Akre, O.

Ekbom, A.

Kvist, U.

Lambe, M.

Montgomery, S. M.

Richiardi, Lorenzo

English

Institutional Research Information System University of Turin

BRIEFCOMMUNICATIONSFecundity and TwinningRates as Measures ofFertility Before Diagnosis ofGerm-Cell Testicular CancerLorenzo Richiardi, Olof Akre, ScottM. Montgomery, Mats Lambe,Ulrik Kvist, Anders EkbomPrevious studies have suggested an as-sociation between subfertility and tes-ticular cancer by using fecundity andsemen characteristics to measure fer-tility. The occurrence of twinning inoffspring may be used to investigatemale reproductive health, becausedizygotic twinning is reduced by malesubfertility. We therefore assessednumber of children and offspringtwinning rates among 4592 Swedishpatients with testicular cancer and12 254 control subjects. Before diag-nosis, case patients had a decreasednumber of children (for testicularcancer, odds ratio [OR]  0.71, 95%confidence interval [CI]  0.62 to0.81; at least three children comparedwith no children), with a lower fre-quency of dizygotic twinning (forunlike-sex twins, OR for the fatherhaving testicular cancer  0.49, 95%CI 0.22 to 1.08). The ratio of unlike-sex to same-sex twins was 0.22 amongchildren of case patients and 0.66among children of control subjects(adjusted P  .03, two-sided Waldtest). We also found an increased oc-currence of twinning after diagnosis,probably attributable to treatmentfor iatrogenic subfertility. Our studystrongly supports evidence of an asso-ciation between subfertility and thesubsequent risk for testicular cancer.[J Natl Cancer Inst 2004;96:145–7]It has been suggested that the in-creased occurrence of testicular cancerand the alleged decline in male fertilityare attributable to the same exposure(s)(1). In support of this hypothesis, obser-vational studies have demonstrated as-sociations between a small number ofchildren fathered (2) or abnormal semencharacteristics (3) and the risk of testic-ular cancer.Twinning rates can be used as a mea-sure of reproductive health, becausedizygotic twinning, but not monozygotictwinning, is reduced by male subfertility(4). Dizygotic twinning rates can be es-timated by the occurrence of unlike-sextwins. Unlike the number of children,the twinning rate has the advantage thatit is not influenced by decisions aboutfamily size.We therefore assessed the number ofchildren and unlike-sex twins fatheredby men who subsequently developedtesticular cancer. These two variablesare independent indicators of fertility,and they permitted us to evaluate thepreviously reported association betweenlow fecundity and the risk of testicularcancer.We used the Swedish Cancer Regis-try to identify patients with germ-celltesticular cancer [International Classifi-cation of Diseases, 7th Revision (ICD-7), code 178 (5)] who were diagnosedbetween January 1, 1958, and December31, 1998; were born after 1915; andwere 18–54 years old at diagnosis. Malecontrol subjects, matched on year ofbirth, age, and county, were identifiedthrough the Swedish Register of Popu-lation and Population Changes. We usedthe Swedish Multi-Generation Registry,which lists known relations betweenfirst-degree relatives for citizens bornafter 1931 who were alive in 1961 (6), toobtain information on date of birth andsex of offspring fathered between Janu-ary 1, 1932, and February 28, 2000, bycase patients and control subjects. Infor-mation on fathers and siblings was usedto exclude case patients (1.6%) with fa-milial testicular cancer. Information in-cluded in the Swedish Register of Pop-ulation and Population Changes allowedexclusion of subjects with incompletefollow-up because of migration. Thestudy was approved by the Ethics Com-mittee at the Karolinska Institutet.We identified 4592 case patients and12 254 control subjects. Two periodswere considered: 1) up to 6 months be-fore diagnosis and 2) at least 2 yearsafter diagnosis. The date of diagnosis foreach case patient was used as the timereference for the corresponding controlsubjects. Analyses on number of chil-dren were restricted to the first period,because subjects’ date of death was un-known. During both periods, 5518 chil-dren were fathered by case patients and18 038 children were fathered by controlsubjects. Multiple deliveries were iden-tified as siblings born in the same 3-dayinterval who shared the same father. Intotal, there were 238 multiple births, in-cluding one set of triplets among thechildren of case patients