Fertility Drugs Associated with Thyroid Cancer Risk: A Systematic …downloads.hindawi.com/journals/bmri/2018/7191704.pdf · 2019. 7. 30. · BioMedResearchInternational Rrd ﬁ hroug

Review ArticleFertility Drugs Associated with Thyroid Cancer RiskA Systematic Review and Meta-Analysis

QingAn Yu12 XiaoYing Lv3 KunPeng Liu1 DaKunMa1 YaoHuaWu1

WenJie Dai 1 and HongChi Jiang 2

1Department of Thyroid Surgery The First Affiliated Hospital Harbin Medical University Harbin 150001 China2Department of Liver Surgery The First Affiliated Hospital Harbin Medical University Harbin 150001 China3Department of Ophthalmic Clinic The First Affiliated Hospital Harbin Medical University Harbin 150001 China

Correspondence should be addressed to WenJie Dai davidhmu163com and HongChi Jiang jianghcvip163com

Received 23 November 2017 Revised 1 March 2018 Accepted 20 March 2018 Published 10 May 2018

Academic Editor Giovanni Mariscalco

Copyright copy 2018 QingAn Yu et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Associations have been demonstrated between fertility drugs and a variety of hormone-sensitive carcinomas The purpose of thisstudy was to determine the relationship between fertility drugs used in the treatment of female infertility and the risk of thyroidcancer To investigate the clinical significance of fertility drugs used for the treatment of female infertility and the risk associatedwith thyroid cancer we performed a literature search using PubMed MEDLINE the Cochrane Library the Web of Science andEBSCOHOST for comparative studies published any time prior to July 21 2017 The studies included women who were treated forinfertility with fertility drugs such as clomiphene citrate gonadotropins or other unspecified fertility agents which reported theincidence of thyroid cancer as the main outcome Eight studies were included in the meta-analyses Among women with infertilitythere was a significant positive association between thyroid cancer risk and the use of fertility drugs (relative risk [RR] = 13595 confidence interval [CI] 112ndash164 119875 = 0002) Additionally among women with infertility the use of clomiphene citrate wasassociated with an increased risk of thyroid cancer compared to women who did not use fertility drugs (RR = 145 95CI 112ndash188119875 = 0005) After pooling results we found that the parity status of infertile women using fertility drugs was not associated withthyroid cancer risk (RR = 099 95 CI 061ndash158 119875 = 095) In summary clomiphene citrate (the most commonly used fertilitydrug) and other fertility drugs are associated with an increased risk of thyroid cancer

1 Introduction

The incidence of thyroid cancer is increasing globally InSEER the trend of increasing thyroid tumor incidence ratesis greater than the trends seen for any other site of tumor[1] Mortality due to thyroid tumors is also increasing [1]Thyroid cancer is more common in women than in men adifference that is especially evident for differentiated thyroidcancer during the reproductive years [2] It has been reportedthat the occurrence of tumors in women is related to estrogenlevels and pregnancy [3ndash7] Therefore the incidence ofthyroid cancer in females has attracted a lot of attention

The incidence of infertility has also increased an esti-mated 9 of couples worldwide experience some form ofinfertility and 56 of these couples seek medical treatment

for their infertility [8] In recent years there has beenan increase in the development of assisted reproductivetechnologies and other treatments to overcome infertility sothere are now more women who use fertility drugs than inthe past The use of fertility drugs that may cause alterationsin endogenous hormones and multiple ovulations has raisedconcerns about the long-term safety of such medications Alot of attention has focused on whether the use of fertility-enhancing drugs can have an effect on malignancies associ-ated with breast cancer endometrial carcinoma ovarian can-cer and cervical cancer [9] Several studies have investigatedthe relationship between the use of fertility drugs and thyroidcancer however their results have been contradictory [10ndash19] Therefore we conducted a meta-analysis based on thecurrent literature and the results are reported in this study

HindawiBioMed Research InternationalVolume 2018 Article ID 7191704 7 pageshttpsdoiorg10115520187191704

2 BioMed Research International

2 Methods

We conducted a meta-analysis of studies that investigated theassociation between fertility drugs and thyroid cancer risk

21 Search Strategy We followed the guidelines on Meta-Analysis of Observational Studies in Epidemiology for con-ducting systematic reviews and meta-analyses of observa-tional studies [20] To investigate the association betweenfertility drugs used in the treatment of female infertility andthyroid cancer five main databases were searched PubMedMEDLINE the Cochrane Library the Web of Science andEBSCOHOST Each database was searched from the dateof inception to July 21 2017 The review was restricted toarticles published in English We used the following searchkeywords and Medical Subject Heading terms ((ThyroidNeoplasms) OR (Neoplasm Thyroid) OR (Thyroid Neo-plasm) OR (Neoplasms Thyroid) OR (Thyroid Carcinoma)OR (Carcinoma Thyroid) OR (Carcinomas Thyroid) OR(Thyroid Carcinomas) OR (Cancer of Thyroid) OR (Thy-roid Cancers) OR (Thyroid Cancer) OR (Cancer Thyroid)OR (Cancers Thyroid) OR (Cancer of the Thyroid) OR(Thyroid Adenoma) OR (Adenoma Thyroid) OR (Adeno-mas Thyroid) OR (Thyroid Adenomas)) AND ((infertility)OR (ovarian stimulation) OR (ovarian hyperstimulation)OR (fertility agents) OR (fertility drugs) OR (clomiphene)OR (gonadotropins) OR (gonadotropin-releasing hormones)OR (induction of ovulation) OR (in vitro fertilization) OR(assisted reproductive technology))

