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Fecundity and Twinning Rates as Measures of Fertility Before Diagnosis of Germ-Cell Testicular Cancer

Lorenzo Richiardi, Olof Akre, Scott M. Montgomery, Mats Lambe, Ulrik Kvist, Anders Ekbom

Affiliations of authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (LR, ML); Unit of Cancer Epidemiology, Centro Ricerca Medicina Sperimentale (CeRMS) and Center for Oncologic Prevention, University of Turin, Turin, Italy (LR); Clinical Epidemiology Unit, Department of Medicine (OA, SMM, AE), Andrology Center, Department of Woman and Child Health (UK), Karolinska Hospital, Stockholm; Department of Epidemiology, Harvard School of Public Health, Boston, MA (AE).

Correspondence to: Lorenzo Richiardi, MD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, SE-171 77 Stockholm, Sweden (e-mail: lorenzo.richiardi{at}meb.ki.se)


    ABSTRACT
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Previous studies have suggested an association between subfertility and testicular cancer by using fecundity and semen characteristics to measure fertility. The occurrence of twinning in offspring may be used to investigate male reproductive health, because dizygotic twinning is reduced by male subfertility. We therefore assessed number of children and offspring twinning rates among 4592 Swedish patients with testicular cancer and 12 254 control subjects. Before diagnosis, case patients had a decreased number of children (for testicular cancer, odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.62 to 0.81; at least three children compared with no children), with a lower frequency of dizygotic twinning (for unlike-sex twins, OR for the father having testicular cancer = 0.49, 95% CI = 0.22 to 1.08). The ratio of unlike-sex to same-sex twins was 0.22 among children of case patients and 0.66 among children of control subjects (adjusted P = .03, two-sided Wald test). We also found an increased occurrence of twinning after diagnosis, probably attributable to treatment for iatrogenic subfertility. Our study strongly supports evidence of an association between subfertility and the subsequent risk for testicular cancer.


It has been suggested that the increased occurrence of testicular cancer and the alleged decline in male fertility are attributable to the same exposure(s) (1). In support of this hypothesis, observational studies have demonstrated associations between a small number of children fathered (2) or abnormal semen characteristics (3) and the risk of testicular cancer.

Twinning rates can be used as a measure of reproductive health, because dizygotic twinning, but not monozygotic twinning, is reduced by male subfertility (4). Dizygotic twinning rates can be estimated by the occurrence of unlike-sex twins. Unlike the number of children, the twinning rate has the advantage that it is not influenced by decisions about family size.

We therefore assessed the number of children and unlike-sex twins fathered by men who subsequently developed testicular cancer. These two variables are independent indicators of fertility, and they permitted us to evaluate the previously reported association between low fecundity and the risk of testicular cancer.

We used the Swedish Cancer Registry to identify patients with germ-cell testicular cancer [International Classification of Diseases, 7th Revision (ICD-7), code 178 (5)] who were diagnosed between January 1, 1958, and December 31, 1998; were born after 1915; and were 18–54 years old at diagnosis. Male control subjects, matched on year of birth, age, and county, were identified through the Swedish Register of Population and Population Changes. We used the Swedish Multi-Generation Registry, which lists known relations between first-degree relatives for citizens born after 1931 who were alive in 1961 (6), to obtain information on date of birth and sex of offspring fathered between January 1, 1932, and February 28, 2000, by case patients and control subjects. Information on fathers and siblings was used to exclude case patients (1.6%) with familial testicular cancer. Information included in the Swedish Register of Population and Population Changes allowed exclusion of subjects with incomplete follow-up because of migration. The study was approved by the Ethics Committee at the Karolinska Institutet.

We identified 4592 case patients and 12 254 control subjects. Two periods were considered: 1) up to 6 months before diagnosis and 2) at least 2 years after diagnosis. The date of diagnosis for each case patient was used as the time reference for the corresponding control subjects. Analyses on number of children were restricted to the first period, because subjects' date of death was unknown. During both periods, 5518 children were fathered by case patients and 18 038 children were fathered by control subjects. Multiple deliveries were identified as siblings born in the same 3-day interval who shared the same father. In total, there were 238 multiple births, including one set of triplets among the children of case patients and two sets of triplets among the children of control subjects. Ninety-eight (41%) of the 238 multiple births were unlike-sex twins.

Odds ratios (ORs) and 95% confidence intervals (CIs) for testicular cancer according to number of children were estimated with unconditional logistic regression (7). Among children of case patients and control subjects, we estimated the odds ratio for being unlike-sex twins according to the case–control status of the father. In addition, we calculated the ratio of unlike-sex to same-sex twins, which is an attenuated measure of the dizygotic/monozygotic twin ratio, because dizygotic twins can be of the same sex. Because in vitro fertilization began to influence twinning rates in Sweden in the 1990s (8), we performed further analyses stratifying by year of birth of offspring, with 1990 as the threshold. Finally, because a decreased proportion of males was previously found among the offspring of patients with testicular cancer (9), but not among the offspring of subfertile men (10), we calculated and compared the sex ratio among singletons born to case patients and control subjects. All statistical tests were two-sided.

