Genetic Aspects of Male Infertility

  • Orhan BukulmezEmail author


Genetic abnormalities may account for 15–30% of male factor infertility. Genes and genomic regulation involved in male genital tract development, gonadal development, and function including those related to spermatogenesis may be involved with male infertility. Although many of the genetic factors are still to be elucidated and many of the predicted genetic perturbations are yet to find their place for clinical applications, it is essential to appraise the current information on genetic basis of male reproductive system disorders.


Genetics in male infertility Genomic regulation of male sexual development Sertoli cells Testis formation Hypospadias Peritubular myoid cells Spermatogenic genes Male genital tract development Spermatogenesis 


  1. 1.
    Ferlin A, Raicu F, Gatta V, Zuccarello D, Palka G, Foresta C. Male infertility: role of genetic background. Reprod Biomed Online. 2007;14:734–45.PubMedGoogle Scholar
  2. 2.
    Wilhelm D, Koopman P. The makings of maleness: towards an integrated view of male sexual development. Nat Rev Genet. 2006;7:620–31.PubMedGoogle Scholar
  3. 3.
    Miyamoto N, Yoshida M, Kuratani S, Matsuo I, Aizawa S. Defects of urogenital development in mice lacking Emx2. Development. 1997;124:1653–64.PubMedGoogle Scholar
  4. 4.
    Tevosian SG, Albrecht KH, Crispino JD, Fujiwara Y, Eicher EM, Orkin SH. Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2. Development. 2002;129: 4627–34.PubMedGoogle Scholar
  5. 5.
    Birk OS, Casiano DE, Wassif CA, Cogliati T, Zhao L, Zhao Y, et al. The LIM homeobox gene Lhx9 is essential for mouse gonad formation. Nature. 2000;403:909–13.PubMedGoogle Scholar
  6. 6.
    Achermann JC, Ito M, Hindmarsh PC, Jameson JL. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet. 1999;22:125–6.PubMedGoogle Scholar
  7. 7.
    Achermann JC, Ozisik G, Ito M, Orun UA, Harmanci K, Gurakan B, et al. Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. J Clin Endocrinol Metab. 2002;87: 1829–33.PubMedGoogle Scholar
  8. 8.
    Ludbrook LM, Harley VR. Sex determination: a ‘window’ of DAX1 activity. Trends Endocrinol Metab. 2004;15:116–21.PubMedGoogle Scholar
  9. 9.
    Ozisik G, Achermann JC, Jameson JL. The role of SF1 in adrenal and reproductive function: insight from naturally occurring mutations in humans. Mol Genet Metab. 2002;76:85–91.PubMedGoogle Scholar
  10. 10.
    Englert C. WT1—more than a transcription factor? Trends Biochem Sci. 1998;23:389–93.PubMedGoogle Scholar
  11. 11.
    Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature. 1990;346:240–4.PubMedGoogle Scholar
  12. 12.
    Wilhelm D, Martinson F, Bradford S, Wilson MJ, Combes AN, Beverdam A, et al. Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signaling during mammalian sex determination. Dev Biol. 2005;287:111–24.PubMedGoogle Scholar
  13. 13.
    Bullejos M, Koopman P. Spatially dynamic expression of Sry in mouse genital ridges. Dev Dyn. 2001;221:201–5.PubMedGoogle Scholar
  14. 14.
    Hammes A, Guo JK, Lutsch G, Leheste JR, Landrock D, Ziegler U, et al. Two splice variants of the Wilms’ tumor 1 gene have distinct functions during sex determination and nephron formation. Cell. 2001;106:319–29.PubMedGoogle Scholar
  15. 15.
    Nef S, Verma-Kurvari S, Merenmies J, Vassalli JD, Efstratiadis A, Accili D, et al. Testis determination requires insulin receptor family function in mice. Nature. 2003;426:291–5.PubMedGoogle Scholar
  16. 16.
    Bullejos M, Koopman P. Delayed Sry and Sox9 expression in developing mouse gonads underlies B6-Y(DOM) sex reversal. Dev Biol. 2005;278:473–81.PubMedGoogle Scholar
  17. 17.
    Taketo T, Lee CH, Zhang J, Li Y, Lee CY, Lau YF. Expression of SRY proteins in both normal and sex-reversed XY fetal mouse gonads. Dev Dyn. 2005;233:612–22.PubMedGoogle Scholar
  18. 18.
    Clark AM, Garland KK, Russell LD. Desert hedgehog (Dhh) gene is required in the mouse testis for formation of adult-type Leydig cells and normal development of peritubular cells and seminiferous tubules. Biol Reprod. 2000;63:1825–38.PubMedGoogle Scholar
  19. 19.
    Bitgood MJ, Shen L, McMahon AP. Sertoli cell signaling by desert hedgehog regulates the male germ line. Curr Biol. 1996;6: 298–304.PubMedGoogle Scholar
  20. 20.
    Canto P, Vilchis F, Soderlund D, Reyes E, Mendez JP. A heterozygous mutation in the desert hedgehog gene in patients with mixed gonadal dysgenesis. Mol Hum Reprod. 2005;11:833–6.PubMedGoogle Scholar
  21. 21.
    Canto P, Soderlund D, Reyes E, Mendez JP. Mutations in the desert hedgehog (DHH) gene in patients with 46, XY complete pure gonadal dysgenesis. J Clin Endocrinol Metab. 2004;89: 4480–3.PubMedGoogle Scholar
  22. 22.
    Kitamura K, Yanazawa M, Sugiyama N, Miura H, Iizuka-Kogo A, Kusaka M, et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet. 2002;32:359–69.PubMedGoogle Scholar
  23. 23.
    Tang P, Park DJ, Marshall Graves JA, Harley VR. ATRX and sex differentiation. Trends Endocrinol Metab. 2004;15: 339–44.PubMedGoogle Scholar
  24. 24.
    Brennan J, Tilmann C, Capel B. Pdgfr-alpha mediates testis cord organization and fetal Leydig cell development in the XY gonad. Genes Dev. 2003;17:800–10.PubMedGoogle Scholar
  25. 25.
    Tanaka SS, Yamaguchi YL, Tsoi B, Lickert H, Tam PP. IFITM/Mil/fragilis family proteins IFITM1 and IFITM3 play distinct roles in mouse primordial germ cell homing and repulsion. Dev Cell. 2005;9:745–56.PubMedGoogle Scholar
  26. 26.
