. (2005b) has estimated thyroid cancer risk after use of gonadotrophins or clomiphene using within cohort analyses. Hence, it is only reasonable to compare our findings with the results from Althuis et al. (2005b) due to anticipated different effects of the different groups of fertility drugs.
Our findings of a 2-fold increased thyroid cancer risk after clomiphene use is partly in line with Althuis et al. (2005b) who reported a 40% non-significantly increased risk. However, after we stratified our analyses for parity, we found that the increased risk mainly was due to a 3-fold increased risk in parous women; although we found no association with parity in the crude analysis. Several epidemiological studies have observed an increased risk of thyroid cancer among parous (Kravdal et al., 1991; Preston-Martin et al., 1993; Negri et al., 1999) and ever pregnant women (McTiernan et al., 1984; Preston-Martin et al., 1987, 1993; Hallquist et al., 1994), indicating that pregnancy itself may be a potential risk factor for thyroid cancer. This relation may be explained by the fact that pregnancy causes elevation in the level of thyroid-stimulating hormone (TSH) which increases the risk of thyroid cancer (Hall and Adami, 2002). Thus, it seems plausible that parity would modify the effect of fertility drugs. It is, however, possible that to some extent the increased risk associated with clomiphene use in parous women may reflect the occurrence of births later in life among exposed women as has been suggested in previous studies (Negri et al., 1999; Rossing et al., 2000). However, when we adjusted for age at last live birth the point estimates remained much the same. In contrast to our findings, Althuis et al. (2005b) reported a 4-fold increased thyroid cancer risk in clomiphene-exposed women who remained nulliparous through the follow-up period.
The mechanisms behind a potential association between clomiphene and thyroid cancer are not completely clear. Estrogen increases the level of TSH which has been hypothesized to enhance mitotic activity in the follicular cells of the thyroid gland and thus increase the risk of malignant transformation (Hall and Adami, 2002). In addition, clomiphene has a relatively long half-life with 5–7 days (Goldstein et al., 2000) compared with the other fertility drugs which have half-lives that do not exceed 24 h. Therefore, our finding of an increased thyroid cancer risk in clomiphene-exposed women may be explained by the fact that clomiphene stays for a longer time in the body. Lastly, however, use of clomiphene could also hypothetically reduce the risk of thyroid cancer because of its anti-estrogenic effect (Lerner-Geva et al., 2006).
In agreement with Althuis et al. (2005b), we found no significantly increased thyroid cancer risk after gonadotrophins use. However, the lack of association with gonadotrophins in our study as well as in the study by Althuis et al. (2005b) might be explained by the low power of both studies. Furthermore, use of hCG or GnRH did not have a strong impart on thyroid cancer risk in our study. For all groups of fertility drugs, we found no association between thyroid cancer risk and number of cycles of use. Similarly, Althuis et al. (2005b) found no relation with number of cycles of use for clomiphene. However, even though a finding of a dose–response relationship would further have supported our results, it does not rule out the potential for a causal relationship.
We found an increased risk associated with use of progesterone. The association, however, was based on only two exposed cases and it is therefore likely that the findings may be solely due to chance. Our study is the first to analyse the association between progesterone in infertility treatment and thyroid cancer risk. In Denmark, progesterone is mainly used as a routine treatment in most IVF and ICSI protocols to enhance implantation of the fertilized oocytes since it increases thickening of the endometrial lining. As IVF/ICSI protocols often involve a regimen of multiple fertility drugs, it is common that women treated with progesterone also receive other types of fertility drugs. In our study, the two cases exposed to progesterone also had used clomiphene, hMG, hCG and GnRH. Thus, we could not establish a potential independent effect of progesterone, and the excess risk associated with progesterone might therefore be explained by the additional use of clomiphene and the other types of fertility drugs. In addition, our findings may have been confounded because progesterone may also have been used to support a threatened pregnancy because progesterone facilitates implantation and prevents rejection of the developing embryo, regardless of the type of infertility treatment that led to a potential pregnancy. Additional, larger studies including more progesterone-exposed cases are clearly needed to confirm or reject our findings.
In general, we found no risk associated with years since last use (latency). However, we observed a non-significant increased thyroid cancer risk among users of gonadotrophins, hCG and GnRH who were followed for 5 years or longer. Althuis et al. (2005b) found no association between years since first use of clomiphene and thyroid cancer risk. However, both the results from our study and from the study by Althuis et al. (2005b) are weakened by the fact that only a small proportion of women were followed for a sufficient amount of time. Longer follow-up time is thus needed to further explore latency effects on thyroid cancer risk after exposure to fertility drugs.
Our study has several strengths. First, even though we included only 29 cases of thyroid in the study, the number is to date the largest number in a study examining the risk of thyroid cancer after use of fertility drugs. Previous cohort studies have only included from four to eight cases (Ron et al., 1987b; Brinton et al., 1989; Modan et al., 1998) with the exception of Althuis et al. (2005b), who included 18 cases. Second, our study contains extensive information about different types of fertility drugs used in infertility treatment and the number of cycles of use. Use of fertility drugs in our infertility cohort resembles the actual use among Danish women in the period, as patterns of use of most fertility drugs in the cohort are in good concordance with sale statistics in the general Danish population in the periods 1973–1993 (Mosgaard et al., 1995) and 1994–1998 (Ministry of the Interior and Health, 2006). Only progesterone seemed somewhat underestimated compared with the actual use among Danish women (Mosgaard et al., 1995; Ministry of the Interior and Health, 2006). Third, our study was linked to several nationwide registers using the unique nature of the Danish CPR-number. This enables a precise linkage between our cohort and the Danish nationwide registers. Therefore, practically no women were lost to follow-up, thus removing selection bias and allowing a precise estimation of the numbers of person-years at risk. Other studies have had problems with loss to follow-up (Brinton et al., 2004; Althuis et al., 2005b). Finally, we had complete ascertainment of thyroid cancer diagnoses through linkage with the nationwide Danish Cancer Registry.
Our study also had some limitations. Even though we had a relatively long follow-up period, the median age at the end of follow-up for the cohort was still relatively low (40 years). Thus, longer follow-up time might have generated more cases and led to stronger risk estimates. In addition, we were unable to estimate the independent effects of the fertility drugs since no cases used only one type. Finally, we did not include potential risk factors for thyroid cancer such as BMI, infertility causes, age at menarche and OC use as these factors were only registered for a small group of women. However, we did perform analyses on the subsets of women who had information about infertility causes, age at menarche and OC use, but these adjustments did not markedly change the overall estimates, indicating that these risk factors are not confounders in the association between fertility drug use and thyroid cancer risk in our study.
In summary, the findings from our nationwide cohort study showed that infertile women who were treated with clomiphene or progesterone may have an increased thyroid cancer risk, and that the increased risk was mainly due to an increased risk in parous women. In contrast, we found no significantly increased risk after use of gonadotrophins, hCG or GnRH. For all groups of fertility drugs, we found no association with number of cycles of use and no marked association with years since first use (latency). In spite of being the largest study to date, the risk estimates in the present study were still based on a relatively small number of cases, so additional long-term follow-up should be performed in order to monitor the association between fertility drug use and the risk of thyroid cancer.
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Funding |
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This research was supported by the Danish Cancer Society.
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Acknowledgement |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionFundingAcknowledgementReferences |
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We thank Nick Martinussen for helping with the data management, and all participating hospital departments and private fertility clinics for their contribution to the data collection.
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References |
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Submitted on June 29, 2007; resubmitted on September 13, 2007; accepted on November 2, 2007.
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