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Male infertility: a biomarker of individual and familial cancer risk

      Associations between male infertility and cancer are gaining clinical attention. Relationships between infertility and cancer have traditionally been studied in women, but recent work has focused on the male component of reproduction. Infertile men are at an elevated risk to develop various malignancies later in life, primarily genitourinary malignancies such as testicular and prostate cancer. Rates of testicular and high-grade prostate cancer in infertile men appear to be at least double the risk in the general population. The link between infertility and malignancy highlights the importance of thorough evaluation and long-term follow up—beyond a simple semen analysis. A detailed urologic evaluation, possibly including scrotal ultrasound, may be beneficial to screen infertile men for testicular cancer. Publications have also demonstrated that male infertility can be a biomarker for cancer risk in first- and second-degree relatives. Testicular cancer risk in first-degree relatives of infertile men is 52% higher than the risk in relatives of fertile control men, and male infertility has been associated with a two- to threefold elevation in risk of childhood cancer in the siblings of infertile men. Links between infertility and malignancy are multifactorial, and exact mechanistic explanations are still not fully understood. Although more studies are needed to assess levels of risk and create screening recommendations in this population, understanding the relationship between male infertility and malignancy is crucial to provide comprehensive counseling for infertile men and their families.

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      References

        • American Society for Reproductive Medicine
        Diagnostic evaluation of the infertile male: a committee opinion.
        Fertil Steril. 2015; 103: 18-25
        • Anderson J.E.
        • Farr S.L.
        • Jamieson D.J.
        Infertility services reported by men in the United States: national survey data.
        Fertil Steril. 2009; 91: 2466-2470
        • Anderson R.E.
        • Hanson H.A.
        • Patel D.P.
        • Johnstone E.
        • Aston K.I.
        • Carrell D.T.
        • et al.
        Cancer risk in first- and second-degree relatives of men with poor semen quality.
        Fertil Steril. 2016; 106: 731-738
        • Salonia A.
        • Matloob R.
        • Gallina A.
        Are infertile men less healthy than fertile men? Results of a prospective case-control survey.
        Eur Urol. 2009; 56: 1025
        • Rogers M.J.
        • Walsh T.J.
        Male infertility and risk of cancer.
        Semin Reprod Med. 2017; 35: 298-303
        • Hanson B.
        • Johnstone E.
        • Dorais J.
        • Silver B.
        • Peterson C.M.
        • Hotaling J.
        Female infertility, infertility-associated diagnoses, and comorbidities: a review.
        J Assist Reprod Genet. 2017; 34: 167-177
        • Eisenberg M.L.
        • Li S.
        • Brooks J.D.
        • Cullen M.R.
        • Baker L.C.
        Increased risk of cancer in infertile men: analysis of U.S. claims data.
        J Urol. 2015; 193: 1596-1601
        • Kroener L.
        • Dumesic D.
        • Al-Safi Z.
        Use of fertility medications and cancer risk: a review and update.
        Curr Opin Obstet Gynecol. 2017; 29: 195-201
      1. Jarow J, Sigman M, Kolettis PN, Lipschultz LR, McClure RD, Nangia AK, et al. The optimal evaluation of the infertile male: American Urological Association best practice statement. 2011. Available at: www.auanet.org/documents//education/clinical-guidance/Male-Infertility-d.pdf. Accessed August 19, 2017.

        • Petok W.
        Infertility counseling (or the lack thereof) of the forgotten male partner.
        Fertil Steril. 2015; 104: 260-266
        • Brinton L.A.
        • Westhoff C.L.
        • Scoccia B.
        • Lamb E.J.
        • Althuis M.D.
        • Mabie J.E.
        • et al.
        Causes of infertility as predictors of subsequent cancer risk.
        Epidemiology. 2005; 16: 500-507
        • Kort J.D.
        • Eisenberg M.L.
        • Millheiser L.S.
        • Westphal L.M.
        Fertility issues in cancer survivorship.
        CA Cancer J Clin. 2014; 64: 118-134
        • Anderson R.E.
        • Hanson H.A.
        • Lowrance W.T.
        • Redshaw J.
        • Oottamasathien S.
        • Schaeffer A.
        • et al.
        Childhood cancer risk in the siblings and cousins of men with poor semen quality.
        J Urol. 2017; 197: 898-905
        • Hanson H.A.
        • Mayer E.N.
        • Anderson R.E.
        • Aston K.I.
        • Carrell D.T.
        • Berger J.
        • et al.
        Risk of childhood mortality in family members of men with poor sperm quality.
        Hum Reprod. 2017; 32: 239-247
        • Tvrda E.
        • Agarwal A.
        • Alkuhaimi N.
        Male reproductive cancer and infertility: a mutual relationship.
        Int J Mol Sci. 2015; 16: 7230-7260
      2. American Cancer Society. What are the key statistics about testicular cancer? 2017. Available at: https://www.cancer.org/cancer/testicular-cancer/about/key-statistics.html. Accessed August 2, 2017.