    Molyneaux KA, Zinszner H, Kunwar PS, Schaible K, Stebler J, Sunshine MJ, et al. The chemokine SDF1/CXCL12 and its receptor CXCR4 regulate mouse germ cell migration and survival. Development. 2003;130:4279–86.PubMedGoogle Scholar
  27. 27.
    Adham IM, Agoulnik AI. Insulin-like 3 signalling in testicular descent. Int J Androl. 2004;27:257–65.PubMedGoogle Scholar
  28. 28.
    Ivell R, Hartung S. The molecular basis of cryptorchidism. Mol Hum Reprod. 2003;9:175–81.PubMedGoogle Scholar
  29. 29.
    Quill TA, Ren D, Clapham DE, Garbers DL. A voltage-gated ion channel expressed specifically in spermatozoa. Proc Natl Acad Sci USA. 2001;98:12527–31.PubMedGoogle Scholar
  30. 30.
    Sha J, Zhou Z, Li J, Yin L, Yang H, Hu G, et al. Identification of testis development and spermatogenesis-related genes in human and mouse testes using cDNA arrays. Mol Hum Reprod. 2002;8: 511–7.PubMedGoogle Scholar
  31. 31.
    Schultz N, Hamra FK, Garbers DL. A multitude of genes expressed solely in meiotic or postmeiotic spermatogenic cells offers a myriad of contraceptive targets. Proc Natl Acad Sci USA. 2003;100: 12201–6.PubMedGoogle Scholar
  32. 32.
    Hermo L, Pelletier RM, Cyr DG, Smith CE. Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 1: background to spermatogenesis, spermatogonia, and spermatocytes. Microsc Res Tech. 2010;73(4):241–78.PubMedGoogle Scholar
  33. 33.
    Saxena R, de Vries JW, Repping S, Alagappan RK, Skaletsky H, Brown LG, et al. Four DAZ genes in two clusters found in the AZFc region of the human Y chromosome. Genomics. 2000;67: 256–67.PubMedGoogle Scholar
  34. 34.
    Yen PH. Putative biological functions of the DAZ family. Int J Androl. 2004;27:125–9.PubMedGoogle Scholar
  35. 35.
    Hopps CV, Mielnik A, Goldstein M, Palermo GD, Rosenwaks Z, Schlegel PN. Detection of sperm in men with Y chromosome microdeletions of the AZFa, AZFb and AZFc regions. Hum Reprod. 2003;18:1660–5.PubMedGoogle Scholar
  36. 36.
    Silber SJ, Repping S. Transmission of male infertility to future generations: lessons from the Y chromosome. Hum Reprod Update. 2002;8:217–29.PubMedGoogle Scholar
  37. 37.
    Nishimune Y, Tanaka H. Infertility caused by polymorphisms or mutations in spermatogenesis-specific genes. J Androl. 2006;27:326–34.PubMedGoogle Scholar
  38. 38.
    Mueller JL, Mahadevaiah SK, Park PJ, Warburton PE, Page DC, Turner JM. The mouse X chromosome is enriched for multicopy testis genes showing postmeiotic expression. Nat Genet. 2008;40:794–9.PubMedGoogle Scholar
  39. 39.
    Roberts LM, Visser JA, Ingraham HA. Involvement of a matrix metalloproteinase in MIS-induced cell death during urogenital development. Development. 2002;129:1487–96.PubMedGoogle Scholar
  40. 40.
    Belville C, Marechal JD, Pennetier S, Carmillo P, Masgrau L, Messika-Zeitoun L, et al. Natural mutations of the anti-Mullerian hormone type II receptor found in persistent Mullerian duct syndrome affect ligand binding, signal transduction and cellular transport. Hum Mol Genet. 2009;18:3002–13.PubMedGoogle Scholar
  41. 41.
    Belville C, Van Vlijmen H, Ehrenfels C, Pepinsky B, Rezaie AR, Picard JY, et al. Mutations of the anti-Mullerian hormone gene in patients with persistent Mullerian duct syndrome: biosynthesis, secretion, and processing of the abnormal proteins and analysis using a three-dimensional model. Mol Endocrinol. 2004;18: 708–21.PubMedGoogle Scholar
  42. 42.
    Hannema SE, Hughes IA. Regulation of Wolffian duct development. Horm Res. 2007;67:142–51.PubMedGoogle Scholar
  43. 43.
    Dravis C, Yokoyama N, Chumley MJ, Cowan CA, Silvany RE, Shay J, et al. Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development. Dev Biol. 2004;271: 272–90.PubMedGoogle Scholar
  44. 44.
    Goodman FR, Bacchelli C, Brady AF, Brueton LA, Fryns JP, Mortlock DP, et al. Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. Am J Hum Genet. 2000;67:197–202.PubMedGoogle Scholar
  45. 45.
    Chandley AC. Genetic contribution to male infertility. Hum Reprod. 1998;13 Suppl 3:76–83. discussion 4-8.PubMedGoogle Scholar
  46. 46.
    Johnson MD. Genetic risks of intracytoplasmic sperm injection in the treatment of male infertility: recommendations for genetic counseling and screening. Fertil Steril. 1998;70:397–411.PubMedGoogle Scholar
  47. 47.
    Ravel C, Berthaut I, Bresson JL, Siffroi JP. Prevalence of chromosomal abnormalities in phenotypically normal and fertile adult males: large-scale survey of over 10,000 sperm donor karyotypes. Hum Reprod. 2006;21:1484–9.PubMedGoogle Scholar
  48. 48.
    O’Flynn O’Brien KL, Varghese AC, Agarwal A. The genetic causes of male factor infertility: a review. Fertil Steril. 2010;93:1–12.PubMedGoogle Scholar
  49. 49.
    Palermo GD, Colombero LT, Hariprashad JJ, Schlegel PN, Rosenwaks Z. Chromosome analysis of epididymal and testicular sperm in azoospermic patients undergoing ICSI. Hum Reprod. 2002;17:570–5.PubMedGoogle Scholar
  50. 50.