22 Inclusion Criteria The included studies had to conformto the following criteria (1) the study consisted of femaleswho had received an explicit and reproducible diagnosis ofinfertility andhad been treatedwith fertility-enhancing drugsand who were compared with infertile untreated controls (2)the study evaluated the association between fertility drugsand the risk of thyroid cancer (3) the design was a cohortor case-control study and (4) the report presented oddsratios (ORs) relative risks (RRs) or hazard ratios (HRs)with 95 confidence intervals (95 CIs) Animal researchcase reports duplicated studies and studies not associatedwith fertility drugs and thyroid cancer risk were all excludedWe extracted information on study design reporting timesample size type of fertility drugs used and number oftreatment cycles parity status thyroid cancer incidence andfollow-up time from these studies

23 Data Extraction and Quality Assessment Two inves-tigators independently extracted data from each includedstudy The data included the name of the first author year ofpublication study design country of origins inclusion andexclusion criteria total sample size number of thyroid cancerpatients in the intervention and control groups matching oradjusted factors and RRs or HRs or ORs with 95CIs for theestimation of thyroid cancer risk related to the use of fertilitydrugs We evaluated and filtered all the included studiesgrading each study according to the NewcastlendashOttawa Scale(NOS) [21] This scale was used to assign a maximum ofnine points for each study Studies with scores of seven or

greater were categorized as high-quality studies and thosewith score of 6 or lower were categorized as low-qualitystudies Disagreements were solved by discussions betweenmembers of the study team

24 Statistical Analysis We classified the selected stud-ies extracted data and performed the meta-analysis usingRevMan 53 software which was provided by the CochraneLibrary The role of fertility drugs in thyroid cancer riskwere assessed by calculating pooled RRs and 95 CIs Thebetween-study heterogeneity was estimated using Cochranrsquos119876 and 1198682 tests and 119875 lt 01 and 1198682 gt 50 implicated obviousbetween-study heterogeneity

3 Results

31 Literature Search and Study Characteristics The detailedsteps regarding the search are shown in Figure 1 Overall1106 records were identified and 102 duplicate records wereexcluded Two additional recordswere identified by screeningthe reference lists of included studies and systematic reviewswe excluded an additional 981 records that were case reportsreview articles research protocol articles articles based onguidelines thewrong type of studies or thewrong populationgroup Of the 22 studies selected for potential analysis afurther 14 were excluded because four had no specific dataabout thyroid cancer two were meta-analyses four werereview articles one was a conference paper one had nocontrol groups one focused on the association betweenthyroid gland disorders and in vitro fertilization (IVF) andone was an investigation of the cancer survival rate Finallyeight studies (six retrospective cohort studies one cohortstudy and one case-cohort study) were included in theanalysis (Table 1) [9ndash13 16ndash18] The studies included wereIsraeli (119899 = 2) Norwegian (119899 = 2) American (119899 = 2)Danish (119899 = 1) and Finnish (119899 = 1) The studies enrolled2215467 patients and had a median follow-up of 165 years(range 73ndash30 years) The details regarding NOS for all theincluded studies are shown in Table 2 all the studies werecategorized as high-quality studies

32 Association between Fertility Drugs and Thyroid CancerRisk After pooling the results of the included studies therewas a significant positive association between the risk ofthyroid cancer for women who used fertility drugs versuswomen who did not use fertility drugs (RR = 135 95 CI112ndash164 119875 = 0002) with no considerable heterogeneity(119875 = 028 1198682 = 19 Figure 2)

As clomiphene citrate is the most widely used fertilitydrugs we pooled results from five studies which describedthe risk of thyroid cancer after using clomiphene citrate[11ndash13 18 19] Among women with infertility the risk ofthyroid cancer was significantly greater for those who usedclomiphene citrate versus women who did not use fertilitydrugs (RR = 145 95 CI 112ndash188 119875 = 0005) with noconsiderable heterogeneity (119875 = 040 1198682 = 1 Figure 3)

33 Parity Status Hannibal et al [12] showed that parousversus nulliparous women who used fertility drugs had a

BioMed Research International 3

Records identified through database searching(n = 1106)

Records aer duplicates were removed(n = 102)

Records screened(n = 1004)

Additional records identified throughscreening of reference lists of includedstudies and systematic reviews (n = 2)

Case report 47Review 29

Title excluded 682Abstract excluded 226

Records excluded (n = 981)

Full-text articles assessed foreligibility (n = 22)

Studies eligible for meta-analysis(n = 8)

yroid cancer related data are not available 4Meta analysis 2

Review of fertility drugs and cancer 4Conference paper 1No control group 1

yroid gland disorders with IVF 1Investigation of cancer survival rate 1

Full-text articles excluded with reasons (n = 14)

Figure 1 Flowchart of the study selection process

Study or Subgroup

Althuis et al 2005Brinton et al 2015Calderon-Margalit et al 2009Hannibal et al 2008Reigstad et al 2015Reigstad et al 2017Ron et al 1987Yli-Kuha et al 2012

Total (95 CI)Total events

8284

1713604

10

144

32763769567598

165255619425759175

92679

10276412

919877

28

1919

Events Total51466123

14463628

7897231297530

25759175

2125363

Weight

471242971

2284401248

1000

M-H Fixed 95 CI126 [050 318]168 [099 285]159 [058 436]149 [072 309]068 [039 117]158 [122 205]

200 [037 1091]125 [049 317]

135 [112 164]

Events TotalExperimental Control Risk Ratio Risk Ratio

M-H Fixed 95 CI

001 01 1 10 100Heterogeneity 2 = 860 d = 7 (P = 028) I2 = 19Test for overall effect Z = 310 (P = 0002)

Figure 2 Forest plots of Risk Ratio with corresponding 95 CIs for the correlation between fertility drugs and thyroid cancer risk CIconfidence interval


Table1Ch

aracteris

ticso

fallinclu

dedstu

dies

Stud

yLo

catio

nStud

ysiz

eStud

ydesig

nEn

rollm

entp

eriod

Fertilitytre

atment

Matchedadjustedfactors

Follo

w-up

(years)