        • Shanmugalingam T.
        • Soultati A.
        • Chowdhury S.
        • Rudman S.
        • van Hemelrijck M.
        Global incidence and outcome of testicular cancer.
        Clin Epidemiol. 2013; 5: 417-427
        • Paduch D.
        Testicular cancer and male infertility.
        Curr Opin Urol. 2006; 16: 419-427
        • McGlynn K.A.
        • Devesa S.S.
        • Sigurdson A.J.
        Trends in the incidence of testicular germ cell tumors in the United States.
        Cancer. 2003; 97: 63-70
        • Hanson H.A.
        • Anderson R.E.
        • Aston K.I.
        • Carrell D.T.
        • Smith K.R.
        • Hotaling J.M.
        Subfertility increases risk of testicular cancer: evidence from population-based semen samples.
        Fertil Steril. 2016; 105: 322-328
        • Jacobsen R.
        • Bostofte E.
        • Engholm G.
        • Hansen J.
        • Olsen J.H.
        • Skakkebaek N.E.
        • et al.
        Risk of testicular cancer in men with abnormal semen characteristics: cohort study.
        BMJ. 2000; 321: 789-792
        • Raman J.D.
        • Nobert C.F.
        • Goldstein M.
        Increased incidence of testicular cancer in men presenting with infertility and abnormal semen analysis.
        J Urol. 2005; 174: 1819-1822
        • Venn A.
        • Healy D.
        • McLachlan R.
        Cancer risks associated with the diagnosis of infertility.
        Best Pract Res Clin Obstet Gynaecol. 2003; 17: 343-367
        • Walsh T.J.
        • Croughan M.S.
        • Schembri M.
        • Chan J.M.
        • Turek P.J.
        Increased risk of testicular germ cell cancer among infertile men.
        Arch Intern Med. 2009; 169: 351-356
        • Pierik F.H.
        • Dohle G.R.
        • van Muiswinkel J.M.
        Is routine scrotal ultrasound advantageous in infertile men?.
        J Urol. 1999; 162: 1618-1620
        • Behre H.M.
        • Kliesch S.
        • Schadel F.
        • Nieschlag E.
        Clinical relevance of scrotal and transrectal ultrasonography in andrological patients.
        Int J Androl. 1995; 18: 27-31
        • Bieniek J.M.
        • Juvet T.
        • Margolis M.
        • Grober E.D.
        • Lo K.C.
        • Jarvi K.A.
        Prevalence and management of incidental small testicular masses discovered on ultrasonographic evaluation of male infertility.
        J Urol. 5 August 2017; (doi: 10.1016/j.juro.2017.08.004. [ePub ahead of print.])
        • Skakkebaek N.E.
        • Rajpert-DeMeyts E.
        • Main K.M.
        Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects.
        Hum Reprod. 2001; 16: 972-978
        • Skakkebaek N.E.
        • Rajpert-DeMeyts E.
        • Buck-Louis G.M.
        • Toppari J.
        • Andersson A.M.
        • Eisenberg M.L.
        • et al.
        Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility.
        Physiol Rev. 2016; 96: 55-97
        • Hadziselimovic F.
        • Herzog B.
        The importance of both and early orchidopexy and germ cell maturation.
        Lancet. 2001; 358: 1156-1157
        • Kolon F.
        Cryptorchidism: diagnosis, treatment and long-term prognosis.
        Urol Clin North Am. 2004; 31: 469-480
        • Cortes D.
        Infertility despite surgery for cryptorchidism in childhood can be classified by patients with normal or elevated follicle-stimulating hormone and identified at orchidopexy.
        BJU Int. 2003; 91: 670-674
        • Ferguson L.
        • Agoulnik A.
        Testicular cancer and cryptorchidism.
        Front Endocrinol. 2013; 4: 32
        • Richiardi L.
        • Akre O.
        • Montgomery S.M.
        Fecundity and twinning rates as measures of fertility before diagnosis of germ-cell testicular cancer.
        J Natl Cancer Inst. 2004; 96: 145-147
        • Richiardi L.
        • Pettersson A.
        • Akre O.
        Genetic and environmental risk factors for testicular cancer.
        Int J Androl. 2007; 30: 230-240
        • Eisenberg M.L.
        • Li S.
        • Cullen M.R.
        • Baker L.C.
        Increased risk of incident medical conditions in infertile men: analysis of United States claims data.
        Fertil Steril. 2016; 105: 629-636
        • Pasqualotto F.F.
        • Lucon A.M.
        • Sobreiro B.P.
        Effects of medical therapy, alcohol, smoking, and endocrine disruptors on male infertility.
        Rev Hosp Clin Fac Med Sao Paulo. 2004; 49: 375-382