    Van Assche E, Bonduelle M, Tournaye H, Joris H, Verheyen G, Devroey P, et al. Cytogenetics of infertile men. Hum Reprod. 1996;11 Suppl 4:1–24. discussion 5-6.PubMedGoogle Scholar
  51. 51.
    American Society for Reproductive Medicine. Evaluation of the azoospermic male. Fertil Steril. 2008;90:S74–7.Google Scholar
  52. 52.
    Walsh TJ, Pera RR, Turek PJ. The genetics of male infertility. Semin Reprod Med. 2009;27:124–36.PubMedGoogle Scholar
  53. 53.
    Friedler S, Raziel A, Strassburger D, Schachter M, Bern O, Ron-El R. Outcome of ICSI using fresh and cryopreserved-thawed testicular spermatozoa in patients with non-mosaic Klinefelter’s syndrome. Hum Reprod. 2001;16:2616–20.PubMedGoogle Scholar
  54. 54.
    Schiff JD, Palermo GD, Veeck LL, Goldstein M, Rosenwaks Z, Schlegel PN. Success of testicular sperm extraction [corrected] and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab. 2005;90:6263–7.PubMedGoogle Scholar
  55. 55.
    Denschlag D, Tempfer C, Kunze M, Wolff G, Keck C. Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review. Fertil Steril. 2004;82:775–9.PubMedGoogle Scholar
  56. 56.
    Blanco J, Egozcue J, Vidal F. Meiotic behaviour of the sex chromosomes in three patients with sex chromosome anomalies (47, XXY, mosaic 46, XY/47, XXY and 47, XYY) assessed by fluorescence in-situ hybridization. Hum Reprod. 2001;16:887–92.PubMedGoogle Scholar
  57. 57.
    Bergere M, Wainer R, Nataf V, Bailly M, Gombault M, Ville Y, et al. Biopsied testis cells of four 47, XXY patients: fluorescence in-situ hybridization and ICSI results. Hum Reprod. 2002;17: 32–7.PubMedGoogle Scholar
  58. 58.
    Levron J, Aviram-Goldring A, Madgar I, Raviv G, Barkai G, Dor J. Sperm chromosome analysis and outcome of IVF in patients with non-mosaic Klinefelter’s syndrome. Fertil Steril. 2000;74: 925–9.PubMedGoogle Scholar
  59. 59.
    Staessen C, Tournaye H, Van Assche E, Michiels A, Van Landuyt L, Devroey P, et al. PGD in 47, XXY Klinefelter’s syndrome patients. Hum Reprod Update. 2003;9:319–30.PubMedGoogle Scholar
  60. 60.
    Tournaye H, Staessen C, Liebaers I, Van Assche E, Devroey P, Bonduelle M, et al. Testicular sperm recovery in nine 47, XXY Klinefelter patients. Hum Reprod. 1996;11:1644–9.PubMedGoogle Scholar
  61. 61.
    Shi Q, Martin RH. Multicolor fluorescence in situ hybridization analysis of meiotic chromosome segregation in a 47, XYY male and a review of the literature. Am J Med Genet. 2000;93:40–6.PubMedGoogle Scholar
  62. 62.
    Gonzalez-Merino E, Hans C, Abramowicz M, Englert Y, Emiliani S. Aneuploidy study in sperm and preimplantation embryos from nonmosaic 47, XYY men. Fertil Steril. 2007;88:600–6.PubMedGoogle Scholar
  63. 63.
    Van der Auwera B, Van Roy N, De Paepe A, Hawkins JR, Liebaers I, Castedo S, et al. Molecular cytogenetic analysis of XX males using Y-specific DNA sequences, including SRY. Hum Genet. 1992;89:23–8.PubMedGoogle Scholar
  64. 64.
    De Braekeleer M, Dao TN. Cytogenetic studies in male infertility: a review. Hum Reprod. 1991;6:245–50.PubMedGoogle Scholar
  65. 65.
    Chantot-Bastaraud S, Ravel C, Siffroi JP. Underlying karyotype abnormalities in IVF/ICSI patients. Reprod Biomed Online. 2008;16:514–22.PubMedGoogle Scholar
  66. 66.
    Martin RH. Cytogenetic determinants of male fertility. Hum Reprod Update. 2008;14:379–90.PubMedGoogle Scholar
  67. 67.
    Ogur G, Van Assche E, Vegetti W, Verheyen G, Tournaye H, Bonduelle M, et al. Chromosomal segregation in spermatozoa of 14 Robertsonian translocation carriers. Mol Hum Reprod. 2006;12:209–15.PubMedGoogle Scholar
  68. 68.
    Mau-Holzmann UA. Somatic chromosomal abnormalities in infertile men and women. Cytogenet Genome Res. 2005;111:317–36.PubMedGoogle Scholar
  69. 69.
    Estop AM, Van Kirk V, Cieply K. Segregation analysis of four translocations, t(2;18), t(3;15), t(5;7), and t(10;12), by sperm chromosome studies and a review of the literature. Cytogenet Cell Genet. 1995;70:80–7.PubMedGoogle Scholar
  70. 70.
    McLachlan RI, O’Bryan MK. Clinical review#: state of the art for genetic testing of infertile men. J Clin Endocrinol Metab. 2010;95:1013–24.PubMedGoogle Scholar
  71. 71.
    Rozen S, Skaletsky H, Marszalek JD, Minx PJ, Cordum HS, Waterston RH, et al. Abundant gene conversion between arms of palindromes in human and ape Y chromosomes. Nature. 2003;423:873–6.PubMedGoogle Scholar
  72. 72.
    Li Z, Haines CJ, Han Y. “Micro-deletions” of the human Y chromosome and their relationship with male infertility. J Genet Genomics. 2008;35:193–9.PubMedGoogle Scholar
  73. 73.
    Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature. 2003;423:825–37.PubMedGoogle Scholar
  74. 74.
    Foresta C, Moro E, Ferlin A. Y chromosome microdeletions and alterations of spermatogenesis. Endocr Rev. 2001;22:226–39.PubMedGoogle Scholar
  75. 75.
    Vollrath D, Foote S, Hilton A, Brown LG, Beer-Romero P, Bogan JS, et al. The human Y chromosome: a 43-interval map based on naturally occurring deletions. Science. 1992;258:52–9.PubMedGoogle Scholar
  76. 76.
