Male Infertility and Subsequent Risk of Cancer Development

Main Article Content

Michael Lao
Stanton C. Honig


infertility, cancer, prostate, testes, oncology


Infertility occurs in 15% of the population; and 30–50% of the time, the problem is due to a male factor. There is active research attempting to elucidate how male factor infertility fits into the picture of overall men’s health. Research in the past has established that a thorough male fertility evaluation can uncover various medical pathologies. There is now growing evidence that suggests male infertility is a potential harbinger for subsequent cancer development. In this review of pertinent articles, the current evidence regarding fertility and development of genitourinary and other cancers will be discussed, in particular, testicular and prostate cancer. In addition, various etiologic factors that explain the pathophysiology of infertility and progression to cancer will also be reviewed. It is possible that male factor infertility is a surrogate marker for subsequent cancer development.


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1. MacLeod, J.: Human male infertility. Obstet Gynecol Surv, 26: 335, 1971
2. Simmons, F. A.: Human infertility. N Engl J Med, 255: 1140, 1956
3. Honig, S. C., Lipshultz, L. I., Jarow, J.: Significant medical pathology uncovered by a comprehensive male infertility evaluation. Fertil Steril, 62: 1028, 1994
4. Kolettis, P. N., Sabanegh, E. S.: Significant medical pathology discovered during a male infertility evaluation. J Urol, 166: 178, 2001
5. Sigman, M., Jarow, J. P.: Endocrine evaluation of infertile men. Urology, 50: 659, 1997
6. Walsh, T. J., Croughan, M. S., Schembri, M. et al..: Increased risk of testicular germ cell cancer among infertile men. Arch Intern Med, 169: 351, 2009
7. Jacobsen, R., Moller, H., Thoresen, S. O. et al..: Trends in testicular cancer incidence in the Nordic countries, focusing on the recent decrease in Denmark. Int J Androl, 29: 199, 2006
8. Huyghe, E., Matsuda, T., Thonneau, P.: Increasing incidence of testicular cancer worldwide: a review. J Urol, 170: 5, 2003
9. Doria-Rose, V. P., Biggs, M. L., Weiss, N. S.: Subfertility and the risk of testicular germ cell tumors (United States). Cancer Causes Control, 16: 651, 2005
10. Raman, J. D., Nobert, C. F., Goldstein, M.: Increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis. J Urol, 174: 1819, 2005
11. Jacobsen, R., Bostofte, E., Engholm, G. et al..: Risk of testicular cancer in men with abnormal semen characteristics: cohort study. BMJ, 321: 789, 2000
12. Moller, H., Skakkebaek, N. E.: Risk of testicular cancer in subfertile men: casecontrol study. BMJ, 318: 559, 1999
13. Moller, H.: Trends in sex-ratio, testicular cancer and male reproductive hazards: are they connected? APMIS, 106: 232, 1998
14. Jacobsen, R., Bostofte, E., Engholm, G. et al..: Fertility and offspring sex ratio of men who develop testicular cancer: a record linkage study. Hum Reprod, 15: 1958, 2000
15. Moller, H., Skakkebaek, N. E.: Testicular cancer and cryptorchidism in relation to prenatal factors: case-control studies in Denmark. Cancer Causes Control, 8: 904, 1997
16. Aetiology of testicular cancer: association with congenital abnormalities, age at puberty, infertility, and exercise. United Kingdom Testicular Cancer Study Group. BMJ, 308: 1393, 1994
17. Pukkala, E., Weiderpass, E.: Socio-economic differences in incidence rates of cancers of the male genital organs in Finland, 1971-95. Int J Cancer, 102: 643, 2002
18. Nudell, D., Castillo, M., Turek, P. J. et al..: Increased frequency of mutations in DNA from infertile men with meiotic arrest. Hum Reprod, 15: 1289, 2000
19. Baker, S. M., Plug, A. W., Prolla, T. A. et al..: Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nat Genet, 13: 336, 1996
20. de Wind, N., Dekker, M., Berns, A. et al..: Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell, 82: 321, 1995
21. Skakkebaek, N. E., Rajpert-De Meyts, E., Main, K. M.: Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod, 16: 972, 2001
22. Walsh, T. J., Schembri, M., Turek, P. J. et al..: Increased risk of high-grade prostate cancer among infertile men. Cancer, 116: 2140, 2010
23. Gronberg, H.: Prostate cancer epidemiology. Lancet, 361: 859, 2003
24. Jorgensen, K. T., Pedersen, B. V., Johansen, C. et al..: Fatherhood status and prostate cancer risk. Cancer, 112: 919, 2008
25. Giwercman, A., Richiardi, L., Kaijser, M. et al..: Reduced risk of prostate cancer in men who are childless as compared to those who have fathered a child: a population based case-control study. Int J Cancer, 115: 994, 2005
26. Negri, E., Talamini, R., Bosetti, C. et al..: Risk of prostate cancer in men who are childless. Int J Cancer, 118: 786, 2006
27. Dennis, L. K., Dawson, D. V.: Meta-analysis of measures of sexual activity and prostate cancer. Epidemiology, 13: 72, 2002
28. Roetzheim, R. G., Pal, N., Tennant, C. et al..: Effects of health insurance and race on early detection of cancer. J Natl Cancer Inst, 91: 1409, 1999
