Table 1.

Epidemiologic studies focused on the association between male infertility and testicular cancer.

Author(s)	Country and Year	Design	Subjects	Finding(s)	Conclusions
Pryor et al. [129]	UK 1983	Case study	2043 males from infertile couples who underwent testicular biopsy from 1955 to 1982.	Carcinoma in situ (CIS) was diagnosed in 8 men (0.39%). 6 patients with CIS cells developed testicular tumors, one remained tumor-free and one was lost to follow-up.	The findings are applicable to the selection of patients for biopsy and appropriate treatment of CIS when diagnosed.
Strader et al. [136]	Western Washington State, USA 1988	Population based case-control study	Patients diagnosed with TC between 1977 and 1983 (n = 333) and 675 healthy controls.	Men with a history of cryptorchidism were 5.9 times more likely to develop TC than men without such history. Men with unilateral cryptorchidism were at a greater risk of tumor development on the side of the nondescent testicle (relative risk of 8.0) than on the opposite side (relative risk of 1.6). The risk tended to be smaller among cryptorchidic men who had undergone orchiopexy before adolescence.	The study supports the hypothesis that one or more local factors may account for the increased risk of germ cell testicular tumors in cryptorchidic men.
Møller and Skakkebæk [137]	Denmark 1999	Population based case-control study	514 patients diagnosed with TC identified in the Danish Cancer Registry and 720 controls randomly selected from the Danish population.	A reduced risk of TC associated with paternity (odds ratio of 0.63). Patients who before TC had a lower number of children than expected, faced a relative risk of 1.98. No corresponding protective effect associated with a higher number of children than expected was found. Similar associations were recorded for seminoma and non-seminoma cases.	Data supporting the hypothesis that compromised male fertility and TC share important etiologies.
Jacobsen et al. [132]	Denmark 2000	Cohort study	3530 Danish men, born between 1945–1980 and diagnosed with TC in the period of 1960–1993. Control: the total population of Danish men born between 1945–1980 (n = 1,488,957) and their biological children (n = 1,250,989).	Men, who developed TC, had a reduced fertility prior to the diagnosis (odds ratio of 0.93). A significantly lower proportion of boys was born to the patients when compared with the general population. The reduction in fertility was more pronounced in men with non-seminoma. The reduction in offspring sex ratio was independent of the TC type.	The study confirms earlier results from less conclusive studies, and indicates that TC, subfertility and a female-biased sex ratio among newborns are interrelated by biological mechanisms.
Jacobsen et al. [134]	Denmark 2000	Cohort study	32,442 men who had a semen analysis done during 1963–1995.	Patients with fertility issues were more likely to develop TC than other men (89 cases, incidence ratio of 1.6). The risk was relatively constant with increasing time between semen analysis and cancer diagnosis. Low semen concentration (incidence ratio of 2.3), poor spermatozoa motility (2.5), and high incidence of morphologically abnormal spermatozoa (3.0) were all associated with an increased risk of TC.	The results emphasize on the existence of common etiologies for low semen quality and TC. Low semen quality may be associated with increased incidence of germ cell tumors.
Pasqualotto et al. [138]	Cleveland, USA 2003	Case study	Seven patients presenting with infertility, followed by eventual TC diagnosis over a 15-year period.	Two men had elevated serum follicle stimulating hormone and luteinizing hormone levels, 1 an abnormally low serum testosterone level prior to the TC diagnosis. Tumor markers were normal in all patients. The tumor was found on the right side in 4 patients and on the left in 3. 5 cases presented with a seminoma, 1 with Leydig cell tumor and 1 carcinoma in situ. Follow-up on fertility status was available in 6 cases, only one patient established a pregnancy.	Most of the men who have TC and male infertility will most likely present with a seminona. Men diagnosed with infertility should be thoroughly investigated to rule out diseases associated with their infertility.
Richiardi et al. [139]	Sweden 2004	Population based case-control study	4592 patients with TC and 12,254 control subjects.	Before diagnosis, TC patients had lower number of children (odds ratio of 0.71), with a lower frequency of dizygotic twinning (odds ratio of 0.49). Increased occurrence of twinning after diagnosis, probably due to treatment for iatrogenic infertility.	The report provides evidence of an association between subfertility and the subsequent risk for TC.
Doria-Rose et al. [135]	Western Washington State, USA 2005	Case-control study	329 TC patients diagnosed from 1977 to 1983, and 672 cancer-free controls.	Decreased TC risk in men who had previously fathered a child (odds ratio of 0.76). Previous diagnosis of infertility was associated with an increased risk of TC (odds ratio of 2.40).	The results are consistent with an increased risk of TC among men with reduced fertility, going beyond the effects of cryptorchidism.
Walsh et al. [2]	State of California, USA 2009	Cohort study	A total of 51,461 couples evaluated for infertility from 1967 to 1998 linked with 22,562 TC patients.	34 post-infertility-diagnosis cases of TC were identified. Men seeking infertility treatment had an increased risk of subsequently developing TC (incidence ratio of 1.3), along with a markedly higher risk among those with known male factor infertility (odds ratio of 2.8).	Men with male factor infertility have an increased risk of subsequently developing TC, suggesting common etiologic factors for infertility and TC.