    Kleiman SE, Bar-Shira Maymon B, Yogev L, Paz G, Yavetz H. The prognostic role of the extent of Y microdeletion on spermatogenesis and maturity of Sertoli cells. Hum Reprod. 2001;16: 399–402.PubMedGoogle Scholar
  77. 77.
    Poongothai J, Gopenath TS, Manonayaki S. Genetics of human male infertility. Singapore Med J. 2009;50:336–47.PubMedGoogle Scholar
  78. 78.
    Vogt PH. Genetics of idiopathic male infertility: Y chromosomal azoospermia factors (AZFa, AZFb, AZFc). Baillieres Clin Obstet Gynaecol. 1997;11:773–95.PubMedGoogle Scholar
  79. 79.
    Sadeghi-Nejad H, Oates RD. The Y chromosome and male infertility. Curr Opin Urol. 2008;18:628–32.PubMedGoogle Scholar
  80. 80.
    Repping S, Skaletsky H, Lange J, Silber S, Van Der Veen F, Oates RD, et al. Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. Am J Hum Genet. 2002;71:906–22.PubMedGoogle Scholar
  81. 81.
    Brown GM, Furlong RA, Sargent CA, Erickson RP, Longepied G, Mitchell M, et al. Characterisation of the coding sequence and fine mapping of the human DFFRY gene and comparative expression analysis and mapping to the Sxrb interval of the mouse Y chromosome of the Dffry gene. Hum Mol Genet. 1998;7:97–107.PubMedGoogle Scholar
  82. 82.
    Chuang RY, Weaver PL, Liu Z, Chang TH. Requirement of the DEAD-Box protein ded1p for messenger RNA translation. Science. 1997;275:1468–71.PubMedGoogle Scholar
  83. 83.
    Foresta C, Ferlin A, Moro E. Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DBY in male infertility. Hum Mol Genet. 2000;9:1161–9.PubMedGoogle Scholar
  84. 84.
    Moro E, Ferlin A, Yen PH, Franchi PG, Palka G, Foresta C. Male infertility caused by a de novo partial deletion of the DAZ cluster on the Y chromosome. J Clin Endocrinol Metab. 2000;85: 4069–73.PubMedGoogle Scholar
  85. 85.
    Sun C, Skaletsky H, Birren B, Devon K, Tang Z, Silber S, et al. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nat Genet. 1999;23:429–32.PubMedGoogle Scholar
  86. 86.
    Geoffroy-Siraudin C, Aknin-Seiffer I, Metzler-Guillemain C, Ghalamoun-Slaimi R, Bonzi MF, Levy R, et al. Meiotic abnormalities in patients bearing complete AZFc deletion of Y chromosome. Hum Reprod. 2007;22:1567–72.PubMedGoogle Scholar
  87. 87.
    Navarro-Costa P, Pereira L, Alves C, Gusmao L, Proenca C, Marques-Vidal P, et al. Characterizing partial AZFc deletions of the Y chromosome with amplicon-specific sequence markers. BMC Genomics. 2007;8:342.PubMedGoogle Scholar
  88. 88.
    Wu B, Lu NX, Xia YK, Gu AH, Lu CC, Wang W, et al. A frequent Y chromosome b2/b3 subdeletion shows strong association with male infertility in Han-Chinese population. Hum Reprod. 2007;22:1107–13.PubMedGoogle Scholar
  89. 89.
    Zhang F, Li Z, Wen B, Jiang J, Shao M, Zhao Y, et al. A frequent partial AZFc deletion does not render an increased risk of spermatogenic impairment in East Asians. Ann Hum Genet. 2006;70:304–13.PubMedGoogle Scholar
  90. 90.
    Zhu XB, Liu YL, Zhang W, Ping P, Cao XR, Liu Y, et al. Vertical transmission of the Yq AZFc microdeletion from father to son over two or three generations in infertile Han Chinese families. Asian J Androl. 2010;12:240–6.PubMedGoogle Scholar
  91. 91.
    Giachini C, Nuti F, Marinari E, Forti G, Krausz C. Partial AZFc deletions in infertile men with cryptorchidism. Hum Reprod. 2007;22:2398–403.PubMedGoogle Scholar
  92. 92.
    Zhang F, Lu C, Li Z, Xie P, Xia Y, Zhu X, et al. Partial deletions are associated with an increased risk of complete deletion in AZFc: a new insight into the role of partial AZFc deletions in male infertility. J Med Genet. 2007;44:437–44.PubMedGoogle Scholar
  93. 93.
    Ferlin A, Arredi B, Speltra E, Cazzadore C, Selice R, Garolla A, et al. Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-year experience in Italy. J Clin Endocrinol Metab. 2007;92:762–70.PubMedGoogle Scholar
  94. 94.
    Mulhall JP, Reijo R, Alagappan R, Brown L, Page D, Carson R, et al. Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: fertilization, normal embryonic development and pregnancy occur when retrieved testicular spermatozoa are used for intracytoplasmic sperm injection. Hum Reprod. 1997;12:503–8.PubMedGoogle Scholar
  95. 95.
    Oates RD, Silber S, Brown LG, Page DC. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod. 2002;17:2813–24.PubMedGoogle Scholar
  96. 96.
    Osborne EC, Lynch M, McLachlan R, Trounson AO, Cram DS. Microarray detection of Y chromosome deletions associated with male infertility. Reprod Biomed Online. 2007;15:673–80.PubMedGoogle Scholar
  97. 97.
    Ferlin A, Moro E, Onisto M, Toscano E, Bettella A, Foresta C. Absence of testicular DAZ gene expression in idiopathic severe testiculopathies. Hum Reprod. 1999;14:2286–92.PubMedGoogle Scholar
  98. 98.
    Lange J, Skaletsky H, van Daalen SK, Embry SL, Korver CM, Brown LG, et al. Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes. Cell. 2009;138:855–69.PubMedGoogle Scholar
  99. 99.
    Lardone MC, Parodi DA, Valdevenito R, Ebensperger M, Piottante A, Madariaga M, et al. Quantification of DDX3Y, RBMY1, DAZ and TSPY mRNAs in testes of patients with severe impairment of spermatogenesis. Mol Hum Reprod. 2007;13:705–12.PubMedGoogle Scholar
  100. 100.