Ronetal[10]

Israel

2575

Retro

spectiv

ecoh

ortstudy

1964

ndash1974

Unk

nown

Unk

nown

123

Alth

uise

tal[11]

USA

8422

Retro

spectiv

ecoh

ortstudy

1965ndash1988

Clom

iphenegon

adotropins

Stud

ysiteagea

tfollow-up

calend

aryear

offollo

w-upgravidity

atentryparityatfollo

w-up

188

Hannibaletal[12]

Denmark

54362

Case-coh

ortstudy

1963ndash1998

Clom

iphenegon

adotropins

progesteronrhCG

GnR

HAge

atfirstliveb

irthparitysta

tus

88

Calderon

-Margalit

etal

[13]

Israel

15030

Retro

spectiv

ecoh

ortstudy

1974ndash1976

Clom

iphenegon

adotropins

otheru

nkno

wnfertilitydrugs

Age

atfirstbirthgeograph

icorigin

socialcla

ssedu

catio

nparitytim

eto

conceptio

nmeanbo

dymass

index

29

Yli-K

uhae

tal[14

]Finland

1835

0coho

rtstu

dy1996ndash1998

IVF

Agem

arita

lstatussocioecono

mic

position

78

Reigstad

etal[17]

Norway

806248

Retro

spectiv

ecoh

ortstudy

1984ndash2010

IVFICSIothers

Age

atsta

rtfollo

w-upparityat

entrymetho

dof

ART

durationof

follo

w-up

73

Brintonetal[18]

USA

9892

Retro

spectiv

ecoh

ortstudy

1965ndash1988

Clom

iphenegon

adotropins

combinatio

n

Racereprodu

ctives

tatusa

tfirst

clinicv

isitreprod

uctiv

estatusa

tfollo

w-upnu

mbero

fbirths

atfollo

w-upagea

tfirstb

irthagea

tmenarcheBM

Iatfi

rstclin

icvisit

ever

smokecauseo

finfertility

30

Reigstad

etal[19]

Norway

1353724

Retro

spectiv

ecoh

ortstudy

1960ndash1996

Clom

iphene

citrateGnR

H

gonado

tropinshCG

BirthyearparityC

Cexpo

sure

region

ofpresentresidencenum

ber

ofchild

renatentryagea

tstartof

follo

w-upagea

tfirstcancertypes

oftre

atmentnu

mbero

fcycleso

fART

doseo

fclomiphene

citrate

18

hCGhum

anchorionicg

onadotropin

GnR

Hgon

adotropin-releasingho

rmon

eIV

Fin

vitro

fertilizatio

nandICSIintracytoplasmicsperm

injection


Study or Subgroup

Althuis et al 2005Brinton et al 2015Calderon-Margalit et al 2009Hannibal et al 2008Reigstad et al 2017


8283

1631

86

32763769362406

38927

46740

10276413

877

991


14463820

1297530

1324082

Weight

7723750

127509

1000

M-H Random 95 CI126 [050 318]168 [099 285]187 [059 593]249 [121 512]118 [082 169]

145 [112 188]


M-H Random 95 CI

001 01 1 10 100Test for overall effect Z = 283 (P = 0005)Heterogeneity 2 = 000 2 = 402 d = 4 (P = 040) I2 = 1

Figure 3 Forest plots of Risk Ratio with corresponding 95 CIs for the correlation between clomiphene citrate and thyroid cancer risk CIconfidence interval

Study or Subgroup

Calderon-Margalit et al 2009Hannibal et al 2008Reigstad et al 2015Reigstad et al 2017


3125

16

36

34515589

15014645

30729

11

1144

57


41549

42963

Weight

3655

238671

1000

M-H Fixed 95 CI193 [020 1844]072 [009 554]078 [027 219]103 [058 183]

099 [061 158]


M-H Fixed 95 CI


Figure 4 Forest plots of Risk Ratio with corresponding 95CIs for the correlation between parity status of infertile womenwhowere treatedwith fertility drugs and thyroid cancer risk CI confidence interval

higher risk of thyroid cancer (RR = 309 95 CI 121ndash788)Therefore we stratified the results based on parity status Inthe meta-analysis we observed that there was no associationbetween the use of fertility drugs and thyroid cancer riskin parous versus nulliparous women (RR = 099 95 CI061ndash158 119875 = 095) with no considerable heterogeneity(119875 = 088 1198682 = 0 Figure 4)

4 Discussion

This study shows that the use of fertility drugs by infertilewomen increases their risk of developing thyroid cancer

The number of infertile women who receive treatmentfor infertility is increasing as the incidence of infertilityincreases Some studies have suggested that there are relation-ships between the use of fertility therapy and the risk of can-cer especially for breast cancer endometrial cancer and otherhormone-related carcinomas [19 22 23] Thyroid cancer isalso a hormone-related cancer elevated estrogen levels canpromote the growth of differentiated thyroid cancer [24ndash28]which may be related to the estrogen receptor pathway [2930] It is unknown whether the use of fertility drugs by infer-tile women is associatedwith an increased risk of thyroid can-cer Therefore we reviewed all related published studies for

this meta-analysisThrough database retrieval and screeningwe enrolled all eligible studies which included eight cohortstudies and involved a total of 2215467 infertile patients ofwhom 92679 received fertility treatment A pooled analysisshowed that fertility therapy increased the risk of thyroidcancer these results were statistically significant with noheterogeneity (RR = 135 95 CI 112ndash164 119875 = 0002)