        • Liu R.Z.
        • Gao J.C.
        • Zhang H.G.
        • Wang R.X.
        • Zhang Z.H.
        • Liu X.Y.
        Seminal plasma zinc level may be associated with the effect of cigarette smoking on sperm parameters.
        J Int Med Res. 2010; 38: 923
        • Srivastava A.
        • Kreiger N.
        Cigarette smoking and testicular cancer.
        Cancer Epidemiol Biomarkers Prev. 2004; 13: 49-54
        • Moirano G.
        • Zugna D.
        • Grasso C.
        • Mirabelli D.
        • Lista P.
        • Ciuffreda L.
        • et al.
        Postnatal risk factors for testicular cancer: the EPSAM case-control study.
        Int J Cancer. 2017;141:1803-10.; (Published online)
        • Hakonsen L.B.
        • Ernst A.
        • Ramlau-Hansen C.H.
        Maternal cigarette smoking during pregnancy and reproductive health in children: a review of epidemiological studies.
        Asian J Androl. 2014; 16: 39-49
        • Walsh T.J.
        • Schembri M.
        • Turek P.J.
        • Chan J.M.
        • Carroll P.R.
        • Smith J.F.
        • et al.
        Increased risk of high-grade prostate cancer among infertile men.
        Cancer. 2010; 116: 2140-2147
        • Ruhayel Y.
        • Giwercman A.
        • Ulmert D.
        • Rylander L.
        • Bjartell A.
        • Manjer J.
        • et al.
        Male infertility and prostate cancer risk: a nested case-control study.
        Cancer Causes Control. 2010; 21: 1635-1643
        • Walsh T.
        Male reproductive health and prostate cancer risk.
        Curr Opin Urol. 2011; 21: 506-513
        • Jorgensen K.T.
        • Pedersen B.V.
        • Johansen C.
        • Frisch M.
        Fatherhood status and prostate cancer risk.
        Cancer. 2008; 112: 919-923
        • Wiren S.M.
        • Drevin Li
        • Carlsson S.V.
        Fatherhood status and risk of prostate cancer: nationwide, population-based case-control study.
        Int J Cancer. 2013; 133: 937-943
        • Eisenberg M.L.
        • Park Y.
        • Brinton L.A.
        • Hollenbeck A.R.
        • Schatzkin A.
        Fatherhood and incident prostate cancer in a prospective US cohort.
        Int J Epidemiol. 2011; 40: 480-487
        • Mao Y.
        • Xu X.
        • Zheng X.
        • Xie L.
        Reduced risk of prostate cancer in childless men as compared to fathers: a systematic review and meta-analysis.
        Sci Rep. 2016; 6: 19210
        • Eisenberg M.L.
        • Betts P.
        • Herder D.
        • Lamb D.J.
        • Lipshultz L.I.
        Increased risk of cancer among azoospermic men.
        Fertil Steril. 2013; 100: 681-685
        • Hotaling J.M.
        • Carrell D.T.
        Clinical genetic testing for male factor infertility: current applications and future directions.
        Andrology. 2014; 2: 339
        • Skeldon S.C.
        • Goldenberg L.
        Bladder cancer: a portal into men’s health.
        Urol Oncol. 2015; 33: 40-44
        • Fritz M.A.
        • Speroff L.
        Clinical gynecologic endocrinology and infertility.
        Lippincott Williams & Wilkins, Philadelphia2011
        • Schultz N.
        • Hamra F.K.
        • Garbers D.L.
        A multitude of genes expressed solely in meiotic or postmeiotic spermatogenic cells offers a myriad of contraceptive targets.
        Proc Natl Acad Sci U S A. 2003; 100: 12201-12206
        • Aston K.I.
        • Conrad D.F.
        A review of genome-wide approaches to study the genetic basis for spermatogenic defects.
        Spermatogenesis. 2012; 927: 397-410
        • Ji G.
        • Long Y.
        • Zhou Y.
        • Huang C.
        • Gu A.
        • Want X.
        Common variants in mismatch repair genes associated with increased risk of sperm DNA damage and male infertility.
        BMC Med. 2012; 10: 49
        • Wei K.
        • Clark A.B.
        • Wong E.
        • Kane M.F.
        • Mazur D.J.
        • Parris T.
        • et al.
        Inactivation of exonuclease 1 in mice results in DNA mismatch repair defects, increased cancer susceptibility, and male and female sterility.
        Genes Dev. 2003; 17: 603-614
        • Terribas E.
        • Bonache S.
        • Garcia-Arevalo M.
        • Sanchez J.
        • Franco E.
        • Bassas L.
        • et al.
        Changes in the expression profile of the meiosis-involved mismatch repair genes in impaired human spermatogenesis.
        J Androl. 2010; 31: 346-357