    Vodicka R, Vrtel R, Dusek L, Singh AR, Krizova K, Svacinova V, et al. TSPY gene copy number as a potential new risk factor for male infertility. Reprod Biomed Online. 2007;14:579–87.PubMedGoogle Scholar
  101. 101.
    Wang PJ, McCarrey JR, Yang F, Page DC. An abundance of X-linked genes expressed in spermatogonia. Nat Genet. 2001;27: 422–6.PubMedGoogle Scholar
  102. 102.
    Cantu JM, Diaz M, Moller M, Jimenez-Sainz M, Sandoval L, Vaca G, et al. Azoospermia and duplication 3qter as distinct consequences of a familial t(X;3) (q26;q13.2). Am J Med Genet. 1985;20:677–84.PubMedGoogle Scholar
  103. 103.
    Lee S, Lee SH, Chung TG, Kim HJ, Yoon TK, Kwak IP, et al. Molecular and cytogenetic characterization of two azoospermic patients with X-autosome translocation. J Assist Reprod Genet. 2003;20:385–9.PubMedGoogle Scholar
  104. 104.
    Nemeth AH, Gallen IW, Crocker M, Levy E, Maher E. Klinefelter-like phenotype and primary infertility in a male with a paracentric Xq inversion. J Med Genet. 2002;39:E28.PubMedGoogle Scholar
  105. 105.
    Olesen C, Silber J, Eiberg H, Ernst E, Petersen K, Lindenberg S, et al. Mutational analysis of the human FATE gene in 144 infertile men. Hum Genet. 2003;113:195–201.PubMedGoogle Scholar
  106. 106.
    Raverot G, Lejeune H, Kotlar T, Pugeat M, Jameson JL. X-linked sex-determining region Y box 3 (SOX3) gene mutations are uncommon in men with idiopathic oligoazoospermic infertility. J Clin Endocrinol Metab. 2004;89:4146–8.PubMedGoogle Scholar
  107. 107.
    Schneider-Gadicke A, Beer-Romero P, Brown LG, Mardon G, Luoh SW, Page DC. Putative transcription activator with alternative isoforms encoded by human ZFX gene. Nature. 1989;342: 708–11.PubMedGoogle Scholar
  108. 108.
    Schneider-Gadicke A, Beer-Romero P, Brown LG, Nussbaum R, Page DC. ZFX has a gene structure similar to ZFY, the putative human sex determinant, and escapes X inactivation. Cell. 1989;57:1247–58.PubMedGoogle Scholar
  109. 109.
    Wang RS, Yeh S, Tzeng CR, Chang C. Androgen receptor roles in spermatogenesis and fertility: lessons from testicular cell-specific androgen receptor knockout mice. Endocr Rev. 2009;30:119–32.PubMedGoogle Scholar
  110. 110.
    Xu Q, Lin HY, Yeh SD, Yu IC, Wang RS, Chen YT, et al. Infertility with defective spermatogenesis and steroidogenesis in male mice lacking androgen receptor in Leydig cells. Endocrine. 2007;32: 96–106.PubMedGoogle Scholar
  111. 111.
    Tsai MY, Yeh SD, Wang RS, Yeh S, Zhang C, Lin HY, et al. Differential effects of spermatogenesis and fertility in mice lacking androgen receptor in individual testis cells. Proc Natl Acad Sci USA. 2006;103:18975–80.PubMedGoogle Scholar
  112. 112.
    De Gendt K, Swinnen JV, Saunders PT, Schoonjans L, Dewerchin M, Devos A, et al. A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proc Natl Acad Sci USA. 2004;101:1327–32.PubMedGoogle Scholar
  113. 113.
    Ferlin A, Vinanzi C, Garolla A, Selice R, Zuccarello D, Cazzadore C, et al. Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations. Clin Endocrinol (Oxf). 2006;65:606–10.Google Scholar
  114. 114.
    Greenland KJ, Zajac JD. Kennedy’s disease: pathogenesis and clinical approaches. Intern Med J. 2004;34:279–86.PubMedGoogle Scholar
  115. 115.
    Finsterer J. Bulbar and spinal muscular atrophy (Kennedy’s disease): a review. Eur J Neurol. 2009;16:556–61.PubMedGoogle Scholar
  116. 116.
    Lazaros L, Xita N, Kaponis A, Zikopoulos K, Sofikitis N, Georgiou I. Evidence for association of sex hormone-binding globulin and androgen receptor genes with semen quality. Andrologia. 2008;40:186–91.PubMedGoogle Scholar
  117. 117.
    Rajpert-De Meyts E, Leffers H, Petersen JH, Andersen AG, Carlsen E, Jorgensen N, et al. CAG repeat length in androgen-receptor gene and reproductive variables in fertile and infertile men. Lancet. 2002;359:44–6.PubMedGoogle Scholar
  118. 118.
    Yong EL, Loy CJ, Sim KS. Androgen receptor gene and male infertility. Hum Reprod Update. 2003;9:1–7.PubMedGoogle Scholar
  119. 119.
    Dowsing AT, Yong EL, Clark M, McLachlan RI, de Kretser DM, Trounson AO. Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene. Lancet. 1999;354:640–3.PubMedGoogle Scholar
  120. 120.
    Stouffs K, Lissens W, Tournaye H, Van Steirteghem A, Liebaers I. Possible role of USP26 in patients with severely impaired spermatogenesis. Eur J Hum Genet. 2005;13:336–40.PubMedGoogle Scholar
  121. 121.
    Nuti F, Krausz C. Gene polymorphisms/mutations relevant to abnormal spermatogenesis. Reprod Biomed Online. 2008;16: 504–13.PubMedGoogle Scholar
  122. 122.
    Akinloye O, Gromoll J, Callies C, Nieschlag E, Simoni M. Mutation analysis of the X-chromosome linked, testis-specific TAF7L gene in spermatogenic failure. Andrologia. 2007;39: 190–5.PubMedGoogle Scholar
  123. 123.
    Ravel C, El Houate B, Chantot S, Lourenco D, Dumaine A, Rouba H, et al. Haplotypes, mutations and male fertility: the story of the testis-specific ubiquitin protease USP26. Mol Hum Reprod. 2006;12:643–6.PubMedGoogle Scholar
  124. 124.