29. Harlap, S., Paltiel, O., Friedlander, Y. et al..: Prostate cancer in fathers with fewer male offspring: the Jerusalem Perinatal Study cohort. J Natl Cancer Inst, 99: 77, 2007
30. Hirata, H., Hinoda, Y., Kawamoto, K. et al..: Mismatch repair gene MSH3 polymorphism is associated with the risk of sporadic prostate cancer. J Urol, 179: 2020, 2008
31. Swerdlow, A. J., Schoemaker, M. J., Higgins, C. D. et al..: Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst, 97: 1204, 2005
32. Wang, C., Baker, H. W., Burger, H. G. et al.: Hormonal studies in Klinefelter’s syndrome. Clin Endocrinol (Oxf), 4: 399, 1975
33. Hasle, H., Mellemgaard, A., Nielsen, J. et al..: Cancer incidence in men with Klinefelter syndrome. Br J Cancer, 71: 416, 1995
34. Swerdlow, A. J., Hermon, C., Jacobs, P. A. et al..: Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet, 65: 177, 2001
35. Hultborn, R., Hanson, C., Kopf, I. et al..: Prevalence of Klinefelter’s syndrome in male breast cancer patients. Anticancer Res, 17: 4293, 1997
36. Eisenberg, M. L., Betts, P., Herder, D. et al..: Increased risk of cancer among azoospermic men. Fertil Steril, 100: 681, 2013
37. Walsh, T. J.: Male reproductive health and prostate cancer risk. Curr Opin Urol, 21: 506, 2011
38. Perinchery, G., Sasaki, M., Angan, A. et al..: Deletion of Y-chromosome specific genes in human prostate cancer. J Urol, 163: 1339, 2000
39. Stahl, P.J., Masson, P., Mielnik, A. et al.: A decade of experience emphasizes that testing for Y microdeletions is essential in American men with azoospermia and severe oligospermia. Fertil Steril, 94: 1753, 2010
40. Nathanson, K. L., Kanetsky, P. A., Hawes, R. et al..: The Y deletion gr/gr and susceptibility to testicular germ cell tumor. Am J Hum Genet, 77: 1034, 2005
41. Bianchi, N. O., Richard, S. M., Pavicic, W.: Y chromosome instability in testicular cancer. Mutat Res, 612: 172, 2006
42. Vogt, P. H., Edelmann, A., Kirsch, S. et al..: Human Y chromosome azoospermia factors (AZF) mapped to different subregions in Yq11. Hum Mol Genet, 5: 933, 1996
43. Reijo, R., Alagappan, R. K., Patrizio, P. et al..: Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet, 347: 1290, 1996
44. Kostiner, D. R., Turek, P. J., Reijo, R. A.: Male infertility: analysis of the markers and genes on the human Y chromosome. Hum Reprod, 13: 3032, 1998
45. Kleiman, S. E., Bar-Shira Maymon, B., Yogev, L. et al..: The prognostic role of the extent of Y microdeletion on spermatogenesis and maturity of Sertoli cells. Hum Reprod, 16: 399, 2001
46. Bermejo, J. L., Sundquist, J., Hemminki, K.: Re: Prostate cancer in fathers with fewer male offspring: the Jerusalem Perinatal Study cohort. J Natl Cancer Inst, 99: 901, 2007
47. James, W. H.: Re: Prostate cancer in fathers with fewer male offspring: the Jerusalem Perinatal Study cohort. J Natl Cancer Inst, 99: 902; author reply 903, 2007
48. Olesen, I. A., Sonne, S. B., Hoei-Hansen, C. E. et al..: Environment, testicular dysgenesis and carcinoma in situ testis. Best Pract Res Clin Endocrinol Metab, 21: 462, 2007
49. Spierings, D. C., de Vries, E. G., Vellenga, E. et al..: The attractive Achilles heel of germ cell tumours: an inherent sensitivity to apoptosis-inducing stimuli. J Pathol, 200: 137, 2003
50. Mosaad, Y. M., Shahin, D., Elkholy, A. A. et al..: CAG repeat length in androgen receptor gene and male infertility in Egyptian patients. Andrologia, 44: 26, 2012
51. Rodriguez-Gonzalez, G., Cabrera, S., Ramirez-Moreno, R. et al..: Short alleles of both GGN and CAG repeats at the exon-1 of the androgen receptor gene are associated to increased PSA staining and a higher Gleason score in human prostatic cancer. J Steroid Biochem Mol Biol, 113: 85, 2009
52. Silva Neto, B., Koff, W. J., Biolchi, V. et al..: Polymorphic CAG and GGC repeat lengths in the androgen receptor gene and prostate cancer risk: analysis of a Brazilian population. Cancer Invest, 26: 74, 2008
53. Das, K., Cheah, P. Y., Lim, P. L. et al..: Shorter CAG repeats in androgen receptor and non-GG genotypes in prostate-specific antigen loci are associated with decreased risk of benign prostatic hyperplasia and prostate cancer. Cancer
Lett, 268: 340, 2008
54. Rajender, S., Avery, K., Agarwal, A.: Epigenetics, spermatogenesis and male infertility. Mutat Res, 727: 62, 2011
55. Jeronimo, C., Bastian, P. J., Bjartell, A. et al..: Epigenetics in prostate cancer: biologic and clinical relevance. Eur Urol, 60: 753, 2011
56. Skinner, M. K., Guerrero-Bosagna, C.: Environmental signals and transgenerational epigenetics. Epigenomics, 1: 111, 2009
57. Phillips, K. P., Tanphaichitr, N.: Human exposure to endocrine disrupters and semen quality. J Toxicol Environ Health B Crit Rev, 11: 188, 2008
58. Prins, G. S.: Endocrine disruptors and prostate cancer risk. Endocr Relat Cancer, 15: 649, 2008
59. Xu, X., Dailey, A. B., Talbott, E. O. et al..: Associations of serum concentrations of organochlorine pesticides with breast cancer and prostate cancer in U.S. adults. Environ Health Perspect, 118: 60, 2010