Table 1 summarizes basic characteristics of the study subjects. The risk of testicular cancer decreased monotonically with increasing number of children fathered before diagnosis (Table 2; OR for testicular cancer = 0.71, 95% CI = 0.62 to 0.81, for at least three children compared with no children). There were no major differences between case patients with seminoma and case patients with nonseminoma, the two major histologic types of testicular cancer, and lag times of 4 or 10 years before diagnosis changed risk estimates only marginally.


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Table 1. Basic characteristics of study subjects (Sweden, 1958–1998)

 

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Table 2. Association between number of children and risk for germ-cell testicular cancer (Sweden, 1958–1998)

 
Before diagnosis, offspring of case patients were less likely to be unlike-sex twins than offspring of control subjects (for unlike-sex twins, OR for the father having testicular cancer = 0.49, 95% CI = 0.22 to 1.08; Table 3). The ratio of unlike-sex to same-sex twins was 0.22 among children of case patients and 0.66 among children of control subjects (adjusted P for difference = .03, two-sided Wald test). Changing the lag time before diagnosis from 6 months to 4 years did not substantially alter the estimates (for unlike-sex twins, OR for the father having testicular cancer = 0.52, 95% CI = 0.15 to 1.77, from three and 17 sets of twins among children of case patients and control subjects, respectively). After 1989, the probability of being unlike-sex twins increased among offspring of case patients.


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Table 3. Association of unlike-sex birth with paternal germ-cell testicular cancer (Sweden, 1958–1998)

 
Analyses of the period after diagnosis revealed that children of case patients had a higher probability of being unlike-sex twins. The association was stronger among children born after 1989. The ratio of unlike-sex twins to same-sex twins was similar among children of case patients (ratio = 1.23) and among children of control subjects (ratio = 1.06).

Singleton sex ratio was not altered before diagnosis of testicular cancer (percentage of males among children of case patients = 51.1% and that among children of control subjects = 50.9%; P = .85), and it was slightly reduced after diagnosis (49.2% and 51.8%, respectively; P = .14). In the latter analysis, we had an 80% power to detect a statistically significant reduction in the proportion of male children ({alpha} level = .05), if the male offspring proportion was 47% or less.

Subfertility, usually defined as at least 1 year of unprotected intercourse without conception (11), may decrease the probability of having a child and of fathering unlike-sex twins. Our findings therefore indicate that fertility is impaired among men who will subsequently develop testicular cancer. Most causes of male subfertility are unknown, but genetic disorders, congenital diseases (including cryptorchidism), life-style factors (such as smoking and nutrition), medical procedures (including radiation and chemotherapy), and environmental exposures are, or may be, implicated in its etiology (12,13).

An association between the number of children and the risk of testicular cancer has been reported previously (2,3,9,14), whereas our findings on twinning rates are novel. A decreased occurrence of dizygotic twinning is associated with male subfertility because of the decreased ability of sperm to fertilize oocytes and to sustain their embryonic development. Furthermore, the difference in frequency of twinning before and after 1990, when use of in vitro fertilization techniques became common in Sweden, suggests that subfertility problems among future testicular cancer patients may, to some extent, have resulted in assisted reproduction. In vitro fertilization is a strong iatrogenic cause of twinning, mostly, but not exclusively, of the dizygotic type (15).

Because testicular cancer occurs at young ages, subfertility after treatment is of concern for many patients, irrespective of its being iatrogenic or already present at the time of cancer diagnosis (16,17). Our findings of a higher likelihood of twinning among patients with a history of testicular cancer probably reflect their need for assisted reproduction, including sperm banking followed by in vitro fertilization or intracytoplasmatic sperm injection techniques (18).

To our knowledge, this is the largest study to investigate fertility before the diagnosis of testicular cancer. The use of population-based registries permitted us to decrease the likelihood of information bias. We did not have information on some possible confounders, such as socio-economic class or history of cryptorchidism, but the consistency of our results on the two independent indicators of fertility decreases the chance of spurious associations. Maternal parity and age influence dizygotic twinning rates (19). We adjusted for the former variable in the analyses and used paternal age as a proxy for the latter variable.

In conclusion, our study strongly supports an association between male subfertility and the risk of subsequent testicular cancer, possibly indicating common etiologic risk factors, probably acting early in life, that interfere with spermatogenesis resulting in subfertility and/or testicular cancer.


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Partially supported by the Special Project "Oncology," Compagnia San Paolo/Fondazione Internationale Ricerca Medicina Sperimentale (FIRMS), Turin, Italy.


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Manuscript received June 24, 2003; revised November 12, 2003; accepted November 26, 2003.


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