    Stouffs K, Willems A, Lissens W, Tournaye H, Van Steirteghem A, Liebaers I. The role of the testis-specific gene hTAF7L in the aetiology of male infertility. Mol Hum Reprod. 2006;12:263–7.PubMedGoogle Scholar
  125. 125.
    Fechner A, Fong S, McGovern P. A review of Kallmann syndrome: genetics, pathophysiology, and clinical management. Obstet Gynecol Surv. 2008;63:189–94.PubMedGoogle Scholar
  126. 126.
    Kim SH, Hu Y, Cadman S, Bouloux P. Diversity in fibroblast growth factor receptor 1 regulation: learning from the investigation of Kallmann syndrome. J Neuroendocrinol. 2008;20: 141–63.PubMedGoogle Scholar
  127. 127.
    Stuhrmann M, Dork T. CFTR gene mutations and male infertility. Andrologia. 2000;32:71–83.PubMedGoogle Scholar
  128. 128.
    Dumur V, Gervais R, Rigot JM, Lafitte JJ, Manouvrier S, Biserte J, et al. Abnormal distribution of CF delta F508 allele in azoospermic men with congenital aplasia of epididymis and vas deferens. Lancet. 1990;336:512.PubMedGoogle Scholar
  129. 129.
    Gervais R, Dumur V, Rigot JM, Lafitte JJ, Roussel P, Claustres M, et al. High frequency of the R117H cystic fibrosis mutation in patients with congenital absence of the vas deferens. N Engl J Med. 1993;328:446–7.PubMedGoogle Scholar
  130. 130.
    Claustres M, Guittard C, Bozon D, Chevalier F, Verlingue C, Ferec C, et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16:143–56.PubMedGoogle Scholar
  131. 131.
    Daudin M, Bieth E, Bujan L, Massat G, Pontonnier F, Mieusset R. Congenital bilateral absence of the vas deferens: clinical characteristics, biological parameters, cystic fibrosis transmembrane conductance regulator gene mutations, and implications for genetic counseling. Fertil Steril. 2000;74:1164–74.PubMedGoogle Scholar
  132. 132.
    Cuppens H, Cassiman JJ. CFTR mutations and polymorphisms in male infertility. Int J Androl. 2004;27:251–6.PubMedGoogle Scholar
  133. 133.
    Cystic fibrosis mutation database. Last updated 1 Apr 2010.
  134. 134.
    Dequeker E, Stuhrmann M, Morris MA, Casals T, Castellani C, Claustres M, et al. Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders—updated European recommendations. Eur J Hum Genet. 2009;17:51–65.PubMedGoogle Scholar
  135. 135.
    Chillon M, Casals T, Mercier B, Bassas L, Lissens W, Silber S, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995;332: 1475–80.PubMedGoogle Scholar
  136. 136.
    Scotet V, Audrezet MP, Roussey M, Rault G, Dirou-Prigent A, Journel H, et al. Immunoreactive trypsin/DNA newborn screening for cystic fibrosis: should the R117H variant be included in CFTR mutation panels? Pediatrics. 2006;118:e1523–9.PubMedGoogle Scholar
  137. 137.
    Kiesewetter S, Macek Jr M, Davis C, Curristin SM, Chu CS, Graham C, et al. A mutation in CFTR produces different phenotypes depending on chromosomal background. Nat Genet. 1993;5: 274–8.PubMedGoogle Scholar
  138. 138.
    American College of Obstetricians and Gynecologists. Update on carrier screening for cystic fibrosis. ACOG Committee Opinion Number 325, December 2005. Obstet Gynecol. 2005;106: 1465–8.Google Scholar
  139. 139.
    Egozcue J, Blanco J, Anton E, Egozcue S, Sarrate Z, Vidal F. Genetic analysis of sperm and implications of severe male ­infertility—a review. Placenta. 2003;24(Suppl B):S62–5.PubMedGoogle Scholar
  140. 140.
    Bernardini L, Gianaroli L, Fortini D, Conte N, Magli C, Cavani S, et al. Frequency of hyper-, hypohaploidy and diploidy in ejaculate, epididymal and testicular germ cells of infertile patients. Hum Reprod. 2000;15:2165–72.PubMedGoogle Scholar
  141. 141.
    Vegetti W, Van Assche E, Frias A, Verheyen G, Bianchi MM, Bonduelle M, et al. Correlation between semen parameters and sperm aneuploidy rates investigated by fluorescence in-situ hybridization in infertile men. Hum Reprod. 2000;15:351–65.PubMedGoogle Scholar
  142. 142.
    Gonsalves J, Sun F, Schlegel PN, Turek PJ, Hopps CV, Greene C, et al. Defective recombination in infertile men. Hum Mol Genet. 2004;13:2875–83.PubMedGoogle Scholar
  143. 143.
    Sun F, Greene C, Turek PJ, Ko E, Rademaker A, Martin RH. Immunofluorescent synaptonemal complex analysis in azoospermic men. Cytogenet Genome Res. 2005;111:366–70.PubMedGoogle Scholar
  144. 144.
    Sun F, Turek P, Greene C, Ko E, Rademaker A, Martin RH. Abnormal progression through meiosis in men with nonobstructive azoospermia. Fertil Steril. 2007;87:565–71.PubMedGoogle Scholar
  145. 145.
    Topping D, Brown P, Judis L, Schwartz S, Seftel A, Thomas A, et al. Synaptic defects at meiosis I and non-obstructive azoospermia. Hum Reprod. 2006;21:3171–7.PubMedGoogle Scholar
  146. 146.
    Sanderson ML, Hassold TJ, Carrell DT. Proteins involved in meiotic recombination: a role in male infertility? Syst Biol Reprod Med. 2008;54:57–74.PubMedGoogle Scholar
  147. 147.
    Miyamoto T, Hasuike S, Yogev L, Maduro MR, Ishikawa M, Westphal H, et al. Azoospermia in patients heterozygous for a mutation in SYCP3. Lancet. 2003;362:1714–9.PubMedGoogle Scholar
  148. 148.
    Aarabi M, Modarressi MH, Soltanghoraee H, Behjati R, Amirjannati N, Akhondi MM. Testicular expression of synaptonemal complex protein 3 (SYCP3) messenger ribonucleic acid in 110 patients with nonobstructive azoospermia. Fertil Steril. 2006;86:325–31.PubMedGoogle Scholar
  149. 149.