and two sets oftriplets among the children of controlsubjects. Ninety-eight (41%) of the 238multiple births were unlike-sex twins.Odds ratios (ORs) and 95% confi-dence intervals (CIs) for testicular can-cer according to number of childrenwere estimated with unconditional lo-gistic regression (7). Among children ofcase patients and control subjects, weestimated the odds ratio for beingunlike-sex twins according to the case–control status of the father. In addition,we calculated the ratio of unlike-sex tosame-sex twins, which is an attenuatedmeasure of the dizygotic/monozygotictwin ratio, because dizygotic twins canbe of the same sex. Because in vitrofertilization began to influence twinningrates in Sweden in the 1990s (8), weperformed further analyses stratifyingby year of birth of offspring, with 1990as the threshold. Finally, because a de-creased proportion of males was previ-ously found among the offspring of pa-tients with testicular cancer (9), but notamong the offspring of subfertile men(10), we calculated and compared thesex ratio among singletons born to caseAffiliations of authors: Department of MedicalEpidemiology and Biostatistics, Karolinska Insti-tutet, Stockholm, Sweden (LR, ML); Unit of Can-cer Epidemiology, Centro Ricerca Medicina Speri-mentale (CeRMS) and Center for OncologicPrevention, University of Turin, Turin, Italy (LR);Clinical Epidemiology Unit, Department of Med-icine (OA, SMM, AE), Andrology Center, Depart-ment of Woman and Child Health (UK), KarolinskaHospital, Stockholm; Department of Epidemiol-ogy, Harvard School of Public Health, Boston,MA (AE).Correspondence to: Lorenzo Richiardi, MD,Department of Medical Epidemiology and Biosta-tistics, Karolinska Institutet, Box 281, SE-171 77Stockholm, Sweden (e-mail: lorenzo.richiardi@meb.ki.se).See “Note” following “References.”DOI: 10.1093/jnci/djh012Journal of the National Cancer Institute, Vol. 96,No. 2, © Oxford University Press 2004, all rightsreserved.Journal of the National Cancer Institute, Vol. 96, No. 2, January 21, 2004 BRIEF COMMUNICATIONS 145 at Uni Torino Dip Sanità Pubblica Microbiologia on April 3, 2012http://jnci.oxfordjournals.org/Downloaded from patients and control subjects. All statis-tical tests were two-sided.Table 1 summarizes basic character-istics of the study subjects. The risk oftesticular cancer decreased monotoni-cally with increasing number of childrenfathered before diagnosis (Table 2; ORfor testicular cancer  0.71, 95% CI 0.62 to 0.81, for at least three childrencompared with no children). There wereno major differences between case pa-tients with seminoma and case patientswith nonseminoma, the two major histo-logic types of testicular cancer, and lagtimes of 4 or 10 years before diagnosischanged risk estimates only marginally.Before diagnosis, offspring of casepatients were less likely to be unlike-sextwins than offspring of control subjects(for unlike-sex twins, OR for the fatherhaving testicular cancer  0.49, 95% CI 0.22 to 1.08; Table 3). The ratio ofunlike-sex to same-sex twins was 0.22among children of case patients and 0.66among children of control subjects (ad-justed P for difference  .03, two-sidedWald test). Changing the lag time beforediagnosis from 6 months to 4 years didnot substantially alter the estimates (forunlike-sex twins, OR for the father hav-ing testicular cancer  0.52, 95% CI 0.15 to 1.77, from three and 17 sets oftwins among children of case patientsand control subjects, respectively). After1989, the probability of being unlike-sextwins increased among offspring of casepatients.Analyses of the period after diagnosisrevealed that children of case patientshad a higher probability of being unlike-sex twins. The association was strongeramong children born after 1989. Theratio of unlike-sex twins to same-sextwins was similar among children ofcase patients (ratio  1.23) and amongchildren of control subjects (ratio 1.06).Singleton sex ratio was not alteredbefore diagnosis of testicular cancer(percentage of males among children ofcase patients  51.1% and that amongchildren of control subjects  50.9%;P  .85), and it was slightly reducedafter diagnosis (49.2% and 51.8%, re-spectively; P  .14). In the latter anal-ysis, we had an 80% power to detect astatistically significant reduction in theproportion of male children ( level .05), if the male offspring proportionwas 47% or less.Subfertility, usually defined as atleast 1 year of unprotected intercoursewithout conception (11), may decreasethe probability of having a child and offathering unlike-sex twins. Our findingstherefore indicate that fertility is im-paired among men who will subse-quently develop testicular cancer. Mostcauses of male subfertility are unknown,but genetic disorders, congenital dis-eases (including cryptorchidism), life-style factors (such as smoking and nu-trition), medical procedures (includingradiation and chemotherapy), and envi-ronmental exposures are, or may be, im-plicated in its etiology (12,13).An association between the numberof children and the risk of testicular can-cer has been reported previously(2,3,9,14), whereas our findings ontwinning rates are novel. A decreasedoccurrence of dizygotic twinning is as-sociated with male subfertility becauseof the decreased ability of sperm to fer-tilize oocytes and to sustain their embry-onic development. Furthermore, the dif-ference in frequency of twinning beforeand after 1990, when use of in vitrofertilization techniques became commonin Sweden, suggests that subfertilityproblems among future testicular cancerpatients may, to some extent, have re-sulted in assisted reproduction. In vitrofertilization is a strong iatrogenic causeof twinning, mostly, but not exclusively,of the dizygotic type (15).Because testicular cancer occurs atyoung ages, subfertility after treatmentis of concern for many patients, irre-spective of its being iatrogenic or al-ready present at the time of cancer diag-nosis (16,17). Our findings of a higherlikelihood of twinning among patientswith a history of testicular cancer prob-ably reflect their need for assisted repro-duction, including sperm banking fol-lowed by in vitro fertilization orintracytoplasmatic sperm injection tech-niques (18).Table 1. Basic characteristics of study subjects (Sweden, 1958–1998)CharacteristicNo. of casepatients (%)*No. of controlsubjects (%)*Year of birthBefore 1945 1667 (36) 4108 (34)1945–1954 1217 (27) 3353 (27)1955–1964 1068 (23) 3021 (25)1965–1974 586 (13) 1635 (13)1975 or after 54 (1) 137 (1)Study areaLargest Swedish cities† 1843 (40) 4895 (40)Northern Sweden 696 (15) 1948 (16)Southern Sweden 2053 (45) 5411 (44)*Age at diagnosis among case patients was 33.7  8.58 years (mean  standard deviation), and ageat recruitment among control subjects was 33.5  8.51 years.†Largest Swedish cities include Stockholm, Malmö, and Göteborg.Table 2. Association between number of children and risk for germ-cell testicular cancer (Sweden, 1958–1998)No. ofchildren6 months before diagnosis* 4 years before diagnosis* 10 years before diagnosis*No. of casepatients OR (95% CI)No. of casepatients OR (95% CI)No. of casepatients OR (95% CI)0 2331 1.00 (referent) 2760 1.00 (referent) 3417 1.00 (referent)1 802 0.84 (0.76 to 0.93) 694 0.81 (0.73 to 0.90) 544 0.88 (0.78 to 0.99)2 997 0.77 (0.70 to 0.85) 797 0.78 (0.70 to 0.87) 464 0.80 (0.70 to 0.91)3 462 0.71 (0.62 to 0.81) 341 0.72 (0.62 to 0.83) 167 0.69 (0.57 to 0.85)*The number of case patients and the odds ratio (OR) adjusted for year of birth, age at diagnosis/recruitment (2-year age groups), and study area (threecategories the largest Swedish cities [Stockholm, Göteborg, and Malmö], northern Sweden, and southern Sweden) were shown. For all time groups, P for lineartrend .001, two-sided Wald test. CI  confidence interval.146 BRIEF COMMUNICATIONS Journal of the National Cancer Institute, Vol. 96, No. 2, January 21, 2004 at Uni Torino Dip Sanità Pubblica Microbiologia on April 3, 2012http://jnci.oxfordjournals.org/Downloaded from To our knowledge, this is the largeststudy to investigate fertility before thediagnosis of testicular cancer. The use ofpopulation-based registries permitted usto decrease the likelihood of informationbias. We did not have information onsome possible confounders, such associo-economic class or history of cryp-torchidism, but the consistency of ourresults on the two independent indica-tors of fertility decreases the chance ofspurious associations. Maternal parityand age influence dizygotic twinningrates (19). We adjusted for the formervariable in the analyses and used pater-nal age as a proxy for the latter variable.In conclusion, our study stronglysupports an association between malesubfertility and the risk of subsequenttesticular cancer, possibly indicatingcommon etiologic risk factors, probablyacting early in life, that interfere withspermatogenesis resulting in subfertilityand/or testicular cancer.REFERENCES(1) Skakkebaek NE, Rajpert-De Meyts E, MainKM. Testicular dysgenesis syndrome: an in-creasingly common developmental disorderwith environmental aspects. Hum Reprod2001;16:972–8.