Of the eight cohort studies seven identified the fertilitytreatment and medication One of the interventions wasIVF [14] but the associated report did not explicitly detailwhat fertility drugs were used Another study used IVFintracytoplasmic sperm injection (ICSI) and other treatmentmodalities but also did not explicitly state what kinds of fertil-ity drugs were used [17] We carried out a further analysis onthe remaining five studies in which the main fertility drugsused were clomiphene citrate gonadotropins progesteronehuman chorionic menopausal (hCG) and gonadotropin-releasing hormone (GnRH) Clomiphene citrate is the mostwidely used fertility drug Thus we carried out furtheranalyses to investigate the impact of clomiphene citrate forthe treatment of infertility Among the study participantswithinfertility we found that those who used clomiphene citratehad a higher risk of thyroid cancer than those who did not(RR = 145 95 CI 112ndash188 119875 = 0005) Due to lack of


Table 2 NewcastlendashOttawa quality assessment of cohort studies

Study Cohortrepresentative

Selection ofnonexposed

cohort

Ascertainmentof exposure

Outcomenegativeat start

Comparablecases andcontrols

Outcomeassessment

Durationof

follow-up

Adequatefollow-up Score

Ron et al [10] A A A A A A A 7Althuis et al [11] A A A A A A A A 8Hannibal et al [12] A A A A A A A A 8Calderon-Margalitet al [13] A A A A A A A A 8

Yli-Kuha et al [14] A A A A B A A A 9Reigstad et al [17] A A A A A A A A 8Brinton et al [18] A A A A A A A A 8Reigstad et al [19] A A A A B A A A 9

specific statistical data we were unable to assess the individ-ual associations of gonadotropins progesterone hCG andGnRH with thyroid cancer risk Hannibal et al [12] showedthat progesterone is associated with thyroid cancer (RR =1014 95 CI 193ndash5334) however Brinton et al [18] andAlthuis et al [11] showed that progesterone is not associatedwith an increased thyroid cancer risk Additionally Hannibalet al [12] showed that gonadotropins hCG and GnRH arenot associated with an increased thyroid cancer risk

Parity status is an important adjustment factor whenstudying fertility treatment Althuis et al [11] Brinton et al[18] and Reigstad et al [19] showed that nulliparous womenwho used fertility drugs had a higher risk of thyroid cancerwhen compared with parous women On the other handHannibal et al [12] arrived at the opposite finding Afterpooling the results we found that the parity status of infertilewomen using fertility drugs was not associated with thyroidcancer risk (RR = 099 95 CI 061ndash158 119875 = 095)

This study had several limitations Relatively few cohortstudies have been published regarding the use of fertilitydrugs and the risk of thyroid cancer more cohort studies areneeded to further confirm the association between the use offertility drugs and the risk of developing thyroid cancer Addi-tionally because of the relatively small quantity of availabledata there was no adjustment for confounding factors relatedto infertility Finally we did not perform a detailed investi-gation of the doses and cycles of the administered fertilitydrugs Althuis et al [11] and Brinton et al [18] showed thatthe doses and cycles of fertility drugs use were not associatedwith thyroid cancer risk AndHannibal et al [12] found for allgroups of fertility drugs there were no substantial differencesin thyroid cancer risk according to number of cycles of use

5 Conclusion

Increased thyroid cancer risk is associated with the use offertility drugs including the most commonly used fertilitydrug clomiphene citrateThe parity status of infertile womenwhouse fertility drugs is not related to their risk of developingthyroid cancer There is a need for further epidemiologicalstudies with large sample sizes to confirm the magnitude of

the association between the use of fertility drugs and the riskof developing thyroid cancer

Ethical Approval

This article does not include any study with human partici-pants or animals that was performed by any of the authors

Conflicts of Interest

The authors declare that they have no conflicts of interest

References

[1] N Howlader A M Noone M Krapcho et al Eds SEERCancer Statistics Review 1975ndash2013 National Cancer Insti-tute BethesdaMdUSA 2016 httpsseercancergovcsr19752013

[2] M Moleti G Sturniolo M Di Mauro M Russo and F Ver-miglio ldquoFemale reproductive factors and differentiated thyroidcancerrdquo Frontiers in Endocrinology vol 8 article 111 2017

[3] C Xhaard C Rubino E Clero et al ldquoMenstrual and repro-ductive factors in the risk of differentiated thyroid carcinomain young women in France A population-based case-controlstudyrdquo American Journal of Epidemiology vol 180 no 10 pp1007ndash1017 2014

[4] S Rajoria R Suriano A George et al ldquoEstrogen inducedmetastatic modulators MMP-2 and MMP-9 are targets of 331015840-diindolylmethane in thyroid cancerrdquo PLoS ONE vol 6 no 1Article ID e15879 2011

[5] P Brindel F Doyon F Rachedi et al ldquoMenstrual and repro-ductive factors in the risk of differentiated thyroid carcinomain native women in French Polynesia a population-based case-control studyrdquoAmerican Journal of Epidemiology vol 167 no 2pp 219ndash229 2008

[6] E Przybylik-Mazurek A Hubalewska-Dydejczyk A Fedorow-icz and D Pach ldquoFactors connected with the female sex seemto play an important role in differentiated thyroid cancerrdquoGynecological Endocrinology vol 28 no 2 pp 150ndash155 2012

[7] E Hognas A Kauppila E Pukkala and J S TapanainenldquoCancer risk in women with 10 or more deliveriesrdquo Obstetricsamp Gynecology vol 123 no 4 pp 811ndash816 2014


[8] J Boivin L Bunting J A Collins and K G Nygren ldquoInterna-tional estimates of infertility prevalence and treatment-seekingpotential need and demand for infertility medical carerdquoHumanReproduction vol 22 no 6 pp 1506ndash1512 2007

[9] L A Brinton V V Sahasrabuddhe and B Scoccia ldquoFertilitydrugs and the risk of breast and gynecologic cancersrdquo Seminarsin Reproductive Medicine vol 30 no 2 pp 131ndash145 2012

[10] E Ron B Lunenfeld J Menczer et al ldquoCancer incidence in acohort of infertile womenrdquo American Journal of Epidemiologyvol 125 no 5 pp 780ndash790 1987