    Meeks M, Bush A. Primary ciliary dyskinesia (PCD). Pediatr Pulmonol. 2000;29:307–16.PubMedGoogle Scholar
  150. 150.
    Loges NT, Olbrich H, Becker-Heck A, Haffner K, Heer A, Reinhard C, et al. Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects. Am J Hum Genet. 2009;85:883–9.PubMedGoogle Scholar
  151. 151.
    Moore A, Escudier E, Roger G, Tamalet A, Pelosse B, Marlin S, et al. RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa. J Med Genet. 2006;43:326–33.PubMedGoogle Scholar
  152. 152.
    Gerber PA, Kruse R, Hirchenhain J, Krussel JS, Neumann NJ. Pregnancy after laser-assisted selection of viable spermatozoa before intracytoplasmatic sperm injection in a couple with male primary cilia dyskinesia. Fertil Steril. 1826;2008(89):e9–12.Google Scholar
  153. 153.
    Dieterich K, Zouari R, Harbuz R, Vialard F, Martinez D, Bellayou H, et al. The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population. Hum Mol Genet. 2009;18:1301–9.PubMedGoogle Scholar
  154. 154.
    Kimmins S, Crosio C, Kotaja N, Hirayama J, Monaco L, Hoog C, et al. Differential functions of the Aurora-B and Aurora-C kinases in mammalian spermatogenesis. Mol Endocrinol. 2007;21: 726–39.PubMedGoogle Scholar
  155. 155.
    Lee C, Iafrate AJ, Brothman AR. Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nat Genet. 2007;39:S48–54.PubMedGoogle Scholar
  156. 156.
    Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, et al. Sequence and organization of the human mitochondrial genome. Nature. 1981;290:457–65.PubMedGoogle Scholar
  157. 157.
    Yakes FM, Van Houten B. Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci USA. 1997;94:514–9.PubMedGoogle Scholar
  158. 158.
    Wei YH, Kao SH, Lee HC. Simultaneous increase of mitochondrial DNA deletions and lipid peroxidation in human aging. Ann N Y Acad Sci. 1996;786:24–43.PubMedGoogle Scholar
  159. 159.
    Rovio AT, Marchington DR, Donat S, Schuppe HC, Abel J, Fritsche E, et al. Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nat Genet. 2001;29:261–2.PubMedGoogle Scholar
  160. 160.
    St John JC, Jokhi RP, Barratt CL. The impact of mitochondrial genetics on male infertility. Int J Androl. 2005;28:65–73.PubMedGoogle Scholar
  161. 161.
    Ropp PA, Copeland WC. Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase gamma. Genomics. 1996;36:449–58.PubMedGoogle Scholar
  162. 162.
    Surani MA. Reprogramming of genome function through epigenetic inheritance. Nature. 2001;414:122–8.PubMedGoogle Scholar
  163. 163.
    Wallace JA, Orr-Weaver TL. Replication of heterochromatin: insights into mechanisms of epigenetic inheritance. Chromosoma. 2005;114:389–402.PubMedGoogle Scholar
  164. 164.
    Margueron R, Trojer P, Reinberg D. The key to development: interpreting the histone code? Curr Opin Genet Dev. 2005;15: 163–76.PubMedGoogle Scholar
  165. 165.
    Kim VN. Small RNAs just got bigger: Piwi-interacting RNAs (piRNAs) in mammalian testes. Genes Dev. 2006;20:1993–7.PubMedGoogle Scholar
  166. 166.
    Papaioannou MD, Nef S. microRNAs in the testis: building up male fertility. J Androl. 2010;31:26–33.PubMedGoogle Scholar
  167. 167.
    Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science. 2001;293:1089–93.PubMedGoogle Scholar
  168. 168.
    Ferguson-Smith AC, Surani MA. Imprinting and the epigenetic asymmetry between parental genomes. Science. 2001;293: 1086–9.PubMedGoogle Scholar
  169. 169.
    Guerrero-Bosagna C, Sabat P, Valladares L. Environmental signaling and evolutionary change: can exposure of pregnant mammals to environmental estrogens lead to epigenetically induced evolutionary changes in embryos? Evol Dev. 2005;7:341–50.PubMedGoogle Scholar
  170. 170.
    MacPhee DG. Epigenetics and epimutagens: some new perspectives on cancer, germ line effects and endocrine disrupters. Mutat Res. 1998;400:369–79.PubMedGoogle Scholar
  171. 171.
    Guerrero-Bosagna CM, Skinner MK. Epigenetic transgenerational effects of endocrine disruptors on male reproduction. Semin Reprod Med. 2009;27:403–8.PubMedGoogle Scholar
  172. 172.
    Bukulmez O. Does assisted reproductive technology cause birth defects? Curr Opin Obstet Gynecol. 2009;21:260–4.PubMedGoogle Scholar
  173. 173.
    Marques CJ, Carvalho F, Sousa M, Barros A. Genomic imprinting in disruptive spermatogenesis. Lancet. 2004;363:1700–2.PubMedGoogle Scholar
  174. 174.
    Marques CJ, Costa P, Vaz B, Carvalho F, Fernandes S, Barros A, et al. Abnormal methylation of imprinted genes in human sperm is associated with oligozoospermia. Mol Hum Reprod. 2008;14: 67–74.PubMedGoogle Scholar
  175. 175.
    Trasler JM. Epigenetics in spermatogenesis. Mol Cell Endocrinol. 2009;306:33–6.PubMedGoogle Scholar
  176. 176.
    Aoki VW, Emery BR, Carrell DT. Global sperm deoxyribonucleic acid methylation is unaffected in protamine-deficient infertile males. Fertil Steril. 2006;86:1541–3.PubMedGoogle Scholar
  177. 177.
    Aoki VW, Emery BR, Liu L, Carrell DT. Protamine levels vary between individual sperm cells of infertile human males and correlate with viability and DNA integrity. J Androl. 2006;27: 890–8.PubMedGoogle Scholar
  178. 178.
    Aoki VW, Liu L, Carrell DT. A novel mechanism of protamine expression deregulation highlighted by abnormal protamine transcript retention in infertile human males with sperm protamine deficiency. Mol Hum Reprod. 2006;12:41–50.PubMedGoogle Scholar
  179. 179.