(2) Moller H, Skakkebaek NE. Risk of testicularcancer in subfertile men: case-control study.BMJ 1999;318:559–62.(3) Jacobsen R, Bostofte E, Engholm G, HansenJ, Olsen JH, Skakkebaek NE, et al. Risk oftesticular cancer in men with abnormal se-men characteristics: cohort study. BMJ 2000;321:789–92.(4) Tong S, Caddy D, Short RV. Use of dizy-gotic to monozygotic twinning ratio as ameasure of fertility. Lancet 1997;349:843–5.(5) International Classification of Diseases.Manual of the international statistical classi-fication of diseases, injuries, and causes ofdeath. Vol 1, 7th ed. Geneva (Switzerland):World Health Organization; 1957. p.86.(6) Statistics Sweden. Bakgrundsfakta tillbefolknings-och va¨lfa¨rdsstatistik. The Multi-Generation Registry. O¨ rebro (Sweden): Stat-istska Centralbyrån (SCB); 2001. p. 22–29.(7) Breslow NE, Day NE. Statistical methods incancer research. Volume I - The analysis ofcase-control studies. IARC Sci Publ;(32):5–338.(8) Bergh T, Ericson A, Hillensjo T, NygrenKG, Wennerholm UB. Deliveries and chil-dren born after in-vitro fertilisation in Swe-den 1982–95: a retrospective cohort study.Lancet 1999;354:1579–85.(9) Jacobsen R, Bostofte E, Engholm G, HansenJ, Skakkebaek NE, Moller H. Fertility andoffspring sex ratio of men who develop tes-ticular cancer: a record linkage study. HumReprod 2000;15:1958–61.(10) Jacobsen R, Bostofte E, Skakkebaek NE,Hansen J, Moller H. Offspring sex ratio ofsubfertile men and men with abnormal spermcharacteristics. Hum Reprod 2000;15:2369–70.(11) Evers JL. Female subfertility. Lancet 2002;360:151–9.(12) de Kretser DM. Male infertility. Lancet1997;349:787–90.(13) Wong WY, Thomas CM, Merkus JM, Ziel-huis GA, Steegers-Theunissen RP. Male fac-tor subfertility: possible causes and the im-pact of nutritional factors. Fertil Steril 2000;73:435–42.(14) Fossa SD, Kravdal O. Fertility in Norwegiantesticular cancer patients. Br J Cancer 2000;82:737–41.(15) The ESHRE Capri Workshop Group. Multi-ple gestation pregnancy. Hum Reprod 2000;15:1856–64.(16) Petersen PM, Skakkebaek NE, Rorth M, Gi-wercman A. Semen quality and reproductivehormones before and after orchiectomy inmen with testicular cancer. J Urol 1999;161:822–6.(17) Lampe H, Horwich A, Norman A, Nicholls J,Dearnaley DP. Fertility after chemotherapyfor testicular germ cell cancers. J Clin Oncol1997;15:239–45.(18) Hallak J, Kolettis PN, Sekhon VS, ThomasAJ Jr, Agarwal A. Sperm cryopreservation inpatients with testicular cancer. Urology1999;54:894–9.(19) Tong S, Short RV. Dizygotic twinning as ameasure of human fertility. Hum Reprod1998;13:95–8.NOTESPartially supported by the Special Project“Oncology,” Compagnia San Paolo/FondazioneInternationale Ricerca Medicina Sperimentale(FIRMS), Turin, Italy.Manuscript received June 24, 2003; revisedNovember 12, 2003; accepted November 26,2003.Table 3. Association of unlike-sex birth with paternal germ-cell testicular cancer (Sweden, 1958–1998)Type of delivery Case patients Control subjectsOdds ratio (95% confidence interval)*Entire period Born before 1990 Born in 1990 or afterBefore diagnosis (6 mo)Singleton, No. 4316 12 542 1.00 (referent) 1.00 (referent) 1.00 (referent)Unlike-sex twins, No. 7 42 0.49 (0.22 to 1.08) 0.40 (0.16 to 1.01) 1.08 (0.21 to 5.66)Frequency, No. per 1000 births 1.6 3.3After diagnosis (2 y)Singleton, No. 1065 5154 1.00 (referent) 1.00 (referent) 1.00 (referent)Unlike-sex twins, No. 16 33 2.03 (1.11 to 3.73) 1.53 (0.42 to 5.55) 2.10 (1.04 to 4.25)Frequency, No. per 1000 births† 14.6 6.3*Odds ratios were adjusted for year of birth, paternal age (each 5-year increase), and number of older siblings (0 or 1, for the period before diagnosis; 0,1, 2, or 3, for the period after diagnosis).†Twin births are included in the denominator of the proportion.Journal of the National Cancer Institute, Vol. 96, No. 2, January 21, 2004 BRIEF COMMUNICATIONS 147 at Uni Torino Dip Sanità Pubblica Microbiologia on April 3, 2012http://jnci.oxfordjournals.org/Downloaded from 

Fecundity and twinning rates as measures of fertility before diagnosis of germ-cell testicular cancer

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Fecundity and twinning rates as measures of fertility before diagnosis of germ-cell testicular cancer

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