[11] M D Althuis B Scoccia E J Lamb et al ldquoMelanoma thyroidcervical and colon cancer risk after use of fertility drugsrdquoAmerican Journal of Obstetrics amp Gynecology vol 193 no 3 pp668ndash674 2005

[12] C G Hannibal A Jensen H Sharif and S K Kjaer ldquoRisk ofthyroid cancer after exposure to fertility drugs results from alarge Danish cohort studyrdquoHuman Reproduction vol 23 no 2pp 451ndash456 2008

[13] R Calderon-Margalit Y Friedlander R Yanetz et al ldquoCancerrisk after exposure to treatments for ovulation inductionrdquoAmerican Journal of Epidemiology vol 169 no 3 pp 365ndash3752009

[14] A-N Yli-Kuha M Gissler R Klemetti R Luoto and EHemminki ldquoCancer morbidity in a cohort of 9175 Finnishwomen treated for infertilityrdquoHuman Reproduction vol 27 no4 pp 1149ndash1155 2012

[15] M Martinez S Rabadan J Domingo A Cobo A Pellicer andJ A Garcia-Velasco ldquoObstetric outcome after oocyte vitrifica-tion and warming for fertility preservation in women with can-cerrdquo Reproductive BioMedicine Online vol 29 no 6 pp 722ndash728 2014

[16] K Pazaitou-Panayiotou K A Toulis S Mandanas and B CTarlatzis ldquoThyroid cancer after in vitro fertilization A retro-spective non-consecutive case-series analysisrdquo GynecologicalEndocrinology vol 30 no 8 pp 569ndash572 2014

[17] MM Reigstad I K Larsen T A Myklebust et al ldquoCancer riskamong parous women following assisted reproductive technol-ogyrdquo Human Reproduction vol 30 no 8 pp 1952ndash1963 2015

[18] L A Brinton K S Moghissi B Scoccia et al ldquoEffects offertility drugs on cancers other than breast and gynecologicmalignanciesrdquo Fertility and Sterility vol 104 no 4 pp 980ndash9882015

[19] M M Reigstad R Storeng T A Myklebust et al ldquoCancerrisk in women treated with fertility drugs according to paritystatusmdasha registry-based cohort studyrdquo Cancer EpidemiologyBiomarkers amp Prevention vol 26 no 6 pp 953ndash962 2017

[20] D F Stroup J A Berlin S C Morton et al ldquoMeta-analysis ofobservational studies in epidemiology a proposal for report-ingrdquo Journal of the American Medical Association vol 283 no15 pp 2008ndash2012 2000

[21] G A Wells B Shea D OrsquoConnel et al ldquoThe Newcastle-Otawa Scale (NOS) for assessing the quality of non randomisedstudies in meta-analysisrdquo in Proceedings of the 3rd Symposiumon Systematic Reviews beyond the Basics Improving Quality andImpact Oxford UK 2000

[22] G Potashnik L Lerner-Geva L Genkin A Chetrit E Lunen-feld and A Porath ldquoFertility drugs and the risk of breastand ovarian cancers Results of a long-term follow-up studyrdquoFertility and Sterility vol 71 no 5 pp 853ndash859 1999

[23] F Parazzini C Pelucchi R Talamini M Montella and C LaVecchia ldquoUse of fertility drugs and risk of endometrial cancer

in an Italian case-control studyrdquo European Journal of CancerPrevention vol 19 no 6 pp 428ndash430 2010

[24] D Manole B Schildknecht B Gosnell E Adams and MDerwahl ldquoEstrogen promotes growth of human thyroid tumorcells by differentmolecularmechanismsrdquoThe Journal of ClinicalEndocrinology ampMetabolism vol 86 no 3 pp 1072ndash1077 2001

[25] Q Zeng G G Chen A C Vlantis and C A Van HasseltldquoOestrogen mediates the growth of human thyroid carcinomacells via an oestrogen receptormdashERK pathwayrdquo Cell Prolifera-tion vol 40 no 6 pp 921ndash935 2007

[26] G G Chen A C Vlantis Q Zeng and C A van HasseltldquoRegulation of cell growth by estrogen signaling and potentialtargets in thyroid cancerrdquo Current Cancer Drug Targets vol 8no 5 pp 367ndash377 2008

[27] AKumar CMKlinge andR EGoldstein ldquoEstradiol-inducedproliferation of papillary and follicular thyroid cancer cells ismediated by estrogen receptors alpha and betardquo InternationalJournal of Oncology vol 36 no 5 pp 1067ndash1080 2010

[28] S Rajoria R Suriano A Shanmugam et al ldquoMetastatic pheno-type is regulated by estrogen in thyroid cellsrdquo Thyroid vol 20no 1 pp 33ndash41 2010

[29] JWYi S-J Kim J KKim et al ldquoUpregulation of the ESR1 geneand ESR ratio (ESR1ESR2) is associated with a worse prognosisin papillary thyroid carcinoma the impact of the estrogenreceptor alphabeta expression on clinical outcomes in papillarythyroid carcinoma patientsrdquo Annals of Surgical Oncology vol24 no 12 pp 3754ndash3762 2017

[30] Y Zhang F Wei J Zhang et al ldquoBisphenol A and estrogeninduce proliferation of human thyroid tumor cells via an estro-gen-receptor-dependent pathwayrdquoArchives of Biochemistry andBiophysics vol 633 pp 29ndash39 2017

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Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom


2 Methods

We conducted a meta-analysis of studies that investigated theassociation between fertility drugs and thyroid cancer risk

21 Search Strategy We followed the guidelines on Meta-Analysis of Observational Studies in Epidemiology for con-ducting systematic reviews and meta-analyses of observa-tional studies [20] To investigate the association betweenfertility drugs used in the treatment of female infertility andthyroid cancer five main databases were searched PubMedMEDLINE the Cochrane Library the Web of Science andEBSCOHOST Each database was searched from the dateof inception to July 21 2017 The review was restricted toarticles published in English We used the following searchkeywords and Medical Subject Heading terms ((ThyroidNeoplasms) OR (Neoplasm Thyroid) OR (Thyroid Neo-plasm) OR (Neoplasms Thyroid) OR (Thyroid Carcinoma)OR (Carcinoma Thyroid) OR (Carcinomas Thyroid) OR(Thyroid Carcinomas) OR (Cancer of Thyroid) OR (Thy-roid Cancers) OR (Thyroid Cancer) OR (Cancer Thyroid)OR (Cancers Thyroid) OR (Cancer of the Thyroid) OR(Thyroid Adenoma) OR (Adenoma Thyroid) OR (Adeno-mas Thyroid) OR (Thyroid Adenomas)) AND ((infertility)OR (ovarian stimulation) OR (ovarian hyperstimulation)OR (fertility agents) OR (fertility drugs) OR (clomiphene)OR (gonadotropins) OR (gonadotropin-releasing hormones)OR (induction of ovulation) OR (in vitro fertilization) OR(assisted reproductive technology))

22 Inclusion Criteria The included studies had to conformto the following criteria (1) the study consisted of femaleswho had received an explicit and reproducible diagnosis ofinfertility andhad been treatedwith fertility-enhancing drugsand who were compared with infertile untreated controls (2)the study evaluated the association between fertility drugsand the risk of thyroid cancer (3) the design was a cohortor case-control study and (4) the report presented oddsratios (ORs) relative risks (RRs) or hazard ratios (HRs)with 95 confidence intervals (95 CIs) Animal researchcase reports duplicated studies and studies not associatedwith fertility drugs and thyroid cancer risk were all excludedWe extracted information on study design reporting timesample size type of fertility drugs used and number oftreatment cycles parity status thyroid cancer incidence andfollow-up time from these studies

23 Data Extraction and Quality Assessment Two inves-tigators independently extracted data from each includedstudy The data included the name of the first author year ofpublication study design country of origins inclusion andexclusion criteria total sample size number of thyroid cancerpatients in the intervention and control groups matching oradjusted factors and RRs or HRs or ORs with 95CIs for theestimation of thyroid cancer risk related to the use of fertilitydrugs We evaluated and filtered all the included studiesgrading each study according to the NewcastlendashOttawa Scale(NOS) [21] This scale was used to assign a maximum ofnine points for each study Studies with scores of seven or

greater were categorized as high-quality studies and thosewith score of 6 or lower were categorized as low-qualitystudies Disagreements were solved by discussions betweenmembers of the study team

24 Statistical Analysis We classified the selected stud-ies extracted data and performed the meta-analysis usingRevMan 53 software which was provided by the CochraneLibrary The role of fertility drugs in thyroid cancer riskwere assessed by calculating pooled RRs and 95 CIs Thebetween-study heterogeneity was estimated using Cochranrsquos119876 and 1198682 tests and 119875 lt 01 and 1198682 gt 50 implicated obviousbetween-study heterogeneity

3 Results

31 Literature Search and Study Characteristics The detailedsteps regarding the search are shown in Figure 1 Overall1106 records were identified and 102 duplicate records wereexcluded Two additional recordswere identified by screeningthe reference lists of included studies and systematic reviewswe excluded an additional 981 records that were case reportsreview articles research protocol articles articles based onguidelines thewrong type of studies or thewrong populationgroup Of the 22 studies selected for potential analysis afurther 14 were excluded because four had no specific dataabout thyroid cancer two were meta-analyses four werereview articles one was a conference paper one had nocontrol groups one focused on the association betweenthyroid gland disorders and in vitro fertilization (IVF) andone was an investigation of the cancer survival rate Finallyeight studies (six retrospective cohort studies one cohortstudy and one case-cohort study) were included in theanalysis (Table 1) [9ndash13 16ndash18] The studies included wereIsraeli (119899 = 2) Norwegian (119899 = 2) American (119899 = 2)Danish (119899 = 1) and Finnish (119899 = 1) The studies enrolled2215467 patients and had a median follow-up of 165 years(range 73ndash30 years) The details regarding NOS for all theincluded studies are shown in Table 2 all the studies werecategorized as high-quality studies

32 Association between Fertility Drugs and Thyroid CancerRisk After pooling the results of the included studies therewas a significant positive association between the risk ofthyroid cancer for women who used fertility drugs versuswomen who did not use fertility drugs (RR = 135 95 CI112ndash164 119875 = 0002) with no considerable heterogeneity(119875 = 028 1198682 = 19 Figure 2)

As clomiphene citrate is the most widely used fertilitydrugs we pooled results from five studies which describedthe risk of thyroid cancer after using clomiphene citrate[11ndash13 18 19] Among women with infertility the risk ofthyroid cancer was significantly greater for those who usedclomiphene citrate versus women who did not use fertilitydrugs (RR = 145 95 CI 112ndash188 119875 = 0005) with noconsiderable heterogeneity (119875 = 040 1198682 = 1 Figure 3)

33 Parity Status Hannibal et al [12] showed that parousversus nulliparous women who used fertility drugs had a
















Study or Subgroup



8284

1713604

10

144

32763769567598

165255619425759175

92679

10276412

919877

28

1919


14463628

7897231297530

25759175

2125363

Weight

471242971

2284401248

1000

M-H Fixed 95 CI126 [050 318]168 [099 285]159 [058 436]149 [072 309]068 [039 117]158 [122 205]

200 [037 1091]125 [049 317]

135 [112 164]


M-H Fixed 95 CI




Table1Ch

aracteris

ticso

fallinclu

dedstu

dies

Stud

yLo

catio

nStud

ysiz

eStud

ydesig

nEn

rollm

entp

eriod

Fertilitytre

atment


Follo

w-up

(years)

Ronetal[10]

Israel

2575

Retro

spectiv

ecoh

ortstudy

1964

ndash1974

Unk

nown

Unk

nown

123

Alth

uise

tal[11]

USA

8422

Retro

spectiv

ecoh

ortstudy

1965ndash1988

Clom

iphenegon

adotropins

Stud

ysiteagea

tfollow-up

calend

aryear

offollo

w-upgravidity


w-up

188

Hannibaletal[12]

Denmark

54362

Case-coh

ortstudy

1963ndash1998

Clom

iphenegon

adotropins

progesteronrhCG

GnR

HAge

atfirstliveb

irthparitysta

tus

88

Calderon

-Margalit

etal

[13]

Israel

15030

Retro

spectiv

ecoh

ortstudy

1974ndash1976

Clom

iphenegon

adotropins

otheru

nkno

wnfertilitydrugs

Age


icorigin

socialcla

ssedu

catio

nparitytim

eto

conceptio

nmeanbo

dymass

index

29

Yli-K

uhae

tal[14

]Finland

1835

0coho

rtstu

dy1996ndash1998

IVF

Agem

arita

lstatussocioecono

mic

position

78

Reigstad

etal[17]

Norway

806248

Retro

spectiv

ecoh

ortstudy

1984ndash2010

IVFICSIothers

Age

atsta

rtfollo

w-upparityat

entrymetho

dof

ART

durationof

follo

w-up

73

Brintonetal[18]

USA

9892

Retro

spectiv

ecoh

ortstudy

1965ndash1988

Clom

iphenegon

adotropins

combinatio

n

Racereprodu

ctives

tatusa

tfirst

clinicv

isitreprod

uctiv

estatusa

tfollo

w-upnu

mbero

fbirths

atfollo

w-upagea

tfirstb

irthagea

tmenarcheBM

Iatfi

rstclin

icvisit

ever

smokecauseo

finfertility

30

Reigstad

etal[19]

Norway

1353724

Retro

spectiv

ecoh

ortstudy

1960ndash1996

Clom

iphene

citrateGnR

H

gonado

tropinshCG

BirthyearparityC

Cexpo

sure

region


ber

ofchild

renatentryagea

tstartof

follo

w-upagea

tfirstcancertypes

oftre

atmentnu

mbero

fcycleso

fART

doseo

fclomiphene

citrate

18

hCGhum

anchorionicg

onadotropin

GnR

Hgon


rmon

eIV

Fin

vitro

fertilizatio


injection


Study or Subgroup



8283

1631

86

32763769362406

38927

46740

10276413

877

991


14463820

1297530

1324082

Weight

7723750

127509

1000

M-H Random 95 CI126 [050 318]168 [099 285]187 [059 593]249 [121 512]118 [082 169]

145 [112 188]


M-H Random 95 CI



Study or Subgroup



3125

16

36

34515589

15014645

30729

11

1144

57


41549

42963

Weight

3655

238671

1000

M-H Fixed 95 CI193 [020 1844]072 [009 554]078 [027 219]103 [058 183]

099 [061 158]


M-H Fixed 95 CI




4 Discussion









cohort




Outcomeassessment

Durationof

follow-up







5 Conclusion



Ethical Approval




References





































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of


































Study or Subgroup



8284

1713604

10

144

32763769567598

165255619425759175

92679

10276412

919877

28

1919


14463628

7897231297530

25759175

2125363

Weight

471242971

2284401248

1000

M-H Fixed 95 CI126 [050 318]168 [099 285]159 [058 436]149 [072 309]068 [039 117]158 [122 205]

200 [037 1091]125 [049 317]

135 [112 164]


M-H Fixed 95 CI




Table1Ch

aracteris

ticso

fallinclu

dedstu

dies

Stud

yLo

catio

nStud

ysiz

eStud

ydesig

nEn

rollm

entp

eriod

Fertilitytre

atment


Follo

w-up

(years)

Ronetal[10]

Israel

2575

Retro

spectiv

ecoh

ortstudy

1964

ndash1974

Unk

nown

Unk

nown

123

Alth

uise

tal[11]

USA

8422

Retro

spectiv

ecoh

ortstudy

1965ndash1988

Clom

iphenegon

adotropins

Stud

ysiteagea

tfollow-up

calend

aryear

offollo

w-upgravidity


w-up

188

Hannibaletal[12]

Denmark

54362

Case-coh

ortstudy

1963ndash1998

Clom

iphenegon

adotropins

progesteronrhCG

GnR

HAge

atfirstliveb

irthparitysta

tus

88

Calderon

-Margalit

etal

[13]

Israel

15030

Retro

spectiv

ecoh

ortstudy

1974ndash1976

Clom

iphenegon

adotropins

otheru

nkno

wnfertilitydrugs

Age


icorigin

socialcla

ssedu

catio

nparitytim

eto

conceptio

nmeanbo

dymass

index

29

Yli-K

uhae

tal[14

]Finland

1835

0coho

rtstu

dy1996ndash1998

IVF

Agem

arita

lstatussocioecono

mic

position

78

Reigstad

etal[17]

Norway

806248

Retro

spectiv

ecoh

ortstudy

1984ndash2010

IVFICSIothers

Age

atsta

rtfollo

w-upparityat

entrymetho

dof

ART

durationof

follo

w-up

73

Brintonetal[18]

USA

9892

Retro

spectiv

ecoh

ortstudy

1965ndash1988

Clom

iphenegon

adotropins

combinatio

n

Racereprodu

ctives

tatusa

tfirst

clinicv

isitreprod

uctiv

estatusa

tfollo

w-upnu

mbero

fbirths

atfollo

w-upagea

tfirstb

irthagea

tmenarcheBM

Iatfi

rstclin

icvisit

ever

smokecauseo

finfertility

30

Reigstad

etal[19]

Norway

1353724

Retro

spectiv

ecoh

ortstudy

1960ndash1996

Clom

iphene

citrateGnR

H

gonado

tropinshCG

BirthyearparityC

Cexpo

sure

region


ber

ofchild

renatentryagea

tstartof

follo

w-upagea

tfirstcancertypes

oftre

atmentnu

mbero

fcycleso

fART

doseo

fclomiphene

citrate

18

hCGhum

anchorionicg

onadotropin

GnR

Hgon


rmon

eIV

Fin

vitro

fertilizatio


injection


Study or Subgroup



8283

1631

86

32763769362406

38927

46740

10276413

877

991


14463820

1297530

1324082

Weight

7723750

127509

1000

M-H Random 95 CI126 [050 318]168 [099 285]187 [059 593]249 [121 512]118 [082 169]

145 [112 188]


M-H Random 95 CI



Study or Subgroup



3125

16

36

34515589

15014645

30729

11

1144

57


41549

42963

Weight

3655

238671

1000

M-H Fixed 95 CI193 [020 1844]072 [009 554]078 [027 219]103 [058 183]

099 [061 158]


M-H Fixed 95 CI




4 Discussion









cohort




Outcomeassessment

Durationof

follow-up







5 Conclusion



Ethical Approval




References





































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Table1Ch

aracteris

ticso

fallinclu

dedstu

dies

Stud

yLo

catio

nStud

ysiz

eStud

ydesig

nEn

rollm

entp

eriod

Fertilitytre

atment


Follo

w-up

(years)

Ronetal[10]

Israel

2575

Retro

spectiv

ecoh

ortstudy

1964

ndash1974

Unk

nown

Unk

nown

123

Alth

uise

tal[11]

USA

8422

Retro

spectiv

ecoh

ortstudy

1965ndash1988

Clom

iphenegon

adotropins

Stud

ysiteagea

tfollow-up

calend

aryear

offollo

w-upgravidity


w-up

188

Hannibaletal[12]

Denmark

54362

Case-coh

ortstudy

1963ndash1998

Clom

iphenegon

adotropins

progesteronrhCG

GnR

HAge

atfirstliveb

irthparitysta

tus

88

Calderon

-Margalit

etal

[13]

Israel

15030

Retro

spectiv

ecoh

ortstudy

1974ndash1976

Clom

iphenegon

adotropins

otheru

nkno

wnfertilitydrugs

Age


icorigin

socialcla

ssedu

catio

nparitytim

eto

conceptio

nmeanbo

dymass

index

29

Yli-K

uhae

tal[14

]Finland

1835

0coho

rtstu

dy1996ndash1998

IVF

Agem

arita

lstatussocioecono

mic

position

78

Reigstad

etal[17]

Norway

806248

Retro

spectiv

ecoh

ortstudy

1984ndash2010

IVFICSIothers

Age

atsta

rtfollo

w-upparityat

entrymetho

dof

ART

durationof

follo

w-up

73

Brintonetal[18]

USA

9892

Retro

spectiv

ecoh

ortstudy

1965ndash1988

Clom

iphenegon

adotropins

combinatio

n

Racereprodu

ctives

tatusa

tfirst

clinicv

isitreprod

uctiv

estatusa

tfollo

w-upnu

mbero

fbirths

atfollo

w-upagea

tfirstb

irthagea

tmenarcheBM

Iatfi

rstclin

icvisit

ever

smokecauseo

finfertility

30

Reigstad

etal[19]

Norway

1353724

Retro

spectiv

ecoh

ortstudy

1960ndash1996

Clom

iphene

citrateGnR

H

gonado

tropinshCG

BirthyearparityC

Cexpo

sure

region


ber

ofchild

renatentryagea

tstartof

follo

w-upagea

tfirstcancertypes

oftre

atmentnu

mbero

fcycleso

fART

doseo

fclomiphene

citrate

18

hCGhum

anchorionicg

onadotropin

GnR

Hgon


rmon

eIV

Fin

vitro

fertilizatio


injection


Study or Subgroup



8283

1631

86

32763769362406

38927

46740

10276413

877

991


14463820

1297530

1324082

Weight

7723750

127509

1000

M-H Random 95 CI126 [050 318]168 [099 285]187 [059 593]249 [121 512]118 [082 169]

145 [112 188]


M-H Random 95 CI



Study or Subgroup



3125

16

36

34515589

15014645

30729

11

1144

57


41549

42963

Weight

3655

238671

1000

M-H Fixed 95 CI193 [020 1844]072 [009 554]078 [027 219]103 [058 183]

099 [061 158]


M-H Fixed 95 CI




4 Discussion









cohort




Outcomeassessment

Durationof

follow-up







5 Conclusion



Ethical Approval




References





































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Study or Subgroup



8283

1631

86

32763769362406

38927

46740

10276413

877

991


14463820

1297530

1324082

Weight

7723750

127509

1000

M-H Random 95 CI126 [050 318]168 [099 285]187 [059 593]249 [121 512]118 [082 169]

145 [112 188]


M-H Random 95 CI



Study or Subgroup



3125

16

36

34515589

15014645

30729

11

1144

57


41549

42963

Weight

3655

238671

1000

M-H Fixed 95 CI193 [020 1844]072 [009 554]078 [027 219]103 [058 183]

099 [061 158]


M-H Fixed 95 CI




4 Discussion









cohort




Outcomeassessment

Durationof

follow-up







5 Conclusion



Ethical Approval




References





































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of























cohort




Outcomeassessment

Durationof

follow-up







5 Conclusion



Ethical Approval




References





































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of
















































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of























of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















Documents

Fertility Drugs Associated with Thyroid Cancer Risk: A Systematic …downloads.hindawi.com/journals/bmri/2018/7191704.pdf · 2019. 7. 30. · BioMedResearchInternational Rrd ﬁ hroug