    Paldi A. Genomic imprinting: could the chromatin structure be the driving force? Curr Top Dev Biol. 2003;53:115–38.PubMedGoogle Scholar
  180. 180.
    Hammoud SS, Purwar J, Pflueger C, Cairns BR, Carrell DT. Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility. Fertil Steril. 2010;94(5):1728–33.PubMedGoogle Scholar
  181. 181.
    Barratt CL, Aitken RJ, Bjorndahl L, Carrell DT, de Boer P, Kvist U, et al. Sperm DNA: organization, protection and vulnerability: from basic science to clinical applications—a position report. Hum Reprod. 2010;25:824–38.PubMedGoogle Scholar
  182. 182.
    Hotaling JM, Walsh TJ. Male infertility: a risk factor for testicular cancer. Nat Rev Urol. 2009;6:550–6.PubMedGoogle Scholar
  183. 183.
    Walsh TJ, Croughan MS, Schembri M, Chan JM, Turek PJ. Increased risk of testicular germ cell cancer among infertile men. Arch Intern Med. 2009;169:351–6.PubMedGoogle Scholar
  184. 184.
    Dieckmann KP, Pichlmeier U. Clinical epidemiology of testicular germ cell tumors. World J Urol. 2004;22:2–14.PubMedGoogle Scholar
  185. 185.
    Nathanson KL, Kanetsky PA, Hawes R, Vaughn DJ, Letrero R, Tucker K, et al. The Y deletion gr/gr and susceptibility to testicular germ cell tumor. Am J Hum Genet. 2005;77:1034–43.PubMedGoogle Scholar
  186. 186.
    Kojima Y, Mizuno K, Kohri K, Hayashi Y. Advances in molecular genetics of cryptorchidism. Urology. 2009;74:571–8.PubMedGoogle Scholar
  187. 187.
    Yan W. Male infertility caused by spermiogenic defects: lessons from gene knockouts. Mol Cell Endocrinol. 2009;306:24–32.PubMedGoogle Scholar
  188. 188.
    Matzuk MM, Lamb DJ. The biology of infertility: research advances and clinical challenges. Nat Med. 2008;14:1197–213.PubMedGoogle Scholar
  189. 189.
    Meng MV, Black LD, Cha I, Ljung BM, Pera RA, Turek PJ. Impaired spermatogenesis in men with congenital absence of the vas deferens. Hum Reprod. 2001;16:529–33.PubMedGoogle Scholar
  190. 190.
    Schlegel PN, Shin D, Goldstein M. Urogenital anomalies in men with congenital absence of the vas deferens. J Urol. 1996;155: 1644–8.PubMedGoogle Scholar
  191. 191.
    Kim ED, Gilbaugh 3rd JH, Patel VR, Turek PJ, Lipshultz LI. Testis biopsies frequently demonstrate sperm in men with azoospermia and significantly elevated follicle-stimulating hormone levels. J Urol. 1997;157:144–6.PubMedGoogle Scholar
  192. 192.
    Schlegel PN, Palermo GD, Goldstein M, Menendez S, Zaninovic N, Veeck LL, et al. Testicular sperm extraction with intracytoplasmic sperm injection for nonobstructive azoospermia. Urology. 1997;49:435–40.PubMedGoogle Scholar
  193. 193.
    Brugh 3rd VM, Maduro MR, Lamb DJ. Genetic disorders and infertility. Urol Clin North Am. 2003;30:143–52.PubMedGoogle Scholar
  194. 194.
    O’Bryan MK, de Kretser D. Mouse models for genes involved in impaired spermatogenesis. Int J Androl. 2006;29:76–89. discussion 105-8.PubMedGoogle Scholar
  195. 195.
    Manzini S, Vargiolu A, Stehle IM, Bacci ML, Cerrito MG, Giovannoni R, et al. Genetically modified pigs produced with a nonviral episomal vector. Proc Natl Acad Sci USA. 2006;103: 17672–7.PubMedGoogle Scholar
  196. 196.
    Boekelheide K, Sigman M. Is gene therapy for the treatment of male infertility feasible? Nat Clin Pract Urol. 2008;5:590–3.PubMedGoogle Scholar
  197. 197.
    Lamb DJ. Would gene therapy for the treatment of male infertility be safe? Nat Clin Pract Urol. 2008;5:594–5.PubMedGoogle Scholar
  198. 198.
    Brinster RL. Germ line stem cell transplantation and transgenesis. Science. 2002;296:2174–6.PubMedGoogle Scholar
  199. 199.
    Brinster RL. Male germ line stem cells: from mice to men. Science. 2007;316:404–5.PubMedGoogle Scholar
  200. 200.
    Nayernia K, Nolte J, Michelmann HW, Lee JH, Rathsack K, Drusenheimer N, et al. In vitro-differentiated embryonic stem cells give rise to male gametes that can generate offspring mice. Dev Cell. 2006;11:125–32.PubMedGoogle Scholar
  201. 201.
    Ryu BY, Orwig KE, Oatley JM, Lin CC, Chang LJ, Avarbock MR, et al. Efficient generation of transgenic rats through the male germ line using lentiviral transduction and transplantation of spermatogonial stem cells. J Androl. 2007;28:353–60.PubMedGoogle Scholar
  202. 202.
    Deepinder F, Chowdary HT, Agarwal A. Role of metabolomic analysis of biomarkers in the management of male infertility. Expert Rev Mol Diagn. 2007;7:351–8.PubMedGoogle Scholar
  203. 203.
    He Z, Chan WY, Dym M. Microarray technology offers a novel tool for the diagnosis and identification of therapeutic targets for male infertility. Reproduction. 2006;132:11–9.PubMedGoogle Scholar
  204. 204.
    Lin YH, Lin YM, Teng YN, Hsieh TY, Lin YS, Kuo PL. Identification of ten novel genes involved in human spermatogenesis by microarray analysis of testicular tissue. Fertil Steril. 2006;86:1650–8.PubMedGoogle Scholar
  205. 205.
    Martinez-Heredia J, de Mateo S, Vidal-Taboada JM, Ballesca JL, Oliva R. Identification of proteomic differences in asthenozoospermic sperm samples. Hum Reprod. 2008;23:783–91.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and GynecologyUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations